Experimentally Increasing Titin Compliance in a Novel Mouse Model Attenuates the Frank-Starling Mechanism but has a Beneficial Effect on Diastole

Abstract

Background. Experimentally upregulating compliant titins has been suggested as a possible therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study.Here we investigate the effect of upregulating compliant titins on diastolic and systolic function in a novel mouse model that we made with a genetically altered titin splicing factor. We employed integrative approaches from intact cardiomyocytes studied with a carbon-fiber force-measuring system to the left ventricular (LV) chamber studied with pressure(P)-volume(V) analysis and Doppler echocardiography. Methods and Results. Compliant titins were upregulated through deletion of the RNA Recognition Motif of the splicing factor RBM20(Rbm20ΔRRMmice). At both cardiomyocyte and LV chamber levels diastolic stiffness was reduced in heterozygous (+/-) Rbm20ΔRRMmice with a further reduction in homozygous (-/-) mice at only the intact myocyte level. Fibrosis was present in only -/- Rbm20ΔRRM hearts. The Frank-Starling Mechanism was reduced in a graded fashion in Rbm20ΔRRM mice, at both the cardiomyocyte and LV chamber levels.Exercise tests revealed an increase in exercise capacity in +/- mice. Conclusions. Results support that titin is not only important in diastolic but also in systolic cardiac function. Upregulating compliant titin isoforms reduces diastolic chamber stiffness due to increased compliance of myocytes but depresses systolic cardiac reserve; under conditions of exercise-induced cardiac stress the beneficial effects on diastolic function dominate. Therapeutic manipulation of the RBM20-based splicing system and careful dosing might be able to avoid effects on fibrosis and systolic function while improving diastolic function of heart failure patients.