Regulation of Cardiomyocyte T-Tubule Organization and Density by Ventricular Wall Stress

Abstract

During heart failure development, t-tubules become disorganized which disrupts Ca2+ homeostasis and weakens contraction of the heart. The mechanisms controlling t-tubular structure in the normal and failing heart remain unknown, but accumulating data suggest that ventricular workload may be an important regulator. In Wistar rats which had developed heart failure 6 weeks following myocardial infarction, we observed that marked t-tubule disruption occurred preferentially in regions of the heart that are proximal to the infarct site, while t-tubule density was normal in distal locations. In vivo imaging by MRI has revealed near-isometric contraction in this proximal zone, with dramatically elevated wall stress due to local thinning of the ventricular wall and elevated diastolic blood pressure. To directly investigate whether elevated wall stress triggers t-tubule disruption, we developed an in vitro model for culturing isolated rat left ventricle papillary muscles in a myobath system (0.5 Hz stimulation, 48 hours). Muscles were subjected to varying amounts of stretch to approximate wall stress values observed in vivo. Muscles exposed to low diastolic wall stress similar to that observed in sham-operated hearts (3.5-4.5 mN/mm2), exhibited well-maintained t-tubule organization during culture (t-tubule fraction of cross-sectional area = 0.174 ± SE 0.007). Exposure to high wall stress (10-15 mN/mm2) triggered marked t-tubule loss during culture (t-tubule fraction = 0.079 ± SE 0.012), and reduction in both peak and between-peak power in Fast-Fourier Transform analyses. In addition, cell size was observed to be markedly increased by elevated wall stress in comparison with muscles that were exposed to low wall stress (cross-sectional area = 1022.71 ± SE 48.00 µm2 vs 564.41 ± SE 25.34 µm2, P < 0.05). Thus, our data indicate that wall stress is an important regulator of both cellular geometry and t-tubular structure.