Role of t-tubule remodeling on mechanisms of abnormal calcium release during heart failure development in canine ventricle

The goal of this work was to investigate the role of t-tubule (TT) remodeling in abnormal Ca^{2 þ} cycling in ventricular myocytes of failing dog hearts. Heart failure (HF) was induced using rapid right ventricular pacing. Extensive changes in echocardiographic parameters, including left and right ventricular dilation and systolic dysfunction, diastolic dysfunction, elevated left ventricular filling pressures, and abnormal cardiac mechanics, indicated that severe HF developed. TT loss was extensive when measured as the density of total cell volume, derived from three-dimensional confocal image analysis, and significantly increased the distances in the cell interior to closest cell membrane. Changes in Ca^{2 þ} transients indicated increases in heterogeneity of Ca² þ release along the cell length. When critical properties of Ca^{2 þ} release variability were plotted as a function of TT organization, there was a complex, nonlinear relationship between impaired calcium release and decreasing TT organization below a certain threshold of TT organization leading to increased sensitivity in Ca^{2 þ} release below a TT density threshold of 1.5%. The loss of TTs was also associated with a greater incidence of triggered Ca^{2 þ} waves during rapid pacing. Finally, virtually all of these observations were replicated by acute detubulation by formamide treatment, indicating an important role of TT remodeling in impaired Ca^{2 þ} cycling. We conclude that TT remodeling itself is a major contributor to abnormal Ca^{2 þ} cycling in HF, reducing myocardial performance. The loss of TTs is also responsible for a greater incidence of triggered Ca^{2 þ} waves that may play a role in ventricular arrhythmias arising in HF. NEW & NOTEWORTHY Three-dimensional analysis of t-tubule density showed t-tubule disruption throughout the whole myocyte in failing dog ventricle. A double-linear relationship between Ca^{2 þ} release and t-tubule density displays a steeper slope at t-tubule densities below a threshold value (1.5%) above which there is little effect on Ca^{2 þ} release (T-tubule reserve). T-tubule loss increases incidence of triggered Ca^{2 þ} waves. Chemically induced t-tubule disruption suggests that t-tubule loss alone is a critical component of abnormal Ca^{2 þ} cycling in heart failure.