Attenuating persistent sodium current-induced atrial myopathy and fibrillation by preventing mitochondrial oxidative stress.

Mechanistically driven therapies for atrial fibrillation (AF), the most common cardiac arrhythmia, are urgently needed, the development of which requires improved understanding of the cellular signaling pathways that facilitate the structural and electrophysiological remodeling that occurs in the atria. Similar to humans, increased persistent Na+ current leads to the development of an atrial myopathy and spontaneous and long-lasting episodes of AF in mice. How increased persistent Na+ current causes both structural and electrophysiological remodeling in the atria is unknown.

Heterogeneity of the action potential duration is required for sustained atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia and accounts for substantial morbidity and mortality. Recently, we created a mouse model with spontaneous and sustained AF caused by a mutation in the NaV1.5 channel (F1759A) that enhances persistent Na+ current, thereby enabling the investigation of molecular mechanisms that cause AF and the identification of novel treatment strategies.

Cardiac CaV1.2 channels require β subunits for β-adrenergic-mediated modulation but not trafficking.

Ca2+ channel β-subunit interactions with pore-forming α-subunits are long-thought to be obligatory for channel trafficking to the cell surface and for tuning of basal biophysical properties in many tissues. Unexpectedly, we demonstrate that transgenic expression of mutant α1C subunits lacking capacity to bind CaVβ can traffic to the sarcolemma in adult cardiomyocytes in vivo and sustain normal excitation-contraction coupling. However, these β-less Ca2+ channels cannot be stimulated by β-adrenergic pathway agonists, and thus adrenergic augmentation of contractility is markedly impaired in isolated cardiomyocytes and in hearts.

Intact calcium signaling in adrenergic-deficient embryonic mouse hearts.

Mouse embryos that lack the ability to produce the adrenergic hormones, norepinephrine (NE) and epinephrine (EPI), due to disruption of the dopamine beta-hydroxylase (Dbh) gene inevitably perish from heart failure during mid-gestation. Since adrenergic stimulation is well-known to enhance calcium signaling in developing as well as adult myocardium, and impairments in calcium signaling are typically associated with heart failure, we hypothesized that adrenergic-deficient embryonic hearts would display deficiencies in cardiac calcium signaling relative to adrenergic-competent controls at a developmental stage immediately preceding the onset of heart failure, which first appears beginning or shortly after mouse embryonic day 10.5 (E10.

Proteolytic cleavage and PKA phosphorylation of α subunit are not required for adrenergic regulation of Ca1.2 in the heart.

Calcium influx through the voltage-dependent L-type calcium channel (Ca1.2) rapidly increases in the heart during "fight or flight" through activation of the β-adrenergic and protein kinase A (PKA) signaling pathway. The precise molecular mechanisms of β-adrenergic activation of cardiac Ca1.

Aberrant sodium influx causes cardiomyopathy and atrial fibrillation in mice.

Increased sodium influx via incomplete inactivation of the major cardiac sodium channel Na(V)1.5 is correlated with an increased incidence of atrial fibrillation (AF) in humans. Here, we sought to determine whether increased sodium entry is sufficient to cause the structural and electrophysiological perturbations that are required to initiate and sustain AF.

The PDZ motif of the α1C subunit is not required for surface trafficking and adrenergic modulation of CaV1.2 channel in the heart.

Voltage-gated Ca(2+) channels play a key role in initiating muscle excitation-contraction coupling, neurotransmitter release, gene expression, and hormone secretion. The association of CaV1.2 with a supramolecular complex impacts trafficking, localization, turnover, and, most importantly, multifaceted regulation of its function in the heart.

β-adrenergic regulation of the L-type Ca2+ channel does not require phosphorylation of α1C Ser1700.

Rationale: Sympathetic nervous system triggered activation of protein kinase A, which phosphorylates several targets within cardiomyocytes, augments inotropy, chronotropy, and lusitropy. An important target of β-adrenergic stimulation is the sarcolemmal L-type Ca(2+) channel, CaV1.2, which plays a key role in cardiac excitation-contraction coupling.

Reduced vascular smooth muscle BK channel current underlies heart failure-induced vasoconstriction in mice.

Excessively increased peripheral vasoconstriction is a hallmark of heart failure (HF). Here, we show that in mice with systolic HF post-myocardial infarction, the myogenic tone of third-order mesenteric resistance vessels is increased, the vascular smooth muscle (VSM) membrane potential is depolarized by ~20 mV, and vessel wall intracellular [Ca(2+)] is elevated relative to that in sham-operated control mice. Despite the increased [Ca(2+)], the frequency and amplitude of spontaneous transient outward currents (STOCs), mediated by large conductance, Ca(2+)-activated BK channels, were reduced by nearly 80% (P<0.

Mice with cardiac overexpression of peroxisome proliferator-activated receptor γ have impaired repolarization and spontaneous fatal ventricular arrhythmias.

Background: Diabetes mellitus and obesity, which confer an increased risk of sudden cardiac death, are associated with cardiomyocyte lipid accumulation and altered cardiac electric properties, manifested by prolongation of the QRS duration and QT interval. It is difficult to distinguish the contribution of cardiomyocyte lipid accumulation from the contribution of global metabolic defects to the increased incidence of sudden death and electric abnormalities.

Methods And Results: In order to study the effects of metabolic abnormalities on arrhythmias without the complex systemic effects of diabetes mellitus and obesity, we studied transgenic mice with cardiac-specific overexpression of peroxisome proliferator-activated receptor γ 1 (PPARγ1) via the cardiac α-myosin heavy-chain promoter.

Cardiac L-type calcium channel (Cav1.2) associates with gamma subunits.

The cardiac voltage-gated Ca(2+) channel, Ca(v)1.2, mediates excitation-contraction coupling in the heart. The molecular composition of the channel includes the pore-forming α1 subunit and auxiliary α2/δ-1 and β subunits.

Protein kinase C isoforms differentially phosphorylate Ca(v)1.2 alpha(1c).

The regulation of Ca(2+) influx through the phosphorylation of the L-type Ca(2+) channel, Ca(v)1.2, is important for the modulation of excitation-contraction (E-C) coupling in the heart. Ca(v)1.

Kcnq1 contributes to an adrenergic-sensitive steady-state K+ current in mouse heart.

It has been suggested that Kcne1 subunits are required for adrenergic regulation of Kcnq1 potassium channels. However, in adult mouse hearts, which do not express Kcne1, loss of Kcnq1 causes a Long QT phenotype during adrenergic challenge, raising the possibility that native Kcnq1 currents exist and are adrenergically regulated even in absence of Kcne1. Here, we used immunoblotting and immunohistochemical staining to show that Kcnq1 protein is present in adult mouse hearts.

Comparative evaluation of HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs.

The purpose of the present study was to comparatively evaluate human HERG currents and QT intervals following challenge with suspected torsadogenic and nontorsadogenic drugs. Various concentrations of 14 different drugs were initially evaluated in terms of their relative potency to block I(HERG) in stably transfected human embryonic kidney cells. Four general categories of drugs were identified: high-potency blockers (IC50 < 0.

Intrinsic cardiac catecholamines help maintain beating activity in neonatal rat cardiomyocyte cultures.

In the present study, we identify intrinsic cardiac adrenergic (ICA) cells in the neonatal rat heart using immunofluorescent histochemical staining techniques with antibodies that specifically recognize the major enzymes in the catecholamine biosynthetic pathway. ICA cells are most concentrated near the endocardial surface of ventricular myocardium, but are also found sporadically throughout the heart. In primary cultures of neonatal rat cardiomyocytes, ICA cells are closely associated with clusters of cardiomyocytes.

Isoproterenol exacerbates a long QT phenotype in Kcnq1-deficient neonatal mice: possible roles for human-like Kcnq1 isoform 1 and slow delayed rectifier K+ current.

To determine whether the neonatal mouse can serve as a useful model for studying the molecular pharmacological basis of Long QT Syndrome Type 1 (LQT1), which has been linked to mutations in the human KCNQ1 gene, we measured QT intervals from electrocardiogram (ECG) recordings of wild-type (WT) and Kcnq1 knockout (KO) neonates before and after injection with the beta-adrenergic receptor agonist, isoproterenol (0.17 mg/kg, i.p.

QTc interval prolongation associated with intravenous methadone.

Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation.

Nicotine induces a long QT phenotype in Kcnq1-deficient mouse hearts.

We have previously shown that targeted disruption of the mouse Kcnq1 gene produces a long QT phenotype in vivo that requires extracardiac factors for manifestation (Casimiro et al., 2001). In the present study, we explore the hypothesis that autonomic neuroeffector transmission represents the "extra cardiac" stimulus that induces a long QT phenotype in mouse hearts lacking Kcnq1.

In vivo androgen treatment shortens the QT interval and increases the densities of inward and delayed rectifier potassium currents in orchiectomized male rabbits.

Objectives: Women have longer rate-corrected QT intervals (QTc) and are at higher risk for developing life-threatening torsades de pointes ventricular arrhythmias than men, especially after taking medications that block cardiac human ether-a-go-go-related gene (HERG)-encoded K(+) channels. The purpose of the present study was to determine if the male sex steroid hormone, dihydrotestosterone (DHT), influences QT intervals in orchiectomized (Orch) male rabbits.

Methods: ECG and whole-cell patch-clamp analyses were employed to evaluate cardiac repolarization and K(+) currents in hearts isolated from orchiectomized (Orch) male New Zealand White rabbits receiving subcutaneous sustained release pellets for either dihydrotestosterone (DHT) or placebo.