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Background Pregnant patients with single ventricle (SV) physiology carry a high risk of spontaneous pregnancy loss (SPL), yet the clinical factors contributing to this risk are not well defined.Methods Single-centre retrospective study of pregnant patients with SV physiology seen in cardio-obstetrics clinic over the past 20 years with chart review of their obstetric history. Patients without a known pregnancy outcome were excluded. Univariable Bayesian panel-data random effects logit was used to model the risk of SPL.Results The study included 20 patients with 44 pregnancies, 20 live births, 21 SPL and 3 elective abortions. All had Fontan palliation except for two with Waterston and Glenn shunts. 10 (50%) had a single right ventricle (RV). 14 (70%) had moderate or severe atrioventricular valve regurgitation (AVVR). Atrial arrhythmias were present in 16 (80%), Fontan-associated liver disease (FALD) in 15 (75%) and FALD stage 4 in 9 (45%). 12 (60%) were on anticoagulation. Average first-trimester oxygen saturation was 93.8% for live births and 90.8% for SPL. The following factors were associated with higher odds of SPL: RV morphology (OR 1.72 (95% credible interval (CrI) 1.0008–2.70)), moderate or severe AVVR (OR 1.64 (95% CrI 1.003–2.71)) and reduced first-trimester oxygen saturation (OR 1.83 (95% CrI 1.03–2.71) for each per cent decrease in O2 saturation.Conclusion Pregnant patients with SV physiology, particularly those with RV morphology, moderate or severe AVVR, and lower first-trimester oxygen saturations, have a higher risk of SPL. Identifying these clinical risk factors can guide preconception counselling by the cardio-obstetrics team.

Abstract Background Community-acquired pneumonia (CAP) is a significant public health concern and a leading cause of hospitalization and inpatient antimicrobial use in the USA. However, determining the etiologic pathogen is challenging because traditional culture methods are slow and insensitive, leading to prolonged empiric therapy with extended-spectrum antibiotics (ESA) that contributes to increased hospital length of stay, and antimicrobial resistance. Two potential ways to reduce the exposure to ESA are (a) rapid diagnostic assays that can provide accurate results within hours, obviating the need for empiric therapy, and (b) de-escalation following negative bacterial cultures in clinically stable patients. Methods We will conduct a large pragmatic 2 × 2 factorial cluster-randomized controlled trial across 12 hospitals in the Cleveland Clinic Health System that will test these two approaches to reducing the use of ESA in adult patients (age ≥ 18 years) with CAP. We will enroll over 12,000 patients and evaluate the independent and combined effects of routine use of rapid diagnostic testing at admission and pharmacist-led de-escalation after 48 h for clinically stable patients with negative cultures vs usual care. We hypothesize that both approaches will reduce days on ESA. Our primary outcome is the duration of exposure to ESA therapy, a key driver of antimicrobial resistance. Secondary outcomes include detection of respiratory viruses, treatment with anti-viral medications, positive pneumococcal urinary antigen test, de-escalation by 72 h from admission, re-escalation to ESA after de-escalation, total duration of any antibiotic, 14-day in-hospital mortality, intensive care unit transfer after admission, healthcare-associated C. difficile infection, acute kidney injury, total inpatient cost, and hospital length-of-stay. Discussion Our study aims to determine whether identifying an etiological agent early and pharmacist-led de-escalation (calling attention to negative cultures) can safely reduce the use of ESA in patients with CAP. If successful, our findings should lead to better antimicrobial stewardship, as well as improved patient outcomes and reduced healthcare costs. Our findings may also inform clinical guidelines on the optimal management of CAP. Trial registration ClinicalTrials.gov NCT05568654 . Registered on October 4, 2022.

Abstract The ECG diagnosis of LVH is predominantly based on the QRS voltage criteria. The classical paradigm postulates that the increased left ventricular mass generates a stronger electrical field, increasing the leftward and posterior QRS forces, reflected in the augmented QRS amplitude. However, the low sensitivity of voltage criteria has been repeatedly documented. We discuss possible reasons for this shortcoming and proposal of a new paradigm. The theoretical background for voltage measured at the body surface is defined by the solid angle theorem, which relates the measured voltage to spatial and non‐spatial determinants. The spatial determinants are represented by the extent of the activation front and the distance of the recording electrodes. The non‐spatial determinants comprise electrical characteristics of the myocardium, which are comparatively neglected in the interpretation of the QRS patterns. Various clinical conditions are associated with LVH. These conditions produce considerable diversity of electrical properties alterations thereby modifying the resultant QRS patterns. The spectrum of QRS patterns observed in LVH patients is quite broad, including also left axis deviation, left anterior fascicular block, incomplete and complete left bundle branch blocks, Q waves, and fragmented QRS. Importantly, the QRS complex can be within normal limits. The new paradigm stresses the electrophysiological background in interpreting QRS changes, i.e., the effect of the non‐spatial determinants. This postulates that the role of ECG is not to estimate LV size in LVH, but to understand and decode the underlying electrical processes, which are crucial in relation to cardiovascular risk assessment.

Abstract Background: Community-acquired pneumonia (CAP) is a leading cause of hospitalizations and mortality in the US. Overuse of extended spectrum antibiotics (ESA) for CAP contributes to antimicrobial resistance. The 2019 Infectious Diseases Society of America/American Thoracic Society CAP guidelines emphasize de-escalation of ESA following negative cultures, early switch to oral (PO) antibiotics, and limited duration of therapy (DOT). This study describes clinicians’ acceptance of an infectious diseases-trained (ID) pharmacist-led stewardship recommendations in hospitalized patients with CAP. Methods: This prospective, single-arm, cohort study included adults admitted with a diagnosis of pneumonia to six Cleveland Clinic hospitals receiving ID pharmacist-led stewardship recommendations. The ID pharmacist provided recommendations for ESA de-escalation, DOT, intravenous (IV) to PO transition, and antimicrobial discontinuation. Descriptive statistics were used to describe clinician acceptance rates. Results: From November 1, 2022, to January 31, 2024, the ID pharmacist made recommendations for 685 patient encounters to 327 clinicians. Of these patients, 52% received an ESA and 15% had severe CAP. There were 959 recommendations: ESA de-escalation (19%), DOT (46%), IV to PO transition (19%), antimicrobial discontinuation (13%), and other (3%). Clinicians accepted 693 recommendations (72%): IV to PO transition (148/184, 80%), ESA de-escalation (141/181 78%), antimicrobial discontinuation (94/128, 73%), DOT (286/437, 65%), and other (24/29, 83%). Conclusion: Clinicians were generally receptive to ID pharmacist-led CAP recommendations with an overall acceptance rate of 72%. Prescribers were most receptive to recommendations for IV to PO conversion and least receptive to limiting DOT.

The spatial and frontal QRS-T angles are electrocardiographic (ECG) predictors for arrhythmia. This work used genetic analyses to identify associated loci and pathways, and explore their relationships with other ECG traits and cardiovascular disease.

Summary: Background: Interventional trials that evaluate treatment effects using surrogate endpoints have become increasingly common. This paper describes four linked empirical studies and the development of a framework for defining, interpreting and reporting surrogate endpoints in trials. Methods: As part of developing the CONSORT (Consolidated Standards of Reporting Trials) and SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) extensions for randomised trials reporting surrogate endpoints, we undertook a scoping review, e-Delphi study, consensus meeting, and a web survey to examine current definitions and stakeholder (including clinicians, trial investigators, patients and public partners, journal editors, and health technology experts) interpretations of surrogate endpoints as primary outcome measures in trials. Findings: Current surrogate endpoint definitional frameworks are inconsistent and unclear. Surrogate endpoints are used in trials as a substitute of the treatment effects of an intervention on the target outcome(s) of ultimate interest, events measuring how patients feel, function, or survive. Traditionally the consideration of surrogate endpoints in trials has focused on biomarkers (e.g., HDL cholesterol, blood pressure, tumour response), especially in the medical product regulatory setting. Nevertheless, the concept of surrogacy in trials is potentially broader. Intermediate outcomes that include a measure of function or symptoms (e.g., angina frequency, exercise tolerance) can also be used as substitute for target outcomes (e.g., all-cause mortality)—thereby acting as surrogate endpoints. However, we found a lack of consensus among stakeholders on accepting and interpreting intermediate outcomes in trials as surrogate endpoints or target outcomes. In our assessment, patients and health technology assessment experts appeared more likely to consider intermediate outcomes to be surrogate endpoints than clinicians and regulators. Interpretation: There is an urgent need for better understanding and reporting on the use of surrogate endpoints, especially in the setting of interventional trials. We provide a framework for the definition of surrogate endpoints (biomarkers and intermediate outcomes) and target outcomes in trials to improve future reporting and aid stakeholders' interpretation and use of trial surrogate endpoint evidence. Funding: SPIRIT-SURROGATE/CONSORT-SURROGATE project is Medical Research Council Better Research Better Health (MR/V038400/1) funded.

Abstract Background Patients receiving intermittent hemodialysis have variable times of recovery to feeling better after dialysis. QT prolongation, a precursor to clinical and subclinical cardiovascular events, may contribute to delayed recovery time. We hypothesized that abnormal electrocardiographic parameters indicating perturbations in ventricular action are associated with longer recovery times thus impacting a patient-centered quality of life. Methods Among 242 incident in-center hemodialysis participants from the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease (PACE) study, corrected QT interval (QTc), QRST angle and heart rate variance were measured on non-dialysis days using a standard 5-min electrocardiograph recording. Left ventricular hypertrophy (LVH) was defined using the Cornell voltage product. Recovery time was ascertained during a phone interview with a standardized validated questionnaire. Associations between QTc, QRST angle, heart rate variance, and LVH and natural log-transformed recovery time were examined using linear regression adjusted for participant characteristics and electrolytes. Results Mean age was 55 (standard deviation 13) years, 55% were male, 72% were African American. Longer QTc interval was associated with increased recovery time (per 10 ms increase in QTc, recovery time increased by 6.2%; 95% confidence interval: 0.0–10.5). QRST angle, heart rate, heart rate variability and LVH were not significantly associated with recovery time. Conclusion Longer QTc intervals are associated with longer recovery time independent of serum electrolytes. This supports a relationship between a patient’s underlying arrhythmic status and time to recovery after hemodialysis. Future studies will determine if maneuvers to reduce QTc improves recovery time and quality of life of patients on hemodialysis.

Background: Adaptive cardiac resynchronization therapy (aCRT) is known to have clinical benefits over conventional CRT, but the mechanisms are unclear. Objective: Compare effects of aCRT and conventional CRT on electrical dyssynchrony. Methods: A prospective, double-blind, 1:1 parallel-group assignment randomized controlled trial in patients receiving CRT for routine clinical indications. Participants underwent cardiac computed tomography and 128-electrode body surface mapping. The primary outcome was change in electrical dyssynchrony measured on the epicardial surface using noninvasive electrocardiographic imaging before and 6 months post-CRT. Ventricular electrical uncoupling (VEU) was calculated as the difference between the mean left ventricular (LV) and right ventricular (RV) activation times. An electrical dyssynchrony index (EDI) was computed as the standard deviation of local epicardial activation times. Results: We randomized 27 participants (aged 64 ± 12 years; 34% female; 53% ischemic cardiomyopathy; LV ejection fraction 28% ± 8%; QRS duration 155 ± 21 ms; typical left bundle branch block [LBBB] in 13%) to conventional CRT (n = 15) vs aCRT (n = 12). In atypical LBBB (n = 11; 41%) with S waves in V5-V6, conduction block occurred in the anterior RV, as opposed to the interventricular groove in strict LBBB. As compared to baseline, VEU reduced post-CRT in the aCRT (median reduction 18.9 [interquartile range 4.3–29.2 ms; P = .034]), but not in the conventional CRT (21.4 [-30.0 to 49.9 ms; P = .525]) group. There were no differences in the degree of change in VEU and EDI indices between treatment groups. Conclusion: The effect of aCRT and conventional CRT on electrical dyssynchrony is largely similar, but only aCRT harmoniously reduced interventricular dyssynchrony by reducing RV uncoupling.

Background: Sex is a well-recognized risk factor for sudden cardiac death (SCD). We hypothesized that sex modifies the association of electrophysiological (EP) substrate with SCD. Objective: The purpose of this study was to determine whether there are sex differences in electrocardiographic (ECG) measures and whether sex modifies the association of ECG measures of EP substrate with SCD. Methods: Participants from the Atherosclerosis Risk in Communities study with analyzable ECGs (n = 14,725; age 54.2 ± 5.8 years; 55% female; 74% white) were included. EP substrate was characterized by heart rate, QRS, QTc, Cornell voltage, spatial ventricular gradient (SVG), and sum absolute QRST integral (SAI QRST) ECG metrics. Two competing outcomes were adjudicated: SCD and non-SCD. Interaction of ECG metrics with sex was studied in Cox proportional hazards and Fine-Gray competing risk models. Model 1 was adjusted for prevalent cardiovascular disease (CVD) and risk factors. Time-updated model 2 was additionally adjusted for incident nonfatal CVD. Relative hazard ratio (RHR) and relative subhazard ratio with 95% confidence interval (CI) for SCD and non-SCD risk for women relative to men were calculated. Model 1 was adjusted for prevalent CVD and risk factors. Time-updated model 2 was additionally adjusted for incident nonfatal CVD. Results: Over median follow-up of 24.4 years, there were 530 SCDs (incidence 1.72; 95% CI 1.58–1.88 per 1000 person-years). Women compared to men experienced a greater risk of SCD associated with Cornell voltage (RHR 1.18; 95% CI 1.06–1.32; P = .003), SAI QRST (RHR 1.16; 95% CI 1.04–1.30; P = .007), and SVG magnitude (RHR 1.24; 95% CI 1.05–1.45; P = .009), independently from incident CVD. Conclusion: In women, the global EP substrate is associated with up to 24% greater risk of SCD than in men, suggesting differences in underlying mechanisms and the need for sex-specific SCD risk stratification.

Objectives There is a controversy about whether both sexes’ response to cardiac resynchronisation therapy (CRT) is similar. We aimed to assess a causal effect of sex on CRT response.Design Secondary analysis of a randomised controlled trial (RCT) data. Doubly robust augmented-inverse-probability-weighted (AIPW) estimation of sex effect on CRT response.Setting The SmartDelay Determined Atrioventricular (AV) Optimisation (SMART-AV) RCT.Participants The SMART-AV RCT enrolled New York Heart Association class III-IV patients with heart failure (HF) with left ventricular ejection fraction (LVEF) ≤35% despite optimal medical therapy and QRS duration ≥120 ms, in sinus rhythm. After exclusion of those with missing outcome or covariates, 741 participants (age 66±11 years; 33% female; 78% white; LVEF 28%±9%; 58% ischaemic cardiomyopathy; 75% left bundle branch block; left ventricular end-systolic volume index (LVESVI) 65±30 mL/m2) were included.Interventions Implanted CRT defibrillator with randomly assigned AV delay as either (1) fixed at 120 ms, or (2) echocardiography-determined, or (3) SmartDelay algorithm-programmed.Outcome A composite of freedom from death and HF hospitalisation and a >15% reduction in LVESVI at 6 month post-CRT was the endpoint.Results The primary endpoint was met by 337 patients (45.5%); 134 were women (55.6% response) and 203 were men (40.6% response); p

Abstract Background The risk of sudden cardiac death (SCD) is known to be dynamic. However, the accuracy of a dynamic SCD prediction is unknown. We aimed to measure the dynamic predictive accuracy of ECG biomarkers of SCD and competing non-sudden cardiac death (non-SCD). Methods Atherosclerosis Risk In Community study participants with analyzable ECGs in sinus rhythm were included (n = 15,716; 55% female, 73% white, age 54.2 ± 5.8 y). ECGs of 5 follow-up visits were analyzed. Global electrical heterogeneity and traditional ECG metrics (heart rate, QRS, QTc) were measured. Adjudicated SCD was the primary outcome; non-SCD was the competing outcome. Time-dependent area under the receiver operating characteristic curve (ROC(t) AUC) analysis was performed to assess the prediction accuracy of a continuous biomarker in a period of 3,6,9 months, and 1,2,3,5,10, and 15 years using a survival analysis framework. Reclassification improvement as compared to clinical risk factors (age, sex, race, diabetes, hypertension, coronary heart disease, stroke) was measured. Results Over a median 24.4 y follow-up, there were 577 SCDs (incidence 1.76 (95%CI 1.63–1.91)/1000 person-years), and 829 non-SCDs [2.55 (95%CI 2.37–2.71)]. No ECG biomarkers predicted SCD within 3 months after ECG recording. Within 6 months, spatial ventricular gradient (SVG) elevation predicted SCD (AUC 0.706; 95%CI 0.526–0.886), but not a non-SCD (AUC 0.527; 95%CI 0.303–0.75). SVG elevation more accurately predicted SCD if the ECG was recorded 6 months before SCD (AUC 0.706; 95%CI 0.526–0.886) than 2 years before SCD (AUC 0.608; 95%CI 0.515–0.701). Within the first 3 months after ECG recording, only SVG azimuth improved reclassification of the risk beyond clinical risk factors: 18% of SCD events were reclassified from low or intermediate risk to a high-risk category. QRS-T angle was the strongest long-term predictor of SCD (AUC 0.710; 95%CI 0.668–0.753 for ECG recorded within 10 years before SCD). Conclusion Short-term and long-term predictive accuracy of ECG biomarkers of SCD differed, reflecting differences in transient vs. persistent SCD substrates. The dynamic predictive accuracy of ECG biomarkers should be considered for competing SCD risk scores. The distinction between markers predicting short-term and long-term events may represent the difference between markers heralding SCD (triggers or transient substrates) versus markers identifying persistent substrate.

Abstract Background Prolonged QT interval in hemodialysis patients may be associated with sudden cardiac death, however, few studies examined the longitudinal associations of modifiable factors such as serum and dialysate concentrations of calcium, potassium, and magnesium with corrected QT (QTc) prolongation in incident hemodialysis patients. Methods In 330 in-center hemodialysis participants from the PACE study who were followed up for one year, we examined the associations of predialysis serum electrolytes (total calcium [Ca], corrected Ca [cCa], ionized Ca [iCa], potassium [K], magnesium [Mg]), dialysate (dCa and dK), and serum-to-dialysate gradient measures with QTc interval and prolongation (≥460 ms in women and ≥ 450 ms in men). Results At the first study visit, 47% had QTc prolongation. Lower iCa and K were associated with longer QTc interval independent of potential confounders (QTc difference = 8.55[95% CI: 2.13, 14.97] ms for iCa; QTc difference = 9.89[1.58, 18.20] ms for K). Lower iCa was also associated with a higher risk of QTc prolongation. At 1 year of follow-up, 31% had persistent QTc prolongation. In longitudinal analyses, the associations of iCa and K with QTc interval remained significant, and lower K was associated with a higher risk of QTc prolongation while the association of iCa with QTc prolongation was borderline statistically significant. Serum Mg, dCa or dK, and respective gradients were not associated with QTc interval or prolongation. Conclusion Prolonged QTc is very common in incident hemodialysis participants and persists over follow-up. Ionized Ca and K are consistently inversely associated with QTc prolongation, which suggests closer monitoring for a low calcium or potassium level to mitigate risk.

Objectives The goal of the study was to determine an association of cardiac ventricular substrate with thrombotic stroke (TS), cardioembolic stroke (ES) and intracerebral haemorrhage (ICH).Design Prospective cohort study.Setting The Atherosclerosis Risk in Communities (ARIC) study in 1987–1989 enrolled adults (45–64 years), selected as a probability sample from four US communities (Minneapolis, Minnesota; Washington, Maryland; Forsyth, North Carolina; Jackson, Mississippi). Visit 2 was in 1990–1992, visit 3 in 1993–1995, visit 4 in 1996–1998 and visit 5 in 2011–2013.Participants ARIC participants with analysable ECGs and no history of stroke were included (n=14 479; age 54±6 y; 55% female; 24% black). Ventricular substrate was characterised by cardiac memory, spatial QRS-T angle (QRS-Ta), sum absolute QRST integral (SAIQRST), spatial ventricular gradient magnitude (SVGmag), premature ventricular contractions (PVCs) and tachycardia-dependent intermittent bundle branch block (TD-IBBB) on 12-lead ECG at visits 1–5.Outcome Adjudicated TS included a first definite or probable thrombotic cerebral infarction, ES—a first definite or probable non-carotid cardioembolic brain infarction. Definite ICH was included if it was the only stroke event.Results Over a median 24.5 years follow-up, there were 899 TS, 400 ES and 120 ICH events. Cox proportional hazard risk models were adjusted for demographics, cardiovascular disease, risk factors, atrial fibrillation, atrial substrate and left ventricular hypertrophy. After adjustment, PVCs (HR 1.72; 95% CI 1.02 to 2.92), QRS-Ta (HR 1.15; 95% CI 1.03 to 1.28), SAIQRST (HR 1.20; 95% CI 1.07 to 1.34) and time-updated SVGmag (HR 1.19; 95% CI 1.08 to 1.32) associated with ES. Similarly, PVCs (HR 1.53; 95% CI 1.03 to 2.26), QRS-Ta (HR 1.08; 95% CI 1.01 to 1.16), SAIQRST (HR 1.07; 95% CI 1.01 to 1.14) and time-updated SVGmag (HR 1.11; 95% CI 1.04 to 1.19) associated with TS. TD-IBBB (HR 3.28; 95% CI 1.03 to 10.46) and time-updated SVGmag (HR 1.23; 95% CI 1.03 to 1.47) were associated with ICH.Conclusions PVC burden (reflected by cardiac memory) is associated with ischaemic stroke. Transient cardiac memory (likely through TD-IBBB) precedes ICH.

Objectives We hypothesised that (1) the prevalent cardiovascular disease (CVD) is associated with global electrical heterogeneity (GEH) after adjustment for demographic, anthropometric, socioeconomic and traditional cardiovascular risk factors, (2) there are sex differences in GEH and (3) sex modifies an association of prevalent CVD with GEH.Design Cross-sectional, cohort study.Setting Prospective African-American The Jackson Heart Study (JHS) with a nested family cohort in 2000–2004 enrolled residents of the Jackson, Mississippi metropolitan area.Participants Participants from the JHS with analysable ECGs recorded in 2009–2013 (n=3679; 62±12 y; 36% men; 863 family units). QRS, T and spatial ventricular gradient (SVG) vectors’ magnitude and direction, spatial QRS-T angle and sum absolute QRST integral (SAI QRST) were measured.Outcome Prevalent CVD was defined as the history of (1) coronary heart disease defined as diagnosed/silent myocardial infarction, or (2) revascularisation procedure defined as prior coronary/peripheral arterial revascularisation, or (3) carotid angioplasty/carotid endarterectomy, or (4) stroke.Results In adjusted mixed linear models, women had a smaller spatial QRS-T angle (−12.2 (95% CI −19.4 to -5.1)°; p=0.001) and SAI QRST (−29.8 (−39.3 to −20.3) mV*ms; p

BackgroundMechanisms of arrhythmogenicity in hypertrophic cardiomyopathy (HCM) are not well understood.ObjectiveTo characterize an electrophysiological substrate of HCM in comparison to ischemic cardiomyopathy (ICM), or healthy individuals.MethodsWe conducted a prospective case-control study. The study enrolled HCM patients at high risk for ventricular tachyarrhythmia (VT) [n = 10; age 61 ± 9 years; left ventricular ejection fraction (LVEF) 60 ± 9%], and three comparison groups: healthy individuals (n = 10; age 28 ± 6 years; LVEF > 70%), ICM patients with LV hypertrophy (LVH) and known VT (n = 10; age 64 ± 9 years; LVEF 31 ± 15%), and ICM patients with LVH and no known VT (n = 10; age 70 ± 7 years; LVEF 46 ± 16%). All participants underwent 12-lead ECG, cardiac CT or MRI, and 128-electrode body surface mapping (BioSemi ActiveTwo, Netherlands). Non-invasive voltage and activation maps were reconstructed using the open-source SCIRun (University of Utah) inverse problem-solving environment.ResultsIn the epicardial basal anterior segment, HCM patients had the greatest ventricular activation dispersion [16.4 ± 5.5 vs. 13.1 ± 2.7 (ICM with VT) vs. 13.8 ± 4.3 (ICM no VT) vs. 8.1 ± 2.4 ms (Healthy); P = 0.0007], the largest unipolar voltage [1094 ± 211 vs. 934 ± 189 (ICM with VT) vs. 898 ± 358 (ICM no VT) vs. 842 ± 90 μV (Healthy); P = 0.023], and the greatest voltage dispersion [median (interquartile range) 215 (161–281) vs. 189 (143–208) (ICM with VT) vs. 158 (109–236) (ICM no VT) vs. 110 (106–168) μV (Healthy); P = 0.041]. Differences were also observed in other endo-and epicardial basal and apical segments.ConclusionHCM is characterized by a greater activation dispersion in basal segments, a larger voltage, and a larger voltage dispersion through LV.Clinical Trial Registrationwww.clinicaltrials.gov Unique identifier: NCT02806479.

Background and Objectives: Patients with pre-existing cardiac disease have a higher prevalence of Obstructive Sleep Apnea (OSA). OSA has been associated with an increased risk of supraventricular and ventricular arrhythmia. We screened subjects with implanted pacemakers and automated implantable cardioverter defibrillators (AICD) for OSA with the Berlin Questionnaire and compared the incidence of ventricular arrhythmias and automated implantable cardioverter defibrillator (AICD) firing between high and low OSA risk groups. Materials and Methods: We contacted 648 consecutive patients from our arrhythmia clinic to participate in the study and performed final analyses on 171 subjects who consented and had follow-up data. Data were abstracted from the electronic health record for the incidence of non-sustained ventricular tachycardia (NSVT), ventricular tachycardia (VT), ventricular fibrillation (VF) and AICD firing and then compared between those at high versus low risk of OSA using the Berlin Questionnaire and multivariate negative binomial regression. Results: The average follow-up period was 24.2 ± 4.4 months. After adjusting for age, gender and history of heart failure, those subjects at high risk of OSA had a higher burden of NSVT vs. those with a low risk of OSA (33.4 ± 96.2 vs. 5.82 ± 17.1 episodes, p = 0.003). A predetermined subgroup analysis of AICD recipients also demonstrated a significantly higher burden of NSVT in the high vs. low OSA risk groups (66.2 ± 128.6 vs. 18.9 ± 36.7 episodes, p = 0.033). There were significant differences in the rates of VT, VF or AICD shock burden between the high and low OSA risk groups and in the AICD subgroup analysis. Conclusions: There was increased ventricular ectopy among pacemaker and AICD recipients at high risk of OSA, but the prevalence of VT, VF or AICD shocks was similar to those with low risk of OSA.

Background Race is an established risk factor for sudden cardiac death (SCD). We sought to determine whether the association of electrophysiological substrate with SCD varies between black and white individuals. Methods and Results Participants from the ARIC (Atherosclerosis Risk in Communities) study with analyzable ECGs (n=14 408; age, 54±6 years; 74% white) were included. Electrophysiological substrate was characterized by ECG metrics. Two competing outcomes were adjudicated: SCD and non‐SCD. Interaction of ECG metrics with race was studied in Cox proportional hazards and Fine‐Gray competing risk models, adjusted for prevalent cardiovascular disease, risk factors, and incident nonfatal cardiovascular disease. At the baseline visit, adjusted for age, sex, and study center, blacks had larger spatial ventricular gradient magnitude (0.30 mV; 95% CI, 0.25–0.34 mV), sum absolute QRST integral (18.4 mV*ms; 95% CI, 13.7–23.0 mV*ms), and Cornell voltage (0.30 mV; 95% CI, 0.25–0.35 mV) than whites. Over a median follow‐up of 24.4 years, SCD incidence was higher in blacks (2.86 per 1000 person‐years; 95% CI, 2.50–3.28 per 1000 person‐years) than whites (1.37 per 1000 person‐years; 95% CI, 1.22–1.53 per 1000 person‐years). Blacks with hypertension had the highest rate of SCD: 4.26 (95% CI, 3.66–4.96) per 1000 person‐years. Race did not modify an association of ECG variables with SCD, except QRS‐T angle. Spatial QRS‐T angle was associated with SCD in whites (hazard ratio, 1.38; 95% CI, 1.25–1.53) and hypertension‐free blacks (hazard ratio, 1.52; 95% CI, 1.09–2.12), but not in blacks with hypertension (hazard ratio, 1.15; 95% CI, 0.99–1.32) (P‐interaction=0.004). Conclusions Race did not modify associations of electrophysiological substrate with SCD and non‐SCD. Electrophysiological substrate does not explain racial disparities in SCD rate.

Background In patients with end‐stage kidney disease, sudden cardiac death is more frequent after a long interdialytic interval, within 6 hours after the end of a hemodialysis session. We hypothesized that the occurrence of paroxysmal arrhythmias is associated with changes in heart rate and heart rate variability in different phases of hemodialysis. Methods and Results We conducted a prospective ancillary study of the Predictors of Arrhythmic and Cardiovascular Risk in End Stage Renal Disease cohort. Continuous ECG monitoring was performed using an ECG patch, and short‐term heart rate variability was measured for 3 minutes every hour (by root mean square of the successive normal‐to‐normal intervals, spectral analysis, Poincaré plot, and entropy), up to 300 hours. Out of enrolled participants (n=28; age 54±13 years; 57% men; 96% black; 33% with a history of cardiovascular disease; left ventricular ejection fraction 70±9%), arrhythmias were detected in 13 (46%). Nonsustained ventricular tachycardia occurred more frequently during/posthemodialysis than pre‐/between hemodialysis (63% versus 37%, P=0.015). In adjusted for cardiovascular disease time‐series analysis, nonsustained ventricular tachycardia was preceded by a sudden heart rate increase (by 11.2 [95% CI 10.1–12.3] beats per minute; P

Background Hypertension is a known risk factor for heart failure (HF), possibly via the mechanism of cardiac remodeling and left ventricular hypertrophy (LVH). We studied the extent to which blood pressure (BP) change and evolving LVH contribute to the effect that lisinopril, doxazosin, and amlodipine have on HF compared with chlorthalidone. Methods and Results We conducted causal mediation analysis of ALLHAT (Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial) data (1994‐2002; in‐trial follow‐up). ALLHAT participants with available serial ECGs and BP measurements were included (n=29 892; mean age 67±4 years; 32% black; 56% men): 11 008 were randomized to chlorthalidone, 5967 to doxazosin, 6593 to amlodipine, and 6324 to lisinopril. Evolving ECG LVH and BP lowering served as mediators. Incident symptomatic HF was the primary outcome. Linear regression (for mediator) and logistic regression (for outcome) models were adjusted for mediator‐outcome confounders (demographic and clinical characteristics known to be associated both with both LVH/hypertension and HF). A large majority of participants (96%) had ECG LVH status unchanged, but 4% developed evolving ECG LVH. On average, BP decreased by 11/7 mm Hg. In adjusted Cox regression analyses, progressing ECG LVH (hazard ratio [HR] 1.78 [95% CI 1.43‐2.22]), resolving ECG LVH (HR 1.33 [95% CI 1.03‐1.70]), and baseline ECG LVH (1.17 [95% CI 1.04‐1.31]) carried risk of incident HF. After full adjustment, evolving ECG LVH mediated 4% of the effect of doxazosin on HF. Systolic BP lowering mediated 12% of the effect of doxazosin, and diastolic BP lowering mediated 10% of the effect of doxazosin, 7% of the effect of amlodipine, and borderline 9% of the effect of lisinopril on HF. Conclusions Evolving ECG LVH and BP change account for 4% to 13% of the mechanism by which antihypertensive medications prevent HF. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000542.

BackgroundECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genome‐wide association study would identify genetic loci related to GEH. Methods and ResultsWe tested genotyped and imputed variants in black (N=3057) and white (N=10 769) participants in the ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study). GEH (QRS‐T angle, sum absolute QRST integral, spatial ventricular gradient magnitude, elevation, azimuth) was measured on 12‐lead ECGs. Linear regression models were constructed with each GEH variable as an outcome, adjusted for age, sex, height, body mass index, study site, and principal components to account for ancestry. GWAS identified 10 loci that showed genome‐wide significant association with GEH in whites or joint ancestry. The strongest signal (rs7301677, near TBX3) was associated with QRS‐T angle (white standardized β+0.16 [95% CI 0.13–0.19]; P=1.5×10−26), spatial ventricular gradient elevation (+0.11 [0.08–0.14]; P=2.1×10−12), and spatial ventricular gradient magnitude (−0.12 [95% CI −0.15 to −0.09]; P=5.9×10−15). Altogether, GEH‐SNPs explained 1.1% to 1.6% of GEH variance. Loci on chromosomes 4 (near HMCN2), 5 (IGF1R), 11 (11p11.2 region cluster), and 7 (near ACTB) are novel ECG phenotype‐associated loci. Several loci significantly associated with gene expression in the left ventricle (HMCN2 locus—with HMCN2; IGF1R locus—with IGF1R), and atria (RP11‐481J2.2 locus—with expression of a long non‐coding RNA and NDRG4). ConclusionsWe identified 10 genetic loci associated with ECG GEH. Replication of GEH GWAS findings in independent cohorts is warranted. Further studies of GEH‐loci may uncover mechanisms of arrhythmogenic remodeling in response to cardiovascular risk factors.

BackgroundA few studies have recently reported clockwise and counterclockwise rotations of QRS transition zone as predictors of mortality. However, their prospective correlates and associations with individual cardiovascular disease (CVD) outcomes are yet to be investigated. Methods and ResultsAmong 13 567 ARIC (Atherosclerosis Risk in Communities) study participants aged 45 to 64 years, we studied key correlates of changes in the status of clockwise and counterclockwise rotation over time as well as the association of rotation status with incidence of coronary heart disease (2408 events), heart failure (2196 events), stroke (991 events), composite CVD (4124 events), 898 CVD deaths, and 3469 non‐CVD deaths over 23 years of follow‐up. At baseline, counterclockwise rotation was most prevalent (52.9%), followed by no (40.5%) and clockwise (6.6%) rotation. Of patients with no rotation, 57.9% experienced counterclockwise or clockwise rotation during follow‐up, with diabetes mellitus and black race significantly predicting clockwise and counterclockwise conversion, respectively. Clockwise rotation was significantly associated with higher risk of heart failure (hazard ratio, 1.20; 95% confidence interval [CI], 1.02–1.41) and non‐CVD death (hazard ratio, 1.28; 95% CI, 1.12–1.46) after adjusting for potential confounders including other ECG parameters. On the contrary, counterclockwise rotation was significantly related to lower risk of composite CVD (hazard ratio, 0.93; 95% CI, 0.87–0.99]), CVD mortality (hazard ratio, 0.76; 95% CI, 0.65–0.88), and non‐CVD deaths (hazard ratio, 0.92; 95% CI, 0.85–0.99 [borderline significance with heart failure]). ConclusionsCounterclockwise rotation, the most prevalent QRS transition zone pattern, demonstrated the lowest risk of CVD and mortality, whereas clockwise rotation was associated with the highest risk of heart failure and non‐CVD mortality. These results have implications on how to interpret QRS transition zone rotation when ECG was recorded.