Loss of insulin signaling may contribute to atrial fibrillation and atrial electrical remodeling in type 1 diabetes.

Atrial fibrillation (AF) is prevalent in diabetes mellitus (DM); however, the basis for this is unknown. This study investigated AF susceptibility and atrial electrophysiology in type 1 diabetic Akita mice using in vivo intracardiac electrophysiology, high-resolution optical mapping in atrial preparations, and patch clamping in isolated atrial myocytes. qPCR and western blotting were used to assess ion channel expression. Akita mice were highly susceptible to AF in association with increased P-wave duration and slowed atrial conduction velocity. In a second model of type 1 DM, mice treated with streptozotocin (STZ) showed a similar increase in susceptibility to AF. Chronic insulin treatment reduced susceptibility and duration of AF and shortened P-wave duration in Akita mice. Atrial action potential (AP) morphology was altered in Akita mice due to a reduction in upstroke velocity and increases in AP duration. In Akita mice, atrial Na+ current (INa) and repolarizing K+ current (IK) carried by voltage gated K+ (Kv1.5) channels were reduced. The reduction in INa occurred in association with reduced expression of SCN5a and voltage gated Na+ (NaV1.5) channels as well as a shift in INa activation kinetics. Insulin potently and selectively increased INa in Akita mice without affecting IK Chronic insulin treatment increased INa in association with increased expression of NaV1.5. Acute insulin also increased INa, although to a smaller extent, due to enhanced insulin signaling via phosphatidylinositol 3,4,5-triphosphate (PIP3). Our study reveals a critical, selective role for insulin in regulating atrial INa, which impacts susceptibility to AF in type 1 DM.

Multimodal imaging shows fibrosis architecture and action potential dispersion are predictors of arrhythmic risk in spontaneous hypertensive rats.

Hypertensive heart disease (HHD) increases risk of ventricular tachycardia (VT) and ventricular fibrillation (VF). The roles of structural vs. electrophysiological remodelling and age vs. disease progression are not fully understood. This cross-sectional study of cardiac alterations through HHD investigates mechanistic contributions to VT/VF risk. Risk was electrically assessed in Langendorff-perfused, spontaneously hypertensive rat hearts at 6, 12 and 18 months, and paced optical membrane voltage maps were acquired from the left ventricular (LV) free wall epicardium. Distributions of LV patchy fibrosis and 3D cellular architecture in representative anterior LV mid-wall regions were quantified from macroscopic and microscopic fluorescence images of optically cleared tissue. Imaging showed increased fibrosis from 6 months, particularly in the inner LV free wall. Myocyte cross-section increased at 12 months, while inter-myocyte connections reduced markedly with fibrosis. Conduction velocity decreased from 12 months, especially transverse to the myofibre direction, with rate-dependent anisotropy at 12 and 18 months, but not earlier. Action potential duration (APD) increased when clustered by age, as did APD dispersion at 12 and 18 months. Among 10 structural, functional and age variables, the most reliably linked were VT/VF risk, general LV fibrosis, a measure quantifying patchy fibrosis, and non-age clustered APD dispersion. VT/VF risk related to a quantified measure of patchy fibrosis, but age did not factor strongly. The findings are consistent with the notion that VT/VF risk is associated with rate-dependent repolarization heterogeneity caused by structural remodelling and reduced lateral electrical coupling between LV myocytes, providing a substrate for heterogeneous intramural activation as HHD progresses. KEY POINTS: There is heightened arrhythmic risk with progression of hypertensive heart disease. Risk is related to increasing left ventricular fibrosis, but the nature of this relationship has not been quantified. This study is a novel systematic characterization of changes in active electrical properties and fibrotic remodelling during progression of hypertensive heart disease in a well-established animal disease model. Arrhythmic risk is predicted by several left ventricular measures, in particular fibrosis quantity and structure, and epicardial action potential duration dispersion. Age alone is not a good predictor of risk. An improved understanding of links between arrhythmic risk and fibrotic architectures in progressive hypertensive heart disease aids better interpretation of late gadolinium-enhanced cardiac magnetic resonance imaging and electrical mapping signals.

Shift of leading pacemaker site during reflex vagal stimulation and altered electrical source-to-sink balance.

KEY POINTS: Vagal reflexes slow heart rate and can change where the heartbeat originates within the sinoatrial node (SAN). The mechanisms responsible for this process - termed leading pacemaker (LP) shift - have not been investigated fully. We used optical mapping to measure the effects of baroreflex, chemoreflex and carbachol on pacemaker entrainment and electrical conduction across the SAN. All methods of stimulation triggered shifts in LP site from the central SAN to one or two caudal pacemaker regions. These shifts were associated with reduced current generation capacity centrally and increased electrical load caudally. Previous studies suggest LP shift is a rate-dependent phenomenon whereby acetylcholine slows central pacemaker rate disproportionately, enabling caudal cells that are less acetylcholine sensitive to assume control. However, our findings indicate the LP region is defined by both pacemaker rate and capacity to drive activation. Shifts in LP site provide an important homeostatic mechanism for rapid switches in heart rate. ABSTRACT: Reflex vagal activity causes abrupt heart rate slowing with concomitant caudal shifts of the leading pacemaker (LP) site within the sinoatrial node (SAN). However, neither the mechanisms responsible nor their dynamics have been investigated fully. Therefore, the objective of this study was to elucidate the mechanisms driving cholinergic LP shift. Optical maps of right atrial activation were acquired in a rat working heart-brainstem preparation during baroreflex and chemoreflex stimulation or with carbachol. All methods of stimulation triggered shifts in LP site from the central SAN to caudal pacemaker regions, which were positive for HCN4 and received uniform cholinergic innervation. During baroreflex onset, the capacity of the central region to drive activation declined with a decrease in amplitude and gradient of optical action potentials (OAPs) in the surrounding myocardium. Accompanying this decline, there was altered entrainment in the caudal SAN as shown by decreased conduction velocity, OAP amplitude, gradient and activation time. Atropine abolished these responses. Chemoreflex stimulation produced similar effects but central capacity to drive activation was preserved before the LP shift. In contrast, carbachol produced a prolonged period of reduced capacity to drive and altered entrainment. Previous studies suggest LP shift is a rate-dependent phenomenon whereby acetylcholine slows central pacemaker rate disproportionately, enabling caudal cells that are less acetylcholine sensitive to assume control. Our findings indicate that cholinergic LP shifts are also determined by altered electrical source-to-sink balance in the SAN. We conclude that the LP region is defined by both rate and capacity to drive atrial activation.

Reduced expression of cardiac ryanodine receptor protects against stress-induced ventricular tachyarrhythmia, but increases the susceptibility to cardiac alternans.

Reduced protein expression of the cardiac ryanodine receptor type 2 (RyR2) is thought to affect the susceptibility to stress-induced ventricular tachyarrhythmia (VT) and cardiac alternans, but direct evidence for the role of RyR2 protein expression in VT and cardiac alternans is lacking. Here, we used a mouse model (crrm1) that expresses a reduced level of the RyR2 protein to determine the impact of reduced RyR2 protein expression on the susceptibility to VT, cardiac alternans, cardiac hypertrophy, and sudden death. Electrocardiographic analysis revealed that after the injection of relatively high doses of caffeine and epinephrine (agents commonly used for stress test), wild-type (WT) mice displayed long-lasting VTs, whereas the crrm1 mutant mice exhibited no VTs at all, indicating that the crrm1 mutant mice are resistant to stress-induced VTs. Intact heart Ca2+ imaging and action potential (AP) recordings showed that the crrm1 mutant mice are more susceptible to fast-pacing induced Ca2+ alternans and AP duration alternans compared with WT mice. The crrm1 mutant mice also showed an increased heart-to-body-weight ratio and incidence of sudden death at young ages. Furthermore, the crrm1 mutant hearts displayed altered Ca2+ transients with increased time-to-peak and decay time (T50), increased ventricular wall thickness and ventricular cell area compared with WT hearts. These results indicate that reduced RyR2 protein expression suppresses stress-induced VTs, but enhances the susceptibility to cardiac alternans, hypertrophy, and sudden death.

Atrial Fibrillation and Ventricular Arrhythmias: Sex Differences in Electrophysiology, Epidemiology, Clinical Presentation, and Clinical Outcomes.

Sex-specific differences in the epidemiology, pathophysiology, clinical presentation, clinical treatment, and clinical outcomes of atrial fibrillation (AF), sustained ventricular arrhythmias, and sudden cardiac death are recognized. Sex hormones cause differences in cardiac electrophysiological parameters between men and women that may affect the risk for arrhythmias. The incidence and prevalence of AF is lower in women than in men. However, because women live longer and AF prevalence increases with age, the absolute number of women with AF exceeds that of men. Women with AF are more symptomatic, present with more atypical symptoms, and report worse quality of life in comparison with men. Female sex is an independent risk factor for death or stroke attributable to AF. Oral anticoagulation therapy for stroke prevention has similar efficacy for men and women, but older women treated with warfarin have a higher residual risk of stroke in comparison with men. Women with AF are less likely to receive rhythm control antiarrhythmic drug therapy, electric cardioversion, or catheter ablation in comparison with men. The incidence and prevalence of sustained ventricular arrhythmias and sudden cardiac death are lower in women than in men. Women receiving implantable cardioverter defibrillators for primary prevention of sudden cardiac death are less likely to experience sustained ventricular arrhythmias in comparison with men. In contrast, women receiving a cardiac resynchronization therapy implantable cardioverter defibrillator for the treatment of heart failure are more likely to benefit than men. Women are less likely to be referred for implantable cardioverter defibrillator therapy despite current guideline recommendations. Women are more likely to experience a significant complication related to implantable cardioverter defibrillator implantation in comparison with men. Whether sex differences in treatment decisions reflect patient preferences or treatment biases requires further study.

Single vs. dual chamber implantable cardioverter-defibrillators or programming of implantable cardioverter-defibrillators in patients without a bradycardia pacing indication: systematic review and meta-analysis.

Aims: Implantable cardioverter-defibrillators (ICDs) are key in the prevention of sudden cardiac death, but outcomes may vary by type of device or programming [single chamber (SC) vs. dual chamber (DC)] in patients without a bradycardia pacing indication. We sought to meta-analyse patient outcomes of randomized trials of SC vs. DC devices or programming. Methods and results: We searched PubMed, Embase, Scopus, Web of Science, and Cochrane trials databases for relevant studies excluding those published before 2000, involving children, or not available in English. Endpoints included mortality, inappropriate ICD therapies, and implant complications. Endpoints with at least three reporting studies were meta-analysed. We identified eight studies meeting inclusion criteria representing 2087 patients with 16.1 months mean follow-up. Mean age was 62.7 years (SD 1.92); in six studies reporting sex, most patients were male (85%). Comparing patients with a SC or DC ICD or programming, we found similar rates of mortality [odds ratio (OR) 0.95, 95% confidence interval (CI) 0.54-1.68; P = 0.86] and inappropriate therapies (OR 1.46, 95% CI 0.97-2.19; P = 0.07) in five and six studies, respectively. In three studies of SC vs. DC ICDs (but not programming) rates of pneumothorax and lead dislodgement were not different (OR 2.12, 95% CI 0.18-24.72; P = 0.55 and OR 0.87, 95% CI 0.32-2.47; P = 0.83, respectively). Conclusion: In this meta-analysis of randomized controlled trials comparing SC vs. DC ICD device or programming, there was no significant difference in inappropriate therapies, mortality, pneumothorax, or lead dislodgement. Future studies should compare these devices over longer follow-up and in specific patient populations.

Suppression of ryanodine receptor function prolongs Ca2+ release refractoriness and promotes cardiac alternans in intact hearts.

Beat-to-beat alternations in the amplitude of the cytosolic Ca2+ transient (Ca2+ alternans) are thought to be the primary cause of cardiac alternans that can lead to cardiac arrhythmias and sudden death. Despite its important role in arrhythmogenesis, the mechanism underlying Ca2+ alternans remains poorly understood. Here, we investigated the role of cardiac ryanodine receptor (RyR2), the major Ca2+ release channel responsible for cytosolic Ca2+ transients, in cardiac alternans. Using a unique mouse model harboring a suppression-of-function (SOF) RyR2 mutation (E4872Q), we assessed the effect of genetically suppressing RyR2 function on Ca2+ and action potential duration (APD) alternans in intact hearts, and electrocardiogram (ECG) alternans in vivo We found that RyR2-SOF hearts displayed prolonged sarcoplasmic reticulum Ca2+ release refractoriness and enhanced propensity for Ca2+ alternans. RyR2-SOF hearts/mice also exhibited increased propensity for APD and ECG alternans. Caffeine, which enhances RyR2 activity and the propensity for catecholaminergic polymorphic ventricular tachycardia (CPVT), suppressed Ca2+ alternans in RyR2-SOF hearts, whereas carvedilol, a ß-blocker that suppresses RyR2 activity and CPVT, promoted Ca2+ alternans in these hearts. Thus, RyR2 function is an important determinant of Ca2+, APD, and ECG alternans. Our data also indicate that the activity of RyR2 influences the propensity for cardiac alternans and CPVT in an opposite manner. Therefore, overly suppressing or enhancing RyR2 function is pro-arrhythmic.

Impact of cardiac resynchronization therapy on hospitalizations in the Resynchronization-Defibrillation for Ambulatory Heart Failure trial.

BACKGROUND: This study reports the impact of cardiac resynchronization therapy (CRT) on hospitalizations in patients randomized to implantable cardioverter-defibrillator (ICD) or ICD-CRT in the Resynchronization-Defibrillation for Ambulatory Heart Failure Trial (RAFT). METHODS AND RESULTS: Hospitalization rates and lengths of hospital stay were compared between the 2 groups. At the 18-month follow-up, the numbers of patients hospitalized for any cause were similar in the ICD (n=351, 38.8%) and ICD-CRT (n=331, 30.0%) groups. The number of patients hospitalized for heart failure was significantly lower in the ICD-CRT (n=101, 11.3%) compared with the ICD (n=141, 15.6%; P=0.003) group. The number of patients hospitalized for a device-related indication was similar in the ICD-CRT group (n=147, 16.4%) and ICD group (n=126, 13.9%; P=0.148). The total number of hospitalizations for any cause (n=1448 versus n=1553; P=0.042), any cardiovascular cause (n=667 versus n=790; P=0.017), and any heart failure cause (n=385 versus n=505; P<0.0001) was significantly lower in ICD-CRT group compared with the ICD group, whereas the number of hospitalizations for device-related causes was significantly higher in the ICD-CRT group compared with the ICD group (246 versus 159; P<0.001). Although the reduction in hospitalizations for heart failure in the CRT-ICD group was offset by an increased number of hospitalizations for device-related indications, the length of hospital stay for any cause was significantly shorter in the ICD-CRT group (8.83±13.30 days) compared with the ICD group (9.59±14.40 days; P=0.005). CONCLUSION: ICD-CRT therapy significantly reduces hospitalizations and total days in hospital in patients with New York Heart Association class II/III heart failure compared with ICD therapy despite increased admissions for device-related indications. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00251251.

Expert commentary: how well has the call from Heart Rhythm Society/European Heart Rhythm Association for improved device monitoring been answered?

This commentary highlights the benefits of remote device monitoring and explores some of the challenges implementation of this technology worldwide.

Intracardiac electrogram T-wave alternans/variability increases before spontaneous ventricular tachyarrhythmias in implantable cardioverter-defibrillator patients: a prospective, multi-center study.

BACKGROUND: T-wave alternans (TWA) increases before ventricular tachycardia (VT) or fibrillation (VF), suggesting that it may warn of VT/VF in implantable cardioverter-defibrillator patients. Recently, we described a method for measuring alternans and nonalternans variability (TWA/V) from electrograms (EGMs) stored in implantable cardioverter-defibrillators before VT/VF. The goal of this prospective, multicenter study was to determine whether EGM TWA/V was greater before VT/VF than at baseline. METHODS AND RESULTS: We enrolled 63 implantable cardioverter-defibrillator patients. TWA/V was computed from stored EGMs before spontaneous VT/VF and from sequential windows of 8 pairs of beats using 4 different control recordings: baseline rhythm, rapid pacing at 105 bpm, segments of ambulatory Holter EGMs matched to the time of VT/VF episodes, and EGMs before spontaneous supraventricular tachycardia. During follow-up, 28 patients had 166 episodes of VT/VF. TWA/V was greater before VT/VF (62.9 ± 3.1 µV; n = 28) than during baseline rhythm (12.8 ± 1.8 µV; P < 0.0001; n = 62), during rapid pacing (14.5 ± 2.0 µV; P < 0.0001; n = 52), before supraventricular tachycardia (27.5 ± 6.1 µV; P < 0.0001; n = 9), or during time-matched ambulatory controls (12.3 ± 3.5 µV; P < 0.0001; n = 16). By logistic regression, the odds of VT/VF increased by a factor of 2.2 for each 10-µV increment in TWA/V (P < 0.0001). CONCLUSIONS: In implantable cardioverter-defibrillator patients, EGM TWA/V is greater before spontaneous VT/VF than in control recordings. Future implantable cardioverter-defibrillators that measure EGM TWA/V continuously may warn patients and initiate pacing therapies to prevent VT/VF.

Sex and racial disparities in catheter ablation.

Sex and racial disparities in the presentation, diagnosis, and management of cardiac arrhythmias are recognized. Sex-specific differences in electrophysiological parameters are well known and are predominantly related to differences in ion channel expression and the influence of sex hormones. However, the relationship between hormonal or racial influence and arrhythmia mechanisms, presentation, and management needs to be better defined. Women and racial and ethnic groups are less likely to undergo catheter ablation procedures for treatment of cardiac arrhythmias. Underrepresentation of women and racial/ethnic groups in clinical trials has resulted in significant knowledge gaps. Whether sex and racial disparities in arrhythmia management reflect barriers in access to care, physician bias, patient values, and preferences or other factors requires further study.

Enhancing the detection of atrial fibrillation from wearable sensors with neural style transfer and convolutional recurrent networks.

Electrocardiograms (ECG) provide an effective, non-invasive approach for clinical diagnosis and monitoring treatment in patients with cardiac diseases including the most common cardiac arrhythmia, atrial fibrillation (AF). Portable ECG recording devices including Apple Watch and Kardia devices have been developed for AF detection. However, the efficacy of these smart devices has not been fully validated. We aimed to develop an open-source deep learning framework for automatic AF detection using the largest publicly available single-lead ECG dataset through a mobile Kardia device enhanced with style transfer-driven data augmentation. We developed and validated a 37-layer convolutional recurrent network (CRN) using 5,834 single-lead ECGs with a mean length of 30 seconds from the 2017 PhysioNet Challenge to automatically detect sinus rhythm and AF. To address the challenge of a lack of a large number of AF samples, we proposed a novel style transfer generator that fuses patient-specific clinical ECGs and mathematically modelled ECG features to synthesize realistic ECGs by five-fold. The differences between synthesized and clinical ECGs were analyzed by studying their average ECG morphologies and frequency distributions. Our results indicated the style transfer-driven data augmentation was not classifier-dependent. Validation on 2,917 clinical ECGs showed an F1 score of 96.4%, with the generated ECGs contributing to a 3% improvement in AF detection for the Kardia event recorder. By developing and evaluating our approach on an open-source ECG dataset, we have demonstrated that our framework is both robust and verifiable, and potentially can be used in portable devices for effective AF classification.

Non-Contact Intracardiac Potential Mapping Using Mesh-Based and Meshless Inverse Solvers.

Atrial fibrillation (AF) is the most common cardiac dysrhythmia and percutaneous catheter ablation is widely used to treat it. Panoramic mapping with multi-electrode catheters has been used to identify ablation targets in persistent AF but is limited by poor contact and inadequate coverage of the left atrial cavity. In this paper, we investigate the accuracy with which atrial endocardial surface potentials can be reconstructed from electrograms recorded with non-contact catheters. An in-silico approach was employed in which "ground-truth" surface potentials from experimental contact mapping studies and computer models were compared with inverse potential maps constructed by sampling the corresponding intracardiac field using virtual basket catheters. We demonstrate that it is possible to 1) specify the mixed boundary conditions required for mesh-based formulations of the potential inverse problem fully, and 2) reconstruct accurate inverse potential maps from recordings made with appropriately designed catheters. Accuracy improved when catheter dimensions were increased but was relatively stable when the catheter occupied >30% of atrial cavity volume. Independent of this, the capacity of non-contact catheters to resolve the complex atrial potential fields seen in reentrant atrial arrhythmia depended on the spatial distribution of electrodes on the surface bounding the catheter. Finally, we have shown that reliable inverse potential mapping is possible in near real-time with meshless methods that use the Method of Fundamental Solutions.