Hypertrophic cardiomyopathy

Abstract

Important insights into the molecular basis of hypertrophic cardiomyopathy and related diseases have been gained by studying families with inherited cardiac hypertrophy. Integrated clinical and genetic investigations have demonstrated that different genetic defects can give rise to the common phenotype of cardiac hypertrophy. Diverse pathways have been identified, implicating perturbations in force generation, force transmission, intracellular calcium homeostasis, myocardial energetics, and cardiac metabolism in causing disease. Although not fully elucidated, the fundamental mechanisms linking gene mutations to clinical disease are being characterized. Further advances will allow a better understanding of pathogenesis, diagnosis, and treatment, not just of relatively rare inherited cardiomyopathies, but potentially also of relevance to more common acquired forms of hypertrophic remodeling.

Figure 1. Pathologic features of HCM

A. Gross pathology showing hypertrophic cardiomyopathy (left) as compared to normal cardiac morphology (right). B: Histologic sections stained with hematoxylin and eosin demonstrate myocyte disarray, where myocytes are oriented at bizarre and variable angles to each other, as well as increased myocardial fibrosis (left), the pathognomonic features of HCM. In contrast, normal myocardium demonstrates a very orderly arrangement of myocytes (right). Courtesy of Dr. Robert Padera, Department of Pathology, Brigham and Women's Hospital, Boston, MA.

Figure 2. Echocardiographic appearance of HCM

A: Normal parasternal long axis view demonstrating normal LV wall thickness, with both interventricular septum and posterior wall measuring 8 mm. B. Parasternal long axis view from a patient with HCM demonstrating severe asymmetric septal hypertrophy. The interventricular septum measures 24 mm, the posterior wall measures 11 mm. IVS= interventricular septum; PW= posterior wall; LV= left ventricle; LA= left atrium; Ao= aorta

Figure 3. Morphologic spectrum of HCM

Asymmetric septal hypertrophy is the most common morphologic pattern in HCM, however a myriad of different locations and extent of LVH have been described, as demonstrated in these still-frame images. No direct correlation between the distribution of LVH and clinical outcomes has been demonstrated. Courtesy of Dr. Barry J. Maron, Minneapolis Heart Institute Foundation, Minneapolis, MN. A: Massive asymmetric septal hypertrophy with VS thickness >50 mm; B: Septal hypertrophy with more prominent distal portion involvement; C: Hypertrophy confined to the proximal septum, just below the aortic valve (arrows); D: Apical HCM (asterisk); E: Relatively mild hypertrophy in a concentric pattern showing similar thicknesses within each segment (paired arrows); F: Inverted pattern with posterior free wall (PW) thicker (40 mm) than anterior VS. VS= ventricular septum; PW= posterior wall; AML= anterior mitral valve leaflet; LV= left ventricle. Calibration marks=1cm

Figure 4. HCM is caused by mutations in the sarcomere, the molecular motor of the heart

The sarcomere is the fundamental unit of contraction in the cardiac myocyte. It is composed of interdigitating thick and thin filaments which generate force by cyclical cross-bridge formation between actin and myosin. Hypertrophic cardiomyopathy is a disease of the sarcomere, caused by dominantly inherited mutations in contractile genes, most commonly β-myosin heavy chain, myosin binding protein C, and cardiac troponins T and I. Adapted from Kamisago M, et al. N Engl J Med 2000;343:1688-96, with permission, © Massachusetts Medical Society.

Figure 5. Molecular structure of myosin heavy chain and location of mutations associated with HCM

This 3-dimensional molecular model is based on the x-ray crystallographic structure of chicken skeletal myosin heavy chain. The residues shown correspond to human residues Asp3 through Lys841. The actin binding domain is shown in green; the ATP binding site in yellow. The myosin regulatory and essential light chains are overlaid in violet and orange, respectively. Mutations which cause HCM are shown in blue, superimposed onto the molecular structure. Light chain mutations are shown in light blue. Courtesy of Steven DePalma. PhD, Department of Genetics, Harvard Medical School, Boston, MA.

Figure 6. The penetrance of left ventricular hypertrophy in HCM is dependent on age and influenced by the underlying sarcomere mutation

HCM caused by mutations in β-myosin heavy chain is typically associated with demonstrable LVH early in life, with near universal expression by the age 20 years. In contrast, HCM due to mutations in the myosin binding protein C gene may not show clinically evident LVH until middle age or later. Adapted with permission from Niimura H, et al New Engl J Med 1998; 338:1248-1257, © Massachusetts Medical Society.

Figure 7. Diastolic abnormalities are present prior to the development of LVH

A. Invasive hemodynamic studies on isolated hearts and intact 6 week old αMHC^403/+ mice have shown decreased minimal peak −dP/dt, decreased rates of LV pressure decline, increased tau (the time constant of isovolumic relaxation), and increased time to peak filling. Gross and histologic LVH, myocyte disarray, and fibrosis are not consistently present until 20–25 weeks of age. B. Echocardiographic studies on genotyped human populations with HCM also demonstrate impaired relaxation prior to the development of LVH in otherwise healthy family members who carry pathogenic sarcomere mutations. Reduced early myocardial relaxation velocity (E' velocity) on tissue Doppler interrogation indicates impaired relaxation. E' velocity is normal and brisk in the genotype-negative control relative (left panel) but mildly reduced in a relative who carries a gene mutation but has not yet developed clinical disease (G+/LVH−; center panel). With development of overt disease, there is a marked reduction in E' velocity (G+/LVH+, right panel).

Figure 8. Intracellular calcium homeostasis is altered in HCM

A. Normal excitation-contraction coupling is initiated when membrane depolarization by the action potential opens voltage-gated L-type calcium channels on the cardiac myocyte membrane. The resultant influx of Ca²⁺ leads to calcium-induced calcium release (CICR) from stores in the sarcoplasmic reticulum (SR) and a more marked increase in intracellular Ca²⁺ concentration. Ca²⁺ binds to the sarcomere, allowing actin-myosin crossbridge formation and generation of the power stroke. Calcium is then taken back up into the SR via the SERCA pump (SR calcium ATPase). B. In HCM, normal calcium cycling may be disrupted, possibly due to “trapping” of calcium in the mutated sarcomere (mutations indicated by *). This may lead to altered intracellular calcium homeostasis with a relative excess of calcium in the sarcomere and relative depletion in the sarcoplasmic reticulum. Adapted from Semsarian et al J. Clin. Invest. 2002 109:1013

Figure 9

The histopathology of metabolic cardiomyoapthies caused by mutations in PRKAG2 (panels A–C) and LAMP2 (panel D) is distinct from HCM and characterized by glycogen-filled vacuoles without significant disarray, fibrosis, or myocyte hypertrophy.

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