Abstract 18131: Increased Cardiomyocyte Stiffness in Cardio-Renal Disease

Abstract

Cardio-renal disease has been associated with diastolic rather than systolic cardiac dysfunction. As diastolic dysfunction cannot be attributed to adverse remodelling, the present study investigated if intrinsic cardiomyocyte stiffness is a determinant of diastolic dysfunction in cardio-renal disease. Thereto, cardiomyocyte function was studied in rats with cardio-renal disease, which was induced by myocardial infarction in rats with chronic renal dysfunction (Munich Wistar Fromter; RD+CD). This group was compared to rats with solely cardiac disease (CD; age-matched Wistar rats), solely renal disease (RD) and healthy rats (Ctrl). Twelve weeks after surgery force was measured in left ventricular Triton-permeabilized cardiomyocytes at different calcium concentrations to assess myofilament function. Maximal force did not differ among groups. In contrast, myocardial infarction significantly increased passive force (CD vs Ctrl; figure), which was even more pronounced in rats with renal dysfunction (RD+CD vs RD; figure). No change in myofilament Ca 2+ -sensitivity was observed in the CD group, whereas Ca 2+ -sensitivity of force was significantly reduced in RD+CD compared to Ctrl. The changes in passive force and Ca 2+ -sensitivity could not be corrected by protein kinase A, which mimics beta-adrenergic stimulation. In contrast, a 2-times increase in expression and activity of protein kinase C (PKC) alpha was found in RD+CD myocardium (Figure). In conclusion, diastolic dysfunction in cardio-renal disease may be partly attributed to increased intrinsic cardiomyocyte stiffness, rather than to adverse remodelling. The increase in cardiomyocyte stiffness may result from increase PKCalpha-mediated phosphorylation of titin, and could represent a target for treatment of diastolic dysfunction in cardio-renal disease.