P331Cardiomyocyte hypertrophy and reduced myofibril density underlie decreased maximum force generating capacity in familial hypertrophic cardiomyopathy

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Abstract

Background

Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in genes encoding sarcomeric proteins. Previously, we observed a reduced maximal force generating capacity (Fmax) of cardiomyocytes from HCM patients with mutations in myosin-binding protein-C (MYBPC3). In this study we investigated the contribution of myofibril density (MyoD) and cross-sectional area (CSA) to the reduction in Fmax.

Methods

We measured Fmax and CSA of single permeabilized ventricular cardiomyocytes of 27 HCM patients with mutations in MYBPC3, myosin heavy chain: MYH7, troponin T: TNNT2 and troponin I: TNNI3 and 10 non-failing donor hearts. MyoD was calculated as the sum of myofibril area related to cell area assessed by electron microscopy.

Results

Average Fmax was significantly lower in hearts with mutations in MYBPC3, MYH7, TMP1, TNNI3 and TNNT2 (23.9 ± 2.4, 13.3 ± 4.8, 12.2, 26.0 ± 1.9 and 21.0 kN/m2 respectively) compared to non-failing donor hearts (37.2 ± 2.3 kN/m2). Figure A shows that MyoD of HCM hearts was significantly reduced compared to donors. CSA of HCM hearts (529 ± 48μm2) was significantly higher compared to donors (342 ± 12μm2). Linear regression analysis revealed a significant negative linear relationship between CSA and Fmax (R2= 0.50, β=-0.023, p=0.014).

Conclusions

Cardiomyocyte hypertrophy and reduced myofibril density underlie depressed Fmax in HCM with mutations in thick and thin sarcomeric proteins.

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