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Voltage-activated outward K currents ( I) are essential for cardiac repolarization and are major factors in the electrophysiological remodeling and arrhythmias seen in heart disease. Mouse models have been useful for understanding cardiac electrophysiology. However, previous methods for separating and quantifying the components of I in mouse myocardium have yielded inconsistencies. In this study, we developed a statistically rigorous method to uniquely quantify various I in adult mouse ventricular myocytes, and concluded that tri-exponential functions combined with depolarizing pulses of duration greater than 20 s are essential to adequately separate the different I components. This method enabled us to reliably dissect the kinetic components of the decay phase of I into fast ( I), intermediate (K1.5-encoded I) and slow (K2-encoded I) components. The most rapid kinetic phase, I, can be further dissected into fast (K4-encoded I) and slow (K1.4-encoded I) components by measuring recovery from inactivation, voltage-dependence of activation and sensitivity to HpTx-2 and 4-AP. The applicability of our dissection method was validated using transgenic mice over-expressing dominant-negative K1.1 transgene which largely abolished the 4-AP-sensitive portion of I (i.e., I) and the I component. We also applied our method to Irx5-deficient mice and verified selective elevations of I in endocardial myocytes. Our method should prove useful in future electrophysiological studies using mouse. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the involvement of nicotinamide adenine dinucleotide (NADH) in the regulation of human cardiac sodium channels (NaV1.5). The study discussed the association of NaV1.5 mutations with Brugada syndrome (BrS.) The researchers used rate neonatal cardiomyocytes and HEK293 cells. The study revealed that pyridine nucleotides regulate NaV1.5, and suggested connection between NAD-dependent energy metabolism with sodium current.

Introduction: Myocardial infarction (MI) disrupts electrical conduction in affected ventricular areas. We investigated the effect of MI on the regional voltage and calcium (Ca) signals and their propagation properties, with special attention to the effect of the site of ventricular pacing on these properties. Methods: New Zealand White rabbits were divided into four study groups: sham-operated (C, n = 6), MI with no pacing (MI, n = 7), MI with right ventricular pacing (MI + RV, n = 6), and MI with BIV pacing (MI + BIV, n = 7). At 4 weeks, hearts were excised, perfused, and optically mapped. As previously shown, systolic and diastolic dilation of the LV were prevented by BIV pacing, as was the reduction in LV fractional shortening. Results: Four weeks after MI, optical mapping revealed markedly reduced action potential amplitudes and conduction velocities (CV) in MI zones, and these increased gradually in the border zone and normal myocardial areas. Also, Ca transients were absent in the infarcted areas and increased gradually 3–5 mm from the border of the normal zone. Neither BIV nor RV pacing affected these findings in any of the MI, border, or normal zones. Conclusions: MI has profound effects on the regional electrical and Ca signals and on their propagation properties in this rabbit model. The absence of differences in these parameters by study group suggests that altering the properties of myocardial electrical conduction and Ca signaling are unlikely mechanisms by which BIV pacing confers its benefits. Further studies into the regional, cellular, and molecular benefits of BIV pacing are therefore warranted. [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]

Deals with the mechanism of a tachyarrhythmia referencing the case of a Caucasian man. Medical background of the patient; Results of the cardiac catheterization and electrophysiological testing; Features of the ventricular tachycardia.

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.

Introduction: The main cardiac sodium channel (Nav1.5) is responsible for the inward depolarizing sodium current that initiates and propagates the action potential throughout the heart. Recent studies by our group have shown that acetylation of Nav1.5 at a specific lysine residue (K1479) within the III-IV intracellular linker downregulates channel membrane expression. Although most notably known for its role in regulating Nav1.5 inactivation, the III-IV linker has previously been shown to upregulate channel localization to the membrane through an interaction with the cytoskeleton anchoring protein α-actinin 2. It is unknown whether acetylation of K1479 alters the effect of α-actinin 2 on Nav1.5. Objective: To evaluate the role of Nav1.5 K1479 in regulating channel localization through α-actinin 2. Methods: Site-directed mutagenesis was used to engineer lysine-to-glutamine (K1479Q) and lysine-to-alanine (K1479A) substitutions to imitate the acetylated channel and a channel that is not acetylatable, respectively. The native and mutant channels were transiently co-transfected into HEK293 cells with or without α-actinin 2 and subjected to whole-cell patch-clamp electrophysiology and co-immunoprecipitation to assess functional channel expression and interaction affinity. Results: Overexpression of α-actinin 2 increased peak sodium current (INa) in the native Nav1.5 K1479 channel but had no effect on the acetylated-mimic K1479Q and non-acetylatable K1479A channels (Figure 1). Furthermore, co-immunoprecipitation studies illustrated that α-actinin 2 bound to the wildtype Nav1.5 channel but not with the mutant Nav1.5 channels. Conclusions: The K1479 residue of Nav1.5 is critical in mediating the effect of α-actinin 2 in upregulating channel surface expression. Acetylation of K1479 may destabilize the channel at the membrane by disrupting its interaction with the cytoskeleton network via α-actinin 2. [ABSTRACT FROM AUTHOR]