Abbreviation Of Action Potential Duration Research Articles

Abstract 15636: NFATC1 Modulates Atrial Excitability and Arrhythmogenesis

Transcription factors have emerged as important loci for atrial fibrillation (AF) susceptibility. We identified a novel mutation (M527L) in a conserved site of the transcription factor NFATC1 in a multigenerational family with an autosomal dominant young onset AF (<40 years old) phenotype. M527L reduces NFATC1 nuclear translocation (nuclear/total cellular ratio: M527L 0.50±0.02; WT 0.64±0.04, p<1E-5; n=10/each), DNA binding (M527L 0.69±0.02; WT 0.83±0.01, p=0.02; n=3/ each), and transcriptional activity (M527L 0.0003±0.00005; WT 0.0009±0.0002, p=0.01; n=5/each) in expression systems, underscoring the functional consequences of this mutation. To study the broader role of NFATC1 in atrial excitability we employed a CRISPR/Cas9 strategy to create an nfatc1 null (KO) zebrafish. KO fish exhibited reduced survival, with ~80% of juvenile fish succumbing to sudden death (log rank test p=0.0001), with no observable change in body or heart gross morphology. Explanted juvenile atria displayed spontaneous tachyarrhythmias or irregular rhythm (29 /40 KO atria vs 11/28 WT atria; Chi-Squared, p=0.0013) accompanied by irregular Ca 2+ handling (10/11 KO atria vs 5/16 WT atria). Furthermore, we found an abbreviated action potential duration in KO atrium (80±1 ms in KO (n=607) vs 91±1 ms in WT (n=441), p=0.0001), but not ventricle (186±3 ms in KO (n=109) vs 191±2 ms in WT (n=160), p=0.8). Taken together, our data suggests that NFATC1 is a modulator of atrial excitability and plays a role in AF susceptibility. Experiments are ongoing to further define the mechanisms underlying arrhythmia susceptibility and to identify the gene networks downstream of NFATC1 in the atria.

Safe electrophysiologic profile of the neprilysin-inhibitor sacubitril in combination with different antiarrhythmic drugs

Abstract Background Observational clinical data suggest a direct effect of sacubitril on cardiac electrophysiology. However, data concerning the impact of combination of sacubitril with antiarrhythmic drug therapy is sparse. Purpose We aimed at characterizing the electrophysiologic effects of a combination therapy of sacubitril with the class III-drug sotalol and the class IB-agent mexiletine in a sensitive, experimental whole-heart model. Methods and results 25 isolated rabbit hearts were retrogradely perfused. Hearts were treated with mexiletine (25 μM, 13 hearts) or sotalol (100 μM, 12 hearts) after generating baseline data. Eight endo- and epicardial monophasic action potentials and ECG recordings demonstrated an abbreviation of action potential duration (APD90, −21 ms, p<0.01) and no significant changes of QT interval (+10ms, p=ns) after administration of mexiletine. Spatial dispersion of repolarization (SDR) remained stable after mexiletine treatment (+6 ms, p=ns) whereas effective refractory periods (ERP) were significantly prolonged (+80 ms, p<0.01). Sotalol prolonged cardiac repolarization (APD90: +1 ms, p=ns; QT: +24 ms, p<0.01) and amplified spatial dispersion (+19 ms, p<0.01) without changing ERP (+8 ms, p=ns). Additional treatment with sacubitril (5 μM) led to a significant reduction of APD90 (−12 ms, p<0.01), QT interval (−20 ms, p<0.01) and ERP (−23 ms, p<0.01) in the presence of a stable SDR (−4 ms, p=ns) in the mexiletine group. In the sotalol group, additional administration of sacubitril abbreviated APD90 (−9 ms, p<0.05) and QT interval (−13 ms, p<0.01) and reduced ERP (−18 ms, p<0.01) without affecting SDR (−3 ms, p=ns). Ventricular vulnerability was assessed by a predefined pacing protocol employing premature extra stimuli and burst stimulation. After lowering the potassium concentration, 30 episodes of torsade de pointes tachycardia were observed after sotalol treatment (vs. 0 episodes under baseline, p<0.05). Additional sacubitril treatment significantly suppressed torsade de pointes tachycardia (8 episodes, p<0.05) in the sotalol-group. No proarrhythmic effect was observed after mexiletine treatment (8 episodes vs. 3 episodes under baseline conditions, p=ns). Additional sacubitril treatment did not increase ventricular vulnerability (32 episods, p=ns). Conclusion Sacubitril in combination with antiarrhythmic drugs demonstrates a safe electrophysiologic profile. In class IB- and class III-pretreated hearts, sacubitril abbreviates cardiac repolarization duration and effective refractory periods without changing spatial dispersion of repolarization. Thereby, sacubitril reduces the occurrence of torsade de pointes-tachycardia in antiarrhythmic pretreated hearts. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Deutsche Stiftung für Herzforschung (to G.F.)

Neuronal nitric oxide synthase inhibition exacerbates atrial electrical remodeling via small-conductance Ca2+-activated K+ channel activation

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): The Japan Society for the Promotion of Science KAKENHI Background The presence of atrial fibrillation (AF) is associated with electrical remodeling processes that promote a substrate for the maintenance of AF itself. Small conductance Ca2+-activated K+ (SK) channels; K+-selective and voltage-independent ion channels are key factors in the atrial electrical remodeling (2, 3). However, the mechanism of its activation remains unclear. A recent study showed that neuronal nitric oxide synthase (nNOS) expression and activity are reduced in AF patients and that nNOS depletion causes the abbreviation of action potential duration (APD), leading to increased AF inducibility in animal experiments (4). Decreased NO production, especially driven by nNOS inhibition, might play a key role in the atrial electrical remodeling, and the downstream alteration of SK channels might result from this process. Purpose We aimed to evaluate the potential of SK channel blocking to mitigate abnormal electrophysiological properties and the inducibility of atrial tachyarrhythmia (ATA) which was induced by nNOS depletion, and to describe the related mechanism. Methods Atrial tachyarrhythmia induction and optical mapping were performed in perfused rat hearts. nNOS was pharmacologically inhibited by S-methylthiocitrulline (SMTC, 100 nM). The influence of the SK channel was examined by a specific channel inhibitor, apamin (100 nM). APD, conduction velocity, and calcium transient (CaT) parameters (CaTD, rise time, time to 50% decay, and tau) were evaluated by voltage and calcium dual optical mapping. Dominant frequency was evaluated to analyze the wave dynamics of AF. Results SMTC increased the inducibility of ATA and apamin mitigated the nNOS inhibition-induced arrhythmogenicity (0% [0/7] vs 62% [8/13] vs 15% [2/13] in control, SMTC and SMTC + apamin). SMTC caused the abbreviation and enhanced spatial dispersion of APD, which were reversed by apamin. In contrast, conduction velocity was not affected by SMTC or apamin. Moreover, apamin reduced the dominant frequency of SMTC-induced ATA. In voltage and calcium optical mapping, STMC and apamin did not alter the parameters associated with CaT, however, SMTC caused the abbreviation of APD, which was reversed by apamin (APD80: 48.4 ± 2.7 msec in control group, 30.8 ± 1.5 msec in SMTC group, p <0.0001 vs. control, 41.8 ± 1.5 msec in SMTC + apamin, p = 0.01 vs. SMTC by One-way ANOVA and Tukey’s multiple-comparison test) (Figure A-C). Conclusion Acute nNOS inhibition abbreviated APD via activating SK channels. A specific SK channel blocker mitigated APD abbreviation without the alteration of CaT, implying an underlying mechanism of post translational modification of SK channels.

PO-630-05 A NOVEL MECHANISM OF SMALL-CONDUCTANCE CA2+-ACTIVATED K+ CHANNEL ACTIVATION VIA NEURONAL NITRIC OXIDE SYNTHASE INHIBITION IN RAT ATRIA

The presence of atrial fibrillation (AF) is associated with electrical remodeling processes that promote a substrate for the maintenance of AF itself. Small-conductance Ca2+-activated K+ (SK) channel is a key factor in the atrial electrical remodeling. However, the mechanism of its activation is unclear. A recent study showed that neuronal nitric oxide synthase (nNOS) expression and activity are reduced in AF patients and that nNOS depletion causes the abbreviation of APD, leading to increased AF vulnerability in animals. Decreased NO production, especially driven by nNOS inhibition, might play a key role in the atrial electrical remodeling, and the downstream alteration of SK channels might result from this process. We aimed to evaluate the potential of SK channel blocking to mitigate abnormal electrophysiological properties and the inducibility of atrial tachyarrhythmia which was induced by neuronal nitric oxide synthase (nNOS) depletion, and to describe the related mechanism. Atrial tachyarrhythmia (ATA) induction and optical mapping were performed on perfused rat hearts. nNOS was pharmacologically inhibited by S-methylthiocitrulline (SMTC, 100nM). The influence of the SK channel was examined by a specific channel inhibitor, apamin (100nM). Action potential duration (APD), conduction velocity, and calcium transient (CaT) parameters (CaTD, Rise time, T 1/2, Tau) were evaluated by voltage and calcium optical mapping. Dominant frequency was examined in the analysis of AF dynamics. SMTC increased the inducibility of ATA and apamin mitigated the nNOS inhibition-induced arrhythmogenicity. SMTC caused the abbreviation and enhanced spatial dispersion of APD, which was reversed by apamin. In contrast, conduction velocity was not affected by SMTC or apamin. Moreover, apamin reduced the dominant frequency of SMTC-induced ATA. In voltage and calcium optical mapping, STMC and apamin does not altered parameters associated with CaT, however, SMTC caused abbreviation APD, which was reversed by apamin. Acute nNOS inhibition abbreviated APD via activating SK channels. A specific SK channel blocker mitigated APD abbreviation without alteration of CaT, implying an underlying mechanism of post translational modification of SK channels.

Cardiovascular risk of energy drinks: Caffeine and taurine facilitate ventricular arrhythmias in a sensitive whole-heart model.

Several case reports have suggested an increased risk of sudden cardiac death due to energy drinks. Therefore, the purpose of this study was to assess acute electrophysiologic effects of caffeine and taurine, two of the main ingredients of energy drinks, in an experimental whole-heart model. Twenty-five rabbit hearts were excised, retrogradely perfused, and assigned to two groups. Hearts were perfused with caffeine (2, 10, and 50 µM) or taurine (2, 10, and 50 µM) after generating baseline data. Eight monophasic action potentials and electrocardiography recordings showed a significant abbreviation of action potential duration (APD90 ), QT interval, and effective refractory periods (ERP) after caffeine treatment. With taurine, cardiac repolarization duration and ERP were significantly shortened. A ventricular vulnerability was assessed by a predefined pacing protocol. With caffeine, we observed a trend towards more ventricular arrhythmias in a dose-dependent manner. After treatment with taurine, significantly more episodes of ventricular arrhythmias occurred. In this experimental whole-heart study, treatment with caffeine and taurine provoked ventricular arrhythmias. The underlying mechanism was an abbreviation of cardiac repolarizations and effective refractory periods that may facilitate re-entry and thereby provokes arrhythmias. These findings help to understand the potentially hazardous and fatal outcomes after intoxication with energy drinks.

The history and geographic distribution of a KCNQ1 atrial fibrillation risk allele

The genetic architecture of atrial fibrillation (AF) encompasses low impact, common genetic variants and high impact, rare variants. Here, we characterize a high impact AF-susceptibility allele, KCNQ1 R231H, and describe its transcontinental geographic distribution and history. Induced pluripotent stem cell-derived cardiomyocytes procured from risk allele carriers exhibit abbreviated action potential duration, consistent with a gain-of-function effect. Using identity-by-descent (IBD) networks, we estimate the broad- and fine-scale population ancestry of risk allele carriers and their relatives. Analysis of ancestral migration routes reveals ancestors who inhabited Denmark in the 1700s, migrated to the Northeastern United States in the early 1800s, and traveled across the Midwest to arrive in Utah in the late 1800s. IBD/coalescent-based allele dating analysis reveals a relatively recent origin of the AF risk allele (~5000 years). Thus, our approach broadens the scope of study for disease susceptibility alleles to the context of human migration and ancestral origins.

Propofol abolishes torsade de pointes in different models of acquired long QT syndrome

There is conflicting evidence regarding the impact of propofol on cardiac repolarization and the risk of torsade de pointes (TdP). The purpose of this study was to elucidate the risk of propofol-induced TdP and to investigate the impact of propofol in drug-induced long QT syndrome. 35 rabbit hearts were perfused employing a Langendorff-setup. 10 hearts were perfused with increasing concentrations of propofol (50, 75, 100 µM). Propofol abbreviated action potential duration (APD90) in a concentration-dependent manner without altering spatial dispersion of repolarization (SDR). Consequently, no proarrhythmic effects of propofol were observed. In 12 further hearts, erythromycin was employed to induce prolongation of cardiac repolarization. Erythromycin led to an amplification of SDR and triggered 36 episodes of TdP. Additional infusion of propofol abbreviated repolarization and reduced SDR. No episodes of TdP were observed with propofol. Similarly, ondansetron prolonged cardiac repolarization in another 13 hearts. SDR was increased and 36 episodes of TdP occurred. With additional propofol infusion, repolarization was abbreviated, SDR reduced and triggered activity abolished. In this experimental whole-heart study, propofol abbreviated repolarization without triggering TdP. On the contrary, propofol reversed prolongation of repolarization caused by erythromycin or ondansetron, reduced SDR and thereby eliminated drug-induced TdP.

Proarrhythmic Effects of Electrolyte Imbalance in Virtual Human Atrial and Ventricular Cardiomyocytes.

Dialysis is prescribed to renal failure patients as a long-term chronic treatment. Whereas dialysis therapeutically normalizes serum electrolytes and removes small toxin molecules, it fails to alleviate fibroblast induced structural fibrosis, and unresponsive uremia. The simultaneous presence of altered electrolytes and fibrosis or uremia is thought to be pro-arrhythmogenic. This study explored potential arrhythmogenesis under pre-dialysis (high electrolyte levels) and post-dialysis (low physiological electrolyte levels) in the presence of fibrosis and uremia in human atrial and ventricular model cardiomyocytes.Two validated human cardiomyocyte models were used in this study that permitted simulation of cardiac atrial and ventricular detailed electrophysiology. Pathological conditions simulating active fibrosis and uremia were implemented in both models. Pre- and post-dialysis conditions were simulated using high and low electrolyte levels respectively. Arrythmogenesis was quantified by computing restitution curves that permitted identification of action potential duration and calcium transient alternans instabilities.In comparison to control conditions, fibrosis abbreviated action potential durations while uremia prolonged the same. Under pre-dialysis conditions, an elevation of serum electrolyte levels caused action potential durations to be abbreviated under both fibrosis and uremia. Alternans instability was observed in the ventricular cardiomyocyte model. Under post-dialysis conditions, lower levels of serum electrolytes promoted an abbreviated action potential duration under fibrosis but caused a large increase of the control and uremic action potential durations. Alternans instabilities were observed in the atrial cardiomyocyte model under post-dialysis conditions at physiological heart rates. The calcium transient restitution showed similar alternans instabilities.Co-existing conditions such as fibrosis and uremia in the presence of unphysiological electrolyte levels promote arrhythmogenesis and may require additional treatment to improve dialysis outcomes.Clinical Relevance. Knowledge of model response to clinically relevant conditions permits use of in silico modeling to better understand and dissect underlying arrhythmia mechanisms.

Pro-arrhythmic Effects of Hydrogen Sulfide in Healthy and Ischemic Cardiac Tissues: Insight From a Simulation Study

Hydrogen sulfide (H2S), an ambient air pollutant, has been reported to increase cardiac events in patients with cardiovascular diseases, but the underlying mechanisms remain not elucidated. This study investigated the pro-arrhythmic effects of H2S in healthy and ischemic conditions. Experimental data of H2S effects on ionic channels (including the L-type Ca2+ channel and ATP-sensitive K+ channel) were incorporated into a virtual heart model to evaluate their integral action on cardiac arrhythmogenesis. It was shown that H2S depressed cellular excitability, abbreviated action potential duration, and augmented tissue’s transmural dispersion of repolarization, resulting in an increase in tissue susceptibility to initiation and maintenance of reentry. The observed effects of H2S on cardiac excitation are more remarkable in the ischemic condition than in the healthy condition. This study provides mechanistic insights into the pro-arrhythmic effects of air pollution (H2S), especially in the case with extant ischemic conditions.

Autophagy exacerbates electrical remodeling in atrial fibrillation by ubiquitin-dependent degradation of L-type calcium channel

Autophagy, a bidirectional degradative process extensively occurring in eukaryotes, has been revealed as a potential therapeutic target for several cardiovascular diseases. However, its role in atrial fibrillation (AF) remains largely unknown. This study aimed to determine the role of autophagy in atrial electrical remodeling under AF condition. Here, we reported that autophagic flux was markedly activated in atria of persistent AF patients and rabbit model of atrial rapid pacing (RAP). We also observed that the key autophagy-related gene7 (ATG7) significantly upregulated in AF patients as well as tachypacing rabbits. Moreover, lentivirus-mediated ATG7 knockdown and overexpression in rabbits were employed to clarify the effects of autophagy on atrial electrophysiology via intracardiac operation and patch-clamp experiments. Lentivirus-mediated ATG7 knockdown or autophagy inhibitor chloroquine (CQ) restored the shortened atrial effective refractory period (AERP) and alleviated the AF vulnerability caused by tachypacing in rabbits. Conversely, ATG7 overexpression significantly promoted the incidence and persistence of AF and decreased L-type calcium channel (Cav1.2 α-subunits), along with abbreviated action potential duration (APD) and diminished L-type calcium current (ICa,L). Furthermore, the co-localization and interaction of Cav1.2 with LC3B-positive autophagosomes enhanced when autophagy was activated in atrial myocytes. Tachypacing-induced autophagic degradation of Cav1.2 required ubiquitin signal through the recruitment of ubiquitin-binding proteins RFP2 and p62, which guided Cav1.2 to autophagosomes. These findings suggest that autophagy induces atrial electrical remodeling via ubiquitin-dependent selective degradation of Cav1.2 and provide a novel and promising strategy for preventing AF development.

LRP5 controls cardiac QT interval by modulating the metabolic homeostasis of L-type calcium channel

BackgroundLow-density lipoprotein receptor-related protein 5 (LRP5) has been intensively studied as a co-receptor for β-catenin-dependent Wnt signaling. Emerging evidences have demonstrated β-catenin-independent functions of LRP5. However, the biological role of LRP5 in the mammalian heart is largely unknown. Methods and resultsConditional cardiac-specific Lrp5 knockout (Lrp5-CKO) mice were generated by crossing Lrp5flox/flox mice with αMHC/MerCreMer mice. Lrp5-CKO mice consistently displayed normal cardiac structure and function. Telemetric electrocardiogram recordings revealed a short QT interval in Lrp5-CKO mice, which was tightly linked to the striking abbreviation of action potential duration (APD) in ventricular myocytes. The analysis of whole-cell currents indicated that a reduction in activity and protein expression of L-type calcium channel (LTCC), rather than other ion channels, contributed to the abnormality in APD. Furthermore, we showed that Lrp5 ablation induced a significant convergence of CaV1.2α1c proteins to the endoplasmic reticulum. Consequently, increased proteasomal degradation of these proteins was observed, which was independent of the Wnt/β-catenin signaling pathway. ConclusionsLRP5 directly modulates the degradation of LTCC to control cardiac QT interval. These findings provide compelling evidence for the potential role of LRPs in cardiac electrophysiology.

Small-conductance Ca2+-activated K+ channel activation deteriorates hypoxic ventricular arrhythmias via CaMKII in cardiac hypertrophy.

The molecular and electrophysiological mechanisms of acute ischemic ventricular arrhythmias in hypertrophied hearts are not well known. We hypothesized that small-conductance Ca2+-activated K+ (SK) channels are activated during hypoxia via the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) as a model of cardiac hypertrophy. The inhibitory effects of SK channels and ATP-sensitive K+ channels on electrophysiological changes and genesis of arrhythmias during simulated global hypoxia (GH) were evaluated. Hypoxia-induced abbreviation of action potential duration (APD) occurred earlier in ventricles from SHRs versus. WKY rats. Apamin, a SK channel blocker, prevented this abbreviation in SHRs in both the early and delayed phase of GH, whereas in WKY rats only the delayed phase was prevented. In contrast, SHRs were less sensitive to glibenclamide, a ATP-sensitive K+ channel blocker, which inhibited the APD abbreviation in both phases of GH in WKY rats. SK channel blockers (apamin and UCL-1684) reduced the incidence of hypoxia-induced sustained ventricular arrhythmias in SHRs but not in WKY rats. Among three SK channel isoforms, SK2 channels were directly coimmunoprecipitated with CaMKII phosphorylated at Thr286 (p-CaMKII). We conclude that activation of SK channels leads to the APD abbreviation and sustained ventricular arrhythmias during simulated hypoxia, especially in hypertrophied hearts. This mechanism may result from p-CaMKII-bound SK2 channels and reveal new molecular targets to prevent lethal ventricular arrhythmias during acute hypoxia in cardiac hypertrophy. NEW & NOTEWORTHY We now show a new pathophysiological role of small-conductance Ca2+-activated K+ channels, which shorten the action potential duration and induce ventricular arrhythmias during hypoxia. We also demonstrate that small-conductance Ca2+-activated K+ channels interact with phosphorylated Ca2+/calmodulin-dependent protein kinase II at Thr286 in hypertrophied hearts.

Acute exposure to progesterone attenuates cardiac contraction by modifying myofilament calcium sensitivity in the female mouse heart.

We investigated myocardial effects of acute application of progesterone. In females, but not males, progesterone attenuates and slows cardiomyocyte contraction with no effect on calcium transients. Progesterone also reduces myofilament calcium sensitivity in female hearts. This may adversely affect heart function, especially when serum progesterone levels are high in pregnancy.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/acute-progesterone-modifies-cardiac-contraction/.

Pitx2c increases in atrial myocytes from chronic atrial fibrillation patients enhancing IKs and decreasing ICa,L.

Atrial fibrillation (AF) produces rapid changes in the electrical properties of the atria (electrical remodelling) that promote its own recurrence. In chronic AF (CAF) patients, up-regulation of the slow delayed rectifier K(+) current (IKs) and down-regulation of the voltage-gated Ca(2+) current (ICa,L) are hallmarks of electrical remodelling and critically contribute to the abbreviation of action potential duration and atrial refractory period. Recent evidences suggested that Pitx2c, a bicoid-related homeodomain transcription factor involved in directing cardiac asymmetric morphogenesis, could play a role in atrial remodelling. However, its effects on IKs and ICa,L are unknown. Real-time quantitative polymerase chain reaction analysis showed that Pitx2c mRNA expression was significantly higher in human atrial myocytes from CAF patients than those from sinus rhythm patients. The expression of Pitx2c was positively and negatively correlated with IKs and ICa,L densities, respectively. Expression of Pitx2c in HL-1 cells increased IKs density and reduced ICa,L density. Luciferase assays demonstrated that Pitx2c increased transcriptional activity of KCNQ1 and KCNE1 genes. Conversely, its effects on ICa,L could be mediated by the atrial natriuretic peptide. Our results demonstrated for the first time that CAF increases Pitx2c expression in isolated human atrial myocytes and suggested that this transcription factor could contribute to the CAF-induced IKs increase and ICa,L reduction observed in humans.

Cold-Inducible RNA-Binding Protein Regulates Cardiac Repolarization by Targeting Transient Outward Potassium Channels

Cold-inducible RNA-binding protein (CIRP) is constitutively expressed at low levels across various tissues. It is rapidly upregulated by multiple stresses, underlying a general role for CIRP in organic adaptations to pathophysiological conditions. However, the role of CIRP in the heart remains unclear. To examine the biofunctions of CIRP in the mammalian heart. Rats with targeted disruption of Cirp were generated using the TALEN (transcription activator-like effector nucleases)-based genome editing technique. The Cirp-knockout rats had structurally and functionally normal hearts. Resting ECG recordings revealed a short rate-corrected QT (QTc) interval in Cirp-null rats without any abnormalities in PR interval, RR interval or QRS waves as compared to wild-type animals. The shortened QTc interval from Cirp ablation was tightly linked to an abbreviated action potential duration in cardiac myocytes, which was attributable to increased transient outward potassium current (Ito). Furthermore, our findings uncovered that CIRP protein selectively bonded to KCND2 and KCND3 mRNAs encoding the functional α-subunits of Ito channel proteins. CIRP deficiency did not change the transcriptional activity of KCND2 or KCND3, but it facilitated their translation. Cirp knockout had no effect on the functional expression of ion channels other than Ito channels. CIRP modulates cardiac repolarization by negatively adjusting the expression and function of Ito channels. Our study may open a window to decipher the potential function of RNA-binding proteins in bioelectric activity.

Atria are More Sensitive Than Ventricles to GS-458967-Induced Inhibition of Late Sodium Current.

The differential response of atrial and ventricular cells to late sodium channel current (late INa) inhibition has not been thoroughly investigated. The aim of the present study was to compare the atrioventricular differences in electrophysiological actions of GS-458967, a potent late INa blocker. Canine coronary-perfused atrial and ventricular preparations and isolated ventricular myocytes were used. Transmembrane action potentials were recorded using standard microelectrode recording techniques. In coronary-perfused preparations paced at a cycle length (CL) of 500 ms, GS-458967 (100-300 nmol/L) significantly abbreviated action potential duration at 50% to 90% (APD50-90) in atria but not in the ventricles. GS-458967 (≥100 nmol/L) prolonged the effective refractory period (ERP) in atria due to the development of postrepolarization refractoriness (PRR) but did not alter ERP in the ventricles. The maximum rate of rise in the action potential upstroke (Vmax) was significantly reduced at concentrations ≥100 nmol/L in atria but not in the ventricles (CL = 300 ms). At slower pacing rates (CL = 2000 ms) and higher concentrations, GS-458967 (100-1000 nmol/L) still failed to abbreviate ventricular APD. However, when APD was prolonged by the rapidly activating delayed rectifier potassium channel blocker E-4031 (1 µmol/L), addition of 1 μmol/L GS-458967 abbreviated APD in the ventricles at slow rates. In contrast, GS-458967 (300 nmol/L) consistently abbreviated APD in untreated isolated ventricular myocytes. In canine coronary-perfused preparations, GS-458967 abbreviates APD, induces PRR, and reduces Vmax in atria but has no significant effect on these parameters in the ventricles, indicating an atrial-selective effect of GS-458967 on both peak and late INa-mediated parameters. In multicellular preparations, GS-458967 abbreviated ventricular APD only under long QT conditions, suggesting a pathology-specific action of GS-458967 in canine ventricular myocardium.

Pulmonary Vein Myocardium as a Possible Pharmacological Target for the Treatment of Atrial Fibrillation

The pulmonary vein has a unique electrophysiological property showing an autonomic electrical activity, and this phenomenon has been further focused on as a source of triggers of atrial fibrillation. The pulmonary vein cardiomyocytes have shorter action potential duration, less negative resting membrane potential, and smaller maximum upstroke velocity than those in the left atrium, whose underlying cellular mechanisms may generate arrhythmogenic substrates such as abnormal automaticity and triggered activity. In diseased conditions including sustained atrial tachycardia or chronic volume overload, its arrhythmogenic profile can be further modified through abbreviation of action potential duration of the pulmonary vein myocardium, which may become a cause of reentry. Recently, antiarrhythmic effects of various drugs have been extensively investigated in isolated pulmonary vein preparations. The present review article highlights the recent advances in our understanding of electrophysiological and pharmacological profiles of the pulmonary vein.

Cardiac resynchronization therapy (CRT): Clinical trials, guidelines, and target populations

Over the last 10 years, several large, well-designed clinical trials have firmly established the role of cardiac resynchronization therapy (CRT) as a recommended treatment strategy for moderate-to-severe heart failure (HF). A review of the relevant results from the MUSTIC, MIRACLE, CONAK-CD, and MIRACLE ICD trials reveals that in patients with New York Heart Association (NYHA) class III-IV HF, CRT produces consistent improvements in quality of life, functional status, and exercise capacity while also providing strong evidence for reverse remodeling and diminished functional mitral regurgitation, resulting in reductions in both HF hospitalizations and all-cause morbidity and mortality. In patients with earlier NYHA class I-II HF, the benefit of CRT has been more controversial. The principal ongoing challenges addressed in this article include the substantial 30% of patients who receive a CRT device but fail to respond, the wide variations in how to define "response" vs "nonresponse," and how to identify patients who will benefit from CRT, especially narrow QRS (<120 ms), those with right bundle branch block, and those with mild-to-moderate (NYHA class I-II) HF. An important result of this uncertainty is the lack of a good sense of the optimal rate of CRT implantation, making consideration of the data reviewed in this article crucial for identifying important gaps of knowledge and mechanisms of action that need to be studied in the near future.

Atrial-selective inhibition of sodium-channel current by Wenxin Keli is effective in suppressing atrial fibrillation

Wenxin Keli is a Chinese herb extract reported to be of benefit in the treatment of cardiac arrhythmias, cardiac inflammation, and heart failure. We evaluated the electrophysiologic effects of Wenxin Keli in isolated canine arterially perfused right atrial preparations with a rim of right ventricular tissue (n = 11). Transmembrane action potentials and a pseudoelectrocardiogram were simultaneously recorded. Acetylcholine (1 μM) was used to induce atrial fibrillation (AF) and to test the anti-AF potential of Wenxin Keli (5 g/L). Wenxin Keli produced preferential abbreviation of action potential duration measured at 90% repolarization (APD(90)) in atria, but caused atrial-selective prolongation of the effective refractory period, due to the development of postrepolarization refractoriness. The maximum rate of rise of the action potential upstroke was preferentially reduced in atria. The diastolic threshold of excitation increased in both atria and ventricles, but much more in atria. The duration of the "P wave" (index of atrial conduction time) was prolonged to a much greater extent than the duration of the "QRS complex" (index of ventricular conduction time). Wenxin Keli significantly reduced I(Na) and shifted steady-state inactivation to more negative potentials in HEK293 cells stably expressing SCN5A. Wenxin Keli prevented the induction of persistent AF in 100% atria (6/6) and, in another experimental series, was found to terminate persistent acetylcholine-mediated AF in 100% of atria (3/3). Wenxin Keli produces atrial-selective depression of I(Na)-dependent parameters in canine isolated coronary-perfused preparations via a unique mechanism and is effective in suppressing AF and preventing its induction, with minimal effects on the ventricular electrophysiology.

Overexpression of ornithine decarboxylase decreases ventricular systolic function during induction of cardiac hypertrophy

Ornithine decarboxylase (ODC), the first enzyme of polyamine metabolism, is rapidly upregulated in response to agents that induce a pathological cardiac hypertrophy. Transgenic mice overexpressing ODC in the heart (MHC-ODC mice) experience a much more dramatic left ventricular hypertrophy in response to β-adrenergic stimulation with isoproterenol (ISO) compared to wild-type (WT) controls. ISO also induced arginase activity in transgenic hearts but not in controls. The current work studies the cooperation between the cardiac polyamines and L-arginine (L-Arg) availability in MHC-ODC mice. Although ISO-induced hypertrophy is well-compensated, MHC-ODC mice administered L-Arg along with ISO showed a rapid onset of systolic dysfunction and died within 48 h. Myocytes isolated from MHC-ODC mice administered L-Arg/ISO exhibited reduced contractility and altered calcium transients, suggesting an alteration in [Ca(2+)] homeostasis, and abbreviated action potential duration, which may contribute to arrhythmogenesis. The already elevated levels of spermidine and spermine were not further altered in MHC-ODC hearts by L-Arg/ISO treatment, suggesting alternative L-Arg utilization pathways lead to dysregulation of intracellular calcium. MHC-ODC mice administered an arginase inhibitor (Nor-NOHA) along with ISO died almost as rapidly as L-Arg/ISO-treated mice, while the iNOS inhibitor S-methyl-isothiourea (SMT) was strongly protective against L-Arg/ISO. These results point to the induction of arginase as a protective response to β-adrenergic stimulation in the setting of high polyamines. Further, NO generated by exogenously supplied L-Arg may contribute to the lethal consequences of L-Arg/ISO treatment. Since considerable variations in human cardiac polyamine and L-Arg content are likely, it is possible that alterations in these factors may influence myocyte contractility.