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<jats:sec> <jats:title>RATIONALE</jats:title> <jats:p>The pathogenesis of MYBPC3-associated hypertrophic cardiomyopathy is still unresolved. We exploited a large and well-characterized patient population carrying the MYBPC3-c.772G&gt;A variant (p. Glu258Lys, E258K) to provide translational insight based on studies on surgical myectomy samples, human-induced pluripotent stem cell (hiPSC)-cardiomyocytes and engineered heart tissues.</jats:p> </jats:sec> <jats:sec> <jats:title>OBJECTIVE</jats:title> <jats:p>To gain insights into the pathogenic mechanisms driven by the MYBPC3-c.772G&gt;A mutation using a comprehensive investigation of human disease models.</jats:p> </jats:sec> <jats:sec> <jats:title>METHODS AND RESULTS</jats:title> <jats:p> Haplotype analysis revealed <jats:italic>MYBPC3-c.772G&gt;A</jats:italic> as a founder mutation in Tuscany. The mutation leads to reduced cMyBP-C (cardiac myosin binding protein-C) expression, supporting haploinsufficiency as the main primary disease mechanism. Functional perturbations were studied in left ventricular samples from 4 patients who underwent myectomy, as well as in human hiPSC-cardiomyocytes and engineered heart tissues harboring c.772G&gt;A, compared with samples from nonfailing nonhypertrophic surgical patients and hiPSC lines from healthy controls. Mechanical studies in single myofibrils and permeabilized muscle strips highlighted faster cross-bridge cycling, and higher energy cost of tension generation. A novel approach based on tissue clearing and advanced optical microscopy supported the idea that the sarcomere energetics dysfunction is intrinsically related with the reduction in cMyBP-C. Studies in single cardiomyocytes (native and hiPSC-derived), intact trabeculae and hiPSC-engineered heart tissues revealed prolonged action potentials, slowerCa <jats:sup>2+</jats:sup> transients and preserved twitch duration, suggesting that the slower excitation-contraction coupling counterbalanced the faster sarcomere kinetics. This conclusion was strengthened by in silico simulations. Of note, the results from patient tissues and hiPSC-derived models obtained from the same patients were essentially the same, supporting the use of hiPSC-models for hypertrophic cardiomyopathy studies. </jats:p> </jats:sec> <jats:sec> <jats:title>CONCLUSIONS</jats:title> <jats:p> Hypertrophic cardiomyopathy–related <jats:italic>MYBPC3</jats:italic> -c.772G&gt;A mutation invariably impairs sarcomere energetics and cross-bridge cycling. Compensatory electrophysiological changes (eg, reduced potassium channel expression) appear to preserve twitch contraction parameters, but may expose patients to greater arrhythmic propensity and disease progression. Therapeutic approaches correcting the primary sarcomeric defects may prevent secondary cardiomyocyte remodeling. </jats:p> </jats:sec>

Original publication




Journal article


Circulation Research


Ovid Technologies (Wolters Kluwer Health)

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