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Ramakrishnan et al.

Hypertensive Heart Editorial


Failure 21

Indian Heart J 2003; 55: 2126

Hypertensive Heart Failure


S Ramakrishnan, SS Kothari, VK Bahl
Department of Cardiology, All India Institute of Medical Sciences, New Delhi

eart failure is being increasingly recognized the world


over. Hypertension and ischemic heart disease are the
two cardinal causes of heart failure.1,2 Over the years, a
voluminous amount of literature has accumulated
regarding various facets of hypertensive heart failure.
Despite this, the risk and mechanisms of heart failure in
patients with hypertension is not completely understood.
Further, due to the common coexistence of coronary artery
disease (CAD) and hypertension in the population, the
relative contributions of CAD and hypertension to heart
failure have been difficult to disentangle. This article
provides an overview of the salient aspects of hypertensive
heart failure (HHF) from a clinical standpoint.

CAD might be clinically underestimated if coronary


angiography is not routinely performed. However, the
contribution of hypertension to heart failure in patients
with significant CAD was not analyzed in the study.
Myocardial infarction (MI) is associated with a five- to sixfold increase in the risk of heart failure in hypertensive
patients. 3 Antecedent hypertension interacts with
neurohumoral activation, and thereby adversely modifies
early ventricular remodeling to increase the risk of heart
failure after MI.8 Taken together, these data suggest that
while hypertension clearly causes or contributes to heart
failure, the absolute risk of heart failure in an individual
remains low in the absence of other factors.

Epidemiology

Individual Risk Assessment

The data on the prevalence of hypertension in patients with


heart failure are rather discordant. In the Framingham
Heart Study cohort, 3 hypertension antedated the
development of congestive heart failure (CHF) in 91% of
cases and was associated with a two- to three-fold risk of
development of CHF after adjusting for age and other risk
factors. Hypertension also had a high populationattributable risk (the percentage of heart failure cases that
can be attributed to hypertension) for CHF, viz. 39% in men
and 59% in women in the Framingham study. In contrast,
hypertension was found to be the primary factor in only
17% of hospitalized heart failure patients.4 Moreover,
hypertension was reported to be the primary etiological
factor in only 4% of heart failure patients in an overview
of 31 studies.5
Recent data from two population-based studies indicate
that hypertension is responsible for CHF in 4%20% of
patients. In a Swedish study of 7500 patients followed up
for 27 years,6 the identified etiological factors for CHF were
hypertension in 20.3%, and CAD either alone or in
combination with hypertension in 58.8%. Fox et al.7 have
reported hypertension to be the primary attributable factor
for CHF in only 4.4% of incident cases of CHF examined
prospectively. This study emphasized the fact that associated

In addition to CAD, several other patient-related risk factors


influence the risk of heart failure. These include age, gender,
race, diabetes, valvular heart disease, obesity, severity of
hypertension, left ventricular hypertrophy (LVH), and
alcoholism. An Italian study9 suggests that in a 60-yearold asymptomatic man with a systolic blood pressure (BP)
of 160 mmHg, the risk of developing heart failure is 0.37%
per year in the absence of LVH, which increases to 0.9%
per year in the presence of hypertrophy. If ischemic heart
disease, valvular heart disease, and diabetes coexist in the
same subject, then the risk of heart failure rises to 5.1%
and 9.5% in the absence and presence of LVH, respectively.
In humans, what degree and duration of hypertension
would cause LVH or heart failure has not been determined.
No threshold of BP has been observed for a substantive
change in risk for heart failure,3,10 yet 70%80% of patients
with heart failure and hypertension have a BP >160/100
mmHg. 3 The incidence of CHF is clearly greater at
increasing levels of blood pressure and lower with lesser
systolic BP.3,10 The etiology of hypertension could also
influence the risk of CHF. Renovascular hypertension is
associated with more target organ damage,11 and possibly
more CHF.
The incidence of heart failure increases as a function of
age.3 In the young and middle-aged, the incidence of heart
failure correlates with diastolic and mean pressures.12
However, in the elderly, both these measures correlate

Correspondence: Professor VK Bahl, Department of Cardiology,


All India Institute of Medical Sciences, New Delhi 110029.
e-mail: vkbahl2002@yahoo.com

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22 Ramakrishnan et al. Hypertensive Heart Failure

poorly with heart failure. Instead, pulse pressure, a measure


of pulsatile load, is a powerful and independent predictor
of heart failure. 13 A wide pulse pressure is either an
indicator or a consequence of aortic stiffness, which
increases the systolic BP and lowers the diastolic BP by a
variety of mechanisms. An increase in the systolic BP
increases the load, and lower diastolic BP reduces the
coronary perfusion pressure, thereby increasing the
vulnerability of the heart to failure.13 Both hypertension
and LVH are stronger risk factors for CHF in women as
compared to men. However, women have a lower
prevalence of LVH than men for any given level of blood
pressure. 14 In obese hypertensive patients, varying
combinations of pressure and volume overload are seen,
resulting in a mixed eccentricconcentric form of LVH.15
Moreover, obesity is an important independent predictor
of left ventricular (LV) mass, and the effects of hypertension
and obesity are additive.16
Diabetes is emerging as an important precursor of heart
failure.3 In the United Kingdom Prospective Diabetic Study
(UKPDS),10 the incidence of heart failure in 4801 white
men with type 2 diabetes was 2.4 per 1000 person-years
follow-up in patients with a systolic BP in the range of 120
129 mmHg, and rose to 7.0 in patients with a systolic BP
>160 mmHg. However, no threshold of BP was seen for
the occurrence of heart failure.
Left Ventricular Hypertrophy
Left ventricular hypertrophy represents the major biological
adaptation to increased pressure load and its limitations.
Thus, understanding ventricular remodeling influences the
entire issue of heart failure in hypertension and its therapy.
Although cardiac failure would possibly occur earlier in the
absence of LVH, LVH is clearly a double-edged sword.
Hypertensive LVH has repeatedly been shown to be an
independent marker of cardiac failure, accelerated
atherosclerosis of the coronary arteries, lethal cardiac
arrhythmias, and sudden death.17 The increased risk of
sudden death can be explained at least in part by the
repolarization abnormalities described in patients with
hypertensive LVH. Graded prolongation of the QT interval
occurs with increasing LV mass index, and measures of QT
dispersion are also related to the LV mass.18 Abnormalities
of the QT interval occur irrespective of the geometry of
LVH.18 Each 50 g/m2 increase in LV mass is associated with
a 1.49 increase in the relative risk of cardiovascular disease
for men and a 1.57 increase for women. 16 However,
individuals differ in their response of LVH to a given
pressure load. Only 15%20% of hypertensive patients

EDITORIAL.p65

22

show echocardiographic evidence of LVH 16 and, in


hypertensive patients, it is estimated that approximately
40% of the variance in LV mass is accounted for by the total
LV load. 19 Further, LVH occurs in the absence of
hypertension and, in some cases, precedes its development
(cardiogenic hypertension).20 Old age, male sex, obesity,
diabetes in women, black race, and certain genetic
influences such as angiotensin-converting enzyme (ACE)
polymorphisms lead to a greater LVH for a given BP.21 The
geometric pattern of LVH in hypertension also influences
the risk. The 10-year incidence of cardiovascular events is
reported to be 30% in those with concentric LVH, 25% in
those with eccentric LVH, 15% in those with concentric
remodeling (increased relative wall thickness with a normal
LV mass), and 9% in those with a normal LV mass.22
Cellular Mechanisms of Left Ventricular
Hypertrophy and Heart Failure
Mechanical forces are thought to be the principal
determinants of cardiac hypertrophy. The principal
mechanical contributor that promotes LVH in early
hypertension is sustained increase in systemic vascular
resistance.19 The molecular mechanisms that translate
increased wall stress to cellular hypertrophy are beginning
to be elucidated.23 Increased wall stress activates a stretch
receptor that releases intracellular calcium and activates
calcineurin, which, acting through a series of subcellular
events, activates fetal cardiac and growth genes, such as cmyc and c-jun, to upregulate protein synthesis.24 The
mechanical forces work in tandem with potent
neurohumoral mediators such as angiotensin II,
norepinephrine, and insulin.23
The hypertrophy that occurs in hypertensive heart
disease (HHD) is not homogeneous. In contrast to the
hypertrophy seen in athletes, in HHD it is disproportionate,
and predominantly involves noncardiomyocytes. Thus, it
is not the quantity but the quality of the myocardium that
distinguishes HHD from the adaptive hypertrophy of the
athlete.25 In certain disease states such as chronic anemia,
small arteriovenous fistula, atrial septal defect, or
hyperthyroidism, cardiac hypertrophy occurs with
preserved homogenecity. These conditions are not
associated with activation of the circulating renin
angiotensin system.26 Several attempts have been made to
differentiate physiologic and pathologic hypertrophy by
noninvasive means. It has been shown that the long-axis
mean annular velocities measured by tissue Doppler are
significantly decreased in HHD as compared to athletes.27
Fibrosis, an integral feature of the adverse structural

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Indian Heart J 2003; 55: 2126

remodeling of the heart seen in HHD, appears in two


morphologically distinct forms: a reactive form expressed
as a perivascular/interstitial fibrosis, and a reparative
fibrosis represented by microscopic scars that replace
necrotic myocytes.26 Adverse accumulation of extracellular
matrix initially increases myocardial stiffness, and its
continued accumulation impairs contractile behavior. Early
evidence suggests that the measurement of serum
concentrations of procollagen type I C-terminal propeptide
(a peptide that is cleaved from procollagen type I during
the synthesis of fibril-forming collagen type I) may provide
indirect information on the extent of myocardial fibrosis.28
Gadolinium-DTPA delayed-enhancement magnetic
resonance imaging (de-MRI) is accurate in assessing
regional fibrosis noninvasively.29
Imaging studies using 111 In-labeled monoclonal
antimyosin antibodies30 have shown that cell damage
occurs early in HHD, and abnormally stimulated apoptosis
of cardiomyocytes and noncardiomyocytes could be
responsible for such cell damage.31 Local factors that may
trigger apoptosis include mechanical forces, oxidative stress,
hypoxia, and an unbalanced presence of growth factors and
cytokines (e.g. angiotensin II) or neurotransmitters (e.g.
norepinephrine).32 Since signals that potentially mediate
hypertrophy are largely the ones proposed to mediate
apoptosis also, it has been proposed that when growth
signals persist chronically in terminally differentiated cells,
they produce a contradictory genetic demand and trigger
the apoptosis.32 The absence of a clear association between
cardiomyocyte apoptosis and absolute BP values indicate
that nonhemodynamic factors, especially angiotensin, may
be more important.32
Clinical Transition to Heart Failure
In humans, HHD leads to three recognizable stages in
evolution of heart failure: LVH, diastolic dysfunction, and
systolic dysfunction, not necessarily in the same order.
Abnormalities of LV diastolic filling are observed in
various forms of hypertension in adults as well as
children,21 and the prevalence may be as high as 22% in
asymptomatic hypertensive patients with a BP of >140/
90 mmHg.33 Diastolic filling abnormalities have been
shown to generally correlate with LV mass,34 and BP.33
However, diastolic dysfunction could precede the onset of
hypertension in the young male offspring of hypertensive
parents.33
In hypertensive patients, diastolic heart failure is
increasingly being recognized as a cause of CHF. However,
the incidence is not clear, as establishing a definite diagnosis

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Ramakrishnan et al. Hypertensive Heart Failure 23

is difficult. In previous published studies on unselected


heart failure populations, the reported prevalence of
patients having preserved systolic function varied widely,
from 13% to 74%.35 Each 1 mmHg increase in pulmonary
capillary wedge pressure, a measure of diastolic
dysfunction, is shown to be associated with a 23% increase
in the risk of all-cause mortality, and a 13% increase in the
risk of cardiovascular events in the 174 patients of
uncomplicated hypertension followed up for 10 years.36
In the absence of MI, hypertensive patients with LVH
commonly have supernormal ejection phase indices on
echocardiography, and a significant decrease in LV ejection
fraction occurs very late in the course of HHD. 37 Yet,
normalcy of these ejection indices may not imply normal
systolic function in hypertension. When indices such as
mid-wall fractional shortening are used, up to 16% of
hypertensive patients were found to have depressed LV
systolic function. 38 Hypertensive patients also have a
depressed end-systolic stress relationship. Furthermore,
hypertension may lead to exercise-induced systolic LV
dysfunction even though the resting LV function may be
normal.39
Acute heart failure (pulmonary edema) in a
hypertensive patient could be due to transient systolic
dysfunction, diastolic dysfunction, ischemia, or mitral
regurgitation. However, nearly 40% of hypertensive
patients have a normal LV ejection fraction indicating
diastolic dysfunction as the cause.40 Normally, the left
ventricle compensates for an increase in systolic load by
increasing end-diastolic volume (i.e., using preload reserve).
In a patient with diastolic dysfunction, this small increase
in left ventricular end-diastolic volume may be associated
with a marked elevation in diastolic pressure, because of
the reduced distensibility of the left ventricle, thereby
precipitating pulmonary edema.41 Common precipitants of
overt heart failure in patients with diastolic dysfunction
include old age, tachycardia, sudden severe increase in
overload such as a hypertensive crisis, and loss of atrial
kick.42 The relative contribution of significant ischemia due
to epicardial obstructive CAD in the causation of
pulmonary edema is difficult to quantify. More than 60%
of hypertensive patients presenting with flash pulmonary
edema had epicardial obstructive CAD in one study.43
Interestingly, however, the flash pulmonary edema
recurred in half the patients even after revascularization.43
The diagnosis of CAD in patients suspected of having
HHF is difficult. The sensitivity and specificity of
noninvasive stress tests are altered by both heart failure and
hypertension. In heart failure patients, noninvasive stress
tests can be less sensitive due to the low level of stress

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24 Ramakrishnan et al. Hypertensive Heart Failure

obtainable, and less specific due to doubtful


echocardiographic pictures and perfusion images of dilated,
hypokinetic ventricles. The baseline electrocardiogram also
often shows intraventricular conduction delays and altered
repolarization at rest. Hence, it has been suggested that in
heart failure patients the coronary angiogram may be the
sole determining test for excluding obstructive epicardial
CAD.44 However, to assign ischemia as the etiology of heart
failure in the presence of hypertension, the anatomic
disease should be associated with regional wall motion
abnormalities, perfusion abnormalities, or ischemic
valvular dysfunction. It has been suggested that in HHF
patients with a preserved LV ejection fraction, two groups
could be identified based on LV mass. If there was a high
degree of reactive hypertrophy, the patients had a lower
chance of a positive stress test, whereas patients with only
moderate hypertrophy have a high rate of epicardial
obstructive CAD.45
Recently, tissue Doppler measurement of the cyclic
variation index of the backscatter signal at the septum level
have shown significant alterations in hypertensive patients,
and it correlates with the LV mass and geometry of LVH.
The alterations could be reversed with antihypertensive
treatment.46 Hence, ultrasonic tissue characterization has
the potential to identify early those hypertensive patients
at risk of adverse remodeling.
Impact of Treatment
The reported median survival following the diagnosis of
heart failure in hypertensive subjects is 1.37 years in men
and 2.48 years in women. The 5-year survival rates are
reported to be 24% in men and 31% in women. 3 The
prognosis may be better for patients with diastolic
dysfunction. For example, in heart failure patients with
preserved systolic function, the annual mortality was
reported to be 8.7% v. 3.0% for matched controls, and in
patients with LV systolic dysfunction, the annual mortality
was 18.9% v. 4.1% for matched controls in the
Framingham cohort.47 Hence, treatment is required before
the onset of clinical heart failure.
The efficacy of antihypertensive medications in reducing
the incidence of heart failure in diastolic48,49 as well as
isolated systolic hypertension50 has been well documented.
Meta-analysis of long-term hypertension has also shown
that sustained lowering of blood pressure is effective in
preventing LVH and CHF, regardless of the agent used,51 a
finding not corroborated by a recent meta-analysis. 52
Currently, there is no clear evidence that one class of
antihypertensive agent is more effective than the other in

EDITORIAL.p65

24

retarding the progression of HHD; however, there, is some


evidence that calcium-channel blockers may be less
effective. In the recently reported ALLHAT study,53 the
amlodipine group had a 38% higher risk of heart failure,
and a 35% higher risk of hospitalized/fatal heart failure as
compared to chlorthalidone. The recent meta-analysis has
also shown that the risk of heart failure was 15% higher
with calcium-channel blockers as compared to betablockers, and 18% higher as compared to ACE inhibitors.52
The relative superiority of ACE inhibitors and diuretics is
not clear, as two recent large trials 53,54 have yielded
conflicting results. In the ALLHAT study,53 the lisinopril
group had a 19% increased risk of heart failure as
compared to patients treated with chlorthalidone, whereas
in the second Australian national blood pressure study,54
the incidence of heart failure was not significantly different
between ACE inhibitor- and diuretic-treated patients.
Management of hypertension should not focus merely
on a reduction in BP, but must also target the adverse
structural remodeling that begets HHD. Such approaches
target diastolic dysfunction, adverse remodeling, apoptosis,
fibrosis, and neurohumoral mediators. Drugs that are
shown to be reparative include ACE inhibitors, angiotensin1 receptor antagonists, endothelin antagonists, and
aldosterone receptor antagonists.25 Two approaches that
influence apoptosis include inhibition of apoptotic signals
that trigger the process, and direct blockade of the
intracellular apoptotic mechanisms. Drugs shown to be
effective antiapoptotics include ACE inhibitors, losartan,
alfa-blockers, and calcium-channel blockers. Hydralazine
and diuretics have been shown to have no effect on
apoptosis.32 Gene therapy, targeting abnormalities of ion
handling, cellular signaling, neurohormonal control, and
apoptosis, hold promise in retarding the progression to
heart failure.55 ACE inhibitors have been shown to cause
regression in fibrosis, leading to improvement in diastolic
dysfunction as compared to diuretics.56 Further progress
on specific therapy is awaited.
Conclusions
The data on the prevalence of hypertension in heart failure
are rather discordant. The duration and severity of
hypertension critical to cause heart failure is not known.
For the same degree of hypertension, several patient-related
factors modify the occurrence of heart failure. In patients
with HHF, CAD needs to be carefully evaluated.
Mechanisms of hypertrophy and remodeling that
contribute to systolic and diastolic dysfunction are
beginning to be understood. Antihypertensive treatment

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reduces the risk of HHF (possibly with some differences


among various antihypertensive drugs). Specific therapies
targeting adverse cardiac remodeling are under
development.
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inhibitors and diuretics for hypertension in the elderly. N Engl J Med
2003; 348: 583592
MacNeill BD, Hayase M, Hajjar RJ. Targeting signaling pathways in
heart failure by gene transfer. Curr Atheroscler Rep 2003; 5: 178185
Brilla CG, Funck RC, Rupp H. Lisinopril-mediated regression of
myocardial fibrosis in patients with hypertensive heart disease.
Circulation 2000; 102: 13881393

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Laroia et al. Infections in Review


Atherogenesis
27
Article

Indian Heart J 2003; 55: 2734

Role of Infections in Atherogenesis


Sandeep T Laroia, Apar Kishor Ganti, Anil Potti
Department of Medicine, University of North Dakota School of
Medicine and Health Sciences, USA

n 1921, Ophuls1 proposed that infections could lead to


atherosclerosis. This hypothesis was based on pathologic
specimens of blood vessels, which showed macrophage
infiltrates and foam cells. Five decades later, in 1978,
Fabricant et al.2 once again showed arterial lesions similar
to atherosclerosis in chicken infected with the avian
herpesvirus. Recent advances in diagnostic techniques have
facilitated the re-emergence of this hypothesis. It is now well
accepted that atherosclerosis is an inflammatory process, and
a natural corollary of this concept is that microorganisms
could be the prime initiators of this process.3 Data from
several studies indicate an increased prevalence of chronic
infections in atherogenesis. The agents that have been
implicated in this process are Chlamydia pneumoniae,
Helicobacter pylori, herpes simplex virus, and cytomegalovirus
(CMV).46 In this article, we evaluate the evidence available
both for and against the different etiological agents, and their
current status in the pathogenesis of atherosclerosis.
Basic Scheme of Atherogenesis
Simplified, atherogenesis is the passage of low-density
lipoprotein (LDL)-cholesterol through dysfunctional
endothelium at points of low shear stress. In addition,
mechanical stress can lead to the aggravation of this
phenomenon. 7 LDL-cholesterol penetrates the
dysfunctional endothelium and undergoes oxidation. The
oxidized LDL causes further endothelial dysfunction.
Monocytes penetrate the endothelium, differentiate into
macrophages, attract more macrophages and the resultant
foam cells, which are lipid-laden macrophages, accumulate
in the region. These cells may ultimately rupture, causing
the release of toxic inflammatory mediators that trigger a
fibroproliferative response from smooth muscles.8, 9
Potential Role of Infections in Atherogenesis
Endothelial dysfunction, the trigger for atherogenesis, can
be induced by systemic or local infection. Multiple
Correspondence: Dr Sandeep T Laroia, Department of Internal Medicine,
University of North Dakota School of Medicine, 1919 Elm Street N, Fargo,
ND 58102, USA. e-mail: sandeeplaroia@meritcare.com

IHJ-328-02.p65

27

mechanisms have been proposed which include the


following:
1. Bacterial endotoxins and tumor necrosis factor (TNFalpha) can inhibit vasodilator nitric oxide generated by
endothelial-dependent processes;10
2. Endothelial stunning, a mechanism which hypothesizes
that periods of endothelial inactivity can be induced by
a brief exposure to endotoxin;11
3. Direct infection of the endothelium by infectious agents,
especially the herpesviruses including CMV;12
4. Altered expression of growth-controlling proteins by
vascular smooth muscles after infection with certain
viruses, which leads to these cells obtaining a growth
advantage and thus may contribute to atherosclerosis
and restenosis.13
Furthermore, C-reactive protein (CRP) and fibrinogen
(acute phase reactants), which are strong independent
predictors of subsequent cardiovascular events, are found
to be elevated in infectious states as well, and elevated levels
of cytokines are found in both infections and acute
coronary syndromes. These circulating cytokines may
cause abnormal endothelial function, increased
thrombosis, and toxic free radical generation, leading to
accelerated atherogenesis.14,15
Evidence for the Role of Infections
in Atherosclerosis
Herpesviridae, especially CMV, H. pylori, and C. pneumoniae,
have been extensively studied for their effect on
atherosclerosis. Tables 1, 2, and 3 list the various studies
that showed a positive correlation between atherogenesis
and infection by herpesviruses,1630 H. pylori, 3141 and
C. pneumoniae,4263 respectively. These studies included both
human and experimental research. The experimental
works listed include those involving both experimental
animals and tissue studies.
Evidence Against the Role of Infections
in Atherosclerosis
Though there are a number of reports favoring the role of

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Indian Heart J 2003; 55: 2734

28 Laroia et al. Infections in Atherogenesis

Table 1. Evidence favoring the role of CMV and other herpesviridae in atherogenesis
Reference

Year

Number of
subjects (n)

Findings

Grattan et al.16

1989

301

Zhu et al.17

2000

238

Muhlestein et al.18

2000

985

Siscovick et al.19

2000

213

Horvath et al.20

2000

244

Sorlie et al.21

2000

515

Kaftan et al.22

1999

310

Neumann et al.23

2000

551

Biocina et al.24

1999

284

Blum et al.25

1998

65

Zhou et al.26

1996

75

Alber et al.27

2000

NA

Lemstrom et al.28

1997

NA

Zhou et al.29

1999

60

Lin et al.30

2000

40

Increased risk of developing vascular lesions in post-transplant patients with clinical


CMV infection
CMV seropositivity associated with increased CRP levels, a significant determinant
of CAD
CMV seropositivity and elevated CRP, in combination, are independent predictors
of mortality in patients with CAD
Presence of IgG antibodies to HSV-1 is associated with a 2-fold increase in the risk
of incident MI and CAD-related death
Genomic DNA of CMV is found in arterial walls at a significantly higher rate in IHD
patients than the nonischemic control group
Population with the highest antibody levels of CMV (approximately the upper 20%)
showed an increased relative risk of CHD
Titer of anti-CMV antibody and the levels of CRP can predict patients with a high
risk of CAD
Previous CMV infection increased the risk of coronary thrombotic events after stent
placement
Patients undergoing orthotopic heart transplantation who experienced CMV disease
had significantly worse long-term survival compared to those with the infection
only or without the infection
Patients with high anti-CMV titer had a higher prevalence of CAD and a higher
restenosis rate than those with a lower antibody titer
Patients who were seropositive for CMV had a greater than 5-fold increased rate of
restenosis following coronary atherotomy
Atheroma formation was accelerated in apo E-/- mice infected with murine gammaherpesvirus-68 compared with control uninfected apo E-/- mice
Treatment with ganciclovir significantly reduced intimal thickening in the presence
of CMV infection
CMV infection of immunocompetent adult rats increased the neointimal response
to vascular injury
Bovine herpesvirus-4 can accelerate the atherosclerotic process in rabbits

CMV: cytomegalovirus; HSV: herpes simplex virus; CRP: C-reactive protein; CAD: coronary artery disease; CHD: coronary heart disease; apo E: apolipoprotein
E; IHD: ischemic heart disease

infections in atherosclerosis, the number of reports arguing


against such a role is equally impressive. In the discussion
that follows, a few reports which showed no effect of
infection in the pathogenesis of atherogenesis have been
listed.
Evidence against herpesviridae: Siscovick et al.19 did not
find any correlation between the presence of IgG antibodies
to CMV and the risk of acute myocardial infarction (AMI)
or coronary artery disease (CAD) in elderly patients.
Choussat et al.63 studied systemic markers of inflammation
in patients with unstable angina or non-Q wave MI, and
the relationship between these markers, seropositivity to
chronic infections (CMV, H. pylori, and C. pneumoniae), and
prognosis. They found no association between the levels of
each inflammatory marker and the serologic status.
Furthermore, levels of inflammatory proteins in patients

IHJ-328-02.p65

28

seronegative to all 3 agents were comparable to those of


patients seropositive to 2 or 3 infectious agents. The
composite end-points of death, MI, recurrent angina, or
revascularization at 1-year follow-up did not differ
according to the serologic status.63 To determine if CMV
infection is a risk factor for primary CAD and the association
between CMV infection and CAD (>50% blockage in any
coronary artery), Adler et al.64 investigated nearly 900
successive nontransplant patients undergoing coronary
angiography. By the use of logistic regression, they found
that CMV seropositivity (p=0.462), the level of IgG
antibodies to CMV whole-cell antigen (p=0.98), or the levels
of IgG antibodies to CMV glycoprotein B (p=0.67) were not
significantly associated with CAD. These data suggest that
CMV infection is not a major risk factor for the development
of primary CAD in adults.64

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Indian Heart J 2003; 55: 2734

Laroia et al. Infections in Atherogenesis 29

Table 2. Evidence favoring the role of Helicobacter pylori in atherogenesis


Reference

Year

Number of
subjects (n)

Findings

Mendall et al.31
Patel et al.32

1994
1995

200
388

Gunn et al.33

2000

556

Kahan et al.34
Farsak et al.35

2000
2000

200
85

Hoffmeister et al.36

2001

405

Pieniazek et al.37
Ameriso et al.38
Laurila et al.39

1999
2001
1999

157
38
880

Markus et al.40
Birnie et al.41

1998
1998

357
136

Seropositivity for H. pylori confers a 2-fold risk of CAD


76.6% of men with ischemia or infarction were seropositive compared with 45.5%
of men with normal electrocardiograms
1.80-fold increase in AMI risk, which increased further to 2.25-fold in subjects <55
years of age
Seropositivity for H. pylori is associated with previous AMI
H. pylori DNA was found in 17 of 46 (37%) endarterectomy specimens with
atherosclerotic plaques and in none of the controls
Significant association is observed between H. pylori infection and decreased
HDL-cholesterol levels
Infection significantly increases the risk of CAD
H. pylori is present in a substantial number of carotid atherosclerotic lesions
The serum triglyceride and total cholesterol concentrations were significantly higher
in males with positive antibody titers than in those with no infection (p<0.001)
H. pylori seropositivity was associated with large-vessel disease and lacunar stroke
Anti-heat shock protein 65 titers correlated with both the severity and extent of
coronary atherosclerosis
Successful eradication led to a significant fall in anti-heat shock protein 65 titers

100

H. pylori: Helicobacter pylori; CAD: coronary artery disease; AMI: acute myocardial infarction; HDL: high-density lipoprotein

Evidence against Helicobacter pylori: A Finnish group


failed to show a statistically significant relationship between
patients infected with H. pylori and CAD; interestingly, this
study showed higher levels of serum triglycerides in patients
seropositive for H. pylori.65 In their study, Tsai and Huang66
showed that H. pylori seropositivity was not associated with
several coronary risk factors in either cases or controls. The
proportion of H. pylori-positive patients was higher among
cases with triple-vessel disease (77.5%) than in those with
double-vessel (67.3%) and single-vessel (65.7%) disease;
however, the differences were not statistically significant.
In this study, no increase was found in H. pylori
seropositivity in subjects with CAD. In a recent review,
Menge et al.67 found that the present data were inconclusive
regarding the association between H. pylori infection and
CAD. They concluded that proposed links between H. pylori
infection and coronary heart disease (CHD), such as
hyperhomocysteinemia or autoimmune mechanisms due
to cross-reacting antibodies to H. pylori heat-shock protein
with human endothelium-derived heat-shock protein, need
further confirmation. Quinn et al.68 studied the relationship
between angiographically defined CAD and serologic
evidence of H. pylori infection in 488 patients undergoing
elective coronary angiography. There was no association
between H. pylori infection and CAD. 68 Basili et al. 69
retrospectively analyzed 149 subjects who underwent an
esophagogastroduodenoscopy, in whom the search for
H. pylori was histologically performed, and found that the

IHJ-328-02.p65

29

prevalence of CAD was not significantly different from that


observed in H. pylori-free patients (26% v. 21%; p=0.527).
Lastly, a meta-analysis of 18 epidemiological studies
involving over 10 000 patients failed to demonstrate any
significant association between H. pylori infection and
CAD.70 Khurshid et al.71 prospectively studied 179 patients
undergoing coronary angiography for suspected CAD and
found that H. pylori infection rates were similar in patients
with normal and abnormal coronary arteries, and infection
with H. pylori was not an independent risk factor for CAD.
In patients with CAD, H. pylori infection was not a risk factor
for more severe disease.71
Evidence against Chlamydia pneumoniae
Patient data: The Physicians Health Study72 prospectively
measured IgG antibodies against C. pneumoniae in 343
participants with first MI. A similar number of age- and
smoking-matched controls were also followed up for a
period of 12 years. The prevalence of seropositivity was the
same in both the groups. 72 Markus et al. 73 obtained
ultrasonic images of the carotid artery to determine the
intimamedia thickness (IMT) and the thickness of any
atheroma plaques, and found no evidence that serological
evidence of C. pneumoniae infection is associated with early
atherosclerosis. They also found no evidence that
C. pneumoniae results in a chronic systemic inflammatory
state.73 Hoffmeister et al.74 investigated the association
between seropositivity to chlamydial lipopolysaccharide

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Indian Heart J 2003; 55: 2734

30 Laroia et al. Infections in Atherogenesis


Table 3. Evidence favoring the role of Chlamydia pneumoniae in atherogenesis
Reference

Year

Number of
subjects (n)

Findings

Hu et al.42
Muhlestein et al.43

1999
1998

40
30

Liu et al.44

2000

NA

Kuo et al.45

1993

36

Muhlestein et al.46

1996

114

Ericson et al.47

2000

60

Maass et al.48

1998

70

Bartels et al.49

1999

58

Farsak et al.35

2000

85

Ouchi et al.50

2000

177

Saikku et al.51

1998

213

Gabriel et al.52

1998

282

Toss et al.53

1998

256

Melnick et al.54

1993

300

Burian et al.55

2001

405

Leowattana et al.56

2000

243

Maass et al.57

2000

188

Kaftan et al.58

2000

160

Sessa et al.59

1999

228

Wong et al.60
Dechend et al.61

1999
1999

804
NA

Fong62

2000

NA

Infection exacerbated the development of atherosclerosis in mice


Intranasal infection accelerated intimal thickening in rabbits given a cholesterolenhanced diet. Also, treatment with azithromycin after exposure prevents
accelerated intimal thickening
Infection for 6 months produced a significantly greater exacerbation of aortic
atherosclerosis in LDLR-/- mice in the presence of a high-cholesterol diet
C. pneumoniae was detected in coronary artery atheromas by immunocytochemistry
and PCR in 20 of 36 autopsy cases with coronary artery atheromas
Atherectomy specimens of patients with symptomatic CAD showed positive
chlamydial antigen by direct immunofluorescence in 73% of patients
Direct immunofluorescence for chlamydial antigen was reactive in 86% of cases
with severe atherosclerosis but in only 6% of cases with mild atherosclerosis
(p<0.01)
Coronary artery endarterectomy specimens showed viable chlamydial organisms
in 16% and chlamydial DNA in 30%
Viable C. pneumoniae was recovered from 16% of occluded vein grafts while except
for 1 native saphenous vein, all control vessels were negative for C. pneumoniae
C. pneumoniae DNA was found in 26% of 46 endarterectomy specimens and none
of the healthy vascular wall specimens (p<0.001)
62% of atherosclerotic plaques from symptomatic patients were infected with C.
pneumoniae compared with just 2% of nonatherosclerotic tissues
In a series of 213 patients with AMI, 38% showed strong seropositivity, 35% showed
intermediate seropositivity, and 28% showed no detectable antibodies
Patients with CAD had a higher prevalence of C. pneumoniae PCR from pharyngeal
specimens (36% v. 22%)
Among 256 patients with unstable angina, increased antibody titers to C. pneumoniae
were more common than in controls (36% v. 19%). Even asymptomatic
atherosclerosis specimens showed increased antibody titers
In 300 patients, cardiac wall thickening seen on ultrasound (a marker for
asymptomatic atherosclerosis) was correlated with positive antibody titers (73% v.
63%)
Presence of high-level antibodies to C. pneumoniae is an independent risk factor for
the development of coronary atherosclerosis
A significantly higher percentage of patients with CAD had positive IgG and IgA
antibodies to C. pneumoniae as compared to healthy controls
C. pneumoniae was detected in 52 (28%) of 188 persons with unstable angina and
in 13 (26%) of 50 persons with MI
Levels of triglyceride, LDL-cholesterol, CRP, fibrinogen, and total cholesterol/HDLcholesterol ratio had a direct relationship, but the level of HDL-cholesterol had a
negative relationship with seropositivity
Significant correlation exists between chronic C. pneumoniae infection and
dyslipidemias in the AMI and CAD groups
Circulating C. pneumoniae DNA is a predictor of CAD in men
Tissue factor, PAI-1, and interleukin-6 expression was increased in infected
cells, and NF- B was activated in human vascular endothelial and smooth muscle
cells
Early institution of antimicrobials with antichlamydial activity within 5 days of
infection largely prevented aortic lesions in New Zealand white rabbits

C. pneumoniae: Chlamydia pneumomiae; CAD: coronary artery disease; AMI: acute myocardial infarction; LDL: low-density lipoprotein; CRP: C-reactive
protein; HDL: high-density lipoprotein; PCR: polymerase chain reaction; PAI: plasminogen activator inhibitor

IHJ-328-02.p65

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Indian Heart J 2003; 55: 2734

(cLPS) or C. pneumoniae and angiographically documented


CAD. They also examined the relationship between
serostatus and markers of systemic inflammation. Their
results indicated no strong association between
C. pneumoniae and CAD, and they concluded that the
increased systemic inflammation in patients with CAD did
not seem to be due to seropositivity to cLPS or
C. pneumoniae.74 In their meta-analysis, Danesh et al.75
reviewed 15 studies to examine the association between
CAD and serum markers of chronic C. pneumoniae infection.
They did not find any strong association between
C. pneumoniae IgG titers and incident CAD. Romeo et al.76
tried to correlate the severity of CAD with seropositivity to
C. pneumoniae prospectively. They found no significant
difference in IgG and IgA seropositivity among patients with
stable CAD, unstable CAD, and controls. They concluded
that only a small percentage of patients with CAD
demonstrate seropositivity against C. pneumoniae. A recent
casecontrol study investigated the relationship between
the presence of C. pneumoniae IgG and IgA and
angiographically diagnosed CAD. When cases were
compared with controls whose angiographic results were
normal, after adjusting for established risk factors
(cholesterol, smoking, hypertension, diabetes, age, gender,
and family history), the estimated risk of CAD was 0.79 for
the presence of IgG and 0.94 for IgA. These results do not
support an association between C. pneumoniae infection and
CAD.77 In a recent review, Wong et al.78 concluded that
more evidence is required before C. pneumoniae can be
accepted as playing a role in atherosclerosis.
Animal data: Aalto-Setala et al.79 infected apolipoprotein
E (apo E)-deficient mice with C. pneumoniae and placed them
on either a high- or low-fat diet. They found that
C. pneumoniae infection did not influence the lesion size in
either mouse strain. They also could not demonstrate
C. pneumoniae by polymerase chain reaction in any of the
atherosclerotic lesions of the infected animals. They did not
find any inflammatory signs in the myocardium of
C. pneumoniae-infected mice. They concluded that
C. pneumoniae infection did not accelerate atherogenic
changes in the aortic root of apo E-deficient mice.79 Blessing
et al.80 inoculated C57BL/6J mice with C. pneumoniae. They
observed inflammatory changes in the heart or aorta in a
small number of chronically infected mice but no evidence
of atherosclerotic lesions in any of them. Their findings
suggested that chronic C. pneumoniae infection could induce
inflammatory changes in the heart and aorta of C57BL/6J
mice but did not initiate definitive atherosclerosis.80 In a
recent review, Haberbosch and Jantos81 concluded from the

IHJ-328-02.p65

31

Laroia et al. Infections in Atherogenesis 31

present data that chronic infection with the pathogen is


not an independent risk factor for atherosclerosis.
Intervention Studies
The ACADEMIC trial 82 reported 302 patients with
seropositivity to C. pneumoniae. Subjects received
azithromycin and placebo for 3 months. At 6 months, the
azithromycin-treated group showed a reduced global index
of inflammation, which comprised CRP, TNF-alpha; and
interleukins 1 and 6 compared with a placebo. However,
cardiovascular events were similar in the two groups at
6 months. At 2-year follow-up, there was a 20%30% risk
reduction.82 Parchure et al.83 carried out a randomized,
prospective, double-blind, placebo-controlled trial in 40
male patients with documented CAD and positive
C. pneumoniae IgG antibody titers. They showed that
patients who received azithromycin had a significant
improvement in flow-mediated dilatation of the brachial
artery. They then concluded that treatment with
azithromycin had a favorable effect on endothelial function
in patients with documented CAD and evidence of
C. pneumoniae infection, irrespective of antibody titer
levels.83
A pilot study of 60 survivors of AMI with persistent
elevated anti-chlamydial antibody titers was designed so
that subjects were randomized to receive placebo or
azithromycin. Azithromycin-treated patients showed an
apparent reduction in cardiovascular events from 28% to
8%. There was no significant difference between a singleand double-dose course of azithromycin.84 The ROXIS
trial85 randomized 202 patients with unstable angina or
non-Q wave MI to roxithromycin or a placebo. At the end
of the treatment period, the rates of recurrent ischemia
were 1% v. 5.4%, MI 0% v. 2.2%, and ischemic events 0% v.
2.2% in the roxithromycin v. placebo group, respectively.85
At 6 months, the individual and composite event rates
remained lower in the roxithromycin group, but the
difference was not statistically significant.86 In the AZACS
trial,87 patients with acute coronary syndromes (unstable
angina or MI) were randomized in a double-blind, placebocontrolled fashion to either azithromycin 500 mg/day
followed by 250 mg/day for 4 days or a matching placebo.
They found that in patients with AMI or unstable angina,
short-term treatment with azithromycin did not have an
effect on the recurrence of ischemic events during a
6-month follow-up period. There was no difference between
patients who tested positive for the presence of
C. pneumoniae antibodies and those who did not.87 Similarly,
in the WIZARD trials,88 which sought to assess the use of

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Indian Heart J 2003; 55: 2734

32 Laroia et al. Infections in Atherogenesis

antibiotics to prevent recurrent CHD, the antibiotic regimen


comprising weekly azithromycin in adult patients >6 weeks
post-MI with elevated C. pneumoniae IgG titers, achieved a
7% nonsignificant reduction in the incidence of recurrent
cardiovascular disease at 11 weeks. The baseline titer of
IgG antibodies against C. pneumoniae had no effect on the
outcome.88
Conclusions
Atherosclerosis is an inflammatory process. Hence,
microorganisms could be the prime initiators of this
process. Endothelial dysfunction, the trigger for
atherogenesis, can be induced by systemic or local infection.
Circulating cytokines, released by any stimulus, may cause
abnormal endothelial function, increased thrombosis and
toxic free-radical generation, leading to accelerated
atherogenesis. As in leprosy, Whipples disease, syphilis and
ehrlichiosis, Kochs postulates cannot be used to determine
the role of infection in atherosclerotic disease. Regarding
the role of infection in CAD, important indirect evidence
comes from prevention of the disease by means of specific
interventions.
The data for and against the role of infection in
atherosclerotic vascular disease are equally impressive.
However, the few prospective clinical trials evaluating the
role of antibiotics in the secondary prevention of CAD have
not shown a significant decrease in clinically major
cardiovascular events. Larger studies with a longer duration
of follow-up may be more useful in assessing the exact
pathogenetic mechanism of infection in atherosclerotic
heart disease, and also the role of antibiotic therapy in the
treatment of CAD.
Based on the current data, however, it is not possible to
be certain one way or the other about the role of infection
in the pathogenesis of atherogenesis, and the subsequent
complications of atherosclerosis. Further studies are
required to solve this complex problem.
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Jose et al. Utility of NT-proBNP for the Diagnosis Original


of Heart Failure
35
Article

Utility of N-Terminal Pro-Brain Natriuretic Peptide


for the Diagnosis of Heart Failure
Jacob V Jose, Satya N Gupta, Dhayakani Selvakumar
Christian Medical College and Hospital, Vellore

Background: The goal of this study was to evaluate the utility of plasma N-terminal pro-brain natriuretic
peptide for the diagnosis of heart failure in patients presenting with shortness of breath.
Methods and Results: We measured plasma levels of N-terminal pro-brain natriuretic peptide in 119 patients
presenting with shortness of breath. The patients were divided into two groups based on the Framingham criteria
and echocardiographic resultsthose with heart failure and those not in heart failure. Plasma levels of
N-terminal pro-brain natriuretic peptide were compared in the two groups. The mean N-terminal pro-brain
natriuretic peptide concentration in patients with heart failure (n=73) was higher than that in those not in
heart failure (389148 fmol/ml v. 14254 fmol/ml, p<0.001). N-terminal pro-brain natriuretic peptide values
increased significantly as the functional severity of heart failure increased (p<0.001). The mean N-terminal
pro-brain natriuretic peptide levels were 26134 fmol/ml for patients in New York Heart Association functional
class I, 300161 fmol/ml for patients in New York Heart Association functional class II, 427103 fmol/ml for
patients in New York Heart Association functional class III and 528170 fmol/ml for patients in New York
Heart Association functional class IV. Using a cut-off value of 200 fmol/ml, the sensitivity of N-terminal
pro-brain natriuretic peptide was 97%, specificity was 89% and accuracy for differentiating heart failure from
other causes of shortness of breath was 93%.
Conclusions: Our results suggest that N-terminal pro-brain natriuretic peptide can be reliably used for the
diagnosis of heart failure in an outpatient setting, and this will improve the ability of clinicians to differentiate
patients with shortness of breath due to heart failure from those with other causes of shortness of breath.
(Indian Heart J 2003; 55: 3539)
Key Words: Heart failure, Natriuretic peptide, Echocardiography

eart failure (HF) is a common disorder, and its


prevalence increases with age. In the Framingham
Heart Study, the prevalence of HF increased from 0.8% in
the 5059 years age group to 9.1% in the population 70
years of age and older. 1,2 The prevalence of HF may
continue to rise as the proportion of elderly people within
the population increases. Heart failure is not only an
important reason for hospitalization but is also second only
to hypertension as a cause of outpatient physician visits.3
Most patients in the emergency department present with
acute shortness of breath. It is extremely important to
differentiate between HF and other causes of shortness of
breath. Symptoms and physical examination alone are not
sufficient to always make an accurate diagnosis. Currently,
echocardiography is considered the gold standard
Correspondence: Dr Jacob V Jose, Department of Cardiology, CMC Hospital,
Vellore 632004

IHJ-378-02.p65

35

diagnostic test to evaluate patients with suspected


ventricular dysfunction but it is expensive and not always
easily available.4
Natriuretic peptides (cardioneurohormones)atrial
natriuretic peptide (ANP) and brain natriuretic peptide
(BNP)are secreted from the heart in response to increased
intracardiac volume or pressure. 5,6 Brain natriuretic
peptides are specifically secreted from the ventricles in
response to volume expansion or pressure overload. Levels
of BNP have been shown to be elevated in patients with left
ventricular dysfunction and correlate with the New York
Heart Association (NYHA) classification, as well as
prognosis.710
Recently, it has been reported that N-terminal pro-brain
natriuretic peptide (NT-proBNP) levels are elevated in
patients with cardiac impairment.11,12 NT-proBNP is derived
from proBNP when it splits into BNP. In normal subjects,
NT-proBNP levels are similar to those of BNP, whereas in

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Indian Heart J 2003; 55: 3539

36 Jose et al. Utility of NT-proBNP for the Diagnosis of Heart Failure

those with cardiac impairment, the proportional and


absolute increment of NT-proBNP above the normal level
exceeds that of BNP, which suggests that it may be a more
discerning marker.13,14 Though there are a number of
studies regarding the role of BNP in HF, NT-proBNP has
not been studied extensively. Thus, this study was
undertaken to evaluate the utility of NT-proBNP for the
diagnosis of HF.
Methods
Patient characteristics: One hundred nineteen patients
presenting with shortness of breath (either acute or
chronic) over a 6-month period to our emergency and
outpatient departments were enrolled in the study.
Associated symptoms were edema, weight gain, cough, or
wheezing. Patients with acute coronary syndromes were
excluded.
All the subjects underwent physical examination, chest
X-ray, supine 12-lead electrocardiogram (ECG) and blood
pressure (BP) measurement. Other data recorded included
history, risk factors, and drug treatment. Echocardiography
was performed in all the patients using a Sonos 5500
machine. Left ventricular end-systolic and diastolic
volumes were measured, and ejection fraction determined
based on the American Society of Echocardiography
recommendations.15
NT-proBNP measurement: Two ml of blood was collected
in a chilled clotted tube and centrifuged immediately. The
plasma was stored at 80 C until the NT-proBNP assay was
carried out. Plasma NT-proBNP concentration was
measured using a Biomedica kit. This kit was a competitive
enzyme immunoassay (EIA) designed to measure the
immunoreactive NT-proBNP in diluted human serum,
plasma or urine samples. To achieve high specificity, the kit
incorporates an immunoaffinity purified sheep antibody
specific for NT-proBNP (8-29) immobilized to the surface
of a microtiter plate well.
The assay is based on competitive reaction of the
unlabeled peptide in the standards or samples, and
horseradish peroxidase-labeled peptide (tracer) for
the limiting binding sites of the NT-proBNP (8-29)
specific antibody. The assay had a detection limit (2 SD)
of 5 fmol/ml. The intra-assay and interassay coefficients of
variation were 6.5% and 4.4%, respectively. The assay was
performed within 3 months of sampling. The author, who
was involved in NT-proBNP measurement, was blinded to
clinical information regarding HF.
Diagnosis of heart failure: We divided our patients into

IHJ-378-02.p65

36

two groups: patients with shortness of breath due to HF


and patients with shortness of breath not due to HF. The
diagnosis of HF was based on the Framingham criteria and
echocardiography.16 For patients with a diagnosis other
than HF, confirmation was attempted using the following
variables: normal chest X-ray and normal left ventricular
function by echocardiogram. In the group of patients with
HF, there were patients with systolic and diastolic
dysfunction: of the 73 patients with HF, 14 had diastolic
dysfunction.
Statistical analysis: To evaluate the utility of NT-proBNP
measurement for the diagnosis of HF, we computed
sensitivity, specificity, and accuracy. All the values are
expressed as mean2 SD. Comparison among values
obtained for the HF group and for those not in HF was made
by multivariate analysis. A value of p<0.05 was considered
statistically significant. The plasma level of NT-proBNP was
also compared in each stage of NYHA functional class in
patients with HF. A receiveroperating characteristics curve
was obtained to determine various cut-off values of
NT-proBNP peptide for the diagnosis of HF.
Baseline characteristics: The baseline characteristics of
the overall study group of 119 patients are shown in
Table 1. The mean age of the study population was
Table 1. Baseline characteristics of patients with and
without heart failure
Heart failure
n=73 (61.3%)

Characteristics

No heart failure
n=46 (38.7%)

Number (%) or meanSD


Demographics
Age (years)
Male sex
History
Hypertension
Diabetes mellitus
History of MI
Smoking
Symptoms
Dyspnea
Orthopnea
Nocturnal cough
Signs
Rales
Increased JVP
Ankle edema
S3 gallop
Resting tachycardia
Cardiomegaly on CXR

53.3511.62
51 (69.8)

54.2613.37
27 (58.6)

33 (45.2)
27 (36.9)
28 (38.3)
31 (42.4)

16 (34.7)
14 (30.7)
6 (13.0)
26 (56.5)

73 (100)
42 (57.5)
16 (21.9)

46 (100)
3 (6.5)
11 (23.9)

49 (67.1)
50 (68.4)
52 (71.2)
36 (49.3)
26 (35.6)
44 (60.2)

17 (36.9)
11 (23.9)
5 (10.8)
2 (4.3)
15 (32.6)
9 (19.5)

MI: myocardial infarction; JVP: jugular venous pressure; CXR: chest X-ray

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Indian Heart J 2003; 55: 3539

Jose et al. Utility of NT-proBNP for the Diagnosis of Heart Failure 37

53.712.4 years. There were 78 men (65.5%) and 41


women (34.5%). Patients were grouped according to
whether they had HF or not, based on the Framingham
criteria. The final assessment revealed that 73 patients
(61.3%) had HF as a cause of their shortness of breath,
while 46 (38.7%) had a cause other than HF; these included
bronchial asthma, chronic obstructive pulmonary disease,
pneumonia, carcinoma lung, psychogenic dyspnea. There
was no significant difference in the age and sex ratio in both
the groups of patients. Patients with HF were more likely
to have had a previous history of myocardial infarction and
clinical signs of HF.
Results
NT-proBNP and final diagnosis: Patients with a final
diagnosis of HF had a mean (SD) NT-proBNP level of
389148 fmol/ml compared with 14254 fmol/ml in
patients not in HF. The difference between the groups was
statistically significant (p<0.001). Figure 1 is a box plot of
NT-proBNP values for patients with HF and those not in
HF.

patients with a left ventricular ejection fraction less than


40% was significantly higher in comparison to its level in
patients with left ventricular ejection fraction more than
40% (406152 fmol/ml v. 17183 fmol/ml).
Receiveroperating characteristics curve: The capacity
of NT-proBNP to differentiate between shortness of breath
due to HF and that due to other causes was assessed with a
receiveroperating characteristics curve analysis (Fig. 4).
The area under the receiveroperating characteristics curve
when NT-proBNP was used to differentiate HF from other
causes of shortness of breath was 0.94 (95% confidence
interval: 0.900.98; p<0.001). An NT-proBNP cut-off
value of 200 fmol/ml had a sensitivity of 97%, a specificity
of 89% and an accuracy of 93% for differentiating between
HF and other causes of shortness of breath.
Multivariate analysis: In multiple logistic regression
analysis, we found that NT-proBNP was a strong
independent predictor for HF with an odds ratio of 8.94

NT-proBNP and clinical severity of heart failure: The


mean NT-proBNP level was 26134 fmol/ml for NYHA
functional class I, 300161 fmol/ml for NYHA functional
class II, 427103 fmol/ml for NYHA functional class III
and 528170 fmol/ml for NYHA functional class IV
patients. NT-proBNP values increase significantly as the
functional severity of HF increases (p<0.001). Figure 2
shows NT-proBNP values in relation to the NYHA
functional class.
NT-proBNP and left ventricular ejection fraction:
There was a significant negative linear correlation between
plasma NT-proBNP and the left ventricular ejection fraction
(r=0.69; p<0.001) (Fig. 3). The level of NT-proBNP in

Fig. 1. N-terminal pro-brain natriuretic peptide levels in patients with and


without heart failure. The boxes show interquartile ranges, and the bars represent
the highest and lowest values.

IHJ-378-02.p65

37

Fig. 2. Plots showing the median level of N-terminal pro-brain natriuretic


peptide levels among patients in each New York Heart Association functional
class. Boxes show interquartile ranges, and bars represent the highest and lowest
values.

Fig. 3. Scatter plot showing the correlation of the left ventricular ejection
fraction (LVEF) with plasma levels of N-terminal pro-brain natriuretic peptide
(NT-proBNP). There was a significant negative linear correlation between LVEF
and NT-proBNP.

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Indian Heart J 2003; 55: 3539

38 Jose et al. Utility of NT-proBNP for the Diagnosis of Heart Failure

Fig. 4. Receiveroperating characteristics curve for various cut-off levels of Nterminal pro-brain natriuretic peptide for the diagnosis of heart failure. The
number in parenthesis is the 95% confidence interval. AUC: area under the
receiveroperating characteristics curve

(95% confidence interval: 3.920.48). The other variable,


which was better than NT-proBNP, was the presence of S3
gallop (Table 2).
Table 2. Multivariate logistic regression analysis of
significant variables for differentiating patients with and
without heart failure
Variable
Rales
Increased JVP
Cardiomegaly
Ankle edema
Orthopnea
NT-proBNP
S3 gallop

Odds ratio

95% CI

p value

1.8
2.86
3.08
6.55
8.8
8.94
11.34

1.202.730
1.674.900
1.665.690
2.8215.18
2.9026.81
3.920.48
2.8644.87

0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001

CI: confidence interval; JVP: jugular venous pressure; NT-proBNP: Nterminal pro-brain natriuretic peptide

Discussion
Our study was designed to assess the diagnostic value of
the plasma level of circulating NT-proBNP as a noninvasive
indicator of HF. Our results suggest that NT-proBNP can
be used as a reliable marker for identification of left
ventricular dysfunction in a group of patients presenting
with shortness of breath. We found that a cut-off value of
200 fmol/ml had an accuracy of 93%.
Echocardiography, although currently the gold standard
for the diagnosis of left ventricular dysfunction, is costly
and has limited availability in an urgent care setting.
Dyspneic patients may be unable to hold their breath long

IHJ-378-02.p65

38

enough during an echocardiographic study for a good


image to be obtained. In addition, technical difficulty due
to obesity and lung disease may also interfere in getting a
good echocardiographic image. Therefore, even if
echocardiography is available in the emergency
department, an accurate, sensitive, and specific blood test
for HF would be a useful addition to the clinical
armamentarium. Brain natriuretic peptide measurement
is a useful tool for evaluating possible left ventricular
dysfunction and ventricular failure.10 Insufficient data are
available on NT-proBNP, but BNP and NT-proBNP appear
to be equivalent markers.17 In our study, the NT-proBNP
level was significantly higher in patients with HF in
comparison with those not in HF. Our results concur with
those reported previously from the West.1822
Our results suggest that the levels of NT-proBNP increase
with increasing severity of HF. NT-proBNP levels were
higher in patients in a higher NYHA class. Our results are
in accordance with the study by Hunt et al.12 Patients with
left ventricular ejection fraction <40% had NT-proBNP
levels of 406152 fmol/ml, whereas patients with left
ventricular ejection fraction >40% had values of 17183
fmol/ml. In the study by Campbell et al.,21 NT-proBNP had
a sensitivity of 100% for differentiating patients with left
ventricular ejection fraction <45%. In our study, NTproBNP levels showed a negative correlation with the left
ventricular ejection fraction (Fig. 3). When we used a cutoff value of 200 fmol/ml for NT-proBNP, the sensitivity was
97% for the diagnosis of HF. Our findings suggest that NTproBNP could be a reliable marker for the diagnosis of HF.
Our results suggest that the determination of cardiac
ventricular peptides substantially improves the diagnostic
accuracy of the assessment of left ventricular dysfunction
in a patient population with suspected HF. The results
demonstrate that measurement of NT-proBNP levels in the
blood improves the ability of the clinician to differentiate
between patients with shortness of breath due to HF and
shortness of breath due to other causes in an acute care
setting. This should be especially true among patients in
whom the diagnosis of HF is not clinically obvious. The
BNP/NT-proBNP test is now available in a rapid form, thus
making diagnostic information immediately available to the
acute care physician. Use of this test in conjunction with
other clinical information should lead to a more accurate
initial diagnosis of HF.
Limitations of the study: As this study was conducted
in a tertiary care center, it needs to be confirmed whether
these results can be generalized to the primary care level.
A larger study, including the patients clinical findings,

5/6/2003, 9:59 AM

Indian Heart J 2003; 55: 3539

Jose et al. Utility of NT-proBNP for the Diagnosis of Heart Failure 39

chest X-ray, and NT-proBNP level may be worthwhile. Also,


we did not look at the group of patients who could not be
diagnosed to have HF by routine clinical methods. Such a
study will give the incremental value of NT-proBNP over
routine clinical methods.
Conclusions: Plasma NT-proBNP is a sensitive indicator
of cardiac dysfunction. Our results suggest that NT-proBNP
can be used reliably for the diagnosis of HF in an outpatient
setting. The results demonstrate that measurement of NTproBNP levels will improve the ability of clinicians to
differentiate between patients with shortness of breath due
to HF and that due to other causes.
Acknowledgment

9.

10.

11.

12.

13.

We would like to express our thanks to Mr Pramod,


statistician, for helping us with the statistical work.
14.

References
1. Cheitlin MD, Zipes DP. Cardiovascular disease in special population.
In: Braunwald E, Zipes DP, Libby P (eds). Heart disease: a text book of
cardiovascular medicine. 6th ed. Philadelphia: WB Saunders Co; 2001.
p. 2019
2. Kannel WB, Belanger AJ. Epidemiology of heart failure. Am Heart J
1991; 121: 951957
3. OConnell JB, Bristow MR. Economic impact of heart failure in the
United States: time for a different approach. J Heart Lung Transplant
1994; 13 (Suppl): S107S112
4. Dao Q, Krishnaswamy P, Kazanegra R, Harrison A, Amirnovin R,
Lenert L, et al. Utility of B-type natriuretic peptide in the diagnosis of
congestive heart failure in an urgent-care setting. J Am Coll Cardiol
2001; 37: 379385
5. Nagagawa O, Ogawa Y, Itoh H, Suga S, Komatsu Y, Kishimoto I, et al.
Rapid transcriptional activation and early mRNA turnover of brain
natriuretic peptide in cardiocyte hypertrophy: evidence for brain
natriuretic peptide as an emergency cardiac hormone against
ventricular overload. J Clin Invest 1995; 96: 12801287
6. Maeda K, Tsutamoto T, Wada A, Hisanaga T, Kinoshita M. Plasma
brain natriuretic peptide as a biochemical marker of high left
ventricular end-diastolic pressure in patients with symptomatic left
ventricular dysfunction. Am Heart J 1998; 135: 825832
7. Clerico A, Iervasi G, Del Chicca MG, Emdin M, Maffei S, Nannipieri M,
et al. Circulating levels of cardiac natriuretic peptides (ANP and BNP)
measured by highly sensitive and specific immunoradiometric assays
in normal subjects and in patients with different degrees of heart
failure. J Endocrinol Invest 1998; 21: 170179
8. Omland T, Aakvaag A, Bonarjee VV, Caidahl K, Lie RT, Nilsen DW, et
al. Plasma brain natriuretic peptide as an indicator of left ventricular
systolic function and long-term survival after acute myocardial
infarction. Comparison with plasma atrial natriuretic peptide and

IHJ-378-02.p65

39

15.

16.
17.

18.

19.

20.

21.

22.

N-terminal proatrial natriuretic peptide Circulation 1996; 93: 1963


1969
Krishnaswamy P, Lubien E, Clopton P, Koon J, Kazanegra R, Wanner
E, et al. Utility of B-natriuretic peptide levels in identifying patients
with left ventricular systolic or diastolic dysfunction. Am J Med 2001;
111: 274279
Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc
P, et al. Rapid measurement of B-type natriuretic peptide in the
emergency diagnosis of heart failure. N Engl J Med 2002; 347: 161
167
Hunt PJ, Yandle TG, Nicholls MG, Richards AM, Espiner EA. The
amino-terminal portion of pro-brain natriuretic peptide (Pro-BNP)
circulates in human plasma. Biochem Biophys Res Commun 1995; 214:
11751183
Hunt PJ, Richards AM, Nicholls MG, Yandle TG, Doughty RN, Espiner
EA. Immunoreactive amino-terminal pro-brain natriuretic peptide
(NT-ProBNP): a new marker of cardiac impairment. Clin Endocrinol
1997; 47: 287296
Richards AM, Nicholls MG, Yandle TG, Frampton C, Espiner EA,
Turner JG, et al. Plasma N-terminal pro-brain natriuretic peptide and
adrenomedullin: new neurohormonal predictors of left ventricular
function and prognosis after myocardial infarction. Circulation 1998;
97: 19211929
Hughes D, Talwar S, Squire IB, Davies JE, Ng LL. An
immunoluminometric assay for N-terminal pro-brain natriuretic
peptide: development of a test for left ventricular dysfunction. Clin Sci
(Lond) 1999; 96: 373380
Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R,
Feigenbaum H, et al. Recommendations for quantification of the left
ventricle by two-dimensional echocardiography. American Society of
Echocardiography Committee on Standards, Subcommittee on
Quantitation of Two-Dimensional Echocardiograms. J Am Soc
Echocardiogr 1989; 2: 358367
Ho KK, Pinsky JL, Kannel WB, Levy D. The epidemiology of heart
failure: the Framingham Study. J Am Coll Cardiol 1993; 22: 6A13A
Mair J, Hammerer-Lercher A, Puschendorf B. The impact of cardiac
natriuretic peptide determination on the diagnosis and management
of heart failure. Clin Chem Lab Med 2001; 39: 571588
Schulz H, Langvik TA, Lund Sagen E, Smith J, Ahmadi N, Hall C.
Radioimmunoassay for N-terminal probrain natriuretic peptide in
human plasma. Scand J Clin Lab Invest 2001; 61: 3342
Hammerer-Lercher A, Neubauer E, Muller S, Pachinger O,
Puschendorf B, Mair J. Head-to-head comparison of N-terminal probrain natriuretic peptide, brain natriuretic peptide and N-terminal
pro-atrial natriuretic peptide in diagnosing left ventricular
dysfunction. Clin Chim Acta 2001; 310: 193197
Pemberton CJ, Yandle TG, Rademaker MT, Charles CJ, Aitken GD,
Espiner EA. Amino-terminal proBNP in ovine plasma: evidence for
enhanced secretion in response to cardiac overload. Am J Physiol
1998; 275: H1200H1208
Campbell DJ, Mitchelhill KI, Schlicht SM, Booth RJ. Plasma aminoterminal pro-brain natriuretic peptide: a novel approach to the
diagnosis of cardiac dysfunction. J Card Fail 2000; 6: 130139
Talwar S, Squire IB, Downie PF, Mccullough AM, Campton MC, Davies
JE, et al. Profile of plasma N-terminal proBNP following acute
myocardial infarction; correlation with left ventricular systolic
dysfunction. Eur Heart J 2000; 21: 15141521

5/6/2003, 9:59 AM

40 Baran et
al. IV Metoprolol in Patients with Positive ITTT
Original
Article

Indian Heart J 2003; 55: 4043

Usefulness of Intravenous Metoprolol During Positive


Isoproterenol Tilt-Table Test in the Choice of Treatment for
Neurocardiogenic Syncope
.
Ibrahim Baran, Kani Gemici, Blent zdemir, Murat Sara, Smeyye Glll, Ali Aydinlar, Jale Cordan
Department of Cardiology, Uludag University, School of Medicine, Bursa, Turkey

Background: Isoproterenol tilt-table testing provides a diagnosis of neurocardiogenic syncope in patients with
syncope or near-syncope. Although acute beta-blockade may prevent the development of syncope during
isoproterenol tilt-table testing, the use of beta-blockers for chronic prophylaxis may not be effective for some
patients who show a positive response to isoproterenol tilt-table testing. We evaluated whether the efficacy of
intravenous metoprolol in preventing symptoms during repeated tests would be helpful in selecting patients
suitable for long-term therapy.
Methods and Results: We studied 55 patients (35 females, 20 males; mean age 3611 years) who had been
chosen from a group referred to our institute with a history of unexplained syncope (>2 syncopal episodes) and
a positive response to isoproterenol tilt-table testing. After a positive response to isoproterenol tilt-table testing,
5 mg metoprolol was infused intravenously as a bolus and the test repeated. Thirty-five patients (group 1) showed
a positive response again and 20 (group II) showed a negative response. We started 50 mg metoprolol once a
day for patients in group 1 while group 2 was divided into 2 subgroups: the first subgroup (group 2a, 12 patients)
was started on 50 mg sertraline or 20 mg paroxetine once a day and the second subgroup (group 2b, 8 patients)
was started on 5 mg midodrine orally once a day. Two months later, isoproterenol tilt-table testing was repeated.
In group 1, 13 of 35 patients (37%) were positive on isoproterenol tilt-table testing while in group 2, 8 of 20
patients (40%) were positive on isoproterenol tilt-table testing (p not statistically significant). The therapies of
the two groups were then interchanged. Two months later (4 months from the beginning of the study), the
isoproterenol tilt-table test was repeated. Eleven patients in group 1 (31%) and 6 in group 2 (30%, p not
statistically significant) showed a positive response again.
Conclusions: We conclude that acute beta-blockade response to positive isoproterenol tilt-table testing is not a
useful predictor for the assessment of chronic prophylaxis for neurocardiogenic syncope. (Indian Heart J 2003;
55: 4043)
Key Words: Neurocardiogenic syncope, Tilt-table test, Beta-blockers

ypotension and bradycardia associated with


neurocardiogenic syncope are thought to be due to a
reflex triggered by enhanced left ventricular
mechanoreceptor activity in response to diminished
ventricular volume and accentuated ventricular
contractility.1 The medications generally considered to be
effective in the treatment of neurocardiogenic syncope
include beta-blockers, selective serotonin re-uptake
Correspondence: Dr Kani Gemici, Uludag University, School of Medicine,
Department of Cardiology, 16059 Grkle, Bursa, Turkey.
e-mail: kani@uludag.edu.tr

IHJ-368-02.p65

40

inhibitors (SSRIs), and midodrine.2 Increased sympathetic


activity preceding this reflex may intensify the response.3
Beta-receptor blockers such as metoprolol have been used
in the treatment of neurocardiogenic syncope due to
negative inotropic and chronotropic effects as well as the
presumed effects on central mechanoreceptors.4
We carried out this study to evaluate whether the use
of intravenous metoprolol in preventing symptoms during
the positive isoproterenol tilt-table test (ITTT) would be
helpful in selecting patients for long-term therapy with
beta-blockers or SSRIs (sertraline or paroxetine) and
midodrine.

5/6/2003, 10:00 AM

Indian Heart J 2003; 55: 4043

Baran et al. IV Metoprolol in Patients with Positive ITTT 41

Methods
Patients: We studied 89 patients (53 females and 36 males;
,
mean age 3816 years) who had been referred to our
institute with a history of unexplained syncope (>2
syncopal episodes). Cardiac and neurologic examination,
electrocardiogram, chest X-ray and echocardiogram were
normal in all the patients. Fifty-five patients (35 females,
20 males; mean age 3611 years) with a positive response
to ITTT (Table 1) formed the study group.
Around 1 week later, the ITTTs were repeated with
standard protocol and completed after an infusion of 5 mg
metoprolol (Table 2). Thirty-five patients (group 1) again
showed a positive response while 20 (group 2) showed a
negative response. We started patients in group 1 on 50
mg metoprolol once a day. Group 2 was divided into two
subgroups; the first subgroup: group 2a (12 patients) was
started on 50 mg sertraline or 20 mg paroxetine once a
day and the second subgroup: group 2b (8 patients) on 5
mg midodrine orally once a day. Two months later, the
ITTTs were repeated. During the ITTT, 3 patterns of
positive response were observed. A vasodepressor response
Table 1. Clinical characteristics of the study groups
Group 1 Group 2a Group 2b
Number of patients
35
Mean age (years)
3712
Women/men ratio
22/13
Syncopal episodes/year
5
Time to positive ITTT (seconds)
39
Baseline heart rate (bpm)
110
Baseline systolic BP (mmHg)
118

12
3410
7/5
4
47
106
121

8
3511
5/3
6
44
103
114

ITTT: isoproterenol tilt-table test; BP: blood pressure; bpm: beats per
minute; p value not statistically significant

was associated with a marked decrease in systolic blood


pressure (a decrease of at least 20 mmHg in the systolic
blood pressure). A cardioinhibitory response was
characterized by a marked decrease in heart rate (20%)
or asystole 5 s at the onset of symptoms. A mixed pattern
of response was characterized by a decrease in both blood
pressure and heart rate, frequently associated with the
development of junctional rhythm.
Tilt-table test protocol: A modified protocol was specially
designed for our clinic (Table 2). Patients were informed
before the test, and the procedure performed in the morning
between 9 and 10 a.m. after all cardioactive and vasoactive
medications had been stopped for at least 5 half-lives. The
patients had only a light breakfast 2 hours before the test.
The study room was cool, semilighted, quiet, and free of
disturbing factors such as noise. The patients lay on a
hydraulic table for 15 min in the supine position. Heart rate,
electrocardiographic, and noninvasive blood pressure
monitoring were performed continuously. Baseline
measurements were obtained every minute in the supine
position. Patients were then tilted to an 80 upright position
.
using a handboard on the hydraulic table. Heart rate, blood
pressure, electrocardiographic changes, and symptoms
were recorded every 12 min. The end-point was either
development of symptoms of syncope or presyncope
accompanied by substantial hypotension with or without
bradycardia, or at the end of a 25-min head-up tilt-table
test.
Definitions: A positive head-up tilt-table test was defined
as the development of hypotension or bradycardia (or
asystole), or both, to a degree sufficient to cause syncope
or presyncope. Syncope was defined as a transient state of
unconsciousness characterized by recovery in the supine

Table 2. The ITTT protocol form prepared for our clinic


Name and surname:
Age:
Symptoms:
Stages

Minutes

Tilt

Step I
Step II
Step III
Step III
Step III

0, 3, 5, 10 and 15
20, 25, 30, 35, 40 and 45
47 and 50
53
55,57 and 60

Step IV
Step IV

61 and 62
64, 66, 68 and 70

Systolic BP

Heart rate

ECG

Symptoms

Isoproterenol

Metoprolol

0
80
0
80
80

3 mcg/min
3 mcg/min
5 mcg/min

0
80

5 mcg/min
5 mcg/min

5 mg i.v.

ITTT: isoproterenol tilt-table test; BP: blood pressure; ECG: electrocardiogram

IHJ-368-02.p65

41

5/6/2003, 10:00 AM

Indian Heart J 2003; 55: 4043

42 Baran et al. IV Metoprolol in Patients with Positive ITTT

position. Presyncope was defined as a state of


lightheadedness associated with symptoms of decreased
vision, nausea, vomiting, partial loss of postural tone or
slow response times to verbal stimuli, which substantially
reproduced the clinical presyncope of the patients.

Discussion

fludrocortisone, midodrine, SSRIs, and etilefrine have been


used for treatment.59
The tilt-table test is an important diagnostic tool for the
evaluation of patients with unexplained syncope.10,11 ITTT
provides a diagnosis of neurocardiogenic syncope in many
patients who faint.12,13
Beta-blockers have been widely used in the treatment
of patients with neurocardiogenic syncope and are
frequently chosen as first-line drug therapy. Metoprolol and
atenolol have been the most frequently studied betablockers in neurocardiogenic syncope. Following a positive
tilt-table test, treatment with beta-blockers may not have a
substantial effect in preventing recurrence of syncope.14
Mahanonda et al.15 performed the only randomized, doubleblind, placebo-controlled trial to evaluate the efficacy of
oral beta-blockers in the treatment of neurocardiogenic
syncope. They compared the efficacy of a beta-blocker with
a placebo in patients who had had at least 1 episode of
syncope or 2 episodes of presyncope within one month
.
before presentation. The response rate after one month of
treatment was 62% versus 5% in the atenolol and control
groups, respectively. However, the efficacy of beta-blockers
was also examined in other studies, yielding controversial
results. Sheldon et al., 14 for example, concluded that
treatment with beta-blockers had no major effect on
recurrence of syncope. Cox et al.16 prospectively evaluated
the efficacy of propranolol in preventing neurocardiogenic
syncope. Oral beta-blockers were found to be effective by
the tilt-test criteria in the majority (94%) of patients. While
taking beta-blockers, 10% of patients had recurrent clinical
symptoms. In conclusion, they stated that intravenous
propranolol was very effective in blocking the neurocardiogenic reflex during tilt-table testing, and that it could
predict a good response to oral beta-blockers.
In our study, we evaluated the efficacy of beta-blockers
compared with midodrine and SSRIs in preventing
recurrences in patients with clinically diagnosed
neurocardiogenic syncope. We followed up the patients for
at least 4 months. Due to the acute efficacy of an
intravenous beta-blocker during a positive ITTT, we hoped
that it would also be useful for long-term therapy. However,
in the long term, beta-blockers did not show as good an
efficacy as expected. Also, the positive response to
intravenous metoprolol did not reliably predict a good
response to long-term oral administration.

The treatment of patients with neurocardiogenic syncope


is controversial. Neither the underlying mechanisms nor
the best modality of treatment have been clarified. Many
drugs, including disopyramide, beta-blockers, scopolamine,

Conclusions: The study is ongoing. We conclude that


acute beta-blockade response to a positive ITTT is not a
useful predictor of the success of beta-blockers in long-term
prophylaxis of neurocardiogenic syncope.

Follow-up: All the patients were followed up to detect


recurrent syncopal or presyncopal attacks, and also
complaints related to adverse effects of the drugs. Two
months later, the ITTTs were repeated, and the previous
treatment changed to an alternative one.
Statistical analysis: Data are expressed as meanSEM.
The paired and unpaired Students t test was used to
compare all numerical variables among the groups. A
p value <0.05 was considered statistically significant.
Results
The study population consisted of 35 females and 20 males
with a positive response to the ITTT. They had had a median
of 4.8 syncopal attacks per year. During the second test
after a positive response to the ITTT, 5 mg metoprolol was
infused as a bolus in the resting supine position and the
patient was tilted again to 80. Thirty-five patients
(group 1) showed a positive response again while 20
(group 2) showed a negative response with metoprolol.
Group 1 was started on 50 mg metoprolol orally once a
day and group 2 subdivided into two subgroupsthe group
given SSRIs and that given midodrine. The SSRIs group
(group 2a) was started on 50 mg sertraline or 20 mg
,
paroxetine once a day and the midodrine group (group 2b)
was started on 5 mg midodrine once a day orally. No patient
suffered from side-effects necessitating stoppage of therapy.
Two months later, the ITTTs were repeated. In group 1, 13
of 35 ITTTs (37%) were positive while 8 of 20 ITTTs (40%)
were positive in group 2 (p not statistically significant).
The therapies of the two groups were interchanged. The
patients in group 1 were given sertraline/paroxetine or
midodrine randomly. Two months later (4 months from
the beginning of the study), the ITTTs were repeated.
Eleven patients in group 1 (31%) and 6 patients in group
2 (30%, p not statistically significant) again showed a
positive response to the ITTTs.

IHJ-368-02.p65

42

5/6/2003, 10:00 AM

Indian Heart J 2003; 55: 4043

References
1. Brignole M, Alboni P, Benditt D, Bergfeldt L, Blanc JJ, Bloch Thomsen
PE, et al. Guidelines on management (diagnosis and treatment) of
syncope. Eur Heart J 2001; 22: 12561306
2. Boudoulas H, Nelson SD, Schaal SF, Lewis RP. Diagnosis and
management of syncope. In: Hursts the heart. 9th ed. McGraw-Hill;
1998. pp. 10591080
3. Perry JC, Garson A Jr. The child with recurrent syncope: autonomic
function testing and beta-adrenergic hypersensitivity. J Am Coll Cardiol
1991; 17: 11681171
4. OMarcaigh AS, MacLellan-Tobert SG, Porter CJ. Tilt-table testing and
oral metoprolol therapy in young patients with unexplained syncope.
Pediatrics 1994; 93: 278283
5. Raviele A, Brignole M, Sutton R, Alboni P, Giani P, Menozzi C, et al.
Effect of etilefrine in preventing syncopal recurrence in patients with
vasovagal syncope: a double-blind, randomized, placebo-controlled
trial. The Vasovagal Syncope International Study. Circulation 1999;
99: 14521457
6. Morillo CA, Leitch JW, Yee R, Klein GJ. A placebo-controlled trial of
intravenous and oral disopyramide for prevention of neurally
mediated syncope induced by head-up tilt. J Am Coll Cardiol 1993;
22: 18431848
7. Madrid AH, Ortega J, Rebollo JG, Manzano JG, Segovia JG, Sanchez A,
et al. Lack of efficacy of atenolol for the prevention of neurally
mediated syncope in a highly symptomatic population: a prospective,
double-blind, randomized and placebo-controlled study. J Am Coll
Cardiol 2001; 37: 554559

IHJ-368-02.p65

43

Baran et al. IV Metoprolol in Patients with Positive ITTT 43


8. Lee TM, Su SF, Chen MF, Liau CS, Lee YT. Usefulness of transdermal
scopolamine for vasovagal syncope. Am J Cardiol 1996; 78: 480482
9. Ward CR, Gray JC, Gilroy JJ, Kenny RA. Midodrine: a role in the
management of neurocardiogenic syncope. Heart 1998; 79: 4549
10. Fogoros RN. Electrophysiological testing, 3rd ed. Blackwell Science;
1999
11. Braunwald E, Zipes DP, Libby PT (eds). Heart disease. A text book of
cardiovascular medicine. Philadelphia: WB Saunders Company; 2001.
pp. 935936
12. Kapoor WN, Brant N. Evaluation of syncope by upright tilt testing
with isoproterenol. A nonspecific test. Ann Intern Med 1992; 116:
358363
13. Zeng C, Zhu Z, Hu W, Liu G, Zhu S, Zhou Y, et al. Value of sublingual
isosorbide dinitrate before isoproterenol tilt test for diagnosis of
neurally mediated syncope. Am J Cardiol 1999; 83: 10591063
14. Sheldon R, Rose S, Flanagan P, Koshman ML, Killam S. Effect of betablockers on the time to first syncope recurrence in patients after a
positive isoproterenol tilt table test. Am J Cardiol 1996; 78: 536539
15. Mahanonda N, Bhuripanyo K, Kangkagate C, Wansanit K, Kulchot
B, Nademanee K, et al. Randomized double-blind, placebo-controlled
trial of oral atenolol in patients with unexplained syncope and positive
upright tilt table test results. Am Heart J 1995; 130: 12501253
16. Cox MM, Perlman BA, Mayor MR, Silberstein TA, Levin E, Pringle L,
et al. Acute and long-term beta-adrenergic blockade for patients with
neurocardiogenic syncope. J Am Coll Cardiol 1995; 26: 12931298

5/6/2003, 10:00 AM

44 Jadhav Article
et al. Endothelial Dysfunction and Prediction of
Original

Indian Heart J 2003; 55: 4448

CAD

Noninvasive Assessment of Endothelial Dysfunction by


Brachial Artery Flow-Mediated Dilatation in Prediction of
Coronary Artery Disease in Indian Subjects
Uday M Jadhav, Anand Sivaramakrishnan, NN Kadam
Department of Non-Invasive Cardiology, MGM New Bombay Hospital, Mumbai

Background: A noninvasive technique for testing endothelial function by ultrasound measurement of flowmediated dilatation has recently generated considerable interest as a marker of atherosclerosis, and in the
prediction of clinical coronary events and coronary artery disease.
Methods and Results: We measured the flow-mediated dilatation of the brachial artery (endotheliumdependent vasodilatation) in 136 subjects, with or without evidence of coronary artery disease. Endothelial
dysfunction was diagnosed if flow-mediated dilatation was less than 4.5%. Of the 136 subjects (age group
4070 years) recruited for the study, 94 were males and 42 females. Sixty-eight subjects had evidence of coronary
artery disease as diagnosed by documented hospitalization due to myocardial infarction or acute coronary
syndrome, proved by coronary angiography when feasible or noninvasive cardiac evaluation. Endothelial
dysfunction was detected in 90 subjects (66.2%). Prevalence of coronary artery disease was higher among
subjects with endothelial dysfunction compared to those without (57.5% v. 34.7%, p=0.013). Prevalence of
endothelial dysfunction was significantly higher among subjects with coronary artery disease as compared to
those without coronary artery disease (76.4% v. 55.8%, p=0.012). The present study showed a sensitivity of
76%, specificity of 44%, positive predictive value of 58% and negative predictive value of 65% for endothelial
dysfunction in the prediction of coronary artery disease. Multiple regression analysis using coronary artery
disease as a dependent variable revealed a statistically significant association with endothelial dysfunction
(p=0.033) even after the inclusion of traditional risk factors into the model.
Conclusions: We conclude that endothelial dysfunction shows a strong association with coronary artery disease
and can be a useful noninvasive tool for the evaluation of coronary artery disease. (Indian Heart J 2003; 55:
4448)
Key Words: Coronary artery disease, Endothelial dysfunction, Doppler ultrasound

rterial endothelial dysfunction (ED) is one of the key


early events in atherogenesis, preceding structural
atherosclerotic changes. It is also important in the late
stages of obstructive atherosclerosis, predisposing to
constriction and/or thrombosis.1 Testing the function of the
endothelium in vivo has proved challenging. Although the
endothelium releases a number of products, no single blood
test has yet proved useful in determining normal endothelial
function or early abnormalities. The most common test used
for the evaluation of endothelial function in vivo to date
depends on measuring endothelium-dependent dilatation
in response to physiologic or pharmacologic stimuli. This
Correspondence: Dr Uday M Jadhav, MGM New Bombay Hospital, Sector
3, Vashi, Navi Mumbai 400703. e-mail: udayj@bom8.vsnl.net.in

IHJ-363-02.p65

44

depends mostly on the ability of the endothelium to release


nitric oxide (NO), which is not only a potent vasodilator
but also an inhibitor of platelet aggregation, monocyte
adhesion, and smooth muscle proliferation.2
Endothelial function can be measured in the coronary
arteries and peripheral vasculature by measuring
vasomotor function after intra-arterial infusion of
pharmacologic substances, which enhance the release of
endothelial NO. The disadvantage of this method is its
invasive nature, which generally makes it unsuitable for
studies involving asymptomatic subjects. For this reason,
noninvasive tests of endothelial function have been
developed. The most widely used of these tests, an
ultrasound-based method, involves measurement of
arterial diameter in response to shear stress, which causes

5/6/2003, 10:01 AM

Indian Heart J 2003; 55: 4448

Jadhav et al. Endothelial Dysfunction and Prediction of CAD 45

endothelium-dependent dilatation. 1 Endotheliumindependent dilatation can be assessed by measuring the


arterial diameter after administration of sublingual
nitroglycerin.
We undertook this study to assess the role of a simple
technique of flow-mediated dilatation (FMD) measurement
in predicting coronary artery disease (CAD). This study
assesses the endothelium-dependent dilatation of conduit
vessels, and there are other methods for resistance vessels.
Differences may exist with regard to endotheliumdependent dilatation of the conduit versus resistance
arteries, and these differences have potential implications.
Methods
A total of 136 patients, both hospitalized as well as
outpatient, were included in the study. Informed consent
was obtained from the study subjects who were divided
into two groups: with CAD (68 subjects) and without CAD
(68 subjects). Coronary artery disease was diagnosed
along with clinical presentation by electrocardiography
(ECG), symptom-limited exercise stress test, Doppler
echocardiography, and coronary angiography, when
feasible. Of the 68 subjects with CAD, 42 had evidence
of myocardial infarction or acute coronary syndrome,
13 had evidence on coronary angiography, and 13 had
ECG, stress test, and echocardiographic manifestations
suggestive of CAD. Of the 136 subjects, 20 had type 2
diabetes mellitus, 51 had hypertension, 37 had diabetes
with concomitant hypertension, and 28 had no diabetes
or hypertension. The mean age was 52 years with a range
of 4074 years. The subjects included 94 males and 42
females.
The ultrasound method for measuring endotheliumdependent and endothelium-independent arterial dilatation
has been described previously. 3,4 The brachial artery
diameter was measured on B-mode ultrasound images,
with the use of a 7.0 MHz linear-array transducer with
Imagepoint Hx ultrasound equipment (Agilent Technology,
India). The right brachial artery was studied in all the
subjects. Brachial artery endothelial function was studied
after the subject had abstained from alcohol, caffeine, and
smoking for 8 h. Scans were obtained with the subject at
rest, during reactive hyperemia and again with the subject
at rest. The subjects were asked to lie quietly for at least 10
min before the first scan. The brachial artery was scanned
in longitudinal section 215 cm above the elbow, and the
center of the artery was identified when the clearest picture
of the anterior and posterior intimal layers was obtained.
The transmit (focus) zone was set to the depth of the near

IHJ-363-02.p65

45

wall, because of the greater difficulty in evaluating the m


line (the interface between the media and adventitia) of the
near wall as compared with that of the far wall.5 Depth and
gain settings were set to optimize images of the interface
between the lumen and the arterial wall, and the images
were magnified. Settings for operating the machine were
not changed during the study.
When a satisfactory transducer position was found, the
skin was marked and the arm was kept in the same position
throughout the study. A resting scan was obtained, and the
velocity of arterial flow measured with a pulsed Doppler
signal at a 70 angle to the vessel, with the range gate (1.5
mm) in the center of the artery. Increased flow was then
induced by the inflation of a sphygmomanometer cuff
placed around the forearm (distal to the scanned part of
the artery) to a pressure of 200 mmHg for 4.5 min, followed
by release. A second scan was performed continuously for
30 s before and 90 s after deflation of the cuff, including a
repeated recording of flow velocity for the first 15 s after
the cuff was released.
Flow-mediated dilatation was calculated, and the
average results of the two observations recorded. The
system software was designed for online recording, which
was assessed visually to ensure that the best possible
recording was obtained and artefacts minimized.
Automatic tracking was not performed. ECG was monitored
throughout the scans and the artery diameter measured
at end-diastole. Interobserver and intraobserver variability
was studied in 20 healthy subjects with a mean age of 42.4
years. Interobserver variability was 1.6% and intraobserver
variability was 2.2%. This method is accurate and
reproducible for measuring small changes in arterial
diameter 6 with low rates of interobserver error in
measuring FMD.3,4 Flow-mediated dilatation was presented
as the percent change from baseline to hyperemia.
Endothelial dysfunction was defined as FMD <4.5%, as has
been previously described.7
Clinical examination included blood pressure
measurement, cardiovascular examination, anthropometrical measurements, and body-mass index (BMI).
Biochemical assessment included fasting blood sugar (FBS)
and post-prandial blood sugar levels, glycated hemoglobin,
urine for microalbumin, and comprehensive lipid profile.
Plasma glucose and lipid estimation were done after an
overnight fast of 12 h. Biochemical analysis was done on
Technicon RA-1000 Auto Analyser. Plasma glucose, serum
cholesterol, serum triglycerides, and high-density
lipoprotein (HDL)-cholesterol (HDL-c) were estimated with
kits supplied by AUTOPAK-Bayer Diagnostics, India. Plasma
glucose estimation was done by the GOD/POD method,

5/6/2003, 10:01 AM

Indian Heart J 2003; 55: 4448

46 Jadhav et al. Endothelial Dysfunction and Prediction of CAD

serum cholesterol by the enzymatic method and


triglycerides by the enzymatic calorimetric method. HDL-c
was estimated after precipitating low-density lipoprotein
(LDL) and chylomicron fractions by the addition of
phosphotungstic acid in the presence of magnesium ions
and very low-density lipoprotein (VLDL). LDL-cholesterol
(LDL-c) was calculated using the Friedewald formula,
namely,
LDL-c = Total cholesterol

+ HDL)
(Triglycerides
5

The baseline characteristics of the study group and the


relevant brief results of the lipid profile are shown in Tables
1 and 2.
Statistical analysis: Data collected were managed on an
Excel spreadsheet. One-way ANOVA or Students t test was

used as appropriate to compare the mean of the continuous


variables. Chi-square test was used to compare proportion.
Pearsons correlation coefficient was used to determine if
an association existed among the risk factors. All the groups
were combined for Pearsons correlation analysis. Multiple
regression analysis was carried out using CAD as the
dependent variable and factors such as BMI, smoking,
hypertension, FBS, serum cholesterol, triglycerides, HDL-c,
LDL-c as independent variables. The subjects were
compared for the age groups less than and greater than 50
years, smokers and non-smokers, BMI <23 kg/m2 and >23
kg/m2, LDL-c <130 mg/dl and >130 mg/dl, HDL-c <40
mg/dl and >40 mg/dl, total cholesterol to HDL-c ratio <5.5
and >5.5, triglycerides <200 mg/dl and >200 mg/dl, and
the subgroup of hypertensiondiabetes mellitus. All
analyses were performed with the SPSS version 10 and p
values less than 0.05 were considered significant.
Results

Table 1. Clinical characteristics of the study group

Values in parentheses are percentages


LDL: low-density lipoprotein; HDL: high-density lipoprotein

The percentage distribution of FMD in subjects with various


risk factors is shown in Table 3. There was a 66.2%
prevalence of ED in the present study population. In
subjects with evidence of CAD, 76.4% had endothelial
dysfunction as indicated by FMD <4.5% as compared to
55.8% in those without obvious evidence of CAD (Table
4). This was highly significant with p<0.001. The
correlation of FMD with CAD is illustrated in Fig.1. The odds
ratio for FMD <4.5% was 3.90 in those with CAD as against
those without obvious CAD, making it an important marker
for preclinical and clinical CAD.
The prevalence of CAD among subjects with FMD
<4.5% was calculated by the following method:

Table 2. Clinical characteristics of the study group in the


context of endothelial dysfunction

Number of subjects with CAD


and FMD <4.5%
Prevalence (%) = 100
Number of subjects with
FMD <4.5%

Parameters

CAD
(n=68)

Non-CAD
(n=68)

Age (years)
56.5311.47
48.7411
Male (%)
50 (53.1)
44 (46.8)
Smoking (%)
51 (75)
17 (25)
Hypertension (%)
21 (30.9)
30 (44.1)
Diabetes mellitus (%)
10 (14.7)
10 (14.7)
Body-mass index (kg/m2)
25.684.14
26.033.66
Fasting plasma glucose (mg/dl) 114.6141.92 114.1150.39
Total cholesterol (mg/dl)
194.9343.71 184.7338.66
LDL-cholesterol (mg/dl)
122.2641.29 111.1833.89
HDL-cholesterol (mg/dl)
40.935.80
41.73 6.10
Triglycerides (mg/dl)
155.0266.96 160.44107.70
CholesterolHDL ratio
4.791.11
4.520.92

Parameters

FMD
<4.5%

Age (years)
53.7311.67
Male (%)
67 (74.4)
Smoking (%)
71 (78.9)
Hypertension (%)
29 (32.2)
Diabetes mellitus (%)
15 (16.7)
Body-mass index (kg/m2)
25.483.89
Fasting plasma glucose (mg/dl) 118.749.1
Total cholesterol (mg/dl)
192.777.9
LDL-cholesterol (mg/dl)
120.039.7
HDL-cholesterol (mg/dl)
41.16.3
Triglycerides (mg/dl)
161.996.7
CholesterolHDL ratio
4.81.1

FMD
>4.5%
50.4812.06
27 (58.7)
42 (91.3)
22 (47.8)
5 (10.9)
26.613.85
106.039.1
141.766.8
110.934.5
41.75.4
150.074.8
4.40.8

Values in parentheses are percentages


LDL: low-density lipoprotein; HDL: high-density lipoprotein

IHJ-363-02.p65

46

p value
0.0001
0.265
0.012
0.374
0.374
0.602
0.951
0.270
0.110
0.457
0.754
0.157

p value
0.130
0.060
0.068
0.048
0.072
0.109
0.140
0.270
0.206
0.634
0.511
0.096

The prevalence of CAD among subjects with FMD


>4.5% and prevalence of FMD <4.5% in subjects with and
without CAD were calculated in the same way. The
prevalence of CAD was significantly higher among subjects
with FMD <4.5% compared to those with FMD >4.5%
(57.5% v. 34.7%, p=0.013). Prevalence of FMD <4.5% was
significantly higher among subjects with CAD compared
to those without CAD (76.4% v. 55.8%, p=0.012). Multiple
regression analysis using CAD as a dependent variable
revealed a statistically significant association with
endothelial dysfunction (p=0.033) even after the inclusion
of traditional risk factors into the model, as shown in
Table 5.

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Indian Heart J 2003; 55: 4448

Jadhav et al. Endothelial Dysfunction and Prediction of CAD 47

Table 3. Percentage distribution of flow-mediated dilatation


in subjects with risk factors
Normal
FMD <4.5%
within subgroup
FMD >4.5%
within subgroup
Total
within subgroup

17
(18.9)
11
(23.9)
28
(20.6)

Type 2 Hyperdiabetes tension


15
(16.7)
5
(10.9)
20
(14.7)

Diabetes with
hypertension

29
(32.2)
22
(47.8)
51
(37.5)

29
(32.2)
8
(17.4)
37
(27.2)

Values in parentheses indicate percentages


FMD: flow-mediated dilatation
Pearson Chi-square= 5.506, p<0.138

Table 4. Correlation of flow-mediated dilatation of the


brachial artery with CAD on univariate analysis

FMD <4.5%
FMD >4.5%
Total

Without CAD

With CAD

Total

38
(55.9)
30
(44.1)
68

52
(76.5)
16
(23.5)
68

90
(66.2)
46
(33.8)
136

Values in parentheses indicate percentages


FMD: % change in flow-mediated dilatation; CAD: coronary artery disease
Pearson Chi-Square=6.439, p=0.011
Odds ratio: FMD <4.5%/FMD >4.5% for CAD=3.90
(95% CI lower: 0.187, CI upper: 0.814)

Fig. 1. Percentage distribution of subjects with endothelial dysfunction in


relation to CAD.

The present study showed ED to have a sensitivity of


76%, specificity of 44%, positive predictive value of 58%
and negative predictive value of 65% in the prediction of
CAD. Changes in the flow velocity during the hyperemic
phase were inconsistent and not statistically significant in
subjects with and without CAD (group without CAD
34.25% to 83.10%, mean 11.03%, SD 28.64; versus
group with CAD 22.06% to 51.91%, mean 14.29%, SD
21.47, p>0.05).

IHJ-363-02.p65

47

Table 5. Multiple regression analysis using CAD as a


dependent variable

Sex
Age
Smoking
BMI >23 kg/m2
Cholesterol >180 mg/dl
LDL-c >130 mg/dl
HDL-c >40 mg/dl
Triglycerides >200 mg/dl
FMD (%) <4.5
Risk groups

p value

Odds ratio

0.934
0.019
0.198
1.000
0.555
0.624
0.539
0.560
0.033
0.173

1.047
1.053
2.411
1.000
1.473
1.395
0.717
1.390
0.321
0.723

BMI: body-mass index; LDL-c: low-density lipoprotein cholesterol;


HDL-c: high-density lipoprotein cholesterol; FMD: flow-mediated
dilatation

Discussion
Ultrasonography is a reliable and accurate technique to
determine FMD in the superficial arteries. Reproduciblity
of FMD determination is best in the brachial artery in
healthy subjects and in patients with atherosclerosis.3,6
B-mode ultrasound scan including brachial artery FMD
may be of clinical value in the screening of patients with
CAD.6
In a study by Schroeder et al.,7 patients with CAD had a
significantly lower FMD% than patients without CAD. They
reported a sensitivity of 71%, a specificity of 81% with a
positive predictive value of 0.95 and a negative predictive
value of 0.41 for FMD in the prediction of CAD. They found
a better specificity and higher sensitivity for FMD as
compared to angina pectoris (sensitivity 95%, specificity
47.6%), exercise ECG (sensitivity 82.4%, specificity 57.1%),
and myocardial perfusion imaging (sensitivity 100%). The
present study showed a sensitivity of 76%, specificity of
44%, positive predictive value of 58%, and negative
predictive value of 65% for ED in the prediction of CAD.
The specificity and positive predictive value can be improved
by the selection of a healthy control group in the true sense,
inclusion of only coronary angiography-documented cases,
and utilizing automated tracking for the measurement of
arterial diameter.
In a study by Neunteufl et al.,8 impaired FMD in CAD
patients was related to the extent of CAD, to the maximum
percent diameter stenosis in one of the major coronary
vessels, brachial artery diameter, and plasma cholesterol
level on univariate analysis. On multiple regression
analysis, the extent of CAD (1-, 2- or 3-vessel disease) and
the baseline brachial artery diameter were independently
associated with FMD in CAD patients.8

5/6/2003, 10:01 AM

Indian Heart J 2003; 55: 4448

48 Jadhav et al. Endothelial Dysfunction and Prediction of CAD

Endothelial-dependent and -independent functions are


impaired in patients with CAD, and the extent of FMD has
been shown to significantly correlate with serum HDL-c
levels on univariate and multivariate analysis.9 Patients
with unstable angina have also been shown to have ED
compared to normal individuals.10 Long-term follow-up of
28 months in subjects with severe ED in the absence of
obstructive CAD was shown to be associated with increased
cardiac events. Coronary ED may play a role in the
progression of coronary atherosclerosis.11
The obvious limitation of the present study is the lack
of angiographic documentation in both the groups, except
for undisputed evidence of CAD in 41 subjects in the CAD
group. This was not performed for ethical, logistic, and
socioeconomic reasons. It was not known whether
participants in the group without CAD with FMD >4.5%
already had significant subclinical atherosclerosis at the
time of enrollment to the study, which can negate the
argument for the above limitation. The present study is not
a prospective cohort study, and a long-term follow-up of
the subjects without CAD is required.
Conclusions: In conclusion, the present study shows that
ED is associated with and is also an independent risk factor
for CAD. Assessment of ED should be included along with
other conventional risk variables such as lipoproteins to
identify individuals at increased risk for CAD at an early
stage, given the paucity of facilities for invasive evaluation
in India. Longitudinal studies are required to demonstrate
the utility of ED as a predictor of CAD in the Indian
population.
Acknowledgment

References
1. Raitakari OT, Celermajer DS. Flow-mediated dilatation. Br J Clin
Pharmacol 2000; 50: 397404
2. Celermajer DS. Testing endothelial function using ultrasound. J
Cardiovasc Pharmacol 1998; 32: 2932
3. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI,
Sullivan ID, et al. Non-invasive detection of endothelial dysfunction
in children and adults at risk of atherosclerosis. Lancet 1992; 340:
11111115
4. Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O,
Robinson J, et al. Cigarette smoking is associated with dose-related
and potentially reversible impairment of endothelium-dependent
dilation in healthy young adults. Circulation 1993; 88: 21492155
5 Wendelhag I, Gustavsson T, Suurkula M, Berglund G, Wikstrand J.
Ultrasound measurement of wall thickness in the carotid artery:
fundamental principles and description of a computerized analysing
system. Clin Physiol 1991; 11: 565577
6. Sorensen KE, Celermajer DS, Spiegelhalter DJ, Georgakopoulus D,
Robinson J, Thomas O, et al. Non-invasive measurement of human
endothelium dependent arterial responses: accuracy and
reproducibility. Br Heart J 1995; 74: 247253
7. Schroeder S, Enderle MD, Ossen R, Meisner C, Baumbach A, Pfohl M,
et al. Noninvasive determination of endothelium-mediated
vasodilation as a screening test for coronary artery disease: pilot study
to assess the predictive value in comparison with angina pectoris,
exercise electrocardiography, and myocardial perfusion imaging. Am
Heart J 1999; 138: 731739
8. Neunteufl T, Katzenschlager R, Hassan A, Klaar U, Schwarzacher S,
Glogar D, et al. Systemic endothelial dysfunction is related to the extent
and severity of coronary artery disease. Atherosclerosis 1997; 129:
111118
9. Zhang X, Zhao SP, Li XP, Gao M, Zhou QC. Endothelium-dependent
and -independent functions are impaired in patients with coronary
heart disease. Atherosclerosis 2000; 149: 1924
10. Esper RJ, Vilarino J, Cacharron JL, Machado R, Ingino CA, Garcia
Guinazu CA, et al. Impaired endothelial function in patients with
rapidly stabilized unstable angina: assessment by noninvasive brachial
artery ultrasonography. Clin Cardiol 1999; 22: 699703
11. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr,
Lerman A. Long-term follow-up of patients with mild coronary artery
disease and endothelial dysfunction. Circulation 2000; 101: 948954

We would like to thank Dr DP Singh for his assistance with


the statistical analysis.

IHJ-363-02.p65

48

5/6/2003, 10:01 AM

Indian Heart J 2003; 55: 4954

Harikrishnan et al. SupravalvarOriginal


Aortic Stenosis
49
Article

Supravalvar Aortic Stenosis: Clinical and Hemodynamic


Profile, and Surgical Outcome
S Harikrishnan, SR Krishna Manohar, Krishna Kumar Nair, JaganmohanTharakan, Thomas Titus,
VK Ajith Kumar, Anil Bhat, S Sivasankaran, Francis Bimal, KM Krishna Moorthy, R Padma Kumar
Departments of Cardiology and Cardiac Surgery, Sree Chitra Tirunal Institute for
Medical Sciences and Technology, Thiruvananthapuram

Background: Supravalvar aortic stenosis is the rarest of left ventricular outflow obstructions. Data on this rare
entity from India are scarce.
Methods and Results: We retrospectively analyzed the data of 15 patients (13 males, mean age 15.510.18
years) with a diagnosis of supravalvar aortic stenosis confirmed by cardiac catheterization. Five patients had
morphological features of Williams syndrome. One patient had diffuse while the rest had discrete type of
supravalvar aortic stenosis. Five patients did not have any associated lesions. A 9-year-old male had an ascending
aortic aneurysm, and 3 patients had associated peripheral pulmonary artery stenosis. One child had a subaortic
ventricular septal defect, and another had severe mitral regurgitation. Twelve patients had electrocardiographic
evidence of left ventricular hypertrophy. Three patients had mild aortic valvar stenosis while 2 had aortic
regurgitation. Six patients had dilated coronary arteries. Two patients with supravalvar aortic gradients of 20
and 40 mmHg were kept on close follow-up. One patient was not willing to undergo surgery while the other is
awaiting surgery. Eleven patients underwent surgical correction. Dacron or pericardial patch aortoplasty was
done in all the patients. In addition, one patient each underwent pulmonary artery plasty, ventricular septal
defect closure, repair of ascending aortic aneurysm, and mitral valve replacement. The patient with diffuse type
of supravalvar aortic stenosis underwent augmentation aortoplasty. Two patients died perioperatively. One was
lost to follow-up. Two had moderate residual gradients. The rest of the patients were in New York Heart Association
functional class I on follow-up of 6.34.7 years.
Conclusions: Repair of supravalvar aortic stenosis by single sinus aortoplasty is safe and produces good results.
(Indian Heart J 2003; 55: 4954)
Key Words: Supravalvar aortic stenosis, Williams syndrome, Aortoplasty

upravalvar aortic stenosis (SVAS) is the least common


form of congenital left ventricular outflow tract (LVOT)
obstruction. Congenital narrowing of the ascending aorta
may be localized or diffuse, originating at the superior
margin of the sinus of Valsalva just above the level of the
origin of the coronary artery.1 The features of SVAS which
distinguish it from other forms of LVOT obstruction are
involvement of the coronary arteries and aortic leaflets, and
an association with characteristic facies and mental
retardation.2,3
Reports regarding this entity are few, especially in the
Indian context. This study is a retrospective one, which
describes our 24-year experience of the clinical, angioCorrespondence: Dr S Harikrishnan, SCTIMST, Thiruvananthapuram
695011. e-mail: drharikrishnan@hotmail.com

IHJ-408-02.p65

49

graphic, and hemodynamic profile of this entity, and our


surgical experience and its outcome.
Methods
We reviewed the medical records of all patients with a
diagnosis of SVAS from our patient database starting
from 1976 till date. Only those patients who had
undergone cardiac catheterization and angiography to
confirm the diagnosis were enrolled in the study. Data
collected included anthropometric particulars, clinical
history and findings, electrocardiograms (ECGs), chest Xrays, and echocardiographic and cardiac catheterization
data. All cine films were retrospectively reviewed by two
experienced angiographers. Surgical data, including the
technique of surgery, peroperative findings, and

5/6/2003, 10:01 AM

Indian Heart J 2003; 55: 4954

50 Harikrishnan et al. Supravalvar Aortic Stenosis

complications were also collected. Follow-up data


were collected and those patients who did not have recent
follow-up data were called for a review and their data
collected.
Results
Among the 12 400 patients who underwent cardiac
catheterization for evaluation of congenital heart disease,
there were 15 patients (0.12%, 13 males) who had the
diagnosis of SVAS confirmed by catheterization and
angiography. The average age was 15.510.18 years. The
youngest was a 15-month-old male child and the oldest
was a 34-year-old male. Five patients had morphological
features of Williams syndrome; of them, only 1 had
hypercalcemia (Tables 1 and 2).
All the patients had discrete type of SVAS (Figs 1 and 2),
except 1 (6.6%) who had the diffuse variety (Fig. 3). The
mean peak gradient across the supra-aortic region was
101.6359.69 mmHg.
The mode of presentation was congestive heart failure
(CHF) in 3 patients. One patient, a 14-year-old male,
presented with severe anemia and CHF (hemoglobin 4 g%),
the other 2 patients presented with CHF in infancy. A 27year-old male patient presented with recurrent presyncope.
He had a very high LVOT gradient of 215 mmHg. Three
patients were in the New York Heart Association (NYHA)

functional class I at presentation. The rest of the patients


were in NYHA class II.
Two patients underwent repeat cardiac catheterization
on follow-up. One 10-year-old boy with class II symptoms,
who had an initial gradient of 24 mmHg, which increased
to 80 mmHg after 6 years, was advised surgery. Another
10-year-old boy whose initial gradient of 31 mmHg
increased to 76 mmHg after 5 years also underwent surgery.
One patient with a gradient of 40 mmHg had the same
echocardiographic gradient 9 years post-catheterization
and has been kept on follow-up.
Associated lesions: Five patients did not have any
associated lesions. One patient, a 9-year-old male, had an
ascending aortic aneurysm necessitating repair. Three
patients had associated peripheral pulmonary artery
stenosis. Of them, 2 patients had features of Williams
syndrome. One patient had moderate aortic regurgitation
(AR) while another had a small perforation in the
noncoronary aortic cusp with mild AR, requiring repair. A
10-year-old child had a subaortic ventricular septal defect
(VSD), and mild valvar AS (AS gradient of 20 mmHg). A
15-month-old child had mitral valve prolapse (MVP), and
moderate-to-severe mitral regurgitation (MR), requiring
mitral valve repair.
Electrocardiograms: Two patients with supravalvar
gradients of 20 and 40 mmHg had normal ECGs. A 6-year-

Table 1. Clinical profile and morphologic data


S.
No.

Age
(years)

Sex

Dysmorphism

Aortic valve

Associated cardiac
lesions

Coronaries

1
2
3
4

14
27
1.25
6

M
F
M
M

Nil
Nil
Nil
Nil

Nil
Valvular AS
MVP MR
Mild AR

Normal
Normal
NA

WS
WS
WS
Nil

Normal
Thickened, stenotic
Normal
Valve commissures fused
to ridge, NCC perforation
Normal
Thickened, stenotic
Normal
Normal

5
6
7
8

16
18
10
27

M
M
M
M

9
10
11

4.5
10
9

M
M
M

WS
Nil
Nil

Adherent LCC
Normal
Normal

12
13
14
15

15
26
10
34

F
M
M
M

Nil
Nil
WS
Nil

Normal
Adherent LCC
Normal
Adherent cusps, AR

Nil
VSD+valvular AS
RPA stenosis
Innominate artery
narrowing
Nil
Nil
Ascending aortic
aneurysm
LPA stenosis
Nil
LPA, RPA stenosis
Nil

Dilated
Normal
Normal
Normal
Dilated
Dilated, tortuous
Normal
Dilated
Normal
Dilated
Dilated, tortuous
Normal

WS: Williams syndrome; LCC: left coronary cusp; NCC: noncoronary cusp; AS: aortic stenosis; VSD: ventricular septal defect; AR: aortic regurgitation;
MVP: mitral valve prolapse; MR: mitral regurgitation; LPA: left pulmonary artery; RPA: right pulmonary artery; NA: data not available

IHJ-408-02.p65

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Indian Heart J 2003; 55: 4954

Harikrishnan et al. Supravalvar Aortic Stenosis

51

Table 2. Electrocardiographic and hemodynamic data, and follow-up


S.
No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15

Age
(years)

Sex

Type

ECG

LV pressure

SV gradient

14
27
1.2
6
16
18
10
27
4.5
10
9
15
26
10
34

M
F
M
M
M
M
M
M
M
M
M
F
M
M
M

Diffuse
Localized
Localized
Localized
Localized
Localized
Localized
Localized
Localized
Localized
Localized
Localized
Localized
Localized
Localized

LVH strain
No LVH
LVH
No LVH
LVH
LVH
LVH
LVH
LVH
No LVH
LVH strain
LVH strain
LVH
LVH
LVH strain

230
120
154
190
120
250
170
340
200
150
302
300
200
205
170

150
20
90
70
56
70
76
215
122
40
200
180
80
100
50

Course/surgery
PA
Medical follow-up
PA+MVR
PA
PA
PA+VSD closure
PA+pulmonary arterioplasty
PA
PA
Medical follow-up
PA+aneurysmorrhaphy
PA
PA
Not willing for surgery
Awaiting surgery

PA: patch aortoplasty; LVH: left ventricular strain; MVR: mitral valve replacement; VSD: ventricular septal defect; SV: supravalvar

old patient with a gradient of 70 mmHg also did not have


left ventricular hypertrophy (LVH). All the other patients
had ECG evidence of LVH. The presence of LV strain did not
correlate with the severity of stenosis.
Aortic valve morphology: Three patients had gradients
across the aortic valve in addition to the gradients at the
supravalvar region. These gradients were minimal (10, 20,
and 14 mmHg) against supravalvar gradients of 120, 170
and 202 mmHg, respectively. All the patients who
underwent surgery had their valves examined
peroperatively and the findings were noted. Nine patients
had normal valves. Details of valve abnormalities are given
in Table 1. No patient needed any intervention for valvular
anomalies except one who had a small noncoronary cusp
perforation which had to be repaired during patch
aortoplasty. One patient with moderate AR is awaiting
surgery.
Coronary morphology: Coronary anatomy was available
for analysis in 13 of the 15 patients. Seven of the 13 patients
had dilated coronary arteries, especially the proximal
coronary arteries (Figs 2 and 3). Two patients had tortuous,
dilated coronary arteries.
Two patients with supravalvar aortic gradients of 20
and 40 mmHg were kept on close follow-up. The relatives
of one 10-year-old male patient were not willing for surgery.
One patient is awaiting surgery. The remaining patients
(n=11) underwent surgical correction.
Surgical technique: All the patients were operated
(n=11) under standard cardiopulmonary bypass (CPB)
with moderate hypothermic and cold cardioplegic

IHJ-408-02.p65

51

myocardial protection. Ten patients, who had a classical


hourglass type of narrowing, underwent repair by the
technique of single sinus aortoplasty, using a diamondshaped dacron patch in 6 patients and gluteraldehydetanned autologous pericardial patch in 4. The child with
diffuse narrowing of the ascending aorta underwent
widening of the ascending aorta with a tanned
pericardial patch from the noncoronary sinus to the
origin of the innominate artery. Associated procedures
in our patients included mitral valve repair, closure of
VSD, repair of saccular aneurysm of the ascending aorta,
and pericardial patch widening of the origin of the right
pulmonary artery (one case each).
Surgical results and follow-up data: There were 2 deaths,
both due to uncontrollable bleeding from the aortic suture
line, which occurred in the immediate postoperative period.
One patient was lost to follow-up. Follow-up was for
6.334.71 years. The patient with diffuse type of SVAS
showed a gradient of 66 mmHg on follow-up
echocardiogram. All the other patients were in NYHA
functional class I on follow-up and echocardiographic
assessment showed good results, except in 2 patients
who showed mild valvar gradient with mild valvar
regurgitation.
Discussion
Supravalvar aortic stenosis is relatively rare and the least
common of the congenital LVOT obstructions.1 The patients
can be classified into three groups according to the mode of
presentation.

5/6/2003, 10:01 AM

Indian Heart J 2003; 55: 4954

52 Harikrishnan et al. Supravalvar Aortic Stenosis

(1) Nonfamilial sporadic cases with normal facies and


intelligence
(2) Autosomal dominant familial cases with normal facies
and intelligence3
(3) WilliamsBeuren's syndrome24 with characteristic elfin
facies and mental retardationnonfamilial.

Fig. 1. Echocardiogram (high parasternal view) showing discrete supravalvar


narrowing of the aorta (arrows).

Fig. 3. Diffuse variety of supravalvar aortic stenosis. Long-segment aortic


narrowing is present. A dilated left main coronary artery is also seen.

Morphologically, SVAS can be categorized into three types.


(1) Hourglass type: the most common type, characterized
by a constricting annular ridge at the superior margin
of the sinus of Valsalva
(2) Membranous type: produced by an intra-aortic fibrous/
fibromuscular circular/semicircular diaphragm with a
central opening
(3) Hypoplastic type: with uniform hypoplasia of the
ascending aorta which may extend into the arch
vessels.

Fig. 2. Discrete variety of supravalvar aortic stenosis. A dilated left main


coronary artery is seen.

IHJ-408-02.p65

52

Supravalvar aortic stenosis is unique among LVOT


obstructions because, among systemic vessels, the coronary
arteries alone are exposed to high systolic pressures,5 which
lead to dilatation, tortuosity and premature atherosclerosis
of these arteries, thus making the patient susceptible to
sudden cardiac death before and after repair. The coronary
ostia may be obstructed by the overhanging thick sinus
rims as well as bound-down aortic cusps. This more
commonly occurs in the left sinus, but can also occur in the
right. Also, the free edges of the aortic cusps (which are
thickened in one-third of patients) may be adherent to the
intraluminal supravalvar aortic ridge. This contributes to
LVOT obstruction, interferes with coronary blood flow, and
is also responsible for the associated aortic regurgitation.
Five of our 15 patients had associated aortic valve

5/6/2003, 10:01 AM

Indian Heart J 2003; 55: 4954

anomalies. In the series by Sharma et al.,6 25% of the patients


had a bicuspid aortic valve,12% had aortic regurgitation,
11% had valvar aortic stenosis, and 10% had subvalvar
stenosis. In the series of 13 patients by Braunstein et al.7
one patient had subaortic obstruction.
WilliamsBeurens syndrome24 is associated with a
microdeletion in the chromosomal region 7q11.23
encompassing, among others, the elastin gene. The
syndrome is routinely confirmed by detecting elastin
hemizygosity by fluorescence in situ hybridization (FISH).
Previous reports suggest that hemizygosity of the elastin
gene is responsible for the typical vasculopathy of this
syndrome, namely, SVAS and pulmonary arterial stenosis.4,5
WilliamsBeurens syndrome is associated with the
nonfamilial form of SVAS, in which there is a peculiar facies
(small chin, large mouth, patulous lips, blunt and upturned
nose, widely set eyes with internal strabismus, epicanthic
folds, broad forehead, baggy cheeks, lacy iris pattern, and
malformed teeth with malocclusion), short stature, and
mental retardation. Adult patients are short-statured, may
have kyphoscoliosis, and may develop progressive joint
limitation and hypertonia. These patients may have
idiopathic infantile hypercalcemia, pulmonary artery
stenosis (especially peripheral pulmonary stenosis), renal
artery anomalies, tortuous retinal arteries, systemic
hypertension, and gastrointestinal and urinary tract
anomalies.
In Williams syndrome, SVAS seems to progress rapidly
while peripheral pulmonary stenosis improves with time.8
Associated cardiac lesions described are pulmonary stenosis
(both valvar and peripheral), mitral valve anomalies with
MR, and aneurysm of the ascending aorta and subaortic
obstruction. Etiologic factors proposed are idiopathic
hypercalcemia, disturbance of vitamin D metabolism and
calcium homeostasis,9 and rubella.
In our series, there were no familial cases of SVAS, but
there were 5 cases of Williams syndrome. Of them, 2 had
peripheral pulmonary artery stenosis and one had aortic
valvar stenosis. Only one of these patients had
hypercalcemia; however, vitamin D challenge or calcium
loading tests were not done in these patients to unmask
calcium homeostatic defects. Seven of the 13 patients in
the series by Braunstein et al.7 and 14 of the 101 patients
in the series by Brown et al.10 had Williams' syndrome.
The treatment of SVAS is surgical if the patient has
significant gradients. SVAS is less amenable to operative
treatment than either valvar or discrete subvalvar stenosis.
Successful surgery for SVAS using patch graft enlargement
of the noncoronary sinus of Valsalva was first reported
from the Mayo clinic.11 After that, many series on surgical
results in patients with SVAS have been reported.6,1018
The discrete type of SVAS is more amenable to surgery

IHJ-408-02.p65

53

Harikrishnan et al. Supravalvar Aortic Stenosis

53

than the diffuse type. In the discrete type, aortotomy is done


above the valve, and the incision carried into the right or
noncoronary sinus of Valsalva. The intimal shelf is then
resected and a diamond-shaped pericardial/dacron patch
incorporated into the incision to enlarge the aortic diameter
to normal.
In the single-center experience of SVAS from the Texas
Heart Institute, 32% of the patients had discrete type of
SVAS, and were treated with simple patch aortoplasty
(placing a diamond-shaped patch across the sinus rim in
the noncoronary sinus of Valsalva) with good results and
only 4% mortality. Though this operation was effective in
relieving the pressure gradients, it did nothing to rebuild/
remodel the diseased aortic root. Doty et al.19 have proposed
bisinus repair by extending a bilobed patch into both the
noncoronary sinus and right coronary sinus for a wider
and anatomically more symmetrical repair, even in cases
with discrete stenosis.
Surgical treatment options for the diffuse form of SVAS
are less well defined. It may become necessary to replace or
widen the entire hypoplastic aorta with an appropriate
prosthesis.16,17 Extended patch aortoplasty and apicoaortic
conduits are the procedures that have been tried. Sharma
et al.6 have treated two patients with the diffuse variety of
SVAS with another technique: extensive endarterectomy
of the ascending aorta and arch, with patch aortoplasty
extended into the aortic arch. Since the morphologic defect
in SVAS involves the media and intima, it seems logical to
remove these by endarterectomy.6
Only 1 of our patients had the diffuse variety of SVAS
(6.66%), compared with 15% of patients in the series by
Sharma et al.6 In the series by Brown et al.,10 28/101
patients had the diffuse variety of SVAS, and they were
treated with either an apical aortic conduit or extensive
endarterectomy with patch aortoplasty, with encouraging
results. In the series by Braunstein et al.,7 2/13 patients
with the diffuse variety of SVAS had excellent results with
bisinus patching and extending the patch to the descending
aorta.
Thirty-three patients in the surgical series by Sharma et
al.6 had other associated obstructive lesions of the LVOT
requiring surgical correction. Though 2 patients in our series
had associated valvar stenosis, this did not warrant surgical
correction. Of patients with SVAS, 30% are reported to have
thickened aortic valve cusps. Two patients (18%) developed
mild AR postoperatively in our series. The exact incidence
of AR in the series by Sharma et al.6 is not clear. However,
the incidence of 44% of new AR in the series by Braunstein
et al.7 is much higher.
Four patients in our series had associated cardiac lesions,
which required surgical correction. PA plasty was done in
1 of our patients. There were no cases which required PA

5/6/2003, 10:01 AM

Indian Heart J 2003; 55: 4954

54 Harikrishnan et al. Supravalvar Aortic Stenosis

plasty in the Braunstein series,7 while 1 patient required PA


plasty in the series by Sharma et al.6 One patient in the
series by Sharma et al. 6 had pseudoaneurysm of the
ascending aorta, while 1 of our patients had an aneurysm
of the ascending aorta requiring aneurysmorrhaphy.
We had 2 early deaths due to bleeding (18.18%) but no
late deaths at a mean follow-up of more than 6 years.
None of our 11 patients required reoperation at a mean
follow-up of more than 6 years. In the series by Sharma et
al.,6 22% of the patients required reoperation at some time
during the follow-up period, and there were 5 late deaths in
those with complex forms of the disease. We had only 1
patient with the diffuse form of the disease who underwent
extended patch aortoplasty but had moderate residual
gradient on follow-up. In a large experience of 101 patients
with SVAS,10 the overall survival including operative
mortality was 98% at 10 years, and 97% at 20 and 30
years.
This study has several weaknesses. It was a retrospective
study, and the numbers were too small to draw conclusions.
The patients did not undergo hemodynamic or
angiographic study postoperatively.
We conclude that repair of SVAS by single sinus
aortoplasty is safe, and produces good results.
References
1. Sissman NJ, Neill CA, Spencer FC, Taussig HB. Congenital aortic
stenosis. Circulation 1959; 19: 458459
2. Williams JCP, Barrat-Boyes BG, Lowe JB. Supravalvar aortic stenosis.
Circulation 1961; 24: 13111314
3. Beuren AJ, Schulze C, Eberle P, Harmjanz E, Apitz J. The syndrome of
supravalvar aortic stenosis, peripheral pulmonary stenosis, mental
retardation and similar facial appearance. Am J Cardiol 1964; 13:
471473
4. Eronen M, Peippo M, Hiippala A, Raatikka M, Arvio M, Johansson
R, et al. Cardiovascular manifestations in 75 patients with Williams

IHJ-408-02.p65

54

syndrome. J Med Genet 2002; 39: 554558


5. Stamm C, Friehs I, Ho SY, Moran AM, Jonas RA, del Nido PJ.
Congenital supravalvar aortic stenosis: a simple lesion? Eur J
Cardiothorac Surg 2001; 19: 195202
6. Sharma BK, Fujiwara H, Hallman GL, Ott DA, Reul GJ, Cooley DA.
Supravalvar aortic stenosis: a 29-year review of surgical experience.
Ann Thorac Surg 1991; 51: 10311039
7. Braunstein PW Jr, Sade RM, Crawford FA Jr, Oslizlok PC. Repair of
supravalvar aortic stenosis: cardiovascular morphometric and
hemodynamic results. Ann Thorac Surg 1990; 50: 700707
8. Giddins NG, Finley JP, Nanton MA, Roy DL. The natural course of
supravalvar aortic stenosis and peripheral pulmonary artery
stenosis in Williams syndrome. Br Heart J 1989; 62: 315319
9. Kruse K, Pankau R, Gosch A, Wohlfahrt K. Calcium metabolism in
WilliamsBeuren syndrome. J Paediatr 1992; 121; 902907
10. Brown JW, Ruzmetov M, Vijay P, Turrentine MW. Surgical repair of
congenital supravalvular aortic stenosis in children. Eur J
Cardiothorac Surg 2002; 21: 5056
11. McGoon DC, Manhin HT, Vlad P, Kirklin JW. The surgical treatment
of supravalvar aortic stenosis. J Thorac Cardiovasc Surg 1961; 41:
125129
12. Rastelli GC, McGoon DC, Ongley PA, Mankin HT, Kirklin JW. Surgical
treatment of supravalvar aortic stenosis. Report of 16 cases and
review of literature. J Thorac Cardiovasc Surg 1966; 51: 873878
13. Thistlethwaite PA, Madani MM, Kriett JM, Milhoan K, Jamieson SW.
Surgical management of congenital obstruction of the left main
coronary artery with supravalvular aortic stenosis. J Thorac
Cardiovasc Surg 2000; 120: 10401046
14. Flaker G, Teske D, Kilman J. Supravalvar aortic stenosis: a 20year
clinical perspective and experience with patch aortoplasty. Am J
Cardiol 1983; 15: 256261
15. McElhinney DB, Petrossian E, Tworetzky W, Silverman NH, Hanley
FL. Issues and outcomes in the management of supravalvar aortic
stenosis. Ann Thorac Surg 2000; 69: 562567
16. Kirklin JW, Barratt-Boyes BG (eds). Cardiac surgery. 2nd ed. New York:
Churchill Livingstone;1993. pp. 11961232
17. Friedman WF. Aortic stenosis. In: Friedman WF (ed). Heart disease
in infants, children and adolescents. 5th ed. Hagerstorm: William and
Wilkins; 1995. pp. 10871111
18. Doty DB. Supravalvar aortic stenosis. Ann Thorac Surg 1991; 51:
886887
19. Doty DB, Polansky DB, Jenson CB. Supravalvular aortic stenosis.
Repair by extended aortoplasty. J Thorac Cardiovasc Surg 1977; 74:
362371

5/6/2003, 10:01 AM

Bharani et al. Sildenafil


in PAH
55
Original
Article

Indian Heart J 2003; 55: 5559

The Efficacy and Tolerability of Sildenafil in Patients With


Moderate-to-Severe Pulmonary Hypertension
Anil Bharani, Vivek Mathew, Ashutosh Sahu, Basant Lunia
Division of Cardiology, Department of Medicine, M.G.M. Medical College and M.Y. Hospital, Indore

Background: Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous
infusion of prostacyclin has proved effective. However, it carries the risk of serious complications arising from
the complex delivery system. Prostacyclin analogs, endothelin antagonists, and the phosphodiesterase-5 inhibitor
sildenafil are emerging promising therapies. This study was aimed at evaluating the utility of oral sildenafil in
patients with pulmonary hypertension of varied etiology, poorly controlled on conventional treatment.
Methods and Results: Ten consecutive patients with pulmonary hypertension, either primary or related to
previous left-to-right shunts, thromboembolism, or interstitial lung disease, poorly controlled on conventional
therapy such as warfarin, calcium antagonists, digitalis, and diuretics, were included. A thorough clinical,
laboratory, and comprehensive echo Doppler evaluation was performed before enrollment in the trial to establish
the diagnosis and obtain baseline data. Subjects received sildenafil 25 mg 8 hourly, or a matching placebo for
two weeks each, in a randomized, double-blind, crossover design. A run-in period of two weeks was permitted
between the two therapies during which patients continued to receive the conventional therapy without any
vasodilator. At the end of each therapy period, the patients were evaluated for symptoms, New York Heart
Association class, distance covered during the 6 min walk test, rating of modified Borg dyspnea score, and
systolic pulmonary artery pressure using echo Doppler. The differences in the above variables at the end of
sildenafil and placebo therapies were compared. Nine patients completed the study protocol. Sildenafil, compared
to placebo, was associated with improved exercise tolerance as determined by the 6 min walk test
(266.67131.45 m v. 170105 m; p<0.005), decrease in modified Borg dyspnea score (3.561.01 v.
5.111.45; p<0.01), decrease in Doppler-estimated pulmonary artery systolic pressures (55.3316.52 mmHg
v. 75.3319.75 mmHg; p<0.005), improvement in New York Heart Association class (2 patients), and
improvement in symptoms. Sildenafil was well tolerated with no untoward effects; further, no significant changes
in heart rate or blood pressure occurred during the study period.
Conclusions: Sildenafil improves exercise capacity and symptoms, and decreases pulmonary artery pressures
in patients with primary or secondary pulmonary hypertension of varied etiology. (Indian Heart J 2003; 55:
5559)
Key Words: Pulmonary hypertension, Sildenafil, Echocardiography

ulmonary arterial hypertension (PAH) is characterized


by a progressive increase of pulmonary vascular
resistance leading to right ventricular failure and death
(WHO 1998).1,2 Pulmonary arterial hypertension includes
primary pulmonary hypertension (PPH) with no apparent
cause, PAH secondary to congenital shunt lesions,
connective tissue disorders, and portal hypertension, druginduced PAH, and HIV-related PAH. 1,2 The current
therapeutic options available for PAH include
Correspondence: Dr Anil Bharani,119, Ravindra Nagar, Indore 452018.
e-mail: tanmaybharani@eth.net

IHJ-395-02.p65

55

anticoagulants, calcium-channel blockers, epoprostenol


(prostacyclin), iloprost, beraprost, the endothelin receptor
antagonist bosentan, and phosphodiesterase type-5 (PDE5)
inhibitor sildenafil.3 However, in many parts of the world,
therapeutic options for patients with PAH are limited in the
absence of availability of prostacyclins3 and thus sildenafil
could be a useful alternative.
Sildenafil-induced inhibition of PDE5 increases
the cellular levels of cGMP, potentiating vascular
smooth muscle relaxation, particularly in the lungs where
PDE5 is found in high concentrations.4 Sildenafil has been
reported to inhibit hypoxia-induced pulmonary

5/6/2003, 10:02 AM

Indian Heart J 2003; 55: 5559

56 Bharani et al. Sildenafil in PAH

hypertension,5 cause sustained reduction in pulmonary


artery pressures and pulmonary vascular resistance
in PPH, 6 blunt the rebound pulmonary hypertension
seen following withdrawal of inhaled nitric oxide,7 lead
to impressive clinical benefits in childhood PPH, 8 and
cause selective pulmonary vasodilatation in a lamb
model of PAH.9
We report the results of a randomized, double-blind,
placebo-controlled, crossover study designed to determine
the efficacy of short-term oral administration of sildenafil
on exercise capacity, symptoms, and Doppler-determined
pulmonary artery pressures in NYHA class IIIV patients
with PAH.

ductus, wherever applicable.11 Echo-Doppler studies (GE


Logic 500, MD, USA) were done by a single experienced
observer who was blind to the therapy patients were
receiving.
Statistical analysis: Changes in variables during
treatment with sildenafil and placebo were analyzed with
the paired Students t test. The null hypothesis was that
there should be no significant difference in the exercise
capacities and the pulmonary systolic pressures before and
after 2 weeks of sildenafil therapy. A probability value of
p<0.05 was considered significant.
Results

Methods
Selection of patients: Ten consecutive, symptomatic
(NYHA class >II) patients with Doppler-estimated
pulmonary systolic pressure >35 mmHg with normal left
ventricular function and no reversible cause for PAH were
taken up for the study. They gave well-informed written
consent for participation in the study and all except one
completed the study protocol. The institutional ethics
committee approved the protocol. Patients were excluded
if they had any contraindications to sildenafil therapy or if
they had any reversible cause for pulmonary hypertension
such as valvular heart disease.
Study design: The study was carried out at a large referral
center of central India as a prospective, randomized,
double-blind, crossover trial. To establish the diagnosis,
patients were subjected to a thorough physical
examination, routine laboratory evaluation, chest X-ray,
electrocardiogram (ECG), and comprehensive echocardiographic evaluation at baseline. Before randomization, they
were allowed a run-in period of one week after stoppage of
their previous vasodilator therapy; they then received either
sildenafil 25 mg 8 hourly or matching placebo for two
weeks in a crossover design with a washout period of at
least two weeks between the two therapies.
Outcome measures: The patients were evaluated for
exercise capacity as indicated by the 6 min walking
distance. The secondary measures of efficacy were change
in symptoms and NHYA functional class, change in
modified Borg dyspnea index10 (a measure of perceived
breathlessness on a scale of 0 to 10, with higher values
indicating more severe dyspnea), and change in resting
pulmonary artery systolic pressures as estimated from
Doppler tricuspid regurgitant jet velocities or from the
gradient across the ventricular septal defect or patent

IHJ-395-02.p65

56

Baseline study group characteristics: There were 5


females and 4 males, 19 to 60 years of age, in NYHA
functional classes IIIV, having pulmonary hypertension
of varied etiologies. They were receiving conventional
therapy including warfarin and nifedipine, and two patients
were on diuretics and digoxin for treatment of heart failure
(Table 1).
Table 1. Study group characteristics
Characteristic
Age
Sex
NYHA class
Baseline

Patients (n)
1860 years
Mean 32.11 years, SD 15.06 years
Male
Female

4
5

II
III
IV

3
5
1

II
III
IV

4
5
0

Post-sildenafil
therapy

Diagnosis
Primary pulmonary hypertension
Pulmonary hypertension associated with:
Interstitial lung disease
Thromboembolism
Eisenmenger syndrome
Ventricular septal defect
Patent ductus arteriosus
Treatment at inclusion
Warfarin
Nifedipine
Frusemide
Spironolactone
Digoxin

5/6/2003, 10:02 AM

3
2
1
2
1
9
4
2
2
2

Indian Heart J 2003; 55: 5559

Bharani et al. Sildenafil in PAH 57

Table 2. Change in 6 min walking distance, modified Borg


dyspnea score and Doppler pulmonary artery pressure
Characteristic
6 min walking
distance (m)
Mean
SD
Borg dyspnea score
Mean
SD
Pulmonary artery
pressure (mmHg)
Mean
SD

Baseline

Placebo Sildenafil

163.89
110.73

170
105

266.67
131.45

5.98

<0.005

5.22
1.64

5.11
1.45

3.56
1.01

3.56

<0.01

80.78
21.30

75.33
19.75

55.33
16.52

4.33

<0.005

Exercise capacity: The distance walked in 6 min at


baseline and at the end of sildenafil or placebo therapies is
given in Table 2. The patients showed a significant
improvement in exercise capacity while on sildenafil
therapy compared to placebo (p<0.005, Fig. 1A).

lead to improved symptoms, hemodynamics, and reduced


mortality. 12 The prostacyclin analogs iloprost 13 and
beraprost14 produce marked clinical benefits in patients
with PAH. The orally administered endothelin receptor
antagonist bosentan15 is reported to be effective and well
tolerated in patients with PAH. While mortality benefits
with these newer agents are yet to be ascertained, each
therapy has certain limitations. Epoprostenol, the current
gold standard of therapy for PPH, is associated with serious
complications arising from the complex delivery system.
Sildenafil, which is currently approved for the treatment
of erectile dysfunction, is emerging as a new promising
therapeutic agent for the treatment of secondary PAH and
PPH.16,17 Through selective inhibition of PDE5, which is
abundant in the lungs, sildenafil increases cellular levels
of cGMP causing vascular smooth muscle relaxation
leading to sustained reduction in pulmonary vascular

Symptoms and Borg dyspnea index: All the patients


showed improvement in symptoms after 2 weeks of
sildenafil therapy compared to placebo. The Borg dyspnea
index of perceived exertion after the 6 min walk showed
statistically significant improvement at the end of sildenafil
therapy (p<0.01, Table 2, Fig. 1B). There was improvement
in the NYHA class in only two patients. There was no
mortality.
Pulmonary artery pressures: Table 2 gives the
pulmonary artery systolic pressures as estimated from the
Doppler studies. Sildenafil therapy was associated with
significant reduction in the pulmonary artery pressures
compared to placebo (p<0.005, Fig. 1C).
Side-effects and tolerance: Sildenafil therapy was
tolerated well with no adverse effects reported during this
short-term study. No substantial changes in heart rate or
systemic arterial pressure were observed during sildenafil
treatment. Two sexually active males included in the study
experienced no change in overall sexual performance or
libido during sildenafil therapy.
Discussion
Primary pulmonary hypertension is a rapidly progressive
disease which is uniformly fatal if untreated. Until 1981,
when heartlung transplantation was introduced, no
treatment was available. Challenged by the limited number
of suitable donors and the complications associated with
organ transplantation, the search for effective medical
therapies is ongoing.1 Continuous epoprostenol infusions

IHJ-395-02.p65

57

Fig. 1. Mean change from baseline at week 8 in results of the (A) 6 minute
walk test, (B) modified Borg dyspnea index, and (C) pulmonary artery systolic
pressure in patients while on sildenafil and placebo. Numbers indicate the mean
values. Standard error of the mean is given in parentheses.

5/6/2003, 10:02 AM

Indian Heart J 2003; 55: 5559

58 Bharani et al. Sildenafil in PAH

resistance and pulmonary artery pressures. 4,8,18 The


salutary effects of sildenafil on symptoms and exercise
performance in patients with PAH have been reported in
small studies16,17 and in anecdotal case reports,8,18 which
are comparable to those of the prostacyclins. However, large
controlled trials with sildenafil to address the issue of
improving survival in patients with PPH and PAH are not
yet available. This short-term, double-blind, placebocontrolled, crossover study has demonstrated that oral
sildenafil in a dosage of 25 mg 8 hourly improves exercise
capacity, symptoms, and causes significant decrease in
Doppler-estimated pulmonary artery pressures.
As in other trials performed on patients with PAH, the
primary end-point of this study was the 6 min walking
distance that has been shown to be an independent
predictor of mortality.19.20 Following treatment, the distance
observed in our patients was 96.67 m, which matches the
effect observed with intravenous epoprostenol in NYHA
class IIIIV patients,20 and with beraprost21 in NYHA class
IIIII patients with PPH. Improvement in the 6 min walking
distance was observed in all patients (NYHA class IIIV) in
our study. However, improvement in the 6 min walk test
was seen only in patients with PPH receiving beraprost but
not in those with secondary PAH.21
Sildenafil alone 16 or in combination with inhaled
iloprost17 has been shown to improve exercise performance
in patients with PPH and secondary PAH. The improvement
in the 6 min walking distance was associated with a
concomitant significant improvement in the perception of
dyspnea, as assessed by a reduction of the Borg dyspnea
score. Perceptual estimates, obtained by psychophysical
ratio-scaling method such as the Borg dyspnea scale, are
very useful in judging the perceptual variation and are
complementary to physiological measurement of work
capacity and physical performance.10 Despite improvement
in symptoms and exercise capacity in all the patients,
improvement in NYHA class was seen in only two patients.
This was perhaps related to the shorter duration of our
study. Similar observations were reported in patients with
PAH who were treated with beraprost for 12 weeks.21
Sildenafil therapy was associated with a significant
decrease in Doppler-estimated tricuspid regurgitation
velocities and pulmonary systolic pressures in our study.
The available studies on sildenafil are few. In a young male
with severe PAH, sildenafil 100 mg five times per day for 3
months led to a decrease in the Doppler-estimated
pulmonary artery pressure from 120 mmHg to 90 mmHg
with improvement in the myocardial oxygen consumption
during exercise, and dramatic improvement in symptoms
and aerobic capacity.18 Similarly, in the case of a 4-year-

IHJ-395-02.p65

58

old girl with severe PPH with poor response to prostacyclin,


oral sildenafil (2 mg/kg 4 hourly) led to a significant
decrease in pulmonary artery pressures, rise in oxygen
saturation, improved exercise capacity, and impressive
clinical recovery, permitting discontinuation of prostacyclin
and oxygen therapy.8
A recent study reported long-lasting reduction in the
mean pulmonary artery pressure and pulmonary vascular
resistance with sildenafil and additional improvement after
iloprost inhalation in patients with PPH. No significant
changes in heart rate or blood pressure were observed
during the treatment.6 Another study reported impressive
clinical benefits associated with combination therapy using
oral sildenafil and inhaled iloprost in patients with severe
PAH.17
In a randomized, double-blind, placebo-controlled study,
sildenafil 100 mg given orally to ten healthy volunteers
inhibited hypoxia-induced pulmonary hypertension, a
response mediated through the eNOSNOcGMP pathway.5
Sildenafil has been reported to blunt the rebound
pulmonary hypertension seen following withdrawal of
inhaled nitric oxide.7,22 In lambs with acute pulmonary
hypertension, sildenafil decreased the pulmonary artery
pressure and pulmonary vascular resistance resulting from
selective pulmonary vasodilatation.9 In a recent study, a
single oral dose of sildenafil (75 mg) was found to be as
effective and as selective a pulmonary vasodilator as inhaled
nitric oxide in patients with severe PAH referred for heart
lung transplantation. Sildenafil was superior to nitric oxide
in that it led to a greater increase in cardiac output and did
not increase wedge pressure.23 Sildenafil was assessed for
childhood and neonatal pulmonary hypertension
(16 patients), given either acutely (0.250.5 mg/kg) prior
to hemodynamic measurements in the cath lab, or
chronically after gradual withdrawal of nitric oxide in
refractory suprasystemic PAH, or for chronic treatment of
PPH or PAH. During cardiac catheterization, the mean
pulmonary artery pressure decreased (508 mmHg to
3812 mmHg, p<0.05), and pulmonary vascular
resistance decreased with no change in the mean systemic
pressure or systemic vascular resistance. During chronic
use, sildenafil attenuated the rise in pulmonary artery
pressure, permitted discontinuation of nitric oxide and led
to 200% improvement in the 6 min walk distance in the
remaining patients.24
Sildenafil has been well tolerated without major sideeffects.3 We did not come across hypotension, syncope, or
any other untoward effect attributable to sildenafil in our
study. Our results concur with those of other studies to
support the safety and impressive clinical benefits

5/6/2003, 10:02 AM

Indian Heart J 2003; 55: 5559

associated with sildenafil therapy in patients suffering from


PPH or secondary PAH.6,8,17,18 Sildenafil therapy was not
found to have any important hemodynamic effect in
patients with stable coronary artery disease25 but caution
must be exercised in patients receiving diuretics and/or
nitrates.
To conclude, our study results show the beneficial effects
of sildenafil in patients with PPH and secondary PAH in
adults. These include significant improvement in exercise
capacity as indicated by improvement in the 6 min walk
distance, decrease in modified Borg dyspnea index of
perceived exertion, and decrease in pulmonary artery
systolic pressures. The drug is well tolerated with no
substantial change in heart rate or blood pressure. The
small sample size and short duration of the study are
acceptable limitations. Large, long-term, randomized,
multicenter trials are needed to answer questions regarding
the long-term utility and survival benefits with the PDE5
inhibitor sildenafil in patients with PPH and secondary
PAH.
Acknowledgments
We acknowledge the help received from Professor LK
Mathur, Department of Biostatistics, M.G.M. Medical
College, Indore, for statistical analysis and Mrs Prasanna
Nair for secretarial assistance.
References
1. Rich S. Executive summary from the World Symposium on Primary
Pulmonary Hypertension 1998. Available from http/www.who.int/
ncd/cvd/pph.html
2. British Cardiac Society Guidelines and Medical Practice Committee.
Recommendations on the management of pulmonary hypertension
in clinical practice. Heart 2001; 86 (Suppl): I1I13
3. Kothari SS, Bahl VK. Primary pulmonary hypertensionan update.
Indian Heart J 2002; 54: 255260
4. Sanchez LS, de la Monte SM, Filippov G, Jones RC, Zapol WM, Bloch
KD. Cyclic-GMP-binding, cyclic-GMP-specific phosphodiesterase
(PDE5) gene expression is regulated during rat pulmonary
development. Pediatr Res 1998; 43: 163168
5. Zhao L, Mason NA, Morrell NW, Kojonazarov B, Sadykov A, Maripov
A, et al. Sildenafil inhibits hypoxia-induced pulmonary hypertension.
Circulation 2001; 104: 424428
6. Wilkens H, Guth A, Konig J, Forestier N, Cremers B, Hennen B, et al.
Effect of inhaled iloprost plus oral sildenafil in patients with primary
pulmonary hypertension. Circulation 2001; 104: 12181222
7. Mychaskiw G, Sachdev V, Heath BJ. Sildenafil (viagra) facilitates
weaning of inhaled nitric oxide following placement of a biventricular-

IHJ-395-02.p65

59

Bharani et al. Sildenafil in PAH 59


assist device. J Clin Anesth 2001; 13: 218220
8. Abrams D, Schulze-Neick I, Magee AG. Sildenafil as a selective
pulmonary vasodilator in childhood primary pulmonary
hypertension. Heart 2000; 84: E4
9. Weimann J, Ullrich R, Hromi J, Fujino Y, Clark MW, Bloch KD, et al.
Sildenafil is a pulmonary vasodilator in awake lambs with acute
pulmonary hypertension. Anesthesiology 2000; 92: 1702 1712
10. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports
Exerc 1982; 14: 377381
11. Oh JK, Seward JB, Tajik AJ. The echo manual. 2nd ed. Philadelphia:
Lippincott Williams & Wilkins; 1999. p. 215
12. Galie N, Manes A, Branzi A. Medical therapy of pulmonary
hypertension. The prostacyclins. Clin Chest Med 2001; 22: 529537
13. Hoeper MM, Galie N, Simonnean G, Rubin LJ. New treatments for
pulmonary arterial hypertension. Am J Respir Crit Care Med 2002;
165: 12091216
14. Nagaya N, Shimizu Y, Satoh T, Oya H, Uematsu M, Kyotani S, et al.
Oral beraprost sodium improves exercise capacity and ventilatory
efficiency in patients with primary or thromboembolic pulmonary
hypertension. Heart 2002; 87: 340345
15. Rubin LJ, Badesch DB, Barst RJ, Galie N, Black CM, Keogh A, et al.
Bosentan therapy for pulmonary artery hypertension. N Engl J Med
2002; 346: 896903
16. Watanabe H, Ohashi K, Takeuchi K, Yamashita K, Yokoyama T, Tran
QK, et al. Sildenafil for primary and secondary pulmonary
hypertension. Clin Pharmacol Ther 2002; 71: 398402
17. Ghobrani HA, Weidmann R, Rose F, Olscherski H, Schermuly RT,
Weissmann N. Combination therapy with oral sildenafil and inhaled
iloprost for severe pulmonary hypertension. Ann Intern Med 2002;
136: 515522
18. Prasad S, Wilkinson J, Gatzoulis MA. Sildenafil in primary pulmonary
hypertension. N Engl J Med 2000; 343: 1342
19. Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, et
al. Clinical correlates and prognostic significance of six-minute walk
test in patients with primary pulmonary hypertension. Comparison
with cardiopulmonary exercise testing. Am J Respir Crit Care Med
2000; 161: 487492
20. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, et al.
A comparison of continuous intravenous epoprostenol (prostacyclin)
with conventional therapy for primary pulmonary hypertension. The
Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;
334: 296302
21. Galie N, Humbert M, Vachiery JL, Vizza CD, Kneussl M, Manes A, et
al. Effects of beraprost sodium, an oral prostacyclin analogue, in
patients with pulmonary arterial hypertension: a randomized, doubleblind, placebo-controlled trial. J Am Coll Cardiol 2002; 39: 14961520
22. Atz AM, Wessel DL. Slidenafil ameliorates effects of inhaled nitric oxide
withdrawal. Anesthesiology 1999; 91: 307310
23. Michelakis ED, Tymchak W, Lien D, Dasilva L, Hashimoto K, Archer
SL. Oral sildenafil is an effective and specific pulmonary vasodilator
in patients with pulmonary arterial hypertension [Abstr]. J Am Coll
Cardiol 2002; 39 (Suppl): 1081
24. Erickson S, Reyes J, Bohn D, Adatia I. Sildenafil (Viagra) in childhood
and neonatal pulmonary hypertension [Abstr]. J Am Coll Cardiol 2002;
39 (Suppl): 10971098
25. Arruda-Olson AM, Mahoney DW, Nehra A, Leckel M, Pellikka PA.
Cardiovascular effects of sildenafil during exercise in men with known
or probable coronary artery disease: a randomized crossover trial.
JAMA 2002; 287: 719725

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60 Puri et Article
al. Polymorphism in the Apo B-100 Gene
Original

Indian Heart J 2003; 55: 6064

Polymorphisms in the Apolipoprotein B-100 Gene:


Association With Plasma Lipid Concentration
and Coronary Artery Disease
Ratna Dua Puri, Satyendra Tewari, Nakul Sinha, V Ramesh, Faisal Khan,
Vivek P Singh, Suraksha Agrawal
Departments of Medical Genetics, Cardiology and Pathology, Sanjay Gandhi Postgraduate
Institute of Medical Sciences, Lucknow

Background: The aim of this study was to investigate the association of apolipoprotein B gene polymorphisms
with coronary artery disease and lipid levels in Indians.
Methods and Results: One hundred patients of angiographically proven atherosclerotic coronary artery disease
and one hundred age- and sex-matched control subjects (treadmill negative) were included in the study. Serum
lipids including cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, very low-density
lipoprotein, and apolipoprotein B were analyzed. Genomic DNA was extracted and the apolipoprotein B 3'
hypervariable region amplified by polymerase chain reaction. Regions carrying Xba1, EcoR1, and Msp1
restriction sites present in the apolipoprotein B gene were amplified and digested separately by the respective
enzymes. Restriction fragment length polymorphism analysis showed that EcoR1 with the R+/R+ genotype was
significantly more common in patients with coronary artery disease. Overall, the genotypes EcoR1+/+, Msp1+/+,
Xba1+/+ and Eco R1+/+ Msp1+/, Xba1/ were significantly more common in patients as compared to controls
(p<0.05). When gene polymorphisms were compared with lipid abnormalities, the genotypes
EcoR1+/+, Xba1/, and Msp1+/+ were more frequent in patients with elevated apolipoprotein B and very
low-density lipoprotein levels. On the other hand, these genotypes were less common in patients with increased
total cholesterol and low-density lipoprotein levels. When we studied the individual alleles of the variable number
of tandem repeats region, we observed that allele 34 was significantly increased in patients with coronary
artery disease as compared to controls. Allele 36 was present with a frequency of 1% in controls while it was
totally absent in patients.
Conclusions: This study identifies the apolipoprotein B gene polymorphism associated with coronary artery
disease. An association between apolipoprotein B gene polymorphisms and elevated apolipoprotein B and very
low-density lipoprotein levels was observed. However, there was no positive association with other elevated lipid
levels in North Indians from Uttar Pradesh. (Indian Heart J 2003; 55: 6064)
Key Words: Apolipoprotein B, Polymorphism, Coronary artery disease

levated serum low-density lipoprotein (LDL)


concentration is an important risk factor for developing
atherosclerotic coronary artery disease (CAD) in humans.1
Apolipoprotein (apo) B-100 is the principal protein
component of LDL. The interaction of apo B-100 with LDL
receptors mediates the uptake of LDL from the liver and
peripheral cells; hence, apo B-100 plays an important role
Correspondence: Professor Suraksha Agrawal, Department of Medical
Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli
Road, Lucknow 226014. e-mail : suraksha@sgpgi.ac.in

IHJ-417-02.p65

60

in cholesterol homeostasis.2 The apo B gene is localized on


chromosome 2, and the complete structure of the human
apo B-100 gene has been elucidated.3
Cloning and sequencing of the apo B gene has made it
possible to study the variation in the apo B gene at the DNA
level. A 15 bp AT-rich hypervariable region (HVR) is located
adjacent to the 3' end of the apo B gene. It consists of a
variable number of tandem repeat sequences (VNTR).
Previous studies have reported that some of the 3' VNTR
alleles46 and restriction fragment length polymorphisms
(RFLP)4,7,8 of apo B-100 are directly associated with CAD,

5/6/2003, 10:03 AM

Indian Heart J 2003; 55: 6064

Puri et al. Polymorphism in the Apo B-100 Gene

or with variations in plasma lipids. Interestingly, the


association of apo B-100 VNTR and RFLPs with plasma
lipid concentration or CAD varies in different ethnic groups9
and has not always been found to be associated with CAD
or hyperlipidemia.10,11
The incidence of CAD is increasing in India, especially
in the younger population. Hence, it is important to
delineate risk factors for CAD in Indians. There are very
few studies from India which report the effect of apo B
polymorphisms on CAD or lipid levels. The present study is
an attempt to analyze the allele frequency of apo B-100 3'
VNTR and apo B-100 RFLPs in the Indian population and
to determine their association with plasma lipid
concentration and CAD.

(VLDL) were analyzed according to methods previously


described.12,13 Apolipoprotein B levels were assessed by the
immunoturbidimetric immunoassay using a commercial
kit (Randox Laboratories Ltd, UK).
DNA preparation: Genomic DNA was extracted by the
high salting-out procedure followed by phenol chloroform
extraction and ethanol precipitation.14
Analysis of VNTR: Apolipoprotein B 3' HVR amplification
was carried out by PCR using a forward and reverse
oligonucleotide primer encompassing the entire
apo B 3' VNTR sequence. The sequence of the primer
used was 5' ATGCAAACGGAGAAATTATG 3' and 5'
CCTTCTCACTTGCCAAATAC 3'. The polymerase chain
reaction (PCR) was performed in an M.J. Research Inc.
Thermocycler, with 26 cycles of denaturation at 94 oC for
1 min, and annealing and extension at 58 oC for 6 min. The
amplified product was electrophoresced in 5%
polyacrylamide gel, and allele sizing was done using the
apo B 3' VNTR allelic ladder and a commercial ladder 50 bp
in size (Fig. 1).

Methods
Subjects: One hundred patients of angiographically
proven CAD evaluated at the Cardiology Department of the
Sanjay Gandhi Postgraduate Institute of Medical Sciences,
Lucknow, Uttar Pradesh, India were included in the study.
Patients less than 6 weeks post-myocardial infarction (MI)
were excluded from the study. One hundred age- and sexmatched controls were also selected for the study. The
controls were subjected to a treadmill test to ensure that
they were not suffering from any CAD. Further, all controls
with hypertension, diabetes, and endocrine or metabolic
disorders were excluded. Informed consent was taken from
both the patients and controls.

Analysis of RFLP: Regions of the apo B gene carrying


EcoR1, Msp1, and Xba1 restriction sites were amplified
separately using their respective primers: 5' CTG, GCT, TGC,
TAA CCT, CTC, TG and 3' GAG, AAG, CTT, CCT, GAA, GCT,
CG for EcoR1, 5' TCT, CGG, GAA, TAT, TCA, GGA, ACT, ATT,
G and 3' CTA, AGG, ATC, CTG, CAA, TGT, CAA, GGT for
Msp1 and 5' GGA,GAC, TAT, TCA, GAA, GCT, AA and
3' GAA, GAG, CCT, GAA, GAC, TGA, CT for Xba1. The
amplified product was separately digested with the
respective enzymes as previously described.15 Alleles of each
polymorphic site were classified as (+) or () according to

Lipid analysis: Blood samples were taken after a fasting


period of 12 hours from all the patients and controls. Serum
lipids including cholesterol, triglycerides, high-density
lipoprotein (HDL), LDL, and very low-density lipoprotein

61

5
349 bp
239 bp
110 bp

675 bp

Lane 1: 25 bp ladder
Lane 2 and 4: Undigested samples
Lane 3 and 5: Digested sample (+/+)

415 bp

35 bp
33 bp
31 bp

260 bp

Lane 13: CAD patients samples


Lane 4: 50 bp ladder

Lane 1: Undigested sample


Lane 2: Digested sample (+/)
Lane 3: 25 bp ladder

Lane 1: Undigested sample


Lane 2: Digested sample (+/)
Lane 3: 50 bp ladder

Fig. 1. Apo B-gene polymorphism. A: Apo B 3' VNTR analysis; B: Msp1 RFLP analysis; C: Xba1 RFLP analysis; D: EcoR1 RFLP analysis

IHJ-417-02.p65

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Indian Heart J 2003; 55: 6064

62 Puri et al. Polymorphism in the Apo B-100 Gene

the presence or absence at the cutting site of each


restriction enzyme, respectively.
Statistical analysis: Allele and genotypic frequency
analysis for apo B 3' VNTR and RFLP was done using the
POPGENE-16 version. The Students t test was used for
comparisons using the SPSS software.
Results
One hundred patients with angiographically proven CAD
(90 males, 10 females) and 100 normal controls (90 males
and 10 females) were evaluated. The mean age of the
patients was 50.749.7 years, while that of the controls
was 50.4112.23 years.
Lipid levels: The mean lipid levels of patients with
CAD and controls were not significantly different.
However, lipid levels were higher in patients as compared
to controls.
Allele frequency and genotyping for EcoR1, Xba1,
and Msp1: The comparison of the genotypic and allele
frequencies of the EcoR1, Xba1, and Msp1 RFLPs of the
apo B gene in patients with CAD and controls is shown in
Table 1. The only significant RFLP pattern was with EcoR1,
with the R+/R+ genotype expressed more frequently in
patients with CAD (p=0.001), while the R+/R genotype was

Table 1. Allele and genotype frequencies of apo B gene


RFLPs in patients with CAD and controls
CAD (n=100)

Controls (n=100)

0.950
0.050
0.285
0.715
0.825
0.175

0.820
0.180
0.225
0.775
0.850
0.150

Genotypic frequency (%)*


R+/R
R+/R+

8
91

34*
65*

Genotypes *
E+ E+ M+ M+ X+ X+
E+ E+ M+ M X X
E+ E M+ M X X

10
20
1

2**
8**
9**

Allele frequency
EcoR1 (+)
EcoR1 ()
Xba1 (+)
Xba1 ()
Msp1 (+)
Msp1 ()

+, refers to the presence or absence of a cutting site for restriction


endonuclease
*only significant genotype frequencies have been shown (p<0.005);
**only significant genotype frequencies have been shown (p<0.001)
Apo B: apolipoprotein B; RFLP: restriction fragment length polymorphism;
CAD: coronary artery disease; R: EcoR1; M: Msp1; X: Xba1

IHJ-417-02.p65

62

Fig. 2. Apo B 3' VNTR allele frequency distribution among patients with CAD
and controls.

more common in controls (p=0.001). The genotypes E+ E+


M+ M+ X+ X+ and E+ E+ M+ M X X were significantly more
prevalent in patients with CAD (p<0.05). The genotype E+
E M+ M X X, on the other hand, was more common in
controls (p<0.05).
VNTR analysis: Relative frequencies of VNTR in patients
with CAD and controls are shown in Fig. 2. The VNTR allele
34 was significantly increased in patients with CAD as
compared to that in controls, while allele 36 was
significantly increased in controls. Interestingly, VNTR
allele 36 was totally absent in patients.
Correlation of VNTR, RFLP, and lipid parameters
with the age of the patients with CAD: When young
patients with CAD (age <45 years, n=46) were analyzed,
there was no significant increase in any allelic and
genotypic frequencies of different apo B polymorphisms as
compared to older patients (age 45 years, n=54). However,
when patients with CAD were compared to controls, the
older patients with CAD had a higher frequency of EcoR1
(+) allele, while the EcoR1 () allele was less common in
both the age subgroups.
Correlation of RFLP and HVR allele with lipid
parameters: In patients with CAD, the genotypes R+/R+,
X/X and M+/M+ were frequent in those with elevated apo
B and VLDL levels. On the other hand, these genotypes were
less frequent in patients with increased total cholesterol and
LDL levels. The allele Msp1 () was significantly less
common in patients with elevated LDL levels.
Among controls, the trend of association was the same
as in the patient group but the results were not significant
in the controls, even in those with elevated apo B and VLDL
levels.

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Indian Heart J 2003; 55: 6064

Discussion
On the basis of evidence obtained over many years from
epidemiological and trial data, LDL- and HDL-cholesterol
levels have been the recommended lipid variables in
international guidelines for treatment. However, new
information shows the importance of apo B and apo A-I as
risk predictors for CAD.16 A reason why apo B may be a
stronger predictor of risk than LDL-cholesterol is that apo B
is present not only in LDL but also in VLDL, intermediate
density lipoprotein, and lipoprotein (a). Therefore, the sum
of apo B concentrations in all atherogenic particles might
be a better risk marker than total cholesterol and LDLcholesterol levels only.16 In our study, the entire lipid levels,
including those of apo B, were higher in patients as
compared to controls; however, these did not reach
statistical significance. One possible explanation for this
could be that lipid-lowering drugs were not withheld prior
to lipid testing for this study as this would not have been
ethically justifiable in patients who had angiographically
proven CAD with dyslipidemia and were already on lipidlowering drugs.
It has been suggested that in addition to quantitative
variation in apo B levels in the plasma, genetic variation at
the apo B locus may be a new and independent risk factor
for CAD.17
It has been reported that different VNTR alleles may be
associated with CAD and hyperlipidemia.46 We found an
association of VNTR 34 in patients with CAD similar to
that reported by Moreel et al.4 The allelic variation of apo B
gene polymorphisms may have some association with
various ethnic groups. Deka et al.9 in a study of allelic
frequency distribution at the hypervariable locus 3' to the
apo B gene in 5 human populations found 12 segregating
alleles in 319 individuals. They found that the two most
frequent alleles, 37 and 39, were present in all the
populations. When we studied VNTR we found that allele
34 was significantly increased in patients as compared to
controls, while allele 36 was completely absent in patients
but present in controls. This clearly demonstrates the
presence of allelic frequency variation in different
populations. These association studies may be of some use
when genetic factors are considered as one of the
predisposing causes.
There are few studies on Indians that show the
association of the apo B gene 3' HVR alleles with CAD and
plasma lipid levels. Renges et al.18 found an association
between Xba1 and ins/del polymorphisms of the apo B gene
with total cholesterol and HDL-cholesterol levels in South
Asians in the UK. Saha et al. 19 reported that DNA
polymorphisms of the apo B gene were associated with

IHJ-417-02.p65

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Puri et al. Polymorphism in the Apo B-100 Gene

63

obesity and serum lipids in healthy Indians in Singapore.


Misra et al.,20 on the other hand, have reported that apo B
(Xba1 and EcoR1) polymorphisms did not appear to
influence serum lipid levels. In our study, we found that
the genotypes R+/R+, X/X and M+/M+ were frequent in
patients with elevated apo B and VLDL levels. However,
these genotypes were decreased in patients with elevated
cholesterol and LDL levels.
Pan et al.6 found that apo B 3' VNTR genotypic variation
had little impact on the risk of dyslipidemia in a Taiwanese
population but despite this, the long apo B 3' VNTR alleles
occurred more frequently in patients with CAD. Hegele et
al.17 also found a significant correlation between apo B gene
polymorphisms and CAD, without any significant
association with either LDL or VLDL. Similar results were
reported in a porcine model of atherosclerosis in which an
apo B genetic variant was associated with atherosclerosis,
despite normal lipid levels.21 Our results show that the apo
B gene variations possibly do not affect the apo BLDLreceptor binding region, and thus do not affect the lipid
levels. Other studies have also shown similar trends.17 We
speculated that a mutation in the protein coding region of
apo B could affect the interaction of LDL with monocyte
macrophages, endothelial cells, ground substance, clotting
factors, or the immune system in a manner that would
promote atherogenesis.22
The clinical relevance of apo B polymorphisms still
remains unclear. All studies in the past reflect the genetic
heterogeneity of the apo B gene. As CAD is a multifactorial
disease, the apo B gene alone may not have a direct effect
on the lipid profile or severity and prematurity of CAD.
However, it does emphasize the importance of such studies,
which may help in future to delineate the high-risk group
for CAD, and may be of use in the genetic screening of
patients with CAD belonging to different populations.
References
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atherosclerotic disease. New perspectives based on the Framingham
Study. Ann Intern Med. 1979; 90: 8591
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atherosclerosis. Sci Am 1984; 251: 5866
3. Knott TJ, Rall SC Jr, Innerarity TL, Jacobson SF, Urdea MS, Levy-Wilson
B, et al. Human apolipoprotein B: structure of carboxyl-terminal
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hypervariable region alleles and coronary artery disease in Finnish
patients with angiographically documented coronary artery disease.
J Intern Med 1992; 231: 4957
11. Turner PR, Talmud PJ, Visvikis S, Ehnholm C, Tiret L. DNA
polymorphisms of the apoprotein B gene are associated with altered
plasma lipoprotein concentration but not with perceived risk of
cardiovascular disease. European Atherosclerosis Research Study.
Atherosclerosis 1995; 116: 221234
12. Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic
determination of total serum cholesterol. Clin Chem 1974; 20: 470
475
13. Fossati P, Prencipe L. Serum triglycerides determined colorometrically
with an enzyme that produces hydrogen peroxide. Clin Chem 1982;
28: 20772080

IHJ-417-02.p65

64

14. Olerup O, Zetterquist H. HLA-DR typing by PCR amplification with


sequence-specific primers (PCR-SSP) in 2 hours: an alternative to
serological DR typing in clinical practice including donorrecipient
matching in cadaveric transplantation. Tissue Antigens 1992; 39:
225235
15. Pan JP, Chiang AN, Tai JJ, Wang SP, Chang MS. Restriction fragment
length polymorphisms of apolipoprotein B gene in Chinese population
with coronary heart disease. Clin Chem 1995; 41: 424429
16. Walldius G, Jungner I, Holme I, Aastveit AH, Kolar W, Steiner E. High
apolipoprotein B, low apolipoprotein A-I, and improvement in the
prediction of fatal myocardial infarction (AMORIS study): a
prospective study. Lancet 2001; 358: 20262033
17. Hegele RA, Huang LS, Herbert PN, Blum CB, Buring JE, Hennekens
CH, et al. Apolipoprotein B-gene DNA polymorphisms associated with
myocardial infarction. N Engl J Med 1986; 315: 15091515
18. Renges HH, Wile DB, McKeigue PM, Marmot MG, Humphries SE.
Apolipoprotein B gene polymorphisms are associated with lipid levels
in men of South Asian descent. Atherosclerosis 1991; 91: 267275
19. Saha N, Tay JS, Heng CK, Humphries SE. DNA polymorphisms of the
apolipoprotein B gene are associated with obesity and serum lipids in
healthy Indians in Singapore. Clin Genet 1993; 44: 113120
20. Misra A, Nishanth S, Pasha ST, Pandey RM, Sethi P, Rawat DS.
Relationship of Xba1 and EcoR1 polymorphisms of apolipoprotein-B
gene to dyslipidemia and obesity in Asian Indians in North India.
Indian Heart J 2001; 53: 177183
21. Rapacz J, Hasler-Rapacz J. Investigations on the relationship between
immunogenetic polymorphisms of betalipoproteins and the
betalipoprotein and cholesterol in swine. In: Lenzi S, Descovich GC
(eds). Atherosclerosis and cardiovascular disease. Bologna: Editrice
Compositori; 1984. pp. 99108
22. Ross R. The pathogenesis of atherosclerosisan update. N Engl J Med
1986; 314: 488500

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Indian Heart J 2003; 55: 6567

Roy et al. Isolation of the Left Subclavian


65
BriefArtery
Report

Isolation of the Left Subclavian Artery


Ambuj Roy, Shyam S Kothari, Harminder Singh, Sanjiv Sharma
Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi

Two cases of isolation of the left subclavian artery from the aortic arch are reported for the rarity of this lesion.
One patient was diagnosed clinically, the other after angiography. The isolated left subclavian artery was
reimplanted in one patient. This rare anomaly has clinical and surgical relevance and should be diagnosed by
diligent clinical and angiographic evaluation. (Indian Heart J 2003; 55: 6567)
Key Words: Isolated left subclavian artery, Subclavian steal, Arch anomalies

solation of the left subclavian artery (LSA) from the right


aortic arch is a rare vascular anomaly,1 in which the left
subclavian artery does not communicate with the aortic
arch but instead is connected to the left pulmonary artery
by the ductus arteriosus. We report two cases of isolated
LSA, one of which was diagnosed clinically.

from the left vertebral artery, suggesting the presence of


isolation of the LSA (Fig. 2). The child underwent corrective
surgery for TOF and reimplantation of the LSA to the left
common carotid artery. He is doing well at follow-up after
6 months.

Case Report
Case 1: A two-year-old child presented to us with a history
of mild cyanosis since 6 months of age and a history of
one episode of a cyanotic spell one month ago. On
examination he had mild cyanosis and clubbing. The left
arm pulse was weaker compared to the right arm. The blood
pressure was 70/40 mmHg in the left arm and 104/60
mmHg in the right arm. Cardiovascular examination
revealed a quiet precordium, single second heart sound, and
a grade III/VI ejection systolic murmur in the left
parasternal area. Chest X-ray showed a right aortic arch,
no cardiomegaly and oligemic lung fields. An
electrocardiogram (ECG) showed right axis deviation with
right ventricular hypertrophy. Typical anatomy of the
tetralogy of Fallot (TOF) was seen on echocardiogram. In
view of TOF, right aortic arch and weak left arm pulse,
isolation of the LSA was suspected. Subsequent
catheterization confirmed the presence of TOF with
confluent and good-sized pulmonary arteries. Aortogram
revealed a right aortic arch. The innominate, right and left
common carotid arteries were normal. On aortography, the
LSA did not show any opacification (Fig. 1). Late frames
showed faint opacification of the LSA by retrograde filling
Correspondence: Dr Shyam S Kothari, Department of Cardiology,
Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi
110029. e-mail: kotharis@del2.vsnl.net.in

IHJ-386-02.p65

65

Fig. 1. Arch aortogram showing the branches of the aortic arch with failure of
opacification of the left subclavian artery.

Case 2: A 3.5-month-old male child was brought with a


history of cyanosis and failure to thrive, and recurrent
episodes of lower respiratory tract infection. There was no
history of stridor, wheezing or loss of consciousness. He
was born at term and the antenatal history was
unremarkable. His present weight was 2.8 kg and the birth
weight was 2.5 kg. His pulse rate was 110/min, regular,
and all peripheral pulses were palpable and equal. He had
mild cyanosis on room air. His blood pressure was 80/56

5/6/2003, 10:03 AM

Indian Heart J 2003; 55: 6567

66 Roy et al. Isolation of the Left Subclavian Artery

Fig. 2. Late frames of the same injection as in Fig.1 show retrograde filling of
the left vertebral artery (white arrow) which supplies the left subclavian artery
(black arrow).

mmHg in the right arm and 82/60 mmHg in the left arm.
The arterial saturation by oximetry was 85% in room air
in all four limbs. Cardiovascular examination revealed
cardiomegaly, single second heart sound, left ventricular
third heart sound, and a pansystolic murmur at the apex.
ECG showed left axis deviation with a counterclockwise loop
and right ventricular hypertrophy. Chest X-ray revealed
cardiomegaly, a right aortic arch, and increased pulmonary
blood flow. Echocardiography showed atrioventricular
septal defect (AVSD) and a double outlet right ventricle
(DORV) with dilated left ventricle and atrium. The great
vessels were malposed with an anterior aorta. There was
no pulmonic stenosis. Cardiac catheterization and
aortography were performed. The aortogram revealed a
right aortic arch with absence of filling of the LSA from
the aorta (Fig. 3) and delayed retrograde filling from the
left vertebral artery. A selective left common carotid
angiogram showed retrograde filling of the LSA through
the left vertebral artery (Fig. 4). Right ventricular
angiogram confirmed the presence of a DORV. Hence, a
diagnosis of cyanotic congenital heart disease with DORV,
AVSD, and isolated LSA was made. The child subsequently
developed lower respiratory tract infection and succumbed
to it.
Discussion
Isolation of the LSA is defined as a loss of continuity
between the LSA and the aorta with a persistent connection
to the homolateral pulmonary artery through the ductus

IHJ-386-02.p65

66

Fig. 3. Arch aortogram showing opacification of the branches of the aortic arch.
Note the absence of opacification of the left subclavian artery.

Fig. 4. Late frames from selective left common carotid angiogram showing
retrograde filling of the left vertebral artery (arrowhead) and the left subclavian
artery (black arrow).

arteriosus, which may be patent or closed. There is


retrograde filling of the LSA through the left vertebral
artery, which is fed via the circle of Willis. This leads to the
congenital subclavian steal phenomenon. However, if the
ductus arteriosus is patent, a shunt between the pulmonary
and the systemic circulation is established. Therefore, the
inverted left vertebral blood flow supplies only the proximal
part of the LSA, before entering the pulmonary artery,
leading to pulmonary artery steal.2 The distal LSA in these
cases is usually supplied by anastomoses between the left
external carotid artery and the LSA.

5/6/2003, 10:03 AM

Indian Heart J 2003; 55: 6567

Isolated LSA has been diagnosed from infancy to as late


as 52 years of age. The condition is diagnosed usually due
to the presence of associated cardiac anomalies. However,
symptoms of subclavian steal and limb ischemia are present
in some patients. Luetmer et al.3 in their review of the
literature reported the presence of symptoms of
vertebrobasilar insufficiency in 5 of 30 patients (17%) and
limb ischemia in 5 patients. These symptomatic patients
are usually older and develop symptoms in the second and
third decades of life.
Isolation of the LSA should be suspected if the left arm
pulse or blood pressure is found to be lower than that of
the right arm in a patient with a right aortic arch, as in the
first case reported here. These features may be absent due
to the associated lesions, which result in equalization of
pressure in the aorta and pulmonary arteries. Bedside
diagnosis of an isolated LSA is difficult under such
circumstances, as in the second case. The diagnosis of an
isolated LSA can be reliably established by aortography,
wherein delayed films show late opacification of the LSA
from the left vertebral artery.
An isolated LSA is a rare congenital anomaly.1 It is almost
always associated with a right aortic arch.3 However, only
0.8% of patients with a right aortic arch have an isolated
LSA. A solitary case of a left arch with an isolated LSA has
been reported in the literature.4 Nearly 60% of the patients
have associated intracardiac anomalies of which TOF is the
most common. 3 Other associations include atrial and
ventricular septal defects, bilateral patent ductus arteriosus,
truncus arteriosus, transposition of the great arteries,
hypoplastic left heart syndrome, and DORV.3,5,6
The diagnosis of a right aortic arch with an isolated LSA
is imperative for the future management of patients with
intracardiac lesions such as TOF,7 as a BlalockTaussig
shunt in these patients is done on the side opposite the arch.
However, because of decreased pressure and flow in an
isolated LSA, it cannot be used for a left BlalockTaussig
shunt in these patients.
The embryogenesis of this entity can be explained by
using the hypothetical double arch system proposed by
Stewart et al.8 and Edwards.9 There is interruption of the
left aortic arch at two levels, one between the left common
carotid artery and the LSA, and the second between the
left ductus arteriosus and left dorsal aortic root. This results
in a right aortic arch with typical branching of this entity.

IHJ-386-02.p65

67

Roy et al. Isolation of the Left Subclavian Artery 67

The branches of the right aortic arch in this entity, in order,


are the left common carotid, the right common carotid, and
the right subclavian arteries. The LSA becomes detached
from the aorta and is connected to the pulmonary artery
by the ductus arteriosus. Similarly, interruption of the left
arch at corresponding points leads to a left aortic arch with
isolation of the right subclavian artery.7,10
Surgical treatment of this condition is required if
symptoms of subclavian steal occur or if surgery is done
for concomitant heart disease. Corrective surgery involves
anastomosis of the LSA with the arch or the left common
carotid artery. Recent catheter-based abolition of
pulmonary steal has been described by closure of the patent
ductus arteriosus.11
References
1. Stewart JR, Kincaid OW, Titus JL. Right aortic arch: plain film
diagnosis and significance. Am J Roentgenol Radium Ther Nucl Med
1966; 97: 377389
2. Carano N, Piazza P, Agnetti A, Squarcia U. Congenital pulmonary steal
phenomenon associated with tetralogy of Fallot, right aortic arch,
and isolation of the left subclavian artery. Pediatr Cardiol 1997; 18:
5760
3. Leutmer PH, Miller GM. Right aortic arch with isolation of the left
subclavian artery: case report and review of the literature. Mayo Clin
Proc 1990; 65: 407413
4. Engelman DA, Mortazavi A. Congenital subclavian steal syndrome
in an adult with a left aortic arch. Tex Heart Inst J 1998; 25: 216
217
5. McMahon CJ, Thompson KS, Kearney DL, Nihill MR. Subclavian steal
syndrome in anomalous connection of the left subclavian artery to
the pulmonary artery in d-transposition of the great arteries. Pediatr
Cardiol 2001; 22: 6062
6. Patel CR, Spector ML, Zahka KG. Hypoplastic left heart syndrome with
right aortic arch, bilateral arterial ducts and origin of the left
subclavian artery from the left pulmonary artery. Cardiol Young 1999;
9: 331334
7. Rodriguez L, Izukawa T, Moes CA, Trusler GA, Williams WG. Surgical
implications of right aortic arch with isolation of left subclavian
artery. Br Heart J 1975; 37: 931936
8. Stewart JR, Kincaid OW, Edwards JE. An atlas of vascular rings and
related malformations of the aortic arch system. Springfield: Illinois.
Charles C Thomas, 1964
9. Edwards JE. Anomalies of the derivatives of the aortic arch system.
Med Clin North Am 1948; 32: 925949
10. Garti IJ, Aygen MM. Left aortic arch with congenital isolation of the
right subclavian artery. Pediatr Radiol 1980; 9: 241243
11. Jones TK, Garabedian H, Grifka RG. Right aortic arch with isolation
of the left subclavian artery, moderate patent ductus arteriosus, and
subclavian steal syndrome: a rare aortic arch anomaly treated with
the GianturcoGrifka vascular occlusion device. Catheter Cardiovasc
Interv 1999; 47: 320322

5/6/2003, 10:03 AM

68 Pandurangi
Brief
Report et al.

Indian Heart J 2003; 55: 6870

Endoepicardial AV Pacing

Temporary Endoepicardial Atrioventricular Sequential


Pacing for Complete Heart Block Following Complex
Surgery for Congenital Heart Disease
Ulhas M Pandurangi, PJ Ruth, Satish C Toal, Snehal Kulkarni, KS Murthy, KM Cherian
Department of Cardiology, Madras Medical Mission, Institute of Cardiovascular Diseases, Chennai

Complete heart block following intracardiac surgical repair for complex congenital heart disease is not
uncommon. In the presence of ventricular dysfunction, ventricular pacing alone may not improve the cardiac
output. We report the feasibility and efficacy of endoepicardial atrioventricular sequential pacing in a case of
postoperative complete heart block. (Indian Heart J 2003; 55: 6870)
Key Words: Complete heart block, Atrioventricular sequential pacing, Cardiac surgery

ntracardiac surgical repair for complex congenital heart


disease is associated with complete heart block (CHB) in
up to 36% of cases. 1 In the presence of ventricular
dysfunction, atrioventricular (AV) sequential pacing is
preferred to ventricular pacing alone.2,3 We report the case
of a 12-year-old girl who developed CHB following mitral
valve replacement for residual mitral regurgitation and
moderate biventricular dysfunction. She had undergone an
intracardiac repair in the past for complex congenital heart
disease. The epicardial ventricular pacing lead provided VVI
pacing. However, the poor hemodynamics resulted in the
patient being dependent on the ventilator. A transvenous
endocardial pacing lead was placed in the right atrium
through the jugular vein and AV sequential pacing
achieved using an epicardial ventricular pacing lead, with
gratifying results. This report highlights the feasibility of
endoepicardial AV sequential pacing and the need for AV
synchrony in cases of postoperative CHB.

redo surgery for new-onset progressive mitral valve


regurgitation. An Omnicarbon prosthetic valve (29 mm)
was placed at the mitral annulus. A bipolar epicardial
ventricular pacing lead was placed as there was CHB
following the surgery (Fig. 1). The patient was paced in the
VVI mode (Fig. 2) using a temporary pacemaker (Medtronic
5346 DDD temporary pulse generator, Minneapolis, MN,
USA). The patient came out of bypass easily. However,
despite good surgical results, the patient could not be
weaned away from the ventilator even 48 hours postprocedure, as there were signs of reduced cardiac output

Fig. 1. Complete heart block following surgery.

Case Report
A 12-year-old girl had undergone surgical closure for atrial
and ventricular septal defects, with subpulmonic resection
at 6 years of age for situs inversus, dextrocardia, atrial and
ventricular septal defects, corrected transposition of the
great arteries (c-TGA), subpulmonic stenosis and
interrupted inferior vena cava. The patient underwent a
Correspondence: Dr Ulhas M Pandurangi, Department of Cardiology,
Institute of Cardiovascular Diseases, Madras Medical Mission, 4-A,
Dr J Jayalalitha Nagar, Mogappair, Chennai 600050.
e-mail: ulhaspandurangi@hotmail.com

IHJ-392-02.p65

68

Fig. 2. Pacing in the VVI mode.

5/6/2003, 10:04 AM

Indian Heart J 2003; 55: 6870

and systemic venous congestion. Despite inotropic support,


the systolic blood pressure remained less than 90 mmHg
and central venous pressure between 16 and 18 mmHg.
The arterial blood gas analyses were suggestive of metabolic
acidosis. The loss of atrial kick was considered a
contributory factor for the reduced cardiac output and AV
sequential pacing was considered to improve the
hemodynamics.4 A temporary bipolar 5 F pacing lead was
placed in the left-sided right atrium through the left internal
jugular vein. The tip of this lead was positioned under the
fluoroscope to achieve stable and satisfactory pacing and
sensing parameters (Fig. 3). This endocardial lead and the
epicardial lead were connected to the AV sequential
pacemaker (Medtronic 5388 Inc., Minneapolis, MN, USA).
The AV delay was adjusted to 100 ms with the aid of venous
pressure monitoring5 and bedside Doppler study6 of the
mitral inflow and mitral regurgitation (Figs 4 and 5). There
was marked improvement in the hemodynamics soon after
AV sequential pacing was initiated. The systolic blood
pressure could be maintained between 120 and 130 mmHg
without inotropic support, and there was prompt
normalization of the central venous pressure and arterial
blood gas parameters. The patient could be successfully
weaned away from the ventilator over 24 hours and
underwent dual-chamber permanent pacemaker
implantation before discharge from the hospital.
Discussion
Complete heart block following cardiac surgery for complex
congenital heart disease, like the one our patient had, is
not uncommon. Surgical repair for defects associated with

Fig. 3. Fluoroscopy (PA view) showing endocardial atrial lead (single arrow)
and epicardial ventricular lead (double arrow).

IHJ-392-02.p65

69

Pandurangi et al. Endoepicardial AV Pacing

69

Fig. 4. Pacing in the VDD mode.

Fig. 5. Pacing in the DDD mode.

c-TGA results in CHB in up to 36% of cases.1,7 Postoperative


CHB may be managed satisfactorily in most cases by
ventricular pacing in the VVI mode alone through
epicardial leads.8,9 However, in certain situations in which
the atrial contribution to ventricular output is critical, as
in our case where there was moderate biventricular
dysfunction, it has been shown that AV sequential pacing
results in better hemodynamics as compared to ventricular
pacing alone. It has been common practice in some surgical
centers to place atrial and ventricular epicardial pacing
leads for post-surgical CHB to achieve AV sequential
pacing.10,11 However, if only one epicardial lead is available
for ventricular pacing, AV sequential pacing can be
obtained by an esophageal lead, which can sense atrial
potentials.12 The disadvantages of using esophageal leads
are unstable lead position and intermittent sensing failure.
In addition, an esophageal lead is not practical in a
conscious patient. Placement of another epicardial lead for
sequential pacing would add to the perioperative morbidity.
Using epicardial leads for ventricular pacing and a Swan
Ganz flow-directed pacing catheter for atrial pacing/sensing
to obtain AV sequential pacing has met with variable
results.13 Endocardial atrial lead placement is another
option for obtaining AV sequential pacing. Since our patient
had interruption of the inferior vena cava, the jugular vein
was used for right atrial access. The left jugular vein was

5/6/2003, 10:04 AM

Indian Heart J 2003; 55: 6870

70 Pandurangi et al. Endoepicardial AV Pacing

chosen as the patient had situs inversus. This case report


highlights the occasional need for AV sequential pacing in
a case of postoperative CHB and the feasibility of achieving
sequential pacing by endoepicardial leads.
References
1. de Leval MR, Bastos P, Stark J, Taylor JF, Macartney FJ, Anderson RH.
Surgical technique to reduce the risks of heart block following closure
of ventricular septal defect in atrioventricular discordance. J Thorac
Cardiovasc Surg 1979; 78: 515526
2. Reiter MJ, Hindman MC. Hemodynamic effects of acute
atrioventricular sequential pacing in patients with left ventricular
dysfunction. Am J Cardiol 1982; 49: 687692
3. Kargul W, Gasior Z, Zajac T, Pruski M, Grzegorzewski B, Krauze J. Effect
of ventricular and sequential stimulation on the left-ventricular
systolic function. Kardiol Pol 1992; 37: 812
4. Leonard JJ, Shaver J, Thompson M. Left atrial transport function. Trans
Am Clin Climatol Assoc 1980; 92: 133141
5. Kern MJ, Deligonul U. Interpretation of cardiac pathophysiology from
pressure waveform analysis: pacemaker hemodynamics. Cathet
Cardiovasc Diagn 1991; 24: 2227

IHJ-392-02.p65

70

6. Romero LR, Haffajee CI, Levin W, Doherty PW, Berkovits BV, Alpert
JS. Non-invasive evaluation of ventricular function and volumes
during atrioventricular sequential and ventricular pacing. Pacing Clin
Electrophysiol 1984; 7: 1017
7. Doty DB, Truesdell SC, Marvin WJ Jr. Techniques to avoid injury of
the conduction tissue during the surgical treatment of corrected
transposition. Circulation 1983; 68: II6369
8. Fitzpatrick A, Sutton R. A guide to temporary pacing. BMJ 1992; 304:
365369
9. Waldo AL, MacLean WAH. Diagnosis and treatment of cardiac
arrhythmias following open heart surgery. 2nd ed. Mt Kisco, New York:
Futura; 1980. p. 64
10. Moungey SJ. Temporary A-V sequential pacemakers. Programming
and troubleshooting. Prog Cardiovasc Nurs 1989; 4: 4960
11. Haywood DL. Temporary A-V sequential pacing using an epicardial
lead system. Crit Care Nurse 1985; 5: 2124
12. Roth JV, Huertas R. Atrioventricular sequential pacing using
transesophageal atrial pacing in combination with a temporary DDD
pacemaker for atrial tracking and ventricular pacing. J Cardiothorac
Vasc Anesth 1995; 9: 255258
13. Roth JV. Temporary transmyocardial pacing using epicardial pacing
wires and pacing pulmonary artery catheters. J Cardiothorac Vasc
Anesth 1992; 6: 663667

5/6/2003, 10:04 AM

Baruah et al. Concurrent Coronary, Iliac and Renal Direct


Stenting
71
Brief
Report

Indian Heart J 2003; 55: 7174

Concurrent Coronary, Bilateral Iliac and Left Renal


Artery Direct Stenting
DK Baruah, NK Panigrahi, AN Srinivas
Department of Cardiology, Apollo Hospitals, Vishakhapatnam

We describe a patient who underwent percutaneous coronary intervention combined with bilateral iliac and
left renal artery angioplasty during the same sitting. Stenting of the coronary and peripheral arteries was
performed employing the direct stenting technique. No complications occurred. The patient was discharged
2 days after the intervention and remains asymptomatic, leading a fully active life during 1 year of follow-up. To
our knowledge, unstaged coronary stenting combined with direct stenting of the renal and both common iliac
arteries has not been reported previously in India. (Indian Heart J 2003; 55: 7174)
Key Words: Coronary artery disease, Peripheral vascular disease, Stenting

therosclerotic vascular disease can involve both the


coronary and peripheral arterial systems.1 Patients
with peripheral vascular disease can present as acute
coronary syndrome due to coexisting coronary artery
disease and require proper therapeutic attention.
Percutaneous intervention to treat both coronary and
peripheral vascular disease may offer an alternative to
surgery in such situations.2 Rapid progress in the design of
coronary devices and, to a degree, advances in the
equipment for peripheral vascular interventions makes it
increasingly possible to combine this technique in clinically
and anatomically challenging patients.3,4 This combined
strategy reduces the need for multiple interventions,
repeated hospitalizations, and is also cost-effective. We
report the case of an elderly woman who presented with
acute anterior wall myocardial infarction and recurrent
postinfarct angina with a background history of severe
claudication of the lower limbs. She was managed by direct
stenting of the left renal and both common iliac arteries in
addition to coronary angioplasty during the same sitting.

A 74-year-old woman presented to us with recurrent


postinfarct angina following acute anterior wall myocardial
infarction. She was a known hypertensive and diabetic for
more than 10 years. She had history of severe claudication
of both legs (Fontaine class IIb), more on the right side. She

had been on drug therapy for peripheral vascular disease


till date. She also gave a history of accelerated hypertension
with an episode of pulmonary edema and was also
diagnosed to have an early stage of nephropathy.
Physical examination showed very feeble right lower limb
pulses and feeble left lower limb pulses with a supine blood
pressure in the right upper limb of 200/110 mmHg.
Electrocardiography revealed Q waves in leads V1V3 with
T wave inversion in leads V4V6. Echocardiogram showed
regional wall motion abnormality in the left anterior
descending coronary artery territory with a left ventricular
ejection fraction of 45%. After informed consent,
angiographic study was performed which revealed 90%
complex stenosis of the left anterior descending coronary
artery (Fig. 1a) with minimal disease of the other coronary
arteries and mild LV systolic dysfunction. A peripheral
angiographic study revealed 90% stenosis of the right
common iliac artery (Fig. 2a), 70% eccentric stenosis of
the left common iliac artery (Fig. 2a) and 80% eccentric
stenosis of the left renal artery (Fig. 3a).
The patient was pretreated with aspirin 325 mg daily
and clopidogrel 75 mg twice a day 48 hours prior to the
procedure and, in anticipation of a large contrast load (in
the presence of borderline nephropathy), the patient was
hydrated with normal saline, 75 ml/hour for 12 hours. To
minimize the amount of radiation, it was decided to use
the direct stenting technique and all attempts were made
to reduce exposure time.

Correspondence: Dr DK Baruah, Director of Cath. Lab., Apollo Hospitals,


Vishakhapatnam

Coronary artery stenting: A 7 F arterial sheath was


placed percutaneously in the left femoral artery and the

Case Report

IHJ-348-02.p65

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Indian Heart J 2003; 55: 7174

72 Baruah et al. Concurrent Coronary, Iliac and Renal Direct Stenting

left coronary artery was engaged using a 6 F Vista Brite


Tip left Judkins catheter (Cordis). The lesion in the left
anterior descending coronary artery was crossed with a
0.014" balance middle weightTM guidewire (Guidant). After
quantitative coronary analysis, a Bx velocity stent (Cordis)
2.5 mm in diameter and 23 mm in length was deployed at
14 atm pressure. The final angiogram (Fig. 1b) showed good
angiographic result with TIMI III flow distally. A total of
10 000 units of heparin was administered intravenously
during the procedure.
Right common iliac artery stenting: We used the
ipsilateral approach for iliac angioplasty in view of the

b
Fig. 1. Left anterior descending coronary artery stenosis before (a) and after
(b) stenting.

IHJ-348-02.p65

ostial location of the lesion and the acute angle of the aortic
bifurcation. After cannulating the right femoral vein with
a 0.38" guidewire, the right femoral artery was punctured
under fluoroscopic guidance. This was done because the
right femoral artery pulsation was very feeble and difficult
to localize. A 7 F sheath was inserted into the right femoral
artery and a retrograde angiogram through the sheath
delineated the tight stenosis of the right common iliac
artery. A peak pressure gradient of 80 mmHg on pull-back
was recorded across the lesion. The lesion was crossed with
a 0.014" balance middle weight coronary guidewire and
exchanged for a 0.035" Amplatz super stiffTM (Boston
Scientific) guidewire. A CorinthianTM stent (Cordis) 17 mm

72

Fig. 2. Right and left common iliac artery stenosis before (a) and after (b)
stenting.

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Indian Heart J 2003; 55: 7174

Baruah et al. Concurrent Coronary, Iliac and Renal Direct Stenting

73

in length and 6 mm in diameter was positioned according


to the bony landmarks with the help of retrograde injection
through the sheath and deployed at 13 atm pressure. A
post-stenting angiogram showed a good result (Fig. 2b).
There was no significant gradient across the stented
segment on pull-back. The activated clotting time at this
point of time was 250 s and 5000 units of heparin were
administered.
Left common iliac artery stenting: Selective left iliac
angiogram was performed through the left femoral sheath
to delineate the lesion in the left common iliac artery.
Simultaneous pressure recording revealed a 47 mmHg peak
pressure gradient across the stenosis. A 0.035" Radifocus
guidewire (Terumo Corporation) was used to cross the
lesion and exchanged to a 0.035" Amplatz super stiff
guidewire. A CorinthianTM stent (Cordis) 17 mm in length
and 6 mm in diameter was deployed to cover the entire
lesion at 13 atm pressure. In view of the bilateral ostial
disease of the iliac arteries, final dilatation of both stents
was carried out by the kissing balloon technique. This
technique helps in avoiding plaque shift and in proper
deployment of both stents. The final injection showed good
angiographic result (Fig. 2b) and no significant pressure
gradient was recorded across the stented segments.
Renal artery stenting: The left renal artery was engaged
using a 6 F right coronary guiding catheter (JR 3.5 Vista
Brite Tip, Cordis) and the lesion was crossed with 0.014"
balance middle weight guidewire. After selective injection
and QCA analysis, a GFX stent (AVE, Medtronic) 3.5 mm
in diameter and 18 mm in length was positioned carefully
and deployed at 14 atm pressure. The post-procedure
angiogram (Fig. 3b) revealed a good result with rapid distal
flow. Usually, a 3.5 mm diameter stent is undersized for a
normal renal artery. In this case, QCA analysis revealed the
size of the left renal artery to be 3.6 mm and the left kidney
to be smaller than the right. Thus, we decided to use a
coronary stent.
The patient was kept under observation for 48 hours
and discharged without complications. At 1-year followup, she is asymptomatic with good effort tolerance and good
lower limb pulses. Her blood pressure is well under control
with only one antihypertensive drug.
Discussion
Patients with coexistent coronary and peripheral vascular
disease constitute a challenging group in clinical practice,
one that requires special therapeutic attention. Coronary
artery bypass surgery in the presence of acute myocardial

IHJ-348-02.p65

73

b
Fig. 3. Left renal artery stenosis before (a) and after (b) stenting.

infarction and peripheral vascular disease carries a


substantial risk of morbidity and mortality.5,6 On the other
hand, it is well established that in patients who undergo
vascular surgery, there is a decrease in survival rate if
coronary artery disease is present.7 In such a clinical
situation, percutaneous treatment offers a promising
alternative to surgery. There has been rapid growth in
interventional cardiology in the past few decades and the
introduction of stents has improved the long-term outcome
of angioplasty.8,9 With constantly improving stent designs,
delivery systems and techniques, multivessel stenting has
become routine in clinical practice. Introduction of direct
stenting has made this procedure more rapid and costeffective with less exposure to radiation and contrast load.10
Various studies have been carried out to assess the efficacy

5/6/2003, 10:04 AM

Indian Heart J 2003; 55: 7174

74 Baruah et al. Concurrent Coronary, Iliac and Renal Direct Stenting

of direct stenting and it has been found to be equivalent in


terms of immediate and long-term results to that of stenting
with predilatation.1113
There are few reports on combined multivessel direct
stenting involving both the coronary and peripheral
vessels.14,15
Our patient was an elderly woman with multiple
coronary risk factors and borderline nephropathy; this
condition not only carries a higher surgical risk but also a
higher risk of complications during percutaneous
intervention. We used the direct stenting technique in this
patient to reduce the contrast load as well as exposure time.
The patient tolerated the procedure well without any major
complications with a satisfactory 1-year follow-up record.
Direct stenting is an evolving technique in interventional
cardiology which, at present, is applied in selected cases
during percutaneous angioplasty. This technique can also
be useful when multivessel angioplasty is contemplated.
References
1. Hertzer NR, Beven EG, Young JR, OHara PJ, Ruschhaupt WF 3rd,
Graor RA, et al. Coronary artery disease in peripheral vascular
patients. A classification of 1000 coronary angiograms and results
of surgical management. Ann Surg 1984; 199: 223233
2. Joseph G, Baruah DK, Zacharias TU, Krishnaswami S. Combined
percutaneous coronary and carotid artery stenting. Indian Heart J
1997; 49: 425426
3. Mathur A, Roubin GS, Yadav JS, Iyer SS, Vitek J. Combined coronary
and bilateral carotid stenting: a case report. Cathet Cardiovasc Diagn
1997; 40: 202206
4. Klez RS, Rozek MM, Bouknight D. Bilateral carotid stenting combined
with three-vessel percutaneous coronary intervention in single sitting.
Cathet Cardiovasc Diagn 2001; 52: 100104

IHJ-348-02.p65

74

5. Hertzer NR, Young JR, Beven EG, OHara PJ, Graor RA, Ruschhaupt
WF, et al. Late results of coronary bypass in patients with peripheral
vascular disease. I. Five-year survival according to age and clinical
cardiac status. Cleve Clin Q 1986; 53: 133143
6. Hertzer NR, Young JR, Beven EG, OHara PJ, Graor RA, Ruschhaupt
WF, et al. Late results of coronary bypass in patients with peripheral
vascular disease. II. Five-year survival according to sex, hypertension,
and diabetes. Cleve Clin J Med 1987; 54: 1523
7. Crawford ES, Bomberger RA, Glaeser DH, Saleh SA, Russell WL.
Aortoiliac occlusive disease: factors influencing survival and function
following reconstructive operation over a twenty-five-year period.
Surgery 1981; 90: 10551067
8. Sigwart U, Puel J, Mirkovitch V, et al. Intravascular stents to prevent
occlusion and restenosis after transluminal angioplasty. N Engl J Med
1991; 316: 1317
9. Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W,
Heyndrickx G, et al. A comparison of balloon-expandable-stent
implantation with balloon angioplasty in patients with coronary
artery disease. Benestent Study Group. N Engl J Med 1994; 331: 489
495
10. Figulla HR, Mudra H, Reifart N, Werner GS. Direct coronary stenting
without predilatation: a new therapeutic approach with a special
balloon catheter design. Cathet Cardiovasc Diagn 1998; 43: 245252
11. Carrie D, Khalife K, Citron B, Izaaz K, Hamon M, Juiliard JM, et al.
Comparison of direct coronary stenting with and without balloon
predilatation in patients with stable angina pectoris. BET (Benefit
Evaluation of Direct Coronary Stenting) Study Group. Am J Cardiol
2001; 87: 693698
12. Wilson SH, Berger PB, Mathew V, Bell MR, Garratt KN, Rihal CS, et al.
Immediate and late outcomes after direct stent implantation without
balloon predilation. J Am Coll Cardiol 2000; 35: 937943
13. Veselka J, Mates M, Tesar DB, Aschermann M, Urbanova T, Honek T.
Direct stenting without predilatation: a new approach to coronary
intervention. Coron Artery Dis 2000; 11: 503507
14. Dorros G, Mathiak L. Direct deployment of the iliofemoral balloon
expandable (Palmaz) stent utilizing a small (7.5 French) arterial
puncture. Cathet Cardiovasc Diagn 1993; 28: 8082
15. Mehan VK, Meier B. Multiple renal artery stenting with half
(disarticulated) PalmazSchatz coronary stents and simultaneous
coronary angioplasty. Indian Heart J 1995; 47: 259260

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Indian Heart J 2003; 55: 7577

Gupta et al. Catheter Ablation Using a New Mapping


System
75
Brief
Report

Catheter Ablation of Atrial Tachycardia Using a Real-Time


Position Management Mapping System
Anoop K Gupta, Alok Maheshwari, Ranjan K Thakur, Yash Y Lokhandwala
Thoracic and Cardiovascular Institute, Sparrow Health System, Michigan State University, Lansing, MI, USA

Catheter ablation for atrial tachycardia is limited by its low success rate and prolonged procedure time because
of difficulties in mapping the site of the tachycardia. A new three-dimensional mapping system, the Cardiac
Pathways mapping system, using an ultrasound transducer, has recently become available. We report a case of
focal atrial tachycardia ablation with this system. (Indian Heart J 2003; 55: 7577)
Key Words: Ablation, Tachyarrhythmia, Cardiac mapping

ocal atrial tachycardias are not randomly distributed


but rather tend to cluster in certain anatomic zones,13 the
commoner site being along the crista terminalis in the right
atrium and from within a pulmonary vein. There are a
variety of approaches to mapping and ablation of focal
atrial tachycardias.
The Carto system has been used to develop an
electroanatomic map of the earliest activation; however,
this system requires that the map be developed point by
point.4 Multielectrode basket catheters have also been
developed, as have noncontact mapping arrays.5 Another
system, Cardiac Pathways, enabling three-dimensional (3-D)
real-time mapping, includes real-time position management
in guiding radiofrequency (RF) catheter ablation. We present
our initial experience with the Cardiac Pathways mapping
system for ablation of focal atrial tachycardia.
Case Report
A 53-year-old woman presented to the arrhythmia clinic
with palpitation. Twenty-four hour Holter monitoring
showed a narrow QRS complex tachycardia with a rate of
128 beats/min with warm-up phenomenon. P-wave
morphology during tachycardia was similar to the sinus
rhythm, suggestive of a focus in the high right atrium
(Fig. 1). Clinical examination, chest X-ray and
echocardiography showed no abnormality.
The patient was taken up for electrophysiologic study
(EPS) after withdrawing all antiarrhythmic drugs for at
least five half-lives. EPS was performed using the Cardiac
Correspondence: Dr Anoop K Gupta, Consultant Cardiologist and
Electrophysiologist, Krishna Heart Institute, Ghuma, Ahmedabad 380058.
e-mail: anoopgupta@msn.com

IHJ-364-02.p65

75

Fig. 1. Panel A: 12-lead ECG showing atrial tachycardia (128 beats/min).


The P wave morphology in the inferior leads is similar to sinus rhythm ECG.
Panel B: 12-lead ECG showing baseline sinus rhythm.

Pathways system. 3-D positional mapping was done with


the ablation catheter using both point and isochronal maps.
Identification of major structures and the deformation map
were performed before mapping the atrium.
Atrial tachycardia was easily inducible with atrial
extrastimuli and continuous pacing. Right atrial mapping
was performed; the earliest activation of 36 ms from the
surface P wave was obtained high at the interatrial septum.
A trans-septal puncture was performed using the standard
technique to map the left atrium. The earliest activation of
42 ms from the surface P wave was obtained in the roof of
the left atrium between the right and left superior
pulmonary veins. Isochronal and point mapping of the left
atrium also suggested earliest activation in the roof of the
left atrium (Figs 2a and b).
Successful RF ablation was performed using a 7 F, 4 mm
tip bidirectional steerable cooled ablation catheter (Cardiac
Pathways, Sunnyvale, CA, USA), keeping the reference

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Indian Heart J 2003; 55: 7577

76 Gupta et al. Catheter Ablation Using a New Mapping System

ghost catheter at the earliest site of activation during the


ablation. No tachycardia could be induced despite a
vigorous atrial stimulation protocol with and without
isoproterenol after radiofrequency ablation (RFA). The
procedure time was 135 min and fluoroscopic time was 18
min. There was no complication during the procedure.
Heparin was given at the rate of 100 unit/kg intravenously
after the trans-septal puncture.
Cardiac Pathways mapping system
Reference and ablation catheters: Two reference catheters
and one mapping/ablation catheter were introduced

b
Fig. 2. Isochrone mapping of the right and left atrium on the Cardiac Pathways
system showing the earliest activation site in the roof of the left atrium.
LAO 40o (a) and RAO 30o (b). The right panel of the pictures shows the
earliest activation signal in the ablation catheter (68 ms early from the
reference catheter). CS: coronary sinus; RV: right ventricle; ABL: ablation
catheter

IHJ-364-02.p65

76

percutaneously using the subclavian and/or femoral


approach. One reference catheter was positioned in the
coronary sinus (CS) and the other in the right ventricular
(RV) apex. For ablation purposes, a 7 F, 4 mm tip
bidirectional steerable cooled ablation catheter (Cardiac
Pathways, Sunnyvale, CA, USA) was used. The reference
catheters (Cardiac Pathways) have a 6 F fixed curve distal
shaft. The shaft of the CS reference catheter contains nine
1 mm ring electrodes and one 2 mm tip electrode
(interelectrode distance 1 mm), whereas the RV reference
and ablation catheters contain three 1 mm ring electrodes
and one 4 mm tip electrode (interelectrode distance 1 mm).
The reference catheters are equipped with four ultrasound
transducers; the ablation catheter contains three
ultrasound transducers. The ultrasound transmitter and
receiver device sends a continuous cycle of ultrasound
pulses (558.5 kHz) to the transducers of the reference and
ablation catheters. By measuring the time delay from the
departure of a transmitted ultrasound pulse and the
reception of this pulse at the other transducers, assuming
a speed of sound in blood of 1550 m/s, the distance between
the individual transducers can be calculated. These data
are subsequently transferred to the computer and used to
define the location of the catheter(s) within the reference
frame. Once the 3-D reference frame is established,
triangulation can be used to track the position of additional
transducers.
Because dimensional and structural characteristics of
the catheter are known, it is possible to construct a realtime 3-D graphic representation of the catheters, including
the position of the electrodes and the transducer. As one of
the transducers is positioned distal to the deflection point
of the shaft of the catheter, it is possible to display the curve
of the catheter as well. Furthermore, the real-time position
management system graphically displays the beat-to-beat
movement of the tip of the catheters.
Real-time position management mapping system: The 3-D realtime position management and mapping system (Cardiac
Pathways) uses ultrasound-ranging techniques to
determine the position of a mapping/ablation catheter
relative to two reference catheters. The mapping system
consists of an acquisition module and an ultrasound
transmitter and receiver unit, both connected to a SPARC
20 computer (Sun Microsystems, Palo Alto, CA, USA). The
system is capable of simultaneously processing: (i) seven
position management catheters; (ii) 24 bipolar/48 unipolar
electrogram signals; (iii) 12-lead ECG; and (iv) two pressure
signals. Signals are sampled at 3 kHz per channel with a
resolution of 14 bits. The high-pass filters are set at 30 Hz
and low-pass filters at 500 Hz. Electrograms and catheter

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Indian Heart J 2003; 55: 7577

Gupta et al. Catheter Ablation Using a New Mapping System 77

positions are stored on an optical disk. The original position


of the reference catheters can be displayed on the real-time
window, thereby allowing repositioning of the catheters
after displacement.
The frame rate of this real-time imaging is: (i) Catheter
cartoon: once per cardiac cycle (ii) Luttle ball of ablation
catheter tip: 15 frames/second.
Discussion
Targeting the site of earliest activation preceding the P wave
during tachycardia best ablates focal atrial tachycardia,
regardless of whether it is due to abnormal automaticity,
triggering, or micro re-entry. Pace mapping to match the
surface P wave during tachycardia can be used
adjunctively, 3 but because of the difficulty in clearly
discerning surface P wave morphology, activation mapping
is more accurate.
A mapping system provides additional help in mapping
atrial tachycardia, especially defining the crista terminalis,
which is the commonest site of atrial tachycardia. In
addition, it helps in understanding the breakthrough left
atrial tachycardia by providing the 3-D anatomy of the
atrium. Isochrone mapping usually draws the sequence of
activation within the atrium with the red color showing
the earliest and violet the late activation.
In our case, although the morphology of tachycardia
was suggestive of right atrial origin, successful ablation was
performed in the left atrium. Left atrial tachycardias usually
arise from near the pulmonary veins but, for several
reasons, initial localization can at times be confusing. First,
activation times during tachycardia in the CS are usually
relatively late with respect to many sites in the right atrium
because the CS is inferior and anterior to the pulmonary
veins, which are inserted in the posterior aspect of the left
atrium. Secondly, rapid conduction from left to right over
the Bachmanns bundle may cause a wrong diagnosis of
right atrial origin. Finally, the right superior pulmonary
vein enters the left atrium just behind the superior posterior
right atrium.
Ultimately, one must identify a site of earliest activation
which precedes P wave onset by more than 30 ms for
successful ablation.1 In our case, the earliest activation was

IHJ-364-02.p65

77

42 ms from the surface P wave. It is mandatory to map the


other atrium if the earliest activation is less than 30 ms.
However, in our case, we did left atrial mapping despite a
good signal in the right atrium to rule out any possibility
of breakthrough left atrial tachycardia.
Although the isochrones and point map depend upon
the earliest activation signal from the surface ECG, making
the activation sequence map does help in localizing the
discrete point. The advantage of the Cardiac Pathways
system over the Carto and other 3-D mapping systems is
that it also indicates the catheter position during mapping;
therefore, it guides catheter manipulation during mapping
and, secondly, availability of the ghost catheter during
ablation, which makes a very appropriate site for focal
ablation and reduces the chances of edema formation
around the site of origin by avoiding burns in the
surrounding area. In addition, the catheters can be re-used
to save the cost of the procedure in developing countries
such as India. It also significantly reduces the fluoroscopic
time as with other electroanatomic mapping systems.
Conclusions: The Cardiac Pathways mapping system
helps in the precise location of ablation of atrial
tachycardia. Our initial experience with this new mapping
system is good. However, its efficacy needs to be evaluated
in more patients.
References
1. Walsh EP, Saul JP, Hulse JE, Rhodes LA, Hordof AJ, Mayer JE, et al.
Transcatheter ablation of ectopic atrial tachycardia in young patients
using radiofrequency current. Circulation 1992; 86: 11381146
2. Kay GN, Chong F, Epstein AE, Dailey SM, Plumb VJ, et al.
Radiofrequency ablation for treatment of primary atrial tachycardias.
J Am Coll Cardiol 1993; 21: 901909
3. Tracy CM, Swartz JF, Fletcher RD, Hoops HG, Solomon AJ, Karasik
PE, et al. Radiofrequency catheter ablation of ectopic atrial
tachycardia using paced activation sequence mapping. J Am Coll
Cardiol 1993; 21: 910917
4. Kottkamp H, Hindricks G, Breithardt G, Borggrefe M. Threedimensional electromagnetic catheter technology: electroanatomical
mapping of the right atrium and ablation of ectopic atrial tachycardia.
J Cardiovasc Electrophysiol 1997; 8: 13321337
5. Eldar M, Fitzpatrick AP, Ohad D, Smith MF, Hsu S, Whayne JG, et al.
Percutaneous multielectrode endocardial mapping during ventricular
tachycardia in the swine model. Circulation 1996; 94: 11251130

5/6/2003, 10:05 AM

78 Kothari
et al.
Brief
Report

Indian Heart J 2003; 55: 7880

An Infant with Dying Spells

An Infant with Dying Spells


Shyam S Kothari, Ambuj Roy, Sanjiv Sharma, Anil Bhan
Cardiothoracic Centre, All India Institute of Medical Sciences, New Delhi

A 45-day-old infant presented with the unusual and intriguing symptom of episodic crying and loss of
consciousness. The infant was discovered to have a vascular compression of the trachea by the innominate
artery, almost serendipitously. He was cured of his symptoms by anterior suspension of the innominate artery.
(Indian Heart J 2003; 55: 7880)
Key Words: Vascular ring, Apnea, Aortopexy

ascular rings and slings in infants usually present as


stridor, feeding difficulties, and recurrent aspiration.
Vascular compression of the trachea by the innominate
artery is rare. It may present with one of these symptoms
or, more dramatically, as reflex apnea. We report such a
case to highlight a rare but curable cause for recurrent
apneic spells.
Case Report

A 45-day-old infant was brought with a history of


recurrent episodes of unconsciousness and apnea triggered
usually (but not exclusively) by crying. He was born at full
term, after an unremarkable pregnancy in a primigravida,
and had an Apgar score of 8/10 at birth. There was no
history of fever, jitteriness, feeding difficulties, seizures,
cyanosis, or stridor, and the baby was otherwise healthy.
The infant had had several episodes of unconsciousness and
apnea since he was 15 days old and was feared dead during
these spells, but would recover spontaneously within 12
minutes.
On examination, his weight was 4.5 kg, and heart rate
120 per minute, regular. His mental and motor milestones
were normal. There were no dysmorphic features. He had
situs inversus, and a pansystolic murmur. The chest X-ray
showed mild cardiac enlargement, situs inversus, and
normal lung fields. Detailed echocardiographic assessment
revealed situs inversus, corrected transposition of the great
vessels (i.e. atrioventricular and ventriculoarterial
discordance), a small ventricular septal defect, and mild
pulmonic stenosis. The electrocardiogram (ECG)
Correspondence: Dr Shyam S Kothari, Department of Cardiology,
Cardiothoracic Centre, All India Institute of Medical Sciences, New
Delhi 110029. e-mail: kotharis@del2.vsnl.net.in

IHJ-441-03.p65

78

demonstrated situs inversus but was otherwise


unremarkable. The electroencephalogram (EEG) and CT
scan of the head were normal.
A seizure disorder, complete heart block, or cyanotic
spells were suspected in view of the history and cardiac
disorder. Breath-holding spells were also considered.
Routine blood chemistry was within normal limits. In the
hospital, the infant was observed to have episodes of crying
and distress followed by apnea and progressive bradycardia,
and even asystole. Two of the episodes required brief
assisted ventilation and cardiac massage. Cardiac
catheterization confirmed the cardiac lesions but could not
explain the symptoms. An aortic angiogram revealed an
L-posed aorta with a slightly medial origin of the
innominate artery (Fig. 1). In the course of illness, a repeat
chest X-ray demonstrated hyperinflated lung fields. In view
of this finding, a chest CT scan was done which revealed a
right aortic arch with anterolateral tracheal compression
by the left-sided innominate artery 1 cm above the carina
(Fig. 2). Cinefluoroscopy confirmed compression of the
trachea at the level of the innominate artery. The infant
underwent aortopexy and left innominatepexy for the relief
of tracheal compression. The left innominate artery and
the aortic arch were plicated to the second costal cartilage.
Subsequently, he has had no recurrence of symptoms and
was doing well at six months follow-up.
Discussion
The absence of stridor in our patient delayed the correct
interpretation of reflex apnea due to tracheal compression
by the innominate artery. Innominate artery compression
is a rare cause of airway obstruction in infants. The
anomalous innominate artery compression syndrome was
first described by Gross and Neuhauser 1 in 1948 as

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Indian Heart J 2003; 55: 7880

Fig. 1. Aortic angiogram shows L-posed aorta but is otherwise unremarkable.


In retrospect, the innominate artery is seen to arise more medially.

Fig. 2. Contrast-enhanced CT scan of the chest 1 cm above the carina showing


tracheal compression by the innominate artery. Note the flattened, trifoliate
appearance of the trachea (arrow).

consisting of cough, stridor, and occasionally apnea. Other


authors24 have subsequently reported abnormal origin and
course of the innominate artery as a cause of airway
compression, with relief of symptoms following
decompressive surgery. However, some authors 5 have
disputed the role of the innominate artery in causing
symptoms in these children, and believe that intrinsic
abnormality of the trachea rather than compression by the
innominate artery is responsible for the symptoms. Strife
et al.6 reported that the innominate artery crosses anterior
to the trachea, and produces mild to moderate anterior
indentation of trachea in 30% of normal children without
causing symptoms. Mustard et al.7 found that only 39 out
of 285 children with innominate artery compression had

IHJ-441-03.p65

79

Kothari et al. An Infant with Dying Spells 79

symptoms marked enough to warrant surgery. Thus, the


innominate artery probably crosses the trachea in almost
all infants, but few children actually have tracheal
compression, and even fewer have symptoms requiring
intervention. Why only some children have symptoms of
compression is not known. A tight or crowded mediastinum
and esophageal dilatation due to any cause are some of the
reasons postulated. The syndrome has been associated with
the presence of congenital heart disease as well as
esophageal atresia. The usual symptoms reported due to
innominate artery compression are stridor, respiratory
distress, recurrent lower respiratory tract infections, and
reflex apnea. Apnea is thought to be due to reflex respiratory
arrest initiated by compression of the trachea. This may
occur as a result of a large bolus of food passing through
the esophagus or from accumulation of secretions in the
tracheobronchial tree. The symptoms are maximal during
infancy with gradual improvement by 2 years of age. The
improvement is probably due to strengthening of the
airways by increased cartilaginous support and cephalad
displacement of the aorta.
The diagnostic modalities are a lateral X-ray that may
show an anterior indentation of the tracheal air column.
In suspected cases MRI imaging confirms the diagnosis, and
is the imaging modality of choice, though a CT scan also
provides adequate information, as in our case. Recently, cine
MRI has been reported to be useful for dynamic imaging of
tracheal compression by the innominate artery.8 Barium
swallow is not helpful because the compression is located
anteriorly. The diagnosis can be further confirmed by
bronchoscopy, which shows anterior tracheal compression
12 cm proximal to the carina. The area of compression is
pulsatile and, when levered anteriorly by the tip of the
endoscope, leads to diminution of the corresponding radial
pulse.
Surgical correction of compression is usually by
suspension of the innominate artery to the undersurface
of the sternum by a row of braided Dacron sutures
(innominatepexy), though some surgeons prefer its
reimplantation lower down the aortic arch. Surgical
outcomes have been excellent in judiciously selected cases
of innominate artery compression.2
References
1. Gross RE, Neuhauser EBD. Compression of the trachea by an
anomalous innominate artery: an operation for its relief. Am J Dis
Child 1948; 75: 570574
2. Hawkins JA, Bailey WW, Clark SM. Innominate artery compression
of the trachea. Treatment by reimplantation of the innominate
artery. J Thorac Cardiovasc Surg 1992; 103: 678682
3. Fearon B, Shortreed R. Tracheobronchial compression by congenital
cardiovascular anomalies in children. Ann Otol 1963; 73: 949969
4. Schuster T, Hecker WC, Ring-Mrozik E, Mantel K, Vogl T. Tracheal

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Indian Heart J 2003; 55: 7880

80 Kothari et al. An Infant with Dying Spells


stenosis by innominate artery compression in infants: surgical
treatment in 35 cases. Prog Pediatr Surg 1991; 27: 231243
5. Fletcher BD, Cohn RC. Tracheal compression and the innominate
artery: MR evaluation in infants. Radiology 1989; 170:
103107
6. Strife JL, Baumel AS, Dunbar JS. Tracheal compression by the
innominate artery in infancy and childhood. Radiology 1981; 139:
7375

IHJ-441-03.p65

80

7. Mustard WT, Bayliss CE, Fearon B, Pelton D, Trusler GA. Tracheal


compression by the innominate artery in children. Ann Thorac Surg
1969; 8: 312319
8. Faust RA, Rimell FL, Remley KB. Cine magnetic resonance imaging
for evaluation of focal tracheomalacia: innominate artery
compression syndrome. Int J Pediatr Otorhinolaryngol 2002; 65:
2733

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Indian Heart J 2003; 55: 8187

Kar et al. LMWH in Coronary


Interventions
81
Current
Perspective

Low-Molecular-Weight Heparins in Percutaneous


Coronary Interventions
AK Kar, I Dutta
Department of Cardiology, Institute of Postgraduate Medical Education and Research, Kolkata

ow-molecular-weight heparins (LMWHs) represent a


major advancement in the management of patients
with acute coronary syndrome (ACS) or as part of the
strategy in candidates undergoing coronary interventions.
LMWH are derived from unfractionated heparins (UFH) by
chemical or enzymatic depolymerization. They have a mean
molecular weight of 40005000, as compared to UFH
which have a mean molecular weight of 15 000 (5000
30 000). UFH inhibit Factors Xa and IIa in a ratio of 1:1,
whereas LMWH inhibit Factors Xa and IIa in ratios between
4:1 and 2:1, depending on their molecular weight. LMWH
potentiate antithrombin (AT) III activity, but are relatively
less efficient in binding thrombin, and thus lead to a higher
ratio of anti-Factor Xa activity to anti-Factor IIa
(antithrombin) activity. The anti-Factor Xa activity is
particularly important, as it can prevent thrombin
generation and interrupt feedback amplification of
thrombin production. The thrombin-binding activity of
heparin lies primarily in the higher weight glycosaminoglycan chains; therefore, the anti-Factor Xa/antiFactor IIa ratio of various LMWH varies according to the
molecular size of the subfractions they contain. The lesser
antithrombin effects of LMWH lead to less prolongation of
the activated partial thromboplastin time (aPTT) than UFH;
thus, there is no need for aPTT monitoring during
therapeutic use of LMWH. LMWH are more resistant to
Factor IV-mediated inhibition of heparin activity and do
not produce the same degree of platelet activation as UFH.
The important pharmacologic characteristics that
distinguish LMWH from UFH include: greater
bioavailability; minimal plasma protein and vessel wall
binding; more predictable and durable anticoagulant
response (T 24 times that of UFH); ease of subcutaneous
or intravenous administration; and inhibition of acutephase release of von Willebrand factor in ACS.
LMWH have earned their place and established their
superiority over UFH in the management of post-surgical
deep vein thrombosis1,2 and ACS, including unstable angina
(UA) and non-Q wave myocardial infarction (NQMI).3,4 The
Efficacy and Safety of Subcutaneous Enoxaparin in NonCorrespondence: Professor AK Kar, 82A, Chowringhee Road,
Kolkata 700020. e-mail: drkar2002@yahoo.co.in

IHJ-365-02.p65

81

q-wave Coronary Events (ESSENCE) study 5 showed


enoxaparin plus aspirin to be superior to UFH plus aspirin
in patients with ACS. The need for urgent revascularization
was significantly lower in the enoxaparin group. The
Heparin and Aspirin Reperfusion Therapy (HART II) study6
showed that enoxaparin was as effective as UFH as an
adjunct to thrombolysis with tissue plasminogen activator
(TPA), with a trend towards higher recanalization rates and
less reocclusion at 5 or 7 days. Thus, several trials have
shown that the LMWH enoxaparin offers the practical and
potential pharmacologic advantages over UFH in multiple
applications, and logically should also provide a similar
benefit during percutaneous coronary intervention (PCI).
However, during coronary and noncoronary
interventions, UFH is conventionally used more frequently
than LMWH. This is largely due to the fact that interventional
cardiologists are sceptical about the efficacy of acute
anticoagulation with LMWH. Furthermore, reversibility of
the action of heparin is far more prompt and accurate with
protamine in case of UFH than with LMWH. Clinicians are
also concerned about the safety of a combination of LMWH
with glycoprotein (Gp) IIb/IIIa inhibitors, and the safety of
transition to the catheterization laboratory in patients who
have already received LMWH on the floor.
From 1994 to 1998, four clinical trials using LMWH
during or after PTCA were published710 (their results are
summarized in Table 1), the most recent being the National
Investigators Collaborating on Enoxaparin (NICE) trials 1,3
and 4 (Table 2). The use of LMWH eliminates the need for
continuous IV infusion, anticoagulation monitoring, and
dose adjustment associated with UFH.
Data from randomized, controlled clinical trials11,12
support the administration of LMWH and/or platelet Gp
IIb/IIIa blockade in patients who present with non-STelevation ACS. Despite evidence-based support for
administering LMWH and/or Gp IIb/IIIa receptor blockers
to patients undergoing PCI and those presenting with ACS,
algorithms for integrating these agents into clinical practice
have not been determined. The NICE trials have evaluated
this issue in detail, and the results of these trials are likely
to have a major impact on the choice of adjunctive therapy
during PCI.1316

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82 Kar et al. LMWH in Coronary Interventions


Table 1. Clinical trials of LMWH after PTCA
Study

Year

Drug

No. of
patients

Protocol

End-point

Relative
benefits

ERA7
REDUCE8
FACT9
ENTICES10

1994
1996
1997
1998

Enoxaparin
Reviparin
Nadroparin
Enoxaparin

458
612
354
123

R, C, B
R, PC, B
R, PC, B
R, C

Clinical and angiographic restenosis


6 months death and MI plus revascularization
3 months angiographic restenosis
30-day death, MI, revascularization, and stent thrombosis

2% (p=ns)
4% (p=ns)
6% (p=ns)
25%

LMWH: low-molecular-weight heparin; PTCA: percutaneous transluminal coronary angioplasty; R: randomized; B: blinded; C: controlled; PC: placebocontrolled; ns: statistically not significant

Table 2. Overview of National Investigators Collaborating on Enoxaparin (NICE) 4 Study


Inclusion criteria (patients)
Study design
Treatment regimen
Primary end-point
Secondary end-points
Results (%): first 310 patients

PCI (excluding planned rotational atherectomy) for acute coronary syndromes


Multicenter, open-label
Enoxaparin 0.75 mg/kg intravenous bolus, followed by abciximab 0.25 mg/kg intravenous bolus and
12-hour infusion (0.125 g/kg/min)*
Major and minor bleeding post-procedure and need for transfusion
Composite of death, MI, urgent revascularization at 30 days post-PCI, creatine kinase (CK) and CK-MB
elevation at 30 days post-PCI
Hemorrhage
Major (0)
Minor (2.9)
Transfusion (0.6)
Death/MI/urgent revascularization (2.3)

*No further heparin of any type was administered after the procedure and vascular access sheaths were removed 4 hours after the enoxaparin bolus
PCI: percutaneous coronary intervention; MI: myocardial infarction

The NICE Story


In the NICE pilot study, 60 patients undergoing PCI were
randomly assigned to receive either UFH 10 000 U as an IV
bolus with supplemental doses to achieve a target activated
clotting time (ACT) greater than 300 s or enoxaparin 1 mg/
kg IV bolus immediately before PCI. There were no
differences in procedural outcomes or bleeding events
observed between the treatment groups in this small
randomized trial. Levels of Factor IIa activity were
significantly higher in the UFH group, though Factor Xa
activity was similar in the two treatment groups.
The pilot trial experience was expanded in the NICE 1
study in which 828 patients undergoing PCI without
planned use of abciximab were administered enoxaparin
1 mg/kg within 15 min of arterial sheath insertion. All the
patients received aspirin in addition, as an antiplatelet
agent. The incidence of major noncoronary artery bypass
grafting (CABG) related bleeding was 10.5%, and the
composite clinical end-point [death, myocardial infarction
(MI), need for urgent revascularization] at 30 days was
7.9%13,14 (Figs 1 and 2).

IHJ-365-02.p65

82

Fig. 1. Major bleeding incidence with or without events related to CABG and
transfusion requirements up to 30 days post-PCI in the NICE 1 and NICE 4
trials.

This large, multicenter experience suggests that


intravenous enoxaparin in a dose of 1 mg/kg provides
adequate, safe, and effective anticoagulation during PCI,
the antithrombin efficacy (anti-Factor Xa activity) being
similar to UFH administered as an IV bolus of 10 000 U. A

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Indian Heart J 2003; 55: 8187

Fig. 2. Ischemic events up to 30 days post-PCI in the NICE 1 and NICE 4


trials.

comparison of the NICE 1 trial with the stent plus placebo


subgroup (UFH 100 U/kg) of the EPISTENT trial (Figs 3
and 4) provides valuable insights, as both trials are
comparable in size, and the definition of major and minor
hemorrhage used in both are similar. Major non-CABG
bleeding events, ischemic adverse outcomes, death, and
need for urgent revascularization at 30 days were similar
in both. Hence, it can be concluded that enoxaparin 1 mg/
kg IV during PCI is as safe and effective as the contemporary
experience utilizing a weight-adjusted heparin (UFH).

Fig. 3. Major and minor bleeding with and without CABG and requirement for
blood product transfusion in the NICE 1 trial versus the EPISTENT stent plus
placebo cohort; events up to 30 days.

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83

Kar et al. LMWH in Coronary Interventions 83

Fig. 4. Comparison of incidence of death and need for urgent revascularization


up to 30 days in the NICE 1 trial versus the EPISTENT stent plus placebo cohort.

The NICE 4 trial: This trial was the first large-scale


experience with the combination of an LMWH and a
platelet Gp IIb/IIIa antagonist during PCI. Patients
undergoing PCI with a Food and Drug Administration
(FDA),USA-approved device (except rotational
atherectomy) were administered enoxaparin 0.75 mg/kg
as an IV bolus followed by a standard dose of abciximab
(0.25 mg/kg IV bolus followed by 0.125 g/kg/min to a
maximum of 10 g/kg). The reduced dose of enoxaparin
was chosen to simulate the weight-adjusted reduction in
heparin dose used in both the EPISTENT17 and EPILOG18
trials. Approximately 800 patients with an average age of
63 years were enrolled in 11 centers; multivessel PCI was
performed in 52%, and stent deployment in 86%. Vascular
sheaths were removed 4 hours following the enoxaparin
bolus, and periprocedural ACT was not monitored. The
primary end-point of NICE 4 was the incidence of major or
minor bleeding and need for transfusion, secondary
end-points being (i) clinical (death, MI, urgent
revascularization), and (ii) biochemical changes (CK, CKMB elevation) in hospital and up to 30 days post-PCI.
(Table 2).
Remarkably, there was no major non-CABG bleeding in
the first 557 patients and the final analysis revealed a
meager 0.2% incidence. The need for transfusion was also
negligible. Comparing NICE 4 with the EPILOG trial (lowdose weight-adjusted heparin 70 U/kg plus abciximab) and
the EPISTENT trial (stent plus abciximab) cohorts (Fig. 5),
it was observed that a combination of low-dose enoxaparin
0.75 mg/kg and abciximab was safe and associated with a
low incidence of non-CABG related bleeding. Addition of
abciximab to 0.75 mg/kg of enoxaparin bolus was

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84 Kar et al. LMWH in Coronary Interventions

Table 3. NICE 3 study findings: enoxaparin and Gp IIb/IIIa


antagonist for patients with ACS including PCI (n=616)
In-hospital clinical outcomes
Death
MI
Urgent revascularization
Death/MI/urgent revascularization
Bleeding
Major
Minor
Transfusion
Non-CABG
Fig. 5. Incidence of death or urgent revascularization (UR) up to 30 days in
the NICE 4 trial versus the EPISTENT (stent plus abciximab) cohort.

associated with a reduction of periprocedural ischemic


events in the NICE 4 trial compared to the NICE 1 trial.
Interestingly, abciximab-associated thrombocytopenia was
lower in NICE 4 than in studies using abciximab plus UFH
regimens. This might be related to the fact that enoxaparin
is less likely than UFH to cause platelet activation
or aggregation, or that thrombocytopenia may result
from an interaction between abciximab and certain
anticoagulants.17
The NICE 1 and NICE 4 trials demonstrated the safety
and efficacy of enoxaparin alone and in combination with
abciximab for procedural anticoagulation. The NICE 3
study16 investigated the use of enoxaparin with one of the
three Gp IIb/IIIa antagonists (abciximab, tirofiban,
eptifibatide) in patients with ACS (including PCI). It aimed
to assess the safety of this combination in the
catheterization laboratory with respect to bleeding and
practicality of usage.
A total of 660 patients were enrolled with rest angina
of less than 24 hours duration at 46 clinical centers in
Canada and the United States. All the patients received IV
enoxaparin 1 mg/kg b.d., aspirin 162325 mg/day, and a
Gp IIb/IIIa antagonist assigned by the institution at a
standard dose. Clinical outcomes in NICE 3 were
comparable to those of prior studiesthe combination of
enoxaparin and Gp IIb/IIIa antagonist did not result in
excess major non-CABG bleeding events (Table 3). In
addition, the study showed that additional UFH was not
required for the study population treated with enoxaparin
and a Gp IIb/IIIa antagonist during coronary intervention,
and patients on combination therapy could safely undergo
PCI.

IHJ-365-02.p65

84

(%)
0.3
3.4
2.1
5.7
27.9
4.5
25
10.5
1.9

Gp: glycoprotein; ACS: acute coronary syndrome; PCI: percutaneous


coronary intervention; MI: myocardial infarction; CABG: coronary artery
bypass grafting

Enoxaparin and Ticlopidine after Elective Stenting


(ENTICES)Trial10 (Table 4)
Enoxaparin has been shown to be beneficial in patients
requiring coronary stent implantation, and its use in
combination with other antiplatelet regimens in stenting
interventions was evaluated in this trial. One hundred
twenty-three patients scheduled for elective intracoronary
stenting were randomized (in a 2:1 ratio) to a combination
of enoxaparin, ticlopidine, and aspirin; or to a conventional
regimen of warfarin, UFH, dextran, dipyridamole, and
aspirin. The composite clinical end-point of death, MI, stent
thrombosis, CABG, repeat PTCA, and stroke at 30 days was
significantly reduced in enoxaparin-treated patients than
in the conventionally treated group. The incidence of
vascular complications and major hemorrhage requiring
transfusion was much less in enoxaparin recipients. This
trial suggested that a modified antithrombotic regimen
incorporating both antiplatelet and anticoagulant drugs
may offer improved outcomes compared to anticoagulant
therapy alone.
Intracoronary LMWH
In the POLONIA study,19 100 patients from 4 centers with
single lesions (single-vessel coronary artery disease) were
randomized to enoxaparin 10 mg administered
intramurally prior to stent implantation, or systemic
heparinization with 100 U/kg of UFH. Follow-up
angiography at 6 months was performed in all but one
patient. The results showed that local delivery of
enoxaparin resulted in significant reduction in the

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Kar et al. LMWH in Coronary Interventions 85

Table 4. Overview of Enoxaparin and Ticlopidine after Elective Stenting (ENTICES) study
Inclusion criteria of patients

Multicenter, randomized

Treatment regimen
Pre-procedure

Control
Enoxaparin
UFH/warfarin, aspirin 325 mg/day,
Aspirin 325 mg/day,
dipyridamole 75 mg 3 times daily,
ticlopidine 250 mg twice
dextran 100 mg/hour
daily, dipyridamole
Dextran and UFH to maintain ACT
UFH to maintain ACT
at 300350 s
of 300350 s
UFH 2500 U IV bolus 6 hours after
Enoxaparin 3060 mg
sheath removal, then infusion until
subcutaneously twice
prothrombin time 5070 s, dextran
daily for 10 days,
until 2 hours after restarting UFH.
*ticlopidine 250 mg twice
Aspirin, dipyridamole, and warfarin
daily for 1 month
(INR 2.03.0) for 30 days
Death, MI, stent thrombosis, bypass surgery (CABG), and repeat PTCA at 30 days, individually
and the composite of all clinical events, in-hospital hemorrhagic complications

Procedure
Post-procedure

Clinical end-points
Results (%)

Control (n=44)

Enoxaparin (n=79)

p value

5
11
7
9
7
20
16

0
4
0
0
1
5
5

0.13
0.13
0.04
0.02
0.13
0.01
0.05

Death
MI
Stent thrombosis
Bypass surgery
Repeat PTCA
Composite
Hemorrhagic/vascular complications

* The enoxaparin dose was 30 mg, 40 mg or 60 mg in patients weighing <70 kg, 70100 kg and >100 kg, respectively.
UFH: unfractionated heparin; IV: intravenous; ACT: activated clotting time; INR: international normalized ratio; PTCA: percutaneous transluminal coronary
angioplasty

incidence of restenosis and the revascularization rate


compared with systemic heparinization. A few other trials
are also currently evaluating the comparison of local
delivery of enoxaparin before stenting with stenting alone.
Safety Considerations
The most common adverse effects reported are
hemorrhagic complications. In most cases, these are minor
bleeds, e.g. injection site ecchymosis, as would be expected
with subcutaneous injections. In the ESSENCE study,3 for
example, minor bleeding was significantly more common
in patients receiving subcutaneous enoxaparin 1 mg/kg
twice daily, than those receiving IV UFH (18.4% v. 14.2%
at 30 days; p<0.001). There were no significant differences
between the 2 treatment groups regarding the incidence
of major hemorrhage. Similarly, when safety results from
other large clinical trials are considered, major bleeding was
reported in <6.5% of patients with CAD treated with
enoxaparin 1 mg/kg twice daily or 40 mg once daily.3 Thus,
there does not appear to be an increased risk of major

IHJ-365-02.p65

85

bleeding with enoxaparin therapy in patients with ACS.


The other important concern is regarding reversibility
of anticoagulant action. Unlike heparin, the action of
LMWH can only be partially reversed with protamine
(50%). The use of fresh frozen plasma to replenish
coagulation factors has been advocated for LMWH.
Timing of PCI
The validated, weight-adjusted dose of enoxaparin to treat
unstable angina patients also seems to be suitable for PCI
within 8 hours of the last injection. In the study of
Percutaneous coronary intervention after subcutaneous
enoxaparin pre-treatment in patients with unstable angina
pectoris,20 carried out in the department of cardiology and
the haemostasis laboratory of the University Hospital, Paris,
France a total of 451 consecutive patients with UA/NQMI
were treated for at least 48 hours with subcutaneous
enoxaparin (1 mg/kg every 12 hours), cycled at 6 a.m. and
6 p.m. Two hundred ninety-three patients underwent a
coronary angiography within 8 hours of the morning

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86 Kar et al. LMWH in Coronary Interventions

LMWH injection, followed by immediate PCI in 132


patients. PCI was performed without monitoring of
coagulation and without any additional bolus of UF/
LMWH heparin. There were no in-hospital abrupt closures
or urgent revascularization needed in the PCI group. The
incidence of death/MI rates in the PCI group was much
lower than in those not undergoing catheterization. The
30-day major bleeding rate in the PCI group was also less
than in those not undergoing catheterization. Sheath
removal was done with manual or pneumatic compression
more than 10 hours after the morning injection of
enoxaparin. Importantly, enoxaparin was not restarted
after PCI and the patients left the hospital the next morning.
This study convincingly shows that PCI can be
performed safely within 8 hours in patients treated with
LMWH, particularly enoxaparin, without additional
anticoagulation. Whether the time window can be
extended to 12 hours is a matter of debate and is being
currently evaluated in the PEPCI trial (Pharmacokinetic
Study of Enoxaparin in Percutaneous Coronary
Interventions). Presumably, an additional bolus of
anticoagulant may be beneficial in procedures performed
between 8 and 12 hours of the last dose of the LMWH.
Role of Monitoring
The role of coagulation monitoring with the use of LMWH
has also been evaluated in the study from France mentioned
above. 20 Anti-Factor Xa activity was measured from
samples collected immediately before catheterization in all
patients undergoing PCI. However, anti-Factor Xa
measurements, obtained retrospectively, were not used for
decision-making during PCI. During the period of medical
stabilization before catheterization, in elderly patients and
those with renal failure, anti-Factor Xa activity was
measured 4 hours after the third injection, and the dose of
enoxaparin adjusted, aiming at a target value of 0.51.0 U
of anti-Factor Xa. The anti-Factor Xa activity at the time
of catheterization was >0.5 IU/ml in 97.6% of patients,
and it was stable over the 8-hour period after the injection
of enoxaparin. The aPTT was also measured prior to
catheterization and there was a weak but significant
correlation with anti-Factor Xa activity.
From the above study, we can conclude that anti-Factor
Xa activity need not be measured routinely before PCI done
within 8 hours of the last dose of enoxaparin. However, in
elderly patients and those with renal failure receiving a
reduced dose of enoxaparin, anti-Factor Xa measurements
may be beneficial.
Pilot studies are on for monitoring of LMWH in the

IHJ-365-02.p65

86

setting of UA. A panel of assays to measure the tissue factor


clotting time (TiFaCT) is being developed. The tests provide
a functional measure of tissue factor, including its
interaction with platelets and plasma components. The
results can be obtained in 15 min2 hours.
The issue of sheath removal following PCI has been
addressed in the NICE 4 trial, in which the vascular sheath
was removed 4 hours after the enoxaparin bolus dose
without any increased incidence of puncture site
complications. In the study reported from France
mentioned above,20 the vascular sheath was pulled out >10
hours after the last enoxaparin injection.
Conclusions
In present day practice, when interventional cardiology is
making rapid progress every day, it is worthwhile
considering safer and easier adjunctive medications during
the procedure. While UFH has been a trusted companion
of interventionists for years, LMWH can offer an easier and
assuring alternative of anticoagulation without
compromising efficacy. The role of LMWH as an
intracoronary injection for the prevention of stent
complications is under evaluation and, if established, would
certainly be a powerful weapon for the prevention of stent
thrombosis. It is debatable whether the benefits
demonstrated with enoxaparin can be extended to other
LMWH. The US FDA classifies each LMWH as a distinct drug
that cannot be interchanged with another. In the ESSENCE
and TIMI-IIB studies, a combination of enoxaparin plus
aspirin was more effective than that of UFH and aspirin.
Inversely, in the FRIC study, dalteparin plus aspirin did not
demonstrate such superiority. Evidence is also
accumulating regarding the role of enoxaparin as an
antithrombotic in the treatment of acute MI. Selection of
an individual LMWH for a particular indication should
reflect the level of evidence for a the agent in that condition.
Thus, at present, evidence-based considerations favor the
use of enoxaparin in the antithrombotic regimen of
patients undergoing PCI.
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2. Dunn CJ, Goa KL. Enoxaparin. A pharmacoeconomic appraisal of its
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3. Cohen M, Demers C, Gurfinkel EP, Turpie AG, Fromell GJ, Goodman S,
et al. A comparison of low-molecular-weight heparin with

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Antman EM, McCabe CH, Gurfinkel EP, Turpie AG, Bernink PJ, Salein
D, et al. Enoxaparin prevents death and cardiac ischemic events in
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Deutsch E, Cohen M, Radley DR. Safety and efficacy of percutaneous
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Faxon DP, Spiro TE, Minor S, Cote G, Douglas J, Gottlieb R, et al. Low
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Lablanche JM, McFadden EP, Meneveau N, Lusson JR, Bertrand B,
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Zidar JP. Enoxaparin and ticlopidine after elective stenting, the
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12. Kereiakes DJ, Grines C, Fry E, Esente A, Barr L, Matthai W, et al.
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13. Kereiakes DJ, Grines C, Fry E, Barr L, Matthai W, Broderick M, et al.
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14. Young JJ, Kereiakes DJ, Grines CL. Low-molecular-weight heparin
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16. Fergusson JJ, Elliott MA, Bates ER, Cohen M, Every N, Harrington RA,
et al. The use of enoxaparin and IIb/IIIa antagonists in acute coronary
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19. Kiesz RS, Buszman P, Rozek MM,Martin JL, Deutsch E, Gaszewska E,
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88
Shrivastava
Point
of Viewet al. Echocardiographic Anatomy of Atrial Septal Defect

Indian Heart J 2003; 55: 8889

Echocardiographic Anatomy of Atrial Septal Defect:


Nomenclature of the Rims
Savitri Shrivastava, S Radhakrishnan
Department of Congenital and Pediatric Heart Disease, Escorts Heart Institute and Research Centre, New Delhi

Fig. 3. Atrioventricular (AV) and atrial rims on (a) transthoracic echocardiography in the subcostal coronal view, and (b) on transesophageal echocardiography in the 4-chamber view.

Fig. 1. Gross anatomic details of various atrial septal defects.

Fig. 4. Aortic rim seen on (a) transthoracic echocardiography in the parasternal


short-axis view, and (b) on transesophageal echocardiography in the basal shortaxis view.
b

Fig. 2. Superior vena caval (SVC) and inferior vena caval (IVC) rims on (a)
transthoracic echocardiography in the subcostal sagittal view, and (b) on
transesophageal echocardiography in the basal long-axis view.

he accuracy of diagnosis of atrial septal defect (ASD)


by two-dimensional (2-D) echocardiography is well
established, and has been utilized in clinical practice for
almost two decades. However, following the easy availability
of various devices for the closure of ASD, a detailed
anatomy of the ASD and the rims around the defect has
assumed great importance. Two-dimensional echocardioCorrespondence: Dr Savitri Shrivastava, Department of Congenital and
Pediatric Heart Disease, Escorts Heart Institute and Research Centre, Okhla
Road, New Delhi 110 025. e-mail: savitri_sh@yahoo.com

IHJ-366-02.p65

88

graphy, both transthoracic (TTE) and transesophageal


(TEE), can clearly show the anatomy and is used for
selecting cases for device closure of the ASD.13 During the
procedure of device closure, TEE serves as the most
important investigation for proper placement of the device.
However, there is some confusion regarding the
nomenclature of the various rims of ASDs, e.g. the rim in
relation to the aorta has been variously called anterior,
posterior, and inferior. We propose that for clarity,
uniformity and mutual communication the rims should be
designated according to the structure they are related to,
e.g. superior vena caval (SVC), inferior vena caval (IVC),
atrioventricular (AV) septal (rim at the crux), aortic and
atrial rims (rim of the superior wall of the atrium near the
right upper pulmonary vein). The gross anatomic details

5/6/2003, 10:06 AM

Indian Heart J 2003; 55: 8889

Shrivastava et al. Echocardiographic Anatomy of Atrial Septal Defect

of an ASD with all the above-mentioned rims are depicted


in Fig. 1.
The SVC and IVC rims are best visualized on TTE in the
subcostal sagittal view (Fig. 2a), and on TEE in the basal
long-axis view (Fig. 2b). The AV septal and atrial rims are
best visualized on TTE in the subcostal coronal view (Fig.
3a), and on TEE in the 4-chamber view (Fig. 3b). The aortic
rim is best seen on TTE in the parasternal short-axis view
(Fig. 4a) and on TEE in the basal short-axis view (Fig. 4b).
The rim between the IVC and SVC, located to the right and
posterior aspect of the fossa ovalis, is not important in
determining the success of transcatheter closure, and
hence has not been considered.

IHJ-366-02.p65

89

89

References
1. Reddy SCB, Rao PS, Evenko J, Koscik R, Wilson AD. Echocardiographic predictors of success of catheter closure of atrial septal defect
with the buttoned device. Am Heart J 1995; 129: 7686
2. Rosenfeld HM, Velde MEV, Sanders SP, Colan SD, Parness IA, Lock
JE, et al. Echocardiographic predictors of candidacy for successful
transcatheter atrial septal defect closure. Cathet Cardiovasc Diagn
1995; 34: 2934
3. Magni G, Hijazi ZM, Pandian NG, Delabays A, Sugeng L, Laskari C,
et al. Two-dimensional and three-dimensional transesophageal
echocardiography in patient selection and assessment of atrial septal
defect closure by the new DAS-Angel Wings Device: initial clinical
experience. Circulation 1997; 96: 17221728

5/6/2003, 10:06 AM

90 Anandaraja et al.
Migration of
Cardiovascular
Images

Indian Heart J 2003; 55: 9091

Proximally Detached Pacemaker Lead

Unusual Migration of Proximally Detached Pacemaker


Lead into the Coronary Sinus
S Anandaraja, N Naik, R Yadav, R Juneja, KK Talwar
Department of Cardiology, All India Institute of Medical Sciences, New Delhi

Fig. 1. Right anterior oblique view (a) and left anterior oblique view (b) showing migrated pacemaker lead in the coronary sinus (arrow). Also visible is a proximally
severed unipolar lead (white arrowhead), and another detached pacemaker lead lying freely within the right atrium (bold arrow). The white arrow indicates the new
pacemaker lead.

72-year-old man had been implanted in 1976 with a


unipolar VVI pulse generator in the right pectoral
pocket for symptomatic complete heart block. The patient
subsequently received a new pulse generator and pacing
lead (both bipolar) in 1991 when the previous generator
had exhausted its battery. This time, the pacemaker was
placed in the left pectoral pocket. The previous generator
was removed although the pacemaker lead was capped and
retained. In 1996, the patient required a new pulse
generator, which was connected to the bipolar pacing lead.
In 1998, there was a fracture of this bipolar pacing lead
resulting in pacing failure. Attempts to remove this lead by
manual traction were unsuccessful, and it was severed at
its entrance into the venous system and sutured to the
pacemaker pocket. Hence, all the pacemaker leads
implanted so far had been retained.
In December 2001, the unipolar lead retained in the
right pectoral pocket spontaneously extruded through the
skin. A local physician tried to extract this lead by traction.
Correspondence: Dr KK Talwar, Department of Cardiology, All India
Institute of Medical Sciences, New Delhi 110029.

IHJ-Images.p65

90

This, however, resulted in fracture of the lead, and a part


of its distal end was retained, anchored to the right
ventricular wall. Six months later, the patient had
pacemaker extrusion from his left pectoral pocket after local
trauma to the pacemaker pocket. The pulse generator was
removed and the infected lead detached, proximally cut
near its entrance into the venous system and retained in
the pacemaker pocket. After a week of antibiotic therapy
the patient was taken up for pacemaker implantation from
the right pectoral side. However, the superior vena cava
(SVC) was blocked and collateral channels connected the
innominate vein to the SVC. It was noticed that the bipolar
lead that had been detached and retained in the pocket a
week back had slipped into the SVC while the previously
implanted permanent pacemaker lead had also got
detached from the pocket and was lying freely in the right
atrial cavity. A left subclavian angiogram (by a catheter
inserted from the femoral vein) demonstrated a collateral
channel draining into the SVCright atrial junction.
Pacemaker lead implantation was attempted from this site
at a second sitting, which was successful and without any
untoward effect. Fluoroscopy repeated during this period

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Indian Heart J 2003; 55: 9091

Anandaraja et al. Migration of Proximally Detached Pacemaker Lead 91

on different days showed a marked migration of these


detached pacemaker leads. Sites of migration included the
inferior vena cava (IVC) and the coronary sinus (Fig. 1a
and b). The patient was advised surgical extraction of the
pacemaker leads, which he refused.
Proximal detachment of the pacemaker lead from its
pectoral pocket is a rare complication that produces lead
migration. This usually occurs if there is concomitant
infection or if the leads are cut short and allowed to
retract.1,2 Although such leads are usually secure, it is not
unusual for sutures to cut through in the presence of local
infection. This allows the lead to slip into the vascular cavity
from where it is prone to migration. Such leads usually
migrate into the IVC or the hepatic veins. This preferential
localization of pacing leads to the lower half of the body is
probably related to their higher specific gravity, due to their
metallic content. However, body position also plays a role
in lead migration and these leads can migrate to unusual
sites. Lead migration into the main and peripheral
pulmonary arteries is reported in the literature.1,2,3 In one
report, the free end of the lead perforated the atrial septum
and caused cerebral embolism.4
In our patient, the lead migrated to various sites and
radiological examination showed the leads to lie coiled in
the right atrial cavity, at the SVCright atrial junction,
within the IVC and hepatic vein, at different points in time.
Migration was also noted deep within the coronary sinus
at one juncture. To the best of our knowledge, migration
into the coronary sinus has not been described previously.
Such extensive migration of the lead is likely to produce
complications. There have even been case reports of sudden
death when patients with proximally detached pacing leads
were treated only medically. Although autopsy findings are
not available in these reports, it can be presumed that death
was related to lead migration. Leads can conceivably
perforate thin-walled structures, such as the right atrium
and coronary sinus, thereby producing lethal
hemopericardium.
Our patient had other lead-related complications. These
included spontaneous extrusion of one of the pacemaker

IHJ-Images.p65

91

leads 26 years after its implantation. The patient also


developed thrombosis of the SVC and, as collateral channels
were adequate, he did not have any evidence of the SVC
syndrome. The retained leads also interfered with
appropriate sensing due to their electrical activity, and the
pacemaker was programmed to VOO mode to ensure
regular pacing.
Extraction of functionless pacemaker leads can be
accomplished by transvenous techniques or surgically. A
success rate of 94%98% has been reported with
transvenous techniques.5,6 Recently, the North American
Society for Pacing and Electrophysiology (NASPE) has come
up with guidelines for the extraction of functionless
transvenous pacing and defibrillator leads.7 According to
the recommendations, a retained lead that poses an
immediate/imminent threat to the patient is a class I
indication for lead extraction. As lead extraction devices
are not available in our country, the patient was advised
surgical extraction of these leads, which he refused.
References
1. Myers MR, Parsonnet V, Bernstein AD. Extraction of implanted
transvenous pacing leads: a review of a persistent clinical problem.
Am Heart J 1991; 121: 881887
2. Rettig G, Doenecke P, Sen S, Volkmer I, Bette L. Complications with
retained transvenous pacemaker electrodes. Am Heart J 1979; 98:
587594
3. Dalvi BV, Rajani RM, Lokhandwala YY, Sathe SV, Kulkarni HL, Kale
PA. Unusual case of pacemaker lead migration. Cathet Cardiovasc Diagn
1990; 21: 9596
4. Bohm A, Banyai F, Komaromy K, Pinter A, Preda I. Cerebral embolism
due to a retained pacemaker lead: a case report. Pacing Clin
Electrophysiol 1998; 21: 629630
5. Kantharia BK, Kutalek SP. Extraction of pacemaker and implantable
cardioverter defibrillator leads. Curr Opin Cardiol 1999; 14: 4451
6. Wilkoff BL, Bryd CL, Love CJ, Hayes DL, Sellers TD, Schaerf R, et al.
Pacemaker lead extraction with the laser sheath: results of the Pacing
Lead Extraction with the Excimer Sheath (PLEXES) trial. J Am Coll
Cardiol 1999; 33: 16711676
7. Love CJ, Wilkoff BL, Bryd CL, Belott PH, Brinker JA, Fearnot NE, et al.
Recommendation for extraction of chronically implanted transvenous
pacing and defibrillator leads: indications, facilities, training. North
American Society of Pacing and Electrophysiology lead extraction
conference faculty. Pacing Clin Electrophysiol 2000; 23: 544551

5/6/2003, 10:07 AM

Letters
to to
the
92 Letters
theEditor
Editor

Tissue Doppler Echocardiography: A


Need for Review

read with great interest the article Tissue Doppler


Echocardiography: Principles and Applications by
Sengupta et al.1 I am concerned about the increasing
number of papers on tissue Doppler echocardiography
(TDE) appearing in leading medical journals. Tissue Doppler
echocardiography is a clear case of misuse of technology.
It could turn out to be the greatest hoax in cardiology.
Doppler is best suited to study the direction of free-moving
objects. In the case of echocardiography it is mainly used
to study free-moving blood cells (blood flow). It is the
direction of motion that is important; velocity
measurements are secondary. A comparison of flow
Doppler [color flow mapping (CFM)] and TDE will make
things clear.
Doppler studies are primarily for the study of the
direction of motion. The red shift in astronomy, for
example, shows the stars moving away from us, indicating
an expanding universe. Calculation of velocities is
supplementary. The key point to note is that Doppler studies
require a priori knowledge of the direction of motion. In
blood flow there is a definite direction of flow and Doppler
can detect any aberration in this. For example, we have prior
knowledge of the direction of blood flow in the circuit
pulmonary veinsleft atriumleft ventricleaorta.
Suitably directed Doppler interrogation can study and
detect any deviation in this circuit. Myocardial motion is
complex and not amenable to Doppler studies. In cardiac
motion there are translational, rotational, and
deformational movements. Besides, many tissues near the
heart movedue to transmitted cardiac motion, vessel
pulsation, respiratory motion, and involuntary muscle
movements. 2 Doppler interrogation at one point will
represent the resultant of all these movements. At a
particular point we can never predict the resultant vector.
Even if known, the resultant is accurately recorded only if
it is in the line of the Doppler beam. This is due to the
inherent problem of directional bias. It is like measuring
the length of a twisted rod with a straight ruler. Cardiac
motion becomes more complicated in the presence of wall
motion abnormalities. Blood flow is simple and suitable for
Doppler study. Here the projectile motion of free-moving
blood cells in one direction at an instant is studied
In flow Doppler there are definite points of
interrogation, which are the normal and abnormal
orifices. In TDE there are no such definite points. In flow

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92

Indian Heart J 2003; 55: 9296

Doppler there is a unique unidirectional flow in one part of


the cardiac cycle at the current interrogation points. For
example, in mitral valve Doppler interrogation, the unique
directional signal is obtained only in diastole. If there is a
signal in systole it becomes abnormal. In TDE the to-andfro motion (systole and diastole) of a tethered
interconnected syncytium of myocytes is imaged. Such
information is useless. This can even otherwise be seen and
analyzed by B-mode imaging. While in flow Doppler higher
velocities are studied, TDE is used to study lower velocities,
i.e. to study hypofunctioning myocardial segments. Lower
velocities are difficult to appreciate. Higher velocities are
easier to appreciate with the help of aliasing and variance.
Thus, hypofunction is difficult to analyze. The derivations
from flow Doppler allow us to get orifice size, amount of
flow, and pressure gradients, which are clinically of great
importance. Thus, Doppler studies are best suited to study
flow.
Color flow mapping allows us to see what we cannot
see with ultrasonic eyes, hence it is of great value. In TDE
we see more or less what we already see by B-mode, hence
its value is marginal. In CFM the anatomic landmarks are
intact as the color is superimposed on the B-mode image.
In TDE the B-mode is eliminated and the entire picture is
Doppler information resulting in a fuzzy image, and
different anatomic regions are difficult to determine. Tissue
Doppler has been a disappointing imaging modality in
clinical practice. This is due to the basic flaw in the
application of the principles of Doppler. Doppler is best
suited for flow studies and applying it to tissue motion is
unreasonable. In flow Doppler the tissue noise is
suppressed and flow is displayed.2 In TDE it is the other way
round. It is like suppressing the PQRST waves in an
electrocardiogram and displaying the noise. Besides, TDE
is ultrasensitive and so the information gathered is almost
useless (too much false-positive information). In fact,
excellent cardiac waveforms can be obtained by placing the
sample volume even outside the cardiac region! Once the
foundation of a modality is wrong, all derivations tend to
be wrong.
It is time to look at TDE more realistically. As a new
modality of imaging it appears exciting. However, its real
clinical utility is doubtful. TDE does not give any additional
information over conventional modalities. Due to the abovementioned deficiencies it could even give misleading
information. Making diagnostic decisions based on this
faulty application of technology should be unacceptable
to the scientific cardiologist.

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Indian Heart J 2003; 55: 9296

References
1. Sengupta PP, Mohan JC, Pandian NG. Tissue Doppler
echocardiography: principles and applications. Indian Heart J 2002;
54: 368378
2. Maslak SH, Freund JG. Color Doppler instrumentation. In: Lanzer P
(ed). Vascular imaging by color Doppler and magnetic resonance. Berlin,
Heidelberg: Springer-Verlag; 1991. pp.87123

George Thomas
Department of Cardiology
Indira Gandhi Co-operative Hospital, Kochi

Reply

e read with great interest the views and concerns


expressed in the letter regarding the use of tissue
Doppler imaging (TDI). While we greatly admire the
authors intelligent analysis of Doppler and its principles,
we disagree on the technical contents cited in the letter that
argue against the clinical use of TDI. Ever since the start of
basic unidimensional echocardiography, it was known that
cardiac motion was a complex combination of rotation,
translation, and deformation in a three-dimensional (3-D)
format, and its resultant vector was difficult to estimate.
However, measures of cardiac motion and function on Mmode or two-dimensional (2-D) echocardiography were
standardized and became invaluable tools for providing
diagnostic and prognostic information. It was not the
absolute 3-D cardiac motion or displacement that was
quantified by these techniques but how these parameters
changed predictably with disease. The use of Doppler with
regard to tissue motion or strain, like earlier techniques,
till date has centered not on quantifying the absolute
displacement or true vector of cardiac motion but how an
altered velocity profile predicts the presence of disease or
provides reliable prognostic information.1,2
The limitation of Doppler in not providing the true
velocity vector holds true for both blood flow and tissue
motion. Blood flow in the heart and blood vessels has a
complex profile. Red blood cells have a steady flow
component and a series of oscillatory flow components. The
mean flow has a parabolic profile while the pulsating
component causes an oscillatory profile, which varies
between parabolic and blunt. At curves the velocity profiles

Letter-to-Editors.p65

93

Letters to the Editor 93

are disturbed giving rise to secondary flows, which persist


for a finite distance.3 Doppler, when used for flow imaging,
does not show all these components. The color data and
spectral velocities merely represent a part of the true
velocity vector in the direction of the transducer. Thus, in
this regard, application of Doppler for blood flow has the
same limitation as its use in tissue motion. On the contrary,
TDI has a superior signal-to-noise ratio than the
corresponding blood flow technique, thereby requiring
fewer echoes for the estimation of mean velocities at each
pixel location.4
Studies with sonomicrometry (which uses the principle
of speed of sound through the cardiac tissue) have already
been carried out for providing veracity of data, and this is a
direct proof that information obtained by tissue Doppler is
correct and scientifically valid.5 The reasons for sustained
clinical and research interest in recent years resulted from
the unique ability of TDI to provide rapid, incremental
information not available currently by any other technique.
Some of the areas where the use of TDI has been a clear
advantage and which are incontrovertible are listed below.
1. A-mode, M-mode and real-time B-mode detect the
motion of tissue boundaries, which is simply displayed
over the screen. TDI detects and measures the motion
of weaker and more complex echoes from within the
layers of the myocardial wall.1,6 Velocity gradients are
known to exist in different layers of the myocardium,
which are altered in diseased states, and can be detected
by TDI.1
2. Use of TDI and strain-rate imaging have already been
shown to be superior to conventional real-time B-mode
imaging for the interpretation of regional wall motion
abnormalities. 6,7 Distinguishing hypokinesis and
akinesis or dyskinesis by conventional echocardiography
has wide interobserver variability. Routine use of TDI
and strain-rate imaging makes this job simple and
quantitative.2,7
3. Longitudinal motion of the mitral valve annulus by Mmode has been used for assessing systolic and diastolic
LV function. This information is now readily available
by pulsed Doppler TDI and strain-rate imaging.1,2
4. Very high temporal resolution (<4 ms) have provided
an insight into a number of physiologic and pathologic
short-lived events during the cardiac cycle, particularly
in relation to the understanding of myocardial ischemia
and its detection. Assessment of segmental viability by
post-systolic thickening or strain is now an invaluable
tool in clinical practice. 2,8 Similarly, estimation of
regional and global isovolumic phases, and ejection and

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Indian Heart J 2003; 55: 9296

94 Letters to the Editor

5.

6.

7.

8.

filling periods is possible within a single cardiac cycle


from a single point of sample volume, even without the
use of an ECG and phonocardiogram. This is the only
technique that provides temporal data of both phases
of the cardiac cycle simultaneously.
Tissue velocity imaging is an invaluable tool for the
assessment of diastolic dysfunction, and can easily
differentiate normal from pseudonormal patterns of
diastolic dysfunction. Compared to hemodynamic flow
Doppler parameters, it is relatively load-independent and
does not fuse even at high heart rates.1
Strain and strain-rate imaging may cause problems in
clinical use because of noise, angle-dependence and
segments being syncytium, but this seems to be the right
direction in which to proceed.2 Strain-rate imaging data
obtained from Doppler ultrasound has good agreement
with that obtained from magnetic resonance tagging.8
TDI has a distinct advantage with regard to the
assessment of right ventricular function, which is
difficult otherwise because of the complex geometry.9
Several well-conducted studies have shown that the
requirement for resynchronization therapy in heart
failure, optimizing benefits, and follow-up is much better
with tissue velocity imaging compared to conventional
parameters.10

The clinical applications of TDI are expanding and,


despite a learning curve, more and more people are willing
to use it. Some of the benefits listed above are obvious, the
most important being its role in making echocardiographic
techniques and measurements quantitative and less
operator-dependent. It certainly is not a hoax, nor confined
to research laboratories alone. Regular use will change
skeptics into converts.

Letter-to-Editors.p65

94

References
1. Waggoner AD, Bierig SM. Tissue Doppler imaging: a useful
echocardiographic method for the cardiac sonographer to assess
systolic and diastolic ventricular function. J Am Soc Echocardiogr 2001;
14: 11431152
2. Pislaru C, Abraham TP, Belohlavek M. Strain and strain rate
echocardiography. Curr Opin Cardiol. 2002; 17: 443454
3. Evans DH, McDicken WN. Doppler ultrasound physics, instrumentation
and signal processing, 2nd ed. West Sussex: John Wiley and Sons; 2000.
pp. 526
4. Evans DH, McDicken WN. Doppler ultrasound physics, instrumentation
and signal processing. 2nd ed. West Sussex: John Wiley and Sons; 2000.
pp. 345347
5. Gorcsan J 3rd, Strum DP, Mandarino WA, Gulati VK, Pinsky MR.
Quantitative assessment of alterations in regional left ventricular
contractility with color-coded tissue Doppler echocardiography.
Comparison with sonomicrometry and pressurevolume relations.
Circulation 1997; 95: 24232433
6. Anderson T, McDicken WN. Measurement of tissue motion. Proc Inst
Mech Eng [H] 1999; 213: 181191
7. Fathi R, Cain P, Nakatani S, Yu HC, Marwick TH. Effect of tissue
Doppler on the accuracy of novice and expert interpreters of
dobutamine echocardiography. Am J Cardiol 2001; 88: 400405
8. Edvardsen T, Gerber BL, Garot J Bluemke DA, Lima JA, Smiseth OA.
Quantitative assessment of intrinsic regional myocardial deformation
by Doppler strain rate echocardiography in humans: validation
against three-dimensional tagged magnetic resonance imaging.
Circulation 2002; 106: 5056
9. Frommelt PC, Ballweg JA, Whitstone BN, Frommelt MA. Usefulness
of Doppler tissue imaging analysis of tricuspid annular motion for
determination of right ventricular function in normal infants and
children. Am J Cardiol 2002; 89: 610613
10. Sogaard P, Egeblad H, Pedersen AK, Kim WY, Kristensen BO, Hansen
PS, et al. Sequential versus simultaneous biventricular
resynchronization for severe heart failure: evaluation by tissue
Doppler imaging. Circulation 2002; 106: 20782084

Partho P Sengupta, Jagdish C Mohan and


Natesa G Pandian
GB Pant Hospital,Delhi,India and
Tufts University, Boston,USA

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Indian Heart J 2003; 55: 9296

Hypertension and Cancer Mortality:


Is There a Place for Antioxidant
Interventions?

he potential association between hypertension and


cancer mortality has been extensively studied over the
past several years but many aspects of this issue remain
obscure.1 A recently published meticulous meta-analysis
of previously published data concluded that hypertension
is associated with an increased mortality from cancer,
particularly renal cell carcinoma.2 Even though the clinical
implications have not been clearly established, it is
reasonable to assume that elucidation of the underlying
pathophysiologic mechanisms could lead to the
development of effective therapeutic strategies.
Notably, oxidative stress seems to play an important role
in the pathophysiology of various disease states such as
hypertension3,4 and cancer.4,5 Several parameters, which
possibly contribute to the evolution of malignancy in
hypertensives, have been associated with oxidative stress.
In particular, the apoptotic process, which controls cellular
growth, can be triggered by intracellular redox imbalance
caused by oxidant stimuli. Furthermore, it is well known
that oxidative stress leads to deregulation of calcium
metabolism. It has been proposed that the accumulation
of this ion leads to activation of several mitogens and
oncogens. In addition, various vasoactive neurohormones
implicated in the pathogenesis of hypertension, such as
angiotensin II, catecholamines, and insulin, apart from
growth-like effects, have been shown to deteriorate
antioxidant status. Presumably, the observation that
diuretics increase cancer risk might be explained by the fact
that the resulting rise in angiotensin II due to volume
depletion exerts significant mitogenic and oxidative effects.
Finally, factors such as aging, smoking, obesity, and
diabetes, which are often related with hypertension, have
also been found to induce oxidative stress.
In a recent hypothesis paper, Gago-Dominguez et al.6
proposed that lipid peroxidation, which is increased in obese
and hypertensive subjects, is the mechanism responsible,
at least in part, for the increased risk of renal carcinoma in
such individuals. To the best of our knowledge, the
hypothesis that oxidative stress contributes to increased
cancer mortality in hypertensives has not yet been tested.
In several observational studies, plasma concentrations of
antioxidant vitamins were inversely associated with
cardiovascular and cancer mortality.7,8 On the other hand,
the evidence in randomized interventional studies that

Letter-to-Editors.p65

95

Letters to the Editor 95

antioxidant vitamin supplementation can reduce


cardiovascular and cancer mortality is scanty or nonexistent. 9,10 Despite these unpromising results, direct
evidence is lacking regarding the impact of antioxidant
status on creased cancer risk observed in individuals with
elevated blood pressure.
It is worth noting that besides pure antioxidants, several
cardiovascular and antihypertensive drugs have been
proposed to have intrinsic antioxidant properties.11,12 These
include carvedilol,13 propranolol,14 nebivolol,12 captopril,15
losartan, 16 calcium-channel blockers, 17 statins, 18,19
trimetazidine,20 aspirin,21 and others. Moreover, it has been
suggested that the anti-inflammatory action of some of
these drugs correlates with their antioxidant capacity.22 It
is prudent to assume that most of these drugs act on
components of neurohormonal activation or have
metabolic and anti-inflammatory action. As previously
mentioned, neurohormonal processes are able to induce
oxidative stress by themselves. Thus, the study of their effect
on oxidative stress in conjunction with cancer mortality
appears to be difficult because their indirect antioxidant
effect may confound their intrinsic free-radical scavenging
capacity. Despite these difficulties, we believe that such
medications may serve as valuable tools in the research of
antioxidant interventions in this setting. Well-designed,
prospective studies in the near future may further elucidate
the association between these two major diseases, and
delineate the role of antioxidant interventions.
References
1. Stumpe KO. Hypertension and the risk of cancer: is there new
evidence? J Hypertens 2002; 20: 565567
2. Grossman E, Messerli FH, Boyko V, Goldbourt U. Is there an association
between hypertension and cancer mortality? Am J Med 2002; 112:
479486
3. Berry C, Brosnan MJ, Fennell J, Hamilton CA, Dominiczak AF.
Oxidative stress and vascular damage in hypertension. Curr Opin
Nephrol Hypertens 2001; 10: 247255
4. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. 3rd
ed. Oxford: Oxford University Press; 1999
5. Kovacic P, Jacintho JD. Mechanisms of carcinogenesis: focus on
oxidative stress and electron transfer. Curr Med Chem 2001; 8: 773
796
6. Gago-Dominguez M, Castelao JE, Yuan JM, Ross RK, Yu MC. Lipid
peroxidation: a novel and unifying concept of the etiology of renal
cell carcinoma. Cancer Causes Control 2002; 13: 287293
7. Jha P, Flather M, Lonn E, Farkouh M, Yusuf S. The antioxidant
vitamins and cardiovascular disease. A critical review of
epidemiologic and clinical trial data. Ann Intern Med 1995; 123: 860
872
8. Khaw KT, Bingham S, Welch A, Luben R, Wareham N, Oakes S, et al.
Relation between plasma ascorbic acid and mortality in men and
women in EPIC-Norfolk prospective study: a prospective population
study. Euroean Prospective Investigation into Cancer and Nutrition.
Lancet 2001; 357: 657663

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96 Letters to the Editor


9. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study
Group. The effect of vitamin E and beta carotene on the incidence of
lung cancer and other cancers in male smokers. N Engl J Med 1994;
330: 10291035
10. Heart Protection Study Collaborative Group. MRC/BHF Heart
Protection Study of antioxidant vitamin supplementation in 20,536
high-risk individuals: a randomised placebo-controlled trial. Lancet
2002; 360: 2333
11. Landmesser U, Harrison DG. Oxidant stress as a marker for
cardiovascular events: ox marks the spot. Circulation 2001; 104:
26382640
12. Luscher TF, Spieker LE, Noll G, Cosentino F. Vascular effects of newer
cardiovascular drugs: focus on nebivolol and ACE-inhibitors. J
Cardiovasc Pharmacol 2001; 38 (Suppl. 3): S3S11
13. Nakamura K, Kusano K, Nakamura Y, Kakishita M, Ohta K, Nagase
S, et al. Carvedilol decreases elevated oxidative stress in human failing
myocardium. Circulation 2002; 105: 28672871
14. Khaper N, Rigatto C, Seneviratne C, Li T, Singal PK. Chronic treatment
with propranolol induces antioxidant changes and protects against
ischemiareperfusion injury. J Mol Cell Cardiol 1997; 29: 33353344
15. Hayek T, Attias J, Smith J, Breslow JL, Keidar S. Antiatherosclerotic
and antioxidative effects of captopril in apolipoprotein E-deficient
mice. J Cardiovasc Pharmacol 1998; 31: 540544
16. Khaper N, Singal PK. Modulation of oxidative stress by a selective
inhibition of angiotensin II type 1 receptors in MI rats. J Am Coll Cardiol
2001; 37: 14611466
17. Sevanian A, Shen L, Ursini F. Inhibition of LDL oxidation and oxidized
LDL-induced cytotoxicity by dihydropyridine calcium antagonists.
Pharm Res 2000; 17: 9991006
18. Delbosc S, Morena M, Djouad F, Ledoucen C, Descomps B, Cristol JP.
Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase

Letter-to-Editors.p65

96

19.

20.

21.

22.

inhibitors, are able to reduce superoxide anion production by NADPH


oxidase in THP-1-derived monocytes. J Cardiovasc Pharmacol 2002;
40: 611617
Delbosc S, Cristol JP, Descomps B, Mimran A, Jover B. Simvastatin
prevents angiotensin II-induced cardiac alteration and oxidative
stress. Hypertension 2002; 40: 142147
Tselepis A, Doulias P, Lourida E, Glantzounis G, Tsimoyiannis E, Galaris
D. Trimetazidine protects low-density lipoproteins from oxidation and
cultured cells exposed to H2O2 from DNA damage. Free Radic Biol Med
2001; 30: 13571364
Lopez-Farre A, Riesco A, Digiuni E, Mosquera JR, Caramelo C, de
Miguel LS, et al. Aspirin-stimulated nitric oxide production by
neutrophils after acute myocardial ischemia in rabbits. Circulation
1996; 94: 8387
Korantzopoulos P, Galaris D, Papaioannides D, Kokkoris S. Does Creactive protein represent an oxidative stress marker in cardiovascular
diseases? Int J Clin Pract 2003 (in press)

Panagiotis Korantzopoulos
Laboratory of Biological Chemistry, University of
Ioannina Medical School, Ioannina, Greece
Dimitrios Papaioannides
Department of Medicine
Arta General District Hospital
Arta, Greece

5/6/2003, 10:07 AM

Selected Summaries
97
Selected
Summaries

Indian Heart J 2003; 55: 97100

In-Stent Restenosis Treated With Stent-Based Delivery of Paclitaxel


Incorporated in a Slow-Release Polymer Formulation
K Tanabe et al. TAXUS III Trial Investigators. Circulation 2003; 107: 559564
Summary

Comments

The TAXUS III trial was a single-arm, 2-center study


evaluating the feasibility and safety of a paclitaxel-eluting
stent for the treatment of in-stent restenosis (ISR). It
enrolled 28 patients with ISR with a lesion length of <30
mm, 50%99% diameter stenosis in vessels with a diameter
between 3 and 3.5 mm. Patients with acute myocardial
infarction, poor ejection fraction (<30%), recent stroke,
renal dysfunction, or contraindication to antithrombotics
were excluded from the present study. The stent used was
TAXUS NIRx paclitaxel-eluting stent (Boston Scientific
Corporation, USA), with a total load of 1.0 g/mm2 of
paclitaxel incorporated into a slow-release copolymer
carrier system that gives biphasic release an early burst over
the first 48 hours followed by slow release over the next 10
days. Predilatation was performed in all cases, and postdilatation was performed when necessary. All the stents
were 15 mm long and 33.5 mm in diameter. During the
procedure, ACT was kept at > 250 s, and standard
antiplatelet regimen was followed post-procedure.
Angiographic and intravascular ultrasonographic (IVUS)
follow-up was performed at 6 months, and clinical followup at 6 months and 1 year. There were clinical,
angiographic, and IVUS-based end-points. Angiographic
follow-up was available in 25 patients, and IVUS follow-up
in 17. The major adverse cardiac event (MACE) rate was
29% (8 patients; 1 non-Q-wave myocardial infarction, 1
coronary artery bypass grafting, and 6 target lesion
revascularization [TLR]). Two patients underwent
revascularization for restenosis in the gap between 2
paclitaxel-eluting stents, 1 for restenosis for a bare stent
implanted at edge dissection, 1 for anginal symptoms but
no restenosis (diameter stenosis of 32.5%), and in 2 patients
not for restenosis but for incomplete stent apposition/
expansion as detected on IVUS study. One patient had target
vessel occlusion but required no intervention as there were
no symptoms. Binary angiographic restenosis occurred in
4 patients (16%). One patient had restenosis of a bare stent
implanted to cover edge dissection due to implantation of
a paclitaxel-coated stent, and 2 patients had restenosis in
the gap between 2 paclitaxel-eluting stents. Thus, of the 4
restenoses, only 1 occurred in the area of paclitaxel delivery.
The diameter stenosis at follow-up was 30.8%, with an
average in-stent late loss of 0.54 mm. Late loss at the
proximal and distal edges was 0.20 and 0.11 mm,
respectively, Of 17 patients undergoing IVUS, the volume
of neointimal hyperplasia was 20.323.1 mm3. There was
no evidence of positive or negative remodeling in the 6
patients undergoing TLR. Thus, paclitaxel-eluting stent
implantation appears to be safe and potentially effective in
the treatment of ISR.

In the current era, use of stents has improved the safety


and success of percutaneous coronary interventions (PCI)
and even reduced the restenosis rate (BENESTENT and
STRESS trials). However, their use has also brought about
the complex and difficult-to-manage problem of ISR and
repeat TLR. Several pharmacologic and mechanical
approaches have been tried to overcome the problem of ISR
but they have limitations. Plain balloon angioplasty for ISR
leads to a re-restenosis rate of 30%85%, depending on
whether it is a focal restenosis or diffuse ISR. Similarly,
directional coronary atherectomy (re-restenosis rate 60%),
and excimer laser (TLR 41%) have not been of much
benefit. Rotablation and the use of cutting balloon may
have some theoretical advantage but large studies to prove
their efficacy are not available. Only radiation therapy has
been found to be consistently useful till date. A number of
double-blind clinical trials using gamma sources (SCRIPPS,
WRIST, GAMMA-1) and a beta source (START, INHIBIT)
have reported a striking efficacy in preventing re-restenosis
in patients with established ISR (17%34%). A major
problem with brachytherapy, however, has been late stent
thrombosis and late restenosis. Implantation of a new stent
in the irradiated segment and withdrawal of clopidogrel/
ticlopidine have been correlated with late thrombosis.
Preliminary evidence from trials using prolonged
antiplatelet regimens (>3 months) have suggested a marked
reduction in this complication. Another major problem
with brachytherapy is the edge effect. Careful analysis has
suggested that these edge effects may represent a
geographic miss of radiation and this problem can be
substantially ameliorated with careful attention to
registering adequate doses of radiation throughout the
instrumented segment of the coronary artery.
Furthermore, brachytherapy is less accessible, and its
delivery requires special handling. In this context, stentbased local drug delivery have revolutionized the field of
PCI. Smith et al. reported use of sirolimus-eluting stents in
15 patients with ISR; at 4 months, MACE occurred in 6.7%
(1/15) cases. One patient died suddenly, and late occlusion
occurred in another. In-stent late loss was 0.02 mm, and
on IVUS, neointimal hyperplasia was 7.80.03 mm2. In
the present study using paclitaxel-coated stents, although
the technical re-restenosis rate is 16%, actual restenosis
occurred in only 1 patient. Similarly, the occurrence of late
loss (0.54 mm) and neointimal hyperplasia (20.3 mm2) was
low. However, these studies are too small and do not have a
placebo arm. Nevertheless, it does seem that drug-eluting
stents may be of use in the therapy of ISR.

IHJ-Selected Summary.p65

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98

Indian Heart J 2003; 55: 97100

Selected Summaries

Major Outcomes in High-Risk Hypertensive Patients Randomized to AngiotensinConverting Enzyme Inhibitor or Calcium-Channel Blocker v. Diuretics
The ALLHAT Collaborative Research Group. JAMA 2002; 288: 29812997
Summary
The Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT) was a randomized,
double-blind, active controlled, clinical trial conducted with
a view to determine which antihypertensive treatment
decreased the risk of coronary artery disease (CAD) or other
cardiovascular disease (CVD) events. It enrolled 33 357
hypertensive subjects, both men and women, >55 years of
age, with at least one other risk factor for CAD from 623
North American centers. The patients were randomized to
receive chlorthalidone 12.525 mg/day (n=15 255),
amlodipine 2.510 mg/day (n=9048), or lisinopril 1040
mg/day (n=9054), and followed up for 8 years. The primary
end-point was a combination of CAD deaths plus nonfatal
myocardial infarction (MI). The secondary end-points were
all-cause mortality, stroke, combined CAD end-point (CAD
death, nonfatal MI, coronary revascularization, or angina
requiring hospitalization), and combined CVD (combined
CAD end-point, stroke, treated angina without
hospitalization, CHF and peripheral arterial disease). At a
mean follow-up of 4.9 years, the primary outcome of CAD
death plus nonfatal MI was not different in any of the
treatment groups. Compared with chlorthalidone (6-year
rate, 11.5%), the relative risks (RRs) were 0.98 (95% CI:
0.901.07) for amlodipine (6-year rate, 11.3%) and 0.99
(95% CI: 0.911.08) for lisinopril (6-year rate, 11.4%).
Similarly, all-cause mortality was also not different.
Chlorthalidone was more effective in controlling systolic
BP as compared to amlodipine and lisinopril (p<0.05 for
both). On the other hand, amlodipine was more effective
in lowering the diastolic BP (p<0.01). Among the
secondary end-points, occurrence of CHF was commoner
in the amlodipine group as compared to the chlorthalidone
group (10.2% v. 7.7%, RR 1.38; 95% CI: 1.251.52).
Similarly, combined CAD end-points (33.3% v. 30.9%, RR
1.10; 95% CI: 1.051.16), stroke (6.3% v. 5.6%, RR 1.15;
95% CI: 1.021.30), and CHF (8.7% v. 7.5%, RR 1.19; 95%
CI: 1.071.31) were all higher in the lisinopril group
compared to chlorthalidone group. The authors concluded
that diuretics are superior to amlodipine or lisinopril in
reducing the cardiovascular morbidity and are much less
expensive.

controls the blood pressure but also reduces cardiovascular


morbidity and, even more importantly, mortality, without
causing side-effects. The cost of drug therapy is also
important, especially because it has to be continued lifelong.
Classically, diuretics and beta-blockers have been
considered drugs of first choice, primarily because of their
effect in reducing mortality. However, these drugs are not
without side-effects, and are besieged with the problems of
diuresis, impotence, and depression, as well as dyslipidemia
and metabolic abnormalities. Angiotensin-converting
enzyme inhibitors (ACE-I) have emerged as a credible
alternative because of their efficacy and ability to prevent
complications such as the progression of renal disease and
stroke. However, till date, no large study has shown
reduction in overall mortality with ACE-I. Calcium-channel
blockers (CCB), on the other hand, though efficacious, have
actually shown increased mortality with the use of shortacting ones. Unfortunately, very few large studies have
undertaken head-to-head comparison of various
antihypertensive agents. In this context, the ALLHAT study
is a landmark one. The major finding of this study was a
striking and unequivocal null result in reducing the
primary end-point, i.e. CAD death plus nonfatal MI (except
doxazocin which was discontinued earlier on in the study).
Because of the large number of subjects involved in the
study, the mortality benefit with diuretics, if at all, is likely
to be very small. However, in the context of reduction of
cardiovascular morbidity, therapy with chlorthalidone does
seem superior to that with amlodipine or lisinopril. In fact,
chlorthalidone was found to be superior to even lisinopril
in reducing 6-year CHF rates (8.7% v. 7.7%; CI: 1.071.31),
a risk reduction of 1.19. However, despite being pathbreaking, the study is still fraught with certain limitations.
The blood pressure control achieved was not similar in all
the groups (SBP was better controlled with chlorthalidone,
while DBP was better controlled with amlodipine). Newer
antihypertensive agents such as ramipril, angiotensin
receptor blockers, selective aldosterone antagonists, and
beta-blockers have not been studied. The most important
message from this study is that, as of now, thiazide-type
diuretics should still be considered first-line therapy because
of their excellent efficacy, low long-term morbidity and
mortality rates, and low cost.

Comments
For decades, the search for an ideal antihypetensive has
been on. An ideal antihypertensive is one which not only

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Indian Heart J 2003; 55: 97100

Selected Summaries 99

Long-Term Effects of Spinal Cord Stimulation and Coronary Artery Bypass


Grafting on Quality of Life and Survival in the ESBY Study
O Ekre et al. Electrical Stimulation versus Coronary Artery Bypass Surgery in Severe Angina Pectoris.
Eur Heart J 2002; 23: 19381945
Summary
Electrical Stimulation versus Coronary Artery Bypass
Surgery in Severe Angina Pectoris (ESBY) was a
randomized, prospective, open-comparison study of
coronary artery bypass grafting (CABG) and spinal cord
stimulation (SCS) in patients with severe angina despite
optimal pharmacologic treatment. Prior to ESBY study, SCS
was used in patients for whom revascularization was not
possible. In ESBY study patients were enrolled if angina was
not controlled with anti-anginal agents, and the patients
were eligible for CABG with an increased but acceptable
risk (as per the ACC/AHA, 1991 indications). Patients
enrolled did not have acute myocardial infarction in the
past 6 months, and were intelligent enough to manage the
SCS device. The mean Higgins score (scoring system for
estimation of preoperative risk) was 4.2. The SCS device
was implanted under local anesthesia. The long-term
outcome regarding quality of life and survival of those 104
patients included in ESBY study (19921995) was
investigated. The quality of life was assessed by the
Nottingham health profile (NHP) and quality of life
questionnaire (angina pectoris). The quality of life at 6
months had shown significant improvement compared to
the run-in (p<0.001). This result persisted even up to 4.8
years of follow-up. In the CABG group, however, there was
a deterioration during the postoperative observational
period. Within 6 months of randomization, 1 patient in the
SCS group and 7 in the CABG group died. At 3 and 5 years,
there was no significant difference in mortality between
the two groups. Three years after randomization, 84.9% in
the SCS group and 76.5% in the CABG group were alive.
At 5 years, 75.5% in the SCS group and 68.6% in the CABG
group were alive.Thus, spinal cord stimulation as well as

IHJ-Selected Summary.p65

99

CABG offered long-lasting improvement in quality of life


and survival up to 5 years was comparable between the
groups.
Comments
SCS or epidural spinal electrical stimulation (ESES) has been
used for treatment of refractory angina. The ESBY study
was published in 1998 with 6 months of follow-up, and
had shown no difference between the CABG and SCS arms.
The present study is a long-term follow-up of the ESBY
patients. The mortality rate in this study was similar to that
seen in the angina subpopulation of the Swedish Council
on Technology Assessment in Health Care patients. As
compared with 0.8% mortality seen in CASS trial or 16%
observed in the ECSS study, the mortality is higher in the
present study. However, the patient population of the ESBY
study does not match that of CASS/ECSS studies. The
survival data in the study showed equivalent survival in
both the arms with equal improvement in the quality of
life. As it is a long-term follow-up study, the placebo effect
will not be seen as it decreases with time. However, the exact
mechanism of benefit is unknown. The antianginal effect
is secondary to an anti-ischemic effect, which in turn seems
to be due to a reduction in myocardial oxygen consumption;
however, a redistribution of coronary blood flow cannot
be excluded. Thus, it seems that SCS, being noninvasive and
less traumatic, may be a therapeutic alternative for patients
with severe angina and high risk for bypass surgery. At
present, SCS treatment is costly and technically more
demanding, thereby limiting its use. Further prospective
studies are needed to compare SCS and revascularization
to establish this as an alternative treatment in patients with
refractory angina.

5/6/2003, 10:08 AM

Indian Heart J 2003; 55: 97100

100 Selected Summaries

Eplerenone, a Selective Aldosterone Blocker, in Patients With Left Ventricular


Dysfunction After Myocardial Infarction
B Pitt et al. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy And
Survival Study (EPHESUS) Trial Investigators N Engl J Med 2003; 348: 13091321
Summary
Eplerenone is an aldosterone antagonist that selectively
inhibits the mineralocorticoid receptors, leaving the
glucocorticoid, progesterone or androgen receptors
unaffected. Its selective action is beneficial in preventing
side-effects such as sexual dysfunction and gynecomastia
that are encountered with the nonselective blockade
provided by spironolactone. This study is a multicenter,
international, randomized, double-blind, placebocontrolled trial that included patients with acute
myocardial infarction (time to randomization 314 days)
and left ventricular dysfunction (LVEF <40%) with clinical
heart failure, except in diabetics in whom the symptoms of
heart failure did not have to be demonstrated. Exclusion
criteria were the use of potassium-sparing diuretics, a
serum creatinine level of 2.5 mg/dl or above, and a serum
potassium concentration of >5 mmol/L. The potassium
level was monitored on subsequent follow-up visits. Six
thousand six hundred forty-two patients were randomized
to eplerenone (25 mg/day initially, titrated to a maximum
of 50 mg/day; 3319 patients), or placebo (3313 patients).
The study continued until 1012 deaths occurred. At
baseline, the 2 groups were not significantly different and
were receiving optimal medical therapy including ACE
inhibitors or angiotensin-receptor blockers (87%), betablockers (75%), aspirin (88%), and diuretics (60%).
The primary end-points were death from any cause and
death from cardiovascular causes, or first hospitalization
for a cardiovascular event including heart failure, recurrent
acute myocardial infarction (AMI), stroke, or ventricular
arrhythmia.
In the mean follow-up period of 16 months, 478 deaths
occurred in the eplerenone group (14.4%) and 554 deaths
in the placebo group (16.7%) (relative risk [RR] 0.85;
p=0.008). Of these deaths, 407 in the eplerenone group
and 483 in the placebo group were attributed to
cardiovascular causes (RR: 0.83; p=0.005), which
included sudden cardiac death, acute myocardial
infarction, and heart failure. The reduction in risk of sudden
death from cardiac causes was statistically significant (RR
0.79; p=0.03). There was a relative reduction of 15% in
the risk of hospitalization for heart failure and there were
23% fewer episodes of hospitalization in those receiving
eplerenone compared to placebo. The rate of death from
any cause or any hospitalization was 8% lower in the
eplerenone than in the placebo group (RR: 0.92; p=0.02).
During the study period, 493 patients in the placebo group
and 528 patients in the eplerenone group discontinued the
drug. There was a significantly greater increase in the
serum creatinine concentration in the eplerenone group
than in the placebo group, but the difference was clinically
small. Serious hyperkalemia occurred in 5.5% of patients
in the eplerenone group, as compared with 3.9% of patients

IHJ-Selected Summary.p65

100

in the placebo group.The incidence of hyperkalemia was


more in patients with a baseline creatinine clearance of
<50 ml/min. Though there were 12 hospitalizations for
serious hyperkalemia in the eplerenone group, there were
no deaths. Three patients in the placebo group were
admitted because of hyperkalemia and there was 1 death.
In conclusion, the study showed that eplerenone
significantly reduces morbidity and mortality in patients
with AMI and LV dysfunction.
Comments
The Randomized Aldactone Evaluation Study (RALES)
proved the importance of aldosterone antagonists in the
management of patients with heart failure. In addition to
reducing mortality by 30%, small doses of spironolactone
resulted in an improvement in the ejection fraction and
enhanced treatment tolerance. It has been shown that
patients with heart failure have high levels of plasma
aldosterone because of increased production and decreased
hepatic clearance. Sustained aldosterone levels promote
endothelial dysfunction and oxidative stress in the
vasculature and also organ fibrosis. The beneficial effect
on ventricular remodeling is evidenced by this study, in
which the relative risk of death was reduced by 15% and
the risk of hospitalization was also reduced by 15%. The
reduction in cardiovascular mortality is mainly due to 21%
reduction in the rate of sudden death due to cardiac causes.
An important point in the EPHESUS trial is that patients
were already receiving optimal therapy (ACE inhibitors in
87% and beta-blockers in 75%). In RALES, beta-blockers
were used in only about 11%, although ACE inhibitors were
given to 94%. One-year mortality among the placebo group
was higher in RALES (25%) as compared with EPHESUS
(13.6%). This difference in mortality may reflect the more
severely depressed systolic function in patients enrolled in
RALES (LVEF averaged 25% in RALES as compared to 33%
in EPHESUS). Taken together, these 2 trials of aldosterone
blockade have enrolled more than 8000 patients with
systolic dysfunction and symptoms of heart failure, and
have shown that the addition of aldosterone antagonists
to these patients can substantially reduce overall mortality
and rate of sudden death. Currently, the guidelines of the
American College of Cardiology and American Heart
Association specify that the use of spironolactone for
patients with mild-to-moderate heart failure has not been
tested. After the RALES and EPHESUS, their beneficial role
in the management of heart failure is quite evident, with
just a little extra effort to monitor the potential side-effects,
especially hyperkalemia. Further studies would determine
whether this class of drugs will prove as efficacious in
patients with less severe symptoms or in those with heart
failure due to diastolic dysfunction.

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Indian Heart J 2003; 55: 101

May 13, 2003, 18th International Meeting on


Clinical Cardiology, Athens, Greece
Contact: Dr P. Toutouzas
Chairman, Organizing Committee
Department of Cardiology
University of Athens, Greece
Tel: 0106401477
Fax: 0106401478

June 2124, 2003, Heart Failure Update 2003,


Strasbourg, France
Contact: European Society of Cardiology
The European Heart House
2035 Route des Colles, Les Templiers BP 179
Sophia Antipolis Cedex 06903, France
Tel: 33 4 9294 7600
Fax: 33 4 9294 7601
e-mail: webmaster@escardio.org

June 2528, 2003, 14th Asian Pacific Congress of


Cardiology (APCC), Singapore, Singapore
Contact: Dr Michael Lim, Chairman, 14th APCC
The Secretariat, 302, Orchard Road
# 16-04, Tong Building, Singapore 238862
Republic of Singapore
Fax: 65 836 0436
e-mail: enquiry@14apcc.com

September 1621, 2003, Transcatheter Cardiovascular Therapeutics 2003, Washington, D.C., USA
Contact: The Course Directors
55 East 59th Street, 6th Floor
New York NY 10022-1112, USA
Tel: 1 212 434 6300
Fax: 1 212 434 6386
e-mail: info@crf.org

Cal of Conference.p65

101

Calendar of Conferences
October 2630, 2003, 69th Annual Scientific
Assembly, American College of Chest Physicians,
Orlando, Florida, USA
Contact: American College of Chest Physicians
3300 Dundee Road, Northbrook IL 60062, USA
Tel: 1 847 498 1400
Fax: 1 847 498 5460

November 25, 2003, 76th Scientific Session,


American Heart Association (AHA), Orlando, Florida,
USA
Contact: American Heart Association
7320 Greenville Avenue, Dallas TX 75231, USA
Tel: 1 214 373 6300
Fax: 1 214 373 3406

December 47, 2003, 55th Annual Conference of


Cardiological Society of India, Kolkata, India
Contact: Dr Asok Kumar Kar, Organizing Secretary
Indian Heart House
P-60, CIT Road, Scheme VIIM,
Kankurgachi, Kolkata 700 054, India
Fax: 033 355 6308
e-mail: csi@cal2.vsnl.net.in

November 710, 2004, 77th Scientific Session,


American Heart Association (AHA), New Orleans,
Louisiana, USA
Contact: American Heart Association
7320 Greenville Avenue, Dallas TX 75231, USA
Tel: 1 214 373 6300
Fax: 1 214 373 3406

5/6/2003, 10:08 AM