Key result
Human hypertrophic cardiomyopathy muscle (n=38 vs 12 donor hearts) universally exhibits increased myofilament Ca sensitivity and impaired length-dependent activation not rescued by PKA in missense mutations.
Why the study?
Do sarcomeric mutations in human hypertrophic cardiomyopathy directly impair sarcomere length-dependent activation and increase myofilament calcium sensitivity compared to non-failing donor hearts?
Do sarcomeric mutations in human hypertrophic cardiomyopathy directly impair sarcomere length-dependent activation and increase myofilament calcium sensitivity compared to non-failing donor hearts?
Answers are grounded in this paper and cite their sources.
This editorial highlights evidence from human myocardium showing that impaired sarcomere length-dependent activation (a defective Frank-Starling mechanism) is a primary consequence of sarcomeric missense mutations in hypertrophic cardiomyopathy, whereas increased calcium sensitivity is largely secondary to PKA hypophosphorylation.
A Trigger of HCM Pathogenesis?The authors discovered a new common finding in human HCM muscle-impaired length-dependent activation, which, in contrast to increased Ca sensitivity, was not rescued by PKA treatment for all sarcomeric missense mutations studied.Furthermore, replacement of mutant with wild-type Tn corrected the impaired length dependence in the 2 mutations that could be studied.Hence, impaired length-dependent activation Familial Hypertrophic CardiomyopathyIs the Frank-Starling Law Kaput?
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Huke et al. (2013) conducted an editorial in Familial Hypertrophic Cardiomyopathy (HCM) (n=50). Sarcomeric gene mutations in hypertrophic cardiomyopathy (evaluated with protein kinase A treatment and wild-type troponin replacement) vs. Non-failing donor hearts (n=12) was evaluated on Myofilament calcium sensitivity and sarcomere length-dependent activation of force development. Human hypertrophic cardiomyopathy muscle (n=38 vs 12 donor hearts) universally exhibits increased myofilament Ca sensitivity and impaired length-dependent activation not rescued by PKA in missense mutations.
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