Caveolin-3 and Caveolae regulate ventricular repolarization.

RATIONALE: Flask-shaped invaginations of the cardiomyocyte sarcolemma called caveolae require the structural protein caveolin-3 (Cav-3) and host a variety of ion channels, transporters, and signaling molecules. Reduced Cav-3 expression has been reported in models of heart failure, and variants in CAV3 have been associated with the inherited long-QT arrhythmia syndrome. Yet, it remains unclear whether alterations in Cav-3 levels alone are sufficient to drive aberrant repolarization and increased arrhythmia risk. OBJECTIVE: To determine the impact of cardiac-specific Cav-3 ablation on the electrophysiological properties of the adult mouse heart. METHODS AND RESULTS: Cardiac-specific, inducible Cav3 homozygous knockout (Cav-3KO) mice demonstrated a marked reduction in Cav-3 expression by Western blot and loss of caveolae by electron microscopy. However, there was no change in macroscopic cardiac structure or contractile function. The QTc interval was increased in Cav-3KO mice, and there was an increased propensity for ventricular arrhythmias. Ventricular myocytes isolated from Cav-3KO mice exhibited a prolonged action potential duration (APD) that was due to reductions in outward potassium currents (Ito, Iss) and changes in inward currents including slowed inactivation of ICa,L and increased INa,L. Mathematical modeling demonstrated that the changes in the studied ionic currents were adequate to explain the prolongation of the mouse ventricular action potential. Results from human iPSC-derived cardiomyocytes showed that shRNA knockdown of Cav-3 similarly prolonged APD. CONCLUSION: We demonstrate that Cav-3 and caveolae regulate cardiac repolarization and arrhythmia risk via the integrated modulation of multiple ionic currents.

Evaluation of an adaptive, rule-based dosing algorithm to maintain therapeutic anticoagulation during atrial fibrillation ablation.

Background: Cerebral thromboembolism during atrial fibrillation (AF) ablation is an infrequent (0.17%) complication in part owing to strict adherence to intraprocedural anticoagulation. Failure to maintain therapeutic anticoagulation can lead to an increase in events, including silent cerebral ischemia. Objective: To evaluate a computerized, clinical decision support system (CDSS) to dose intraprocedural anticoagulation and determine if it leads to improved intraprocedural anticoagulation outcomes during AF ablation. Methods: The Digital Intern dosing algorithm is an adaptive, rule-based CDSS for heparin dosing. The initial dose is calculated from the patient's weight, baseline activated clotting time (ACT), and outpatient anticoagulant. Subsequent recommendations adapt based on individual patient ACT changes. Outcomes from 50 cases prior to algorithm introduction were compared to 139 cases using the algorithm. Results: Procedures using the dosing algorithm reached goal ACT (over 300 seconds) faster (17.6 ± 11.1 minutes vs 33.3 ± 23.6 minutes pre-algorithm, P < .001). ACTs fell below goal while in the LA (odds ratio 0.20 [0.10-0.39], P < .001) and rose above 400 seconds less frequently (odds ratio 0.21 [0.07-0.59], P = .003). System Usability Scale scores were excellent (96 ± 5, n = 7, score >80.3 excellent). Preprocedure anticoagulant, weight, baseline ACT, age, sex, and renal function were potential predictors of heparin dose to achieve ACT >300 seconds and final infusion rate. Conclusion: A heparin dosing CDSS based on rules and adaptation to individual patient response improved maintenance of therapeutic ACT during AF ablation and was rated highly by nurses for usability.

Shared Decision Making in Cardiac Electrophysiology Procedures and Arrhythmia Management.

Shared decision making (SDM) has been advocated to improve patient care, patient decision acceptance, patient-provider communication, patient motivation, adherence, and patient reported outcomes. Documentation of SDM is endorsed in several society guidelines and is a condition of reimbursement for selected cardiovascular and cardiac arrhythmia procedures. However, many clinicians argue that SDM already occurs with clinical encounter discussions or the process of obtaining informed consent and note the additional imposed workload of using and documenting decision aids without validated tools or evidence that they improve clinical outcomes. In reality, SDM is a process and can be done without decision tools, although the process may be variable. Also, SDM advocates counter that the low-risk process of SDM need not be held to the high bar of demonstrating clinical benefit and that increasing the quality of decision making should be sufficient. Our review leverages a multidisciplinary group of experts in cardiology, cardiac electrophysiology, epidemiology, and SDM, as well as a patient advocate. Our goal is to examine and assess SDM methodology, tools, and available evidence on outcomes in patients with heart rhythm disorders to help determine the value of SDM, assess its possible impact on electrophysiological procedures and cardiac arrhythmia management, better inform regulatory requirements, and identify gaps in knowledge and future needs.

Artificial Intelligence and Machine Learning in Arrhythmias and Cardiac Electrophysiology.

Artificial intelligence (AI) and machine learning (ML) in medicine are currently areas of intense exploration, showing potential to automate human tasks and even perform tasks beyond human capabilities. Literacy and understanding of AI/ML methods are becoming increasingly important to researchers and clinicians. The first objective of this review is to provide the novice reader with literacy of AI/ML methods and provide a foundation for how one might conduct an ML study. We provide a technical overview of some of the most commonly used terms, techniques, and challenges in AI/ML studies, with reference to recent studies in cardiac electrophysiology to illustrate key points. The second objective of this review is to use examples from recent literature to discuss how AI and ML are changing clinical practice and research in cardiac electrophysiology, with emphasis on disease detection and diagnosis, prediction of patient outcomes, and novel characterization of disease. The final objective is to highlight important considerations and challenges for appropriate validation, adoption, and deployment of AI technologies into clinical practice.

Persistent Asthma Is Associated With Increased Risk for Incident Atrial Fibrillation in the MESA.

BACKGROUND: Asthma and atrial fibrillation (AF) share an underlying inflammatory pathophysiology. We hypothesized that persistent asthmatics are at higher risk for developing AF and that this association would be attenuated by adjustment for baseline markers of systemic inflammation. METHODS: The MESA (Multi-Ethnic Study of Atherosclerosis) is a prospective longitudinal study of adults free of cardiovascular disease at baseline. Presence of asthma was determined at exam 1. Persistent asthma was defined as asthma requiring use of controller medications. Intermittent asthma was defined as asthma without use of controller medications. Participants were followed for a median of 12.9 (interquartile range, 10-13.6) years for incident AF. Multivariable Cox regression models were used to assess associations of asthma subtype and AF. RESULTS: The 6615 participants were a mean (SD) 62.0 (10.2) years old (47% male, 27% black, 12% Chinese, and 22% Hispanic). AF incidence rates were 0.11 (95% CI, 0.01-0.12) events/10 person-years for nonasthmatics, 0.11 (95% CI, 0.08-0.14) events/10 person-years for intermittent asthmatics, and 0.19 (95% CI, 0.120.49) events/10 person-years for persistent asthmatics (log-rank P=0.008). In risk-factor adjusted models, persistent asthmatics had a greater risk of incident AF (hazard ratio, 1.49 [95% CI, 1.03-2.14], P=0.03). IL (Interleukin)-6 (hazard ratio, 1.26 [95% CI, 1.13-1.42]), TNF (tumor necrosis factor)-α receptor 1 (hazard ratio, 1.09 [95% CI, 1.08-1.11]) and D-dimer (hazard ratio, 1.10 [95% CI, 1.02-1.20]) predicted incident AF, but the relationship between asthma and incident AF was not attenuated by adjustment for any inflammation marker (IL-6, CRP [C-reactive protein], TNF-α R1, D-dimer, and fibrinogen). CONCLUSIONS: In a large multiethnic cohort with nearly 13 years follow-up, persistent asthma was associated with increased risk for incident AF. This association was not attenuated by adjustment for baseline inflammatory biomarkers.

Impact of a novel protocol for atrial fibrillation management in outpatient gastrointestinal endoscopic procedures: a retrospective cohort study.

BACKGROUND: Atrial fibrillation (AF) may result in procedure cancellations and emergency department (ED) referrals for patients presenting for outpatient GI endoscopic procedures. Such cancellations and referrals delay patient care and can lead to inefficient use of resources. METHODS: All consecutive patients presenting in AF for a colonoscopy or upper endoscopy to the University of Wisconsin Digestive Health Center between October 2013 and September 2014 were defined as the pre-intervention group (Group 1). In 2015, a protocol was initiated for peri-procedural management of patients presenting in AF, new onset or previously known. All consecutive patients after initiation of the protocol from October 2015 to September 2016 were analyzed as the post intervention group (Group 2). Patients with heart failure, hypotension, or chest pain were excluded from the protocol. RESULTS: One hundred nine and 141 patients were included in Groups 1 and Group 2, respectively. Following protocol initiation, patients were less likely to present to the ED (6.4% Group 1 vs. 1.4% Group 2, RR 0.22, p = 0.04). There was also a trend towards a reduction in procedure cancelations (5.5% Group 1 vs. 1.4% Group 2, RR 0.26, p = 0.08). All attempted procedures were completed and there were no complications in the intervention group. CONCLUSIONS: Implementation of a standardized protocol for management of atrial fibrillation in patients presenting for outpatient gastrointestinal endoscopic procedures resulted in a significant decrease in emergency department visits with an additional trend toward decreased procedural cancellations without an increased risk of complications.

Machine Learning Algorithm Predicts Cardiac Resynchronization Therapy Outcomes: Lessons From the COMPANION Trial.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in heart failure patients with reduced left ventricular function and intraventricular conduction delay. However, individual outcomes vary significantly. This study sought to use a machine learning algorithm to develop a model to predict outcomes after CRT. METHODS AND RESULTS: Models were developed with machine learning algorithms to predict all-cause mortality or heart failure hospitalization at 12 months post-CRT in the COMPANION trial (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure). The best performing model was developed with the random forest algorithm. The ability of this model to predict all-cause mortality or heart failure hospitalization and all-cause mortality alone was compared with discrimination obtained using a combination of bundle branch block morphology and QRS duration. In the 595 patients with CRT-defibrillator in the COMPANION trial, 105 deaths occurred (median follow-up, 15.7 months). The survival difference across subgroups differentiated by bundle branch block morphology and QRS duration did not reach significance (P=0.08). The random forest model produced quartiles of patients with an 8-fold difference in survival between those with the highest and lowest predicted probability for events (hazard ratio, 7.96; P<0.0001). The model also discriminated the risk of the composite end point of all-cause mortality or heart failure hospitalization better than subgroups based on bundle branch block morphology and QRS duration. CONCLUSIONS: In the COMPANION trial, a machine learning algorithm produced a model that predicted clinical outcomes after CRT. Applied before device implant, this model may better differentiate outcomes over current clinical discriminators and improve shared decision-making with patients.

Outcomes of cardiac resynchronization therapy in patients with intermittent atrial fibrillation or atrial flutter in the COMPANION trial.

BACKGROUND: Controlled clinical trial data are lacking for cardiac resynchronization therapy (CRT) outcomes in patients with advanced heart failure (HF) from reduced left ventricular ejection fraction (HFrEF) and intermittent atrial fibrillation or flutter (IAF/AFL). OBJECTIVE: The purpose of this study was to describe CRT outcomes in patients with IAF/AFL and advanced HF. METHODS: HF outcomes in patients in the COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trial with New York Heart Association class III or IV HFrEF, left ventricular ejection fraction ≤0.35, sinus rhythm at randomization, and no history of baseline arrhythmia were compared with those with a history of IAF/AFL. RESULTS: In those with no history of baseline arrhythmia (n = 887), compared with optimal pharmacological therapy (OPT) with no CRT, the CRT + OPT arms exhibited a significant reduction in the end points of death or any hospitalization (hazard ratio [HR] 0.73 [95% Confidence Interval (CI): 0.60 to 0.89]; P = .002) and death or HF hospitalization (HR 0.53 [95% CI: 0.41 to 0.68]; P < .001). In contrast, in the IAF/AFL subgroup (n = 293), CRT did not result in improved outcomes compared with OPT (death or any hospitalization: HR 1.16 [95% CI: 0.83 to 1.63]; P = .38; death or HF hospitalization: HR 0.97 [95% CI: 0.64 to 1.46]; P = .88). The interaction between history of AF/AFL and CRT was statistically significant for both outcomes (P < .05). CONCLUSION: In the COMPANION trial, patients with moderate to severe HFrEF and a history of IAF/AFL had no benefit from CRT.

Long-Term Outcome of Patients with Bifascicular Block and Unexplained Syncope Following Cardiac Pacing.

BACKGROUND: According to the ACC/AHA/HRS guidelines, cardiac pacing is reasonable in patients with bifascicular block (BF-B) and syncope when other causes have been excluded. The purpose of this study was to assess the long-term outcome of patients with BF-B and unexplained syncope following cardiac pacing. METHODS AND RESULTS: Between 2009 and 2015, we identified 43 consecutive patients (mean age of 78 ± 12 years, 64% males) who presented with syncope and BF-B and had received a pacemaker (PM). During a mean follow-up period of 31 ± 21 months, syncope recurred in seven patients (16%): 7% (95% standard error [SE] ± 3%) at 1 year and 18% (95% SE ± 7%) at 5 years. At univariable analysis, the only predictor of syncope recurrence was empiric pacing (P = 0.03). There were no syncope recurrences in the 12 patients who received a PM following a positive electrophysiological study (EPS) and the five patients with documentation of paroxysmal atrioventricular block (AVB) during cardiac monitoring (insertable loop recorder [ILR]), (EPS/ILR Group, n = 17) compared to seven of 26 (27%) patients who received empiric pacing (Empiric Group, n = 26; P = 0.02). Progression to high-degree AVB was documented during follow-up in 16 (37%) patients: nine of 17 (53%) patients in the EPS/ILR Group and seven of 26 (27%) patients in the Empiric Group (P = 0.11). There were no injuries reported during ILR monitoring. CONCLUSIONS: We have shown that syncope recurs not infrequently in patients with BF-B who received pacing for syncope. Nearly one in four patients who had empiric pacing suffered syncope recurrence compared to no recurrences in patients who received a PM following a positive EPS or documentation of transient AVB.

KCNJ2 mutation causes an adrenergic-dependent rectification abnormality with calcium sensitivity and ventricular arrhythmia.

BACKGROUND: KCNJ2 mutations are associated with a variety of inherited arrhythmia syndromes including catecholaminergic polymorphic ventricular tachycardia 3. OBJECTIVE: To characterize the detailed cellular mechanisms of the clinically recognized KCNJ2 mutation R67Q. METHODS: Kir2.1 current density was measured from COS-1 cells transiently transfected with wild-type human Kir-2.1 (WT-Kir2.1) and/or a heterozygous missense mutation in KCNJ2 (R67Q-Kir2.1) by using the whole-cell voltage clamp technique. Catecholamine activity was simulated with protein kinase A-stimulating cocktail exposure. Phosphorylation-deficient mutants, S425N-Kir2.1 and S425N-Kir2.1/R67Q-S425N-Kir2.1, were used in a separate set of experiments. HA- or Myc-Tag-WT-Kir2.1 and HA-Tag-R67Q-Kir2.1 were used for confocal imaging. RESULTS: A 33-year-old woman presented with a catecholaminergic polymorphic ventricular tachycardia-like clinical phenotype and was found to have KCNJ2 missense mutation R67Q. Treatment with nadolol and flecainide resulted in the complete suppression of arrhythmias and symptom resolution. Under baseline conditions, R67Q-Kir2.1 expressed alone did not produce inward rectifier current while cells coexpressing WT-Kir2.1 and R67Q-Kir2.1 demonstrated the rectification index (RI) similar to that of WT-Kir2.1. After PKA stimulation, R67Q-Kir2.1/WT-Kir2.1 failed to increase peak outward current density; WT-Kir2.1 increased by 46% (n = 5), while R67Q-Kir2.1/WT-Kir2.1 decreased by 6% (n = 6) (P = .002). Rectification properties in R67Q-Kir2.1/WT-Kir2.1 demonstrated sensitivity to calcium with a decreased RI in the high-calcium pipette solution (RI 20.3% ± 4.1%) than in the low-calcium pipette solution (RI 36.5% ± 5.7%) (P < .05). Immunostaining of WT-Kir2.1 and R67Q-Kir2.1 individually and together showed a normal membrane expression pattern and colocalization by using the Pearson correlation coefficient. CONCLUSIONS: R67Q-Kir2.1 is associated with an adrenergic-dependent clinical and cellular phenotype with rectification abnormality enhanced by increased calcium. These findings are a significant advancement of our knowledge and understanding of the phenotype-genotype relationship of arrhythmia syndromes related to KCNJ2 mutations.