1. health and fitness
2. disease

REVIEW
European Heart Journal (2012) 33, 1724–1733
doi:10.1093/eurheartj/ehs150
Controversies in cardiovascular medicine
Pharmacological treatment options
for hypertrophic cardiomyopathy: high
time for evidence
Roberto Spoladore1*, Martin S. Maron2, Rossella D’Amato 1, Paolo G. Camici 1,
and Iacopo Olivotto 3
Received 2 March 2012; revised 22 April 2012; accepted 3 May 2012; online publish-ahead-of-print 19 June 2012
Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease, affecting over one million individuals in Europe. Hypertrophic cardiomyopathy patients often require pharmacological intervention for control of symptoms, dynamic left ventricular outflow obstruction, supraventricular and ventricular arrhythmias, and microvascular ischaemia. Current treatment strategies in HCM are predicated on
the empirical use of long-standing drugs, such as beta-adrenergic and calcium blockers, although with little evidence supporting their clinical
benefit in this disease. In the six decades since the original description of the disease, ,50 pharmacological studies enrolling little over 2000
HCM patients have been performed, the majority of which were small, non-randomized cohorts. As our understanding of the genetic basis
and pathophysiology of HCM improves, the availability of transgenic and preclinical models uncovers clues to novel and promising treatment
modalities. Furthermore, the number of patients identified and followed at international referral centres has grown steadily over the decades.
As a result, the opportunity now exists to implement adequately designed pharmacological trials in HCM, using established as well as novel
drug therapies, to potentially intervene on the complex pathophysiology of the disease and alter its natural course. Therefore, it is timely to
review the available evidence for pharmacological therapy of HCM patients, highlight the most relevant gaps in knowledge, and address some
of the most promising areas for future pharmacological research, in an effort to move HCM into the era of evidence-based management.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Hypertrophic cardiomyopathy † Pharmacological treatment † Outcome † Randomized trials
Introduction
Hypertrophic cardiomyopathy (HCM) is the most common
genetic heart disease,1 – 7 with a prevalence in the general population of 1:500, i.e. an estimate of .1 000 000 affected individuals in
Europe, representing a leading cause of sudden cardiac death in the
young3 and a prevalent cause of heart failure and stroke.1 Hypertrophic cardiomyopathy is characterized by a very complex pathophysiological background, reflecting into heterogeneous clinical
manifestations and natural history. Established features of the
disease include a constellation of asymmetric left ventricular (LV)
hypertrophy, deranged cardiomyocyte energetics, diastolic dysfunction, microvascular ischaemia, enhanced myocardial fibrosis,
abnormal sympathetic innervation, and multifactorial arrhythmogenesis:8 – 10 each represents a potential objective for treatment.
In addition, dynamic LV outflow tract (LVOT) obstruction is
present in approximately 70% of HCM patients, either at rest or
with physiological provocation. Left ventricular outflow tract obstruction is a major determinant of symptoms, such as dyspnoea,
chest pain, or presyncope, and has represented the most visible
and consistent target of therapeutic efforts in HCM (possibly
with the exception of sudden death prevention), based both on
drugs and invasive septal reduction strategies.11
Pharmacological interventions in patients with HCM are often
necessary for control of limiting heart failure and anginal symptoms, LVOT obstruction, and arrhythmias.12 However, medical
treatment strategies remain largely predicated on a small number
of clinical studies, and are most often empirically based on personal
experience or extrapolation from other cardiac conditions.13 Thus,
although valuable clinical guidelines exist for HCM,1,2 the strength
of recommendations for pharmacological treatment is largely not
evidence based.
* Corresponding author. Tel: +39 0226437608, Fax: +39 0226437359, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: [email protected]
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1
Cardiothoracic and Vascular Department, Vita-Salute University and San Raffaele Scientific Institute Milan, Milan 20132, Italy; 2HCM Center, Tufts Medical Center, Boston, MA,
USA; and 3Referral Center for Cardiomyopathies, Careggi University Hospital, Florence, Italy
Pharmacological treatment of HCM
In recent years, the widespread use of imaging and genetic
testing, coupled with an increasing awareness in the cardiology
community, have led to the identification of large populations of
individuals with HCM, regularly followed at international referral
centres.14 At the same time, a number of genetic and pathophysiological studies have highlighted novel potential targets for diseasespecific treatments. As a result, the opportunity now exists to implement adequately designed pharmacological trials in HCM, using
established as well as novel drug therapies, to potentially intervene
on the complex pathophysiology of the disease and alter its natural
course. Therefore, we believe it is timely to review the available
evidence for pharmacological treatment of HCM, and highlight
some of the relevant disease pathways which could be targeted
by current or emerging drug therapies.
The evidence: a systematic review
In a comprehensive Medline search (pubmed.gov), original articles,
reviews, and editorials published in English were tracked, addressing
the use of any pharmacological agent employed in HCM cohorts in
the period 1950–2011, with the exception of case reports. References in each of the papers retrieved, as well as in HCM and
heart failure guidelines, were also searched. A total of 45 studies
were identified over the last 60 years (i.e. ,1 per year), enrolling
a total of 2121 HCM patients (Supplementary material online,
Table S1). Study design in the majority of cases was prospective
(n ¼ 40, 87%); however, only 5 were randomized, double-blind
placebo-controlled trials. The number of papers in a comparison
of the period 1991–2011 vs. 1971–1990 demonstrated no increase
in the number of studies (Figure 1A), and only a modest increase in
the number of patients enrolled (627 vs. 1473 patients, respectively).
With regard to sample size, only 7 studies (15%) enrolled .50
patients, whereas 22 (49%) had ,20 patients (Figure 1B). The
maximum number of patients in a single prospective study was
118, in a disopyramide multicentre registry.15
The majority of studies assessed b-blockers or calcium channel
blockers (n ¼ 36), while a smaller number focused on amiodarone
(n ¼ 5), disopyramide (n ¼ 4), or a variety of other agents [angiotensin receptors blockers, propafenone, angiotensin-converting
enzyme (ACE) inhibitors, perhexilline, and statins] (Figure 2).
Thirty-nine studies were based on a single drug, and 6 assessed
multiple drugs, including 4 studies with direct comparison of two
agents (Supplementary material online, Table S2). The clinical endpoints assessed included non-invasive measurement of diastolic
function (n ¼ 13; 29%), relief of dynamic LVOT obstruction (n ¼
11; 25%), and prevention of arrhythmias and sudden death (n ¼
6; 13%) (Supplementary material online, Table S1). Of note, none
of the studies has prospectively addressed the issue of the longterm outcome.
b-Adrenoceptor blockers
b-Blockers represent the mainstay of therapy and have proved effective in patients with angina or dyspnoea on effort, particularly
when associated with LVOT obstruction, and are often employed
to reduce the prevalence of non-sustained ventricular arrhythmias.1,2 These beneficial effects are mediated by sympathetic
modulation of heart rate, ventricular contractility, and stiffness,
leading to improved ventricular relaxation, increased time for diastolic filling, and reduced excitability.12,13 Despite these advantages,
whether long-term treatment with b-blockers ultimately impacts
outcome in HCM patients remains still undefined.4 Furthermore,
it is unknown whether any specific agent is superior to the
others, given the substantial dissimilarities of b-blockers with
regard to pharmacodynamic profile, b-1 selectivity, metabolic
interaction, and antiarrhythmic properties.
Five types of b-blockers have been used in 12 studies enrolling a
total of 391 patients. Propanolol has been assessed in four early
prospective studies focusing on acute gradient reduction and
symptom relief in obstructive patients (Figure 3), and in one retrospective outcome study in a young HCM patient cohort.16 – 20 Furthermore, a double-blind placebo-controlled trial demonstrated
symptomatic benefit with the use of nadolol over verapamil,
whereas another, double-blind crossover trial showed sotalol to
be effective in suppressing supraventricular and ventricular arrhythmias.21,22 Intriguingly, Melacini et al.15 in a retrospective evaluation
reported that none of the patients on long-term treatment with
sotalol in the Padua cohort experienced sudden cardiac death
over a 7-year follow-up.
By virtue of their efficacy in reducing LVOT obstruction and
myocardial ischaemia, current guidelines recommend b-blockers
Figure 1 Number, design, and sample size of hypertrophic cardiomyopathy pharmacological studies according to period of publication (A)
and sample size (B).
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Number and design of available studies
1725
1726
R. Spoladore et al.
Figure 2 Number of hypertrophic cardiomyopathy pharmacological studies (A) and number of patients enrolled (B), based on the type of
drug employed. ACE-I, angiotensin converting enzyme inhibitors; ARBs, angiotensin receptor blockers.
mm
Hg
240
160
L.V.
B.A.
80
40
0
C.O. 8.40 L/min.
A.O. 0.88 cm2
C.O. 8.62 L/min.
A.O. 0.76 cm2
C.O. 8.24 L/min.
A.O. 0.86 cm2
After receptor blockade
mm
Hg
240
0.5 sec.
160
80
40
0
C.O. 6.62
A.O. 1.05
Control
C.O. 5.58
A.O. 0.90
Exercise
C.O. 6.13
A.O. 1.03
Post-exercise
Figure 3 Effects of beta-adrenergic blockade on subaortic obstruction. Simultaneous pressures recorded in the left ventricle (LV) and brachial artery (BA). Observations prior to the beta-adrenergic-blocking agent Nethalide are shown in the top three panels, while the observations
following Nethalide administration are shown in the bottom three panels. Control measurements before exercise in each instance are on the
left, measurements at the completion of the exercise period are in the centre, and after the cessation of exercise on the right. CO, cardiac
output; AO, effective outflow orifice. The stippled area represents the LV – BA pressure gradient. Reproduced from Harrison et al.99
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Before receptor blockade
1727
Pharmacological treatment of HCM
as first line agents in symptomatic patients, both with or without
resting obstruction.1,2 With regard to inducible obstruction, two
recent studies have consistently shown marked reduction or abolition in exercise-induced LVOT obstruction with bisoprolol at
well-tolerated doses (S. Nistri, submitted for publication).23
Disopyramide
An old class I A antiarrhythmic drug, disopyramide has been used
successfully to attenuate the pressure gradient and improve symptoms in patients with LVOT obstruction, generally in association
with b-blockers.46 – 58 The beneficial effect of disopyramide is due
to its negative inotropic action, reducing the drag forces that
trigger dynamic subaortic obstruction. Its efficacy and safety have
been demonstrated in a large retrospective registry.49 Nevertheless,
concerns regarding QTc prolongation and significant anticholinergic
side-effects may limit its long-term use. In our own practice, disopyramide is often used the short-term as a bridge to surgical myectomy
in symptomatic patients with severe LV outflow obstruction.4
Amiodarone
Early data stimulated hopes that amiodarone might be highly protective in HCM, with regard to potentially malignant ventricular
arrhythmias.50 – 53 However, its efficacy in preventing sudden
death is now considered suboptimal, based on the fact that 20%
of patients dying suddenly in one retrospective study were on
active amiodarone treatment at the time of death.15 In addition,
the well-known adverse side-effects of this drug render its longterm use challenging. At present, amiodarone remains the most
effective and widely used treatment for atrial fibrillation (AF),
Other drugs
Very limited data exist regarding the use of angiotensin converting
enzyme inhibitors in HCM. A relatively old study showed the acute
effects of combined treatment of intracoronary enalapril and sublingual captopril in restoring coronary flow reserve.54 Four subsequent prospective randomized pilot trials suggested a potential
benefit of renin–angiotensin –aldosterone (RAAS) inhibitors on
LV function and progression of hypertrophy,55 – 57 but have not
been followed by larger studies. In addition, Valsartan is effective
in suppressing the synthesis of type I collagen in HCM patients, suggesting potential beneficial effects for prevention of myocardial
fibrosis.58 A single study suggested a positive effect of intravenous
propafenone in reducing LVOT obstruction.59 Finally, a pilot study
enrolling 21 HCM patients, based on promising pre-clinical
data, failed to prove significant modifications in echocardiographic
indexes of LV hypertrophy following treatment with atorvastatin.60
Pharmacological control of left
ventricular outflow tract obstruction
The pharmacological treatment of LVOT obstruction and related
symptoms in HCM patients is based on a time-honoured combination of negative inotropic agents, including b-blockers, calcium
antagonists, and disopyramide.1,2 In general, b-blockers are most
effective on the latent, exercise-related form of LVOT obstruction,
but tend to be less effective when severe obstruction is present at
rest. Non-dihidropiridinic calcium antagonists such as verapamil or
diltiazem are even less effective, because their negative inotropic
action is partly counteracted by their gradient-enhancing vasodilating properties. Disopyramide has been proven safe and effective,
but can be problematic in the long-term due to its anticholinergic
side-effects and, in a significant percentage of patients, to a loss of
clinical benefits decrease over time.7 As a result of these limitations, pharmacological control of symptoms in obstructive HCM
patients is often less than optimal and may be poor. In the presence of drug refractory, disabling symptoms, invasive options
such as surgical septal myectomy or, in a very selected subset of
patients, septal alcohol ablation, represent the treatment of
choice.61 Of note, obstructive HCM patients undergoing surgical
myectomy have shown excellent long-term survival and reduced
risk of sudden cardiac death compared with those treated conservatively with drugs.7,62
Management of atrial fibrillation
Atrial fibrillation is a common occurrence in HCM population,
often representing a turning point in the clinical course by virtue
of HCM-related mortality, symptomatic deterioration, and risk of
stroke.1,2 The powerful independent association of AF with
HCM-related mortality and morbidity underlines the necessity
for aggressive therapeutic strategies in these patients,63 including
early initiation of oral anticoagulation for the prevention of
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Calcium channel blockers
Non-dihydropiridine calcium-channel blockers such as verapamil
and diltiazem have been successfully employed in symptomatic
patients with non-obstructive HCM. Conversely, HCM guidelines
suggest caution in using calcium channel blockers in patients with
significant LVOT obstruction, due to their potentially adverse
haemodynamic effects.24 – 31 The beneficial effects of calcium
channel blockers are largely mediated by their negative inotropic
and chronotropic effects, leading to prolonged LV filling time and
improved redistribution of flow towards the subendocardial
layers of the LV.12,13,32 Verapamil is the single most studied agent
in HCM, with 367 patients enrolled in 12 studies, of which 8
were single drug and 4 were multiple drug evaluations. Eight of
these studies were prospective. To date, there is no definite evidence that verapamil effectively improves functional capacity in
HCM, although the drug has been used for decades to ameliorate
quality of life in non-obstructive patients, and is considered standard treatment.1,2,21,33 – 40 Diltiazem has been studied in 4 small prospective trials enrolling 55 HCM patients in total. In three,
diltiazem was shown to improve LV diastolic parameters, either
acutely or at mid-term administration, whereas one showed beneficial effects of the drug on myocardial ischaemia assessed by
exercise-single photon emission computerized tomography (Supplementary material online, Table S1).41 – 44 Following intriguing
pre-clinical evidence (reviewed below), an ongoing study is
testing the hypothesis that diltiazem may prevent development
of the HCM phenotype in genotype-positive individuals.45
although no study has specifically addressed such indication in
HCM.50 – 53 In addition, the drug is often used for control of asymptomatic ventricular ectopics, and to minimize the likelihood of appropriate discharge in patients with implantable defibrillators. To
our knowledge, there is no systematic experience with dronedarone in HCM patients.
1728
Pre-clinical studies
We found nine experimental studies assessing pharmacological
treatment in HCM animal models (Supplementary material
online, Table S3). Long-term treatment with N-Acetilcysteine, a
precursor to the most abundant intracellular non protein thiol
pool against oxidative stress, reversed cardiac and myocyte hypertrophy and interstitial fibrosis, prevented LV systolic dysfunction,
and improved arrhythmogenic propensity in an established transgenic rabbit model of human HCM. Resolution of cardiac and
myocyte hypertrophy and prevention of cardiac systolic dysfunction with NAC are novel findings. The data suggest the potential
beneficial effects of this drug in reversal of cardiac phenotype in
HCM and prevention of global cardiac systolic dysfunction.66,67
In a randomized placebo-controlled study in transgenic rabbits,
the administration of atorvastatin prior to phenotypic expression
prevented the development of cardiac hypertrophy over a 1-year
period of observation. Prevention of cardiac hypertrophy was
demonstrated at organ, cell, and molecular levels.68 Similar
results were obtained by the administration of simvastatin.69 Furthermore, two randomized studies in mice and rats showed how
RAAS antagonists, alone or in combination with aldosterone,
were able to prevent and reverse myocardial fibrosis and hypertrophy,70,71 and two prospective studies demonstrated diltiazem
to be effective in preventing development of hypertrophy and diastolic dysfunction in transgenic HCM mice.72,73 Finally, trimetazidine, a metabolic modulator with anti-Ca2+ properties, was
effective in increasing survival and reducing heart and liver hypertrophy in cardiomyopathic Syrian hamsters.74
difficulties and limited efforts directed at clinical research initiatives
in this area. Most of these studies have employed surrogate endpoints such as exercise tolerance, change in LVOT gradients, or
indexes of cardiac performance, and were therefore not
powered to assess the impact of therapeutic interventions on
the natural history and outcome of HCM. Thus, evidence-based
approaches to novel treatments in HCM patients represent an
urgent priority, emphasized by the recent report of the Working
Group of the National Heart, Lung, and Blood Institute on ‘Research Priorities in Hypertrophic Cardiomyopathy’.14
It is true that genetic cardiomyopathies pose a number of significant challenges with respect to designing and implementing properly powered, prospective randomized clinical trials. Hypertrophic
cardiomyopathy is a relatively uncommon disease in which a
limited number of patients are available for participation in randomized trials, even within the major international tertiary referral
centres for this disease. Furthermore, in view of the relatively
low event rates of hard cardiovascular endpoints associated with
HCM, large populations are theoretically required in order to
detect a benefit of any given treatment on prognosis. On the
other hand, designing studies which incorporate ‘softer’ clinical
endpoints, such as those based on non-invasive testing or serum
biomarkers, is not optimal because they might represent a
further hurdle to randomization.
Based on these considerations, for example, specific issues such
as the long-term comparison of the survival benefits of surgical
myectomy vs. alcohol septal ablation appear exceedingly difficult
to address.75 On the other hand, the potential availability of integrated networks among international referral centres, several of
which actively follow cohorts of .1000 HCM patients, might
render the performance of these large trials possible. In selected
subgroups, such as patients with evidence of adverse LV remodelling, at high risk of end-stage progression, pharmacological studies
addressing outcome might be easier to perform, due to the substantially higher event rates expected.76
While hard endpoints including total cardiovascular mortality,
heart failure-related and sudden cardiac death remain the gold
standard of any therapeutic investigation in HCM patients, it is reasonable to consider prospective studies incorporating more attainable but sound clinical endpoints, reflecting important features of
the disease pathophysiology, which have previously been shown
to have prognostic value. Specifically, advanced imaging techniques
can be exploited to quantitate the effect of novel treatments on
parameters such LV coronary microvascular function and myocardial tissue fibrosis.2,14,77 Clinical pilot studies designed with these
endpoints might provide the rationale for the larger multicentre,
international prospective studies necessary to determine, over a
reasonable period of time, the benefit of novel treatments on
the natural history of HCM.
Limitations of clinical trials
in HCM
Potential treatment targets
To date, the studies evaluating specific medical treatments for
HCM have included little more than 2000 patients—i.e. a study
sample less than a single, small multicentre heart failure, or coronary disease trial. The number of pharmacological studies per year
has not increased over the last four decades, reflecting both
Plausible options for treatment of HCM patients include both
novel indications of well-known drugs as well as the development
of novel agents targeting disease-specific abnormalities. The latter approach, certainly the most promising, must necessarily derive from
the clinical translation of advanced basic research. Therefore,
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cardioembolic stroke, which should be considered even after a
single episode of paroxysmal AF.1,2 Control of AF-related symptoms may be achieved with adequate rate control in older patients,
using b-blockers or calcium channel blockers.1,2 However, rhythm
control appears highly preferable in the young, because of poor
haemodynamic adaptation to permanent AF. Because there is a
paucity of data on rhythm control in patients with HCM, evidence
from other patient populations is extrapolated to HCM.64 Amiodarone is safe and effective in HCM patients, and is considered
the drug of choice in most instances.1,2 Disopyramide has been
shown to be safe when prescribed for control of LVOT obstruction, but its efficacy in prevention of recurrent AF is not well established.1,2,64 Furthermore, there are no data regarding the efficacy of
other class I antiarrhythmic agents, sotalol, or dronedarone in
HCM.1,2,64 Catheter-based ablation techniques have recently
shown promising results in HCM patients with symptomatic AF refractory to medical treatment, but need to be assessed in larger
cohorts and over longer follow-up periods.65
R. Spoladore et al.
Pharmacological treatment of HCM
better understanding of the major mechanisms involved in HCM
pathophysiology remains an essential pre-requisite for any groundbreaking advance in pharmacological treatment14 (Figures 4 and 5).
Aldosterone/angiotensin II and
myocardial fibrosis
In transgenic mouse models of HCM, aldosterone and angiotensin II
(A-II) have been implicated in the pathogenesis of myocyte
1729
hypertrophy and disarray as well as increased interstitial fibrosis.71,78
In addition, myocardial aldosterone levels are increased up to fourfold in HCM patients compared with normal controls.79 These
observations suggest that the RAAS feedback loop may be upregulated in HCM, similar to other chronic conditions where both A-II
and aldosterone directly contribute to adverse cardiac and vascular
remodelling. These changes ultimately lead to the promotion of myocardial fibrosis, a feature of HCM with relevant functional and prognostic implications.78 Further studies are needed to determine more
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Figure 4 Disease pathways of hypertrophic cardiomyopathy, and potential therapeutic interventions. Various signalling pathways and disease
mechanisms can be activated as the result of a specific gene mutation. (A) Disturbed biomechanical stress sensing. (B) Impaired calcium cycling
and sensitivity. (C) Altered energy homeostasis. (D) Increased fibrosis. These pathways should not be considered in isolation because they can
act in concert. LTCC, voltage-dependent L-type calcium channel; PLB, cardiac phospholamban; RyR2, ryanodine receptor 2; SERCA2, sarcoplasmic/endoplasmic reticulum calcium ATPase 2; SR, sarcoplasmic reticulum; TGF-b, transforming growth factor b; T-tubule, transverse
tubule. Reproduced from Frey et al.92
1730
R. Spoladore et al.
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Figure 5 Physiopathology of myocardial ischaemia in hypertrophic cardiomyopathy.
precisely the mechanisms responsible for local upregulation of these
molecular mediators in HCM hearts. Nevertheless, experiments in
rodent models of HCM have shown that drugs that inhibit aldosterone (e.g. spironolactone) or A-II (e.g. angiotensin II blockers) reduce
myocardial fibrosis, attenuate the extent of myocyte disarray, and
improve diastolic function.69,70 These observations have led to
human HCM cross-sectional studies demonstrating that serum
markers of collagen synthesis are increased over degradation and
related to diastolic function.80
At present, the clinical efficacy of anti-remodelling drugs in HCM is
uncertain. However, evidence derived from patients with other
forms of heart disease such as hypertensive cardiomyopathy in
which there are structural abnormalities of the intramural arterioles
and patterns of fibrosis similar to HCM support a potential beneficial
effect of these drugs on coronary microvascular remodelling, fibrosis,
and diastolic function. Greater insight in this area will hopefully be
gained following the completion of an on-going single-centre randomized, double-blind, placebo-controlled trial exploring whether
mineral corticoid receptor blockade reduce myocardial fibrosis in
HCM patients [Martin Maron, MD, oral communication]. The
primary endpoint of this study is the effect of spironolactone on
serial measurements of serum markers of collagen synthesis
Pharmacological treatment of HCM
1731
and degradation at baseline and 12 months follow-up. Promising
applications of aldosterone/A-II inhibition include prevention of
development of the HCM phenotype in genotype-positive individuals, and prevention to end-stage progression in patients with
adverse LV remodelling and declining cardiac function.14
Cascade of myocardial ischaemia
Myocardial ischaemia due to severe coronary microvascular
dysfunction is a well-established pathophysiologic feature of
HCM81 (Figure 5). Marked structural abnormalities of the small
intramural coronary arteries, including medial hypertrophy,
intimal hyperplasia, and decreased luminal size, are considered
the most relevant substrate producing microvascular dysfunction
and myocardial ischaemia in HCM. Microvascular ischaemia
appears to occur more frequently in patients with evidence of
sarcomere myofilament mutations (Figure 6).82 Additional features
such as myocyte disarray, interstitial fibrosis, and reduced capillary
density may contribute to the impairment of tissue perfusion.83
Severe coronary microvascular dysfunction is a strong,
independent predictor of clinical deterioration and death.84,85
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Figure 6 Impact of genetic status on microvascular function. Upper panel: comparison of myocardial blood flow following dipyridamole
between genotype-positive and -negative patients with hypertrophic cardiomyopathy. Bottom panel: (A and B) cardiac magnetic resonance
short-axis and (C and D) four-chamber views in a 15-year-old girl with HCM-causing MHY7 mutation (left) and 16-year-old boy with negative
genetic screening (right). Both patients have the typical HCM phenotype with severe asymmetric hypertrophy localized at the interventricular
septum. Polar maps obtained with positron emission tomography after dipyridamole infusion show severe microvascular dysfunction in the (E)
genotype-positive (mean Dip-MBF 1.6 mL/min/g) but not in the (F ) genotype-negative patient, in whom myocardial blood flow appears to be
preserved (mean Dip-MBF 3.9 mL/min/g). Dip-MBF, myocardial blood flow following dipyridamole; HCM, hypertrophic cardiomyopathy;
MYBPC3, myosin-binding protein C; MYH7, beta-myosin heavy chain. Reproduced from Olivotto et al.97
1732
Deranged intracellular energy utilization
Hypertrophic cardiomyopathy is characterized by abnormal cardiomyocyte energetics, as reflected by a reduced phosphocreatine/ATP
ratio, measured by means of magnetic resonance spectroscopy,
both in animal models and in patients.92 Inefficient energy handling
and energy depletion are believed to represent a cause of hypertrophy in HCM.92 Thus, agent improving the energetic profile of cardiomyocytes may prove very useful in counteracting a fundamental
mechanism of disease. Perhexiline, a metabolic modulator which
inhibits the metabolism of free fatty acids and enhances carbohydrate utilization by the cardiomyocyte,93 has recently been
employed in a randomized double-blind placebo-controlled trial enrolling 46 non-obstructive HCM patients. Following 4.6 months of
treatment with 100 mg/day, perhexiline ameliorated the energetic
profile of the LV, resulting in improved diastolic function and exercise capacity.94 This important study provides a rationale for further
consideration of metabolic therapies in HCM.92,93
Late sodium current and calcium
handling abnormalities
Hypertrophic cardiomyopathy is associated with a complex electrophysiological cardiomyocyte remodelling involving multiple
changes in transmembrane currents. Enhanced late sodium
current has recently been described in isolated cardiomyocytes
from HCM patients, causing intracellular calcium (Ca2+) overload
and ultimately leading to abnormal energy handling and increased
arrhythmogenicity. Selective late sodium current inhibition by
ranolazine markedly improved these abnormalities in vitro.95
Thus, ranolazine represents a promising therapeutic option in
HCM patients, with potential benefits similar or even greater
than those described in patients with coronary artery disease.96
A multicentre, double-blind, placebo-controlled pilot study is currently underway to test the efficacy of ranolazine on exercise tolerance and diastolic function in symptomatic HCM patients
(EUDRA-CT 2011-004507-20).
In addition, studies on HCM patients and animal models have
highlighted several direct consequences of sarcomere gene mutations on intracellular calcium handling, pointing to SERCA2a, phospholamban, and related proteins as promising therapeutic
targets.92 A strategy currently under scrutiny is based on the observation that inhibition of plasma membrane L-type Ca2+ channels by diltiazem normalizes aberrant levels of Ca2+ and
prevents fibrosis and cardiac dysfunction in mouse models of
HCM.97,98 Consequently, an ongoing trial is evaluating the effect
of ‘prophylactic’ treatment with diltiazem in genotype–positive
hypertrophy-negative HCM patients, with the aim of preventing
the development of LV hypertrophy (NCT00319982).
Conclusions
Five decades following the original description of HCM, there is
still a dismal paucity of data supporting pharmacological treatment
strategies for this complex disease. By comparison, device-based,
percutaneous, and surgical treatments of LVOT obstruction have
received significantly greater attention, although rarely in a doubleblind randomized fashion. This can be regarded as a paradox, as
only a minority of patients requires surgery or a device, whereas
the large majority is treated pharmacologically. Of all the potential
new targets for pharmacological treatment, three seem to be
closer to fruition, i.e. cardiomyocyte electrophysiological and
metabolic dysfunction, coronary microvascular dysfunction, and
increased interstitial fibrosis.
Drugs capable of improving the metabolic efficiency of the cardiomyocyte are now available, which hold promise in targeting the
intracellular pathways of hypertrophy and dysfunction in HCM
hearts. Coronary microvascular dysfunction can lead to myocardial
ischaemia and replacement fibrosis in HCM, resulting in adverse LV
remodelling and dysfunction. Likewise, increased interstitial fibrosis
appear to derive from an upregulated RAAS feedback loop, similar
to other chronic conditions where both A-II and aldosterone directly contribute to adverse cardiac and vascular remodelling. Pilot,
proof of principle studies are in the process to be started to ascertain if established drugs, proven effective in other conditions, may
lead to reversal of this phenomenon in HCM.
In the next future, as our understanding of the pathophysiology
of HCM increases, the availability of transgenic models of the
disease, functional imaging techniques, and genome-wide analysis
capabilities will hopefully provide clues to novel and promising
treatment modalities for HCM. However, these will only remain
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Microvascular dysfunction is often present in patients with only
mild or no symptoms and can precede clinical deterioration by
years.86 Thus, the pathophysiologic cascade of events, leading
from remodelling and dysfunction of the intramural coronary
arterioles to myocardial ischaemia and replacement fibrosis, is an
ideal therapeutic target (Figure 5).
There is no proven treatment capable of improving coronary
microvascular function in HCM.87 However, the anatomic and
functional features of coronary microvascular remodelling in
HCM are very similar to those described in hypertensive cardiomyopathy. Mourad et al.87 carried out a pilot study using PET to
investigate the effects on the coronary microcirculation of 6
months of antihypertensive treatment with a very low-dose combination of the ACE inhibitor, perindopril, and the diuretic, indapamide. The study results suggest that treatment with this drug
combination can improve coronary microvascular function in
hypertensive patients. A subsequent PET study by Neglia et al.88
confirmed the results in hypertensive patients. In addition, in an ancillary study, these authors demonstrated, in a well-established
animal model of LV hypertrophy (the spontaneously hypertensive
rat—SHR) that the effects of perindopril plus indapamide on myocardial blood flow are due to reverse remodelling of coronary
arterioles and reduction in vessel rarefaction.
Other drugs, with different mechanisms of action, have the potential to improve coronary microvascular function in HCM. Some of
these drugs act on the extravascular component of coronary resistance by improving diastolic relaxation (ranolazine)89 or prolonging
filling of the coronary reservoir by prolonging diastole (ivabradine)90
others, such as the activators of soluble guanylate cyclase (cGMP),91
might provide additional, direct anti remodelling effect on the microvasculature. Based on recent genetic and molecular insights, further
studies are needed to address novel pharmacological approaches to
microvascular dysfunction in HCM.92
R. Spoladore et al.
Pharmacological treatment of HCM
hypotheses until systematic clinical evidence can be systematically
obtained from adequately designed clinical trials. The changing
epidemiology of the disease now allows what was previously impossible: it is high time to move HCM into the era of evidencebased management.
Supplementary material
Supplementary material is available at European Heart Journal
online.
Funding
This work was supported by the European Union (STREP Project
241577 ‘BIG HEART,’ 7th European Framework Program).
Conflict of interest: P.G.C. is consultant for Servier International.
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