T-Tubule Remodeling Causes Ca2+ Cycling Defects during the Progression to Heart Failure in the Intact Spontaneously Hypertensive Rat Heart

Severe disruption of the t-tubule network in cardiac myocytes has been found in nearly all animal and human models of heart failure. T-tubule disorganization would be expected to cause alterations in the EC coupling because of a separation of junctional SR from trigger Ca entry and the increase in orphaned ryanodine receptors. However, little is currently known about changes in t-tubules during the early stages of disease development, before heart failure (HF) develops. The goal of this study was to measure the relationship between cardiac function, t-tubule organization and Ca2+ cycling defects in whole hearts during the progression to HF. We combined echocardiography with confocal measurements of t-tubule organization (di-4-ANEPPS) and Ca2+ (fluo-4AM) in intact hearts of spontaneously hypertensive rats (SHR) ranging from 4 to 18 months of age. Echocardiography demonstrated defects in cardiac function that correlated with an increasing number of myocytes showing decreased t-tubule organization (calculated from FFTs of confocal images). In addition, t-tubule disorganization caused progressive development of Ca2+ cycling defects, explaining the reduced overall cardiac function. Our data suggest that the progression from hypertension to HF in SHRs occurs as the number of myocytes showing poor t-tubule organization and Ca2+ cycling defects increases and the fraction of normal cells decreases.