Abstract
Hereditary hypertrophic cardiomyopathy (HCM), due to mutations in sarcomere proteins, occurs in more than 1/500 individuals and is the leading cause of sudden cardiac death in young people. The clinical course exhibits appreciable variability. However, typically, heart morphology and function are normal at birth, with pathological remodeling developing over years to decades, leading to a phenotype characterized by asymmetric ventricular hypertrophy, scattered fibrosis and myofibrillar/cellular disarray with ultimate mechanical heart failure and/or severe arrhythmias. The identity of the primary mutation-induced changes in sarcomere function and how they trigger debilitating remodeling are poorly understood. Support for the importance of mutation-induced hypercontractility, e.g., increased calcium sensitivity and/or increased power output, has been strengthened in recent years. However, other ideas that mutation-induced hypocontractility or non-uniformities with contractile instabilities, instead, constitute primary triggers cannot yet be discarded. Here, we review evidence for and criticism against the mentioned hypotheses. In this process, we find support for previous ideas that inefficient energy usage and a blunted Frank–Starling mechanism have central roles in pathogenesis, although presumably representing effects secondary to the primary mutation-induced changes. While first trying to reconcile apparently diverging evidence for the different hypotheses in one unified model, we also identify key remaining questions and suggest how experimental systems that are built around isolated primarily expressed proteins could be useful.
Highlights
Published: 16 February 2022Hereditary hypertrophic cardiomyopathy began to attract appreciable attention in the mid-20th century [1] but it was not until the 1990s that mutations in cardiac sarcomere proteins were found to be causative [1,2,3,4]
With β-myosin heavy chain (β-MHC) mutations, it has been found in several studies using isolated subfragment 1 (S1) motor fragments that mutations causing hypercontractility often are associated with hypertrophic cardiomyopathy (HCM), whereas mutations causing hypocontractility often are associated with dilated cardiomyopathy (DCM) [112,174]
This is consistent with the results presented above, from studies using human induced pluripotent stem cells (hiPSC)-derived cardiomyocytes which pinpoint metabolic factors (e.g., References [32,133]; see Reference [11]) and calciumrelated signaling [32] as early steps in the HCM remodeling
Summary
Hereditary hypertrophic cardiomyopathy began to attract appreciable attention in the mid-20th century [1] but it was not until the 1990s that mutations in cardiac sarcomere proteins were found to be causative [1,2,3,4]. Changes in cell signaling and other early secondary effects [10] lead to typical histologic/anatomic hallmarks of the disease These include asymmetric hypertrophy (often in different parts of the interventricular septum), myofibrillar/cellular disarray and scattered fibrosis (e.g., reviewed in References [7,11,12,13]). A hypothesis that has received appreciable attention recently is the idea that hypercontractility, as a direct consequence of the mutations, is a key initiator of pathologic remodeling [14,15,16] This functional change is broadly characterized by increased power output and inefficient energy usage [16], but it includes features such as slow/incomplete relaxation associated with increased calcium sensitivity of contraction and diastolic dysfunction.
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