Disease Pathways and Novel Therapeutic Targets in Hypertrophic Cardiomyopathy

Abstract

As described in earlier reviews in this series on the molecular basis of hypertrophic cardiomyopathy (HCM), HCM is one of the archetypal monogenic cardiovascular disorders to be understood at the molecular level. Twenty years after the discovery of the first HCM disease gene, genetic studies still confirm that HCM is principally a disease of the sarcomere. At the biophysical level, myofilament mutations generally enhance Ca 2+ sensitivity, maximal force production, and ATPase activity. These defects ultimately appear to converge on energy deficiency and altered Ca 2+ handling as major common paths leading to the anatomic (hypertrophy, myofiber disarray, and fibrosis) and functional features (pathological signaling and diastolic dysfunction) characteristic of HCM. In this review, we provide an account of the consequences of HCM mutations and describe how specifically targeting these molecular features has already yielded early promise for novel therapies for HCM. Although substantial efforts are still required to understand the molecular link between HCM mutations and their clinical consequences, HCM endures as an exemplar of how novel insights derived from molecular characterization of Mendelian disorders can inform the understanding of biological processes and translate into rational therapies.

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

“…In the modern era, specific pathophysiological HCM derangements have been targeted in the preclinical realm, and trials are beginning in patients 15,87,88 . Targeting cellular energetic impairment is a promising paradigm in HCM.…”

“…In this Perspectives article, we focus primarily on the energy depletion hypothesis, but we also summarize the evidence for Ca 2+ sensitization, and discuss how the two theories overlap. Increasing evidence indicates that energy depletion has an important role in the development of hypertrophy and in the wider pathophysiology of HCM [9][10][11][12][13][14][15] . We summarize this evidence, and then discuss the phenotypic manifestations of energy depletion in three realms of cardiac function: diastolic dysfunction, dynamic systolic dysfunction (especially against imposed afterload), and arrhythmogenesis.…”

CD36 Protein Influences Myocardial Ca2+ Homeostasis and Phospholipid Metabolism

“…This suggested that CD36 depletion reduces SR Ca 2ϩ reuptake delaying Ca 2ϩ clearance. This would diminish ability of cells to regulate and synchronize beating frequency (35,36).…”

“…2ϩ Handling-Cytosolic Ca 2ϩ reuptake by the SR in preparation for the next excitation is accomplished by the ATPase (SERCA) enzyme, which is tightly regulated via interaction with its inhibitor PLN (35). Phosphorylation of PLN by protein kinase A (PKA) reverses the inhibition and increases SERCA activity and the rate of SR Ca 2ϩ uptake (56).…”

“…CD36-mediated Ca 2ϩ signaling in the heart and its relevance to myocardial metabolism and physiology are currently unknown. Alterations in cardiomyocyte Ca 2ϩ flux and plasma membrane (sarcolemma) composition could compromise heart contractile function typically during cellular stresses (35,36). We determined how CD36 deletion impacts the functional adaptation of the myocardium to fasting and whether it is associated with disturbances in the metabolism of Ca 2ϩ and/or phospholipid.…”