Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs.

The species-specific determinants of repolarization are poorly understood. This study compared the contribution of various currents to cardiac repolarization in canine and human ventricle. Conventional microelectrode, whole-cell patch-clamp, molecular biological and mathematical modelling techniques were used.

Phosphodiesterase-2 is up-regulated in human failing hearts and blunts β-adrenergic responses in cardiomyocytes.

Objectives: This study investigated whether myocardial phosphodiesterase-2 (PDE2) is altered in heart failure (HF) and determined PDE2-mediated effects on beta-adrenergic receptor (β-AR) signaling in healthy and diseased cardiomyocytes.

Background: Diminished cyclic adenosine monophosphate (cAMP) and augmented cyclic guanosine monophosphate (cGMP) signaling is characteristic for failing hearts. Among the PDE superfamily, PDE2 has the unique property of being able to be stimulated by cGMP, thus leading to a remarkable increase in cAMP hydrolysis mediating a negative cross talk between cGMP and cAMP signaling.

Unique quantitative trait loci in synergy permanently improve diastolic dysfunction.

Background: Diastolic dysfunction often precedes the onset of diastolic heart failure. We previously demonstrated that diastolic dysfunction and left ventricular hypertrophy (LVH) in Dahl salt-sensitive rats can be ameliorated by quantitative trait loci (QTLs).

Methods: We analyzed cardiac phenotypes of 2 "single" congenic strains, C10S.

Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca²⁺ in adult cardiac myocytes.

Endothelin receptors are present on the nuclear membranes in adult cardiac ventricular myocytes. The objectives of the present study were to determine 1) which endothelin receptor subtype is in cardiac nuclear membranes, 2) if the receptor and ligand traffic from the cell surface to the nucleus, and 3) the effect of increased intracellular ET-1 on nuclear Ca(2+) signaling. Confocal microscopy using fluorescently-labeled endothelin analogs confirmed the presence of ETB at the nuclear membrane of rat cardiomyocytes in skinned-cells and isolated nuclei.

Adenosine testing in atrial flutter ablation: unmasking of dormant conduction across the cavotricuspid isthmus and risk of recurrence.

Background: Adenosine-induced hyperpolarization may identify pulmonary veins at risk of reconnection following electrical isolation for atrial fibrillation. The potential role of adenosine testing in other arrhythmic substrates, such as cavotricuspid isthmus (CTI)-dependent atrial flutter, remains unclear. We assessed whether dormant conduction across the CTI may be revealed by adenosine after ablation-induced bidirectional block, and its association with recurrent flutter.

Regulation of cardiac nitric oxide signaling by nuclear β-adrenergic and endothelin receptors.

At the cell surface, βARs and endothelin receptors can regulate nitric oxide (NO) production. β-adrenergic receptors (βARs) and type B endothelin receptors (ETB) are present in cardiac nuclear membranes and regulate transcription. The present study investigated the role of the NO pathway in the regulation of gene transcription by these nuclear G protein-coupled receptors.

Atrial fibrillation promotion by endurance exercise: demonstration and mechanistic exploration in an animal model.

Objectives: The goal of this study was to assess mechanisms underlying atrial fibrillation (AF) promotion by exercise training in an animal model.

Background: High-level exercise training promotes AF, but the underlying mechanisms are unclear.

Methods: AF susceptibility was assessed by programmed stimulation in rats after 8 (Ex8) and 16 (Ex16) weeks of daily 1-h treadmill training, along with 4 and 8 weeks after exercise cessation and time-matched sedentary (Sed) controls.

MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation.

Atrial fibrillation (AF) is a highly prevalent arrhythmia with pronounced morbidity and mortality. Inward-rectifier K+ current (IK1) is believed to be an important regulator of reentrant-spiral dynamics and a major component of AF-related electrical remodeling. MicroRNA-26 (miR-26) is predicted to target the gene encoding KIR2.

Unique cardiac Purkinje fiber transient outward current β-subunit composition: a potential molecular link to idiopathic ventricular fibrillation.

Rationale: A chromosomal haplotype producing cardiac overexpression of dipeptidyl peptidase-like protein-6 (DPP6) causes familial idiopathic ventricular fibrillation. The molecular basis of transient outward current (I(to)) in Purkinje fibers (PFs) is poorly understood. We hypothesized that DPP6 contributes to PF I(to) and that its overexpression might specifically alter PF I(to) properties and repolarization.

MicroRNA29: a mechanistic contributor and potential biomarker in atrial fibrillation.

Background: Congestive heart failure (CHF) causes atrial fibrotic remodeling, a substrate for atrial fibrillation (AF) maintenance. MicroRNA29 (miR29) targets extracellular matrix proteins. In the present study, we examined miR29b changes in patients with AF and/or CHF and in a CHF-related AF animal model and assessed its potential role in controlling atrial fibrous tissue production.

Combining distinctive and novel loci doubles BP reduction, reverses diastolic dysfunction and mitigates LV hypertrophy.

Objectives: Diastolic dysfunction often represents the onset of diastolic heart failure (DHF). We previously showed in principle that diastolic function in Dahl salt-sensitive rats (DSS) can be genetically determined by quantitative trait loci (QTLs) that also modulate blood pressure (BP).

Methods: We analyzed cardiac phenotypes of four 'single' congenic strains by echocardiography, in which a specific DSS chromosome segment was replaced by its normotensive Lewis homologue.

Electrical storm: recent pathophysiological insights and therapeutic consequences.

The implantable cardioverter-defibrillator significantly improves survival in patients with malignant ventricular arrhythmias but does not target the underlying pathological substrate responsible for arrhythmic events. A significant proportion of defibrillator recipients experience multiple ventricular tachycardia/fibrillation episodes over a short period of time, termed electrical storm (ES). The current therapeutic strategy for ES is complex and unsatisfactory because simultaneous administration of several medications and additional invasive procedures are often required to control ES.

Nuclear factor of activated T cells mediates RhoA-induced fibronectin upregulation in glomerular podocytes.

Glomerulosclerosis is featured by accumulation of the extracellular matrixes in the glomerulus. We showed previously that activation of the small GTPase RhoA in podocytes induces heavy proteinuria and glomerulosclerosis in the mouse. In the current study, we investigated the mechanism by which RhoA stimulates the production of one of the extracellular matrixes, fibronectin, by podocytes, specifically testing the role of nuclear factor of activated T cells (NFAT).

Losartan prevents heart fibrosis induced by long-term intensive exercise in an animal model.

Rationale: Recently it has been shown that long-term intensive exercise practice is able to induce myocardial fibrosis in an animal model. Angiotensin II is a profibrotic hormone that could be involved in the cardiac remodeling resulting from endurance exercise.

Objective: This study examined the antifibrotic effect of losartan, an angiotensin II type 1 receptor antagonist, in an animal model of heart fibrosis induced by long-term intense exercise.

Congestive heart failure effects on atrial fibroblast phenotype: differences between freshly-isolated and cultured cells.

Introduction: Fibroblasts are important in the atrial fibrillation (AF) substrate resulting from congestive heart failure (CHF). We previously noted changes in in vivo indices of fibroblast function in a CHF dog model, but could not detect changes in isolated cells. This study assessed CHF-induced changes in the phenotype of fibroblasts freshly isolated from control versus CHF dogs, and examined effects of cell culture on these differences.

Role of the Wnt-Frizzled system in cardiac pathophysiology: a rapidly developing, poorly understood area with enormous potential.

Abstract  The Wnt-Frizzled (Fzd) G-protein-coupled receptor system, involving 19 distinct Wnt ligands and 10 Fzd receptors, plays key roles in the development and functioning of many organ systems. There is increasing evidence that Wnt-Fzd signalling is important in regulating cardiac function. Wnt-Fzd signalling primarily involves a canonical pathway, with dishevelled-1-dependent nuclear translocation of β-catenin that derepresses Wnt-sensitive gene transcription, but can also include non-canonical pathways via phospholipase-C/Ca(2+) mobilization and dishevelled-protein activation of small GTPases.

Region-specific gene expression profiles in the left atria of patients with valvular atrial fibrillation.

Background: Previous studies have demonstrated that atrial regions contribute differently to atrial fibrillation (AF) substrate. Pulmonary vein and the surrounding left atrial junction (LA-PV junction) are crucial areas in AF substrates and important ablation targets.

Objective: To identify regional differences in the left atria of patients with AF by using a genome-wide approach.

Atrial fibrillation-associated remodeling does not promote atrial thrombus formation in canine models.

Background: The most important complication of atrial fibrillation (AF) is thromboembolic stroke. Although AF-related remodeling is considered important in atrial thrombogenesis, its role never has been directly tested. This study assessed effects of AF-related remodeling on the atrial thrombogenic milieu by using radiofrequency ablation (RFA) to create a quantifiable prothrombotic nidus.

Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation.

Background: Fibroblast proliferation and differentiation are central in atrial fibrillation (AF)-promoting remodeling. Here, we investigated fibroblast regulation by Ca(2+)-permeable transient receptor potential canonical-3 (TRPC3) channels.

Methods And Results: Freshly isolated rat cardiac fibroblasts abundantly expressed TRPC3 and had appreciable nonselective cation currents (I(NSC)) sensitive to a selective TPRC3 channel blocker, pyrazole-3 (3 μmol/L).

A proposal for new clinical concepts in the management of atrial fibrillation.

Atrial fibrillation (AF) represents a growing public health burden. It is a complex condition, involving a number of etiologic factors and arrhythmia mechanisms associated with atrial remodeling. Greater understanding of these mechanisms may improve therapy.