Experimentally Increasing Titin Compliance in a Novel Mouse Model Attenuates the Frank-Starling Mechanism but has a Beneficial Effect on Diastole
Background—Experimentally upregulating compliant titins has been suggested as a therapeutic for lowering pathological diastolic stiffness levels. However, how increasing titin compliance impacts global cardiac function requires in-depth study. We investigate the effect of upregulating compliant titins in a novel mouse model with a genetically altered titin splicing factor; integrative approaches were used from intact cardiomyocyte mechanics to 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 (Rbm20ΔRRM mice). A genome-wide exon expression analysis and a candidate approach revealed that the phenotype is likely to be dominated by greatly increased lengths of titin's spring-elements. At both cardiomyocyte and left ventricular (LV)chamber levels diastolic stiffness was reduced in heterozygous (+/-) Rbm20ΔRRM mice with a further reduction in homozygous (-/-) mice at only the intact myocyte level. Fibrosis was present in only -/- RRbm20ΔRRM 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—Titin is not only important in diastolic but also in systolic cardiac function. Upregulating compliant titins reduces diastolic chamber stiffness due to increased compliance of myocytes but depresses end-systolic elastance; under conditions of exercise the beneficial effects on diastolic function dominate. Therapeutic manipulation of the RBM20-based splicing system might be able to minimize effects on fibrosis and systolic function while improving diastolic function of heart failure patients.
- passive stiffness
- integrative physiology
- mouse models
- Frank-Starling mechanisms
- diastolic function
- diastolic dysfunction
- mechanical stretch
- Received August 13, 2013.
- Revision received February 13, 2014.
- Accepted February 21, 2014.