Genetic Pathogenesis of Hypertrophic and Dilated Cardiomyopathy

Abstract

Sarcomere cardiomyopathies are genetic diseases that perturb contractile function and lead to hypertrophic or dilated myocardial remodeling. Identification of preclinical mutation carriers has yielded insights into the earliest biomechanical defects that link pathogenic variants to cardiac dysfunction. Understanding this early molecular pathophysiology can illuminate modifiable pathways to reduce the emergence of overt cardiomyopathy and curb adverse outcomes. Here, the authors review current understandings of how human hypertrophic cardiomyopathy- and hypertrophic dilated cardiomyopathy-linked mutations disrupt the normal structure and function of the sarcomere.

Keywords: Dilated cardiomyopathy; Hypertrophic cardiomyopathy; Interacting-heads motif; Sarcomere physiology.

Figure 1. The Sarcomere

Cardiac sarcomeres are composed of highly organized thick and thin myofilaments that produce bands that are visible by microscopy (Top image). One sarcomere encompasses the region between two Z bands, where titin and thin filaments are anchored and interact with other Z-disc proteins. The I band denotes the region lacking thick filaments motor proteins that reside in the A band. The M band is an overlap region that interconnects sarcomere proteins within each sarcomere. Each titin molecule spans from the Z disc to the M band, encompassing ½ of a sarcomere. The thick filament fulfills motor and regulatory functions through proteins much as cardiac β-myosin heavy chain (MYH7) and myosin binding protein C (MYBPC3). The thin filament system contains actin, as well as the troponin-tropomyosin calcium-regulatory apparatus that enable and regulate actomyosin interactions. Titin titin plays multiple roles in sarcomere function, stability, and regulation.

Figure 2. A Schematic of Sarcomere Conformations and Associated Energy Consumption throughout the Cardiac Cycle

A pair of myosin molecules is depicted, with each head denoted as blocked (BH) or free (FH). During contraction both the BH and FH are available for actomyosin interactions and ATP hydrolysis. During relaxation, myosins assume two dynamic and asymmetric conformations though myosin interacting-heads motif. In disordered relaxation (DRX) one myosin head is bound onto the thick filament backbone and is unavailable for actomyosin interactions. Energy consumption is at an intermediate level during DRC. In super relaxation (SRX) both myosin heads are docked onto the thick filament and energy conservation is maximized as both myosin ATPase domains are inhibited.