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The editorial in Circulation discusses the genetic basis of long-QT syndrome, focusing on the KCNH2 gene mutations that cause the condition. Genetic testing is recommended for patients with long-QT syndrome to guide treatment decisions, but challenges remain in interpreting the significance of genetic variants. A recent study by O'Neil and colleagues used a high-throughput assay to assess the effects of thousands of KCNH2 gene variants on channel trafficking, shedding light on the pathogenicity of previously uncertain variants. The findings have important clinical implications for the management of long-QT syndrome and highlight the potential of genetic testing in personalized medicine. [Extracted from the article]

Decreased peak sodium current (I Na) and increased late sodium current (I Na,L), through the cardiac sodium channel Na V 1.5 encoded by SCN5A, cause arrhythmias. Many Na V 1.5 posttranslational modifications have been reported. A recent report concluded that acute hypoxia increases I Na,L by increasing a small ubiquitin-like modifier (SUMOylation) at K442-Na V 1.5. The purpose of this study was to determine whether and by what mechanisms SUMOylation alters I Na , I Na,L , and cardiac electrophysiology. SUMOylation of Na V 1.5 was detected by immunoprecipitation and immunoblotting. I Na was measured by patch clamp with/without SUMO1 overexpression in HEK293 cells expressing wild-type (WT) or K442R-Na V 1.5 and in neonatal rat cardiac myocytes (NRCMs). SUMOylation effects were studied in vivo by electrocardiograms and ambulatory telemetry using Scn5a heterozygous knockout (SCN5A+/–) mice and the de-SUMOylating protein SENP2 (AAV9-SENP2), AAV9-SUMO1, or the SUMOylation inhibitor anacardic acid. Na V 1.5 trafficking was detected by immunofluorescence. Na V 1.5 was SUMOylated in HEK293 cells, NRCMs, and human heart tissue. HyperSUMOylation at Na V 1.5-K442 increased I Na in NRCMs and in HEK cells overexpressing WT but not K442R-Na v 1.5. SUMOylation did not alter other channel properties including I Na,L. AAV9-SENP2 or anacardic acid decreased I Na , prolonged QRS duration, and produced heart block and arrhythmias in SCN5A+/– mice, whereas AAV9-SUMO1 increased I Na and shortened QRS duration. SUMO1 overexpression enhanced membrane localization of Na V 1.5. SUMOylation of K442-Na v 1.5 increases peak I Na without changing I Na,L , at least in part by altering membrane abundance. Our findings do not support SUMOylation as a mechanism for changes in I Na,L. Na v 1.5 SUMOylation may modify arrhythmic risk in disease states and represents a potential target for pharmacologic manipulation. [Display omitted] [ABSTRACT FROM AUTHOR]

Inherited conditions that lead to cardiac arrhythmias and sudden cardiac death remain an important cause of morbidity and mortality. Identifying the genes responsible for these rare conditions can provide insights into the more common and heritable forms of sudden cardiac death seen in patients with structural heart disease. We and others have used candidate gene approaches and positional cloning in large families to show that mutations in ion channels and ion channel related proteins cause familial arrhythmia syndromes including long QT and Brugada syndromes. The genes responsible for many familial arrhythmia syndromes and the vast majority of the predisposition to common arrhythmias remain unknown. Using whole exome sequencing in families with Brugada syndrome and idiopathic ventricular fibrillation, we now seek to identify mutations in genes previously not thought to play a significant role in the heart. [ABSTRACT FROM AUTHOR]

T-wave altemans (TWA) is a proarrhythmic repolarization instability that is common in congestive heart failure (CHF). Although transgenic mice are commonly used to study the mechanisms of arrhythmogenesis in CHF, little is known about the dynamics of TWA in these species. We hypothesized that TWA is present in a TNF-α model of CHF and can be further promoted by adrenergic stimulation. We studied 16 TNF-α mice and 12 FVB controls using 1) in vivo intracardiac electrophysiological testing and 2) ambulatosy telemetry during 30 mm before and after an intraperitoneal injection of isoproterenol. TWA was examined using both linear and nonlinear filtering applied in the time domain. In addition, changes in the mean amplitude of the T wave and area under the T wave were computed. During intracardiac electrophysiological testing, none of the animals had TWA or inducible arrhythmias before the injection of isoproterenol. After the injection, sustained TWA and inducible ventricular tachyarrhythmias were observed in TNF-α mice but not in FVB mice. In ambulatory telemetry, before the isoproterenol injection, the cardiac cycle length (CL) was longer in TNF-α mice than in FVB mice (98 ± 9 and 88 ± 3 ms, P = 0.04). After the injection of isoproterenol, the CL became 8% and 6% shorter in TNF-α and FVB mice (P < 10-4); however, the 2% difference between the groups in the magnitude of CL changes was not significant. In TNF-α mice, the magnitude of TWA was 1.5-2 times greater than in FVB mice both before and after the isoproterenol injection. The magnitude of TWA increased significantly after the isoproterenol injection compared with the baseline in TNF-α mice (P = 0.003) but not in FVB mice. The mean amplitude of the T wave and area under the T wave increased 60% and 80% in FVB mice (P = 0.006 and 0.009) but not in TNF-α mice. hi conclusion, TWA is present in a TNF-α model of CHF and can be further promoted by adrenergic stimulation, along with the enhanced susceptibility for ventricular arrhythmias. [ABSTRACT FROM AUTHOR]

Recent studies demonstrate that statins decrease ventricular arrhythmias in internal cardioverter defibrillator (ICD) patients. The mechanism is unknown, but evidence links increased inflammatory and oxidative states with increased arrhythmias. We hypothesized that statin use decreases oxidation. Methods. 304 subjects with ICDs were surveyed for ventricular arrhythmia. Blood was analyzed for derivatives of reactive oxygen species (DROMs) and interleukin-6 (IL-6). Results. Subjects included 252 (83%) men, 58% on statins, 20% had ventricular arrhythmias. Average age was 63 years and ejection fraction (EF) 20%. ICD implant duration was 29 ± 27 months. Use of statins correlated with lower ICD events (r = 0.12, P = .02). Subjects on statins had lower hsCRP (5.2 versus 6.3; P = .05) and DROM levels (373 versus 397; P = .03). Other factors, including IL-6 and EF did not differ between statin and nonstatin use, nor did beta-blocker or antiarrhythmic use. Multivariate cross-correlation analysis demonstrated that DROMs, statins, IL-6 and EF were strongly associated with ICD events. Multivariate regression shows DROMs to be the dominant predictor. Conclusion. ICD event rate correlates with DROMs, a measure of lipid peroxides. Use of statins is associated with reduced DROMs and fewer ICD events, suggesting that statins exert their effect through reducing oxidation. [ABSTRACT FROM AUTHOR]

Abstract Introduction  Cardiac morbidity and mortality after aneurysmal subarachnoid hemorrhage (SAH) are attributable to myocardial injury, decreased ventricular function, and ventricular arrhythmia (VA). Our objective was to test the relationships between QTc prolongation, VA, and survival after SAH. Methods  In 200 subjects with acute aneurysmal SAH, electrocardiograms, echocardiograms, and telemetry were evaluated. Serum electrolytes and troponin were also evaluated. Results  Initial QTc (mean 460 ± 45 ms) was prolonged (≥470 ms) in 38% of subjects and decreased on follow-up (469 ± 49 initial vs. 435 ± 31 ms follow-up; N = 89; P P = 0.084). Multivariate analysis demonstrated significant predictors of VA after SAH were increasing age (OR 1.3/5 years; P = 0.025), increasing stroke severity (OR 1.8; P = 0.009), decreasing heart rate (OR 0.5/10 beats/min; P= 0.006), and the absence of angiotensin converting enzyme inhibitor or angiotensin II receptor antagonist use at SAH onset (OR 0.10; P = 0.027). All-cause mortality was 19% (25/135) at 3 months and subjects with VA had significantly higher mortality than those without VA (37% vs. 16%; P = 0.027). Conclusions  These data demonstrate that QTc prolongation and arrhythmias are frequently noted after SAH, but arrhythmias are often not associated with QTc prolongation. In addition, the presence of VA identified subjects at greater risk of mortality following their SAH. [ABSTRACT FROM AUTHOR]

Mouse models are becoming an increasingly accepted method of studying human diseases. Knockin and knockout techniques have several advantages over traditional transgenic overexpression, and the versatility of the knockin mouse allows the study of both gain of function mutations through targeted mutagenesis, as well as the replacement of one gene by another functional gene. Here, we will review the methods available to generate knockin mice; provide an overview of the techniques used to study electrophysiology in the mice at the cellular, organ, and whole animal level; and highlight knockin mice that have implications for inherited arrhythmias. Specifically, we will focus on models that used knockin mice to clarify gene expression, identify similarities and differences between related genes, and model human arrhythmia syndromes. Our goal is to provide the reader with a general understanding of studies done on knockin mouse models of inherited arrhythmias as well as ideas for future directions. [ABSTRACT FROM AUTHOR]

Background: Brugada and long QT type 3 syndromes are linked to sodium channel mutations and clinically cause arrhythmias that lead to sudden death. We have identified a novel threonine-to-isoleucine missense mutation at position 353 (T353I) adjacent to the pore-lining region of domain I of the cardiac sodium channel (SCN5A) in a family with Brugada syndrome. Both male and female carriers are symptomatic at young ages, have typical Brugada-type electrocardiogram changes, and have relatively normal corrected QT intervals.Objectives: To characterize the properties of the newly identified cardiac sodium channel (SCN5A) mutation at the cellular level.Results: Using whole-cell voltage clamp, we found that heterologous expression of SCN5A containing the T353I mutation resulted in 74% +/- 6% less peak macroscopic sodium current when compared with wild-type channels. A construct of the T353I mutant channel fused with green fluorescent protein failed to traffic properly to the sarcolemma, with a large proportion of channels sequestered intracellularly. Overnight exposure to 0.1 mM mexiletine, a Na(+) channel blocking agent, increased T353I channel trafficking to the membrane to near normal levels, but the mutant channels showed a significant late current that was 1.6% +/- 0.2% of peak sodium current at 200 ms, a finding seen with long QT mutations.Conclusions: The clinical presentation of patients carrying the T353I mutation is that of Brugada syndrome and could be explained by a cardiac Na(+) channel trafficking defect. However, when the defect was ameliorated, the mutated channels had biophysical properties consistent with long QT syndrome. The lack of phenotypic changes associated with the long QT syndrome could be explained by a T353I-induced trafficking defect reducing the number of mutant channels with persistent currents present at the sarcolemma. [ABSTRACT FROM AUTHOR]

Mice that overexpress the inflammatory cytokine tumor necrosis factor-α in the heart (TNF mice) develop heart failure characterized by atrial and ventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias, and increased mortality (males > females). Abnormalities in Ca2+ handling, prolonged action potential duration (APD), calcium alternans, and reentrant atrial and ventricular arrhythmias were previously observed with the use of optical mapping of perfused hearts from TNF mice. We therefore tested whether altered voltage-gated outward K+ and/or inward Ca2+ currents contribute to the altered action potential characteristics and the increased vulnerability to arrhythmias. Whole cell voltage-clamp recordings of K+ currents from left ventricular myocytes of TNF mice revealed an ∼50 decrease in the rapidly activating, rapidly inactivating transient outward K+ current Ito and in the rapidly activating, slowly inactivating delayed rectifier current IK,slow1, an ∼25% decrease in the rapidly activating, slowly inactivating delayed rectifier current IIK,slow2, and no significant change in the steady-state current Iss. compared with controls. Peak amplitudes and inactivation kinetics of the ʟ-type Ca2+ current ICa,L were not altered. Western blot analyses revealed a reduction in the proteins underlying Kv4.2. Kv4.3, and Kv1.5. Thus decreased K+ channel expression is largely responsible for the prolonged APD in the TNF mice and may, along with abnormalities in Ca2+ handling, contribute to arrhythmias. [ABSTRACT FROM AUTHOR]

Transgenic mice overexpressing the inflammatory cytokine TNF-α in the heart develop a progressive heart failure syndrome characterized by biventricular dilatation, decreased ejection fraction, decreased survival compared with non-transgenic littermates, and earlier pathology in males. TNF-α mice (TNF1.6) develop atrial arrhythmias on ambulatory telemetry monitoring that worsen with age and are more severe in males. We performed in vivo electrophysiological testing in transgenic and control mice, ex vivo optical mapping of voltage in the atria of isolated perfused TNF1.6 hearts, and in vitro studies on isolated atrial muscle and cells to study the mechanisms that lead to the spontaneous arrhythmias. Programmed stimulation induces atrial arrhythmias (n = 8/32) in TNF1.6 but not in control mice (n = 0/37), with a higher inducibility in males. In the isolated perfused hearts, programmed stimulation with single extra beats elicits reentrant atrial arrhythmias (n = 6/6) in TNF1.6 but not control hearts due to slow heterogeneous conduction of the premature beats. Lowering extracellular Ca2+ normalizes conduction and prevents the arrhythmias. Atrial muscle and cells from TNF1.6 compared with control mice exhibit increased collagen deposition, decreased contractile function, and abnormal systolic and diastolic Ca2+ handling. Thus abnormalities in action potential propagation and Ca2+ handling contribute to the initiation of atrial arrhythmias in this mouse model of heart failure. [ABSTRACT FROM AUTHOR]

Introduction: Estrogen is an important modulator of cardiovascular risk, but its mechanism of action is not fully understood. We investigated the effect of ovariectomy and its timing on the cardiac electrophysiology in mice.Methods: Thirty female mice (age 18.8 +/- 3.1 weeks) underwent in vivo electrophysiologic testing before and after autonomic blockade. Fifteen mice were ovariectomized prepuberty (PRE) and ten postpuberty (POST), 2 weeks prior to electrophysiologic testing. Five age-matched sham-operated female mice (Control) served as controls. A subset of 13 mice (5 PRE, 3 POST, and 5 Controls) underwent 24-hour ambulatory monitoring.Results: With ambulatory monitoring, the average (668 +/- 28 vs 769 +/- 52 b/min, P = 0.008) and minimum (485 +/- 47 vs 587 +/- 53 b/min, P = 0.02) heart rates were significantly slower in the ovariectomized mice (PRE and POST groups) compared to the Control group. At baseline electrophysiologic testing, there were no significant differences among the ovariectomized and intact mice in any of the measured parameters. With autonomic blockade, the Control group had a significantly larger change (delta) in the atrioventricular (AV) nodal Wenckebach (AVW) periodicity (deltaAVW = 11.3 +/- 2.9 vs 2.1 +/- 7.3 ms, P = 0.05) and functional refractory period (deltaFRP = 11.3 +/- 2.1 vs 1.25 +/- 6.8 ms, P = 0.02) compared to the ovariectomized mice. These results were not altered by the time of ovariectomy (PRE vs POST groups).Conclusion: Our results suggest that estrogen modulates the autonomic inputs into the murine sinus and AV nodes. These findings, if replicated in humans, might underlie the observed clustering of certain arrhythmias around menstruation and explain the higher incidence of arrhythmias in men and postmenopausal women. [ABSTRACT FROM AUTHOR]

Discusses results of a study monitoring the occurrence of calcium-dependent arrhythmias in transgenic mice with heart failure. Ventricular action potentials in tumor necrosis factor-alpha transgenic mice; Abnormalities in repolarization; Contributing effect of calcium handling to arrhythmias.

Provides information on long OT and ventricular arrhythmias in transgenic mice expressing the N terminus. Methodology used to gather the information; Indepth look at mutations of the K+ channel genes; Preparation of isolated myocytes.

Transgenic and gene-targeted mice now are frequently used to study cardiac arrhythmias due to the ease with which the mouse genome can be manipulated. Marked electrophysiologic differences are present between the mouse and human heart, however, and the utility of the mouse as a model for arrhythmias and sudden death remains controversial. Tachyarrhythmias, bradyarrhythmias, and ECG in the mouse need to be interpreted with extreme care and without preconceptions based on our experience with humans. Despite its limitations, the mouse can provide a powerful tool to further our understanding of basic mechanisms that underlie human cardiac electrophysiology. [ABSTRACT FROM AUTHOR]

The article provides information concerning the amiodarone and atrial fibrillation in the U.S. The author says that atrial fibrillation is the most common arrhythmia syndrome, affecting more than 3 million American people. It is most commonly associated with conditions such as hypertension, cardiomyopathies of ischemic or nonischemic origin, and others.

The article provides information on the studies that have sought to identify the molecular events that couple preconditioning to cardioprotection, with the hope that they would lead to therapies that salvage ischemic myocardium in humans. The initial cascade of events that occurs prior to the prolonged ischemic episode is called a trigger while pathways that operate during and after that episode are called mediators and end-effectors.

Comments on a study about the electrophysiologic abnormalities identified in sterol carrier protein-2 (SPC2) mice. Effect of high-phytol diet on SCP2 mice; Potential role for high serum concentrations of certain fatty acids in heart block; Suggestion that these findings can be used to determine the mechanisms by which elevated levels of phytanic acid lead to abnormalities in cardiac electrophysiology; Implications for Refsum disease.

The cardiac sodium channel Na V 1.5, encoded by SCN5A , produces the rapidly inactivating depolarizing current I Na that is responsible for the initiation and propagation of the cardiac action potential. Acquired and inherited dysfunction of Na V 1.5 results in either decreased peak I Na or increased residual late I Na (I Na,L), leading to tachy/bradyarrhythmias and sudden cardiac death. Previous studies have shown that increased cellular NAD+ and NAD+/NADH ratio increase I Na through suppression of mitochondrial reactive oxygen species and PKC-mediated Na V 1.5 phosphorylation. In addition, NAD+-dependent deacetylation of Na V 1.5 at K1479 by Sirtuin 1 increases Na V 1.5 membrane trafficking and I Na. The role of NAD+ precursors in modulating I Na remains unknown. To determine whether and by which mechanisms the NAD+ precursors nicotinamide riboside (NR) and nicotinamide (NAM) affect peak I Na and I Na,L in vitro and cardiac electrophysiology in vivo. The effects of NAD+ precursors on the NAD+ metabolome and electrophysiology were studied using HEK293 cells expressing wild-type and mutant Na V 1.5, rat neonatal cardiomyocytes (RNCMs), and mice. NR increased I Na in HEK293 cells expressing Na V 1.5 (500 μM: 51 ± 18%, p =.02, 5 mM: 59 ± 22%, p =.03) and RNCMs (500 μM: 60 ± 26%, p =.02, 5 mM: 74 ± 39%, p =.03) while reducing I Na,L at the higher concentration (RNCMs, 5 mM: −45 ± 11%, p =.04). NR (5 mM) decreased Na V 1.5 K1479 acetylation but increased I Na in HEK293 cells expressing a mutant form of Na V 1.5 with disruption of the acetylation site (Na V 1.5-K1479A). Disruption of the PKC phosphorylation site abolished the effect of NR on I Na. Furthermore, NAM (5 mM) had no effect on I Na in RNCMs or in HEK293 cells expressing wild-type Na V 1.5, but increased I Na in HEK293 cells expressing Na V 1.5-K1479A. Dietary supplementation with NR for 10–12 weeks decreased QTc in C57BL/6 J mice (0.35% NR: −4.9 ± 2.0%, p =.14; 1.0% NR: −9.5 ± 2.8%, p =.01). NAD+ precursors differentially regulate Na V 1.5 via multiple mechanisms. NR increases I Na , decreases I Na,L , and warrants further investigation as a potential therapy for arrhythmic disorders caused by Na V 1.5 deficiency and/or dysfunction. • The NAD+ precursor Nicotinamide Riboside (NR) increases peak sodium current (I Na) and reduces late I Na. • NR decreases Nav1.5 K1479 deacetylation. • The effect of NR on increasing I Na is mediated through the PKC-dependent phosphorylation site S1503. • Nicotinamide (NAM) has differential effects on peak I Na which are dependent on the Sirtuin-dependent acetylation-site K1479. • Dietary NR supplementation reduced QTc in C57BL/6 mice, consistent with a decrease in I Na,L. [ABSTRACT FROM AUTHOR]