Impaired calcium handling and mitochondrial metabolic dysfunction as early markers of hypertrophic cardiomyopathy.

Abstract

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder, characterised by myocyte remodeling, disorganisation of sarcomeric proteins, impaired energy metabolism and altered cardiac contractility. Gene mutations encoding cardiac contractile proteins account for 60% of HCM aetiology. Current drug therapy including L-type calcium channel antagonists, are used to manage symptoms in patients with overt HCM, but no treatment exists that can reverse or prevent the cardiomyopathy. Design of effective drug therapy will require a clear understanding of the early pathophysiological mechanisms of the disease. Numerous studies have investigated specific aspects of HCM pathophysiology. This review brings these findings together, in order to develop a holistic understanding of the early pathophysiological mechanisms of the disease. We focus on gene mutations in cardiac myosin binding protein-C, β-cardiac myosin heavy chain, cardiac troponin I, and cardiac troponin T, that comprise the majority of all HCM sarcomeric gene mutations. We find that although some similarities exist, each mutation leads to mutation-specific alterations in calcium handling, myofilament calcium sensitivity and mitochondrial metabolic function. This may contribute to the observed clinical phenotypic variability in sarcomeric-related HCM. An understanding of early mutation-specific mechanisms of the disease may provide useful markers of disease progression, and inform therapeutic design.

• Authors: Helena M Viola, Livia C Hool
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 665 Pg. 166-174 (04 15 2019) ISSN: 1096-0384 [Electronic] United States
• PMID: 30885674 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• Troponin T
• Calcium

Topics

• Animals
• Biomarkers (metabolism)
• Calcium (metabolism)
• Cardiomyopathy, Hypertrophic (metabolism)
• Humans
• Mitochondria, Heart (metabolism)
• Troponin T (metabolism)