Abstract
SummaryArrhythmogenesis during heart failure is a major clinical problem. Regional electrical gradients produce arrhythmias, and cellular ionic transmembrane gradients are its originators. We investigated whether the nanoscale mechanosensitive properties of cardiomyocytes from failing hearts have a bearing upon the initiation of abnormal electrical activity. Hydrojets through a nanopipette indent specific locations on the sarcolemma and initiate intracellular calcium release in both healthy and heart failure cardiomyocytes, as well as in human failing cardiomyocytes. In healthy cells, calcium is locally confined, whereas in failing cardiomyocytes, calcium propagates. Heart failure progressively stiffens the membrane and displaces sub-sarcolemmal mitochondria. Colchicine in healthy cells mimics the failing condition by stiffening the cells, disrupting microtubules, shifting mitochondria, and causing calcium release. Uncoupling the mitochondrial proton gradient abolished calcium initiation in both failing and colchicine-treated cells. We propose the disruption of microtubule-dependent mitochondrial mechanosensor microdomains as a mechanism for abnormal calcium release in failing heart.
Highlights
Pump failure and sudden cardiac death remain a major clinical problem despite conventional therapies
This study suggests that microtubular and mitochondrial derangement play pivotal roles in the initiation of abnormal calcium release during progression toward heart failure and provides an additional mechanism for nonaction potential-mediated intracellular calcium release, which could lead to triggered activity and arrhythmias
Structural and Mechanical Properties of Failing Cardiomyocytes We scanned the structural features of the sarcolemma of normal and failing cardiomyocytes using scanning ion conductance microscopy (SICM) at different time points following myocardial infarction (MI)
Summary
Pump failure and sudden cardiac death remain a major clinical problem despite conventional therapies. The structural remodeling that occurs during heart failure involves the cell membrane (loss of T-tubules; Lyon et al, 2009), intercalated disks (Ferreira-Cornwell et al, 2002), and sub-membrane microdomains involving ryanodine receptors (RyRs) and the sarcoplasmic reticulum (Dobrev and Wehrens, 2014). Mitochondria change their subcellular location (Piquereau et al, 2013; Rosca et al, 2013) and the inter-fibrillar mitochondria alignment is altered early following myocardial infarction (Dague et al, 2014). We have employed scanning ion conductance microscopy (SICM) and surface
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