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Ryanodine receptor dispersion disrupts Ca²⁺ release in failing cardiac myocytes.

ABSTRACT: Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca²⁺ release from Ryanodine Receptors (RyRs). We investigated whether this deficit can be traced to nanoscale RyR reorganization. Using super-resolution imaging, we observed dispersion of RyR clusters in cardiomyocytes from post-infarction HF rats, resulting in more numerous, smaller clusters. Functional groupings of RyR clusters which produce Ca²⁺ sparks (Ca²⁺ release units, CRUs) also became less solid. An increased fraction of small CRUs in HF was linked to augmented 'silent' Ca²⁺ leak, not visible as sparks. Larger multi-cluster CRUs common in HF also exhibited low fidelity spark generation. When successfully triggered, sparks in failing cells displayed slow kinetics as Ca²⁺ spread across dispersed CRUs. During the action potential, these slow sparks protracted and desynchronized the overall Ca²⁺ transient. Thus, nanoscale RyR reorganization during HF augments Ca²⁺ leak and slows Ca²⁺ release kinetics, leading to weakened contraction in this disease.

SUBMITTER: Kolstad TR

PROVIDER: S-EPMC6245731 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Ryanodine receptor dispersion disrupts Ca2+ release in failing cardiac myocytes.

Kolstad Terje R TR van den Brink Jonas J MacQuaide Niall N Lunde Per Kristian PK Frisk Michael M Aronsen Jan Magnus JM Norden Einar S ES Cataliotti Alessandro A Sjaastad Ivar I Sejersted Ole M OM Edwards Andrew G AG Lines Glenn Terje GT Louch William E WE

eLife 20181030

Reduced cardiac contractility during heart failure (HF) is linked to impaired Ca2+ release from Ryanodine Receptors (RyRs). We investigated whether this deficit can be traced to nanoscale RyR reorganization. Using super-resolution imaging, we observed dispersion of RyR clusters in cardiomyocytes from post-infarction HF rats, resulting in more numerous, smaller clusters. Functional groupings of RyR clusters which produce Ca2+ sparks (Ca2+ release units, CRUs) also ...[more]

PMID: 30375974

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Project description:Sudden cardiac death (SCD) from ventricular tachycardia/fibrillation (VT/VF) is a leading cause of death, but current therapies are limited. Despite extensive research on drugs targeting sarcolemmal ion channels, none have proven sufficiently effective for preventing SCD. Sarcoplasmic ryanodine receptor 2 (RyR2) Ca2+ release channels, the downstream effectors of sarcolemmal ion channels, are underexplored in this context. Recent evidence implicates reactive oxygen species (ROS)-mediated oxidation and hyperactivity of RyR2s in the pathophysiology of SCD. We tested the hypothesis that RyR2 inhibition of failing arrhythmogenic hearts reduces sarcoplasmic Ca2+ leak and repolarization lability, mitigates VT/VF/SCD and improves contractile function. We used a guinea pig model that replicates key clinical aspects of human nonischemic HF, such as a prolonged QT interval, a high prevalence of spontaneous arrhythmic SCD, and profound Ca2+ leak via a hyperactive RyR2. HF animals were randomized to receive dantrolene (DS) or placebo in early or chronic HF. We assessed the incidence of VT/VF and SCD (primary outcome), ECG heart rate and QT variability, echocardiographic left ventricular (LV) structure and function, immunohistochemical LV fibrosis, and sarcoplasmic RyR2 oxidation. DS treatment prevented VT/VF and SCD by decreasing dispersion of repolarization and ventricular arrhythmias. Compared to placebo, DS lowered resting heart rate, preserved chronotropic competency during transient β-adrenergic challenge, and improved heart rate variability and cardiac function. Inhibition of RyR2 hyperactivity with dantrolene mitigates the vicious cycle of sarcoplasmic Ca2+ leak-induced increases in diastolic Ca2+ and ROS-mediated RyR2 oxidation, thereby reducing repolarization lability and protecting against VT/VF/SCD. Moreover, the consequent increase in sarcoplasmic Ca2+ load improves contractile function. These potentially life-saving effects of RyR2 inhibition warrant further investigation, such as clinical studies of repurposing dantrolene as a potential new therapy for heart failure and/or SCD.

Dataset Information

Ryanodine receptor dispersion disrupts Ca²⁺ release in failing cardiac myocytes.

Publications

Ryanodine receptor dispersion disrupts Ca<sup>2+</sup> release in failing cardiac myocytes.

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