Background-Hypertrophic cardiomyopathy (HCM), typically characterized by asymmetrical left ventricular hypertrophy, frequently is caused by mutations in sarcomeric proteins. We studied if changes in sarcomeric properties in HCM depend on the underlying protein mutation. Methods and Results-Comparisons were made between cardiac samples from patients carrying a MYBPC3 mutation (MYBPC3 mut ; nϭ17), mutation negative HCM patients without an identified sarcomere mutation (HCM mn ; nϭ11), and nonfailing donors (nϭ12). All patients had normal systolic function, but impaired diastolic function. Protein expression of myosin binding protein C (cMyBP-C) was significantly lower in MYBPC3 mut by 33Ϯ5%, and similar in HCM mn compared with donor. cMyBP-C phosphorylation in MYBPC3 mut was similar to donor, whereas it was significantly lower in HCM mn . Troponin I phosphorylation was lower in both patient groups compared with donor. Force measurements in single permeabilized cardiomyocytes demonstrated comparable sarcomeric dysfunction in both patient groups characterized by lower maximal force generating capacity in MYBPC3 mut and HCM mn, compared with donor (26.4Ϯ2.9, 28.0Ϯ3.7, and 37.2Ϯ2.3 kN/m 2 , respectively), and higher myofilament Ca 2ϩ -sensitivity (EC 50 ϭ2.5Ϯ0.2, 2.4Ϯ0.2, and 3.0Ϯ0.2 mol/L, respectively). The sarcomere length-dependent increase in Ca Key Words: cardiomyopathy Ⅲ myofilament proteins Ⅲ mutation Ⅲ myocardial contraction H ypertrophic cardiomyopathy (HCM), most often caused by mutations in genes encoding sarcomeric proteins, is a major cause of morbidity and mortality affecting Ϸ1:500 people worldwide at a relatively young age. 1,2 It often is characterized by asymmetrical left ventricular (LV) hypertrophy, predominantly involving the interventricular septum, occurring in the absence of other cardiac or systemic disease (such as hypertension or aortic stenosis). Clinical presentation is very heterogeneous in HCM as some patients reach old age with virtually no complaints, while others progress to end-stage heart failure or die at a young age from sudden cardiac arrest. To develop a targeted treatment to prevent or delay HCM, it is highly relevant to understand the pathophysiology of this disease.
Clinical Perspective on p 46During the last 2 decades, many disease causing mutations have been identified, mainly in genes encoding sarcomeric proteins. 3,4 Despite improved genetic testing the causal gene mutation remains unidentified in over 40% of HCM patients. 5 Furthermore, the pathophysiological mechanism leading from a Recently we have provided evidence for sarcomeric dysfunction in manifest HCM patients with truncating MYBPC3 founder mutations (c.2373dupG and c.2864_2865delCT). 12 The sarcomeric dysfunction included a reduction in maximal force generating capacity and a higher myofilament Ca 2ϩ -sensitivity compared with nonfailing human myocardium, which may be the result of altered sarcomeric protein composition as we observed haploinsufficiency (ie, reduced cardiac myosin binding protein C [cMyBP...