Properties of mutant contractile proteins that cause hypertrophic cardiomyopathy

Abstract

Hypertrophic cardiomyopathy (HCM) is one of the most frequently occurring inherited cardiac disorders, affecting up to 1 in 500 of the population. Molecular genetic analysis has shown that HCM is a disease of the sarcomere, caused by mutations in certain contractile protein genes. To date seven disease-associated genes have been identified, those encoding beta-myosin heavy chain, both regulatory and essential myosin light chains, myosin binding protein-C, cardiac troponin T, cardiac troponin I and alpha-tropomyosin. Here we review the analyses of how these mutations affect the in vitro contractile protein function and the hypotheses derived to explain the development of the disease state.

Determinants of myocardial energetics and efficiency in symptomatic hypertrophic cardiomyopathy

“…Nonetheless, impaired energy metabolism in HCM exists even in the absence of hypertrophy, suggesting that compromised energetics precede hypertrophy and may play a causal role in the development of the HCM phenotype [28]. Concordantly, HCM cardiomyocytes exhibit sarcomeric mutations resulting in inefficient ATP utilization, with subsequent increased cost of force generation and excess demand on myocytes [29].…”

Myosin binding protein C: Structural abnormalities in familial hypertrophic cardiomyopathy

“…This proline/charge rich insert, while always present in the cardiac isoform, varies greatly in its sequence and length (Fig 5), and has been identified as a possible target binding region for an, as yet, unidentified ligand. One suggestion is that this insert forms an SH3 domain recognition sequence, perhaps binding the Calmodulin class -II (CaM-II) like kinase that co-purifies with cardiac MyBPC [12,43,62]. However, only the human cardiac isoform conforms to the PXXP-PXXP sequence usually required for SH3 target recognition.…”

Myocardial energy depletion and dynamic systolic dysfunction in hypertrophic cardiomyopathy

“…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.…”