Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy

Abstract

Hypertrophic cardiomyopathy (HCM) is a genetic disorder that is characterized by left ventricular hypertrophy unexplained by secondary causes and a nondilated left ventricle with preserved or increased ejection fraction. It is commonly asymmetrical with the most severe hypertrophy involving the basal interventricular septum. Left ventricular outflow tract obstruction is present at rest in about one third of the patients and can be provoked in another third. The histological features of HCM include myocyte hypertrophy and disarray, as well as interstitial fibrosis. The hypertrophy is also frequently associated with left ventricular diastolic dysfunction. In the majority of patients, HCM has a relatively benign course. However, HCM is also an important cause of sudden cardiac death, particularly in adolescents and young adults. Nonsustained ventricular tachycardia, syncope, a family history of sudden cardiac death, and severe cardiac hypertrophy are major risk factors for sudden cardiac death. This complication can usually be averted by implantation of a cardioverter-defibrillator in appropriate high-risk patients. Atrial fibrillation is also a common complication and is not well tolerated. Mutations in over a dozen genes encoding sarcomere-associated proteins cause HCM. MYH7 and MYBPC3, encoding β-myosin heavy chain and myosin-binding protein C, respectively, are the 2 most common genes involved, together accounting for ≈50% of the HCM families. In ≈40% of HCM patients, the causal genes remain to be identified. Mutations in genes responsible for storage diseases also cause a phenotype resembling HCM (genocopy or phenocopy). The routine applications of genetic testing and preclinical identification of family members represents an important advance. The genetic discoveries have enhanced understanding of the molecular pathogenesis of HCM and have stimulated efforts designed to identify new therapeutic agents.

Keywords: cardiomyopathy; cardiomyopathy, hypertrophic; death, sudden, cardiac; heart failure; human; mutation; myosin heavy chains.

Figure 1. HCM as a disease of sarcomere proteins

A schematic structure of a sarcomere composed of thick and thin filaments and Z discs is depicted along with its protein constituents involved in HCM. Established causal genes for HCM and their population frequencies are listed.

Figure 2. Pathogenesis of HCM

The primary defect is the mutation in the sarcomere, composed of thick and thin filaments and the Z disks. A change in the amino acid sequence in the sarcomere protein or the deficiency of a sarcomere protein (the primary defect) instigates a series of initial (or proximal defects, such as altered levels of the sarcomere protein, calcium sensitivity, or ATPase activity. These initial defects activate expression of a series of intermediary molecular or secondary changes, such as altered transcriptomics or signaling pathways. The latter set of the molecular changes induce histological and morphological changes in the myocardium, such as myocyte hypertrophy and fibrosis, which could be considered tertiary phenotypes. These molecular and histological changes lead to the clinical or quaternary phenotypes of HCM, such as cardiac arrhythmias and heart failure.

Figure 3. Determinants of phenotype in HCM

Selected factors contributing to expression of cardiac phenotype in HCM are shown. The causal mutation imparts the main effect and several others, such as other pathogenic genetic variants (modifiers), genomics (such as non-coding RNAs), proteomics (such as post-translational modifications), and environmental factors (such as isometric exercises) contributing to expression of the phenotype.

Figure 4. Variability in the phenotypic expression of HCM

A. A truncated pedigree depicting dizygotic twins with HCM caused by the p.Ser48Pro mutation in the MYOZ2 gene. Despite sharing the same causal mutation, one expresses mild and the other severe cardiac hypertrophy, as reflected in the electrocardiograms (B) and echocardiographic images (C).

Figure 5. Echocardiographic phenotypes of HCM

A. A parasternal view of the ventricles showing septal hypertrophy; B. A parasternal short axis view showing concentric cardiac hypertrophy; C. Systolic anterior motion (SAM) of mitral leaflets, contributing to left ventricular outflow tract obstruction; D. Doppler velocities recorded at the left ventricular outflow tract showing about 100 mmHg gradient; E. Tissue Doppler recording of the interventricular septum showing reduced velocities; F. Color Doppler M mode imaging of the left ventricle showing velocity of flow progression in the left ventricle during a cardiac cycle, which is used, along with other indices, to assess diastolic function.

Figure 6. Histological phenotypes

A. A normal thin myocardial section stained with H&E. B. A low magnification (×4) H&E stained thin myocardial section from a patient heart with HCM showing disorganized myocardial architecture. C. A higher magnification (×20) H&E stained myocardial section showing myocyte disarray (×20). D. A thin myocardial section (×20) stained with Masson trichrome in blue showing areas of interstitial fibrosis.