The Many Faces of Hypertrophic Cardiomyopathy: From Developmental Biology to Clinical Practice

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease, characterized by complex pathophysiology, heterogeneous morphology, and variable clinical manifestations over time. Besides cardiac hypertrophy, the HCM phenotype is characterized by a host of manifestations, including mitral valve and subvalvar abnormalities, subaortic and mid-ventricular left ventricular (LV) obstruction, microvascular dysfunction, myocardial fibrosis, disarray, atrial remodeling, myocardial bridging of epicardial coronary arteries, LV apical aneurysms, and autonomic nervous system abnormalities. Such heterogeneous phenotype still lacks a comprehensive explanation, which cannot be accounted solely by genetic heterogeneity, despite the large number of genes and mutations involved. It is likely that pre-natal and acquired features deriving from the primary genetic defect interact with the environment to produce the final result evident in each patient. Based on novel insights provided by cardiac developmental biology, a common lineage ancestry of several HCM manifestations might be traced back to the pluripotent epicardium-derived cells, which early during heart development differentiate into interstitial fibroblasts, coronary smooth muscle cells, and atrio-ventricular endocardial cushions as mesenchymal cells. To date, the different faces of HCM have not been sufficiently liked or explained. We here attempt to address these issues by describing the various components of the disease, their origin, interaction, and clinical significance.

Differentiating physiology from pathology in elite athletes. Left ventricular hypertrophy versus hypertrophic cardiomyopathy

“…Common features of HCM on the tissue level are cardiomyocyte disarray, microvascular dysfunction, and fibrosis [30]. The disarray is a profound disorganisation of cardiomyocyte alignment, expressed as a lack of parallel orientation of cells with additional branching intensifying an impression of disorder.…”

Pseudophosphorylation of cardiac myosin regulatory light chain: a promising new tool for treatment of cardiomyopathy

“…Unfortunately, there is currently no cure for HCM, and it is now becoming evident that any effective therapy must target the underlying mechanisms involved in the pathogenesis of the disease (Granzier and de Tombe 2015;Moore et al 2012;Tardiff et al 2015). Current approaches solely rely on the symptomatic treatments of diastolic dysfunction, a hallmark of HCM, and include the use of β-blockers and Ca 2+ channel blockers to slow heart rate and increase the diastolic filling time (Ho et al 2002;Olivotto et al 2009). Clinicians and researchers all agree that targetspecific therapies hold the most future promise for treating HCM (Bers and Harris 2011; Olivotto et al 2009).…”

“…Current approaches solely rely on the symptomatic treatments of diastolic dysfunction, a hallmark of HCM, and include the use of β-blockers and Ca 2+ channel blockers to slow heart rate and increase the diastolic filling time (Ho et al 2002;Olivotto et al 2009). Clinicians and researchers all agree that targetspecific therapies hold the most future promise for treating HCM (Bers and Harris 2011; Olivotto et al 2009). The recent discovery of omecamtiv mecarbil and MYK-461, small molecules specifically targeting the function of myosin, the major force-generating protein of the heart, highlights the importance of such approaches (Green et al 2016;Malik et al 2011).…”

Gender Differences of Clinical Manifestation and Cardiac Remodeling in Idiopathic Hypertrophic Cardiomyopathy in Elderly Patients

“…Известно, что идиопатическая ГКМП характери-зуется различным возрастом манифестации первых клинических проявлений заболевания, многообра-зием клинических и морфологических признаков [2,[6][7][8]. Эта фенотипическая гетерогенность обуслов-лена как генетическими причинами, такими как патогенные генетические дефекты [6][7][8] и поли-морфные варианты генов-модификаторов, так и негенетическими потенциально модифицируе-мыми факторами кардиометаболического риска (ожирение, артериальная гипертензия) [8].…”

“…Эта фенотипическая гетерогенность обуслов-лена как генетическими причинами, такими как патогенные генетические дефекты [6][7][8] и поли-морфные варианты генов-модификаторов, так и негенетическими потенциально модифицируе-мыми факторами кардиометаболического риска (ожирение, артериальная гипертензия) [8]. Известно, что демографические детерминанты -пол и воз-раст -вносят свой вклад в особенности течения многих заболеваний сердечно-сосудистой системы, в том числе, идиопатической ГКМП [9].…”