A Titin Missense Variant Causes Atrial Fibrillation.

Rare and common genetic variants contribute to the risk of atrial fibrillation (AF). Although ion channels were among the first AF candidate genes identified, rare loss-of-function variants in structural genes such as have also been implicated in AF pathogenesis partly by the development of an atrial myopathy, but the underlying mechanisms are poorly understood. While truncating variants (tvs) have been causally linked to arrhythmia and cardiomyopathy syndromes, the role of missense variants (mvs) remains unclear.

Modulation of NOX2 causes obesity-mediated atrial fibrillation.

Obesity is linked to an increased risk of atrial fibrillation (AF) via increased oxidative stress. While NADPH oxidase 2 (NOX2), a major source of oxidative stress and reactive oxygen species (ROS) in the heart, predisposes to AF, the underlying mechanisms remain unclear. Here, we studied NOX2-mediated ROS production in obesity-mediated AF using Nox2-knockout mice and mature human induced pluripotent stem cell-derived atrial cardiomyocytes (hiPSC-aCMs).

Isolated Cardiac Ryanodine Receptor Function Varies Between Mammals.

Concerted robust opening of cardiac ryanodine receptors' (RyR2) Ca release 1oplasmic reticulum (SR) is fundamental for normal systolic cardiac function. During diastole, infrequent spontaneous RyR2 openings mediate the SR Ca leak that normally constrains SR Ca load. Abnormal large diastolic RyR2-mediated Ca leak events can cause delayed after depolarizations (DADs) and arrhythmias.

Inositol 1,4,5-trisphosphate receptor - reactive oxygen signaling domain regulates excitation-contraction coupling in atrial myocytes.

The inositol 1,4,5-trisphosphate receptor (InsPR) is up-regulated in patients with atrial fibrillation (AF) and InsP-induced Ca release (IICR) is linked to pro-arrhythmic spontaneous Ca release events. Nevertheless, knowledge of the physiological relevance and regulation of InsPRs in atrial muscle is still limited. We hypothesize that InsPR and NADPH oxidase 2 (NOX2) form a functional signaling domain where NOX2 derived reactive oxygen species (ROS) regulate InsPR agonist affinity and thereby Ca release.

JNK2, a Newly-Identified SERCA2 Enhancer, Augments an Arrhythmic [Ca] Leak-Load Relationship.

Rationale: We recently discovered pivotal contributions of stress kinase JNK2 (c-Jun N-terminal kinase isoform 2) in increased risk of atrial fibrillation through enhanced diastolic sarcoplasmic reticulum (SR) calcium (Ca) leak via RyR2 (ryanodine receptor isoform 2). However, the role of JNK2 in the function of the SERCA2 (SR Ca-ATPase), essential in maintaining SR Ca content cycling during each heartbeat, is completely unknown.

Objective: To test the hypothesis that JNK2 increases SERCA2 activity SR Ca content and exacerbates an arrhythmic SR Ca content leak-load relationship.