Transverse Tubule Structure is Related to Contractile Function in Human Heart Failure

Abstract

The transverse tubules (t-tubules) of cardiac myocytes facilitate a rapid and synchronous contraction. Loss of t-tubule structure has been reported in several animal models of cardiac failure and also in human heart failure. The loss of t-tubule structure is thought to disrupt calcium induced calcium release and contribute to impaired cardiac contraction. We sought to determine if a relationship between contractile performance and t-tubule structure may contribute to human heart failure. To test this idea we exploited the regional heterogeneity in contractility found within the failing human heart. MRI analysis was performed on patients with non-ischemic dilated cardiomyopathy awaiting a cardiac transplant. Tagged MRI was used to locate regions of different fractional shortening (circumferential strain) within the same heart. A model of the diseased heart was then created using MRI images from which a sampling map was created and used to sample tissue regions from the patient's heart (at transplantation). Using this methodology we were able obtain 14 tissue samples from 5 diseased hearts with corresponding contractility data ranging from poor (%Sc 2) to near normal function (%Sc 15). Tissue sections from these regions were labelled with fluorescent wheat germ agglutinin (WGA) and imaged using confocal microscopy. Fourier analysis of WGA labelled t-tubule images was used to assess t-tubule integrity of the cardiac myocytes using a modification of an established technique. Briefly, the height of the peak in the power spectrum corresponding to sarcomere spacing of t-tubules provided a metric of integrity (TT power). The mean TT power showed a strong positive relationship with fractional shortening data (R2=0.61 p<0.001) suggesting that loss of t-tubule structure plays a role in reduced contractile function in human heart failure.