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Many widely used medications may cause or exacerbate a variety of arrhythmias. Numerous antiarrhythmic agents, antimicrobial drugs, psychotropic medications, and methadone, as well as a growing list of drugs from other therapeutic classes (neurological drugs, anticancer agents, and many others), can prolong the QT interval and provoke torsades de pointes. Perhaps less familiar to clinicians is the fact that drugs can also trigger other arrhythmias, including bradyarrhythmias, atrial fibrillation/atrial flutter, atrial tachycardia, atrioventricular nodal reentrant tachycardia, monomorphic ventricular tachycardia, and Brugada syndrome. Some drug-induced arrhythmias (bradyarrhythmias, atrial tachycardia, atrioventricular node reentrant tachycardia) are significant predominantly because of their symptoms; others (monomorphic ventricular tachycardia, Brugada syndrome, torsades de pointes) may result in serious consequences, including sudden cardiac death. Mechanisms of arrhythmias are well known for some medications but, in other instances, remain poorly understood. For some drug-induced arrhythmias, particularly torsades de pointes, risk factors are well defined. Modification of risk factors, when possible, is important for prevention and risk reduction. In patients with nonmodifiable risk factors who require a potentially arrhythmia-inducing drug, enhanced electrocardiographic and other monitoring strategies may be beneficial for early detection and treatment. Management of drug-induced arrhythmias includes discontinuation of the offending medication and following treatment guidelines for the specific arrhythmia. In overdose situations, targeted detoxification strategies may be needed. Awareness of drugs that may cause arrhythmias and knowledge of distinct arrhythmias that may be drug-induced are essential for clinicians. Consideration of the possibility that a patient's arrythmia could be drug-induced is important.

Coronavirus disease 2019 (COVID-19) is a global pandemic that is wreaking havoc on the health and economy of much of human civilization. Electrophysiologists have been impacted personally and professionally by this global catastrophe. In this joint article from representatives of the Heart Rhythm Society, the American College of Cardiology, and the American Heart Association, we identify the potential risks of exposure to patients, allied healthcare staff, industry representatives, and hospital administrators. We also describe the impact of COVID-19 on cardiac arrhythmias and methods of triage based on acuity and patient comorbidities. We provide guidance for managing invasive and noninvasive electrophysiology procedures, clinic visits, and cardiac device interrogations. In addition, we discuss resource conservation and the role of telemedicine in remote patient care along with management strategies for affected patients., (Copyright © 2020. Published by Elsevier Inc.)

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.

Background: Cardiac resynchronization therapy (CRT) improves heart failure outcomes but has significant nonresponse rates, highlighting limitations in ECG selection criteria: QRS duration (QRSd) ≥150 ms and subjective labeling of left bundle branch block (LBBB). We explored unsupervised machine learning of ECG waveforms to identify CRT subgroups that may differentiate outcomes beyond QRSd and LBBB., Methods: We retrospectively analyzed 946 CRT patients with conduction delay. Principal component analysis (PCA) dimensionality reduction obtained a 2-dimensional representation of preCRT 12-lead QRS waveforms. k -means clustering of the 2-dimensional PCA representation of 12-lead QRS waveforms identified 2 patient subgroups (QRS PCA groups). Vectorcardiographic QRS area was also calculated. We examined following 2 primary outcomes: (1) composite end point of death, left ventricular assist device, or heart transplant, and (2) degree of echocardiographic left ventricular ejection fraction (LVEF) change after CRT., Results: Compared with QRS PCA Group 2 ( n =425), Group 1 ( n =521) had lower risk for reaching the composite end point (HR, 0.44 [95% CI, 0.38-0.53]; P <0.001) and experienced greater mean LVEF improvement (11.1±11.7% versus 4.8±9.7%; P <0.001), even among patients with LBBB with QRSd ≥150 ms (HR, 0.42 [95% CI, 0.30-0.57]; P <0.001; mean LVEF change 12.5±11.8% versus 7.3±8.1%; P =0.001). QRS area also stratified outcomes but had significant differences from QRS PCA groups. A stratification scheme combining QRS area and QRS PCA group identified patients with LBBB with similar outcomes to non-LBBB patients (HR, 1.32 [95% CI, 0.93-1.62]; difference in mean LVEF change: 0.8% [95% CI, -2.1% to 3.7%]). The stratification scheme also identified patients with LBBB with QRSd <150 ms with comparable outcomes to patients with LBBB with QRSd ≥150 ms (HR, 0.93 [95% CI, 0.67-1.29]; difference in mean LVEF change: -0.2% [95% CI, -2.7% to 3.0%])., Conclusions: Unsupervised machine learning of ECG waveforms identified CRT subgroups with relevance beyond LBBB and QRSd. This method may assist in objective classification of bundle branch block morphology in CRT.

Background: The P wave on an ECG is a measure of atrial electric function, and its characteristics may serve as predictors for atrial arrhythmias. Increased mean P-wave duration and P-wave terminal force traditionally have been used as markers for left atrial enlargement, and both have been associated with increased risk of atrial fibrillation. Here, we explore the genetic basis of P-wave morphology through meta-analysis of genome-wide association study results for P-wave duration and P-wave terminal force from 12 cohort studies., Methods and Results: We included 44 456 individuals, of which 6778 (16%) were of African ancestry. Genotyping, imputation, and genome-wide association study were performed at each study site. Summary-level results were meta-analyzed centrally using inverse-variance weighting. In meta-analyses of P-wave duration, we identified 6 significant ( P <5×10 - 8 ) novel loci and replicated a prior association with S CN10A. We identified 3 loci at SCN5A , TBX5 , and CAV1/CAV2 that were jointly associated with the PR interval, PR segment, and P-wave duration. We identified 6 novel loci in meta-analysis of P-wave terminal force. Four of the identified genetic loci were significantly associated with gene expression in 329 left atrial samples. Finally, we observed that some of the loci associated with the P wave were linked to overall atrial conduction, whereas others identified distinct phases of atrial conduction., Conclusions: We have identified 6 novel genetic loci associated with P-wave duration and 6 novel loci associated with P-wave terminal force. Future studies of these loci may aid in identifying new targets for drugs that may modify atrial conduction or treat atrial arrhythmias., (© 2017 American Heart Association, Inc.)

Background: The relationship between QRS narrowing and response to cardiac resynchronization therapy (CRT) has been controversial., Objective: We sought to analyze the relationship between QRS narrowing and reverse remodeling in patients undergoing CRT, taking into account potential confounders including pre-CRT QRS duration and underlying QRS morphology., Methods: We reviewed pre- and postimplant electrocardiograms and echocardiograms in a cohort of 233 patients undergoing the new implantation of a CRT device between December 2001 and September 2006. For inclusion in the final cohort, patients had New York Heart Association classes II-IV heart failure, left ventricular ejection fraction (LVEF) ≤ 40%, and QRS duration ≥120 ms. Response to CRT was defined as a reduction in left ventricular end-systolic volume (LVESV) of ≥10%. A multivariate model was constructed to determine the relationship between QRS change and response to CRT., Results: Patients with QRS narrowing had significantly greater reductions in left ventricular end-diastolic volume (LVEDV) (mL) (-26.5 ± 52.5 vs -4.8 ± 44.0, P = 0.002) and LVESV (mL) (-34.0 ± 55.5 vs -9.9 ± 45.8, P = 0.002) and improvement in LVEF (%) (8.9 ± 12.8 vs 4.5 ± 9.0, P = 0.007) than patients without narrowing. In univariate analysis, female gender (P = 0.0002), percent QRS narrowing from baseline (P = 0.008), lack of nitrate (P≤0.0001) and antiarrhythmic medication use (P = 0.01), lack of a nonspecific intraventricular conduction delay (=0.02), nonischemic cardiomyopathy (P = 0.003), and lower pre-CRT LVEDV (P = 0.006) and LVESV [P = 0.01]) were associated with responders. In a multivariate model, QRS narrowing, indexed to the baseline QRS duration, remained strongly associated with response (odds ratio 0.08 [0.01-0.56], P = 0.01)., Conclusions: After adjusting for potential confounders, QRS narrowing, indexed to baseline QRS duration, is associated with enhanced reverse ventricular remodeling following CRT., (©2011, The Authors. Journal compilation ©2011 Wiley Periodicals, Inc.)

Background: QRS fragmentation (fQRS) has been shown to be a marker of scar in patients with left ventricular dysfunction. Whether fQRS is associated with progressive left ventricular remodeling and increased mortality in patients receiving cardiac resynchronization therapy (CRT) is unclear., Methods: We reviewed the preimplant and follow-up echocardiograms in 233 patients undergoing the new implantation of a CRT device between December 2001 and November 2006. Patients were included if they had a pre-CRT ECG with appropriate filter settings (filter 0.16-100 or 0.16-150 Hz, 25 mm/s, 10 mm/mV), a left ventricular ejection fraction (LVEF) ≤40%, and New York Heart Association class II-IV symptoms on standard medical therapy. The 12-lead electrocardiogram (ECG) was interpreted by two blinded reviewers for the presence of fQRS. Remodeling end points, including changes in LVEF and left ventricular end-diastolic (LVEDV) and systolic (LVESV) volumes, were compared between patients with and without contiguous fQRS, and an assessment of all-cause mortality was made., Results: Two hundred thirty-two patients met inclusion criteria, of which 50 demonstrated fQRS in contiguous leads. There was no difference in improvement in LVEF (%) (7.9 ± 12.9 vs 6.8 ± 11.0, P = 0.60) or reduction in LVEDV (mL) (-30.1 ± 57.2 vs -15.7 ± 47.6) or LVESV (mL) (-33.7 ± 58.1 vs -22.7 ± 50.6, P = 0.40) between patients with and without contiguous fQRS. At a mean follow-up of 4.4 ± 1.9 years, there were a total of 89 deaths, 22 (44.0%) in patients with contiguous fQRS and 67 (36.8%) without (log rank P = 0.31)., Conclusions: QRS fragmentation is not a predictor of progressive ventricular remodeling or mortality in heart failure patients undergoing CRT., (©2011, Wiley Periodicals, Inc.)

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

Postimplant QRS narrowing may predict clinical response after cardiac resynchronization therapy (CRT), but identification of nonresponders remains difficult. We studied the predictive value of electrocardiographic characteristics for mortality or cardiac transplantation in patients after CRT. Patients who had electrocardiograms available for review from before and after CRT device implantation were identified from a clinical database. Bivariate and multivariate Cox regression analyses were performed for the end point of death or transplantation. Of 337 patients (age 65+/-12 years, 76% men, left ventricular ejection fraction 22+/-12%, pre-QRS 175+/-30 ms), 84 died and 7 underwent transplantation during a follow-up of 27+/-15 months. Variables predictive of death or transplantation included QRS increase after CRT (45% vs 32%, p=0.03), older age, higher New York Heart Association class, lower left ventricular ejection fraction, and higher tertile of postimplant QRS (p=0.04), but not preimplant rhythm, QRS duration, or QRS morphology. After adjusting for confounding variables, independent predictors of mortality were older age (hazard ratio [HR] 1.03, 95% confidence interval [CI] 1.00 to 1.05, p=0.04), lack of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (HR 2.17, 95% CI 1.16 to 4.08, p<0.02), and longer postimplant QRS by tertile (HR 1.50, 95% CI 1.09 to 2.05, p=0.01). In conclusion, wider QRS after CRT device implantation is an independent predictor of mortality or transplantation. In patients with increased QRS durations despite CRT, closer follow-up or reassessment for alternative management strategies may be warranted.

BACKGROUND:Genetic variants at the SCN5A/SCN10A locus are strongly associated with electrocardiographic PR and QRS intervals. While SCN5A is the canonical cardiac sodium channel gene, the role of SCN10A in cardiac conduction is less well characterized. METHODS:We sequenced the SCN10A locus in 3699 European-ancestry individuals to identify variants associated with cardiac conduction, and replicated our findings in 21,000 individuals of European ancestry. We examined association with expression in human atrial tissue. We explored the biophysical effect of variation on channel function using cellular electrophysiology. RESULTS:We identified 2 intronic single nucleotide polymorphisms in high linkage disequilibrium (r  2=0.86) with each other to be the strongest signals for PR (rs10428132, β=-4.74, P=1.52×10-14) and QRS intervals (rs6599251, QRS β=-0.73; P=1.2×10-4), respectively. Although these variants were not associated with SCN5A or SCN10A expression in human atrial tissue (n=490), they were in high linkage disequilibrium (r  2≥0.72) with a common SCN10A missense variant, rs6795970 (V1073A). In total, we identified 7 missense variants, 4 of which (I962V, P1045T, V1073A, and L1092P) were associated with cardiac conduction. These 4 missense variants cluster in the cytoplasmic linker of the second and third domains of the SCN10A protein and together form 6 common haplotypes. Using cellular electrophysiology, we found that haplotypes associated with shorter PR intervals had a significantly larger percentage of late current compared with wild-type (I962V+V1073A+L1092P, 20.2±3.3%, P=0.03, and I962V+V1073A, 22.4±0.8%, P=0.0004 versus wild-type 11.7±1.6%), and the haplotype associated with the longest PR interval had a significantly smaller late current percentage (P1045T, 6.4±1.2%, P=0.03). CONCLUSIONS:Our findings suggest an association between genetic variation in SCN10A, the late sodium current, and alterations in cardiac conduction.

Electrocardiographic PR interval measures atrio-ventricular depolarization and conduction, and abnormal PR interval is a risk factor for atrial fibrillation and heart block. Our genome-wide association study of over 92,000 European-descent individuals identifies 44 PR interval loci (34 novel). Examination of these loci reveals known and previously not-yet-reported biological processes involved in cardiac atrial electrical activity. Genes in these loci are over-represented in cardiac disease processes including heart block and atrial fibrillation. Variants in over half of the 44 loci were associated with atrial or blood transcript expression levels, or were in high linkage disequilibrium with missense variants. Six additional loci were identified either by meta-analysis of ~105,000 African and European-descent individuals and/or by pleiotropic analyses combining PR interval with heart rate, QRS interval, and atrial fibrillation. These findings implicate developmental pathways, and identify transcription factors, ion-channel genes, and cell-junction/cell-signaling proteins in atrio-ventricular conduction, identifying potential targets for drug development.

The electrocardiographic QRS duration, a measure of ventricular depolarization and conduction, is associated with cardiovascular mortality. While single nucleotide polymorphisms (SNPs) associated with QRS duration have been identified at 22 loci in populations of European descent, the genetic architecture of QRS duration in non-European populations is largely unknown. We therefore performed a genome-wide association study (GWAS) meta-analysis of QRS duration in 13,031 African Americans from ten cohorts and a transethnic GWAS meta-analysis with additional results from populations of European descent. In the African American GWAS, a single genome-wide significant SNP association was identified (rs3922844, P = 4 × 10-14) in intron 16 of SCN5A, a voltage-gated cardiac sodium channel gene. The QRS-prolonging rs3922844 C allele was also associated with decreased SCN5A RNA expression in human atrial tissue (P = 1.1 × 10-4). High density genotyping revealed that the SCN5A association region in African Americans was confined to intron 16. Transethnic GWAS meta-analysis identified novel SNP associations on chromosome 18 in MYL12A (rs1662342, P = 4.9 × 10-8) and chromosome 1 near CD1E and SPTA1 (rs7547997, P = 7.9 × 10-9). The 22 QRS loci previously identified in populations of European descent were enriched for significant SNP associations with QRS duration in African Americans (P = 9.9 × 10-7), and index SNP associations in or near SCN5A, SCN10A, CDKN1A, NFIA, HAND1, TBX5 and SETBP1 replicated in African Americans. In summary, rs3922844 was associated with QRS duration and SCN5A expression, two novel QRS loci were identified using transethnic meta-analysis, and a significant proportion of QRS-SNP associations discovered in populations of European descent were transferable to African Americans when adequate power was achieved.

In the past year, there have been numerous advances in our understanding of arrhythmia mechanisms, diagnosis, and new therapies. We have seen advances in basic cardiac electrophysiology with data suggesting that secretoneurin may be a biomarker for patients at risk of ventricular arrhythmias, and we have learned of the potential role of an NPR-C (natriuretic peptide receptor-C) in atrial fibrosis and the role of an atrial specific 2-pore potassium channel TASK-1 as a therapeutic target for atrial fibrillation. We have seen studies demonstrating the role of sensory neurons in sleep apnea-related atrial fibrillation and the association between bariatric surgery and atrial fibrillation ablation outcomes. Artificial intelligence applied to electrocardiography has yielded estimates of age, sex, and overall health. We have seen new tools for collection of patient-centered outcomes following catheter ablation. There have been significant advances in the ability to identify ventricular tachycardia termination sites through high-density mapping of deceleration zones. We have learned that right ventricular dysfunction may be a predictor of survival benefit after implantable cardioverter-defibrillator implantation in patients with nonischemic cardiomyopathy. We have seen further insights into the role of His bundle pacing on improving outcomes. As our understanding of cardiac laminopathies advances, we may have new tools to predict arrhythmic event rates in gene carriers. Finally, we have seen numerous advances in the treatment of arrhythmias in patients with congenital heart disease. [ABSTRACT FROM AUTHOR]