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...

myocytes (MCT 0.08 5 0.01 mm vs CON 0.04 5 0.01 mm, P < 0.001). MCT n = 25 cells; CON n = 18 cells, 2 way RM ANOVA. We conclude that the shorter resting SL in MCT myocytes is due to the formation of Ca 2þ -independent cross-bridges, we speculate that these are formed in response to disturbances in cellular metabolism, by mechanisms currently under investigation. Adult cardiac muscle adapts to changes in the environment by growth and remodeling via a variety of mechanisms. Hypertrophy develops when the heart is subjected to chronic mechanical overload. In ventricular pressure overload (due to aortic stenosis) the heart typically reacts by concentric hypertrophic growth, characterized by wall thickening due to myocyte thickening when sarcomeres are added in parallel. In ventricular volume overload, an increase in filling pressure (due to mitral regurgitation) leads to eccentric hypertrophy as myocytes grow axially by adding sarcomeres in series leading to ventricular cavity enlargement that is typically accompanied by some wall thickening. The specific biomechanical stimuli that stimulate different modes of hypertrophy are still poorly understood. Recently, we proposed that cardiac myocytes grow longitudinally to maintain a preferred sarcomere length in response to increased fiber strain and axially to maintain interfilament lattice spacing in response to increased crossfiber strain. Here, we test whether this growth law is able to predict concentric and eccentric hypertrophy in response to aortic stenosis and mitral valve regurgitation, respectively, in a computational model of the adult canine heart coupled to a closed loop model of circulatory hemodynamics. A finite element model of the beating canine ventricles coupled to the circulation that was used. After inducing valve alterations, the ventricles were allowed to adapt in shape in response to mechanical stimuli over time. The proposed growth law was able to reproduce major acute and chronic physiological responses when integrated with comprehensive models of the pressure-and volume-overloaded canine heart, coupled to a closed-loop circulation. We conclude that strainbased biomechanical stimuli consistent with in-vitro studies of myocyte stretch responses can drive cardiac growth, including wall thickening during pressure overload.