Paradoxical SERCA dysregulation contributes to atrial fibrillation in a model of diet-induced obesity.

Obesity is a major risk factor for atrial fibrillation (AF) the most common serious cardiac arrhythmia, but the molecular mechanisms underlying diet-induced AF remain unclear. In this study, we subjected mice to a chronic high-fat diet and acute sympathetic activation ('two-hit' model) to study the mechanisms by which diet-induced obesity promotes AF. Surface electrocardiography revealed that diet-induced obesity and sympathetic activation synergize during intracardiac tachypacing to induce AF.

Abnormal myocardial expression of SAP97 is associated with arrhythmogenic risk.

Synapse-associated protein 97 (SAP97) is a scaffolding protein crucial for the functional expression of several cardiac ion channels and therefore proper cardiac excitability. Alterations in the functional expression of SAP97 can modify the ionic currents underlying the cardiac action potential and consequently confer susceptibility for arrhythmogenesis. In this study, we generated a murine model for inducible, cardiac-targeted Sap97 ablation to investigate arrhythmia susceptibility and the underlying molecular mechanisms.

Atrial Infarction-Induced Spontaneous Focal Discharges and Atrial Fibrillation in Sheep: Role of Dantrolene-Sensitive Aberrant Ryanodine Receptor Calcium Release.

Background: The mechanisms underlying spontaneous atrial fibrillation (AF) associated with atrial ischemia/infarction are incompletely elucidated. Here, we investigate the mechanisms underlying spontaneous AF in an ovine model of left atrial myocardial infarction (LAMI).

Methods And Results: LAMI was created by ligating the atrial branch of the left anterior descending coronary artery.

Fatty Infiltration of the Myocardium and Arrhythmogenesis: .

Anatomical evidence in several species shows highly heterogeneous fat distribution in the atrial and ventricular myocardium. Atrial appendages have fat deposits, and more so on the posterior left atrium. Although such fat distributions are considered normal, fatty infiltration is regarded arrhythmogenic, and various cardiac pathophysiological conditions show excess myocardial fat deposits, especially in the epicardium.

Scn2b Deletion in Mice Results in Ventricular and Atrial Arrhythmias.

Background: Mutations in SCN2B, encoding voltage-gated sodium channel β2-subunits, are associated with human cardiac arrhythmias, including atrial fibrillation and Brugada syndrome. Because of this, we propose that β2-subunits play critical roles in the establishment or maintenance of normal cardiac electric activity in vivo.

Methods And Results: To understand the pathophysiological roles of β2 in the heart, we investigated the cardiac phenotype of Scn2b null mice.

Extracellular Matrix-Mediated Maturation of Human Pluripotent Stem Cell-Derived Cardiac Monolayer Structure and Electrophysiological Function.

Background: Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) monolayers generated to date display an immature embryonic-like functional and structural phenotype that limits their utility for research and cardiac regeneration. In particular, the electrophysiological function of hPSC-CM monolayers and bioengineered constructs used to date are characterized by slow electric impulse propagation velocity and immature action potential profiles.

Methods And Results: Here, we have identified an optimal extracellular matrix for significant electrophysiological and structural maturation of hPSC-CM monolayers.

Risk Factors and Genetics of Atrial Fibrillation.

Atrial fibrillation (AF) is by far the most common sustained tachyarrhythmia, affecting 1% to 2% of the general population. AF prevalence and the total annual cost for treatment are alarming, emphasizing the need for an urgent attention to the problem. Thus, having up-to-date information on AF risk factors and appreciating how they promote maintenance of AF maintenance are essential.

Free Fatty Acid Effects on the Atrial Myocardium: Membrane Ionic Currents Are Remodeled by the Disruption of T-Tubular Architecture.

Background: Epicardial adiposity and plasma levels of free fatty acids (FFAs) are elevated in atrial fibrillation, heart failure and obesity, with potentially detrimental effects on myocardial function. As major components of epicardial fat, FFAs may be abnormally regulated, with a potential to detrimentally modulate electro-mechanical function. The cellular mechanisms underlying such effects of FFAs are unknown.

Ionic mechanisms of arrhythmogenesis.

The understanding of ionic mechanisms underlying cardiac rhythm disturbances (arrhythmias) is an issue of significance in the medical science community. Several advances in molecular, cellular, and optical techniques in the past few decades have substantially increased our knowledge of ionic mechanisms that are thought to underlie arrhythmias. The application of these techniques in the study of ion channel biophysics and regulatory properties has provided a wealth of information, with some important therapeutic implications for dealing with the disease.

Risk factors and genetics of atrial fibrillation.

Atrial fibrillation (AF) is by far the most common sustained tachyarrhythmia, affecting 1% to 2% of the general population. AF prevalence and the total annual cost for treatment are alarming, emphasizing the need for an urgent attention to the problem. Thus, having up-to-date information on AF risk factors and appreciating how they promote maintenance of AF maintenance are essential.

Inhibition of platelet-derived growth factor-AB signaling prevents electromechanical remodeling of adult atrial myocytes that contact myofibroblasts.

Background: Persistent atrial fibrillation (PAF) results in electromechanical and structural remodeling by mechanisms that are poorly understood. Myofibroblast proliferation and fibrosis are major sources of structural remodeling in PAF. Myofibroblasts also interact with atrial myocytes via direct physical contact and release of signaling molecules, which may contribute to remodeling.

The ionic bases of the action potential in isolated mouse cardiac Purkinje cell.

Background: Collecting electrophysiological and molecular data from the murine conduction system presents technical challenges. Thus, only little advantage has been taken of numerous genetically engineered murine models to study excitation through the cardiac conduction system of the mouse.

Objective: To develop an approach for isolating murine cardiac Purkinje cells (PCs), to characterize major ionic currents and to use the data to simulate action potentials (APs) recorded from PCs.

Redox-sensitive sulfenic acid modification regulates surface expression of the cardiovascular voltage-gated potassium channel Kv1.5.

Rationale: Kv1.5 (KCNA5) is expressed in the heart, where it underlies the I(Kur) current that controls atrial repolarization, and in the pulmonary vasculature, where it regulates vessel contractility in response to changes in oxygen tension. Atrial fibrillation and hypoxic pulmonary hypertension are characterized by downregulation of Kv1.

Dynamic reciprocity of sodium and potassium channel expression in a macromolecular complex controls cardiac excitability and arrhythmia.

The cardiac electrical impulse depends on an orchestrated interplay of transmembrane ionic currents in myocardial cells. Two critical ionic current mechanisms are the inwardly rectifying potassium current (I(K1)), which is important for maintenance of the cell resting membrane potential, and the sodium current (I(Na)), which provides a rapid depolarizing current during the upstroke of the action potential. By controlling the resting membrane potential, I(K1) modifies sodium channel availability and therefore, cell excitability, action potential duration, and velocity of impulse propagation.

Subcellular heterogeneity of sodium current properties in adult cardiac ventricular myocytes.

Background: Sodium channel α-subunits in ventricular myocytes (VMs) segregate either to the intercalated disc or to lateral membranes, where they associate with region-specific molecules.

Objective: To determine the functional properties of sodium channels as a function of their location in the cell.

Methods: Local sodium currents were recorded from adult rodent VMs and Purkinje cells by using the cell-attached macropatch configuration.

Left-to-right ventricular differences in I(KATP) underlie epicardial repolarization gradient during global ischemia.

Background: The ionic mechanisms of electrical heterogeneity in the ischemic ventricular epicardium remain poorly understood.

Objective: This study sought to test the hypothesis that the adenosine triphosphate (ATP)-activated K+ current (I(KATP)) plays an important role in mediating repolarization differences between the right ventricle (RV) and left ventricle (LV) during global ischemia.

Methods: Electrical activity in Langendorff-perfused guinea pig hearts was recorded optically during control, ischemia, and reperfusion.

Purkinje cell calcium dysregulation is the cellular mechanism that underlies catecholaminergic polymorphic ventricular tachycardia.

Background: Inherited arrhythmias can be caused by mutations in the cardiac ryanodine receptor (RyR2). The cellular source of these arrhythmias is unknown. Isolated RyR2(R4496C) mouse ventricular myocytes display arrhythmogenic activity related to spontaneous Ca(2+) release during diastole.

Regulation of cardiac inward rectifier potassium current (I(K1)) by synapse-associated protein-97.

Synapse-associated protein-97 (SAP97) is a membrane-associated guanylate kinase scaffolding protein expressed in cardiomyocytes. SAP97 has been shown to associate and modulate voltage-gated potassium (Kv) channel function. In contrast to Kv channels, little information is available on interactions involving SAP97 and inward rectifier potassium (Kir2.