Spatial Ventricular Gradient Magnitude Research Articles

The Spatial Ventricular Gradient Is Associated With Inducibility of Ventricular Arrhythmias During Electrophysiology Study

BackgroundMyocardial electrical heterogeneity is critical for normal cardiac electromechanical function, but abnormal or excessive electrical heterogeneity is proarrhythmic. The spatial ventricular gradient (SVG), a vectorcardiographic measure of electrical heterogeneity, has been associated with arrhythmic events during long-term follow-up, but its relationship with short-term inducibility of ventricular arrhythmias (VAs) is unclear. ObjectiveThis study was designed to determine associations between SVG and inducible VAs during electrophysiology study. MethodsA retrospective study was conducted of adults without prior sustained VA, cardiac arrest, or implantable cardioverter-defibrillator who underwent ventricular stimulation for evaluation of syncope and nonsustained ventricular tachycardia or for risk stratification before primary prevention implantable cardioverter-defibrillator implantation. The 12-lead electrocardiograms were converted into vectorcardiograms, and SVG magnitude (SVGmag) and direction (azimuth and elevation) were calculated. Odds of inducible VA were regressed by logistic models. ResultsOf 143 patients (median age, 69 years; 80% male; median left ventricular ejection fraction [LVEF], 47%; 52% myocardial infarction), 34 (23.8%) had inducible VAs. Inducible patients had lower median LVEF (38% vs 50%; P < .0001), smaller SVGmag (29.5 vs 39.4 mV·ms; P = .0099), and smaller cosine SVG azimuth (cosSVGaz; 0.64 vs 0.89; P = .0007). When LVEF, SVGmag, and cosSVGaz were dichotomized at their medians, there was a 39-fold increase in adjusted odds (P = .002) between patients with all low LVEF, SVGmag, and cosSVGaz (65% inducible) compared with patients with all high LVEF, SVGmag, and cosSVGaz (4% [n = 1] inducible). After multivariable adjustment, SVGmag, cosSVGaz, and sex but not LVEF or other characteristics remained associated with inducible VAs. ConclusionAssessment of electrical heterogeneity by SVG, which reflects abnormal electrophysiologic substrate, adds to LVEF and identifies patients at high and low risk of inducible VA at electrophysiology study.

Limits of the spatial ventricular gradient and QRST angles in patients with normal electrocardiograms and no known cardiovascular disease stratified by age, sex, and race.

Measurement of the spatial ventricular gradient (SVG), spatial QRST angles, and other vectorcardiographic measures of myocardial electrical heterogeneity have emerged as novel risk stratification methods for sudden cardiac death and other adverse cardiovascular events. Prior studies of normal limits of these measurements included primarily young, healthy, White volunteers, but normal limits in older patients are unknown. The influence of race and body mass index (BMI) on these measurements is also unclear. Normal 12-lead electrocardiograms (ECGs) from a single center were identified. Patients with abnormal cardiovascular, pulmonary, or renal history (assessed by International Classification of Disease[ICD-9/ICD-10] codes)or abnormal cardiovascular imaging were excluded. The SVG and QRST angles were measured and stratified by age, sex, and race. Multivariable linear regression was used to assess the influence of age, BMI, and heart rate (HR) on these measurements. Among 3292 patients, observed ranges of SVG and QRST angles (peak and mean) differed significantly based on sex, age, and race. Sex differences attenuated with increasing age. Men tended to have larger SVG magnitude (60.4 [46.1-77.8] vs. 52.5 [41.3-65.8] mv*ms, p < .0001) and elevation, and more anterior/negative SVG azimuth (-14.8 [-25.1 to -4.3] vs. 1.3 [-9.8 to 10.5] deg, p < .0001) compared to women. Men also had wider QRST angles. Observed ranges varied significantly with BMI and HR. SVG and QRST angle measurements were robust to different filtering bandwidths and moderate fiducial point annotation errors, but were heavily affected by changes in baseline correction. Age, sex, race, BMI, and HR significantly affect the range of SVG and QRST angles in patients with normal ECGs and no known cardiovascular disease, and should be accounted for in future studies. An online calculator for prediction of these "normal limits" given demographics is provided at https://bivectors.github.io/gehcalc/.

MP-453088-9 THE SPATIAL VENTRICULAR GRADIENT IS ASSOCIATED WITH CARDIAC MAGNETIC RESONANCE MARKERS OF OF DIFFUSE MYOCARDIAL FIBROSIS

Cardiac MRI (CMR) markers of diffuse myocardial fibrosis are of prognostic importance in cardiomyopathies. However, CMR is expensive, time-consuming, and not readily available. An ECG correlate for diffuse fibrosis, via its effect on myocardial electrical heterogeneity, would be useful. The spatial ventricular gradient (SVG), a vectorcardiographic (VCG) measurement of myocardial electrical heterogeneity, is a promising ECG correlate of CMR detected diffuse fibrosis. To assess the relationship of the SVG to extracellular volume (ECV) and native T1 values in patients referred for CMR. Retrospective cohort study of all patients referred for CMR from 2015 to 2022 at a single academic medical center who had ECG(s) performed within 30 days of CMR. Median VCGs were constructed from the 12-lead ECGs, and SVG was calculated as the area under the X, Y, and Z median beats. ECV and native T1 values were regressed on SVG vector magnitude, QT interval, and QRS duration using linear regression. Median values were compared using the rank-sum test. We evaluated 679 patients who underwent CMR and had ECV and T1 measurements and a recent ECG. The sample was 60% male and the mean age was 55 +/- 16 years. The figure shows how SVG vector magnitude was inversely correlated with both T1 and ECV (p<0.001 for both). In the lowest and highest quartiles of both ECV (0.03-0.28 vs 0.35-0.68) and T1 (1041-1227 vs 1315-1535 ms), the median SVG magnitude was significantly lower: 48.7 vs 32.3 mv*ms for ECV, and 48.5 vs 30 mv*ms for T1 (p<0.001 for both). In a multivariable model, the SVG remained independently associated with ECV and T1 after adjustment for QT interval, QRS duration, age, and sex (p<0.001). SVG magnitude is independently associated with CMR measures of extracellular fibrosis. Patients with higher SVG magnitude are unlikely to have a significant burden of diffuse fibrosis.

The Spatial Ventricular Gradient Is an Independent Predictor of Anthracycline-Associated Cardiotoxicity

BackgroundAnthracyclines are effective chemotherapies that are limited by cardiotoxicity. The spatial ventricular gradient (SVG) is a marker of electrical heterogeneity linked to adverse cardiovascular outcomes, including sudden cardiac death and heart failure (HF). ObjectivesThe purpose of this study was to assess if SVG values before chemotherapy are associated with the risk of anthracycline-associated HF or cardiomyopathy (CM). MethodsWe analyzed 12-lead electrocardiograms obtained within 6 months before initiation of anthracyclines in a retrospective cohort treated for cancer between 1992 and 2019 at a single academic medical center. Incident HF and CM were defined by ICD-9/10 codes and confirmed by chart review. Vectorcardiograms were constructed from baseline electrocardiograms, and the SVG was calculated. The cumulative incidence of anthracycline-associated HF or CM was regressed on SVG vector orientation and magnitude with death as a competing risk. ResultsIn 889 patients (47% male; mean age 58 ± 16 years; 71% hematologic malignancies), larger SVG magnitude prechemotherapy was associated with decreased risk of HF or CM after multivariable adjustment, with a subhazard ratio of 0.76 per 1 SD increase (95% CI: 0.59-0.96; P = 0.024). SVG vector orientation, specifically a more leftward oriented VGx, was associated with decreased risk of HF or CM with a subhazard ratio of 0.77 per 1 SD increase (95% CI: 0.61-0.96; P = 0.023). ConclusionsLarger SVG magnitude and more leftward SVG orientation were associated with a decreased risk of anthracycline cardiotoxicity in a large retrospective cohort. Improved cardiac risk stratification algorithms incorporating the SVG could personalize both cancer and cardioprotective therapy.

The spatial ventricular gradient is associated with adverse outcomes in acute pulmonary embolism.

The spatial ventricular gradient (SVG) is a vectorcardiographic measurement that reflects cardiac loading conditions via electromechanical coupling. We hypothesized that the SVG is correlated with right ventricular (RV)strain and is prognostic of adverse events in patients with acute pulmonary embolism (PE). Retrospective, single-center study of patients with acute PE. Electrocardiogram (ECG), imaging, and outcome data were obtained. SVG components were regressed on tricuspid annular plane systolic excursion (TAPSE), qualitative RV dysfunction, and RV/left ventricular (LV) ratio. Odds of adverse outcomes (30-day mortality, vasopressor requirement, or advanced therapy) after PE were regressed on demographics, RV/LV ratios, traditional ECG signs of RV dysfunction, and SVG components using a logit model. ECGs from 317 patients (48% male, age 63.1 ± 16.6 years) with acute PE were analyzed; 36 patients (11.4%) experienced an adverse event. Worse RV hypokinesis, larger RV/LV ratio, and smaller TAPSE were associated with smaller SVG X and Y components, larger SVG Z components, and smaller SVG vector magnitude (p < .001 for all). In multivariable logistic regression, odds of adverse events after PE decreased with increasing SVG magnitude and TAPSE (OR 0.32 and 0.54 per standard deviation increase; p=.03 and p=.004, respectively). Receiver operating characteristic (ROC) analysis showed that, when combined with imaging, replacing traditional ECG criteria with the SVG significantly improved the area under the ROC from 0.70 to 0.77 (p=.01). The SVG is correlated with RV dysfunction and adverse outcomes in acute PE and has a better prognostic value than traditional ECG markers.

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...

B-PO04-150 SPATIAL VENTRICULAR GRADIENT IS ASSOCIATED WITH INDUCIBLE VENTRICULAR ARRHYTHMIAS DURING ELECTROPHYSIOLOGY STUDY

The spatial ventricular gradient (SVG) is a vectorcardiographic measure of global electrical heterogeneity that has been associated with sudden cardiac death (SCD) in the general population. The association between SVG and inducibility of ventricular tachycardia (VT) or ventricular fibrillation (VF) during electrophysiology study (EPS) is unknown. To test the association between SVG and inducible VT/VF during EPS. We performed a retrospective study of patients presenting for EPS for evaluation of syncope or risk stratification of SCD prior to primary prevention ICD implantation between 6/2016-12/2020. 12-lead ECGs prior to EPS were converted to vectorcardiograms, and SVG magnitude, azimuth (direction in the XZ transverse plane), and elevation (direction in the XY frontal plane) were calculated. SVG components were dichotomized above and below their median values. Variables were compared with the t-test except for SVG azimuth (a circular variable), which was compared with the Mardia-Watson-Wheeler test. The odds of inducible VT/VF were regressed using a logistic model. Among 100 patients presenting for EPS (mean age 65.5 ± 12.1 y, 77% male, mean LVEF 46 ± 12 %), 20 had inducible VT/VF. Patients with inducible VT/VF had lower LVEF (40 ± 8 vs. 48 ± 12 %, p=0.017) and more posteriorly directed SVG azimuth (25.3 vs. 15.2 deg, p=0.01) than those who were non-inducible. Unadjusted logistic regression demonstrated that the OR for inducible VT/VF was 3.86 (95% CI 1.28-11.64, p=0.017) for SVG magnitude < 41.2 mv*ms and 8.07 (95% CI 2.19-29.78, p=0.002) for absolute SVG azimuth > 46.6 deg. SVG elevation, QRS duration, and QT interval were not associated with VT/VF. After adjustment for age, gender, LVEF, and prior MI, both SVG magnitude and absolute azimuth remained significantly associated with inducible VT/VF: adjusted OR for inducible VT/VF was 6.66 (95% C1.82-24.43, p=0.004) for SVG magnitude < 41.2 mv*ms and 7.53 (95% CI 1.81-31.35, p=0.005) for absolute SVG azimuth > 46.6 deg. Smaller SVG magnitude and more extreme anterior or posterior SVG azimuth are associated with inducible VT/VF. SVG warrants prospective studies for risk stratification in patients undergoing EPS.

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.

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.

Global Electrical Heterogeneity: Mechanisms and Clinical Significance.

This review summarizes recent findings and discusses a clinical significance of a vectorcardiographic (VCG) Global electrical heterogeneity (GEH). GEH concept is based on the concept of the spatial ventricular gradient (SVG), which is a global measure of the dispersion of total recovery time. We quantify GEH by measuring five features of the SVG vector (SVG magnitude, direction (azimuth and elevation), a scalar value, and spatial QRS-T angle) on orthogonal XYZ ECG. In analysis of more than 20,000 adults we showed that GEH is independently associated with sudden cardiac death (SCD) after adjustment for demographics, cardiovascular disease (time-updated incident non-fatal cardiovascular events [coronary heart disease, heart failure, stroke, atrial fibrillation, use of beta-blockers], and known risk factors [cholesterol, triglycerides, physical activity index, smoking, diabetes, obesity, hypertension, anti-hypertensive medications, creatinine, alcohol intake, left ventricular ejection fraction, and time-updated ECG metrics (heart rate, QTc, QRS duration, ECG-left ventricular hypertrophy, bundle branch block or interventricular conduction delay)]. This finding suggests that GEH represents an independent electrophysiological substrate of SCD.

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.

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.

Abstract 30: Global Electrical Heterogeneity on Electrocardiogram is Associated with Sudden Cardiac Death After Adjustment for Ejection Fraction

Introduction: Electrocardiographic (ECG) measures of myocardial global electrical heterogeneity (GEH) are associated with sudden cardiac death (SCD) in middle-age adults. Hypothesis: We hypothesized that time-updated ECG GEH measures are associated with SCD in elderly adults after LVEF adjustment. Methods: We analyzed data from 2 prospective cohorts: The Atherosclerosis Risk in Communities (ARIC, n=15,366; mean age 54.1±5.8 y; 44.6% male; 73.2% white) and the Cardiovascular Health Study (CHS, n=5,016; mean age 72.8±5.6 y; 43.1% male; 95.3% white). Mean spatial QRS-T angle, azimuth, elevation, and magnitude of spatial ventricular gradient (SVG), and sum absolute QRST integral (SAI QRST) were calculated from digital 12-lead ECGs and analyzed as baseline variables in ARIC and as time-updated longitudinal variables in CHS (measured yearly at 10 consecutive visits). The primary outcome was adjudicated SCD. Cox regression models were constructed: Model 1 adjusted for age, sex and race. Model 2 further adjusted for cardiovascular disease, beta-blocker use, creatinine, BMI, hypertension, diabetes, smoking, total cholesterol, HDL, triglycerides, physical activity and alcohol use. Model 3 included Model 2 variables and heart rate, QTc, LV hypertrophy and bundle branch block or intra-ventricular conduction delay. Model 4 in CHS included all Model 3 variables plus baseline LVEF and time-updated incident HF and coronary heart disease. Results: During median 13-14 y of follow-up SCD incidence was 1.51 (95%CI 1.35-1.69) per 1,000 person-yrs in ARIC, and 2.78 (95%CI 2.41-3.21) per 1,000 person-yrs in CHS. In both cohorts (Table) QRS-T angle, SVG and SAI QRST were associated with SCD. Among older adults (CHS), longitudinal SAI QRST, QRS-T angle and SVG magnitude were associated with SCD independent of LVEF. Conclusions: Baseline and longitudinal GEH ECG parameters are independently associated with SCD in middle-age and older adults, respectively. In older adults, GEH ECG parameters provide information on SCD risk beyond LVEF.

Normal limits of the spatial QRS-T angle and ventricular gradient in 12-lead electrocardiograms of young adults: dependence on sex and heart rate

Background and purpose Normal limits of the spatial QRS-T angle and spatial ventricular gradient (SVG) are only available from Frank vectorcardiograms (VCGs) of male subjects. We determined normal limits for these variables derived from standard 12-lead electrocardiograms (ECGs) of 660 male and female students aged 18 to 29 years. Methods A computer algorithm was used that constructed approximated VCG leads by inverse Dower matrix transformation of the 12-lead ECG and subsequently calculated the spatial QRS-T angle, SVG magnitude, and orientation. Results In female subjects, the QRS-T angle was more acute (females, 66° ± 23°; normal, 20°-116°; males, 80° ± 24°; normal, 30°-130°; P < .001), and the SVG magnitude was smaller (females, 81 ± 23 mV·ms; normal, 39-143 mV·ms; males, 110 ± 29 mV·ms; normal, 59-187 mV·ms; P < .001) than in male subjects. The male SVG magnitude in our study was larger than that computed in Frank VCGs (79 ± 28 mV·ms; P < .001). Conclusions The spatial QRS-T angle and SVG depend strongly on sex. Furthermore, normal limits of SVG derived from Frank VCGs differ markedly from those derived from VCGs synthesized from the standard ECG. As nowadays, VCGs are usually synthesized from the 12-lead ECG; normal limits derived from the standard ECG should preferably be used.

Early changes in rat hearts with developing pulmonary arterial hypertension can be detected with three-dimensional electrocardiography

The study aim was to assess three-dimensional electrocardiogram (ECG) changes during development of pulmonary arterial hypertension (PAH). PAH was induced in male Wistar rats (n = 23) using monocrotaline (MCT; 40 mg/kg sc). Untreated healthy rats served as controls (n = 5). ECGs were recorded with an orthogonal three-lead system on days 0, 14, and 25 and analyzed with dedicated computer software. In addition, left ventricular (LV)-to-right ventricular (RV) fractional shortening ratio was determined using echocardiography. Invasively measured RV systolic pressure was 49 (SD 10) mmHg on day 14 and 64 (SD 10) mmHg on day 25 vs. 25 (SD 2) mmHg in controls (both P < 0.001). Baseline ECGs of controls and MCT rats were similar, and ECGs of controls did not change over time. In MCT rats, ECG changes were already present on day 14 but more explicit on day 25: increased RV electromotive forces decreased mean QRS-vector magnitude and changed QRS-axis orientation. Important changes in action potential duration distribution and repolarization sequence were reflected by a decreased spatial ventricular gradient magnitude and increased QRS-T spatial angle. On day 25, LV-to-RV fractional shortening ratio was increased, and RV hypertrophy was found, but not on day 14. In conclusion, developing PAH is characterized by early ECG changes preceding RV hypertrophy, whereas severe PAH is marked by profound ECG changes associated with anatomical and functional changes in the RV. Three-dimensional ECG analysis appears to be very sensitive to early changes in RV afterload.