Kcne4 deletion sex-specifically predisposes to cardiac arrhythmia via testosterone-dependent impairment of RISK/SAFE pathway induction in aged mice.
ABSTRACT: Sudden cardiac death (SCD) is associated with both electrical and ischemic substrates, and is a major cause of ischemic heart disease mortality worldwide. Male sex predisposes to SCD but the underlying mechanisms are incompletely understood. KCNE4, a cardiac arrhythmia-associated potassium channel ?-subunit, is upregulated by 5?-dihydrotestosterone (DHT). Thus, ventricular Kcne4 expression is low in young adult female mice, but high in males and postmenopausal (12+ months) females. Despite causing a sex-independent electrical substrate at 13 months of age (22% QT prolongation in both males and females; P?
Project description:Voltage-gated potassium (Kv) channels formed by Kv7 (KCNQ) ?-subunits are recognized as crucial for vascular smooth muscle function, in addition to their established roles in the heart (Kv7.1) and the brain (Kv7.2-5). In vivo, Kv7 ?-subunits are often regulated by KCNE subfamily ancillary (?) subunits. We investigated the effects of targeted germline Kcne4 deletion on mesenteric artery reactivity in adult male and female mice. Kcne4 deletion increased mesenteric artery contractility in response to ?-adrenoceptor agonist methoxamine, and decreased responses to Kv7.2-7.5 channel activator ML213, in male but not female mice. In contrast, Kcne4 deletion markedly decreased vasorelaxation in response to isoprenaline in both male and female mice. Kcne4 expression was 2-fold lower in the female versus the male mouse mesenteric artery, and Kcne4 deletion elicited only moderate changes of other Kcne transcripts, with no striking sex-specific differences. However, Kv7.4 protein expression in females was twice that in males, and was reduced in both sexes by Kcne4 deletion. Our findings confirm a crucial role for KCNE4 in regulation of Kv7 channel activity to modulate vascular tone, and provide the first known molecular mechanism for sex-specificity of this modulation that has important implications for vascular reactivity and may underlie sex-specific susceptibility to cardiovascular diseases.
Project description:Cardiac arrhythmias are common causes of death in patients with myotonic dystrophy (dystrophia myotonica [DM]). Evidence shows that atrial tachyarrhythmia is an independent risk factor for sudden death; however, the relationship is unclear.Control wild-type (Mbnl1+/+; Mbnl2+/+ ) and DM mutant (Mbnl1-/-; Mbnl2+/- ) mice were generated by crossing double heterozygous knockout (Mbnl1+/-; Mbnl2+/- ) mice. In vivo electrophysiological study and optical mapping technique were performed to investigate mechanisms of ventricular tachyarrhythmias. Transmission electron microscopy scanning was performed for myocardium ultrastructural analysis. DM mutant mice were more vulnerable to anesthesia medications and program electrical pacing: 2 of 12 mice had sudden apnea and cardiac arrest during premedication of general anesthesia; 9 of the remaining 10 had atrial tachycardia and/or atrioventricular block, but none of the wild-type mice had spontaneous arrhythmias; and 9 of 10 mice had pacing-induced ventricular tachyarrhythmias, but only 1 of 14 of the wild-type mice. Optical mapping studies revealed prolonged action potential duration, slower conduction velocity, and steeper conduction velocity restitution curves in the DM mutant mice than in the wild-type group. Spatially discordant alternans was more easily inducible in DM mutant than wild-type mice. Transmission electron microscopy showed disarranged myofibrils with enlarged vacuole-occupying mitochondria in the DM mutant group.This DM mutant mouse model presented with clinical myofibril ultrastructural abnormality and cardiac arrhythmias, including atrial tachyarrhythmias, atrioventricular block, and ventricular tachyarrhythmias. Optical mapping studies revealed prolonged action potential duration and slow conduction velocity in the DM mice, leading to vulnerability of spatially discordant alternans and ventricular arrhythmia induction to pacing.
Project description:PURPOSE:Implantable cardioverter-defibrillators (ICDs) improve survival of systolic heart failure (HF) patients who are at risk of sudden cardiac death (SCD). We recently showed that electrocardiographic (ECG) global electrical heterogeneity (GEH) is independently associated with SCD in the community-dwelling cohort and developed GEH SCD risk score. The Global Electrical Heterogeneity and Clinical Outcomes (GEHCO) study is a retrospective multicenter cohort designed with two goals: (1) validate an independent association of ECG GEH with sustained ventricular tachyarrhythmias and appropriate ICD therapies and (2) validate GEH ECG risk score for prediction of sustained ventricular tachyarrhythmias and appropriate ICD therapies in systolic HF patients with primary prevention ICD. METHODS:All records of primary prevention ICD recipients with available data for analysis are eligible for inclusion. Records of ICD implantation in patients with inherited channelopathies and cardiomyopathies are excluded. Raw digital 12-lead pre-implant ECGs will be used to measure GEH (spatial QRST angle, spatial ventricular gradient magnitude, azimuth, and elevation, and sum absolute QRST integral). The primary endpoint is defined as a sustained ventricular tachyarrhythmia event with appropriate ICD therapy. All-cause death without preceding sustained ventricular tachyarrhythmia with appropriate ICD therapy will serve as a primary competing outcome. The study will draw data from the academic medical centers. RESULTS:We describe the study protocol of the first multicenter retrospective cohort of primary prevention ICD patients with recorded at baseline digital 12-lead ECG. CONCLUSION:Findings from this study will inform future trials to identify patients who are most likely to benefit from primary prevention ICD. TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov . Unique identifier: NCT03210883.
Project description:INTRODUCTION:Several retrospective or single-centre studies demonstrated the efficacy of transplacental treatment of fetal tachyarrhythmias. Our retrospective nationwide survey showed that the fetal therapy will be successful at an overall rate of 90%. For fetuses with hydrops, the treatment success rate will be 80%. However, standard protocol has not been established. The objective of this study is to evaluate the efficacy and safety of the protocol-defined transplacental treatment of fetal tachyarrhythmias. Participant recruitment began in October 2010. METHODS AND ANALYSIS:The current study is a multicentre, single-arm interventional study. A total of 50 fetuses will be enrolled from 15 Japanese institutions. The protocol-defined transplacental treatment is performed for singletons with sustained fetal tachyarrhythmia ?180?bpm, with a diagnosis of supraventricular tachycardia or atrial flutter. Digoxin, sotalol, flecainide or a combination is used for transplacental treatment. The primary endpoint is disappearance of fetal tachyarrhythmias. The secondary endpoints are fetal death related to tachyarrhythmia, proportion of preterm birth, rate of caesarean section attributable to fetal arrhythmia, improvement in fetal hydrops, neonatal arrhythmia, neonatal central nervous system disorders and neonatal survival. Maternal, fetal and neonatal adverse events are evaluated at 1?month after birth. Growth and development are also evaluated at 18 and 36 months of corrected age. ETHICS AND DISSEMINATION:The Institutional Review Board of the National Cerebral and Cardiovascular Center of Japan has approved this study. Our findings will be widely disseminated through conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER:UMIN Clinical Trials Registry UMIN000004270.
Project description:Danqi soft capsule (DQ) is a traditional Chinese medicine containing Salvia miltiorrhiza and Panax notoginseng; it is safe and efficient in treating ischaemic heart diseases. The purpose of the present study was to assess whether DQ could prevent infarct border zone (IBZ) remodelling and decrease ventricular arrhythmias occurrence in post-myocardial infarction (MI) stage. MI was induced by a ligation of the left anterior descending coronary artery. DQ was administered to the post-MI rats started from 1 week after MI surgery for 4 weeks. The results showed that DQ treatment significantly attenuated tachyarrhythmia induction rates and arrhythmia score in post-MI rats. In echocardiography, DQ improved left ventricular (LV) systolic and diastolic function. Histological assessment revealed that DQ significantly reduced fibrotic areas and myocyte areas, and increased connexin (Cx) 43 positive areas in IBZ. Western blot revealed that DQ treatment significantly reduced the protein expression levels of type I and III collagens, α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1) and Smad3 phosphorylation, while increasing Cx43 amounts. Overall, these findings mainly indicated that DQ intervention regulates interstitial fibrosis, Cx43 expression and myocyte hypertrophy by TGF-β1/Smad3 pathway in IBZ, inhibits LV remodelling and reduces vulnerability to tachyarrhythmias after MI. This study presents a proof of concept for novel antiarrhythmic strategies in preventing IBZ remodelling, modifying the healed arrhythmogenic substrate and thus reducing susceptibility to ventricular arrhythmias in the late post-MI period.
Project description:There are representative electrical parameters for understanding the mechanism of reentrant waves in studies on tachyarrhythmia, namely the action potential duration (APD), dominant frequency, phase singularity, and filament. However, there are no studies that have directly identified the correlation between these electrophysiological parameters and cardiac contractility. Therefore, we have identified individual and integrative correlations between these electrical phenomena and contractility during tachyarrhythmia by deriving regression equations and also investigated the electrophysiological parameters affecting cardiac contractility during tachyarrhythmia. We simulated ventricular tachyarrhythmia with 48 types of electrical patterns by applying four reentry generation methods and changing the electrical conductivity of the potassium channel, which has the greatest effect on ventricular tissue. The mechanical responses reflecting electrical complexity were obtained through deterministic simulations of excitation-contraction coupling. We used the stroke volume and amplitude of myocardial tension (ampTens) as the variables representing contractility. We derived stochastic models through single- and multivariable regression analyses to identify the electrical parameters affecting contractility during tachyarrhythmia. In single-variable regression analysis, the APD, dominant frequency, and filament, excluding phase singularity, have statistically significant correlations with the stroke volume and ampTens. Among them, the APD has the maximum influence on these two mechanical parameters (standard beta coefficient: 0.859 for stroke volume, 0.930 for ampTens). The stochastic model using all four electrical parameters fails to accurately predict contractility owing to the multicollinearity between the APD and dominant frequency. We have rederived the multi-variable stochastic model using three electrical parameters without the APD. The filament has the greatest effect on the stroke volume stochastically (standard beta coefficient: 0.853 and 0.752). The dominant frequency has the greatest effect on ampTens statistically (standard beta coefficient: -0.813). We conclude that among the electrical parameters, the APD has the highest individual influence on mechanical contraction, and the filament has the highest integrative influence in both statistical terms.
Project description:Sex-based differences in human susceptibility to cardiac ventricular tachyarrhythmias likely result from the emergent effects of multiple intersecting processes that fundamentally differ in male and female hearts. Included are measured differences in the genes encoding key cardiac ion channels and effects of sex steroid hormones to acutely modify electrical activity. At the genome-scale, human females have recently been shown to have lower expression of genes encoding key cardiac repolarizing potassium currents and connexin43, the primary ventricular gap-junction subunit. Human males and females also have distinct sex steroid hormones. Here, we developed mathematical models for male and female ventricular human heart cells by incorporating experimentally determined genomic differences and effects of sex steroid hormones into the O'Hara-Rudy model. These "male" and "female" model cells and tissues then were used to predict how various sex-based differences underlie arrhythmia risk. Genomic-based differences in ion channel expression were alone sufficient to determine longer female cardiac action potential durations (APD) in both epicardial and endocardial cells compared to males. Subsequent addition of sex steroid hormones exacerbated these differences, as testosterone further shortened APDs, while estrogen and progesterone application resulted in disparate effects on APDs. Our results indicate that incorporation of experimentally determined genomic differences from human hearts in conjunction with sex steroid hormones are consistent with clinically observed differences in QT interval, T-wave shape and morphology, and critically, in the higher vulnerability of adult human females to Torsades de Pointes type arrhythmias. The model suggests that female susceptibility to alternans stems from longer female action potentials, while reentrant arrhythmia derives largely from sex-based differences in conduction play an important role in arrhythmia vulnerability.
Project description:BACKGROUND:Optimal cell type as cell-based therapies for heart failure (HF) remains unclear. We sought to compare the safety and efficacy of direct intramyocardial transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) in a porcine model of HF. METHODS:Eight weeks after induction of HF with myocardial infarction (MI) and rapid pacing, animals with impaired left ventricular ejection fraction (LVEF) were randomly assigned to receive direct intramyocardial injection of saline (MI group), 2 × 108 hESC-CMs (hESC-CM group), or 2 × 108 hiPSC-MSCs (hiPSC-MSC group). The hearts were harvested for immunohistochemical evaluation after serial echocardiography and hemodynamic evaluation and ventricular tachyarrhythmia (VT) induction by in vivo programmed electrical stimulation. RESULTS:At 8 weeks post-transplantation, LVEF, left ventricular maximal positive pressure derivative, and end systolic pressure-volume relationship were significantly higher in the hiPSC-MSC group but not in the hESC-CM group compared with the MI group. The incidence of early spontaneous ventricular tachyarrhythmia (VT) episodes was higher in the hESC-CM group but the incidence of inducible VT was similar among the different groups. Histological examination showed no tumor formation but hiPSC-MSCs exhibited a stronger survival capacity by activating regulatory T cells and reducing the inflammatory cells. In vitro study showed that hiPSC-MSCs were insensitive to pro-inflammatory interferon-gamma-induced human leukocyte antigen class II expression compared with hESC-CMs. Moreover, hiPSC-MSCs also significantly enhanced angiogenesis compared with other groups via increasing expression of distinct angiogenic factors. CONCLUSIONS:Our results demonstrate that transplantation of hiPSC-MSCs is safe and does not increase proarrhythmia or tumor formation and superior to hESC-CMs for the improvement of cardiac function in HF. This is due to their immunomodulation that improves in vivo survival and enhanced angiogenesis via paracrine effects.
Project description:Heterogenous data about the prognostic impact of atrial fibrillation (AF) in patients with ventricular tachyarrhythmias exist. Therefore, this study evaluates this impact of AF in patients presenting with ventricular tachyarrhythmias. 1,993 consecutive patients presenting with ventricular tachyarrhythmias (i.e. ventricular tachycardia and fibrillation (VT, VF)) on admission at one institution were included (from 2002 until 2016). All medical data of index and follow-up hospitalizations were collected during the complete follow-up period for each patient. Statistics comprised univariable Kaplan-Meier and multivariable Cox regression analyses in the unmatched consecutive cohort and after propensity-score matching for harmonization. The primary prognostic endpoint was long-term all-cause mortality at 2.5 years. AF was present in 31% of patients presenting with index ventricular tachyarrhythmias on admission (70% paroxysmal, 9% persistent, 21% permanent). VT was more common (67% versus 59%; p?=?0.001) than VF (33% versus 41%; p?=?0.001) in AF compared to non-AF patients. Long-term all-cause mortality at 2.5 years occurred more often in AF compared to non-AF patients (mortality rates 40% versus 24%, log rank p?=?0.001; HR?=?1.825; 95% CI 1.548-2.153; p = 0.001), which may be attributed to higher rates of all-cause mortality at 30 days, in-hospital mortality and mortality after discharge (p?<?0.05) (secondary endpoints). Mortality differences were observed irrespective of index ventricular tachyarrhythmia (VT or VF), LV dysfunction or presence of an ICD. In conclusion, this study identifies AF as an independent predictor of death in patients presenting consecutively with ventricular tachyarrhythmias.
Project description:OBJECTIVES:The study objective was to determine the predictors of new-onset arrhythmia among infants with single-ventricle anomalies during the post-Norwood hospitalization and the association of those arrhythmias with postoperative outcomes (ventilator time and length of stay) and interstage mortality. METHODS:After excluding patients with preoperative arrhythmias, we used data from the Pediatric Heart Network Single Ventricle Reconstruction Trial to identify risk factors for tachyarrhythmias (atrial fibrillation, atrial flutter, supraventricular tachycardia, junctional ectopic tachycardia, and ventricular tachycardia) and atrioventricular block (second or third degree) among 544 eligible patients. We then determined the association of arrhythmia with outcomes during the post-Norwood hospitalization and interstage period, adjusting for identified risk factors and previously published factors. RESULTS:Tachyarrhythmias were noted in 20% of subjects, and atrioventricular block was noted in 4% of subjects. Potentially significant risk factors for tachyarrhythmia included the presence of modified Blalock-Taussig shunt (P = .08) and age at Norwood (P = .07, with risk decreasing each day at age 8-20 days); the only significant risk factor for atrioventricular block was undergoing a concomitant procedure at the time of the Norwood (P = .001), with the greatest risk being in those undergoing a tricuspid valve procedure. Both tachyarrhythmias and atrioventricular block were associated with longer ventilation time and length of stay (P < .001 for all analyses). Tachyarrhythmias were not associated with interstage mortality; atrioventricular block was associated with mortality among those without a pacemaker in the unadjusted analysis (hazard ratio, 2.3; P = .02), but not after adding covariates. CONCLUSIONS:Tachyarrhythmias are common after the Norwood procedure, but atrioventricular block may portend a greater risk for interstage mortality.