Updating the Physiology and Pathophysiology of Cardiac Myosin-Binding Protein-C

Myofilament Proteins in Genetic and Acquired Heart DiseaseAlterations of myofilament proteins have long been recognized in cardiomyopathic states.A variety of mutations play a prominent role in both hypertrophic and dilated cardiomyopathy (DCM). 1 Thus, mutations in myosin heavy chain (MyHC) that cause enhanced mechanical performance often underlie hypertrophic cardiomyopathy, whereas those causing reduced performance lead to DCM. 2 As summarized in Table 1, posttranslational modifications, most prominently isoform variations and phosphorylation state, have received considerable attention in patients with DCM.In response to experimental acquired disease in rodents, MyHC undergoes a major shift from its normally predominant α-isoform to the β-isoform, resulting in lower myofibrillar ATPase activity and reduced mechanical performance.3,4 The same directional shift occurs in humans; because human myocardium normally consists of ≈90% β-MyHC, its magnitude is small and functional consequences seem modest.4,5 Ventricular expression of the atrial isoform of the myosin essential light chain is elevated in DCM and would be expected to improve contractile performance.6 Titin, the giant protein that accounts for cardiomyocyte passive stiffness, undergoes a shift to its more compliant N2BA isoform in human DCM.Protein kinase (PKA) and PKG phosphorylate identical sites on titin.Phosphorylation of these sites is reduced in DCM, which increases stiffness and offsets the isoform shift.7 The net result seems to be a decrease in cardiomyocyte stiffness.Reduced phosphorylation of troponin I (TnI) and myosin regulatory light chain have also been reported in human DCM and are thought to contribute to impaired thin filament activation and contractility.8,9 Pertinent to the papers in this issue of Circulation: Heart Failure that are the subject of this editorial, 10,11 there are few reports of the phosphorylation state of cardiac myosin-binding protein C (MyBP-C) as a regulator of myofilament function at the whole heart level.Of note, reduced phosphorylation of PKA sites on MyBP-C has been reported in human DCM. 12