T-Tubule Loss is a Prominent Feature of HFrEF but not HFpEF

Abstract

T-tubules are invaginations of the sarcolemmal membrane which are important for effective excitation-contraction coupling. Accumulating data indicate that cardiomyocyte t-tubular structure is disrupted during heart failure with reduced ejection fraction (HFrEF), resulting in impaired Ca2+ release and contractility. Much less is known about t-tubule structure during heart failure with preserved ejection fraction (HFpEF). Based on our recent data, indicating that increased wall stress promotes t-tubule degradation during HFrEF (Frisk et al. Cardiovasc Res, 2016), we hypothesized that t-tubule structure would be safeguarded by maintained wall stress during HFpEF. In HFpEF patients with mild diastolic dysfunction (E/e’ = 10.9±2.7 and deceleration time < 235ms), we observed that t-tubule density was maintained compared to healthy patient hearts. Interestingly, patients with more severe diastolic dysfunction (E/e’ = 13.4±2.7 and deceleration time > 305ms) showed increased t-tubule density. Closer examination of t-tubule architecture revealed that the observed rise in t-tubule density was a result of maintained transversely-oriented tubules and increased levels of longitudinally-oriented tubules. In contrast, t-tubules were lost and disorganized in patients with dilated cardiomyopathy. To investigate if t-tubule maintenance or proliferation are general features of non-dilated hypertrophic hearts we investigated the t-tubule network in patients with hypertrophic cardiomyopathy or aortic stenosis. In both conditions, t-tubule density was increased due to a larger fraction of transversely-oriented tubules. We thus conclude that t-tubule density is maintained or even increased in the non-dilated hypertrophic human ventricular myocardium. These findings are consistent with a key role of increased wall stress, a hallmark of dilated ventricular remodeling, in triggering t-tubule degradation in HFrEF.