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

Haikel Dridi, Alexander Kushnir, Ran Zalk, Qi Yuan, Zephan Melville, Andrew R Marks
Nature Reviews. Cardiology 2020 June 18
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.

Full Text Links

We have located links that may give you full text access.


You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read

Save your favorite articles in one place with a free QxMD account.


Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"