Triggered Arrhythmias Research Articles

Acute interaction between human epicardial adipose tissue and human atrial myocardium induces arrhythmic susceptibility.

Epicardial adipose tissue (EAT) deposition has a strong clinical association with atrial arrhythmias; however, whether a direct functional interaction exists between EAT and the myocardium to induce atrial arrhythmias is unknown. Therefore, we aimed to determine whether human EAT can be an acute trigger for arrhythmias in human atrial myocardium. Human trabeculae were obtained from right atrial appendages of patients who have had cardiac surgery (n = 89). The propensity of spontaneous contractions (SCs) in the trabeculae (proxy for arrhythmias) was determined under physiological conditions and during known triggers of SCs (high Ca2+, β-adrenergic stimulation). To determine whether EAT could trigger SCs, trabeculae were exposed to superfusate of fresh human EAT, and medium of 24 h-cultured human EAT treated with β1/2 (isoproterenol) or β3 (BRL37344) adrenergic agonists. Without exposure to EAT, high Ca2+ and β1/2-adrenergic stimulation acutely triggered SCs in, respectively, 47% and 55% of the trabeculae that previously were not spontaneously active. Acute β3-adrenergic stimulation did not trigger SCs. Exposure of trabeculae to either superfusate of fresh human EAT or untreated medium of 24 h-cultured human EAT did not induce SCs; however, specific β3-adrenergic stimulation of EAT did trigger SCs in the trabeculae, either when applied to fresh (31%) or cultured (50%) EAT. Additionally, fresh EAT increased trabecular contraction and relaxation, whereas media of cultured EAT only increased function when treated with the β3-adrenergic agonist. An acute functional interaction between human EAT and human atrial myocardium exists that increases the propensity for atrial arrhythmias, which depends on β3-adrenergic rather than β1/2-adrenergic stimulation of EAT.

Catecholaminergic polymorphic ventricular tachycardia due to de novo RyR2 mutation: recreational cycling as a trigger of lethal arrhythmias.

1. Napolitano C, Priori SG. (2007). Diagnosis and treatment of catecholaminergic polymorphic ventricular tachycardia Heart Rhythm. 4: 675-8. Google Scholar

Atrial arrhythmia triggering electromechanical dissociation and ventricular fibrillation in a patient with atrial switch operation.

Atrial arrhythmia triggering electromechanical dissociation and ventricular fibrillation in a patient with atrial switch operation.

Short-Long Heart Rate Variation Increases Dispersion of Action Potential Duration in Long QT Type 2 Transgenic Rabbit Model

The initiation of polymorphic ventricular tachycardia in long QT syndrome type 2 (LQT2) has been associated with a characteristic ECG pattern of short-long RR intervals. We hypothesize that this characteristic pattern increases APD dispersion in LQT2, thereby promoting arrhythmia. We investigated APD dispersion and its dependence on two previous cycle lengths (CLs) in transgenic rabbit models of LQT2, LQT1, and their littermate controls (LMC) using random stimulation protocols. The results show that the short-long RR pattern was associated with a larger APD dispersion in LQT2 but not in LQT1 rabbits. The multivariate analyses of APD as a function of two previous CLs (APDn = C + α1CLn−1 + α2CLn−2) showed that α1 (APD restitution slope) is largest and heterogeneous in LQT2 but uniform in LQT1, enhancing APD dispersion under long CLn−1 in LQT2. The α2 (short-term memory) was negative in LQT2 while positive in LQT1, and the spatial pattern of α1 was inversely correlated to α2 in LQT2, which explains why a short-long combination causes a larger APD dispersion in LQT2 but not in LQT1 rabbits. In conclusion, short-long RR pattern increased APD dispersion only in LQT2 rabbits through heterogeneous APD restitution and the short-term memory, underscoring the genotype-specific triggering of arrhythmias in LQT syndrome.

P5641Impact of lethal arrhythmias on medical castration in patients with prostate cancer

Abstract Background Prostate cancer is the most common non-cutaneous malignancy in men and has been steadily rising in an aging society. Medical castration had been widely applied as a treatment for prostate cancer. Sex steroid hormones regulate cardiac ion channels. However, the proarrhythmic properties of medical castration have not been reported. Methods This prospective observational study consisted of 149 patients (75±6 years) who underwent hormonal therapy using gonadotropin-releasing hormone with or without anti-androgen for prostate cancer. The changes of electrocardiogram (ECG) findings during the therapy and the associations of ECG findings with lethal arrhythmias were studied. Results QT (394±32 to 406±39 ms, p<0.001) and QTc intervals (416±27 to 439±31 ms, p<0.001) significantly prolonged during the therapy as compared to baseline. Heart rate significantly increased during the therapy as compared to baseline (68±11 to 71±14 / min, p=0.006). PQ interval and QRS duration were similar before and during the therapy. During the hormonal therapy, 2 patients (1.3%) presented with torsades de pointes and ventricular fibrillation. The first patient was 71 year-old and the second patient was 70 year-old. The period of the therapy was 6 and 45 months, respectively. Both patients had no structural heart disease. The magnitude of QTc interval change during the therapy as compared to baseline (Δ QTc interval) was significantly greater in patients with VF than those without (p<0.001), however the magnitude of Δ heart rate, Δ PQ interval, and Δ QRS duration were similar between the 2 groups. Conclusions Medical castration significantly prolonged QT/QTc interval and could be a trigger of lethal arrhythmias in patients with prostate cancer.

P3832Dantrolene reduces CaMKII-mediated arrhythmogenesis

Abstract Rationale In atrial and ventricular rhythm disorders, an increased diastolic sarcoplasmatic reticulum (SR) calcium leak can induce a depolarizing transient inward current, serving as a trigger for cellular arrhythmias. Dantrolene has been shown to also stabilize the cardiac ryanodine receptor. However, the detailed mechanism of the mode of action remains unknown. This study aims to investigate the effects of dantrolene on calcium/calmodulin-dependent kinase II (CaMKII) mediated arrhythmogenesis. Methods and results Right atrial cardiomyocytes (CM) were isolated from patients with atrial fibrillation. To investigate SR Ca2+ leak, measurements of diastolic SR Ca2+ sparks were performed by confocal microscopy using Fluo-4 AM. Dantrolene (10 μmol/l) potently reduced Ca2+-spark-frequency (CaSpF) by 90±26% (p<0.05, n=21 cells dantrolene vs. 19 cells control) leading to a reduction of the calculated diastolic SR-Ca2+-leak by 91±31% (p<0.05, n=21 vs. 19). Interestingly, CaMKII-inhibition using Autocamtide-2-Related Inhibitory Peptide (AIP) did not further reduced SR Ca2+ leak compared to dantrolene alone in human cardiomyocytes. This observation may suggest (secondary) inhibitory effects of dantrolene on CaMKII. To elucidate the role of CaMKII in dantrolene-mediated antiarrhythmic effects, we investigated atrial CM from mice overexpressing CaMKII (TG) and respective wildtype controls (WT). CaSpF and SR Ca2+ leak were reduced by dantrolene in both TG and WT mice (p<0.005, TG: dantrolene vs. vehicle n=132 vs 127 cells (9 mice); WT: dantrolene vs. vehicle n=61 vs 61 cells (5 mice)). However, proarrhythmogenic Ca2+ waves were only significantly reduced by dantrolene in TG mice (p<0.05, TG: dantrolene vs. vehicle 10.8% vs. 26.2%, n=154 vs 164 cells). Correspondingly, the incidence of delayed afterdepolarizations (DADs) in TG cells was significantly diminished by dantrolene (p<0.05, TG: dantrolene vs. vehicle 1/14 vs. 9/15 cells, n=5 mice). In contrast, DADs were not reduced by dantrolene in WT cells without increased CaMKII activity (p=n.s., WT: dantrolene vs vehicle 3/16 vs 2/13 cells, n=5 mice). In preliminary in vivo experiments, intraperitoneal injection of 40 mg/kg body weight dantrolene reduced the inducibility of arrhythmias by ventricular burst stimulation in CaMKII TG mice compared to vehicle (dantrolene 0/2 mice vs. vehicle 2/2 mice, p<0.05 Chi-Square). Conclusion Dantrolene beneficially altered Ca2+ homeostasis in human AF CM and murine CM. Dantrolene seems to exert its antiarrhythmic potential in a CaMKII-dependent manner. Thus, dantrolene as an already clinically approved compound might be a potential antiarrhythmic drug that merits clinical investigation. Acknowledgement/Funding Deutsche Forschungsgemeinschaft (MA 1981/5-1 and 7-1 to LSM). Marga und Walter Boll-Stiftung (SS).

Abstract 506: Trpm4 Contributes to Ca 2+ -dependent Triggered Arrhythmias in Pathological Conditions

Rationale: TRPM4 is a Ca 2+ -activated non-selective cation channel that is abundantly expressed in the heart. Mutations in the Trpm4 gene are associated with human cardiac conduction disorders, including Progressive Familial Heart Block type I (PFHBI) and Brugada Syndrome. However, the mechanistic role and in vivo significance of TRPM4 in the triggering of cardiac arrhythmias is still completely unclear. Objective: To investigate the role of TRPM4 during pathological Ca 2+ handling in the heart. Methods and results: Using three in vivo pro-arrhythmic assays, we found that Trpm4 -/- mice show a reduced arrhythmic burden compared to control mice. First, aconitine intoxication resulted in severe cardiac arrhythmias, both in WT and Trpm4 -/- animals, but Trpm4 -/- mice developed significantly less ventricular ectopic beats (VEBs) and showed a lower arrhythmic score. Second, during ischemia-reperfusion, induced by 30 min of LAD ligation, significantly more WT animals developed arrhythmias compared to Trpm4 -/- mice. Third, catecholaminergic polymorphic ventricular tachycardia (CPVT) mice, carrying mutations in RyR2, were subjected to a stress test. Significantly more RyR +/R2474S -Trpm4 +/+ animals developed arrhythmias compared to RyR +/R2474S -Trpm4 -/- mice. Conclusion: Our data establish that TRPM4 represents a novel target in the prevention and treatment of cardiac arrhythmias.

A computational model of induced pluripotent stem-cell derived cardiomyocytes incorporating experimental variability from multiple data sources.

Key points Induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) capture patient‐specific genotype–phenotype relationships, as well as cell‐to‐cell variability of cardiac electrical activityComputational modelling and simulation provide a high throughput approach to reconcile multiple datasets describing physiological variability, and also identify vulnerable parameter regimesWe have developed a whole‐cell model of iPSC‐CMs, composed of single exponential voltage‐dependent gating variable rate constants, parameterized to fit experimental iPSC‐CM outputsWe have utilized experimental data across multiple laboratories to model experimental variability and investigate subcellular phenotypic mechanisms in iPSC‐CMsThis framework links molecular mechanisms to cellular‐level outputs by revealing unique subsets of model parameters linked to known iPSC‐CM phenotypes There is a profound need to develop a strategy for predicting patient‐to‐patient vulnerability in the emergence of cardiac arrhythmia. A promising in vitro method to address patient‐specific proclivity to cardiac disease utilizes induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs). A major strength of this approach is that iPSC‐CMs contain donor genetic information and therefore capture patient‐specific genotype–phenotype relationships. A cited detriment of iPSC‐CMs is the cell‐to‐cell variability observed in electrical activity. We postulated, however, that cell‐to‐cell variability may constitute a strength when appropriately utilized in a computational framework to build cell populations that can be employed to identify phenotypic mechanisms and pinpoint key sensitive parameters. Thus, we have exploited variation in experimental data across multiple laboratories to develop a computational framework for investigating subcellular phenotypic mechanisms. We have developed a whole‐cell model of iPSC‐CMs composed of simple model components comprising ion channel models with single exponential voltage‐dependent gating variable rate constants, parameterized to fit experimental iPSC‐CM data for all major ionic currents. By optimizing ionic current model parameters to multiple experimental datasets, we incorporate experimentally‐observed variability in the ionic currents. The resulting population of cellular models predicts robust inter‐subject variability in iPSC‐CMs. This approach links molecular mechanisms to known cellular‐level iPSC‐CM phenotypes, as shown by comparing immature and mature subpopulations of models to analyse the contributing factors underlying each phenotype. In the future, the presented models can be readily expanded to include genetic mutations and pharmacological interventions for studying the mechanisms of rare events, such as arrhythmia triggers.

Individual periodic limb movements with arousal are temporally associated with nonsustained ventricular tachycardia: a case-crossover analysis.

Both periodic limb movements during sleep (PLMS) and arousals are associated with sympathetic nervous system activation and may be arrhythmogenic. We hypothesize a temporal relationship exists between individual PLMS, particularly with arousal, and nonsustained ventricular tachycardia (NSVT) events. A bidirectional time-stratified case-crossover design was used to assess temporal associations between PLMS and NSVT during sleep in 49 Osteoporotic Fractures in Men Sleep Study participants with NSVT in a community-based cohort (n = 2,911). Sleep time was divided into approximate 30-min segments. For each NSVT (n = 141), we selected a preceding 30-s hazard period and three randomly chosen 30-s control periods from sleep within the same segment and evaluated for PLMS, respiratory events, minimum saturation, and arousals. Odds ratios and 95% confidence intervals-OR (95% CI)-were determined by conditional logistic regression; covariates included EEG arousals, minimum saturation, and respiratory events in the same hazard/control period. Participants with NSVT were 79.5 ± 6.2 years with a PLMS index of 32.1 (IQR: 10.1, 61.4) and apnea-hypopnea index of 17.1 (IQR: 9.4, 26.1). PLMS without arousal were not significantly associated with NSVT (OR = 0.80, 95% CI: 0.41-1.59). PLMS with arousal were associated with NSVT in unadjusted analyses (OR = 2.50, 95% CI: 1.11-5.65) and after adjustment (OR = 2.31, 95% CI: 1.02-5.25). Arousals associated with PLMS were associated with NSVT in unadjusted (OR = 2.84, 95% CI: 1.23-6.56) and adjusted analyses (OR = 2.61, 95% CI: 1.13-6.05). PLMS with (but not without) arousals are temporally associated with a greater than twofold higher odds of subsequent NSVT episodes. PLMS-related arousals may be physiologically important ventricular arrhythmia triggers. ClinicalTrials.gov, NCT00070681.

Effect of Successful Edge-to-Edge Mitral Valve Repair on Ventricular Arrhythmic Burden in Patients With Functional Mitral Regurgitation and Implantable Cardiac Devices

Significant mitral regurgitation (MR) may be present in up to half of patients with heart failure (HF) and it is associated with adverse cardiac remodeling and myocardial stretch. These are potential triggers for ventricular arrhythmias (VA) in patients with HF, and therefore MR may enhance electrical ventricular vulnerability. Our aim was to evaluate VA burden before and after percutaneous mitral valve repair (PMVR) in patients with implantable cardiac devices. We conducted a prospective registry of all consecutive patients (n = 34, age 69.0 ± 12.2 years, 77% male) with significant functional mitral regurgitation (FMR) who underwent MitraClip implantation in 2 centers between June 2014 and July 2018. VA burden was defined as the total number of events during device follow-up before and after PMVR. Among patients presenting VA during follow-up before or after PMVR, device success at hospital discharge was related to a significant reduction in the incidence of Nonsustained ventricular tachycardia (VT, p = 0.002) and any sustained VT or rapid VT/ventricular fibrillation (p = 0.034). Regarding implantable cardiac defibrillator (ICD) therapies, successful PMVR was related to a reduction in incidence of either antitachycardia pacing or appropriate shocks (p = 0.045) and in the occurrence of any defibrillation shocks (p = 0.045). Overall, effective repair lead to a significant reduction in the VA burden, with a significant decrease in the occurrence of any VA (p = 0.004) and any ICD therapies (p = 0.045). In conclusion, device success after PMVR was related to a reduction in overall arrhythmic burden and ICD therapies in our cohort.

AAV9-Mediated Overexpression of TRPM4 Increases the Incidence of Stress-Induced Ventricular Arrhythmias in Mice.

Ca2+ activated non-selective (CAN) cation channels have been described in cardiomyocytes since the advent of the patch clamp technique. It has been hypothesized that this type of ion channel contributes to the triggering of cardiac arrhythmias. TRPM4 is to date the only molecular candidate for a CAN cation channel in cardiomyocytes. Its significance for arrhythmogenesis in living animals remains, however, unclear. In this study, we have tested whether increased expression of wild-type (WT) TRPM4 augments the risk of arrhythmias in living mice. Overexpression of WT TRPM4 was achieved via tail vein injection of adeno-associated viral vector serotype 9 (AAV9) particles, which have been described to be relatively cardiac specific in mice. Subsequently, we performed ECG-measurements in freely moving mice to determine their in vivo cardiac phenotype. Though cardiac muscle was transduced with TRPM4 viral particles, the majority of viral particles accumulated in the liver. We did not observe any difference in arrhythmic incidents during baseline conditions. Instead, WT mice that overexpress TRPM4 were more vulnerable to develop premature ventricular ectopic beats during exercise-induced β-adrenergic stress. Conduction abnormalities were rare and not more frequent in transduced mice compare to WT mice. Taken together, we provide evidence that overexpression of TRPM4 increases the susceptibility of living mice to stress-induced arrhythmias.

From the Literature

From the Literature

Premature ventricular beats in young athletes: interpretation and diagnostic pathway

Adolescents and adults with cardiovascular disease who are engaged in sports activity have an increased risk of sudden cardiac death (SCD) related to the sports practice that acts as a trigger for life-threatening ventricular arrhythmias. Premature ventricular beats (PVBs) detected in athletes at the time of pre-participation screening may be a sign of heart disease at risk of SCD but are also found in athletes without cardiovascular abnormalities. Thus, the interpretation of PVBs could represent a clinical dilemma. However, while some characteristics of PVBs can be considered common and benign, others occur uncommonly in the athletic population and raise the suspicion of underlying cardiovascular disease. This review discusses the prevalence and the clinical significance of PVBs in the athlete, with a focus on exercise-induced PVBs, on the analysis of PVB's morphology at 12-lead ECG, and on the morphological substrates identified by imaging techniques. The implications on eligibility for competitive sports participation are also discussed, according to the relevance of PVBs detection for disqualifying athletes from competitions.

Regional modulation of action potential duration and arrhythmias by ß1- and ß2-adrenergic receptor stimulation in the porcine right ventricle

The right ventricular outflow tract (RVOT) is the main origin of idiopathic ventricular tachycardia (IVTs). Sympathetic stimulation is involved in IVTs but mechanisms underlying this preferential origin remain unknown. To determine the role of ß1- and ß2-adrenergic receptors (ß1-AR, ß2-AR) in the regional modulation of right ventricular (RV) electrophysiological properties and arrhythmias. Porcine RVs were isolated and perfused via both right and left coronary arteries. Epicardial (EPI) electrical activity was optically mapped (di-4-ANEPPS 20 μM) and APD measured at 80% repolarization (APD80) in the RVOT and posterior RV free wall region (RVFW). Regional mRNA and protein expression for ß1-AR and ß2-AR was determined respectively by RT-PCR and Western-Blot. Combined ß1- and ß2-AR stimulation (50 nM isoprenaline, ISO) shortened APD80 EPI with a larger effect in the RVFW than the RVOT. Interestingly, isolated ß2-AR stimulation (10–25 μM salbutamol, SALBU with 4 μM metoprolol, METO) only decreased APD80 significantly in the RVOT EPI ( P < 0.05). ß2-AR stimulation did not affect APD80 in the RVOT endocardium leading to a larger transmural APD gradient in this region ( P < 0.01). ß1-AR expression was lower in the RVOT than in the RVFW EPI at the mRNA and protein levels. Conversely, ß2-AR protein expression was greater in the RVOT EPI ( P < 0.05). ISO (1.8 nM–1 μM) led to a significant increase in spontaneous arrhythmias while isolated ß2-AR did not (SALBU 10–50 μM). At higher concentrations (500nM-1 μM) ISO triggered VT episodes that originated from the RVOT or the anterior RV. ß2-AR blockade (ICI 118,551 100 nM) accelerated while ß1-AR blocker METO (4 μM) slowed or abolished VT. Conlcusion These results suggest a ß2-AR specific regulation of RVOT electrophysiology but its role in the triggering of arrhythmias in this region requires further studies.

Iznenadna srčana smrt - mere prevencije i preporuke za bavljenje fizičkom aktivnošću

Physical activity provides many well-documented health benefits, while physical inactivity is a leading risk factor for cardiovascular morbidity and mortality. In order to achieve these benefits, one must expose himself to relatively moderate physical activity. However, many athletes and recreationists go beyond these limits and engage in higher level of physical activity. Occasionally, intense physical activity is associated with sudden death in individuals with concealed heart disease. Despite the media attention provided by such accident, the reputation of physical activity remains intact, as most deaths can be explained by a basic cardiac abnormality where exercise is only the trigger of a fatal arrhythmia, not the actual cause of death. The paradox is that athletes with these abnormalities show identical performance in the form of minute heart volume compared to healthy individuals. In athletes younger than 35, congenital heart disease, especially hypertrophic cardiomyopathy and congenital coronary artery abnormalities, are the leading cause of sudden cardiac death, while most athletes older than 35 die due to atherosclerotic changes in the coronary arteries. Pre-competition screening with apparently healthy individuals is the only way to prevent sudden cardiac death in sports. When diagnosing a specific condition of the cardiovascular system, it is necessary to determine the risk of sudden cardiac death associated with continued physical activity and competitive sports activity, and to define clear disqualification criteria for each athlete individually.

Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice.

It has been suggested that protein directly activated by cAMP (Epac), one of the downstream signaling molecules of β-adrenergic receptor (β-AR), may be an effective target for the treatment of arrhythmia. However, there have been no reports on the anti-arrhythmic effects or cardiac side-effects of Epac1 inhibitors in vivo. Methods and Results: In this study, the roles of Epac1 in the development of atrial and ventricular arrhythmias are examined. In addition, we examined the usefulness of CE3F4, an Epac1-selective inhibitor, in the treatment of the arrhythmias in mice. In Epac1 knockout (Epac1-KO) mice, the duration of atrial fibrillation (AF) was shorter than in wild-type mice. In calsequestrin2 knockout mice, Epac1 deficiency resulted in a reduction of ventricular arrhythmia. In both atrial and ventricular myocytes, sarcoplasmic reticulum (SR) Ca2+ leak, a major trigger of arrhythmias, and spontaneous SR Ca2+ release (SCR) were attenuated in Epac1-KO mice. Consistently, CE3F4 treatment significantly prevented AF and ventricular arrhythmia in mice. In addition, the SR Ca2+ leak and SCR were significantly inhibited by CE3F4 treatment in both atrial and ventricular myocytes. Importantly, cardiac function was not significantly affected by a dosage of CE3F4 sufficient to exert anti-arrhythmic effects. These findings indicated that Epac1 is involved in the development of atrial and ventricular arrhythmias. CE3F4, an Epac1-selective inhibitor, prevented atrial and ventricular arrhythmias in mice.

Degradation of T-Tubular Microdomains and Altered cAMP Compartmentation Lead to Emergence of Arrhythmogenic Triggers in Heart Failure Myocytes: An in silico Study.

Heart failure (HF) is one of the most common causes of morbidity and mortality worldwide. Although many patients suffering from HF die from sudden cardiac death caused by arrhythmias, the mechanism linking HF remodeling to an increased arrhythmogenic propensity remains incomplete. HF is typically characterized by a progressive loss of transverse tubule (T-tubule) domains, which leads to an altered distribution of L-type calcium channels (LTCCs). Microdomain degradation also causes the disruption of the β2 adrenergic receptor (β2AR) and phosphodiesterase (PDE) signaling localization, normally confined to the dyadic space. The goal of this study was to analyze how these subcellular changes affect the function of LTCCs and lead to the emergence of ventricular cell-level triggers of arrhythmias. To accomplish this, we developed a novel computational model of a human ventricular HF myocyte in which LTCCs were divided into six different populations, based on their location and signaling environment they experience. To do so, we included T-tubular microdomain remodeling which led to a subset of LTCCs to be redistributed from the T-tubular to the surface membrane and allowed for different levels of phosphorylation of LTCCs by PKA, based on the presence of β2ARs and PDEs. The model was used to study the behavior of the LTCC current (ICaL) under basal and sympathetic stimulation and its effect on cellular action potential. Our results showed that channels redistributed from the T-tubular membrane to the bulk of the sarcolemma displayed an altered function in their new, non-native signaling domain. Incomplete calcium dependent inactivation, which resulted in a longer-lasting and larger-in-magnitude LTCC current, was observed when we decoupled LTCCs from ryanodine receptors and removed them from the dyadic space. The magnitude of the LTCC current, especially in the surface sarcolemma, was also increased via phosphorylation by the redistributed β2ARs and PDEs. These changes in LTCC current led to the development of early afterdepolarizations. Thus, our study shows that altered LTCC function is a potential cause for the emergence of cell-level triggers of arrhythmia, and that β2ARs and PDEs present useful therapeutic targets for treatment of HF and prevention of sudden cardiac death.

Dangerous encounters: triggers of fatal ventricular arrhythmias and safety of interventional treatment strategies.

Dangerous encounters: triggers of fatal ventricular arrhythmias and safety of interventional treatment strategies.

Lower sarcoplasmic reticulum Ca2+ threshold for triggering afterdepolarizations in diabetic rat hearts

Type 2 diabetes (T2D) increases arrhythmia risk through incompletely elucidated mechanisms. Ventricular arrhythmias could be initiated by delayed afterdepolarizations (DADs) resulting from elevated spontaneous sarcoplasmic reticulum (SR) Ca2+ release (SR Ca2+ leak). The purpose of this study was to test the role of DADs and SR Ca2+ leak in triggering arrhythmias in T2D hearts. We compared rats with late-onset T2D that display pancreatic and cardiac phenotypes similar to those in humans with T2D (HIP rats) and their nondiabetic littermates (wild type [WT]). HIP rats showed higher propensity for premature ventricular complexes and ventricular tachyarrhythmias, whereas HIP myocytes displayed more frequent DADs and had lower SR Ca2+ content than WT. However, the threshold SR Ca2+ at which depolarizing transient inward currents (Itis) are generated was also significantly decreased in HIP myocytes and was below the actual SR Ca2+ load, which explains the increased DAD incidence despite reduced Ca2+ in SR. In agreement with these findings, Ca2+ spark frequency was augmented in myocytes from HIP vs WT rats, which suggests activation of ryanodine receptors (RyRs) in HIP hearts. Indeed, RyR phosphorylation (by CaMKII and protein kinase A) and oxidation are enhanced in HIP hearts, whereas there is no RyR O-GlcNAcylation in either HIP or control hearts. CaMKII inhibition dissipated the difference in Ca2+ spark frequency between HIP and WT myocytes. The threshold SR Ca2+ for generating depolarizing Itis is lower in T2D because of RyR activation after hyperphosphorylation and oxidation, which favors the occurrence of DADs despite low SR Ca2+ loads.

Hypokalemia-Induced Arrhythmias and Heart Failure: New Insights and Implications for Therapy.

Routine use of diuretics and neurohumoral activation make hypokalemia (serum K+ < 3. 5 mM) a prevalent electrolyte disorder among heart failure patients, contributing to the increased risk of ventricular arrhythmias and sudden cardiac death in heart failure. Recent experimental studies have suggested that hypokalemia-induced arrhythmias are initiated by the reduced activity of the Na+/K+-ATPase (NKA), subsequently leading to Ca2+ overload, Ca2+/Calmodulin-dependent kinase II (CaMKII) activation, and development of afterdepolarizations. In this article, we review the current mechanistic evidence of hypokalemia-induced triggered arrhythmias and discuss how molecular changes in heart failure might lower the threshold for these arrhythmias. Finally, we discuss how recent insights into hypokalemia-induced arrhythmias could have potential implications for future antiarrhythmic treatment strategies.