Circulation Journal

Official Journal of the Japanese Circulation Society

FOCUS REVIEWS ON HEART FAILURE
http://www. j-circ.or.jp

From Left Ventricular Hypertrophy to

Dysfunction and Failure
Davide Lazzeroni, MD; Ornella Rimoldi, MD; Paolo G Camici, MD

Left ventricular hypertrophy (LVH) is growth in left ventricular mass caused by increased cardiomyocyte size. LVH
can be a physiological adaptation to strenuous physical exercise, as in athletes, or it can be a pathological condition,
which is either genetic or secondary to LV overload. Physiological LVH is usually benign and regresses upon reduc-
tion/cessation of physical activity. Pathological LVH is a compensatory phenomenon, which eventually may become
maladaptive and evolve towards progressive LV dysfunction and heart failure (HF). Both interstitial and replacement
fibrosis play a major role in the progressive decompensation of the hypertrophied LV. Coronary microvascular dys-
function (CMD) and myocardial ischemia, which have been demonstrated in most forms of pathological LVH, have
an important pathogenetic role in the formation of replacement fibrosis and both contribute to the evolution towards
LV dysfunction and HF. Noninvasive imaging allows detection of myocardial fibrosis and CMD, thus providing unique
information for the stratification of patients with LVH.   (Circ J 2016; 80: 555 – 564)

Key Words: Coronary microvascular dysfunction; Heart failure; Left ventricular hypertrophy; Myocardial fibrosis;
Myocardial ischemia

L
eft ventricular hypertrophy (LVH) is growth in left
ventricular (LV) mass caused by increased cardiomyo-
cyte size.1 The process is compounded by a complex
series of transcriptional, signaling, structural, electrophysio-
logical and functional events that affect all the cardiac cell
types.2–4
LVH can be a physiological adaptation to strenuous physi-
cal exercise, as in athletes, or it can be a pathological condi-
tion, which is either genetic or secondary to LV overload.
Physiological LVH is usually benign and regresses upon reduc-
tion/cessation of physical activity. Pathological LVH is a
compensatory phenomenon that eventually may become mal-
adaptive and evolve towards progressive LV dysfunction and
heart failure (HF).
The aim of this article is to review the present understand-
ing of the mechanisms involved in the transition from LVH to
LV dysfunction and HF, with particular emphasis on the poten-
tial role of coronary microvascular dysfunction (CMD) and
ischemia.
Physiological LVH
Intense training results in a physiological adaptation of the
heart, characterized by increased LV mass (LVM), cavity
dimensions and wall thickness, known as the ‘athlete’s heart’.
The changes in cardiac structure differ depending on the type
of training: dynamic exercise, such as running and swimming,
produces an increase in volume load whereas static exercise,
such as weight lifting, causes mainly pressure overload.
Accordingly, athletes may develop eccentric (eg, runners) or
concentric (weight lifters) LVH. LVM in highly trained ath-
letes may exceed that in matched nonathletic controls by up to
60% and usually reverts to normal values after a period of
deconditioning, which can take up to several years in athletes
with evidence of marked LV cavity enlargement. Similarly,
wall thickness in athletes has been shown to decrease signifi-
cantly after deconditioning, together with cavity dimensions,
although in some elite athletes, the LV cavity may remain
enlarged even after cessation of training.5 Athletes with LVH
generally have a normal ejection fraction (EF) and no evi-
dence of either systolic or diastolic dysfunction.
Pathological LVH
LV geometry can be classified using 2 simple parameters:
relative wall thickness (RWT), calculated as posterior wall
thickness×2/LV internal diameter at end-diastole, and the LVM
index (LWMi, normalized for body surface area or height).
This classification permits categorization of LV geometry into
4 types: normal (RWT ≤0.42 and normal LWMi), concentric
remodeling (normal LWMi with RWT >0.42), concentric
(increased LWMi and RWT >0.42) or eccentric hypertrophy
(increased LWMi and RWT ≤0.42) (Figure 1).6

Received January 22, 2016; accepted January 22, 2016; released online February 5, 2016
Prevention and Rehabilitation Unit, Don Gnocchi Foundation & University of Parma, Parma (D.L.); CNR IBFM, Segrate (O.R.); and
Vascular and Cardio-thoracic Department, San Raffaele Scientific Institute and Vita-Salute University San Raffaele, Milan (D.L., P.G.C.),
Italy
Mailing address:  Paolo G Camici, Professor, MD, FESC, FACC, FAHA, FRCP, Vita-Salute University and Scientific Institute San Raffaele
Milan, Via Olgettina 60, 20132, Milan, Italy.   E-mail: camici.paolo@hsr.it
ISSN-1346-9843  doi: 10.1253/circj.CJ-16-0062
All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: cj@j-circ.or.jp

Circulation Journal  Vol.80, March 2016

556
Primary LVH
Variable degrees of LVH are present in most forms of primary
myocardial diseases, including hypertrophic (HCM) and dilated
(DCM) cardiomyopathy.
HCM   Given its Mendelian inheritance, HCM was the first
cardiomyopathy to be associated with a genetic origin,7 and
specific mutations in genes encoding sarcomeric proteins can
be identified in over 50% of patients. The mechanisms respon-
sible for LVH development in HCM remain incompletely
understood. Impaired myofibrillar contractile function, mainly
caused by abnormal cardiomyocyte calcium cycling and sen-
sitivity, is thought to be the key mechanism triggering com-
pensatory hypertrophy, although other factors may play a role,
including disturbed biomechanical stress sensing and altered
energy homeostasis.8,9 Hypertrophy is generally asymmetrical
(with wall thickness >15 mm) and affects predominantly the
interventricular septum, although it may also be symmetrical
or localized to the apex or posterior wall. LV volumes are
normal or reduced, systolic function is preserved and there is
often evidence of hypercontractility with EF higher than nor-
mal and near obliteration of the cavity in systole. HCM is
characterized by variable degrees of diastolic dysfunction that
may be severe enough to cause symptoms of HF despite a
normal EF. In a minority of patients, the disease evolves towards
severe remodeling of the LV with cavity enlargement, wall
thinning and progressive impairment of systolic function, a
condition known as endstage HCM.
DCM   Progressive LV cavity enlargement, wall thinning
and hypertrophy caused by an in-series disposition of sarco-
meres with slippage of the fibers characterize DCM. The LV
tends to become spherical and hypertrophy is eccentric. Gene
mutations can be detected in 20–30% of patients with the
DCM phenotype and involve proteins of the membrane-scaf-
folding apparatus, sarcomeric proteins, nuclear envelope pro-
teins, calcium-handling proteins and transcription cofactors of
the cell energy-generating machinery.10 In all other cases,
Circulation Journal  Vol.80, March 2016
LAZZERONI D et al.
Figure 1.   Classification of left ventricular
(LV) geometry based on relative wall thick-
ness and LV mass index. (Reproduced with
permission from Lang RM, et al.6)
DCM is generally caused by viral/bacterial myocarditis, expo-
sure to cardiotoxic substances or is a manifestation of a sys-
temic disease. Before cell death and fibrotic repair occur,
multiple factors contribute to contractile dysfunction, includ-
ing abnormalities in sarcolemmal integrity, energy production,
calcium handling and force transmission.10 Both systolic and
diastolic dysfunction worsen with time and EF is progressively
reduced, with symptoms and signs of HF.
Secondary LVH
Cardiomyocyte hypertrophy is the primary mechanism by
which the heart counteracts a protracted increase in stress (or
load) on the ventricular wall.11 According to Laplace’s law,12
wall stress is directly related to LV cavity size and intracavi-
tary pressure and inversely related to wall thickness. Thus,
wall thickening will counteract, at least in part, the increased
stress and oxygen demand caused by pressure or volume over-
load, although, in the long run, this compensatory mechanism
may become maladaptive. On the other hand, several other
nonhemodynamic factors, including activation of the adrener-
gic and renin-angiotensin-aldosterone (RAAS) systems, release
of growth factors and cytokines, contribute to the development
of LVH.13,14
Pressure Overload  In most cases, pressure overload man-
ifests as arterial hypertension (AH) or aortic stenosis (AS).
Hypertensive Heart  The most common condition associ-
ated with an increase in cardiac afterload and wall stress is
AH.15 Approximately 20–60% of patients with uncomplicated
AH have evidence of increased LVM on echocardiography.16
LVM can increase from wall thickening, chamber dilatation
or both. Wall thickening occurs more commonly in response
to pressure overload whereas chamber dilation occurs more
commonly in response to volume overload. Although LV wall
thickness is more closely related to systemic diastolic blood
pressure (concentric hypertrophy), reflecting pure pressure
load caused by increased systemic vascular resistance, LVM
From LV Hypertrophy to Dysfunction 557

Figure 2.   Classification of left ventricular hypertrophy (LVH) and prognostic implications according to Khouri MG, et al. 32 AR,
aortic regurgitation; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; HFpEF, heart failure with preserved ejec-
tion fraction; HFrEF, heart failure with reduced ejection fraction; MR, mitral regurgitation; RCM, restrictive cardiomyopathy. (Repro-
duced with permission from Khouri MG, et al.32)

is more closely related to systolic blood pressure, suggesting
an influence of both pressure and volume load (eccentric
hypertrophy).17,18
In most patients with mild to moderate AH and LVH, sys-
tolic performance at rest is normal or mildly increased and a
varying degree of diastolic dysfunction can be present. LVH
may evolve to overt systolic or diastolic dysfunction (or both)
with the corresponding clinical presentation of HF with pre-
served (HFpEF) or reduced EF (HFrEF).
AS  Valvular AS is the second-most prevalent adult valve
disease, occurring in 4% of patients older than 75 years.19
Severe LVH is found in 17% of symptomatic patients with
mild to moderate AS20 and in 67% of those with asymptomatic
severe AS.21 The increased LV afterload produced by AS results
in a structural hypertrophic adaptation that is generally con-
centric, characterized by wall thickening with normal LV
cavity dimensions.22 Systolic performance at rest is normal or
mildly increased and diastolic dysfunction is present.22 The
natural history of AS is characterized, in most cases, by pro-
gressive LV dysfunction and HF, although it may be favorably
changed by valve replacement, particularly in those patients
with preserved EF before surgery.23
Volume Overload  In most cases of volume overload, the
enlarged intracavitary volume contributes to the increased LV
systolic pressure and afterload, leading to a combined pressure
and volume overload and an eccentric pattern of hypertrophy.
Mitral Regurgitation (MR)  Isolated MR is the only heart
disease that generates a pure volume overload because the
extra volume is ejected into a low-pressure chamber (left
atrium).24 Pure volume overload induces an increase in dia-
stolic stress, leading to an in-series disposition of the sarco-
meres and thus increasing myocyte length. This in turn produces
an increase in LV chamber volume, allowing the LV to aug-
ment stroke volume to accommodate the extra volume lost in
regurgitation. This high-volume/low-pressure state produces
an enlarged, thin-walled chamber that represents the classical
geometry of eccentric hypertrophy. This eccentric remodeling
has a temporary favorable influence on diastolic function,
which is usually supra normal in patients with compensated
disease.25,26 Clinical HF occurs lately, with the development
of a progressive reduction in systolic and diastolic function.
Aortic Regurgitation (AR)  Volume overload in AR is
caused by the back flow of blood into the LV during diastole.
As in MR, the LV cavity is enlarged and the stroke volume
increased. Moreover, the interaction of the large stroke vol-
ume with the elasticity of the aorta increases systolic blood
pressure. In fact, although many AR patients are normoten-
sive, systolic pressure in AR is approximately 50 mmHg higher
than in MR.27 This unique combined pressure and volume
overload leads to hypertrophic remodeling that is both eccen-
tric and concentric,28 producing the heaviest LV in valvular
heart disease,29 which eventually results in both diastolic and
systolic dysfunction and overt HF.30,31

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558 LAZZERONI D et al.

Table.  Myocardial Perfusion and Coronary Flow Reserve in Normal Controls, and Primary and Secondary LVH Patients
MBFR MBFH
Method n CFR Reference
(ml/g/min) (ml/g/min)
Normal controls
  PET 3.484 0.82±0.06 2.86±1.29 3.55±1.36 Gould et al38
Physiologic
  LVH
    PET 10 0.74±0.17 2.69±1.15 3.58±1.02 Radvan et al41
    PET 14 0.8±0.2 NA 6.1±1.9 Toraa et al42
    Doppler 52 10.6±3.1 (ml/min) 61.9±17.8 (ml/min) 5.9±1.0 Hildick-Smith et al43
Primary LVH
  HCM
    PET 345 0.90±0.10 1.57±0.33 1.84±0.36 Gould et al38
    PET 23 1.02±0.39 1.55±0.58 1.51±0.48 Camici et al44
    PET 51 0.84±0.31 1.50±0.69 1.80±0.70 Cecchi et al48
    PET 61 – 1.90±0.90 – Olivotto et al45
  DCM
    PET 22 0.80±0.25 1.91±0.76 2.38±0.5　　 Neglia et al49
    PET 67 0.69±0.23 1.53±0.79 2.22±0.89 Neglia et al50
Secondary LVH
  Hypertensive heart
    PET 20 0.69±0.13 1.42±0.32 NA Neglia et al52
    PET 30 0.89±0.18 1.9±0.62 2.18±0.74 Rimoldi et al51
  Aortic stenosis
    PET 20 1.05±0.26 1.99±0.78 1.9±0.6 Rajappan et al54
    Doppler 24 23.3±10.1 (cm/s) 37.8±11.3 (cm/s) 1.76±0.5　　 Hildick-Smith et al55
  Mitral regurgitation
    Doppler 31 28±8 (cm/s) 56±14 (cm/s) 2.1±0.5 Akasaka et al56
CFR, coronary flow reserve; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVH, left ventricular hypertrophy; MBFH,
myocardial blood flow during hyperemia; MBFR, myocardial blood flow at rest; NA, not available; PET, positron emission tomography.

mechanism of myocardial ischemia.36 Abnormalities in the

LV Geometry and Prognosis
Khouri et al have proposed a new classification of LVH into 4
subgroups: eccentric non-dilated (or indeterminate hypertrophy),
eccentric dilated, concentric non-dilated LVH and concentric
dilated LVH (Figure 2).32 According to this classification,
patients with eccentric hypertrophy can be subclassified into a
low-risk (indeterminate hypertrophy or eccentric non-dilated
LVH) and a high-risk group (dilated hypertrophy). Similarly,
concentric hypertrophy can be subdivided into 2 risk groups:
thick hypertrophy and both thick and dilated hypertrophy where
the latter is the phenotype carrying the highest risk. Bang et al
proved the prognostic validity of this classification in 939
hypertensive patients of the LIFE study (mean follow-up of 4
years), identifying a low-risk subset with eccentric non-dilated
LVH and 3 subsets of LVH at high risk of developing LV
dysfunction and HF.33 Garg et al validated this classification
using cardiac magnetic resonance in 2,458 subjects, demon-
strating that the risk of HF and cardiovascular death was greater
in those subject with either dilated hypertrophy or both thick
and dilated hypertrophy.34 In patients with concentric dilated
LVH, diastolic LV dysfunction is a frequent finding and is the
functional determinant predisposing to HFpEF. On the other
hand, systolic dysfunction (which can be associated with vary-
ing degrees of diastolic dysfunction) is characteristic of eccen-
tric dilated LVH and is the substrate of HFrEF (Figure 2).35
CMD in LVH
In the past 2 decades, CMD has emerged as an additional
function and structure of the coronary microcirculation impair
the control of myocardial blood flow (MBF) and can contrib-
ute to the pathogenesis of myocardial ischemia.37,38 According
to Camici and Crea,37 patients with LVH have type 2 CMD
(ie, occurring in the absence of demonstrable coronary artery
disease (CAD), but with evidence of myocardial disease).39
CMD determines significant blunting of hyperemic MBF and
reduction of coronary flow reserve (CFR) (Table). This impair-
ment of coronary physiology predicts development of LV
dysfunction in patients with LVH (Figure 3).40
CMD in Physiological LVH
Radvan et al measured MBF and CFR with positron emission
tomography in a group of elite rowers (all with LVMi >131 g/m2)
and a group of age- and sex-matched sedentary controls. They
found that both resting and hyperemic (dipyridamole) MBF
and CFR in the athletes and normal controls were comparable
(Table).41 Similar results were obtained in subsequent studies
comparing MBF and CFR in elite athletes and control sub-
jects,42,43 suggesting that MBF and CFR are preserved in ath-
letes with physiological LVH.
CMD in Primary LVH
In HCM, both severe structural remodeling of intramural cor-
onary arterioles and increased perivascular fibrosis has been
described. These structural changes, in addition to the increased
extravascular compression, cause severe CMD that can be
demonstrated by a severely blunted maximal MBF and reduced
CFR.44,45 The anatomical basis of CMD is supported by the

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From LV Hypertrophy to Dysfunction 559

Figure 3.   Proposed chain of pathophysiologic events linking microvascular remodeling and dysfunction to myocardial ischemia
and left ventricular remodeling and their consequences on patient outcome. (Reproduced with permission from Camici PG, et
al.40)

study of Basso et al46 who found evidence of ischemic damage

at autopsy in 19 patients with HCM who died suddenly. Within
the septal myocardium, the small intramural coronary arteries
showed varying degrees of medial hypertrophy-dysplasia and
intimal hyperplasia and were closely related to fibrotic scars
(Figure 4). The damage was either acute/subacute necrosis or
fibrotic scarring, lending support to the clinical picture of
ischemia occurring in the natural history of HCM. The patchy
distribution of fibrosis may also contribute to life-threatening
electrical instability.46 The degree of hyperemic MBF impair-
ment is a powerful long-term predictor of adverse LV remod-
eling and systolic dysfunction,47 as well as an independent
predictor of death and unfavorable outcome in HCM.48
In DCM, different studies have shown not only that MBF
abnormalities occur even in the early stages of the disease and
in the absence of epicardial stenosis, but also that myocardial
ischemia attributable to CMD may have an independent role Figure 4.   Hypertrophic cardiomyopathy. Intramural coronary
in the progression of the disease.49 Furthermore, it has been arterioles with increased medial thickness and luminal steno-
demonstrated that the severity of the hyperemic MBF impair- sis (black arrows) and perivascular fibrosis (white arrow) are
ment is a predictor of poor prognosis independent of the associated with myocardial ischemic micro scarring (yellow
degree of LV functional impairment and of the presence of arrow) (azan mallory staining, original magnification ×10).
(Courtesy of Giulia d’Amati, MD PhD, Department of Radiol-
overt HF.50 ogy, Oncology and Pathology, ‘‘Sapienza’’ University of Rome,
Rome, Italy.)
CMD in Secondary LVH
Patients with AH often have symptoms and signs suggestive
of myocardial ischemia despite normal coronary angiograms.
The abnormalities of the coronary microcirculation may be

Circulation Journal  Vol.80, March 2016

560
unrelated to the degree of LVH and cause a reduction in
maximum MBF and CFR.51 In the hypertensive heart there is
remodeling of intramural coronary arterioles, because of
hypertrophy of smooth muscle cells, and increased collagen
deposition in the tunica media, with varying degrees of intimal
thickening and perivascular fibrosis. Although the anatomic
changes affecting the microcirculation are similar in hyperten-
sion and HCM, they are usually more severe in the latter
condition. The remodeled, hypertrophied vascular wall leads
to an increase in medial wall area, with a relative reduction of
the vessel’s lumen. These changes are induced, at least in part,
by excessive activation of the RAAS. In fact, treatment with
angiotensin-converting enzyme inhibitors may revert micro-
vascular remodeling and improve MBF in experimental and
clinical AH.52 In patients with stage 1 or 2 AH and LVH, CFR
is transmurally blunted and inversely related to systolic blood
pressure.51 Detection of CMD is crucial to identify patients
with AH at higher risk of developing LV dysfunction and HF.
In a study investigating the prognostic role of CMD in 2,783
consecutive patients with suspected or known CAD (80% of
patients had AH), it was found that CFR was a powerful,
independent predictor of cardiac mortality and provided mean-
ingful incremental risk stratification over other known risk
factors.53 In particular, patients in the highest tertile of CFR,
indicating preserved vasodilator function, had an extremely
low rate of cardiac mortality (<0.5%/year). Conversely, inter-
mediate and severely reduced CFR were associated with an
adjusted hazard ratio for cardiac mortality of 3.4 and 5.6,
respectively. In that study, the addition of CFR to clinical
variables, such as rest LVEF, LVEF reserve and the extent of
myocardial scarring, resulted in the correct reclassification of
approximately one-third of all intermediate risk patients.
In patients with severe AS, CFR impairment is directly
proportional to the reduction of aortic valve area and diastolic
perfusion time, but there is no significant correlation with
LVM (Table).54 Moreover, CFR increases after aortic valve
replacement and this increase occurs in parallel with regres-
sion of LV hypertrophy.55
Reduced CFR can be demonstrated not only in patients with
pressure overload but also in those with volume overload,
such as MR, where CFR is reduced mainly because of eleva-
tion of the baseline resting flow velocity (Table). This reduc-
tion of CFR correlates with the increase in LV preload, mass
and volume overload and CFR improves after mitral valve
surgery.56 A reduced CFR was demonstrated only in an animal
model of AR.57
Myocardial Ischemia, Tissue Fibrosis and
Progression From LVH to LV Dysfunction and HF
Myocardial fibrosis is an important determinant in the patho-
genesis of HF, regardless of etiology. It may be regional, such
as the replacement fibrosis observed following myocardial
infarction, or a more diffusely distributed interstitial fibrosis
as observed in the most advanced cardiomyopathies.58 Histo-
pathological studies have shown that the myocardial fibrosis
in HCM,59 AH and AS60 is associated with increased risk of
cardiac sudden death and congestive HF.61–63 Cardiovascular
magnetic resonance (CMR) offers a unique opportunity to
noninvasively quantify LVM and myocardial fibrosis with high
accuracy and reproducibility, by means of late gadolinium
enhancement (LGE). Replacement myocardial fibrosis follow-
ing experimental myocardial infarction in animals coincides
with areas of LGE in which transmural extension is also used
to assess myocardial viability.64–67 Midwall LGE is present in
Circulation Journal  Vol.80, March 2016
LAZZERONI D et al.
nonischemic DCM, where it has been associated with adverse
cardiac remodeling and increased risk of malignant arrhyth-
mia.68–70 Even in the absence of replacement fibrosis, increased
extracellular collagen (interstitial fibrosis) is found in many
cardiac conditions.71–73 Diffuse myocardial fibrosis and remod-
eling of the myocardial extracellular space can be measured
through changes in native (non-contrast) myocardial T1 relax-
ation times, post-contrast T1times, and derived estimates of
extracellular volume (ECV), using both native and post-con-
trast T1 values.74 These techniques can help to discriminate
the different etiologies of LVH and detect progression of
disease.75,76
Myocardial Fibrosis in Primary LVH
In HCM, replacement fibrosis can be the consequence of
chronic, repeated episodes of microvascular ischemia, leading
to myocyte death and replacement of the space with myofi-
broblasts, leading to progressive systolic impairment.47,77,78
Approximately 70% of HCM patients have evidence of LGE
on CMR.79,80 Olivotto et al found substantial amounts of LGE
in a subset of patients with HCM and low-normal EF values
(50–65%) in comparison with patients with higher EF,81 but
little or no association was found between EF and several
standard clinical and demographic parameters, such as age,
sex, LV cavity dimensions, wall thickness or LVM. Myocar-
dial fibrosis was an independent predictor of adverse outcome
in the study by O’Hanlon et al, which assessed the presence,
amount and prognostic role of LGE in 217 patients with HCM
followed for 3.1±1.7 years.82 LGE is also associated with an
increased prevalence of ventricular tachyarrhythmia and sud-
den death.83,84 A word of caution is necessary, though; indeed
Ismail et al confirmed that the amount of myocardial fibrosis
was a strong predictor of sudden cardiac death, but this effect
was offset after adjusting for LVEF.85 Thus, despite being a
valuable marker, LGE does not provide the incremental inde-
pendent prognostic information to LVEF and further work is
required to clarify the reciprocal role of myocardial fibrosis
and other markers of risk in HCM.
In DCM, diffuse interstitial fibrosis can be frequently
observed in histological specimens and can lead in the long
term to irreversible replacement fibrosis.86,87 The occurrence
of replacement fibrosis in patients with DCM is approximately
35%.88 Myocardial fibrosis in DCM patients has been identi-
fied as an independent predictor of adverse clinical out-
comes.89,90 The presence of midwall fibrosis is an independent
predictor of all-cause mortality and cardiovascular hospitaliza-
tion, independent of ventricular remodeling and EF.70,91 In
addition, midwall fibrosis predicts sudden cardiac death and
ventricular tachyarrhythmia, especially if the conduction sys-
tem is involved, suggesting a potential role for CMR in the
risk stratification of patients with DCM who may need device
therapy.91
Myocardial Fibrosis in Secondary LVH
In 83 patients with AS, AH, or HCM, LGE was present with
a high prevalence in all forms of LVH (AS 62%, AH 50%,
HCM 72%) without significant differences between primary
and secondary LVH, and correlated with the LVMi.80 The
results of that study suggest that LGE is a common finding in
adaptive LVH caused by pressure overload and the patchy
pattern is most likely caused by focal ischemic necrosis. In a
study of AH, patients with nocturnal non-dipper blood pres-
sure patterns had larger LVM and scar volume than those with
dipper patterns.92
In moderate and severe AS, both ischemic subendocardial
From LV Hypertrophy to Dysfunction
Figure 5.   Contribution of myocardial ischemia in the progression from left ventricular hypertrophy (LVH) to heart failure. cLVH,
concentric LVH; EF, ejection fraction; MI, myocardial infarction. (Adapted with permission from Drazner MH. 100)
patterns and midwall fibrosis have been described, their pres-
ence purportedly a respective 6-fold and 8-fold increase in
all-cause mortality compared with patients without fibrosis,
independent of the severity of AS, LVM EF or concomitant
CAD.93 A simple noninvasive marker, myocardial ECG strain,
defined as ≥1-mm concave downsloping ST-segment depres-
sion with asymmetrical T-wave inversion in the lateral leads,
has been strongly associated with midwall and diffuse myo-
cardial fibrosis and impaired LV performance. All these non-
invasive markers could be used as independent predictors of
cardiovascular death or aortic valve replacement.94 In both AS
and AR, early morphologic studies suggested that fibrosis
precedes and may be related to the development of congestive
HF.95,96 Further, a recent investigation in rabbits with experi-
mental AR has highlighted abnormal extracellular matrix (ECM)
production featuring a relative abundance of non-collagen
ECM, specifically including fibronectin.97 For the time being,
this difference in tissue composition cannot be discriminated
by available CMR sequences.
Even in the absence of overt LV dysfunction, patients with
moderate to severe primary MR may show myocardial fibrosis
on CMR, and progressive LV dilatation is associated with
LGE. Moreover, approximately 30% of this patient cohort
developed these signs of myocardial damage well before the
LV endsystolic diameter had reached the cut-off value of
45 mm, but it has to be pointed out that this small study was
limited by the lack of association between LGE and clinical
data.98 Similarly, in patients with asymptomatic MR, a spec-
trum of patterns of myocardial fibrosis associated with myo-
cardial dysfunction can be identified: lengthening of native
T1, midwall fibrosis and expanded ECV. Elevated global ECV
occurred before any conventional class 1 indications for sur-
gery were detected on echocardiography. The expansion of the
ECV was independently associated with increased LV endsys-
tolic and atrial volumes, decreased longitudinal function, EF
and exercise capacity.99
Circulation Journal  Vol.80, March 2016
561
Conclusions
Pathological LVH develops in response to different genetic,
physical and biochemical stimuli and represents the first step
in ventricular remodeling. Although LVH can be initially com-
pensatory, eventually it may become maladaptive and evolve
towards progressive LV dysfunction and HF.
Both interstitial and replacement fibrosis play a major role
in the progressive decompensation of the hypertrophied LV.
CMD and myocardial ischemia, which have been demon-
strated in most forms of pathological LVH, have an important
pathogenetic role in the formation of replacement fibrosis and
contribute to the evolution towards LV dysfunction and HF
(Figure 5).100 Noninvasive imaging allows detection of myo-
cardial fibrosis and CMD, thus providing unique information
for the stratification of patients with LVH.
Disclosures
P.G.C. acts as a consultant for Servier.
References
   1. Lorell BH, Carabello A. Left ventricular hypertrophy: Pathogene-
sis, detection and prognosis. Circulation 2000; 102: 470 – 479.
   2. Burchfield JS, Xie M, Hill JA. Pathological ventricular remodeling:
Mechanisms: Part 1 of 2. Circulation 2013; 128: 388 – 400.
   3. Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive
heart disease. J Clin Invest 2007; 117: 568 – 575.
   4. Schwartzkopff B, Motz W, Frenzel H, Vogt M, Knauer S, Strauer
BE. Structural and functional alterations of the intramyocardial
coronary arterioles in patients with arterial hypertension. Circula-
tion 1993; 88: 993 – 1003.
  5. Pelliccia A, Maron BJ, De Luca R, Di Paolo FM, Spataro A,
Culasso F. Remodeling of left ventricular hypertrophy in elite ath-
letes after long-term deconditioning. Circulation 2002; 105:
944 – 949.
  6. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A,
Ernande L, et al. Recommendations for cardiac chamber quantifica-
tion by echocardiography in adults: An update from the American
562
Society of Echocardiography and the European Association of  
Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015;
16: 233 – 270.
   7. Wigle ED, Rakowski H, Kimball BP, Williams WG. Hypertrophic
cardiomyopathy: Clinical spectrum and treatment. Circulation  
1995; 92: 1680 – 1692.
   8. Frey N, Luedde M, Katus HA. Mechanisms of disease: Hypertro-
phic cardiomyopathy. Nat Rev Cardiol 2011; 9: 91 – 100.
  9. Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W,  
Vosberg HP, et al. α-tropomyosin and cardiac troponin T mutations
cause familial hypertrophic cardiomyopathy: A disease of the sar-
comere. Cell 1994; 77: 701 – 712.
  10. Watkins H, Ashrafian H, Redwood C. Inherited cardiomyopathies.
N Engl J Med 2011; 364: 1643 – 1656.  
  11. Hill JA, Olson EN. Cardiac plasticity. N Engl J Med 2008; 358:
1370 – 1380.
  12. Grossman W, Jones D, McLaurin LP. Wall stress and patterns of
hypertrophy in the human left ventricle. J Clin Invest 1975; 56:  
56 – 64.
  13. Frohlich ED, Tarari RC. Is arterial pressure the sole factor respon-
sible for hypertensive cardiac hypertrophy? Am J Cardiol 1979; 44:
959 – 963.  
  14. Tarazi RC, Frohlich ED. Is reversal of cardiac hypertrophy a desir-
able goal of antihypertensive therapy? Circulation 1987; 75: 113 –  2015; 12: 48 – 62.
117.  
  15. Cuspidi C, Rescaldani M, Sala C, Negri F, Grassi G, Mancia G.
Prevalence of electrocardiographic left ventricular hypertrophy in  
human hypertension: An updated review. J Hypertens 2012; 30:
2066 – 2073.
  16. Devereux RB, Casale PN, Hammond IW, Savage DD, Alderman
MH, Campo E, et al. Echocardiographic detection of pressure-
overload left ventricular hypertrophy: Effect of criteria and patient  
population. J Clin Hypertens 1987; 3: 66 – 78.
  17. Kahan T, Bergfeldt L. Left ventricular hypertrophy in hypertension:  
Its arrhythmogenic potential. Heart 2005; 91: 250 – 256.
  18. Messerli FH, Sundgaard-Riise K, Ventura HO, Dunn FG, Oigman
W, Frohlich ED. Clinical and hemodynamic determinants of left  
ventricular dimensions. Arch Intern Med 1984; 144: 477 – 481.
 19. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG,
Enriquez-Sarano M. Burden of valvular heart diseases: A popula-  
tion-based study. Lancet 2006; 368: 1005 – 1011.
  20. Cioffi G, de Simone G, Cramariuc D, Mureddu GF, Gerdts E. Inap-
propriately high left-ventricular mass in asymptomatic mild-mod-  
erate aortic stenosis. J Hypertens 2012; 30: 421 – 428.
  21. Cioffi G, Faggiano P, Vizzardi E, Tarantini L, Cramariuc D, Gerdts
E, et al. Prognostic effect of inappropriately high left ventricular
mass in asymptomatic severe aortic stenosis. Heart 2011; 97:  
301 – 307.
  22. Rader F, Sachdev E, Arsanjani R, Siegel RJ. Left ventricular hyper-
trophy in valvular aortic stenosis: Mechanisms and clinical implica-
tions. Am J Med 2015; 128: 344 – 352.
  23. Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP,  
Guyton RA, et al. 2014 AHA/ACC guideline for the management
of patients with valvular heart disease: A report of the American
College of Cardiology/American Heart Association Task Force on
Practice Guidelines. J Am Coll Cardiol 2014; 63: e57 – e185,  
doi:10.1016/j.jacc.2014.02.536.
  24. Carabello BA. Volume overload. Heart Fail Clin 2012; 8: 33 – 42.
  25. Zile MR, Tomita M, Nakano K, Mirsky I, Usher B, Lindroth J, et
al. Effects of left ventricular volume overload produced by mitral  
regurgitation on diastolic function. Am J Physiol 1991; 261: 1471 –  F, et al. Relevance of coronary microvascular flow impairment to
1480.
  26. Corin WJ, Murakami T, Monrad ES, Hess OM, Krayenbuehl HP.
Left ventricular passive diastolic properties in chronic mitral regur-  
gitation. Circulation 1991; 83: 797 – 807.
  27. Wisenbaugh T, Spann JF, Carabello BA. Differences in myocardial
performance and load between patients with similar amounts of  
chronic aortic versus chronic mitral regurgitation. J Am Coll Car-
diol 1984; 3: 916 – 923.
  28. Feiring AJ, Rumberger JA. Ultrafast computed tomography analy-
sis of regional radius-to-wall thickness ratios in normal and vol-
ume-overloaded human left ventricle. Circulation 1992; 85:  
1423 – 1432.
  29. Carabello BA. The relationship of left ventricular geometry and
hypertrophy to left ventricular function in valvular heart disease. J
Heart Valve Dis 1995; 4: S132 – S138.  
  30. Schwarz F, Flameng W, Schaper J, Hehrlein F. Correlation between
myocardial structure and diastolic properties of the heart in chronic
aortic valve disease: Effects of corrective surgery. Am J Cardiol
1978; 42: 895 – 903.  
Circulation Journal  Vol.80, March 2016
LAZZERONI D et al.
31. Krayenbuehl HP, Hess OM, Monrad ES, Schneider J, Mall G,
Turina M. Left ventricular myocardial structure in aortic valve
disease before, intermediate, and late after aortic valve replacement.
Circulation 1989; 79: 744 – 755.
32. Khouri MG, Peshock RM, Ayers CR, de Lemos JA, Drazner MH.
A 4-tiered classification of left ventricular hypertrophy based on
left ventricular geometry: The Dallas heart study. Circ Cardiovasc
Imaging 2010; 3: 164 – 171.
33. Bang CN, Gerdts E, Aurigemma GP, Boman K, de Simone G,
Dahlöf B, et al. Four-group classification of left ventricular hyper-
trophy based on ventricular concentricity and dilatation identifies a
low-risk subset of eccentric hypertrophy in hypertensive patients.
Circ Cardiovasc Imaging 2014; 7: 422 – 429.
34. Garg S, de Lemos JA, Ayers C, Khouri MG, Pandey A, Berry JD,
et al. Association of a 4-tiered classification of LV hypertrophy
with adverse CV outcomes in the general population. JACC Car-
diovasc Imaging 2015; 8: 1034 – 1041.
35. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with
preserved ejection fraction: Comorbidities drive myocardial dys-
function and remodeling through coronary microvascular endothe-
lial inflammation. J Am Coll Cardiol 2013; 62: 263 – 271.
36. Camici PG, D’amati G, Rimoldi O. Coronary microvascular dys-
function: Mechanisms and functional assessment. Nat Rev Cardiol
37. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J
Med 2007; 356: 830 – 840.
38. Gould KL, Johnson NP, Bateman TM, Beanlands RS, Bengel FM,
Bober R, et al. Anatomic versus physiologic assessment of coro-
nary artery disease: Role of coronary flow reserve, fractional flow
reserve, and positron emission tomography imaging in revascular-
ization decision-making. J Am Coll Cardiol 2013; 62: 1639 – 1653.
39. Crea F, Camici PG, Bairey Merz CN. Coronary microvascular
dysfunction: An update. Eur Heart J 2013; 35: 1101 – 1111.
40. Camici PG, Olivotto I, Rimoldi O. The coronary circulation and
blood flow in left ventricular hypertrophy. J Mol Cell Cardiol 2012;
52: 857 – 864.
41. Radvan J, Choudhury L, Sheridan DJ, Camici PG. Comparison of
coronary vasodilator reserve in elite rowing athletes versus hyper-
trophic cardiomyopathy. Am J Cardiol 1997; 80: 1621 – 1623.
42. Toraa M, Pouillard F, Merlet P, Friemel F. Cardiac hypertrophy and
coronary reserve in endurance athletes. Can J Appl Physiol 1999;
24: 87 – 95.
43. Hildick-Smith DJR, Johnson PJ, Wisbey CR, Winter EM, Shapiro
LM. Coronary flow reserve is supranormal in endurance athletes:
An adenosine transthoracic echocardiographic study. Heart 2000;
84: 383 – 389.
44. Camici PG, Chiriatti G, Lorenzoni R, Bellina RC, Gistri R, Italiani
G, et al. Coronary vasodilation is impaired in both hypertrophied
and non-hypertrophied myocardium of patients with hypertrophic
cardiomyopathy: A study with nitrogen-13ammonia and positron
emission tomography. J Am Coll Cardiol 1991; 17: 879 – 886.
45. Olivotto I, Girolami F, Sciagra’ R, Michael J, Ackerman MJ, Sotgia
B, et al. Microvascular function is selectively impaired in patients
with hypertrophic cardiomyopathy and sarcomere myofilament
gene mutations. J Am Coll Cardiol 2011; 58: 839 – 848.
46. Basso C, Thiene G, Corrado D, Buja G, Melacini P, Nava A.
Hypertrophic cardiomyopathy and sudden death in the young:
Pathologic evidence of myocardial ischemia. Hum Pathol 2000; 31:
988 – 998.
47. Olivotto I, Cecchi F, Gistri R, Lorenzoni R, Chiriatti G, Girolami
long-term remodeling and systolic dysfunction in hypertrophic
cardiomyopathy. J Am Coll Cardiol 2006; 47: 1043 – 1048.
48. Cecchi F, Olivotto I, Gistri R, Lorenzoni R, Chiriatti G, Camici PG.
Coronary microvascular dysfunction and prognosis in hypertrophic
cardiomyopathy. N Engl J Med 2003; 349: 1027 – 1035.
49. Neglia D, Parodi O, Gallopin M, Sambuceti G, Giorgetti A, Pratali
L, et al. Myocardial blood flow response to pacing tachycardia and
to dipyridamole infusion in patients with dilated cardiomyopathy
without overt heart failure: A quantitative assessment by positron
emission tomography. Circulation 1995; 92: 796 – 804.
50. Neglia D, Michelassi C, Trivieri MG, Sambuceti G, Giorgetti A,
Pratali L, et al. Prognostic role of myocardial blood flow impair-
ment in idiopathic left ventricular dysfunction. Circulation 2002;
105: 186 – 193.
51. Rimoldi O, Rosen SD, Camici PG. The blunting of coronary flow
reserve in hypertension with left ventricular hypertrophy is trans-
mural and correlates with systolic blood pressure. J Hypertens
2014; 32: 2465 – 2471.
52. Neglia D, Fommei E, Varela-Carver A, Mancini M, Ghione S,
From LV Hypertrophy to Dysfunction
Lombardi M, et al. Perindopril and indapamide reverse coronary
microvascular remodelling and improve flow in arterial hyperten-  
sion. J Hypertens 2011; 29: 364 – 372.
  53. Murthy VL, Naya M, Foster CR, Hainer J, Gaber M, Di Carli G, et
al. Improved cardiac risk assessment with noninvasive measures of
coronary flow reserve. Circulation 2011; 124: 2215 – 2224.
  54. Rajappan K, Rimoldi OE, Dutka DP, Ariff B, Pennell DJ, Sheridan
DJ, et al. Mechanisms of coronary microcirculatory dysfunction in  
patients with aortic stenosis and angiographically normal coronary
arteries. Circulation 2002; 105: 470 – 476.
  55. Hildick-Smith DJ, Shapiro LM. Coronary flow reserve improves
after aortic valve replacement for aortic stenosis: An adenosine
transthoracic echocardiography study. J Am Coll Cardiol 2000; 36:
1889 – 1896.  
  56. Akasaka T, Yoshida K, Hozumi T, Takagi T, Kaji S, Kawamoto T,
et al. Restricted coronary flow reserve in patients with mitral regur-
gitation improves after mitral reconstructive surgery. J Am Coll
Cardiol 1998; 32: 1923 – 1930.  
  57. Gascho JA, Mueller TM, Eastham C, Marcus ML. Effect of vol-
ume-overload hypertrophy on the coronary circulation in awake
dogs. Cardiovasc Res 1982; 16: 288 – 292.
  58. Mewton N, Liu CY, Croisille P, Bluemke D, Lima JA. Assessment  
of myocardial fibrosis with cardiovascular magnetic resonance. J
Am Coll Cardiol 2011; 57: 891 – 903.
  59. Varnava AM, Elliott PM, Sharma S, McKenna WJ, Davies MJ.
Hypertrophic cardiomyopathy: The interrelation of disarray, fibro-  
sis, and small vessel disease. Heart 2000; 84: 476 – 482.
  60. Anderson KR, Sutton MG, Lie JT. Histopathological types of car-
diac fibrosis in myocardial disease. J Pathol 1979; 128: 79 – 85.
  61. Fabre A, Sheppard MN. Sudden adult death syndrome and other  
non-ischaemic causes of sudden cardiac death. Heart 2006; 92:
316 – 320.
  62. Emoto R, Yokota Y, Miki T, Nomura H, Miki T, Usuki S, et al.
Prognosis of hypertrophic cardiomyopathy: Echocardiographic and
postmortem histopathologic study of 30 patients. J Cardiol 1988;  
18: 695 – 703.
  63. Brandenburg RO. Cardiomyopathies and their role in sudden death.
J Am Coll Cardiol 1985; 5: 185B – 189B.
  64. Kim RJ, Fieno DS, Parrish TB, Harris K, Chen EL, Simonetti O, et
al. Relationship of MRI delayed contrast enhancement to irrevers-  
ible injury, infarct age, and contractile function. Circulation 1999;
100: 1992 – 2002.
  65. Schelbert EB, Hsu LY, Anderson SA, Mohanty BD, Karim SM,  
Kellman P, et al. Late gadolinium-enhancement cardiac magnetic
resonance identifies postinfarction myocardial fibrosis and the bor-
der zone at the near cellular level in ex vivo rat heart. Circ Cardio-
vasc Imaging 2010; 3: 743 – 752.
  66. Kim RJ, Wu E, Rafael A, Chen EL, Parker MA, Simonetti O, et al.  
The use of contrast-enhanced magnetic resonance imaging to iden-
tify reversible myocardial dysfunction. N Engl J Med 2000; 343:
1445 – 1453.
  67. Bodi V, Sanchis J, Lopez-Lereu MP, Losada A, Nunez J, Pellicer
M, et al. Usefulness of a comprehensive cardiovascular magnetic  
resonance imaging assessment for predicting recovery of left ven-
tricular wall motion in the setting of myocardial stunning. J Am
Coll Cardiol 2005; 46: 1747 – 1752.
  68. Iles L, Pfluger H, Lefkovits L, Butler MJ, Kistler PM, Kaye DM, et  
al. Myocardial fibrosis predicts appropriate device therapy in
patients with implantable cardioverter defibrillators for primary
prevention of sudden cardiac death. J Am Coll Cardiol 2011; 57:  
821 – 828.
  69. McCrohon JA, Moon JCC, Prasad SK, McKenna WJ, Lorenz CH,
Coats AJS, et al. Differentiation of heart failure related to dilated  
cardiomyopathy and coronary artery disease using gadolinium-
enhanced cardiovascular magnetic resonance. Circulation 2003;
108: 54 – 59.
  70. Gulati A, Jabbour A, Ismail TF, Guha K, Khwaja J, Raza S, et al.
Association of fibrosis with mortality and sudden cardiac death in  
patients with nonischemic dilated cardiomyopathy. JAMA 2013;
309: 896 – 908.
  71. Kasner M, Westermann D, Lopez B, Gaub R, Escher F, Kuhl U, et
al. Diastolic tissue Doppler indexes correlate with the degree of
collagen expression and cross-linking in heart failure and normal  
ejection fraction. J Am Coll Cardiol 2011; 57: 977 – 985.
  72. Weber KT, Brilla CG. Pathological hypertrophy and cardiac inter-
stitium: Fibrosis and renin-angiotensin-aldosterone system. Circu-
lation 1991; 83: 1849 – 1865.
  73. Flett AS, Hasleton J, Cook C, Hausenloy D, Quarta G, Ariti C, et  
al. Evaluation of techniques for the quantification of myocardial
scar of differing etiology using cardiac magnetic resonance. JACC
Circulation Journal  Vol.80, March 2016
563
Cardiovasc Imaging 2011; 4: 150 – 156.
74. Moon JC, Messroghli DR, Kellman P, Piechnik SK, Robson MD,
Ugander M, et al. Myocardial T1 mapping and extracellular volume
quantification: A Society for Cardiovascular Magnetic Resonance
(SCMR) and CMR Working Group of the European Society of
Cardiology consensus statement. J Cardiovasc Magn Reson 2013;
15: 92.
75. Hinojar R, Varma N, Child N, Goodman B, Jabbour A, Yu CY, et
al. T1 Mapping in discrimination of hypertrophic phenotypes:
Hypertensive heart disease and hypertrophic cardiomyopathy:
Findings from the International T1 Multicenter Cardiovascular
Magnetic Resonance Study. Circ Cardiovasc Imaging 2015; 8:
e003285, doi:10.1161/CIRCIMAGING.115.003285.
76. Flett AS, Hasleton J, Cook C, Hausenloy D, Quarta G, Ariti C, et
al. Evaluation of techniques for the quantification of myocardial
scar of differing etiology using cardiac magnetic resonance. JACC
Cardiovasc Imaging 2011; 4: 150 – 156.
77. Harris KM, Spirito P, Maron MS, Zenovich AG, Formisano F,
Lesser JR, et al. Prevalence, clinical profile, and significance of left
ventricular remodeling in the end-stage phase of hypertrophic car-
diomyopathy. Circulation 2006; 114: 216 – 225.
78. Sotgia B, Sciagrà R, Olivotto I, Casolo G, Rega L, Betti I, et al.
Spatial relationship between coronary microvascular dysfunction
and delayed contrast enhancement in patients with hypertrophic
cardiomyopathy. J Nucl Med 2008; 49: 1090 – 1096.
79. Moon JC, Mogensen J, Elliott PM, Smith GC, Elkington AG,
Prasad SK, et al. Myocardial late gadolinium enhancement cardio-
vascular magnetic resonance in hypertrophic cardiomyopathy
caused by mutations in troponin I. Heart 2005; 91: 1036 – 1040.
80. Rudolph A, Abdel-Aty H, Bohl S, Boyé P, Zagrosek A, Dietz R, et
al. Noninvasive detection of fibrosis applying contrast-enhanced
cardiac magnetic resonance in different forms of left ventricular
hypertrophy relation to remodeling. J Am Coll Cardiol 2009; 53:
284 – 291.
81. Olivotto I, Maron BJ, Appelbaum E, Harrigan CJ, Salton C, Gibson
CM, et al. Spectrum and clinical significance of systolic function
and myocardial fibrosis assessed by cardiovascular magnetic reso-
nance in hypertrophic cardiomyopathy. Am J Cardiol 2010; 106:
261 – 267.
82. O’Hanlon R, Grasso A, Roughton M, Moon JC, Clark S, Wage R,
et al. Prognostic significance of myocardial fibrosis in hypertrophic
cardiomyopathy. J Am Coll Cardiol 2010; 56: 867 – 874.
83. Adabag AS, Maron BJ, Appelbaum E, Harrigan CJ, Buros JL,
Gibson CM, et al. Occurrence and frequency of arrhythmias in
hypertrophic cardiomyopathy in relation to delayed enhancement
on cardiovascular magnetic resonance. J Am Coll Cardiol 2008; 51:
1369 – 1374.
84. Chan RH, Maron BJ, Olivotto I, Pencina MJ, Assenza GE, Haas T,
et al. Prognostic value of quantitative contrast-enhanced cardiovas-
cular magnetic resonance for the evaluation of sudden death risk in
patients with hypertrophic cardiomyopathy. Circulation 2014; 130:
484 – 495.
85. Ismail TF, Jabbour A, Gulati A, Mallorie A, Raza S, Cowling TE,
et al. Role of late gadolinium enhancement cardiovascular magnetic
resonance in the risk stratification of hypertrophic cardiomyopathy.
Heart 2014; 100: 1851 – 1858.
86. Brooks A, Schinde V, Bateman AC, Gallagher PJ. Interstitial fibrosis
in the dilated nonischaemic myocardium. Heart 2003; 89: 1255 – 
1256.
87. Weber KT, Brilla CG, Janicki JS. Myocardial fibrosis: Functional
significance and regulatory factors. Cardiovasc Res 1993; 27: 341 – 
348.
88. McCrohon JA, Moon JC, Prasad SK, McKenna WJ, Lorenz CH,
Coats AJ, et al. Differentiation of heart failure related to dilated
cardiomyopathy and coronary artery disease using gadolinium-
enhanced cardiovascular magnetic resonance. Circulation 2003; 108:
54 – 59.
89. Leong DP, Chakrabarty A, Shipp N, Molaee P, Madsen PL, Joerg
L, et al. Effects of myocardial fibrosis and ventricular dyssynchrony
on response to therapy in new presentation idiopathic dilated car-
diomyopathy: Insights from cardiovascular magnetic resonance and
echocardiography. Eur Heart J 2012; 33: 640 – 648.
90. Lehrke S, Lossnitzer D, Schob M, Steen H, Merten C, Kemmling
H, et al. Use of cardiovascular magnetic resonance for risk stratifi-
cation in chronic heart failure: Prognostic value of late gadolinium
enhancement in patients with non-ischaemic dilated cardiomyopa-
thy. Heart 2011; 97: 727 – 732.
91. Assomull RG, Prasad SK, Lyne J, Smith G, Burman ED, Khan M,
et al. Cardiovascular magnetic resonance, fibrosis, and prognosis in
dilated cardiomyopathy. J Am Coll Cardiol 2006; 48: 1977 – 1985.
564 LAZZERONI D et al.

  92. Yokota H, Imai Y, Tsuboko Y, Tokumaru AM, Fujimoto H, Harada
K. Nocturnal blood pressure pattern affects left ventricular remod-
eling and late gadolinium enhancement in patients with hyperten-
sion and left ventricular hypertrophy. PLoS One 2013; 8: e67825,
doi:10.1371/journal.pone.0067825.
  93. Dweck MR, Joshi S, Murigu T, Alpendurada F, Jabbour A, Melina
G, et al. Midwall fibrosis is an independent predictor of mortality
in patients with aortic stenosis. J Am Coll Cardiol 2011; 58: 1271 –    98. Van De Heyning CM, Magne J, Piérard LA, Bruyère PJ, Davin L,
1279.
  94. Shah AS, Chin CW, Vassiliou V, Cowell SJ, Doris M, Kwok TC,
et al. Left ventricular hypertrophy with strain and aortic stenosis.
Circulation 2014; 130: 1607 – 1616.
 95. Krayenbuehl HP, Hess OM, Monrad ES, Schneider J, Mall G,
Turina M. Left ventricular myocardial structure in aortic valve
disease before, intermediate, and late after aortic valve replacement.
Circulation 1989; 79: 744 – 755.
  96. Maron BJ, Ferrans VJ, Roberts WC. Myocardial ultrastructure in
patients with chronic aortic valve disease. Am J Cardiol 1975; 35:
725 – 739.
  97. Borer JS, Truter S, Herrold EM, Falcone DJ, Pena M, Carter JN, et
al. Myocardial fibrosis in chronic aortic regurgitation: Molecular
and cellular responses to volume overload. Circulation 2002; 105:
1837 – 1842.
De Maeyer C, et al. Late gadolinium enhancement CMR in primary
mitral regurgitation. Eur J Clin Invest 2014; 44: 840 – 847.
  99. Edwards NC, Moody WE, Yuan M, Weale P, Neal D, Townend JN,
et al. Quantification of left ventricular interstitial fibrosis in asymp-
tomatic chronic primary degenerative mitral regurgitation. Circ
Cardiovasc Imaging 2014; 7: 946 – 953.
100. Drazner MH. The progression of hypertensive heart disease. Circu-
lation 2011; 123: 327 – 334.

Circulation Journal  Vol.80, March 2016