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Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target.

ABSTRACT: Ca²⁺ is a fundamental second messenger in all cell types and is required for numerous essential cellular functions, including cardiac and skeletal muscle contraction. The intracellular concentration of free Ca²⁺ ([Ca²⁺]) is regulated primarily by ion channels, pumps (ATPases), exchangers and Ca²⁺-binding proteins. Defective regulation of [Ca²⁺] is found in a diverse spectrum of pathological states that affect all the major organs. In the heart, abnormalities in the regulation of cytosolic and mitochondrial [Ca²⁺] occur in heart failure (HF) and atrial fibrillation (AF), two common forms of heart disease and leading contributors to morbidity and mortality. In this Review, we focus on the mechanisms that regulate ryanodine receptor 2 (RYR2), the major sarcoplasmic reticulum (SR) Ca²⁺-release channel in the heart, how RYR2 becomes dysfunctional in HF and AF, and its potential as a therapeutic target. Inherited RYR2 mutations and/or stress-induced phosphorylation and oxidation of the protein destabilize the closed state of the channel, resulting in a pathological diastolic Ca²⁺ leak from the SR that both triggers arrhythmias and impairs contractility. On the basis of our increased understanding of SR Ca²⁺ leak as a shared Ca²⁺-dependent pathological mechanism in HF and AF, a new class of drugs developed in our laboratory, known as rycals, which stabilize RYR2 channels and prevent Ca²⁺ leak from the SR, are undergoing investigation in clinical trials.

SUBMITTER: Dridi H

PROVIDER: S-EPMC8362847 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsTachycardia is a reversible event that may cause hemodynamic decompensation but may not necessarily cause direct damages to the myocardium. To evaluate the clinical outcomes of patients with heart failure (HF) and atrial fibrillation (AF), whose acute decompensation was tachycardia mediated.Methods and resultsThe Korean Acute Heart Failure registry was a prospective registry that consecutively enrolled 5625 patients with acute HF. Patients were classified into three groups according to the rhythm and aggravating factor: (i) 3664 (65.1%) patients with sinus rhythm (SR), (ii) 1033 (18.4%) patients with AF whose decompensation was tachycardia-mediated, AF-TM (+), and (iii) N = 928 (16.5%) patients with AF whose decompensation was not tachycardia-mediated, AF-TM (-). The primary outcomes were in-hospital and post-discharge 1 year all-cause mortality. At admission, the mean heart rate was 90.8 ± 23.4, 86.8 ± 26.8, and 106.3 ± 29.7 beats per minute for the SR, AF-TM (-), and AF-TM (+) groups, respectively. The AF-TM (+) group had more favourable characteristics such as de novo onset HF, less diabetes, ischaemic heart disease, and higher blood pressure than the AF-TM (-) group. In-hospital mortality rates were 5.1%, 6.5%, and 1.7% for SR, AF-TM (-), and AF-TM (+) groups, respectively. In logistic regression analysis, the AF-TM (+) group had lower in-hospital mortality after adjusting the significant covariates (odds ratio, 0.49; 95% confidence interval, 0.26-0.93). The mortality rate did not differ between SR and AF-TM (-) groups. During 1 year follow-up, 990 (18.5%) patients died. In univariate and multivariate Cox proportional regression analyses, there was no difference in 1-year all-cause mortality between the three groups.ConclusionsIn patients with HF and AF, patients whose acute decompensation is tachycardia-mediated have better in-hospital, but similar post-discharge outcomes compared with those with SR or those with AF whose decompensation is not tachycardia-mediated.Clinical trial registrationClinicalTrial.gov NCT01389843.

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Intracellular calcium leak in heart failure and atrial fibrillation: a unifying mechanism and therapeutic target.

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