Abstract:
:Background Recent studies suggest that mavacamten (Myk461), a small myosin-binding molecule, decreases hypercontractility in myocardium expressing hypertrophic cardiomyopathy-causing missense mutations in myosin heavy chain. However, the predominant feature of most mutations in cardiac myosin binding protein-C ( cMyBPC ) that cause hypertrophic cardiomyopathy is reduced total cMyBPC expression, and the impact of Myk461 on cMyBPC -deficient myocardium is currently unknown. Methods and Results We measured the impact of Myk461 on steady-state and dynamic cross-bridge ( XB ) behavior in detergent-skinned mouse wild-type myocardium and myocardium lacking cMyBPC (knockout (KO)). KO myocardium exhibited hypercontractile XB behavior as indicated by significant accelerations in rates of XB detachment (krel) and recruitment (kdf) at submaximal Ca2+ activations. Incubation of KO and wild-type myocardium with Myk461 resulted in a dose-dependent force depression, and this impact was more pronounced at low Ca2+ activations. Interestingly, Myk461-induced force depressions were less pronounced in KO myocardium, especially at low Ca2+ activations, which may be because of increased acto-myosin XB formation and potential disruption of super-relaxed XB s in KO myocardium. Additionally, Myk461 slowed krel in KO myocardium but not in wild-type myocardium, indicating increased XB " on" time. Furthermore, the greater degree of Myk461-induced slowing in kdf and reduction in XB recruitment magnitude in KO myocardium normalized the XB behavior back to wild-type levels. Conclusions This is the first study to demonstrate that Myk461-induced force depressions are modulated by cMyBPC expression levels in the sarcomere, and emphasizes that clinical use of Myk461 may need to be optimized based on the molecular trigger that underlies the hypertrophic cardiomyopathy phenotype.
journal_name
J Am Heart Assocjournal_title
Journal of the American Heart Associationauthors
Mamidi R,Li J,Doh CY,Verma S,Stelzer JEdoi
10.1161/JAHA.118.009627subject
Has Abstractpub_date
2018-09-04 00:00:00pages
e009627issue
17issn
2047-9980journal_volume
7pub_type
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