The Frank-Starling Mechansim is Attenuated by a Dilated Cardiomyopathy-Associated Tropomyosin Mutation

Abstract

Sarcomere length-dependent activation (LDA) of force development in cardiac muscle is the cellular basis of the Frank-Starling mechanism, and is often blunted in heart failure. In patients with dilated cardiomyopathy (DCM), LDA may be affected differently depending on the sarcomeric protein mutation underlying the disorder, thus complicating strategies for therapeutic intervention. We investigated the effects of the DCM-associated tropomyosin mutation D230N (TpmD230N) on LDA by measuring force generation and twitch kinetics at short (∼2.0μm) and long (∼2.3μm) sarcomere lengths (SL) of intact and demembranated trabeculae/papillary muscles from hearts of a transgenic murine model (>6 months of age) containing the TpmD230N mutation. Both types of preparations were mounted between a force transducer and linear motor. Intact trabeculae were perfused with oxygenated physiological solution (30°C) and stimulated at 2Hz. Demembranated muscle preparations were bathed in physiological solutions (15°C) containing varying Ca2+ concentrations and allowed to generate steady-state force. As expected, for intact WT trabeculae, the twitch force (Tp) and maximum rate of force development increased and the time to peak tension decreased when muscles were stretched from short to long SL (p<0.02). In contrast, TpmD230N trabeculae did not show significant changes in these parameters between short and long SL. There were no significant length-dependent changes in twitch relaxation kinetics for either WT or TpmD230N trabeculae. In demembranated muscle preparations, pCa50 (the [Ca2+] required to generate half-maximal force) decreased for TpmD230N preparations at both SL compared with WT preparations (with a larger effect at long SL), and the increase in pCa50 with stretch from SL ∼2.0μm to ∼2.3μm was greater for WT compared to TpmD230N preparations (p<0.05). Together, these results demonstrate an attenuated LDA in cardiac muscle of DCM TpmD230N hearts and suggest a role for tropomyosin in modulating LDA. Funding: HL111197.