Cardiovascular Predictive Value and Genetic Basis of Ventricular Repolarization Dynamics

Abstract

Background: Early prediction of cardiovascular risk in the general population remains an important issue. The T-wave morphology restitution (TMR), an ECG marker quantifying ventricular repolarization dynamics, is strongly associated with cardiovascular mortality in patients with heart failure. Our aim was to evaluate the cardiovascular prognostic value of TMR in a UK middle-aged population and identify any genetic contribution.

Methods: We analyzed ECG recordings from 55 222 individuals from a UK middle-aged population undergoing an exercise stress test in UK Biobank (UKB). TMR was used to measure ventricular repolarization dynamics, exposed in this cohort by exercise (TMR during exercise, TMR^ex) and recovery from exercise (TMR during recovery, TMR^rec). The primary end point was cardiovascular events; secondary end points were all-cause mortality, ventricular arrhythmias, and atrial fibrillation with median follow-up of 7 years. Genome-wide association studies for TMR^ex and TMR^rec were performed, and genetic risk scores were derived and tested for association in independent samples from the full UKB cohort (N=360 631).

Results: A total of 1743 (3.2%) individuals in UKB who underwent the exercise stress test had a cardiovascular event, and TMR^rec was significantly associated with cardiovascular events (hazard ratio, 1.11; P=5×10^-7), independent of clinical variables and other ECG markers. TMR^rec was also associated with all-cause mortality (hazard ratio, 1.10) and ventricular arrhythmias (hazard ratio, 1.16). We identified 12 genetic loci in total for TMR^ex and TMR^rec, of which 9 are associated with another ECG marker. Individuals in the top 20% of the TMR^rec genetic risk score were significantly more likely to have a cardiovascular event in the full UKB cohort (18 997, 5.3%) than individuals in the bottom 20% (hazard ratio, 1.07; P=6×10^-3).

Conclusions: TMR and TMR genetic risk scores are significantly associated with cardiovascular risk in a UK middle-aged population, supporting the hypothesis that increased spatio-temporal heterogeneity of ventricular repolarization is a substrate for cardiovascular risk and the validity of TMR as a cardiovascular risk predictor.

Keywords: T-wave morphology; exercise; genetic analyses; genetic risk score; middle aged; risk.