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RationaleGiven its rising prevalence in both the adult and pediatric populations, obesity has become an increasingly important risk factor in the development of atrial fibrillation. However, a better mechanistic understanding of obesity-related atrial fibrillation is required. Serum glucocorticoid kinase 1 (SGK1) is a kinase positioned downstream of multiple obesity-related pathways, and prior work has shown a pathologic role for SGK1 signaling in ventricular remodeling and arrhythmias.ObjectiveTo determine the mechanistic basis of obesity associated atrial fibrillation and explore the therapeutic potential of targeting SGK1 in this context.Methods and ResultsWe utilized a mouse model of diet induced obesity to determine the atrial electrophysiologic effects of obesity using electrophysiologic studies, optical mapping, and biochemical analyses. In C57BL/6J mice fed a high fat diet, there was upregulation of SGK1 signaling along with an increase in AF inducibility determined at electrophysiology (EP) study. These changes were associated with an increase in fibrotic and inflammatory signaling. Transgenic mice expressing a cardiac specific dominant negative SGK1 (SGK1 DN) were protected from obesity-related AF as well as the fibrotic and inflammatory consequences of AF. Finally, optical mapping demonstrated a shorter action potential duration and patch clamp revealed effects onINa, with a decreased peak current as well as a depolarizing shift in activation/inactivation properties in atrial myocytes.ConclusionsDiet induced obesity leads to increased cardiac SGK1 signaling as well as an increase in AF inducibility in obese mice. Genetic SGK1 inhibition reduced AF inducibility, and this effect may be mediated by effects on inflammation, fibrosis, and cellular electrophysiology.

Background There are limited data on the comparative analyses of TightRailTM rotating dilator sheath (Philips) and laser sheath for lead extraction. Objective To evaluate the effectiveness and safety of the TightRailTM sheath as a primary or secondary tool for TLE. Methods Retrospective cohort analysis of 202 consecutive patients who underwent TLE using either TightRailTM sheath and/or GlideLightTM laser sheath (Philips) in our hospital. The study population was divided into three groups: Group A underwent TLE with laser sheath only (N = 157), Group B with TightRailTM sheath only (N = 22), and Group C with both sheaths (N = 23). Results During this period, 375 leads in 202 patients were extracted, including 297 leads extracted by laser sheath alone, 45 leads by TightRailTM sheath alone, and 33 by both TightRailTM sheath and laser sheaths. The most common indications included device infection (44.6%) and lead-related complications (44.1%). The median age of leads was 8.9 years. TightRailTM sheath (Group B) achieved similar efficacy as a primary extraction tool compared with laser sheath (Group A), with complete procedure success rate of 93.3% (vs. 96.6%, P = 0.263) and clinical success rate of 100.0% (vs. 98.1%, P = 0.513). Among 32 leads in which TightrailTM was used after laser had failed (Group C), the complete procedure success rate was 75.8%. No significant difference in procedural adverse events were observed. Conclusion Our single-center experience confirms that the TightRailTM system is an effective first-line and second-line method for TLE. Further investigation is required to guide the selection of mechanical and laser sheaths in lead extraction cases. This article is protected by copyright. All rights reserved.

INTRODUCTION We previously introduced the inverse solution guidance algorithm (ISGA) methodology using a Single Equivalent Moving Dipole model of cardiac electrical activity to localize both the exit site of a re-entrant circuit and the tip of a radiofrequency (RF) ablation catheter. The purpose of this study was to investigate the use of ISGA for ablation catheter guidance in an animal model. METHODS Ventricular tachycardia (VT) was simulated by rapid ventricular pacing at a target site in eleven Yorkshire swine. The ablation target was established using three different techniques: a pacing lead placed into the ventricular wall at the mid-myocardial level (Type-1), an intracardiac mapping catheter (Type-2), and an RF ablation catheter placed at a random position on the endocardial surface (Type-3). In each experiment, one operator placed the catheter/pacing lead at the target location, while another used the ISGA system to manipulate the RF ablation catheter starting from a random ventricular location to locate the target. RESULTS The average localization error of the RF ablation catheter tip was 0.31 ± 0.08 cm. After analyzing approximately 35 cardiac cycles of simulated VT, the ISGA system's accuracy in locating the target was 0.4 cm after four catheter movements in the Type-1 experiment, 0.48 cm after six movements in the Type-2 experiment, and 0.67 cm after seven movements in the Type-3 experiment. CONCLUSION We demonstrated the feasibility of using the ISGA method to guide an ablation catheter to the origin of a VT focus by analyzing a few beats of body surface potentials without electro-anatomic mapping.

Background: Ibrutinib is a Bruton tyrosine kinase inhibitor with remarkable efficacy against B-cell cancers. Ibrutinib also increases the risk of atrial fibrillation (AF), which remains poorly understood. Methods: We performed electrophysiology studies on mice treated with ibrutinib to assess inducibility of AF. Chemoproteomic analysis of cardiac lysates identified candidate ibrutinib targets, which were further evaluated in genetic mouse models and additional pharmacological experiments. The pharmacovigilance database, VigiBase, was queried to determine whether drug inhibition of an identified candidate kinase was associated with increased reporting of AF. Results: We demonstrate that treatment of mice with ibrutinib for 4 weeks results in inducible AF, left atrial enlargement, myocardial fibrosis, and inflammation. This effect was reproduced in mice lacking Bruton tyrosine kinase, but not in mice treated with 4 weeks of acalabrutinib, a more specific Bruton tyrosine kinase inhibitor, demonstrating that AF is an off-target side effect. Chemoproteomic profiling identified a short list of candidate kinases that was narrowed by additional experimentation leaving CSK (C-terminal Src kinase) as the strongest candidate for ibrutinib-induced AF. Cardiac-specific Csk knockout in mice led to increased AF, left atrial enlargement, fibrosis, and inflammation, phenocopying ibrutinib treatment. Disproportionality analyses in VigiBase confirmed increased reporting of AF associated with kinase inhibitors blocking Csk versus non-Csk inhibitors, with a reporting odds ratio of 8.0 (95% CI, 7.3–8.7; P Conclusions: These data identify Csk inhibition as the mechanism through which ibrutinib leads to AF. Registration: URL: https://ww.clinicaltrials.gov ; Unique identifier: NCT03530215.

A 67-year-old female with prior medical history of HTN and asthma presented with acute-onset dyspnea and nausea for 4 days prior to admission. Upon initial encounter in the emergency room, she was found to have findings of abnormal pulmonary infiltrates and consequent workup revealed COVID-19. During further hospital course, the patient developed abnormal EKG and echocardiographic findings consistent with stress-induced cardiomyopathy.

Atrial fibrillation (AF) is the most common sustained arrhythmia encountered in humans and is a significant source of morbidity and mortality. Despite its prevalence, our mechanistic understanding is incomplete, the therapeutic options have limited efficacy, and are often fraught with risks. A better biological understanding of AF is needed to spearhead novel therapeutic avenues. Although “natural” AF is nearly nonexistent in most species, animal models have contributed significantly to our understanding of AF and some therapeutic options. However, the impediments of animal models are also apparent and stem largely from the differences in basic physiology as well as the complexities underlying human AF; these preclude the creation of a “perfect” animal model and have obviated the translation of animal findings. Herein, we review the vast array of AF models available, spanning the mouse heart (weighing 1/1000th of a human heart) to the horse heart (10× heavier than the human heart). We attempt to highlight the features of each model that bring value to our understanding of AF but also the shortcomings and pitfalls. Finally, we borrowed the concept of a SWOT analysis from the business community (which stands for strengths, weaknesses, opportunities, and threats) and applied this introspective type of analysis to animal models for AF. We identify unmet needs and stress that is in the context of rapidly advancing technologies, these present opportunities for the future use of animal models.

Rationale: Cardiac pacing is a critical technology for the treatment of arrhythmia and heart failure. The impact of specific pacing strategies on myocardial function is an area of intense research and high clinical significance. Mouse models have proven extremely useful for probing mechanisms of heart disease, but there is currently no reliable technology for long-term pacing in the mouse. Objective: We sought to develop a device for long-term pacing studies in mice. We evaluated the device for (1) treating third-degree atrioventricular block after macrophage depletion, (2) ventricular pacing-induced cardiomyopathy, and (3) high-rate atrial pacing. Methods and Results: We developed a mouse pacemaker by refashioning a 26 mm×6.7 mm clinical device powered by a miniaturized, highly efficient battery. The electrode was fitted with a single flexible lead, and custom software extended the pacing rate to up to 1200 bpm. The wirelessly programmable device was implanted in the dorsal subcutaneous space of 39 mice. The tunneled lead was passed through a left thoracotomy incision and attached to the epicardial surface of the apex (for ventricular pacing) or the left atrium (for atrial pacing). Mice tolerated the implantation and both long-term atrial and ventricular pacing over weeks. We then validated the pacemaker’s suitability for the treatment of atrioventricular block after macrophage depletion in Cd11b DTR mice. Ventricular pacing increased the heart rate from 313±59 to 550 bpm ( P Conclusions: Long-term pacing with a fully implantable, programmable, and battery-powered device enables previously impossible investigations of arrhythmia and heart failure in the mouse.

Atrial fibrillation (AF) is a prevalent arrhythmia associated with substantial morbidity, mortality and costs. Available management strategies generally have limited efficacy and are associated with potential adverse effects. In part, the limited efficacy of approaches to managing AF reflect an incomplete understanding of the biological mechanisms underlying the arrhythmia, and only a partial understanding of how best to individualise management. Over the last several decades, a greater understanding of genome biology has led to recognition of a widespread genetic susceptibility to AF. Through genome-wide association studies, at least 30 genetic loci have been identified in association with AF, most of which implicate mechanisms not previously appreciated to be involved in the development of AF. We now recognise that AF is a polygenic condition, yet a great deal of work lies ahead to better understand the precise mechanisms by which genomic variation causes AF. Understanding the genetic basis of AF could provide a better understanding of AF mechanisms and cardiovascular biology, inform the management of patients through risk-guided approaches and facilitate the development of novel therapeutics.

Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation (VT/VF). We hypothesized that, in early hypertension, the susceptibility to stress-induced VT/VF increases. We compared the susceptibility of 5- to 6-month-old male spontaneously hypertensive rats (SHR) and age/sex-matched normotensive rats (NR) to VT/VF during challenge with oxidative stress (H2 O2 ; 0.15 mmol l(-1) ). We found that only SHR hearts exhibited left ventricular fibrosis and hypertrophy. H2 O2 promoted VT in all 30 SHR but none of the NR hearts. In 33% of SHR cases, focal VT degenerated to VF within 3 s. Simultaneous voltage-calcium optical mapping of Langendorff-perfused SHR hearts revealed that H2 O2 -induced VT/VF arose spontaneously from focal activations at the base and mid left ventricular epicardium. Microelectrode recording of SHR hearts showed that VT was initiated by early afterdepolarization (EAD)-mediated triggered activity. However, despite the increased susceptibility of SHR hearts to VT/VF, patch clamped isolated SHR ventricular myocytes developed EADs and triggered activity to the same extent as NR ventricular myocytes, except with larger EAD amplitude. During the early stages of hypertension, when challenged with oxidative stress, SHR hearts showed an increased ventricular arrhythmogenicity that stems primarily from tissue remodelling (hypertrophy, fibrosis) rather than cellular electrophysiological changes. Our findings highlight the need for early hypertension treatment to minimize myocardial fibrosis, ventricular hypertrophy, and arrhythmias.

Studies have demonstrated non-myocytes, including fibroblasts, can electrically couple to myocytes in culture. However, evidence demonstrating current can passively spread across scar tissue in the intact heart remains elusive. We hypothesize electrotonic conduction occurs across non-myocyte gaps in the heart and is partly mediated by Connexin43 (Cx43). We investigated whether non-myocytes in ventricular scar tissue are electrically connected to surrounding myocardial tissue in wild type and fibroblast-specific protein-1 driven conditional Cx43 knock-out mice (Cx43fsp1KO). Electrical coupling between the scar and uninjured myocardium was demonstrated by injecting current into the myocardium and recording depolarization in the scar through optical mapping. Coupling was significantly reduced in Cx43fsp1KO hearts. Voltage signals were recorded using microelectrodes from control scars but no signals were obtained from Cx43fsp1KO hearts. Recordings showed significantly decreased amplitude, depolarized resting membrane potential, increased duration and reduced upstroke velocity compared to surrounding myocytes, suggesting that the non-excitable cells in the scar closely follow myocyte action potentials. These results were further validated by mathematical simulations. Optical mapping demonstrated that current delivered within the scar could induce activation of the surrounding myocardium. These data demonstrate non-myocytes in the scar are electrically coupled to myocytes and coupling depends on Cx43 expression.

Hypertension is a risk factor for sudden cardiac death caused by ventricular tachycardia and fibrillation (VT/VF). We hypothesized that during the early stages of uncontrolled hypertension, the susceptibility to otherwise benign stress promotes VT/VF. To test this hypothesis we compared the susceptibility of 5-6-month-old male spontaneously hypertensive rats (SHR) and age/gender-matched normotensive rats (NR) to VT/VF during challenge with mild oxidative stress (H2O2, 0.15 mmol/L). H2O2 initiated spontaneous VT in all 30 SHR but none of the NR hearts. In 33% of SHR cases, focal VT degenerated to VF within 3 s. Simultaneous voltage-Ca optical mapping of Langendorff-perfused SHR hearts revealed that H2O2-induced VT/VF arose spontaneously from focal activations at the base and mid left ventricular epicardium. Microelectrode recording of SHR hearts showed that VT was initiated by early afterdepolarization (EAD)-mediated triggered activity. However, despite the increased susceptibility of SHR hearts to VT/VF, patch-clamped isolated SHR ventricular myocytes developed EADs and triggered activity to the same extent as NR ventricular myocytes, except that SHR myocytes had a relatively larger EAD amplitude. Histopathological and echocardiographic studies showed that compared to NR, SHR hearts exhibited increased left ventricular fibrosis and mild hypertrophy. We conclude that during the early stages of hypertension (i.e., prior to the development of overt heart failure) SHR hearts manifest increased susceptibility to VT/VF when challenged with mild oxidative stress that appears to be related to tissue remodeling (i.e., hypertrophy, fibrosis) moreso than cellular electrophysiological remodeling. Our findings highlight the need for aggressive treatment during the stages of early hypertension to minimize myocardial fibrosis, ventricular hypertrophy, and arrhythmias.

Background— Right ventricular failure (RVF) in pulmonary hypertension (PH) is associated with increased incidence of sudden death by a poorly explored mechanism. We test the hypothesis that PH promotes spontaneous ventricular fibrillation (VF) during a critical post-PH onset period characterized by a sudden increase in mortality. Methods and Results— Rats received either a single subcutaneous dose of monocrotaline (MCT, 60 mg/kg) to induce PH-associated RVF (PH, n=24) or saline (control, n=17). Activation pattern of the RV-epicardial surface was mapped using voltage-sensitive dye in isolated Langendorff-perfused hearts along with single glass-microelectrode and ECG-recordings. MCT-injected rats developed severe PH by day 21 and progressed to RVF by approximately day 30. Rats manifested increased mortality, and ≈30% rats died suddenly and precipitously during 23–32 days after MCT. This fatal period was associated with the initiation of spontaneous VF by a focal mechanism in the RV, which was subsequently maintained by both focal and incomplete reentrant wave fronts. Microelectrode recordings from the RV-epicardium at the onset of focal activity showed early afterdepolarization–mediated triggered activity that led to VF. The onset of the RV cellular triggered beats preceded left ventricular depolarizations by 23±8 ms. The RV but not the left ventricular cardiomyocytes isolated during this fatal period manifested significant action potential duration prolongation, dispersion, and an increased susceptibility to depolarization-induced repetitive activity. No spontaneous VF was observed in any of the control hearts. RVF was associated with significantly reduced RV ejection fraction ( P P P Conclusions— PH-induced RVF is associated with a distinct phase of increased mortality characterized by spontaneous VF arising from the RV by an early afterdepolarization–mediated triggered activity.

Selective glycolytic inhibition (GI) promotes electromechanical alternans and triggered beats in isolated cardiac myocytes. We sought to determine whether GI promotes triggered activity by early afterdepolarization (EAD) or delayed afterdepolarizations in intact hearts isolated from adult and aged rats. Dual voltage and intracellular calcium ion (Cai2+) fluorescent optical maps and single cell glass microelectrode recordings were made from the left ventricular (LV) epicardium of isolated Langendorff-perfused adult (∼4 mo) and aged (∼24 mo) rat hearts. GI was induced by replacing glucose with 10 mM pyruvate in oxygenated Tyrode's. Within 20 min, GI slowed Cai2+transient decline rate and shortened action potential duration in both groups. These changes were associated with ventricular fibrillation (VF) in the aged hearts (64 out of 66) but not in adult hearts (0 out of 18; P < 0.001). VF was preceded by a transient period of focal ventricular tachycardia caused by EAD-mediated triggered activity leading to VF within seconds. The VF was suppressed by the ATP-sensitive K (KATP) channel blocker glibenclamide (1 μM) but not (0 out of 7) by mitochondrial KATPblock. The Ca-calmodulin-dependent protein kinase II (CaMKII) blocker KN-93 (1 μM) prevented GI-mediated VF ( P < 0.05). Block of Na-Ca exchanger (NCX) by SEA0400 (2 μM) prevented GI-mediated VF (3 out of 6), provided significant bradycardia did not occur. Aged hearts had significantly greater LV fibrosis and reduced connexin 43 than adult hearts ( P < 0.05). We conclude that in aged fibrotic unlike in adult rat hearts, GI promotes EADs, triggered activity, and VF by activation of KATPchannels CaMKII and NCX.

Background— Hypokalemia is known to promote ventricular arrhythmias, especially in combination with class III antiarrhythmic drugs like dofetilide. Here, we evaluated the underlying molecular mechanisms. Methods and Results— Arrhythmias were recorded in isolated rabbit and rat hearts or patch-clamped ventricular myocytes exposed to hypokalemia (1.0–3.5 mmol/L) in the absence or presence of dofetilide (1 μmol/L). Spontaneous early afterdepolarizations (EADs) and ventricular tachycardia/fibrillation occurred in 50% of hearts at 2.7 mmol/L [K] in the absence of dofetilide and 3.3 mmol/L [K] in its presence. Pretreatment with the Ca-calmodulin kinase II (CaMKII) inhibitor KN-93, but not its inactive analogue KN-92, abolished EADs and hypokalemia-induced ventricular tachycardia/fibrillation, as did the selective late Na current ( I Na ) blocker GS-967. In intact hearts, moderate hypokalemia (2.7 mmol/L) significantly increased tissue CaMKII activity. Computer modeling revealed that EAD generation by hypokalemia (with or without dofetilide) required Na-K pump inhibition to induce intracellular Na and Ca overload with consequent CaMKII activation enhancing late I Na and the L-type Ca current. K current suppression by hypokalemia and dofetilide alone in the absence of CaMKII activation were ineffective at causing EADs. Conclusions— We conclude that Na-K pump inhibition by even moderate hypokalemia plays a critical role in promoting EAD-mediated arrhythmias by inducing a positive feedback cycle activating CaMKII and enhancing late I Na . Class III antiarrhythmic drugs like dofetilide sensitize the heart to this positive feedback loop.

Previous studies have raised the question of whether an association exists between physical activity and atrial fibrillation (AF). We used the Multi-Ethnic Study of Atherosclerosis (MESA) database to examine the association between physical activity and AF in a diverse population without clinically recognized cardiovascular disease (CVD). MESA participants (n = 5,793) with complete baseline physical activity and covariate data were included. Cox proportional hazards models were used to calculate hazard ratios (HRs) for incident AF by levels of total intentional exercise and vigorous physical activity, independently and in combination. Multivariate models were adjusted for demographics and CVD risk factors. During a mean follow-up of 7.7 ± 1.9 years, 199 AF cases occurred. In the overall MESA population, neither vigorous physical activity nor total intentional exercise was independently associated with incident AF after adjusting for covariates. However, within the group that reported any vigorous physical activity, there was a statistically significant inverse association between total intentional exercise (modeled as a continuous variable) and incident AF. In those who reported any vigorous physical activity, the top tertile of total intentional exercise was associated with a significantly lower risk of incident AF compared with the group with no total intentional exercise in the fully adjusted model (HR 0.46, 95% confidence interval 0.22 to 0.98). In conclusion, neither total intentional exercise nor vigorous physical activity alone was associated with incident AF, but greater total intentional exercise was associated with a lower risk of incident AF in those who participated in any vigorous physical activity. As importantly, no subgroup of participants demonstrated an increased risk of incident AF with greater physical activity. The results re-emphasize the beneficial role of physical activity for cardiovascular health.

Introduction: Prior studies have raised the question of whether an association exists between physical activity (PA) and atrial fibrillation (AF), with mixed results. We sought to use the Multi-Ethnic Study of Atherosclerosis (MESA) database to examine the association between PA and AF in a diverse population without clinically recognized prevalent cardiovascular disease (CVD). Hypothesis: Increased exercise will have a protective influence on AF incidence. Methods: MESA participants (N=5793) with a completed baseline PA survey and complete covariate data were included. Incident AF events were determined based on hospital discharge ICD-9 codes and Medicare inpatient claims. Total intentional exercise (TIE), defined as a sum of walking for exercise, dance/sport, and conditioning, was used as our independent variable of interest. The MESA population was stratified based on whether they reported participation in any vigorous physical activity (VPA), which was defined as “heavy effort” expended in household chores, lawn/yard/garden/farm work, conditioning activities, and occupational/volunteering work. Cox models, adjusted for demographics and CVD risk factors, were used to determine hazard ratios (HR) for incident AF based on total intentional exercise (TIE) for the subgroups. We performed similar analyses using TIE as a categorical variable stratified into tertiles. Results: During a mean follow-up of 7.7±1.9 years, 199 AF cases occurred. In the overall MESA population, TIE alone was not associated with incident AF. However, within the group that reported any VPA (N=1866), there was a statistically significant protective influence of increasing TIE on incident AF (HR=0.658, p=0.014). Additionally, among the same group, the top tertile of TIE was associated with a significantly lower risk of incident AF compared with the group with no TIE (HR=0.48, p=0.048). Conclusions: TIE was associated with a lower risk of incident AF among those that participated in any VPA, and this protective influence was most notable among those that performed the most TIE. Perhaps as importantly, no subgroup of participants demonstrated an increased risk of incident AF with TIE. These results re-emphasize the beneficial role of exercise for cardiovascular health.

Unlike young hearts, aged hearts are highly susceptible to early afterdepolarization (EAD)-mediated ventricular fibrillation (VF). This differential may result from age-related structural remodeling (fibrosis) or electrical remodeling of ventricular myocytes or both. We used optical mapping and microelectrode recordings in Langendorff-perfused hearts and patch-clamp recordings in isolated ventricular myocytes from aged (24–26 mo) and young (3–4 mo) rats to assess susceptibility to EADs and VF during either oxidative stress with ANG II (2 μM) or ionic stress with hypokalemia (2.7 mM). ANG II caused EAD-mediated VF in 16 of 19 aged hearts (83%) after 32 ± 7 min but in 0 of 9 young hearts (0%). ANG II-mediated VF was suppressed with KN-93 (Ca2+/calmodulin-dependent kinase inhibitor) and the reducing agent N-acetylcysteine. Hypokalemia caused EAD-mediated VF in 11 of 11 aged hearts (100%) after 7.4 ± 0.4 min. In 14 young hearts, however, VF did not occur in 6 hearts (43%) or was delayed in onset (31 ± 22 min, P < 0.05) in 8 hearts (57%). In patch-clamped myocytes, ANG II and hypokalemia ( n = 6) induced EADs and triggered activity in both age groups ( P = not significant) at a cycle length of >0.5 s. When myocytes of either age group were coupled to a virtual fibroblast using the dynamic patch-clamp technique, EADs arose in both groups at a cycle length of

BackgroundCompared to young adult rat hearts, aged rat hearts exhibit marked fibrosis and increased susceptibility to ventricular tachycardia and fibrillation (VT/VF) when exposed to oxidative and ionic stress.ObjectiveTo evaluate the contributions of aging-related structural tissue changes (fibrosis) vs. cellular electrophysiological properties in the increased arrhythmia risk of aged ventricles, we exposed intact hearts and single myocytes from aged and young adult rats to oxidative stress with angiotensin II (ATII) or ionic stress with hypokalemia and assessed for occurrences of VT/VF and their triggers.Methods & ResultsTrichrome staining revealed markedly more fibrosis in ventricular tissue from aged than from young adult rats (38 ± 12% vs. 2.0 ± 0.6%, P 4s), but only in aged myocytes at more rapid pacing cycle lengths (1-3 s)ConclusionFibrosis plays a central role in the increased vulnerability of aged hearts to VT/VF during ATII or hypokalemia exposure, although aging-related cellular electrophysiological changes may contribute modestly.

We previously have shown that pulmonary hypertension (PH)-induced right ventricular failure (RVF) is associated with increased incidence of sudden death caused by spontaneous ventricular fibrillation (VF). We also discovered that estrogen (E2) therapy rescues severe PH and RVF and results in 100% survival. Here we hypothesized that E2 abolishes spontaneous VF associated with RVF by restoring RVEF, reversing fibrosis and restoring PH-induced downregulation of repolarizing K-channel proteins Kv1.5 and KCNE-2 and SERCA-2a expression. Chronic PH-associated RVF was induced in male rats by s.c. monocrotaline (MCT, 60 mg/kg, n=10). Some MCT-rats were treated with E2 (42.5 ug/kg/day, s.c.) from day 21 (severe PH-stage) to day-30 (n=8). Saline treated rats served as control (n=8). At ∼day 30, hearts were studied in isolated-perfused Langendorff setting. RV-epicardial activation pattern was optically mapped using fluorescent voltage-sensitive dye (RH-237). By ∼day 30, 30% RVF rats died suddenly but none in the control or E2-groups. RVF hearts manifested EADs and spontaneous VF during normal Tyrode’s perfusion with wavefront dynamics supported by both focal and multiple wavelet patterns. No VF was initiated in any of the control or E2-treated hearts. SERCA-2a was reduced (∼15-fold) in RVF (0.06±0.01 vs. 1±0.26 control) that was reversed in E2-group (0.77±0.13, p