Global Electric Heterogeneity Risk Score for Prediction of Sudden Cardiac Death in the General Population

Abstract

Background Asymptomatic individuals account for a majority of sudden cardiac deaths (SCDs). Development of effective, low-cost, and non-invasive SCD risk stratification tools are necessary. Methods and Results 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; 56% female; 77% white) were followed for 14.0 years (median). Five ECG markers of global electrical 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 ECG parameters and SCD. A SCD competing risks score was derived using demographics, comorbidities, and GEH parameters. SCD incidence was 1.86 per 1,000 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, hypertension, coronary heart disease, and 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. Net reclassification index was 18.3%. Conclusions Abnormal electrophysiological substrate quantified by GEH parameters is independently associated with SCD in the general population. Addition of GEH parameters to clinical characteristics improves SCD risk prediction.

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

“…The CHS (Cardiovascular Health Study) is an ongoing, prospective cohort study assessing risk factors, progression, and outcomes of CVD in 5888 community participants aged >65 years (42% male, 85% white) recruited from 4 US communities 26. We excluded participants with reported race other than white or black, uninterpretable ECGs,12 arrhythmias (second or third degree atrioventricular block, atrial fibrillation [AF]), Wolff–Parkinson–White ECG phenotype, implanted pacemaker, QRS duration ≥120 ms, using class I and III antiarrhythmic medications or digoxin, history of coronary heart disease (CHD) or heart failure (HF) as previously defined,12 participants with extreme phenotype (> ±4 SD), and participants missing genotype data. The final ARIC study population included 2465 black participants and 8038 white participants.…”

“…GEH ECG measurements were calculated as previously described12 (Figure 1). SAI QRST was calculated as the arithmetic sum of areas under the QRS‐T curve 15, 17.…”

“…SVG is a vector sum of spatial QRS and T vectors, reflecting implication of the spatial QRS‐T angle 9. Spatial QRS‐T angle is a well‐known marker9 of the risk of ventricular tachyarrhythmias10 and sudden cardiac death (SCD)11, 12 in the general population, heart failure (HF) patients, and other populations 13, 14…”

“…Abnormal GEH is associated with a risk for ventricular arrhythmias10, 15, 16, 19 and SCD, independent of time‐updated CVD, its risk factors, left ventricular ejection fraction, and traditional ECG measurements (heart rate, corrected QT interval (QTc), QRS duration, ventricular conduction abnormalities, and left ventricular hypertrophy) 12. To understand the biology underlying GEH, we performed a genome‐wide meta‐analysis using data from 2 genome‐wide association studies (GWAS) of GEH.…”

Risk Stratification of Sudden Cardiac Death After Acute Myocardial Infarction

“…104 The SVG vector has not yet been tested prospectively as a risk stratification tool in post-MI patients, although it has been associated with sudden death in the general population. 105 In a subanalysis of the MADIT-II trial, increased SAI QRST was associated with increased rates of appropriate ICD therapies for VT/VF or sudden death (HR: 1.33 per 100 mV*ms; p = 0.002), although the HR was similar for total-mortality (HR: 1.27 per 100 mV*ms; p = 0.022). 106 In the prospective PROSE-ICD study, a low SAI QRST was associated with a threefold higher risk of appropriate ICD therapies for VT/VF.…”