Abstract
Hypertrophic cardiomyopathy (HCM) is a relatively common, primary disorder of the myocardium characterized by unexplained left ventricular hypertrophy affecting perhaps as many as 1 in 500 people. HCM is underscored by profound phenotypic and genotypic heterogeneity, with currently more than 20 genes associated with HCM. The underlying genetic mechanism for approximately 30%–60% of HCM remains elusive. Although many genotype–phenotype relationships have been observed, only a few carry enough clinical significance to aid physicians predicting genotype, course, and prognosis of the disease. Current treatment for HCM is aimed at symptom relief, but (animal) studies and clinical trials are underway to test (genotype-specific) pharmacologic treatments for prevention or regression of cardiac hypertrophy. This chapter details the clinical presentation of HCM, its genetic and nongenetic predisposition, important genotype–phenotype relationships, implications for genetic counseling and family screening, and treatment options for the disease.
Keywords
Beta-myosin heavy chain ( MYH7 ), echocardiography, genetics, genetic testing, hypertrophic cardiomyopathy (HCM), hypertrophy, left ventricular hypertrophy (LVH), myofilament, myosin binding protein C ( MYBPC3 ), sarcomere, sudden cardiac death (SCD), whole exome sequencing (WES)
Chapter Outline
Definitions, Clinical Presentation, and Diagnosis 103
Molecular Genetics of Hypertrophic Cardiomyopathy 106
HCM Phenocopies 109
Role of Modifiers in HCM 109
Genotype–Phenotype Relationships in HCM 110
Next Generation Sequencing and Interpretation of the Genetic Test 112
Screening and Treatment for HCM 113
HCM Genetic Testing in Clinical Practice 113
Follow-up and Sports Participation 115
Pharmacological Therapy for (Obstructive) HCM 116
Pharmacogenomics 116
Septal Reduction Therapies for the Treatment of Obstructive HCM Refractory to Pharmacotherapy 117
Implantable Cardioverter-Defibrillator 118
Conclusions 119
References
Further Reading 126
Definitions, Clinical Presentation, and Diagnosis
Introduction
Hypertrophic cardiomyopathy (HCM) is defined as unexplained left ventricular hypertrophy (LVH) in the absence of precipitating factors such as hypertension or aortic stenosis. HCM is a disease of vast phenotypic and genotypic heterogeneity. Affecting an estimated 1 in 500 people, it is the most prevalent genetic cardiovascular disease, and more importantly, it is one of the most common causes of sudden cardiac death (SCD) under the age of 40, especially in young athletes . HCM can manifest with negligible-to-extreme hypertrophy, minimal-to-extensive fibrosis and myocyte disarray, absent-to-severe left ventricular outflow tract (LVOT) obstruction, and distinct patterns of hypertrophy.
Clinical Presentation and Diagnosis
The clinical presentation of HCM is underscored by extreme variability that can range from an asymptomatic disease course to that of severe heart failure, arrhythmias, and SCD. Many patients remain asymptomatic or will only be mildly symptomatic throughout the course of life. HCM commonly manifests between the second and fourth decades of life but can present at the extremes of age. The most common symptoms at presentation of disease are exertional dyspnea, chest pain, and syncope or presyncope. Infants and young children may present with severe hypertrophy leading to heart failure, which is often associated with a poor prognosis. More often, SCD can be the tragic sentinel event for HCM in children, adolescents, or young adults. Approximately 5% of patients with HCM progress to “end-stage” disease characterized by left ventricular dilatation and heart failure. In such cases, cardiac transplantation may be considered. Other serious, life-threatening complications include embolic stroke and cardiac arrhythmias. Histologically, HCM is characterized by cardiomyocyte hypertrophy, interstitial fibrosis, and myofibrillar disarray.
Echocardiography
Conventional two-dimensional echocardiography is the initial diagnostic imaging modality of choice for the clinical diagnosis of HCM. On the echocardiogram, unexplained and usually asymmetric, diffuse or segmental hypertrophy associated with a nondilated left ventricle (LV) independent of presence or absence of LV outflow tract obstruction (LVOTO) can be seen. A left ventricular wall thickness of ≤12 mm is typically regarded as normal, with measurements of 13–15 mm labeled as “borderline hypertrophy.” A maximal LV end-diastolic wall thickness exceeding 15 mm represents the absolute, minimum dimension generally accepted for the clinical diagnosis of HCM in adults (in children, two or more standard deviations from the mean relative to body surface area) . Echocardiography can also provide details of location and degree of hypertrophy. While there are a large number of morphologic, hypertrophic patterns of the myocardium, four different morphological subtypes of HCM are most commonly recognized: sigmoid septum, reverse septal curvature, apical, and neutral contour variant named according to the septal shape and distribution of hypertrophy observed ( Fig. 7.1 ).
Dynamic LVOTO is a common feature of HCM but is not required for the its diagnosis. The existence of LVOTO is diagnosed by demonstration of a resting or provocable Doppler gradient of >30 mmHg. LVOTO is produced by the interaction of the hypertrophied septum and systolic anterior motion of the mitral valve’s anterior leaflet. The latter results from abnormal blood flow vectors across the valve and abnormal anterior positioning of the valve and its support structures. Variable in severity, posteriorly directed mitral regurgitation is a common finding.
Most patients at presentation manifest some degree of impaired diastolic function, ranging from abnormal relaxation to severe myocardial stiffness, elevated LV end-diastolic pressure, elevated atrial pressure and pulmonary congestion, leading to exercise intolerance and fatigue. Systolic cardiac function, as measured by ejection fraction, is usually preserved. It is notable that newer measures of systolic performance such as tissue velocity and strain imaging suggest a decrease in systolic function in patients with HCM and may even be present in HCM-genotype patients before hypertrophy can be detected. “End-stage disease” is characterized by LV dilatation, poor systolic function, and heart failure.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) constitutes an important additional diagnostic tool, especially in patients with suboptimal echocardiography or unusual segmental involvement of the myocardium. Late gadolinium enhancement (LGE) on MRI is an excellent tool to identify areas of scarring, replacement fibrosis, or irreversible myocardial injury. Early studies demonstrated a higher risk of SCD associated with LGE as well as an association with genotype-positive status in HCM patients . A recent, large study among 1293 patients with HCM showed extent of LGE was indeed associated with increased in SCD events . LGE was however most useful in patients who were otherwise considered at lower risk, whereby LGE ≥15% of LV mass demonstrated a two-fold increase in SCD events, with an estimated likelihood of SCD events of 6% at 5 years .
Molecular Genetics of Hypertrophic Cardiomyopathy
Since the sentinel discovery of the first locus for familial HCM on chromosome 14 in 1989 and the first mutations involving the MYH7- encoded beta myosin heavy chain in 1990 as the pathogenic basis for HCM , mutations in more than 20 genes encoding various sarcomeric proteins (myofilaments and Z-disc associated proteins), calcium-handling proteins as well in genes encoding phenocopies for the disease, have been identified ( Tables 7.1 and 7.2 ). The most common genetically mediated subtype of HCM is myofilament-HCM, with hundreds of disease-associated mutations in nine genes encoding proteins critical to the sarcomere’s myofilament: myosin binding protein C ( MYBPC3 ), β-myosin heavy chain ( MYH7) , regulatory myosin light chain ( MYL2 ), essential myosin light chain ( MYL3 ), cardiac troponin T ( TNNT2 ), cardiac troponin I ( TNNI3 ), cardiac troponin C ( TNNC1 ), α-tropomyosin ( TPM1) , and actin ( ACTC ) . Mutations in other myofilament genes ( MYH6 -encoded alpha-myosin heavy chain , TNNC 1-encoded cardiac troponin C , and TTN -encoded titin ) have been reported but are relatively rare. Among all genes, most evidence surrounds the association of sarcomere/myofilament gene mutations to HCM, and MYBPC3 and MYH7 are by far the most common HCM associated genes ( Table 7.1 ).
| Gene | Locus | Protein | Frequency (%) |
|---|---|---|---|
| Myofilament HCM | |||
| MYBPC3 | 11p11.2 | Cardiac myosin-binding protein C | 15–25 |
| MYH7 | 14q11.2–q12 | β-Myosin heavy chain | 15–25 |
| TNNI3 | 19p13.4 | Cardiac troponin I | <5 |
| TNNT2 | 1q32 | Cardiac troponin T | <5 |
| TPM1 | 15q22.1 | α-Tropomyosin | <5 |
| MYL2 | 12q23–q24.3 | Ventricular regulatory myosin light chain | <2 |
| ACTC | 15q14 | α-Cardiac actin | <1 |
| MYH6 | 14q11.2–q12 | α-Myosin heavy chain | <1 |
| MYL3 | 3p21.2–p21.3 | Ventricular essential myosin light chain | <1 |
| TNNC1 | 3p21.3–p14.3 | Cardiac troponin C | <1 |
| TTN | 2q24.3 | Titin | <1 |
| Z-disc HCM | |||
| LBD3 | 10q22.2–q23.3 | LIM binding domain 3 (alias: ZASP) | 1–5 |
| ACTN2 | 1q42–q43 | Alpha-actinin 2 | <1 |
| ANKRD1 | 10q23.33 | Ankyrin repeat domain 1 (alias: CARP) | <1 |
| CSRP3 | 11p15.1 | Muscle LIM protein | <1 |
| MYOZ2 | 4q26–q27 | Myozenin 2 | <1 |
| TCAP | 17q12–q21.1 | Telethonin | <1 |
| VCL | 10q22.1–q23 | Vinculin/metavinculin | <1 |
| Calcium-handling HCM | |||
| JPH2 | 20q12 | Junctophilin-2 | <1 |
| PLN | 6q22.1 | Phospholamban | <1 |
| Gene | Locus | Protein | Syndrome |
|---|---|---|---|
| AGL | 1p21 | Amylo-1,6-glucosidase | Forbes disease |
| DTNA | 18q12 | α-Dystrobrevin | Barth syndrome/LVNC |
| FXN | 9q13 | Frataxin | Friedrich’s ataxia |
| GAA | 17q25.2–q25.3 | α-1,4-Glucosidase deficiency | Pompe’s disease |
| GLA | Xq22 | α-Galactosidase A | Fabry’s disease |
| KRAS | 12p12.1 | v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog | Noonan’s syndrome |
| LAMP2 | Xq24 | Lysosome-associated membrane protein 2 | Danon’s syndrome/WPW |
| PRKAG2 | 7q35–q36.36 | AMP-activated protein kinase | WPW/HCM |
| PTPN11 | 12q24.1 | Protein tyrosine phosphatase, nonreceptor type 11, SHP-2 | Noonan’s syndrome, LEOPARD syndrome |
| RAF1 | 3p25 | V-RAF-1 murine leukemia viral oncogene homolog 1 | Noonan’s syndrome, LEOPARD syndrome |
| SOS1 | 2p22–p21 | Son of sevenless homolog 1 | Noonan’s syndrome |
| TAZ | Xq28 | Tafazzin (G4.5) | Barth syndrome/LVNC |
Over the last few years, the spectrum of HCM-associated genes has expanded beyond the various cardiac myofilaments to encompass additional subgroups that could be classified as “Z-disc HCM” and “calcium-handling HCM” ( Table 7.1 ), although their overall contribution to genotype-positive HCM is minimal. Due to the Z-disc’s close proximity to the contractile apparatus of the myofilament, its structure–function relationship with regard to cyto-architecture, and its role in the stretch-sensor mechanism of the sarcomere, attention has focused on genes encoding the proteins of the Z-disc, which are involved in the structural and mechanical stability of the sarcomere as they appear to serve as a docking station for transcription factors, Ca 2+ signaling proteins, kinases, and phosphatases . Initial HCM-associated mutations were described in CSRP3- encoded muscle LIM protein and TCAP -encoded telethonin , an observation replicated in a large cohort of unrelated patients with HCM . Subsequently, mutations in patients with HCM have been detected in LDB3 -encoded LIM domain binding 3, ACTN2 -encoded alpha-actinin 2 and VCL -encoded vinculin/metavinculin , MYOZ2 -encoded myozenin 2 , ANKRD1 -encoded ankyrin repeat domain-1 (also known as CARP, cardiac ankyrin repeat protein) among others.
As the critical ion in the excitation–contraction coupling of the cardiomyocyte, calcium, and proteins involved in calcium-induced calcium release have always been of high interest in the pathogenesis of HCM. Although with very low frequency, mutations have been described in the promoter and coding region of PLN -encoded phospholamban, an important inhibitor of cardiac muscle sarcoplasmic reticulum Ca(2+)-ATPase (SERCA) , the RYR2 -encoded cardiac ryanodine receptor , and the JPH2- encoded type 2 junctophilin .
HCM Phenocopies
An important subset of patients with HCM are those with HCM phenocopies: patients with seemingly unexplained LVH mimicking the HCM phenotype. In these cases, LVH is often the primary or even sole presenting feature of a much larger, complicated syndrome or disease. However, sometimes only genetics can elucidate the presence of this underlying disease and distinguish it from a primary cardiomyopathy, such as HCM. More importantly, for many of the underlying diseases in patients with such phenocopies, specific treatments are available. The most common or clinically important genes associated with phenocopies capable of mimicking HCM are summarized in Table 7.2 . In 2001, the first mutations in PRKAG2 -encoded AMP-activated protein kinase gamma-2, a protein involved in the energy homeostasis of the heart, were described in two families with severe HCM and aberrant AV-conduction and ventricular preexcitation in some individuals, which subsequently were shown to be caused by a glycogen storage disease rather than HCM . Another glycogen storage disease in patients presenting with HCM was identified in patients with mutations in lysosome-associated membrane protein-2 encoded by LAMP2 (Danon’s syndrome) .
Akin to PRKAG2 and LAMP2, Fabry’s disease can express predominant cardiac features of seemingly unexplained LVH. Over the years, mutations in GLA -encoded alpha-galactosidose A have been found in patients with this multisystem disorder . Other diseases for which LVH mimicking the phenotype of HCM can be the presenting feature are Noonan’s syndrome, Leopard’s syndrome, and Friedrich’s ataxia ( Table 7.2 ).
Role of Modifiers in HCM
The role of modifiers of the HCM phenotype, either by the presence of common polymorphisms or founder mutations, has been the subject of ongoing genetic studies. One of the earliest studies involves the major components of the renin–angiotensin–aldosterone system (RAAS). Polymorphisms in the RAAS pathway [angiotensionogen-I converting enzyme (ACE), angiotensin receptor 1 (AGTR1), chymase 1 (CMA), angiotensin I (AGT) and cytochrome P450, polypeptide 2 (CYP11B2): DD- ACE , CC- AGTR1 , AA- CMA , T174M- and M235T- AGT , and CC- CYP11B2 ] appear to attenuate the HCM phenotype, in particular the severity of LVH . Among patients with the DD-ACE genotype, there was greater LVH than among those with an ID or II genotype . More importantly, a combined “pro-LVH” profile of presence of these five polymorphisms in the RAAS genes was associated with higher degree of LVH in one particular, founder MYPBC3-HCM pedigree (319.5 ± 112.8 g for patients with the pro-LVH genotype compare to 189.9 ± 47.6 g in patients without; P =0.02) and in among myofilament, genotype negative patients large cohort of HCM patients (LVWT ranging from 20.8±6.7 in setting of 0 polymorphisms to 33.5±9.2 mm when all 5 pro-LVH polymorphisms were present; P =0.02) . Additionally, sex hormone polymorphisms also modified the HCM phenotype . Fewer CAG repeats in the AR -encoded androgen receptor were associated with thicker myocardial walls in males ( P =0.008) and male carriers of the A allele in the promoter of ESR1 -encoded estrogen receptor 1 (SNP rs6915267) exhibited a 11% decrease in LV wall thickness ( P =0.047) compared to GG-homozygote males . HCM modifier polymorphisms, such as these, could all contribute to the clinical differences variable expressivity and penetrance in HCM. Importantly, these discoveries were made in the era of single gene explorations, most studies were based on (relatively) small datasets, and only few were validated or replicated in independent cohorts. Nevertheless, they provided early insights into the role of genetic modifiers in heritable diseases where a primary defect was identified. Furthermore, the release of the public exome and genome data, reasonable costs to perform whole exome or even whole genome sequencing, and increased computational power for complex bioinformatic analyses will aid significantly in the search for potential new modifiers in HCM on a much larger, genomic, and bioinformatics scale.
Genotype–Phenotype Relationships in HCM
Since the discovery of the first HCM-associated mutations, multiple studies have tried to identify phenotypic characteristics most indicative of myofilament-HCM to facilitate genetic counseling and strategically direct clinical genetic testing . Until 2001, it was thought that specific mutations or “hot-spots” in these myofilament genes were inherently “benign” or “malignant” . However, subsequent follow-up and large cohort studies showed that there was no direct association between specific gene mutations and their associated phenotype and outcome indicating that in HCM, great caution must be exercised in assigning prognostic significance to any specific mutation .
In contrast, while using phenotype–genotype relationships at a mutation-specific level is not clinically informative, on a gene levelthese studies have in fact elucidated important differences. Overall, various, independent cohort studios have shown that patients with genotype-positive disease demonstrate a much stronger clinical phenotype of HCM compared to genotype-negative patients, most commonly reflected by a younger age at diagnosis, more hypertrophy, a stronger family history of HCM and/or SCD, and the presence of a reverse septal contour on echocardiography . Further, most studies demonstrated that the two most common forms of genetically mediated HCM—MYH7-HCM and MYBPC3-HCM—are phenotypically similar. Recently, a study using a multi-institutional cohort of patients with thin filament mutations (ACTC, TNNI3, TNNT2, and TPM1) showed that compared to thick-filament HCM, patients with mutations in these genes usually have milder and atypically distributed hypertrophy, less LVOTO, higher rate of progression to NYHA class III or IV, and higher prevalence of abnormal LV filling patterns; there was no difference in rates of ventricular arrhythmias and SCD . In fact, an earlier longitudinal study showed that patients genotype-positive for mutations in any of the myofilement genes had an overall increased risk of cardiovascular death, nonfatal stroke, or progression to NYHA class III/IV compared to those patients with a negative genetic test (25% vs 7%, respectively; P =0.002) .
Lastly, it has been observed that patients with multiple mutations (i.e., compound or double heterozygotes), detected in about 3%–5% of genotype-positive patients, have a more severe phenotype and increased incidence of sudden death , suggesting that a gene-dosage effect might contribute to disease severity. Interestingly, in the majority of cases of double heterozygosity, one of the mutations usually involves MYBPC3 . In their longitudinal study, Olivotto et al. observed a similar trend, showing that patients with double mutations (of which one was usually MYBPC3 ) had greater disease severity than myofilament-negative patients or patients with a single MYBPC3 , thick filament, or thin filament mutation combined. This dosage effect was also evident in a small subset of patients hosting three myofilaments as these patients, albeit rare, demonstrated increased risk of end-stage progression and ventricular arrhythmias .
In summary, although clinical prognostication must be rendered with great caution for specific gene domains or specific genetic mutations, a positive HCM genetic test in general portends a greater likelihood of disease progression, particularly as it pertains to systolic and diastolic dysfunction and propensity to develop symptoms later in life. As such, clinical genetic testing may thereby aid in the prognostication of a patient’s disease outcome.
Over time, many studies have attempted to predict the a priori outcome of a genetic test to facilitate clinical diagnosis and genetic testing. Following early age-dependent and genetic observations in a small number of patients , the echocardiographically determined septal morphology was linked to the underlying genetic substrate in 2006 . In this subsequent larger study ( n =382), a reverse septal curvature ( Fig. 7.1 ) was the strongest predictor for the presence of a myofilament mutation, regardless of age (odds ratio 21, P <0.001) .
Building on several genotype–phenotype correlations, a clinical genotype predictor model was developed recently that, aside from morphology, uses five additional clinical markers to predict the a priori yield of the HCM genetic test. Herein, any of the markers shown to be commonly associated with genotype status in HCM (age at diagnosis <45 years, maximum left ventricular wall thickness (MLVWT) >20 mm, family history of HCM, family history of SCD, reverse septal contour, and the presence of concomitant hypertension) were found to be independent predictors of genotype status, with all being a positive predictor, except for hypertension. When one subsequently gives 1 point for each of the risk factors present (−1 point for hypertension), the sum of this score predicts the chance that the patient will have a positive finding from their genetic test, ranging from 6% for patients with a score of −1 (only concomitant hypertension was present) to 80% when all positive clinical predictors were present ( Fig. 7.2 ) . This observation was subsequently validated in an independent cohort of genotyped patients from the same institution . Using clinical tools such as this one can help guide the decision to pursue genetic testing and facilitate subsequent family screening for HCM.
