Familial Hypertrophic Cardiomyopathy
Is the Frank–Starling Law Kaput?
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Building on work by Otto Frank in the late 19th century, Ernest Starling described in the early 20th century the ability of the heart to change its force of contraction and therefore stroke volume in response to changes in venous return, which has been called the Frank–Starling law of the heart in honor of these 2 physiologists. The Frank–Starling effect enables the heart to match cardiac output to venous return on a beat-to-beat basis.1 A major mechanism responsible for the Frank–Starling effect and hence the beat-to-beat autoregulation of cardiac output is the sarcomere length-dependent activation of force development.2
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In this issue of Circulation Research, Sequeira et al3 investigate both the Ca- and length-dependent regulation of force development in cardiomyocytes harvested from patients with hypertrophic cardiomyopathy (HCM), a familial disorder commonly associated with mutations in genes encoding sarcomeric proteins.4 Consistent with previous animal and human studies,5 myofilament Ca sensitivity was increased in all 38 HCM patient samples compared with 12 nonfailing donor hearts. Notable, the authors observed that length-dependent activation was impaired, which, unlike the Ca sensitivity increase, seemed to be a primary effect of the mutant sarcomeric proteins because (1) it could not be rescued by increasing protein kinase A (PKA) phosphorylation and (2) was normalized when mutant troponin (Tn) proteins were replaced with wild-type protein. These new results suggest that impaired length-dependent activation and hence a defective Frank–Starling effect importantly contribute to the pathogenesis of HCM (Figure).
Reduced Maximal Ca-Activated Force and Increased Ca Sensitivity Are Central Findings in Human HCM
HCM is a familial disorder commonly associated with mutations in genes encoding sarcomeric proteins. Mutation carriers develop progressive heart hypertrophy and fibrosis and are at a high risk for sudden death because of ventricular arrhythmia. More than 1000 mutations in >11 genes have been identified, which can lead to this disease. …