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Diagnosis and Management of Left Ventricular
Diastolic Dysfunction in the Hypertensive Patient
Maurizio Galderisi1
The progression of hypertensive involvement toward heart
failure includes myocardial fibrosis and changes of left ventricular
(LV) geometry. In the presence of these abnormalities, diastolic
abnormalities occur and are defined as LV diastolic dysfunction
(DD). They include alterations of both relaxation and filling, precede
alterations of chamber systolic function and can induce symptoms of
heart failure even when ejection fraction is normal. The prevalence
of heart failure with normal ejection fraction (HFNEF) increased
over time whereas the rate of death from this disorder remained
unchanged. In this view, diagnosis, prognosis, and therapeutic
management of DD and HFNEF in hypertensive patients is a growing
public health problem. DD may be asymptomatic and identified
occasionally during a Doppler-echocardiographic examination. This
tool has gained, therefore, important clinical position for diagnosis of
DD. Comprehensive assessment of diastolic function should be done
not by a simple classification of DD progression but by estimating
the degree of LV filling pressure (FP), a true determinant of symptoms
Arterial hypertension is the most common risk factor for heart
failure in the general population.1 The progression of hyper-
tensive left ventricular (LV) involvement toward heart failure
includes serial structural abnormalities (mainly myocardial
fibrosis) and geometric changes of the left ventricle—LV con-
centric remodelling and LV hypertrophy (LVH) with high LV
mass/volume ratio—whose prognostic role is recognized.2–4
In the presence of these abnormalities, parallel abnormalities
of LV diastolic properties occur. These abnormalities are glo-
bally defined as LV diastolic dysfunction (DD). They include
alterations of both relaxation and filling,5,6 precede alterations
of LV chamber systolic function and can per se induce symp-
toms/signs of heart failure even when ejection fraction (EF) is
normal (heart failure with normal ejection fraction (HFNEF)).
Noteworthy, compared to those with reduced systolic func-
tion, patients with HFNEF are more often female, older, and
less predisposed to have coronary artery disease and more
likely to have hypertension.7 The growing interest for DD and
HFNEF rises from the knowledge that ~60% of patients with
heart failure have a normal or near normal EF.7 The prevalence
1Cardioangiology Unit with CCU, Department of Clinical and
Experimental Medicine, Federico II University Hospital, Naples, Italy.
Correspondence: Maurizio Galderisi (mgalderi@unina.it)
Received 22 August 2010; first decision 23 September 2010; accepted 14 October 2010.
© 2011 American Journal of Hypertension, Ltd.
AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 5 | 507-517 | May 2011
STATE OF THE ART
Downloaded from http://ajh.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on November 13, 2014
and prognosis. This can be obtained by different ultrasound
maneuvers/tools but the ratio between transmitral E velocity and
pulsed tissue Doppler–derived early diastolic velocity (E/e′ ratio)
is the most feasible and accurate. The identification of left atrial
enlargement may be useful in uncertain cases. The recommended
management of DD in hypertensive patients should correspond to
blood pressure (BP) lowering and to the attempt of reducing LV mass
and normalizing LV geometry. Prospective studies with well-defined
entry criteria are needed to establish whether this approach could
reflect a better prognosis.
Keywords: arterial hypertension; blood pressure; diastolic dysfunction;
heart failure with normal ejection fraction; hypertension;
left ventricular filling pressure; renin–angiotensin–aldosterone system
American Journal of Hypertension, advance online publication 16 December 2010;
doi:10.1038/ajh.2010.235
of HFNEF has increased over the last 15-year period—it possi-
bly reflects also on the greater number of patients undergoing
Doppler-echocardiographic examination—while the rate of
death from this disorder remained unchanged.8 Accordingly,
diagnosis, prognosis, and therapeutic management of DD and
HFNEF in hypertensive patients is a growing public health
problem.
Physiology of Diastole
The traditional definition of diastole (διαστολε = “expansion”),
includes the part of the cardiac cycle starting at the aortic valve
closure—when LV pressure falls below aortic pressure—and
finishing at the mitral valve closure. A normal diastolic func-
tion is clinically defined as the capacity of the left ventricle to
receive a filling volume and its ability to guarantee an adequate
stroke volume, operating at a low pressure regimen. In descrip-
tive terms, diastole can be divided in four phases:
1. Isovolumetric relaxation: This is the period occurring
between the end of systolic ejection (aortic valve closure)
and the opening of the mitral valve, when LV pressure con-
tinues its rapid fall, while LV volume remains constant.
2. LV rapid filling: This begins when LV pressure falls below
left atrial (LA) pressure and the mitral valve opens. During
this period the blood has an acceleration which achieves
a maximal extent, directly related to the magnitude of
507
STATE OF THE ART
a­ trio-ventricular pressure, and stops when this gradi-
ent ends. This period represents a complex interaction
between LV suction (active relaxation) and visco-elastic
properties of the myocardium (compliance).
3. Diastasis: This occurs when LA and LV pressures are
almost equal and LV filling is essentially maintained by
the flow coming from pulmonary veins—with left atrium
representing a passive conduit—with an amount depend-
ing on LV pressure, function of LV “compliance”.
4. Atrial systole: This corresponds to LA contraction and
ends at the mitral valve closure. This period depends
on LV compliance and, to a lower extent, on pericardial
resistance, atrial force, and atrio-ventricular synchronicity
(electrocardiogram-derived PR interval).
Globally, LV filling is determined by interaction between LV
filling pressure (LVFP) and filling properties, which in turn are
regulated by extrinsic factors (mainly pericardial restraint and
ventricular interaction) and by intrinsic factors such as cham-
ber stiffness (cardiomyocytes and extracellular matrix), myo-
cardial tone, chamber geometry, and wall thickness. Increased
LVFP is the main physio-pathologic consequence of DD. It is
determined by filling and passive properties of LV walls, and
may be additionally controlled by incomplete LV relaxation
and alterations of myocardial diastolic tone. Main morpho-
logical and functional correlates of DD include LV concentric
geometry, LA enlargement and function, and pulmonary arte-
rial hypertension.
Ultrastructural Features of Lv Diastolic
Dysfunction in Arterial Hypertension
The extracellular matrix, corresponding to fibrillar collagen,
is important for both myocardial contraction and relaxation
processes. It facilitates the arrangement of the cardiomyocytes
into the most suitable allocation for the development of force
and shortening, giving a substantial support to the maintenance
of an effective myocardial performance.9 The hypertensive-
derived LV remodelling is accompanied by changes of both
myocardial cell factors and of extracellular matrix where fibrob-
last proliferation, collagen network alteration, and increase
in interstitial/perivascular collagen are strongly promoted by
renin–angiotensin–aldosterone system.10 Extracellular matrix
undergoes an intense turnover due to metalloproteases, proteo-
lytic enzymes activated by several factors including BNP, and
tissue inhibitors counterbalancing the activity of metallopro-
teases.11 Myocardial fibrosis occurs because of an imbalance
where collagen deposition prevails over its degradation. In this
context, the total amount of collagen is not only a main deter-
minant of DD but also distribution, configuration, disorgani-
zation of collagen fibers (crosshatching), and collagen type I/
collagen type III ratio plays an important role.9
508
Diastolic Dysfunction in Arterial Hypertension
Doppler-Echocardiographic Diagnosis
of Lv Diastolic Dysfunction
The physical examination of patients with HFNEF allows to
collect the same signs occurring for systolic heart failure and
even the thoracic X-ray cannot be useful to distinguish the two
entities. Electrocardiogram can show signs of LVH mainly due
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to arterial hypertension. DD may be even asymptomatic and
identified occasionally during a Doppler-echocardiographic
examination. The diagnostic importance of this tool rises from
the high feasibility of transmitral Doppler indexes of diastolic
function (ratio between early (E) and late (atrial-A) ventricular
filling velocity (E/A ratio), deceleration time, isovolumic relaxa-
tion time (IVRT)), shown even in studies on population,12 and
demonstrated to be satisfactory for serial evaluations over time.
This traditional approach permits to recognize normal diastole
as well as to classify the progression of DD from the pattern of
abnormal relaxation (grade I of DD: E/A ratio <1 and prolonged
deceleration time) until pseudonormal (grade II: E/A ratio >1
and intermediate values of deceleration time) and restrictive
patterns (reversible and irreversible, grade III–IV respectively;
E/A ratio >1.5 and shortened deceleration time).13 However, a
modern comprehensive assessment of diastolic function should
be performed not by classifying the progression of DD but by
estimating the degree of LVFP, a true determinant of symptoms/
signs and prognosis of heart failure. In order to achieve this
goal the standard Doppler assessment of mitral inflow can be
enriched with the following maneuvers and/or ultrasound tools:
(i) valsalva maneuver applied to the same mitral inflow pattern,
(ii) pulmonary venous flow pattern (duration of atrial reverse
velocity), (iii) velocity flow propagation (the slope of the first
aliasing velocity during early filling, measured from the mitral
valve to the apex by color M-mode (Vp)), (iv) pulsed tissue
Doppler of the mitral annuls (average of septal and lateral early
diastolic (e′) velocity)14,15 (Table 1). All the indexes obtainable
by these ultrasound evaluations have advantages and limita-
tions. The pulmonary atrial reverse-transmitral A–duration
Table 1 | Noninvasive Doppler echocardiographic estimation
of left ventricular filling pressure
Parameter Normal value Increased LVFP
ΔE/A ratio during valsalva <−50% ≥−50%
ΔAR-A (m/sec) <30 ≥30
E/Vp ratio <2.5 ≥2.5
E/e′ ratio <8 >15
LAVi (ml/m2) <34 ≥34
AR, atrial retrograde velocity; E/A, transmitral ratio between early and late ventricular
filling velocity; E/e′, transmitral early diastolic velocity to pulsed tissue Doppler–derived
annular early diastolic velocity ratio; E/Vp, transmitral early diastolic velocity to velocity
flow propagation ratio; LAVi, left atrial volume index; LVFP, left ventricular filling pressure;
Vp, velocity propagation.
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Diastolic Dysfunction in Arterial Hypertension STATE OF THE ART

difference is relatively age-­independent and enables to identify
patients even with elevated LV end-diastolic pressure but nor-
mal mean LA pressure, an initial stage of LVFP increase. Vp and
pulsed tissue Doppler–derived e′ are relatively load independ-
a Mitral inflow
ent, ­characterize well LV relaxation and can, therefore, be used
to adjust the preload dependence of transmitral E velocity and
to obtain an estimation of LVFP degree. In addition, e′ velocity
is able to “read” the percentage of myocardial fibrosis,16 primum
movens of DD. Vp and E/Vp ratio are limited in hypertensive
patients with LV concentric geometry—which can induce itself

E
b c
Septal mitral annulus Lateral mitral annulus
e’ e’
Figure 1 | Methodology to calculate the ratio between standard Doppler–
derived transmitral early diastolic velocity (E) and pulsed Doppler–derived early
diastolic velocity of the mitral annulus (e′); e′ can be measured either at the
septal site or at the lateral site of the mitral annulus. However, recommendations
on diastolic function encourage the average of septal and lateral e′.
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an increase of Vp—and in those with normal LV volumes and
EF, who may present misleadingly normal Vp despite increased
LVFP. Valsalva maneuver applied to transmitral inflow and
pulmonary venous flow have poor feasibility (60% and 80%,
respectively)17 whereas E/e′ ratio (Figure  1) is performable
in nearly 100% of the patients.17 This index is also accurate in
patients with sinus tachycardia18 and atrial fibrillation19 and
has gained relevance in the clinical practice. The detection of
LA enlargement can add further information in the intermedi-
ate, gray range of E/e′ ratio = 9–14, it being the expression of a
chronic increase of LVFP, but cannot identify a sudden increase
of LVFP.15 Two-dimensional echocardiographic estimation of
LA volume (average of LA volumes in apical 4- and 2-cham-
ber view) reflects LA pressure much better than the simple LA
antero-posterior diameter, has a recognized prognostic value20
and can be used to categorize appropriately the magnitude of
LA enlargement. Accordingly, recommendations for the evalu-
ation of LV diastolic function have introduced LA volume in
the algorithms built for the estimation of LVFP (Figure  2).15
Further information on DD can be obtained by integrated back-

E/e′ ≤8 E/e′ ≤9–14 E/e′ septal ≥15

Septal, lateral, Septal, lateral, E/e′ lateral ≥12
or average or average E/e′ average ≥13

LA volume <34 ml/m2 LA volume ≥34 ml/m2

AR – A <30 ms AR – A >30 ms
Valsalva ∆ E/A <0.5 Valsalva ∆ E/A ≥0.5
PAPs <30 mm Hg PAPs ≥30 mm Hg

Normal LAP Normal LAP ↑ LAP ↑ LAP

Figure 2 | Diagnostic algorithm for the estimation of left ventricular filling pressure in patients with normal ejection fraction. A normal transmitral early diastolic
velocity to pulsed tissue Doppler–derived annular early diastolic velocity ratio (E/e′) ratio (<8) indicates normal invasively estimated left atrial pressure (LAP); an
abnormally increased E/e′ ratio corresponds to pathologically elevated LAP. For intermediate range of E/e′ ratio additional findings are needed: increased left
atrial/LA volume, or pulmonary venous flow derived atrial reverse (AR) velocity-transmitral atrial (A) velocity >30 ms, or reduction (Δ) of transmitral ratio between
early and late ventricular filling velocity (E/A ratio) >0.5, or pulmonary arterial systolic pressure (PAPs) > 35 mm Hg. Modified from Nagueh et al.15

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 5 | may 2011 509

STATE OF THE ART
scatter, whose cardiac cycle–dependent variation is negatively
correlated with the collagen deposition and thus with the extent
of myocardial fibrosis,21,22 and by two-dimensional-derived
speckle tracking echocardiography, which allows to quantify the
multidirectional components of LV deformation (strain) either
in systole or in diastole.23
Lv Diastolic Dysfunction
in the Hypertensive Setting
All these concepts can be largely applied in arterial hyperten-
sion. Although systolic and diastolic function (mitral decelera-
tion index) do not seem to improve the ability of LV mass in
predicting cardiovascular (CV) risk did not improve signifi-
cantly in 5,380 hypertensives (mean follow-up = 3.5 years),24
the simple Doppler transmitral inflow pattern has been tested
successfully in stratifying the hypertensive prognosis in epi-
demiologic studies. In the PIUMA study25 an E/A ratio lower
than that predicted individually by age and heart rate (approxi-
mately a pattern of abnormal relaxation) increased the risk of
CV events (odds ratio 1.57, 95% confidence interval 1.1–2,18, P
< 0.01) in a population of 1,839 hypertensives during a 11-year
follow-up. Of interest, this prognostic value was independ-
ent on the effect of LV mass and 24-h blood pressure (BP).
However, two other large epidemiological studies,26,27 both
assessing populations with high prevalence of hypertension,
revealed the intrinsic limitation of the simple transmitral inflow
assessment with a “U-shaped” prognostic behavior of E/A ratio:
prediction of CV events from E/A ratio <1 (pattern of abnor-
mal relaxation) and >1.5 (likewise restrictive pattern) but no
prognostic value of intermediate range of E/A ratio encompass-
ing either patients with normal or unidentified, pseudonormal
patterns (Figure 3). In the first one, the Cardiovascular Health
study26 (2,671 participants, mean follow-up = 5.2 years), E/A
25
Incidence of heart failure (%)
20
15
10
5 5
0
<0.7
Figure 3 | Incidence of congestive heart failure (left panel, Cardiovascular Heart Study26) and of overall mortality (right panel, Strong Heart Study27) according to
transmitral ratio between early and late ventricular filling velocity (E/A ratio).
510
Diastolic Dysfunction in Arterial Hypertension
ratio <0.7 and >1.5 predicted incident heart failure even after
adjusting for LV mass, age, BP, and level of stress-corrected LV
systolic function. In the second one, the Strong Heart study27
(3,008 American Indians, mean follow-up = 3 years), E/A ratio
<0.6 was associated to a doubled increase of mortality risk—de-
spite not independent on other covariates—while an E/A ratio
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>1.5 was associated to a threefold increase of cardiac mortal-
ity, independent on LV mass and EF. These two studies suggest:
(i) the predisposition of elevated LVFP (restrictive pattern) to
worse outcome, independently on LVH and systolic dysfunc-
tion, (ii) the need of distinguishing pseudonormal from nor-
mal pattern, which occurs when LVFP rises to increase the
early filling caused by impaired relaxation and to maintain
normal cardiac output. In this pseudonormal stage, patients
often asymptomatic or pauci-symptomatic may receive benefit
from more frequent follow-up and aggressive antihyperten-
sive therapy.28 Figure  4 shows the clinical progression of an
old hypertensive patient from a pattern of abnormal relaxation
toward a pseudonormal pattern which was unmasked by using
E/e′ ratio. Of interest, the prognostic value of e′ is recognized in
the hypertensive setting29 and E/e′ ratio has demonstrated to be
a prognosticator in 116 patients hospitalized for heart failure,
including hypertensives with normal EF.30
Correlates of Diastolic Dysfunction
in Arterial Hypertension
In the hypertensive heart alterations of myocardial composi-
tion and, thus of diastolic properties might be mediated by
changes of coronary microcirculation. Today, coronary micro-
circulation may be evaluated by transthoracic echocardiogra-
phy, by visualizing the distal left anterior descending artery31–33
and measuring coronary flow reserve (CFR) (hyperemic to
resting velocities ratio).31–33 CFR has excellent concord-
25
20
Overall mortality (%)
15
10
0.7–1.5 >1.5 <0.6 0.6–1.5 >1.5
Transmitral E/A ratio
MAY 2011 | VOLUME 24 NUMBER 5 | AMERICAN JOURNAL OF HYPERTENSION
Diastolic Dysfunction in Arterial Hypertension
ance with intracoronary Doppler flow wire–derived CFR,31
high feasibility,32 and reproducibility.32 In absence of epicar-
dial coronary stenosis, impaired CFR indicates a coronary
microvascular dysfunction.33 DD is evident in hypertensives
free of coronary artery disease when CFR impairment is also
detectable.34 This association is not surprising because coro-
nary flow occurs predominantly during diastole. A change in
the invasively measured time constant of LV isovolumic pres-
sure fall (τ) is associated with decreased coronary flow even in
patients without coronary artery disease.35 Both reduced CFR
and DD are associated with factors coexisting with hyperten-
sion such as insulin resistance,36,37 LV concentric remodeling/
hypertrophy,38,39 abnormalities of renin–angiotensin–aldos-
terone system,40,41 and endothelial dysfunction.42,43 We can,
therefore, hypothesize that coronary microvascular dam-
age plays a mechanistic role for DD or vice versa. Also the
arterial stiffness has a great impact on DD through the ven-
tricular-arterial coupling in different populations including
hypertensives44,45 and elderly subjects.46 A correlation between
arterial stiffness and LA size was also observed in hypertensive
patients.47 Attempts have been made to establish the best arte-
rial stiffness index in identifying preclinical DD: pulse wave
velocity appears to be superior to central or brachial pulse pres-
sure in older subjects.48 The combination of DD and increased
systolic ventricular-arterial stiffness strongly sustains the onset
of HFNEF49 but the presence of DD seems to be more impor-
E/A ratio = 0.84
E/A ratio = 1.32 E/e′ ratio = 15.2
Figure 4 | Clinical case of a hypertensive patient, 74 years old. In the upper
panel the patient refers for a first Doppler echocardiographic examination
showing a tramsmitral inflow pattern of left ventricular delayed relaxation.
In the lower panels, the patient refers for a control after 6 months:
the transmitral ratio between early and late ventricular filling velocity
(E/A ratio) is 1.32 and only the transmitral early diastolic velocity to pulsed
tissue Doppler–derived annular early diastolic velocity ratio (E/e′)
(e′ of the septal annulus) = 15.2 allows to diagnose a pseudonormal pattern.
AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 5 | may 2011
STATE OF THE ART
tant in the disease progression.50,51 The assessment of arterial
stiffness and ventricular-arterial coupling is becoming a clini-
cally relevant issue in hypertensive DD.52
Lv Systolic Function and Dd in Arterial
Hypertension
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When myocardial fibrosis develops, the collagen accumulation
increases myocardial stiffness and induces DD but also deprives
cardiomyocytes of the skeleton needed for myocardial contrac-
tion. Therefore, it is easily understandable how the degree of
myocardial fibrosis could be associated with the same extent to
the impairment of both systolic and diastolic properties.16 This
was been firstly demonstrated in the hypertensive setting by
an independent association found between IVRT and midwall
fractional shortening, in presence of normal or supernormal
EF53 and even of electrocardiogram-derived LVH.54 By using
two-dimensional speckle tracking echocardiography, early
impairment of global longitudinal strain (GLS) was observed in
young hypertensives55 and even in prehypertensive stages.56 A
relation between reduced GLS and increased E/e′ ratio was also
detected in juvenile hypertension.55 EF is a rather insensitive
indicator of true myocardial contractility and subclinic altera-
tions of LV systolic function are already overt in HFNEF.57,58
Evidences by speckle tracking echocardiography suggest that
GLS and global radial systolic strain are reduced in HFNEF
whereas preserved LV torsion and circumferential strain allow
to maintain EF in the normal range.59,60 Accordingly, GLS pro-
gressively deteriorates in hypertensive patients from New York
Heart Association I–IV class while LV circumferential systolic
impairment appears in New York Heart Association III–IV
classes.61 GLS is a powerful predictor of cardiac events and a
better prognostic parameter than EF in heart failure.62
Therapeutic Management of Diastolic
Dysfunction in Arterial Hypertension
The objectives of the therapeutic management of DD in the
hypertensive setting include the improvement of hemody-
namic conditions, by reducing both preload and afterload.
The volume overload, such to induce episodes of acute heart
failure, can be prevented or reduced by a moderate diuretic
administration or by low salt diet.63
Drugs acting on renin–angiotensin–aldosterone system,
such as angiotensin-converting enzyme inhibitors (ACEIs) and
angiotensin-II receptor blockers (ARBs), appear conceptually
to be the optimal drugs for the treatment of DD because they
reduce both afterload and preload, induce reversal of LV con-
centric geometry, regression of LVH and decrease of myocardial
fibrosis.64 Experimental data suggest a synergistic attenuation
of myocardial fibrosis (significant decrease in total collagen
concentration, ratio of collagen type I to type III, and collagen
c­ rosslinking) by combining ACEIs and ARBs.65 The clinical effect
511
STATE OF THE ART
of ARBs on DD has been assessed in the recent years. Long-term
treatment with valsartan improved both cyclic variation of myo-
cardial integrated backscatter signal and DD in 43 hypertensives
with normal EF.66 Irbesartan, but not atenolol, induced parallel
changes of circulating levels of the carboxy-terminal propeptide
of procollagen type I (an index of collagen type I synthesis) and
of IVRT67 and reduced E/e′ ratio68 in uncomplicated hyperten-
sives. The regression of LVH induced by 12-month telmisartan
therapy was accompanied by a parallel shortening of IVRT and
decrease of LA volume.69 In the VALIDD (Valsartan in Diastolic
Dysfunction) study, 38-week valsartan therapy, added to con-
comitant antihypertensive agents, induced a significantly greater
improvement of IVRT (P = 0.03) and of systolic velocity (s′) of
the mitral annulus (P < 0.02) in comparison with matched pla-
cebo in hypertensives with DD (e′ velocity <10 cm/s in patients
aged 45–54 years, <9 cm/s for age 55–65 years, <8 cm/s for age
>65 years).70 In the Hong Kong Diastolic Heart Failure study, the
addition of ramipril or irbesartan to diuretics resulted in lower
N-terminal prohormone of brain natriuretic peptide levels and
higher annular s′ and e′ velocities.71 The novel renin inhibitors
aliskiren showed beneficial effects on myocardial remodeling
in experimental studies72 and efficacy in reducing LV mass of
hypertensives with LVH73 but its influence on DD has not been
tested in the clinical setting.
Also the antifibrotic effects of aldosterone antagonists might
be a valuable strategy in treating hypertensive-derived DD.
Spironolactone has been demonstrated to be effective in reduc-
ing myocardial fibrosis74 and canrenone in improving DD in
arterial hypertension.75 Eplerenone attenuated the increase in
procollagen type-III aminoterminal peptide at 12 months but
was associated with only modest effect on DD, without any
impact on clinical symptoms/signs or brain natriuretic peptide.76
Results from ongoing trials using these drugs are expected.
Tachycardia and atrial fibrillation are two determinants of
DD, also able to induce or worsen signs/symptoms in HFNEF.
Lower heart rate induces prolongation of LV filling time, allow-
ing to counterbalance the resistance to the diastolic inflow of
a stiffened left ventricle. The heart rate control is, therefore,
an important objective of management of DD. β-Blockers
and calcium antagonist verapamil77 can be useful. The selec-
tive β-blocker atenolol increased transmitral E/A ratio in
115 hypertensives with LVH.78 Last generation β-blockers
(carvedilol, nebivolol), which has vasodilation activity, could
be conceptually indicated for the management of DD. In
the SWEDIC (Swedish Doppler-Echocardiographic) study
6-month carvedilol therapy improved E/A ratio in comparison
with marched placebo, especially in presence of higher base-
line heart rate.79 It seems, therefore, that the key feature in this
study was heart rate reduction, which could also be achieved
with other β-blocking agents. In another study, after 6-month
therapy, nebivolol much more than atenolol induced increase
512
Diastolic Dysfunction in Arterial Hypertension
of E/A ratio and reduction of “wedge” pressure, both at rest
and during exercise, in 26 patients with HFNEF.80 Potential
methodological limitation of this study include, however, the
poor sample size and the higher heart rate at baseline and dur-
ing treatment in the atenolol group. Worthy of note, nebivolol
reduced pulse wave velocity81 and improved LVFP as well as
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CFR in uncomplicated hypertensives.82 The association found
between CFR increase and LVFP reduction indicates a possi-
ble common denominator between improvement of coronary
microcirculation and myocardial stimulation of nitric oxide
release on LV function induced by the drug.82
The use of statins in the setting of DD, for treatment of either
DD or overt HFNEF, is an area of research interest with practi-
cal clinical implications83 and future development.
Based on experimental observations, novel drugs such as
ivrabadine,84 an I(f) inhibitor acting primarily on the sinoatrial
node, and ranolazine,85 which inhibits late I(Na), and reduces
intracellular (Na+)(i) and diastolic (Ca2+)(i) overload improving
myocardial relaxation, appear very promising for the treatment
of DD but clinical studies with these drugs are still lacking. No
rationale exists about the use of digoxin for the therapy of DD. A
clinical trial failed to demonstrate the effect of digoxin on mor-
tality in patients with HFNEF and normal sinus rhythm.86
Outcome Registries and Clinical Trials on Heart
Failure with Normal Ejection Fraction
In HNEF registries, the effect of therapy on mortality resulted
controversial87–90 (Table 2). Of note, none of these registries
provided information about either LV geometry or diastolic
indexes.
In the last 15 years, pharmaceutical industry organized clin-
ical trials to evaluate the prognostic impact of several drugs
(ACEIs, ARBs, and β-blockers) on HFNEF. Vasodilator in
heart failure therapy: enalapril vs. hydralazine/isosorbide dini-
trate study91 and Study of Effects of Nebivolol Intervention on
Outcomes and Rehospitalization in Seniors in elderly patients92
cannot be considered true trials on HFNEF because the cho-
sen baseline values of EF for patients selection were >35%.
Well established echo-derived normal cut-off points of EF are,
in fact, ≥55%.93 The three remaining studies (Candesartan
in Heart Failure—Assessment of Reduction in Mortality-
Preserved, PEP-CHF, and I-PRESERVE) dealt better with the
issue. CHARM-Preserved (Candesartan in Heart Failure—
Assessment of Reduction in Mortality) study94 did not show
an improvement of the primary outcome (CV death or admis-
sion to hospital for heart failure) but only a mild reduction of
hospitalization rate with candesartan in comparison with pla-
cebo. PEP-CHF (Perindopril in Elderly People with Chronic
Heart Failure) study95 compared perindopril (4 mg daily) and
placebo in elderly patients (≥70 years) with evidence of LVH,
LA dilation and abnormal LV filling pattern but did not show
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Diastolic Dysfunction in Arterial Hypertension STATE OF THE ART

Table 2 | Characteristics and findings of outcome registries on HFNEF

Characteristics Dobre et al.87 Massie et al.88 Tribouilloy et al.89 Hernandez et al.90
Number of patients 443 700 358 4,153
Normal EF ≥40% >40% ≥50% ≥40%
CAD origin of HF 36.1% (previous MI) 51% 27.5% Not reported

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HTN origin of HF 49.4 % 24% 54% Not reported
Diastolic indexes Not evaluated Not evaluated Not evaluated Not evaluated
Prevalent LV geometry Not evaluated Not evaluated Not evaluated Not evaluated
Drug tested β-blockers Carvedilol ACEI β-blockers
Mean duration of follow-up 25 months 1 year 5 years 60–90 days
Effect on mortality 43 % reduction HR = 0.57 6 % reduction 30 % reduction HR = 0.51 HR = 0.94
(95% CI = 0.37–0.88) P < 0.01 HR not reported (95% CI = 0.43–0.87) P = 0.006 (95% CI = 0.84–1.07)
Effect on hospitalization Not evaluated Not evaluated Not evaluated HR = 0.98
(95%CI = 0.90–1.06)
ACEI, angiotensin-converting enzyme inhibitor; CAD, coronary artery disease; CI, confidence interval; EF, ejection fraction; HF, heart failure; HFNEF, heart failure with normal ejection
fraction; HTN, hypertension; HR, hazard ratio; LV, left ventricular; MI, myocardial infarction.

Table 3 | Characteristics and findings of the three major clinical trials on heart failure with normal ejection fraction
Characteristics CHARM-Preserved94 PEP-CHF95 I-PRESERVE96
Number of randomized patients 3,023 850 4,128
Normal EF <40% >40% >45%
CAD origin of HF 56% 39% 25%
HTN origin of HF 22% 79% 64%
Diastolic indexes Not assessed IVRT >105 ms or E/A <0.5 or Not assessed
DT >280 ms or LAD >25 mm/m2
(or >40 mm)
Prevalent LV geometry Eccentric Concentric Concentric
Drug tested Candesartan Perindopril Irbesartan
Duration of follow-up 36.6 months (median) 2.1 years (median) 49.5 months (mean)
Primary outcome CV death or HF Hosp All death or HF Hosp All deaths or CV Hosp
Secondary outcome Hosp for HF Individual components of primary All death
outcome CV Hosp
Effects on primary outcome HR = 0.89 HR = 0.92 HR = 0.95
(95% CI = 0.77–10.3) P = 0.118 (95% CI = 0.70–1.21) P = 0.545 (95% CI = 0.86–1.05) P = 0.35
Effects on secondary outcome 230 (15.2%) candesartan vs. CV death 0.98 (0.63–1.53) P = 0.93 All death 1.00 (0.88–1.14) P = 0.98
279 (18.5%) placebo HF Hosp 0.86 (0.61–1.20) P = 0.38 CV Hosp 0.95 (0.85–1.08) P = 0.44
P = 0.017 HF Wors 0.89 (0.68–1.18) P = 0.41
CAD, coronary artery disease; CI, confidence interval; CV, cardiovascular; DT, deceleration time; E/A, ratio between early and late ventricle filling velocity; EF, ejection fraction; HF, heart
failure; Hosp, hospitalization; HR, hazard ratio; HTN, hypertension; IVRT, isovolumic relaxation time; LAD, left atrial diameter; LV, left ventricular; Wors, worsening.

any difference in mortality and hospitalization for heart fail-
ure. I-PRESERVE trial96 enrolled patients ≥60 years, randomly
assigned to irbesartan (300 mg daily) or placebo but mortality
or hospitalization rates for CV causes were not improved by
irbesartan. Important methodological concerns of these three
trials involve again identification and recruitment of HNEF
patients. Mainly, the cut-off point of EF was lower than 55%,
LV geometry was often eccentric and a variable proportion
of patients had an ischemic origin.97 In addition, poor or no
information on LV diastolic function was available (Table 3).
Clinical Approach To the Treatment of Diastolic
Dysfunction in Arterial Hypertension
The recommended pharmacological management of DD
in hypertensive patients should correspond first of all to BP
lowering. In the VALIDD study, BP reduction—obtained by

AMERICAN JOURNAL OF HYPERTENSION | VOLUME 24 NUMBER 5 | may 2011 513

 STATE OF THE ART
1.1
0.9
Increase in e′ velocity (cm/s)
0.7
0.5
0.3
0.1
<0 1–9 10–21
Systolic BP reduction (mm Hg)
Figure 5 | Change in diastolic function (lateral early diastolic (e′) velocity)
for each quartile of systolic blood pressure (BP) reduction. Modified from
Solomon et al.70 Error bar are s.e.
either valsartan or agents that did not interrupt the renin sys-
tem (about 40% of patients treated with a β-blocker, which
suppresses renin secretion)—was the main determinant of
DD improvement (annular e′ velocity) irrespective of antihy-
pertensive agents used (Figure 5).70 This finding is in agree-
ment with an experience in which the achievement of a good
BP control (by candesartan 16 mg or bendroflumethiazide
2.5 mg) and the enhancement of LV systolic function induced
an increase of e′ velocity only after 3 months.98 A very recent
study compared the effect of intensive antihypertensive treat-
ment (systolic BP target <130 mm Hg) and standard treatment
(systolic BP target <140 mm Hg) in 228 hypertensive patients
with uncontrolled hypertension over a follow-up period of 24
weeks: the degree of e′ velocity was associated with the extent
of systolic BP reduction, and patients with the lowest achieved
systolic BP had the highest final e′ velocity.99
The best management should also include the attempt in
reducing LV mass and normalizing LV geometry. Long-term
(9–12 months) pharmacotherapy with β-blockers, calcium
channel blockers, or ACEI reduced LVH by 8–14%, with an
effect which was parallel to a marked improvement in CFR
and DD.100 In the Losartan Intervention For Endpoint reduc-
tion study the beneficial effect induced by 1-year therapy with
atenolol or losartan on LV geometry (reduced rate of LV con-
centric remodeling and LVH)101 was associated with a similar
extent to LV filling improvement (reduced rate of abnormal
and likewise pseudonormal/restrictive pattern).
Conclusions and Perspectives
The progression of hypertensive involvement toward heart fail-
ure includes LV geometric changes and DD. Comprehensive
514
Diastolic Dysfunction in Arterial Hypertension
assessment of DD should be performed not by simply
c­ lassifying DD progression but by estimating LV FP degree, a
true determinant of symptoms and prognosis. The practitioner
approach to hypertensive patient with DD should correspond
to BP lowering and to the attempt of reducing LV mass and
normalizing LV geometry. Prospective studies with well-de-
Downloaded from http://ajh.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on November 13, 2014
fined entry criteria (“true” normal EF, LV concentric geometry,
standardized assessment of LV diastolic function) are needed to
establish whether this approach could reflect a better prognosis
in patients with arterial hypertension.
Disclosure: The author declared no conflict of interest.
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