Sheet-Like Remodeling of the Transverse Tubular System in Human Heart Failure Impairs Excitation-Contraction Coupling and Functional Recovery by Mechanical Unloading

Abstract

Background Cardiac recovery in response to mechanical unloading by left ventricular assist devices (LVADs) has been demonstrated in subgroups of chronic heart failure (HF) patients. Hallmarks of HF are depletion and disorganization of the transverse tubular system (t-system) in cardiomyocytes. Here, we investigated remodeling of the t-system in human end-stage HF and its role in cardiac recovery. Methods Left ventricular biopsies were obtained from 5 donors (CTRL) and 26 chronic HF patients undergoing implantation of LVADs. Three-dimensional confocal microscopy and computational image analysis were applied to assess t-system structure, density, and distance of ryanodine receptor (RyR) clusters to the sarcolemma, including the t-system. Recovery of cardiac function in response to mechanical unloading was assessed by echocardiography during turn-down of the LVAD. Results The majority of HF myocytes showed remarkable t-system remodeling, particularly sheet-like invaginations of the sarcolemma. Circularity of t-system components was decreased in HF vs CTRL (0.37±0.01 vs 0.46±0.02, p<0.01), and the volume/length ratio was increased in HF (0.36±0.01μm2 vs 0.25±0.02μm2, p<0.0001). T-system density was reduced in HF, leading to increased RyR-sarcolemma distances (0.96±0.05μm vs 0.64±0.1μm, p<0.01). Low RyR-sarcolemma distances at time of LVAD implantation predicted high post-LVAD left-ventricular ejection fractions (EF, p<0.01) and EF increase during unloading (p<0.01). EF in patients with pre-LVAD RyR-sarcolemma distances larger than 1μm did not improve following mechanical unloading. Additionally, calcium transients were recorded in field-stimulated isolated human cardiomyocytes and analyzed with respect to local t-system density. Calcium release in HF myocytes was restricted to regions proximal to the sarcolemma. Local calcium upstroke was delayed (23.9±4.9ms vs 10.3±1.7ms, p<0.05) and more asynchronous (18.1ms±1.5ms vs 8.9±2.2ms, p<0.01) in HF cells with low t-system density versus cells with high t-system density. Conclusions The t-system in end-stage human HF presents a characteristic novel phenotype consisting of sheet-like invaginations of the sarcolemma. Our results suggest that the remodeled t-system impairs excitation-contraction coupling and functional recovery during chronic LVAD unloading. An intact t-system at time of LVAD implantation may constitute a precondition and predictor for functional cardiac recovery following mechanical unloading.

Remodeling of the transverse tubular system after myocardial infarction in rabbit correlates with local fibrosis: A potential role of biomechanics

“…These “t-sheets” were dilated in longitudinal myocyte direction and still connected to the outer sarcolemma (Fig. 2F), showing high similarity to the phenotype observed in human end-stage heart failure (Seidel et al, 2017). These results support that WGA reliably stains the t-system in normal and remodeled rabbit myocytes.…”

“…While t-system remodeling in rodents leads mainly to disorganized orientation and increased axial components (Chen et al, 2012; Wagner et al, 2012; Wei et al, 2010), the predominant remodeling in humans and larger mammals, such as canine or pig, is loss and dilation of t-tubules (Biesmans et al, 2011; Crossman et al, 2017; Kostin et al, 1998; Sachse et al, 2012). We recently described the 3D structure of a sheet-like remodeled t-tubules (t-sheets) in humans, which is symptomatic for end-stage heart failure (Seidel et al, 2017). It still remains unclear if t-sheets are also present in animal models of heart failure, but most likely not in mice or rats because these species have already been studied extensively.…”

“…To show similar correlations in patients is more difficult, but recent studies underpin the importance of t-system remodeling as a pathomechanism and potential prognostic factor also in human failing hearts (Crossman et al, 2015; Seidel et al, 2017). At the cellular level, a loss of t-tubules increases the number of non-junctional RyRs, which impairs excitation-contraction coupling because a smaller number of RyR clusters is synchronously activated (Dries et al, 2013; Heinzel et al, 2008; Sachse et al, 2012; Seidel et al, 2017). Additionally, it was suggested that t-tubules may fail to conduct action potentials.…”

“…Studies on ventricular tissue from a rat model of myocardial infarction and cultured papillary muscle preparations support these ideas by demonstrating that elevated wall stress is associated with t-system remodeling (Frisk et al, 2016). In our recent work on ventricular tissue from human end-stage heart failure, we extended these concepts by proposing that cardiac fibrosis might cause t-system remodeling (Seidel et al, 2017). This hypothesis is supported by the recent discovery of increased amounts of the extracellular matrix protein type VI collagen within the lumen of dilated t-tubules in human heart failure (Crossman et al, 2017).…”

Plasma cBIN1 Score (CS) Identifies HFpEF and Can Predict Cardiac Hospitalization in Stable Ambulatory Patients

“…T-tubule remodeling and the resultant abnormal calcium transients are central to the pathophysiology of HF [13,17,[37][38][39][40][41][42][43][44][45]. Our groups and others have identified that t-tubule remodeling can be a consequence of reduced cBIN1 [9,10].…”