Hypertrophic cardiomyopathy: from myofilament (dys)function to risk stratification471Perturbed length-dependent activation in human HCM with sarcomere mutations in thin filament proteins

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The Frank-Starling mechanism describes the intrinsic relationship between ventricular filling (end-diastolic volume) and contraction (stroke volume) and is based on length-dependent activation of cardiac sarcomeres. An increase in sarcomere length with increased end-diastolic volume increases myofilament Ca2+-sensitivity and thereby contraction. In the present study we investigated if length-dependent activation is altered in human hypertrophic cardiomyopathy (HCM) with known mutations in thin filament proteins.


Comparisons were made between cardiac samples from a patient harboring a homozygous TNNT2 (troponin T) mutation, a patient carrying a heterozygous TPM1 (tropomyosin) mutation, two patients harboring a heterozygous TNNI3 (troponin I) mutation and non-failing donors. Force measurements were performed in single Triton-permeabilized cardiomyocytes at various [Ca2+] and sarcomere lengths of 1.8 and 2.2 μm, with and without protein kinase A (PKA)-pretreatment.


Myofilament Ca2+-sensitivity at 2.2 μm did not significantly differ between TNNT2, TPM1 and TNNI3 (EC50=2.51 ± 0.10, 2.16 ± 0.19 and 2.69 ± 0.16 μmol/L, respectively), while it was significantly higher compared to donors (EC50=3.09 ± 0.09 μmol/L). The length-dependent increase in myofilament Ca2+-sensitivity was not significantly different between TNNT2, TPM1 and TNNI3 (ΔEC50=0.41 ± 0.17, 0.30 ± 0.14 and 0.29 ± 0.15 μmol/L, respectively), but significantly reduced compared to donors (ΔEC50=0.76 ± 0.06 μmol/L). PKA-treatment did not alter myofilament Ca2+-sensitivity in the TNNT2 sample, whereas Ca2+-sensitivity was significantly reduced in the TNNI3 and TPM1 to values observed in donor. PKA-pretreatment did not restore the reduced length-dependent activation of HCM-groups.


Perturbed length-dependent activation may represent a feature of HCM and contribute to impaired cardiac function in HCM-patients. Our data show that responsiveness to β-adrenergic receptor stimulation mimicked by PKA-treatment is absent in a HCM-homozygous TNNT2 mutation. Although hearts with a mutation in TPM1 and TNNI3 responded to PKA, evident from a reduction in myofilament Ca2+-sensitivity, the blunted length-dependent activation was not corrected by PKA.

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