Cardiometabolic and Inflammatory Predictors of Life‐Threatening Ventricular Arrhythmias in Adults Without Structural Heart Diseases

Background Life‐threatening ventricular arrhythmias (LTVAs) can occur in individuals without apparent structural heart disease, yet the cardiometabolic and inflammatory determinants remain unclear. We aimed to identify clinical, sociodemographic, and lifestyle determinants of LTVAs in structurally normal hearts. Methods We included 423 186 UKB (UK Biobank) participants after excluding coronary artery disease, heart failure, cardiomyopathy, and valvular and congenital heart disease at baseline and during follow‐up. The primary end point was incident LTVAs, defined as ventricular tachyarrhythmias, cardiac arrest, sudden cardiac death, and related resuscitation or ablation procedures. Cox models estimated adjusted hazard ratios (HRs) with 95% CIs. Model discrimination was assessed using Harrell's concordance index and explained variance ( R 2 ). Results Over a median 13.3 (interquartile range, 12.6–14.0) years, 1116 LTVAs occurred. Cases were older (61 versus 57 years) and more often men (56.1% versus 42.6%). Hypertension (HR, 2.21 [95% CI, 1.90–2.57]), current smoking (HR, 1.78 [95% CI, 1.48–2.13), and male sex (HR, 1.67 [95% CI, 1.45–1.92]) showed the strongest associations with LTVAs. Additional factors associated with increased risk included nonideal sleep, previous smoking, physical inactivity, older age, and higher high‐sensitivity C‐reactive protein. Low‐density lipoprotein cholesterol showed a modest inverse association (HR, 0.89 [95% CI, 0.82–0.97]). Age and hypertension showed the highest discrimination (concordance index, 0.629 and 0.615; R 2 0.0082 and 0.0101), and overall model discrimination was modest. Findings were consistent across sexes and in sensitivity analyses. Conclusions In adults without structural heart disease, hypertension, smoking, and male sex show the strongest associations with LTVAs, with additional contributions from age, inflammation, and other lifestyle factors.