Increased SERCA2a sub-cellular heterogeneity in right-ventricular heart failure inhibits excitation-contraction coupling and modulates arrhythmogenic dynamics

Abstract

The intracellular calcium handling system of cardiomyocytes is responsible for controlling excitation-contraction coupling (ECC) and has been linked to pro-arrhythmogenic cellular phenomena in conditions such as heart failure (HF). SERCA2a, responsible for intracellular uptake, is a primary regulator of calcium homeostasis, and remodelling of its function has been proposed as a causal factor underlying cellular and tissue dysfunction in disease. Whereas adaptations to the global (i.e. whole-cell) expression of SERCA2a have been previously investigated in the context of multiple diseases, the role of its spatial profile in the sub-cellular volume has yet to be elucidated. We present an approach to characterize the sub-cellular heterogeneity of SERCA2a and apply this approach to quantify adaptations to the length-scale of heterogeneity (the distance over which expression is correlated) associated with right-ventricular (RV)-HF. These characterizations informed simulations to predict the functional implications of this heterogeneity, and its remodelling in disease, on ECC, the dynamics of calcium-transient alternans and the emergence of spontaneous triggered activity. Image analysis reveals that RV-HF is associated with an increase in length-scale and its inter-cellular variability; simulations predict that this increase in length-scale can reduce ECC and critically modulate the vulnerability to both alternans and triggered activity. This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.

Patchy fibrosis promotes trigger–substrate interactions that both generate and maintain atrial fibrillation

“…Gaussian random fields were used to generate spatially varying patterns (e.g. [12,34]), and thresholds were then applied to impose a total fibrotic area of either 25% or 50% of the tissue. This allowed small (seed = 10) and large (seed = 50) fibrosis patches to be imposed at each desired total fibrosis area (figure 3B).…”

Correlative super-resolution analysis of cardiac calcium sparks and their molecular origins in health and disease

“…Increasing structural heterogeneity, including local t-tubule remodelling [45][46][47] , local regions of RyR fragmentation 17,38,48 , diminishing regularity of the expression patterns Ca 2+ handling proteins over nanometre/micron length-scales 49 , is now understood to be a hallmark of wide-ranging cardiac pathologies. In MCT-RV, we have previously observed evidence of heterogeneous RyR cluster fragmentation 31 and the receding subdomains of RyR-modulators and molecular tethers, junctophilin-2 (JPH2) 32 and BIN-1 from some clusters 18 .…”

Correlative super-resolution analysis of cardiac calcium sparks and their molecular origins in health and disease

“…Increasing structural heterogeneity, including local t-tubule remodelling [45][46][47], local regions of RyR2 fragmentation [17,38,48] and diminishing regularity of the expression patterns Ca 2+ handling proteins over nanometre/micron length-scales [49], are now understood to be hallmarks of wide-ranging cardiac pathologies. In MCT-RV, we have previously observed evidence of heterogeneous RyR2 cluster fragmentation [31] and the receding sub-domains of RyR2modulators and molecular tethers, junctophilin-2 (JPH2) [32] and BIN-1 from some clusters [18].…”