Abstract 17857: Diastolic Destiffening of Failing Human Cardiomyocytes
High cardiomyocyte resting tension (RT) raises diastolic left ventricular (LV) stiffness of failing human hearts. Protein kinase A (PKA), PKG or the reducing agent dithiothreitol (DTT) lower RT through posttranslational modifications of titin. Gelsolin-induced extraction of actin also modulates RT through disruption of titin-actin interaction. Disruption at the I-band lowers RT but disruption at the Z-disc raises RT and shortens sarcomere slack length. Reversibility of high RT was assessed using these interventions. LV myocardial samples were obtained from 16 heart failure (HF) patients and from 5 donor hearts (Con). Isolated cardiomyocytes (HF: n=59; Con: n=30) were stretched to 2.2 μm sarcomere length. RT in HF (6.2±0.9 kN/m2) was higher than in Con (2.5±0.2 kN/m2; p=0.001) and slack sarcomere length in HF (13±0.5 a.u.) was shorter than in Con (14.9±0.6 a.u.; p=0.031). Although PKA, PKG or DTT lowered RT in HF to 4.4±0.6, 4.2±0.7 and 4.0±0.4 kN/m2 respectively, it still exceeded (p<0.05) RT in Con. Gelsolin treatment caused a larger fall of RT in Con (36.3±4.1%) than in HF (22.2±4.1%; p=0.027) and shortened slack sarcomere length only in HF. This implied more disruption of Z-disc titin-actin interaction in HF probably because of altered Z-disc structure evident from larger Z-disc width (p=0.032) and higher colocalization of actin and alpha-actinin (p=0.004).
Conclusions: Administration of PKA, PKG or DTT only partially reverse high RT of HF cardiomyocytes. Smaller slack sarcomere length, RT response to gelsolin and altered Z-disc structure suggest modified Z-disc titin-actin interaction as a mechanism for the residual RT elevation.
- © 2010 by American Heart Association, Inc.