Sum Absolute QRST Integral Research Articles

Latent profiles of global electrical heterogeneity: the Hispanic Community Health Study/Study of Latinos.

Despite the highest prevalence of stroke, obesity, and diabetes across races/ethnicities, paradoxically, Hispanic/Latino populations have the lowest prevalence of atrial fibrillation and major Minnesota code-defined ECG abnormalities. We aimed to use Latent Profile Analysis in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) population to obtain insight into epidemiological discrepancies. We conducted a cross-sectional analysis of baseline HCHS/SOL visit. Global electrical heterogeneity (GEH) was measured as spatial QRS-T angle (QRSTa), spatial ventricular gradient azimuth (SVGaz), elevation (SVGel), magnitude (SVGmag), and sum absolute QRST integral (SAIQRST). Statistical analysis accounted for the stratified two-stage area probability sample design. We fitted a multivariate latent profile generalized structural equation model adjusted for age, sex, ethnic background, education, hypertension, diabetes, smoking, dyslipidaemia, obesity, chronic kidney disease, physical activity, diet quality, average RR' interval, median beat type, and cardiovascular disease (CVD) to gain insight into the GEH profiles. Among 15 684 participants (age 41 years; 53% females; 6% known CVD), 17% had an increased probability of likely abnormal GEH profile (QRSTa 80 ± 27°, SVGaz -4 ± 21°, SVGel 72 ± 12°, SVGmag 45 ± 12 mVms, and SAIQRST 120 ± 23 mVms). There was a 23% probability for a participant of being in Class 1 with a narrow QRSTa (40.0 ± 10.2°) and large SVG (SVGmag 108.3 ± 22.6 mVms; SAIQRST 203.4 ± 39.1 mVms) and a 60% probability of being in intermediate Class 2. A substantial proportion (17%) in the Hispanic/Latino population had an increased probability of altered, likely abnormal GEH profile, whereas 83% of the population was resilient to harmful risk factors exposures.

Competing risks of monomorphic vs. non-monomorphic ventricular arrhythmias in primary prevention implantable cardioverter-defibrillator recipients: Global Electrical Heterogeneity and Clinical Outcomes (GEHCO) study.

Ablation of monomorphic ventricular tachycardia (MMVT) has been shown to reduce shock frequency and improve survival. We aimed to compare cause-specific risk factors for MMVT and polymorphic ventricular tachycardia (PVT)/ventricular fibrillation (VF) and to develop predictive models. The multicentre retrospective cohort study included 2668 patients (age 63.1 ± 13.0 years; 23% female; 78% white; 43% non-ischaemic cardiomyopathy; left ventricular ejection fraction 28.2 ± 11.1%). Cox models were adjusted for demographic characteristics, heart failure severity and treatment, device programming, and electrocardiogram metrics. Global electrical heterogeneity was measured by spatial QRS-T angle (QRSTa), spatial ventricular gradient elevation (SVGel), azimuth, magnitude (SVGmag), and sum absolute QRST integral (SAIQRST). We compared the out-of-sample performance of the lasso and elastic net for Cox proportional hazards and the Fine-Gray competing risk model. During a median follow-up of 4 years, 359 patients experienced their first sustained MMVT with appropriate implantable cardioverter-defibrillator (ICD) therapy, and 129 patients had their first PVT/VF with appropriate ICD shock. The risk of MMVT was associated with wider QRSTa [hazard ratio (HR) 1.16; 95% confidence interval (CI) 1.01-1.34], larger SVGel (HR 1.17; 95% CI 1.05-1.30), and smaller SVGmag (HR 0.74; 95% CI 0.63-0.86) and SAIQRST (HR 0.84; 95% CI 0.71-0.99). The best-performing 3-year competing risk Fine-Gray model for MMVT [time-dependent area under the receiver operating characteristic curve (ROC(t)AUC) 0.728; 95% CI 0.668-0.788] identified high-risk (> 50%) patients with 75% sensitivity and 65% specificity, and PVT/VF prediction model had ROC(t)AUC 0.915 (95% CI 0.868-0.962), both satisfactory calibration. We developed and validated models to predict the competing risks of MMVT or PVT/VF that could inform procedural planning and future randomized controlled trials of prophylactic ventricular tachycardia ablation. URL:www.clinicaltrials.gov Unique identifier:NCT03210883.

Reproducibility of global electrical heterogeneity measurements on 12-lead ECG: The Multi-Ethnic Study of Atherosclerosis

ObjectiveVectorcardiographic (VCG) global electrical heterogeneity (GEH) metrics showed clinical usefulness. We aimed to assess the reproducibility of GEH metrics. MethodsGEH was measured on two 10-s 12‑lead ECGs recorded on the same day in 4316 participants of the Multi-Ethnic Study of Atherosclerosis (age 69.4 ± 9.4 y; 2317(54%) female, 1728 (40%) white, 1138(26%) African-American, 519(12%) Asian-American, 931(22%) Hispanic-American). GEH was measured on a median beat, comprised of the normal sinus (N), atrial fibrillation/flutter (S), and ventricular-paced (VP) beats. Spatial ventricular gradient's (SVG's) scalar was measured as sum absolute QRST integral (SAIQRST) and vector magnitude QT integral (VMQTi). ResultsTwo N ECGs with heart rate (HR) bias of −0.64 (95% limits of agreement [LOA] -5.68 to 5.21) showed spatial area QRS-T angle (aQRST) bias of −0.12 (95%LOA −14.8 to 14.5). Two S ECGs with HR bias of 0.20 (95%LOA −15.8 to 16.2) showed aQRST bias of 1.37 (95%LOA −33.2 to 35.9). Two VP ECGs with HR bias of 0.25 (95%LOA −3.0 to 3.5) showed aQRST bias of −1.03 (95%LOA −11.9 to 9.9). After excluding premature atrial or ventricular beat and two additional beats (before and after extrasystole), the number of cardiac beats included in a median beat did not affect the GEH reproducibility. Mean-centered log-transformed values of SAIQRST and VMQTi demonstrated perfect agreement (Bias 0; 95%LOA −0.092 to 0.092). ConclusionGEH measurements on N, S, and VP median beats are reproducible. SVG's scalar can be measured as either SAIQRST or VMQTi. SignificanceSatisfactory reproducibility of GEH metrics supports their implementation.

Electrophysiological ventricular substrate of stroke: a prospective cohort study in the Atherosclerosis Risk in Communities (ARIC) study

ObjectivesThe goal of the study was to determine an association of cardiac ventricular substrate with thrombotic stroke (TS), cardioembolic stroke (ES) and intracerebral haemorrhage (ICH).DesignProspective cohort study.SettingThe Atherosclerosis Risk in...

Competing risks in patients with primary prevention implantable cardioverter-defibrillators: Global Electrical Heterogeneity and Clinical Outcomes study

Global electrical heterogeneity (GEH) is associated with sudden cardiac death in the general population. Its utility in patients with systolic heart failure who are candidates for primary prevention (PP) implantable cardioverter-defibrillators (ICDs) is unclear. The purpose of this study was to investigate whether GEH is associated with sustained ventricular tachycardia/ventricular fibrillation leading to appropriate ICD therapies in patients with heart failure and PP ICDs. We conducted a multicenter retrospective cohort study. GEH was measured by spatial ventricular gradient (SVG) direction (azimuth and elevation) and magnitude, QRS-T angle, and sum absolute QRST integral on preimplant 12-lead electrocardiograms. Survival analysis using cause-specific hazard functions compared the strength of associations with 2 competing outcomes: sustained ventricular tachycardia/ventricular fibrillation leading to appropriate ICD therapies and all-cause death without appropriate ICD therapies. We analyzed 2668 patients (mean age 63 ± 12 years; 624 (23%) female; 78% white; 43% nonischemic cardiomyopathy; left ventricular ejection fraction 28% ± 11% from 6 academic medical centers). After adjustment for demographic, clinical, device, andtraditional electrocardiographic characteristics, SVG elevation (hazard ratio [HR] per 1SD 1.14; 95% confidence interval [CI] 1.04-1.25; P = .004), SVG azimuth (HR per 1SD 1.12; 95% CI 1.01-1.24; P = .039), SVG magnitude (HR per 1SD 0.75; 95% CI0.66-0.85; P < .0001), and QRS-T angle (HR per 1SD 1.21; 95% CI 1.08-1.36; P = .001) were associated with appropriate ICD therapies. Sum absolute QRST integral had different associations in infarct-related cardiomyopathy (HR 1.29; 95% CI 1.04-1.60) and nonischemic cardiomyopathy (HR 0.78; 95% CI 0.62-0.96) (Pinteraction = .022). In patients with PP ICDs, GEH is independently associated with appropriate ICD therapies. The SVG vector points in distinctly different directions in patients with 2 competing outcomes.

Does sex modify an association of electrophysiological substrate with sudden cardiac death? The Atherosclerosis Risk in Communities (ARIC) study

BackgroundSex is a well-recognized risk factor for sudden cardiac death (SCD). We hypothesized that sex modifies the association of electrophysiological (EP) substrate with SCD.ObjectiveThe 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.MethodsParticipants 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.ResultsOver 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.ConclusionIn 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.

P5645Lifetime sex-specific sudden cardiac death prediction using ECG global electrical heterogeneity: the atherosclerosis risk in communities (ARIC) study

Abstract Background Sex-based differences in sudden cardiac death (SCD) exist and screening methods for SCD are inadequate. Purpose To develop sex-specific lifetime risk prediction models using electrocardiographic (ECG) global electrical heterogeneity (GEH) and clinical characteristics. Methods Participants from the Atherosclerosis Risk in Communities study with analyzable ECGs (n=14,725; age, 54.2±5.8 yrs; 55% female, 74% white) were followed up for 24.4 years (median). Traditional ECG and GEH variables were measured on 12-lead ECGs. A Cox regression model was used to develop a prediction model. In women, the final model included race, age, coronary heart disease (CHD), stroke, hypertension, diabetes, smoking, high-density lipoprotein, albumin, uric acid, education level, heart rate, QTc, sum absolute QRST integral, spatial peak QRS-T angle. In men, the final prediction model included age, race, CHD, stroke, hypertension, diabetes, total cholesterol, physical activity, smoking, serum phosphorus, albumin, chronic kidney disease, spatial area QRS-T angle, area spatial ventricular gradient (SVG) elevation and magnitude, and peak SVG magnitude. Results There were a total of 530 SCDs. Our prediction models showed robust prediction of SCD in both sexes [(Harrell's C-statistic women 0.863 (95% CI 0.845–0.882), men 0.786 (95% CI 0.786–0.803)]. In women when ECG and GEH variables were added to clinical variables, the net reclassification improved by 9% (P=0.001) (Table). In men there was no significant reclassification improvement. Net reclassification Lifetime SCD Risk: Clinical + ECG + GEH Variables Women Men &lt;5% 5–15% &gt;15% Total &lt;5% 5–15% &gt;15% Total SCD Cases &lt;5% 82 14 0 96 103 16 0 119 5–15% 7 59 10 76 12 116 12 140 &gt;15% 0 0 20 20 0 5 74 79 Lifetime SCD Risk: Total 89 73 30 192 115 137 86 338 Clinical Variables Only Non-Cases &lt;5% 6,956 131 2 7,089 4,411 264 0 4,675 5–15% 180 509 42 731 210 1,059 48 1,317 &gt;15% 0 28 84 112 0 56 214 270 Total 7,136 668 128 7,932 4,621 1,379 262 6,262 Conclusions We were the first to develop sex-specific lifetime SCD prediction models. The addition of ECG GEH to clinical variables improved SCD risk reclassification in women, but not in men. Prediction of SCD was more accurate in women as compared to men.

Changes in global electrical heterogeneity associated with dofetilide, quinidine, ranolazine, and verapamil

Electrocardiographic (ECG) markers of antiarrhythmic drug (AAD) activity could be used to optimize efficacy and minimize toxicity. Vectorcardiographic global electrical heterogeneity (GEH) is associated with ventricular arrhythmias and sudden death, but it is unclear how GEH measurements change in response to AADs. The purpose of this study was to characterize acute effects of AADs on GEH measurements. We analyzed double-blind placebo-controlled trial data from healthy volunteers given 1 dose of placebo, dofetilide, quinidine, ranolazine, or verapamil on subsequent visits. Serial ECGs and plasma drug concentrations were collected. Vectorcardiographic GEH parameters (spatial ventricular gradient [SVG], spatial QRST angle, sum absolute QRST integral, and SVG-QRS peak angle) were measured. Placebo-corrected change from baseline was regressed on drug concentration stratified by sex using linear mixed effects models. Among 22 persons (11 (50%) male median age 27 ± 5 years), 5232 ECGs were analyzed. Dofetilide and quinidine were associated with significant changes in more GEH parameters (5) compared with verapamil (2) and ranolazine (1). The most notable change occurred in SVG azimuth, with largest changes (degrees per unit normalized drug concentration) in dofetilide (6.1; 95% confidence interval [CI] 4.2-8.0) and quinidine (9.4; 95% CI 6.7-12.0), and smaller effects in verapamil (4.4; 95% CI 2.9-5.9) and ranolazine (5.4; 95% CI 3.5-7.3). AAD-induced GEH changes significantly differed in men and women. AADs change GEH measurements. These changes, which differ by sex, are likely driven by alterations in ion channel function and dispersion of depolarization or repolarization. GEH measurement may allow early assessment of favorable or adverse AAD effects.

The Reproducibility of Global Electrical Heterogeneity ECG Measurements.

Global electrical heterogeneity (GEH) is a useful predictor of adverse clinical outcomes. However, reproducibility of GEH measurements on 10-second routine clinical ECG is unknown. Data of the prospective cohort study of incident hemodialysis patients (n=253; mean age 54.6±13.5y; 56% male; 79% African American) were analysed. Two random 10-second segments of 5-minute ECG recording in sinus rhythm were compared. GEH was measured as spatial QRS-T angle, spatial ventricular gradient (SVG) magnitude and direction (azimuth and elevation), and a scalar value of SVG measured by (1) sum absolute QRST integral (SAI QRST), and (2) QT integral on vector magnitude signal (iVMQT). Bland-Altman analysis was used to calculate agreement. For all studied vectorcardiographic metrics, agreement was substantial (Lin's concordance coefficient >0.98), and precision was perfect (>99.99%). 95% limits of agreement were ±14° for spatial QRS-T angle, ±13° for SVG azimuth, ±4° for SVG elevation, ±14 mV*ms for SVG magnitude, and ±17 mV*ms for SAI QRST. SAI QRST and iVMQT were in substantial agreement with each other. Reproducibility of a 10-second automated GEH ECG measurements was substantial, and precision was perfect.

Importance of the heart vector origin point definition for an ECG analysis: The Atherosclerosis Risk in Communities (ARIC) study

AimOur goal was to investigate the effect of a global XYZ median beat construction and the heart vector origin point definition on predictive accuracy of ECG biomarkers of sudden cardiac death (SCD). MethodsAtherosclerosis Risk In Community study participants with analyzable digital ECGs were included (n = 15,768; 55% female, 73% white, mean age 54.2 ± 5.8 y). We developed an algorithm to automatically detect the heart vector origin point on a median beat. Three different approaches to construct a global XYZ beat and two methods to locate origin point were compared. Global electrical heterogeneity was measured by sum absolute QRST integral (SAI QRST), spatial QRS-T angle, and spatial ventricular gradient (SVG) magnitude, azimuth, and elevation. Adjudicated SCD served as the primary outcome. ResultsThere was high intra-observer (kappa 0.972) and inter-observer (kappa 0.984) agreement in a heart vector origin definition between an automated algorithm and a human. QRS was wider in a median beat that was constructed using R-peak alignment than in time-coherent beat (88.1 ± 16.7 vs. 83.7 ± 15.9 ms; P < 0.0001), and on a median beat constructed using QRS-onset as a zeroed baseline, vs. isoelectric origin point (86.7 ± 15.9 vs. 83.7 ± 15.9 ms; P < 0.0001). ROC AUC was significantly larger for QRS, QT, peak QRS-T angle, SVG elevation, and SAI QRST if measured on a time-coherent median beat, and for SAI QRST and SVG magnitude if measured on a median beat using isoelectric origin point. ConclusionTime-coherent global XYZ median beat with physiologically meaningful definition of the heart vector's origin point improved predictive accuracy of SCD biomarkers.

Vectorcardiographic QRS area is associated with long-term outcome after cardiac resynchronization therapy

Recent studies have suggested that vectorcardiographic measures predict left ventricular (LV) reverse remodeling and clinical outcome in patients receiving cardiac resynchronization therapy (CRT). The objectives of this study were to compare predictive abilities of different vectorcardiographic measures (QRS area and sum absolute QRS-T integral) and transformation methods (Kors and inverse Dower) and to assess the independent association between the best predictor and outcomes in CRT recipients. This retrospective study included CRT recipients with a digital baseline electrocardiogram, QRS duration ≥120 ms, and ejection fraction ≤35%. The end point was a composite of heart transplantation, LV assist device implantation, or all-cause death. Analyses were performed for the overall cohort and for a prespecified subgroup of patients with left bundle branch block (LBBB). Of 705 included patients with a mean age of 66.6 ± 11.5 years, 492 (70%) were men, 374 (53%) had ischemic heart disease, and 465 (66%) had LBBB. QRS area from vectorcardiograms derived via the Kors transformation demonstrated the best predictive value. In multivariable Cox regression, patients with a smaller QRS area (≤95 μVs) had an increased hazard in the overall cohort (adjusted hazard ratio 1.65; 95% CI 1.25-2.18 P < .001) and in the LBBB subgroup (adjusted hazard ratio 1.95; 95% CI 1.38-2.76 P < .001). QRS area was associated with outcome in patients with QRS duration <150 ms (unadjusted hazard ratio 3.85; 95% CI 2.02-7.37 P<.001) and in patients with QRS duration ≥150 ms (unadjusted hazard ratio 1.76; 95% CI 1.32-2.34 P < .001). Vectorcardiographic QRS area is associated with survival free from heart transplantation and LV assist device implantation in CRT recipients.

Baseline adverse electrical remodeling and the risk for ventricular arrhythmia in Cardiac Resynchronization Therapy Recipients (MADIT CRT).

Adverse electrical remodeling (AER), represented here as the sum absolute QRST integral (SAI QRST), has previously been shown to be directly associated with the risk for ventricular arrhythmia (VA). Cardiac resynchronization therapy (CRT) is known to reduce the risk for VA through various mechanisms, including reverse remodeling, and we aimed to evaluate the association between baseline AER and the risk for VA in CRT recipients. The study population comprised 961 CRT-D implanted patients from the MADIT CRT study. The relationship between SAI QRST, VA risk, and VA risk/death was evaluated as a continuous and as a categorical variable-tertiles (T1 ≤ 0.527, T2 0.528-0.766, T3>0.766). In a multivariable model, AER was inversely associated with the risk of VA. Each unit increase in SAI QRST was associated with 64% (P=0.007) and 54% (P=0.003) decrease in the risk of VA and VA/death, respectively. Patients with high SAI QRST (T3) and medium SAI QRST (T2) had 52% (P<0.001) and 32% (P=0.027) reduced risk for VA and 44% (P=0.002) and 26% (P=0.055) reduced risk for VA/death as compared with patients with low SAI QRST (T1), respectively. In CRT implanted patients with mild heart failure, baseline AER was inversely associated with the risk for VA and VA/death; this is a finding that contradicts the relationship previously reported in non-CRT implanted patients. We theorize that CRT may abate the process of AER; however, characterization of this mechanism requires further study.

Genome-Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study).

Background ECG 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.

Improving sudden cardiac death risk stratification by evaluating electrocardiographic measures of global electrical heterogeneity and clinical outcomes among patients with implantable cardioverter-defibrillators: rationale and design for a retrospective, multicenter, cohort study.

Implantable cardioverter-defibrillators (ICDs) improve survival of systolic heart failure (HF) patients who are at risk of sudden cardiac death (SCD). We recently showed that electrocardiographic (ECG) global electrical heterogeneity (GEH) is independently associated with SCD in the community-dwelling cohort and developed GEH SCD risk score. The Global Electrical Heterogeneity and Clinical Outcomes (GEHCO) study is a retrospective multicenter cohort designed with two goals: (1) validate an independent association of ECG GEH with sustained ventricular tachyarrhythmias and appropriate ICD therapies and (2) validate GEH ECG risk score for prediction of sustained ventricular tachyarrhythmias and appropriate ICD therapies in systolic HF patients with primary prevention ICD. All records of primary prevention ICD recipients with available data for analysis are eligible for inclusion. Records of ICD implantation in patients with inherited channelopathies and cardiomyopathies are excluded. Raw digital 12-lead pre-implant ECGs will be used to measure GEH (spatial QRST angle, spatial ventricular gradient magnitude, azimuth, and elevation, and sum absolute QRST integral). The primary endpoint is defined as a sustained ventricular tachyarrhythmia event with appropriate ICD therapy. All-cause death without preceding sustained ventricular tachyarrhythmia with appropriate ICD therapy will serve as a primary competing outcome. The study will draw data from the academic medical centers. We describe the study protocol of the first multicenter retrospective cohort of primary prevention ICD patients with recorded at baseline digital 12-lead ECG. Findings from this study will inform future trials to identify patients who are most likely to benefit from primary prevention ICD. URL: http://www.clinicaltrials.gov . Unique identifier: NCT03210883.

Global ECG Measures and Cardiac Structure and Function: The ARIC Study (Atherosclerosis Risk in Communities).

Electric excitation initiates myocardial mechanical contraction and coordinates myocardial pumping. We hypothesized that ECG global electric heterogeneity (GEH) and its longitudinal changes are associated with cardiac structure and function. Participants from the ARIC study (Atherosclerosis Risk in Communities) (N=5114; 58% female; 22% blacks) with resting 12-lead ECGs (visits 1-5) and echocardiographic assessment of left ventricular (LV) ejection fraction, LV global longitudinal strain, LV mass index, LV end-diastolic volume index, and LV end-systolic volume index at visit 5 were included. Longitudinal analysis included ARIC participants (N=14 609) with measured GEH at visits 1 to 4. GEH was quantified by spatial ventricular gradient, QRS-T angle, and sum absolute QRS-T integral. Cross-sectional and longitudinal regressions were adjusted for manifest and subclinical cardiovascular disease. Having 4 abnormal GEH parameters was associated with a 6.4% (95% confidence interval, 5.5-7.3) LV ejection fraction decline, a 24.2 g/m2 (95% confidence interval, 21.5-26.9) increase in LV mass index, a 10.3 mL/m2 (95% confidence interval, 8.9-11.7) increase in LV end-diastolic volume index, and a 7.8 mL/m2 (95% confidence interval, 6.9-8.6) increase in LV end-systolic volume index. Altogether, clinical and ECG parameters accounted for approximately one third of LV volume and 20% of systolic function variability. The associations were significantly stronger in cardiovascular disease. Sum absolute QRS-T integral increased by 20 mV*ms for each 3-year period in participants who demonstrated LV dilatation at visit 5. Sudden cardiac death victims demonstrated rapid GEH worsening, whereas those with LV dysfunction demonstrated slow GEH worsening. Healthy aging was associated with a distinct pattern of spatial ventricular gradient azimuth decrement. GEH is a marker of subclinical abnormalities in cardiac structure and function.

Abstract 12990: Genome-wide Associations of Global Electrical Heterogeneity ECG Phenotype: The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies

Introduction: Abnormal myocardial electrophysiological substrate quantified by global electrical heterogeneity (GEH) is independently associated with sudden cardiac death in the general population. The genetic basis of GEH has not been previously studied. Hypothesis: We hypothesized that a genome-wide association study (GWAS) would identify genetic loci related to GEH. Methods: We tested 22-26 million genotyped and imputed variants in African American (AA, N=3,378) and European American (EA, N=12,802) participants in the Atherosclerosis Risk in Communities and Cardiovascular Health Study cohorts. Five ECG markers of GEH (sum absolute QRST integral (SAI), spatial QRST angle (QRSTA), and spatial ventricular gradient (SVG) magnitude (SVGmag), elevation (SVGel), and azimuth (SVGaz)) were measured on standard 12-lead ECGs. Adjusted linear regression models were constructed with each GEH parameter as an outcome. Results: Ten significant susceptibility loci with 17 SNPs were identified. Multiple GEH parameters were associated with identical SNPs. A low frequency polymorphism (minor allele frequency 0.02) of SCN5A (rs7638275) was strongly associated with SAI (βGWAS -0.30; P=8.71x10 -11 in EA; P=3.49x10 -11 in combined EA/AA). QRSTA, SVGmag, SVGel, and SVGaz were associated with 9 loci, including transcriptional factors ( TBX3, HAND1, NFIA ), implicated in fetal gene program, facilitating molecular remodeling in response to stress. Our strongest association (rs7301677), associated with QRSTA (β GWAS 0.16; P=1.46x10 -26 in the combined EA/AA), was previously reported associated with QRS duration and PR interval, and mapped near the TBX3 gene, which plays a critical role in cardiac conduction system development. Both SAI (P=2.21x10 -10 ) and SVGmag (P=2.40x10 -09 ) were associated with rs7029396 (β GWAS 0.09 in combined EA/AA), mapped near the NCS1 gene, which plays a role in CaMKII-dependent cardiac hypertrophy. SAI was associated with 5 loci; genes in these loci included transcription factors ACTB, SPI-1, IGF1R, GINS3 , and LUZP1 , implicated in cardiac hypertrophy. Conclusions: We identified 10 genetic loci associated with ECG manifestation of GEH. There is a strong association between GEH and genetic signals for molecular remodeling.

195 - Dynamic Changes in High Sensitivity Cardiac Troponin I are Associated with Dynamic Changes in Sum Absolute QRST Integral on Surface Electrocardiogram in Acute Decompensated Heart Failure

Background A three-dimensional electrocardiographic (ECG) metric, the sum absolute QRST integral (SAI QRST), predicts ventricular arrhythmias in heart failure (HF) patients with implantable cardioverter defibrillator and mechanical response to cardiac resynchronization therapy. We hypothesized that there is an association between patient-specific changes in SAI QRST and myocardial injury as measured by high-sensitivity troponin I (hsTnI). Methods Sum absolute integral QRST on resting 12-lead ECG and hsTnI were measured simultaneously, every 3 hours, and during 12-hour observation period in a prospective cohort of emergency department patients (n = 398; mean age 57.8 ± 13.2 years; 54% female, 64% black), diagnosed with acute coronary syndrome (ACS, n = 28), acutely decompensated HF (acute decompensated heart failure, n = 35), cardiac non-ACS (n = 19), or noncardiac condition (n = 316). Random-effects linear regression analysis assessed the association of SAI QRST and myocardial injury, with adjustment for demographics (age, sex, race), prevalent cardiovascular disease (myocardial infarction, history of revascularization, stroke, and HF), risk factors (diabetes, smoking, hypercholesterolemia, hypertension, and cocaine use), and left bundle branch block. Results Within the entire cohort, SAI QRST decreased by 3 (95%CI −5 to −1) mV*ms every 3 hours. A 10-fold increase in hsTnI was associated with a 7.7 (0.6–14.9) mV*ms increase in SAI QRST. In the subgroup of acutely decompensated HF patients (n = 35), a 10-fold increase in hsTnI was associated with a 61.0 (5.9–116.1) mV*ms increase in SAI QRST. Conclusion Patient-specific time-varying changes in the surface ECG scalar measure of global electrical heterogeneity, as measured by SAI QRST, and in myocardial injury as measured by hsTnI, are independently and directly associated with each other, likely reflecting a common underlying mechanism.

Global Electric Heterogeneity Risk Score for Prediction of Sudden Cardiac Death in the General Population: The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health (CHS) Studies.

Asymptomatic individuals account for the majority of sudden cardiac deaths (SCDs). Development of effective, low-cost, and noninvasive SCD risk stratification tools is necessary. Participants from the Atherosclerosis Risk in Communities study and Cardiovascular Health Study (n=20 177; age, 59.3±10.1 years; age range, 44-100 years; 56% female; 77% white) were followed up for 14.0 years (median). Five ECG markers of global electric heterogeneity (GEH; sum absolute QRST integral, spatial QRST angle, spatial ventricular gradient [SVG] magnitude, SVG elevation, and SVG azimuth) were measured on standard 12-lead ECGs. Cox proportional hazards and competing risks models evaluated associations between GEH electrocardiographic parameters and SCD. An SCD competing risks score was derived from demographics, comorbidities, and GEH parameters. SCD incidence was 1.86 per 1000 person-years. After multivariable adjustment, baseline GEH parameters and large increases in GEH parameters over time were independently associated with SCD. Final SCD risk scores included age, sex, race, diabetes mellitus, hypertension, coronary heart disease, stroke, and GEH parameters as continuous variables. When GEH parameters were added to clinical/demographic factors, the C statistic increased from 0.777 to 0.790 (P=0.008), the risk score classified 10-year SCD risk as high (>5%) in 7.2% of participants, 10% of SCD victims were appropriately reclassified into a high-risk category, and only 1.4% of SCD victims were inappropriately reclassified from high to intermediate risk. The net reclassification index was 18.3%. Abnormal electrophysiological substrate quantified by GEH parameters is independently associated with SCD in the general population. The addition of GEH parameters to clinical characteristics improves SCD risk prediction.

Dynamic Changes in High-Sensitivity Cardiac Troponin I Are Associated with Dynamic Changes in Sum Absolute QRST Integral on Surface Electrocardiogram in Acute Decompensated Heart Failure.

A three-dimensional electrocardiographic (ECG) metric, the sum absolute QRST integral (SAI QRST), predicts ventricular arrhythmias in heart failure (HF) patients with implantable cardioverter defibrillator and mechanical response to cardiac resynchronization therapy. We hypothesized that there is an association between patient-specific changes in SAI QRST and myocardial injury as measured by high-sensitivity troponin I (hsTnI). Sum absolute integral QRST on resting 12-lead ECG and hsTnI were measured simultaneously, every 3 hours, and during 12-hour observation period in a prospective cohort of emergency department patients (n = 398; mean age 57.8 ± 13.2 years; 54% female, 64% black), diagnosed with acute coronary syndrome (ACS, n = 28), acutely decompensated HF (acute decompensated heart failure, n = 35), cardiac non-ACS (n = 19), or noncardiac condition (n = 316). Random-effects linear regression analysis assessed the association of SAI QRST and myocardial injury, with adjustment for demographics (age, sex, race), prevalent cardiovascular disease (myocardial infarction, history of revascularization, stroke, and HF), risk factors (diabetes, smoking, hypercholesterolemia, hypertension, and cocaine use), and left bundle branch block. Within the entire cohort, SAI QRST decreased by 3 (95%CI -5 to -1) mV*ms every 3 hours. A 10-fold increase in hsTnI was associated with a 7.7 (0.6-14.9) mV*ms increase in SAI QRST. In the subgroup of acutely decompensated HF patients (n = 35), a 10-fold increase in hsTnI was associated with a 61.0 (5.9-116.1) mV*ms increase in SAI QRST. Patient-specific time-varying changes in the surface ECG scalar measure of global electrical heterogeneity, as measured by SAI QRST, and in myocardial injury as measured by hsTnI, are independently and directly associated with each other, likely reflecting a common underlying mechanism.

Usefulness of the Sum Absolute QRST Integral to Predict Outcomes in Patients Receiving Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT) reduces mortality and morbidity in selected patients with heart failure (HF), but up to 1/3 of patients are nonresponders. Sum absolute QRST integral (SAI QRST) recently showed association with mechanical response on CRT. However, it is unknown whether SAI QRST is associated with all-cause mortality and HF hospitalizations in patients undergoing CRT. The study population included 496 patients undergoing CRT (mean age 69 ± 10years, 84% men, 65% left bundle branch block [LBBB], left ventricular ejection fraction 23 ± 6%, 63% ischemic cardiomyopathy). Preimplant digital 12-lead electrocardiogram was transformed into orthogonal XYZ electrocardiogram. SAI QRST was measured as an arithmetic sum of areas under the QRST curve on XYZ leads and was dichotomized based on the median value (302mV ms). All-cause mortality served as the primary end point. A composite of 2-year all-cause mortality, heart transplant, and HF hospitalization was a secondary end point. Cox regression models were adjusted for known predictors of CRT response. Patients with preimplant low mean SAI QRST had an increased risk of both the primary (hazard ratio [HR] 1.8, 95% CI 1.01 to 3.2) and secondary (HR 1.6, 95% CI 1.1 to 2.2) end points after multivariate adjustment. SAI QRST was associated with secondary outcome in subgroups of patients with LBBB (HR 2.1, 95% CI 1.5 to 3.0) and with non-LBBB (HR 1.7, 95% CI 1.0 to 2.6). In patients undergoing CRT, preimplant SAI QRST <302mV ms was associated with an increased risk of all-cause mortality and HF hospitalization. After validation in another prospective cohort, SAI QRST may help to refine selection of CRT recipients.