Felix qui potuit rerum cognoscere causas
Happy is he who has been able to learn the causes of things
––Virgil, Georgiche, II, 489
Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease defined clinically
by the presence of unexplained left ventricular (LV) hypertrophy (LVH). In most patients,
HCM is caused by mutations in genes encoding proteins of the cardiac sarcomere.1,
2, 3, 4 Symptoms include dyspnea on exertion, fatigue, angina, atypical chest pain,
syncope, and palpitations. A significant proportion of patients are asymptomatic throughout
life and the diagnosis often follows the incidental finding of abnormal ECG results
or the detection of a cardiac murmur. The natural history is variable. Many patients
have a normal life expectancy, whereas others may experience disease progression with
profound exercise limitation, recurrent arrhythmias, and premature death largely caused
by heart failure.5, 6 Sudden cardiac death (SCD) is relatively rare, occurs more commonly
in young patients, and is mainly caused by ventricular arrhythmias that can be effectively
treated with an implantable cardioverter‐defibrillator.7, 8
HCM is a typical example of monogenic disease where a single nucleotide mutation is
sufficient to cause a complex pathologic phenotype.9 Genetic testing identifies pathogenic
or likely pathogenic variants in 30% to 50% of patients with HCM, and over 1 000 distinct
mutations in genes encoding 11 different components of the sarcomere have been identified.10,
11, 12, 13 Using genetic testing to identify possible mutations may help streamline
family evaluation and longitudinal follow‐up.14 After 25 years of genetic testing,
however, we are still unable to predict phenotypes and outcomes from a gene‐based
model. HCM is an extremely heterogeneous disease with regard to clinical onset and
presentation, phenotype, and clinical course, even within the same pedigree. Both
penetrance and expressivity are thought to be influenced by epigenetic and environmental
mechanisms, although the quality and extent of these interactions remain elusive.15
In this review, we focus on the complex interplay between genetics and potential modifiers
of disease expression including demographic features, physiological challenges such
as pregnancy and physical exercise, as well as comorbid conditions. Some of the potential
modifiers (Table 1) will be used as examples to discuss gene–environment interaction
in this particular clinical setting.
Table 1
Potential Environmental Modifiers of Phenotypic Expression in HCM
Phenotypic Expression
Modifiers
Effects
LVH
Sex
↑ LVH in men
Ethnicity
↑ LVH in Afro‐Caribbean athletes
Obesity
↑ LV mass in obese individuals
Hypertension
↑ LVH in patients with hypertension
Renal disease
↑ LVH in CKD
Sport
No clear effects
Diet
No clear effects
Microvascular dysfunction
Hypertension
↑ Microvascular ischemia
Autoimmune disease
↑ Microvascular ischemia
CAD
↑ Microvascular and macrovascular ischemia
Cocaine abuse
↑ Microvascular and macrovascular ischemia
Thrombophilic status
↑ Microvascular and macrovascular ischemia
Hemodynamic status/obstruction
Dehydration
↓ Venous return,↑ LV gradients
Anemia
↑ LV gradients
Thyroid disease
↑ LV gradients
Pregnancy
↓ LV gradients
Pharmacological treatment (inotropes, vasodilators, diuretics)
↑ LV gradients
Acquired valvular heart disease
↑↓ LV gradients
↑ indicates increased; ↓, decreased; CAD, coronary artery disease; CKD, chronic kidney
disease; HCM, hypertrophic cardiomyopathy; LV, left ventricular; LVH, left ventricular
hypertrophy.
John Wiley & Sons, Ltd
Life Cycle
Age
Although age cannot be considered an environmental factor sensu stricto, the effects
of aging on the heart are indisputable. In recent years, older patients with HCM have
been increasingly recognized because of greater awareness of the disease and advances
in cardiac imaging techniques. Young patients appear to have a higher risk of arrhythmic
SCD, which is rare in those older than 60 years.16 Such an inverse relationship between
advanced age and SCD‐related risk in HCM inevitably affects management decisions,
particularly regarding implantable cardioverter‐defibrillator implantation. Conversely,
the burden of disease in terms of atrial fibrillation and heart failure–related complications
peaks in patients aged 50 to 70 years and it may be attributable to long‐standing
microvascular ischemia and progressive myocardial fibrosis leading to remodeling of
the left ventricle and left atrial chambers.17 In this regard, while younger patients
rarely develop heart failure‐related issues, an early onset of disease is associated
with markedly increased risk of HCM complications after midlife.17
Pregnancy
Pregnancy is characterized by significant physiological changes in the cardiovascular
system, including increases in cardiac output, extracellular fluid volume and arterial
compliance, and reduction in blood pressure and total peripheral resistance. Hormonal
changes include increased levels of estrogens and progesterone, which result in vasodilatation.
A substantial activation of the renin‐angiotensin‐aldosterone system occurs early
in pregnancy and results in increased plasma volume.18 These physiological changes
also affect the heart, with significant increase in LV wall thickness and mass. Preexisting
cardiovascular disease can therefore be exacerbated by the adaptations that occur
during gestation.19
Despite these concerns, pregnancy is well tolerated by asymptomatic or mildly symptomatic
women with HCM. The hypertrophied LV can accommodate the rise in cardiac output and
blood volume, and the reduction of systemic vascular resistance is generally without
consequences on LV filling pressures. Development of heart failure symptoms is uncommon
during pregnancy, occurring in <5% of patients with previously asymptomatic HCM. The
most common issues are related to diastolic dysfunction, LV outflow tract (LVOT) obstruction,
and arrhythmias. In pregnant patients with HCM, preexisting heart failure symptoms,
pulmonary hypertension, and severe LVOT obstruction are the main predictors of maternal
and neonatal events.20 Of note, multiple pregnancies are not likely to affect the
natural history of the disease, nor its phenotypic expression.3
Demographic Features
Ethnicity
Epidemiological data in different ethnicities show that the prevalence and clinical
profile of HCM do not differ among various populations.21 Because most of the studies
addressing phenotypic expression and natural history of HCM are based on white patients,
data on individuals of other ethnicities are limited. However, observations in athletes
and patients with hypertension reveal that individuals of African/Afro‐Caribbean descent
show more significant morphological changes, degree of LVH, and ECG abnormalities
compared with whites.22 Awareness of such differences is important in order to avoid
overdiagnosis of HCM in healthy individuals exhibiting phenotypes that are within
physiological limits for their ethnicity. A recent study by Sheikh et al23 showed
that black patients with HCM almost always exhibit an abnormal ECG, with high prevalence
of T‐wave inversion; moreover, black patients more often had apical or concentric
patterns of hypertrophy compared with white patients. Although hypertension is more
common in black individuals, the greater burden of LVH does not appear related to
hypertension and probably rest on a polygenic basis. Indeed, the morphological differences
persisted after excluding patients with hypertension and likely reflect a true impact
of ethnicity on the HCM phenotype. In the same study, black patients did not exhibit
a higher prevalence of conventional risk markers for SCD, and ethnicity was not a
determinant of the composite primary outcome of death, cardiac arrest, or appropriate
implantable cardioverter‐defibrillator therapy.
Sex
The Mendelian mode of HCM inheritance is autosomal dominant, which implies that equal
numbers of men and women are carriers of the underlying disease‐causing mutation.
However, men are consistently more prevalent in published cohorts, typically with
a 3:2 ratio to women. Although male predominance may reflect a similar lack of awareness
that is well recorded in other cardiovascular diseases in women, the difference in
disease expression among the sexes is likely to be influenced by genetic and endocrine
factors. Women with HCM are older at presentation, more symptomatic, and more likely
to have resting LV obstruction compared with men.24 While LV mass indexed for body
surface area is lower in women, suggesting milder phenotypic expression25 (Figure 1),
women are more prone to heart failure–related mortality and HCM‐related complications.26,
27 Furthermore, women with HCM have comparable rates of SCD compared with men,24,
28, 29 although they may be less exposed to arrhythmic events triggered by strenuous
exercise.30, 31 As women are less likely to be diagnosed with HCM at routine medical
examination, a higher index of diagnostic suspicion and lower threshold for referral
to a specialist are warranted.
Figure 1
Sex differences in left ventricular (LV) mass in patients with hypertrophic cardiomyopathy.
Men exhibit significantly higher values of indexed LV mass. Reprinted from Olivotto
et al25 with permission. Copyright ©2008, Elsevier.
Little is known regarding the impact of sex hormones on the development of myocardial
hypertrophy in HCM, although the older, often postmenopausal age at presentation in
women with HCM support a protective role of estrogens. Indeed, estrogens are known
to have a protective role in secondary hypertrophic response, while exposure of cardiac
myocytes to androgens may result in LVH. In healthy individuals, increase in cardiac
mass following puberty is greater in men, and estrogens have been shown to exert preventive
effects on cardiac hypertrophy.31 However, the physiological actions of androgens
in the heart remained largely unclear compared with those of estrogens. Some studies
have shown that androgens are prohypertrophic,32, 33 via a direct androgen receptors–mediated
pathway. Furthermore, a study by Lind et al33 showed that variations at the androgen
receptor gene were associated with LVH in men with HCM in a cohort of 200 unrelated
patients. Experiments in mouse models carrying MYBPC3 mutations showed significant
sex differences in terms of sarcomeric force generation. These differences were even
more evident in mutant mice engaged in an exercise protocol, suggesting that physiological
stimuli elicit a sexually dimorphic cardiac response.32
Habits and Lifestyle
Exercise and Sport
Regular exercise has a favorable effect on many of the established risk factors for
ischemic cardiovascular disease, thereby decreasing morbidity and mortality.33, 34,
35 However, strenuous exercise is known to trigger SCD in athletes with an underlying
cardiac disease.36, 37 HCM is believed to be a common cause of SCD in young athletes,38
and the interplay of the pathological substrate characterized by myocardial disarray,
fibrosis, and microvascular remodeling with physiological mechanical stressors and
potentially adverse effects of intense exercise such as dehydration, sympathetic stimulation,
electrolyte abnormalities, and acid base disturbances may trigger fatal arrhythmias
during exertion.39 Therefore, consensus statements recommend that individuals with
HCM should refrain from participating in competitive physical activity.40, 41 These
recommendations are based on reasonable pathophysiological assumptions and are ultimately
aimed at protecting athletes by preventing SCD.
There are, however, several scientific, epidemiological, and ethical matters of debate
related to exercise participation in patients with HCM. First, the rate of exercised‐induced
SCD in HCM is unclear. Recent data suggest that SCD occurs during sport in less than
20% of patients with a postmortem diagnosis of HCM, and that young age and male sex
are the main independent variables associated with exercise‐induced SCD.42 Second,
while HCM has been historically reported as the most common cause of SCD in young
athletes in the United States, other conditions such as arrhythmogenic right ventricular
cardiomyopathy or sudden arrhythmic death syndrome with a normal cardiac autopsy may
be more frequent.43, 44, 45 Furthermore, novel entities such as, unexplained or “idiopathic”
LVH (ie, LVH without evidence of significant myocardial disarray) has been reported
as a relatively common finding in athletes and nonathletes who died suddenly.44, 45
The significance of idiopathic LVH is unclear and postulated theories range from part
of the spectrum of HCM, to trigger for fatal arrhythmias in individuals with an underlying
arrhythmogenic syndrome, because LVH exacerbates electric instability. These data
imply that the epidemiologic burden of HCM as a cause of SCD in athletes may be lower
than previously reported.
Another important point of debate is whether long‐term exercise has a role in the
natural history of HCM. There are no data to support a detrimental effect of exercise
in patients with HCM and no evidence that long‐term athletic training may promote
an exacerbation of the underlying disease process. In animal models, routine exercise
before the development of cardiac phenotype prevented subsequent fibrosis, myocyte
disarray, and induction of markers of hypertrophy in mutant myosin heavy chain mice.46
Conversely, in non‐mutant rats conditioned to run vigorously for up to 16 weeks, cardiac
fibrosis, changes in ventricular function, and increased arrhythmic propensity were
observed.47 To date, none of these effects have been demonstrated in humans, and data
on the effects of exercise as a natural history modifier, as seen in arrhythmogenic
cardiomyopathy,34 are lacking in HCM.
Based on the plethora of benefits of moderate exercise for the cardiovascular system
and general well‐being, recreational exercise should be encouraged in most individuals
with HCM.37 At present, most patients are less active than the general population
and report purposefully reducing or even stopping their activity after diagnosis,48
an attitude that is likely to adversely affect their long‐term outcome. A recent randomized
study showed that moderate‐intensity exercise, compared with usual activity, resulted
in a significant increase in exercise participation and capacity in patients with
HCM, without a significant increase in the burden of arrhythmias or other adverse
events.49 This study supports regular adoption of aerobic training in HCM following
the Greek philosophical principle of Metron ariston (ie, moderation is best), based
on the tailoring of exercise activity to reasonable thresholds based on age and fitness
level.
Another important matter of debate is the management of genotype positive–phenotype
negative (G+/P−) individuals, a rapidly increasing population following the widespread
adoption of genetic testing. Often, individuals identified by this term have no evidence
of LVH but are not truly “phenotype negative,” because of the presence of ancillary
HCM manifestations such as LV crypts, mitral valve abnormalities, and mild regional
diastolic impairment at the septal level. Although the European Society of Cardiology
recommendation is restrictive and states that athletes with a G+/P− should have the
same limitations as patients with overt HCM, a detrimental role of exercise in these
individuals has not been demonstrated,50 and their access to competitive sports is
not restricted in the United States.
Diet and Fluid Intake
The role of dietary habits is crucial to both the development and prevention of cardiovascular
disease. Diet and lifestyle have been a main focus of research in coronary artery
disease (CAD) for decades.51 Benefits and harms of diet are not limited to the mechanistic
interactions underlying the progression of atherosclerosis but extend to other scenarios,
including primary cardiomyopathies. For example, a soy diet was associated with progressive
to severe end‐stage cardiomyopathy and heart failure in a transgenic mouse model of
α‐myosin heavy chain HCM, possibly through induction of augmented cell growth and
apoptosis. Conversely, such evolution was prevented by a casein diet.52 To date, however,
the impact of different dietary regimens on patients with HCM has not been investigated.
In clinical practice, apart from the obvious implications related to weight control
and cardiovascular prevention, dietary advice to patients with HCM should deal with
the effects of meals on quality of life and symptomatic status. Following food intake,
splanchnic blood flow sequestration results in decreased circulating plasma volume,
thereby increasing LV outflow gradients.53, 54 Thus, postprandial symptoms of angina,
dyspnea and—occasionally—syncope, are common in obstructive HCM. Patients should be
recommended to avoid large meals and reduce levels of postprandial activity. Dehydration,
which results in reduced preload, increased contractility, and possibly a worsening
of dynamic LV obstruction should also be avoided. Finally, alcohol should be consumed
with moderation by patients with HCM, as it has been shown to decrease arterial blood
pressure and increase systolic anterior motion severity and degree of intraventricular
obstruction55 (Figure 2).
Figure 2
Alcohol and left ventricular (LV) obstruction in hypertrophic cardiomyopathy. After
ethanol ingestion the average LV gradients increase from an average of 38.1 to 62.2 mm Hg.
Reprinted from Paz et al55 with permission. Copyright ©1996, the Massachusetts Medical
Society.
Acquired Comorbidities
Hypertension
Hypertension is conventionally regarded as a potential exclusion criterion for the
diagnosis of HCM.3 However, many patients with unequivocal HCM may present with or
develop some degree of hypertension, given the high prevalence of hypertension in
the adult population.56 In most patients with hypertension, LV wall thickness is normal
or only mildly increased (≤13 mm). Only a minority of patients, often with secondary
forms of hypertension or of Afro‐Caribbean or African descent, have more substantial
hypertrophy (up to 16 mm) and fall into a “grey zone” of potential overlap with HCM.23
When differentiating hypertensive heart disease from HCM, a number of additional features,
including mitral valve abnormalities and lack of extracardiac organ damage may be
suggestive of the latter.57
In a recent study, hypertension was an independent predictor of outcome in patients
with HCM, irrespective of ethnicity, sex, or age.23 A significant increase in afterload
and neuroendocrine activation may further increase LV mass and adversely affect the
clinical expression of the disease. Aggressive management of uncontrolled hypertension
is therefore mandatory in HCM, but may be challenging, as most vasodilators will exacerbate
dynamic LVOT obstruction.58, 59
The question of whether a quota of secondary LVH might worsen the phenotypic expression
of HCM in patients with hypertension remains unresolved. Afterload increase and neuroendocrine
activation may plausibly contribute to an augmented LV mass. Likewise, appropriate
treatment of hypertension might reduce “nongenetic” LVH. This intuitive concept, although
not proven, is supported by studies showing regression of LVH following septal reduction
therapies. Of note, reduction of LV mass following resolution of afterload mismatch
occurred in regions of HCM hearts remote from the septum, suggesting that reverse
remodeling may occur in this disease on removal of pathologic environmental stimuli.60,
61 This general concept of partial reversibility of LVH in patients with HCM requires
further investigation and is of relevance to other potential determinants such as
sport, obesity, and renal failure.
Another interesting concept is that polymorphisms in the renin‐angiotensin‐aldosterone
system, which have been associated with LVH in untreated hypertension, may be potential
disease modifiers in HCM.62 and may specifically impact the clinical phenotype of
HCM.63
Obesity
Obesity is a rising public health problem and a known risk factor for cardiovascular
diseases. Because of its maladaptive effects on various cardiovascular risk factors
and its adverse effects on cardiac structure and function, obesity has a major impact
on morbidity and mortality. As recently demonstrated, its prevalence in HCM is remarkably
high, reaching almost 40%. Obesity is independently associated with increased LV mass
(Figure 3), an adverse prognostic factor in HCM, contributing to more rapid clinical
progression and worsening of heart failure symptoms.64 Interestingly, however, LV
mass increase in obese patients with HCM seems to merely reflect LV cavity enlargement,
physiologically aimed at increasing cardiac output65 to meet the increased requirements
of excessive body weight. Conversely, maximal LV thickness is similar in normal weight
versus obese patients with HCM, suggesting that the genetic design of asymmetric septal
LVH is independent of body mass index.48 Of note, LV obstruction is more common in
obese patients and observed in more than 50% with body mass index >30, because of
distinctively higher predisposition to provocable (as opposed to resting) gradients.
A beneficial impact of weight reduction on the severity of LVOT obstruction is plausible
but remains unproven.66 Finally, although the role of obesity as an independent risk
factors for SCD in HCM has not been established, the susceptibility of obese patients
with HCM to fatal arrhythmias is a potential area of research.67
Figure 3
Relationship between left ventricular (LV) mass and body mass index (BMI) (A) and
LV mass indexed for body surface area and BMI (B) in patients with hypertrophic cardiomyopathy.
Obese individuals (BMI >30) exhibit higher values of LV mass and indexed LV mass.
Reprinted from Olivotto et al64 with permission. Copyright ©2013, Elsevier.
Obstructive Sleep Apnea
Obstructive sleep apnea (OSA) is a common condition in Western countries, characterized
by repetitive interruption of ventilation and hypoxia during sleep, which affects
a large proportion of patients with hypertension, obesity, CAD, atrial fibrillation,
and stroke. In peripheral OSA this is caused by collapse of the pharyngeal airway,
while central OSA is related to malfunction of the respiratory control centers in
the brainstem.
In recent years there have been rapid advances in the understanding of the relationship
between OSA and cardiovascular disease, including HCM.68 OSA has been reported in
up to 70% of patients with HCM.69 LVOT obstruction is generally exacerbated by sympathetic
stimulation, and the nocturnal hypoxia‐induced hyperadrenergic state characteristic
of OSA would be expected to worsen the hemodynamics of HCM. This vicious pathophysiological
cycle translates into increased symptom burden during the day. Furthermore, peripheral
vasoconstriction, apnea‐induced hypoxemia, carbon dioxide retention, renal retention
of salt and water, and increased renin‐angiotensin‐aldosterone activity may contribute
to arrhythmogenesis in an already vulnerable pathological substrate.70 Whether OSA
is associated with a higher rate of ventricular arrhythmias or SCD and in general
with adverse prognosis in HCM remains unclear. Nevertheless, treatment of sleep apnea,
whether by weight loss, continuous positive airway pressure, or postural therapy provides
important benefit in the general population and should be sought in patients with
HCM.
Coronary Artery Disease
Myocardial ischemia is often observed in patients with HCM, occurring at the microvascular
level as a result of structural abnormalities of the intramural coronary arterioles,
characterized by thickening of the intima and medial layers of the vessel wall associated
with decreased luminal cross‐sectional area.71, 72 Adult patients with HCM are not
immune from epicardial CAD, which may be difficult to diagnose, given the high frequency
of microvascular angina and the striking ECG repolarization abnormalities present
at rest, which hinder the interpretation of exercise ECG testing. Concomitant atherosclerotic
disease has an important impact on the natural course of HCM. Given the increased
myocardial mass and high myocardial oxygen demand, patients with HCM are particularly
susceptible to the additional ischemic burden of one or multiple epicardial coronary
artery stenosis.73 Not unexpectedly, CAD is a major prognostic indicator in HCM and
is associated with an increase in overall mortality, SCD, and cardiac events, with
a synergistic rather than additive effect.56 Preventive strategies for atherosclerotic
disease should always be considered in patients with HCM and the standards for control
of modifiable cardiovascular risk factors should arguably reflect those used for secondary
rather than primary prevention of CAD because of the intrinsic frailty of the HCM
myocardium to ischemic insults.
Myocardial bridging is a rare but modifiable mechanism of ischemia, acute myocardial
infarction, and even SCD in young patients with HCM.74 Myocardial bridging occurs
when the epicardial coronary arteries, usually the proximal left anterior descending
artery, are intramyocardial, resulting in systolic compression of a coronary artery
on coronary angiography. While bridging also occurs in normal healthy controls, it
is much more common in patients with HCM, reaching a prevalence of 30% to 40%. Because
only a fraction of these lesions have been associated with SCD, generally in children,
the role of bridging as a risk predictor in adult patients is debated but probably
limited. Only when associated with clear hemodynamic abnormalities and symptoms, myocardial
bridging should be treated with a surgical deroofing procedure.75
Sarcomere Protein Gene Profile and Predisposition to Cardiac Disease
Sarcomere gene mutations have been identified in the general population by large‐scale
screening studies. Most carriers do not have a cardiomyopathy and may express no or
only mild and nonspecific phenotypic stigmata. However, these variants seem to retain
a generic capacity to trigger cardiac disease in the presence of environmental stimuli,
creating a sort of nonspecific frailty of the myocardium. In a landmark study, a common
25 mb MYBPC3 deletion was associated with increased risk of heart failure in South
Asians exposed to secondary risk factors, such as hypertension and hypercholesterolemia,
posing a lifelong threat to carriers.76 Furthermore, a role for truncating titin mutations
has been recently proposed in the development of peripartum cardiomyopathy,77 suggesting
the possible interaction between a genetic predisposition and additional environmental
(pregnancy) or genetic stimuli. These observations add a broader dimension to the
interactions between cardiomyopathies and the environment: from relatively uncommon,
genetically driven diseases that are only modestly influenced by external stimuli,
to a common genetic trait that is not pathogenic per se, but may provide predisposition
to cardiac disease in the presence of risk factors and high‐risk lifestyles (Figure 4).
Understanding these complex interactions may prove critical to the identification
of novel therapeutic targets for cardiovascular disease in the future.
Figure 4
Continuum between genetic predisposition and environmental influences in hypertrophic
cardiomyopathy. Multiple variants usually have a severe phenotypic expression that
is less likely to be dependent from environment, while, in individuals harboring a
single mutation, the effect of other acquired conditions may be more relevant. Multiple
variants, each with small effect size, may interact with nongenetic factors to produce
a hypertrophic cardiomyopathy phenotype. Genetic variants recognized as pathogenic
may be present in healthy individuals where the phenotypic expression emerges only
after the interaction with a specific environmental factor. CAD indicates coronary
artery disease; OSA, obstructive sleep apnea.
Conclusions
Our genetic destiny is hardly written in stone. Virtually all human diseases result
from the interaction of genetic susceptibility factors with modifiable environmental
influences. When we observe that even “classic” inherited diseases can be modified
by environmental conditions, it becomes clear that the relationship between the two
is much more complex than a simple one gene–one disease model linear relationship.
HCM is not an exception to this general rule. Overall, however, physiological stimuli
and comorbidities seem to exert a modest impact especially on the phenotypic expression
of HCM. Future research targeting HCM variability should rather focus on molecular
aspects including modifier genes, epigenetic factors, and the role of regulatory systems
such as microRNAs, the ubiquitine‐proteasome complex, or nonsense‐mediated RNA decay.78,
79
Nevertheless, identifying modifiable risk factors that may aggravate HCM phenotype
and the clinical course remains important in clinical practice, even in the absence
of specific studies, along the general principles of contemporary cardiovascular medicine.
Because of the intrinsic fragility of HCM hearts, it may be reasonable to manage patients
according to the standards of established atherosclerotic disease, ie, of secondary
rather than primary cardiovascular prevention, including strict targets for lipid
profile, blood pressure and weight control, and lifestyle advice including appropriate
exercise and diet (Table 2).
Table 2
Proposed Management of Modifiable Risk Factors in Patients With HCM
Lifestyle/Clinical Variables
Possible Effects
LDL <100 mg/dLa
↓ Risk of CAD and myocardial ischemia
BP <130/80 mm Hga
↓ Risk of secondary LVH caused by increased afterload
Moderate exercise
Improvement in diastolic function and exercise capacity
↓ Risk of obesity
Weight management
↓ Risk of obesity
↓ Risk of development of a more marked LVH caused by increased afterload
↓ indicates decreased; BP, blood pressure; HCM, hypertrophic cardiomyopathy; LDL,
low‐density lipoprotein; LVH, left ventricular hypertrophy.
a
The standards for control of modifiable cardiovascular risk factors should arguably
recapitulate those used for secondary prevention in patients with coronary artery
disease (CAD), in all genetic cardiomyopathies, based on the principle that superimposed
atherosclerotic disease seems to have synergistic rather than additive effects.
John Wiley & Sons, Ltd
In the era of evidence‐based medicine, the conundrum behind gene‐environment interactions
in genetic inherited cardiac diseases should be unraveled through improved access
to empiric knowledge from randomized control trials, as well as, increasingly, from
“Big Data.”80 Extensive research is warranted to identify environmental factors that
may effectively act as natural history modifiers. Only through a deepened understanding
of this interplay we will be able to address the many questions related to the extreme
heterogeneity of clinical expression and natural history of HCM.
Sources of Funding
Olivotto was supported by the Italian Ministry of Health (“Left Ventricular Hypertrophy
in Aortic Valve Disease and Hypertrophic Cardiomyopathy: Genetic Basis, Biophysical
Correlates, and Viral Therapy Models”) (RF‐2013‐02356787) and NET‐2011‐02347173 (“Mechanisms
and Treatment of Coronary Microvascular Dysfunction in Patients With Genetic or Secondary
Left Ventricular Hypertrophy”) and by the ToRSADE project (FAS‐Salute 2014, Regione
Toscana). Finocchiaro was supported by the charity Cardiac Risk in the Young and the
Charles Wolfson Charitable Trust. Papadakis and Sharma are supported by Cardiac Risk
in the Young.
Disclosures
None.