Hypertrophic Cardiomyopathy



Hypertrophic Cardiomyopathy


Ali J. Marian



INTRODUCTION

Hypertrophic cardiomyopathy (HCM) is a genetic disorder of cardiac myocytes that is diagnosed by the presence of cardiac hypertrophy, not explained by secondary causes; a nondilated left ventricle; and typically an increased left ventricular ejection fraction (LVEF). Cardiac hypertrophy is often asymmetric with a predominant involvement of the interventricular septum, which is referred to as asymmetric septal hypertrophy (ASH). However, hypertrophy may involve the apex of the left ventricle only, which is denoted as apical HCM. Rarely, hypertrophy is restricted to other regions of the left ventricle, including the lateral or posterior wall. The expression of cardiac hypertrophy is age-dependent. It is infrequent in childhood, typically develops during adolescence, and seldom initially manifests after the fifth decade of life.1

A unique phenotypic feature of HCM is the presence of left ventricular outflow tract obstruction (LVOTO), which is present at rest in about one-third of the patients and inducible by exercise or inotropic stimulation in another third. Myocyte disarray is the pathologic hallmark of HCM. Other pathologic features include myocyte hypertrophy and interstitial fibrosis.


Epidemiology

HCM is among the most common genetic cardiovascular disorders. The estimated prevalence of HCM varies between 1:300 and 1:600 individuals in the general adult population without a particular geographic, ethnic, or sex predilection.2 Estimates of the HCM prevalence are based on detection of a left ventricular wall thickness of greater than or equal to 13 mm (or ≥15 mm in some centers) on an echocardiogram. Estimating the prevalence of HCM based on the expression of cardiac hypertrophy is confounded by age-dependent expression of cardiac hypertrophy. Accordingly, about half of the family members of patients with known HCM mutations express cardiac hypertrophy by the third decade of life and approximately three quarter by the sixth decade.1,3 Conversely, using cardiac hypertrophy alone to estimate the prevalence of HCM has the risk of including phenocopy conditions, such as storage diseases. At the genetic level, approximately 1:167 individuals (0.6%) carry pathogenic variants in the known HCM genes and hence might develop HCM.4


Genetic Basis of Hypertrophic Cardiomyopathy

HCM is a familial disease with an autosomal dominant pattern of inheritance in about 60% of the patients. It is sporadic in the remainder. Whether sporadic or familial, HCM is a genetic disease, commonly caused by mutations in genes encoding sarcomere proteins.5 Accordingly, a single mutation is responsible and sufficient to cause familial HCM, albeit with variable penetrance. Moreover, phenotypic expression of the disease, including age of onset and severity of the disease, is influenced by a number of factors other than the causal mutation.

Christine and Jonathan Seidman identified the first causal mutation for HCM as a missense mutation in the MYH7 gene, encoding the sarcomere protein myosin heavy chain 7 (or βMYH).6 The discovery led to partial elucidation of the molecular genetic basis of HCM upon identification of additional genes. The well-established causal genes for HCM primarily code for proteins involved in sarcomere structure and function. Therefore, HCM to a large degree is considered a disease of the sarcomere.

Mutations in the MYH7 and MYBPC3 genes, the latter coding for myosin binding protein C3, are the most common causes for HCM, being responsible for 40% to 50% of HCM.5 Mutations in the TNNT2 (cardiac troponin T), TNNI3 (cardiac troponin I), TPM1 (a-tropomyosin), ACTC1 (cardiac a-actin), MYL2 (myosin light chain), MYL3 (myosin light chain 3), and CSRP3 (muscle LIM protein) genes are responsible for less than 10% of the HCM cases. Genes implicated as causes of HCM are listed in Table 71.1.

Despite these remarkable discoveries, the causal genes in approximately 40% of HCM have been difficult to identify. The so-called missing causal genes primarily pertain to HCM in sporadic cases and small families, as the causal genes in large families have been identified through genetic linkage, co-segregation analysis, and candidate gene sequencing. This is in contrast to sporadic cases or small families, wherein unambiguous ascertainment of pathogenicity of the genetic variants is difficult to establish. The challenge is further compounded by the incomplete and often low penetrance of the pathogenic variants in the sporadic cases and small families, which is reflective of their modest- to moderate-effect sizes. Finally, two or more pathogenic variants have been reported in ˜5% of patients with sporadic cases or small families with HCM, suggesting that a small subset of HCM is oligogenic.7,8,9,10


Cardiac Histopathology

Gross cardiac pathology is notable for increased heart weight and left ventricular wall thickness, but a small ventricular

cavity. Hypertrophy might also involve the right ventricle but seldom in isolation. Cardiac hypertrophy is typically asymmetric with predominant involvement of the basal interventricular septum. HCM may be restricted to the cardiac apex as in apical HCM. It occasionally involves the posterior or lateral wall only. Other morphologic features include elongation of the mitral valve leaflets or abnormal insertion of the papillary muscles.








Myocyte hypertrophy, disarray, is defined as disorganized orientation of myocytes; and interstitial fibrosis comprise histologic features of HCM (Figure 71.1). Although myocyte hypertrophy and interstitial fibrosis are common to various myocardial diseases, disarray, typically involving greater than 10% of the myocardium, is the pathologic hallmark of HCM. Interstitial fibrosis, clinically assessed by detection of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) imaging, is common in patients with HCM.11


Cardiac Physiology

HCM is characterized by a hyperdynamic left ventricle and therefore an increased or a high-normal LVEF. Left ventricular end-diastolic volume is either normal or reduced because of concentric hypertrophy, and end-systolic volume is small because of the hyperdynamic contraction. Despite an increased LVEF, regional systolic myocardial dysfunction, detected by various imaging modalities, is common in HCM and often precedes expression of cardiac hypertrophy.12 Left ventricular relaxation is commonly impaired because of the increased bound state of the actomyosin complex, elevated diastolic intracellular calcium (Ca2+) concentration, and increased myocardial fibrosis. Diastolic dysfunction leads to elevated left atrial pressure and symptoms of heart failure. It is also associated with the development of atrial fibrillation in HCM. Diastolic dysfunction is worse during physical exertion and is the main reason for exercise-induced dyspnea.






A unique characteristic of HCM is the presence of LVOTO, which occurs because of encroachment of the hypertrophic septum on the left ventricular outflow tract (LVOT) and systolic anterior motion of the mitral valve anterior leaflet owing to Venturi effect induced by the hyperdynamic contraction. LVOTO is typically detected by Doppler echocardiography or cardiac catheterization upon documentation of a systolic pressure gradient between the left ventricular cavity and the subaortic valve region (Figure 71.2). LVOTO varies with changes in contractility, preload, and afterload. Increased contractility or reduced left ventricular volume increases LVOTO. Conversely, negative inotropic agents and increased left ventricular volume reduce LVOTO. The Valsalva maneuver provokes or increases LVOTO during the straining phase.

Approximately one-third of patients with HCM have LVOTO at rest, whereas it could be provoked upon Valsalva or other interventions in another third. Patients with severe obstruction usually have elevated left ventricular diastolic pressure and experience exertional dyspnea. A small subfraction of patients with HCM—particularly the elderly with long-standing LVOTO, severe myocardial fibrosis, and concomitant coronary artery disease—develop heart failure with reduced LVEF.


PATHOGENESIS

For simplicity, pathogenesis of HCM could be classified into sequential sets of events, comprised of the primary effect, functional defects, secondary molecular changes, histologic and physiologic phenotype, and clinical features.


Primary Effect

The primary defect in HCM, a genetic disease, is the causal mutation (aka, pathogenic variant). Therefore, the initial stimulus in the pathogenesis of the phenotype has to originate from the causal pathogenic variant(s). In view of the genetic diversity of HCM, the initial impetus is diverse according to the type of the genetic variant and the function(s) of the gene involved.

HCM is commonly caused by a heterozygous mutation; therefore, only one copy of the gene is affected. A gene carrying the missense mutation is typically expressed into messenger ribonucleic acid (mRNA) and protein, albeit somewhat at a lower efficiency. Nevertheless, both normal and mutant proteins are expressed in the heart and to a large extent equally.
The mutant protein carrying the missense mutation is typically incorporated into the sarcomere, although the efficiency of incorporation might be reduced. The phenotypic effect results from a dominant-negative effect of the mutant protein.






Alternatively, the mutation could lead to premature truncation of the protein because of a gain or loss of a stop codon or insertion/deletion mutation shifting the codon frame. Intracellular mechanisms target such mutant mRNAs for decay. Whenever the mutant mRNA escapes the surveillance mechanisms, the encode truncated protein is expressed but is quickly targeted by unfolded protein response and the ubiquitin-proteasome pathways for degradation. The net effect is haploinsufficiency because the protein is expressed from the healthy but not the mutant copy of the gene. Haploinsufficiency is relatively an uncommon mechanism in HCM because most mutations are missense mutations except those in the MYBPC3 gene.


Functional Defects

Sarcomeres containing the mutant proteins exhibit a diverse array of functional effects, such as impaired Ca2+ sensitivity, altered actin-myosin cross-bridge cycling, and inefficient force generation. Functional effects of the mutations vary among different mutations and the involved genes. Mutations in the MYH7 and MYBPC3 proteins typically affect adenosine diphosphate/adenosine triphosphate (ADP/ATP)-dependent association and dissociation of actin and myosin molecules during a cardiac cycle, and consequently, inefficient force generation. Likewise, increased Ca2+ sensitivity of the myofilaments is the main effect of mutations involving the thin filament proteins. The net effect of this functional phenotype at the molecular level is an increased number of myosin molecules bound to actin at any given moment during a cardiac cycle.


Secondary Molecular Changes

The initial functional defects in the sarcomeres provoke expression and activation of stress-responsive and Ca2+-activated transcriptional regulators, which then induce the expression of genes involved in cardiac hypertrophy and fibrosis, among others. A large set of transcriptional regulators and biologic pathways are activated in HCM, including calcineurin, mitogen-activated protein kinases, and transforming growth factor β pathways.13,14 Overall, these secondary molecular changes are largely similar to those involved in various forms of secondary cardiac hypertrophy and fibrosis, with some variability pertaining to the biologic functions of the causal HCM genes.


Histologic and Morphologic Phenotypes

Histologic phenotype of HCM such as myocyte hypertrophy and myocardial fibrosis are tertiary phenotypes, resulting from activation of the molecular pathways consequent of function defects in sarcomeres.


Clinical Phenotype

Histologic and molecular changes induce gross morphologic and functional changes in HCM, which are responsible for the clinical manifestations of HCM, including heart failure with preserved ejection fraction (HFpEF), LVOTO, and cardiac arrhythmias.


CLINICAL PRESENTATION


Symptoms and Signs

The majority of patients with HCM are asymptomatic or have minimal symptoms that do not interfere with their lifestyle. Symptoms are typically reflective of cardiac arrhythmias, diastolic dysfunction, and LVOTO. Reduced exercise capacity and exertional dyspnea are the early symptoms that occur
because of worsening of diastolic dysfunction during exercise. Chest pain is also a relatively common symptom and occurs because of increased oxygen demand of a hypertrophic myocardium often in the presence of reduced blood flow as a result of microvascular abnormalities.

Palpitations, often caused by supraventricular tachycardia (SVT) or nonsustained ventricular tachycardia (NSVT), is a common symptom in patients with HCM. NSVT is present in 20% to 30% of the patients and is a risk factor for sudden cardiac death (SCD), particularly in the symptomatic young patients.15 Syncope is relatively uncommon but a serious manifestation of HCM, as it is usually caused by cardiac arrhythmias and less commonly by severe LVOTO or autonomic dysfunction.

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May 8, 2022 | Posted by in CARDIOLOGY | Comments Off on Hypertrophic Cardiomyopathy

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