Entropy, Assessed by Homeostatic Dysregulation on Electrocardiograms Predicts Fracture and Mortality

Entropy, characterized by increased disorder throughout biological systems, can be quantified by homeostatic dysregulation (HD). One potential measure of HD is the dispersion of points from a normal value, approximated at the individual level by Mahalanobis distance (D_M). We hypothesized that greater HD in electrocardiogram (ECG) would also reflect greater HD in the musculoskeletal system which, in turn, would be associated with age and manifest as an increased risk of fracture independently of age, bone mineral density (BMD), and history of fracture. We further hypothesized that greater ECG-HD would be associated with increased risk of all-cause mortality. A cohort of 7738 individuals aged 40 years or older who underwent a screening 12-lead ECG between 2007 and 2018 was analyzed (mean age 63.5 years; 59.5% women; 5.5 years follow-up). ECG-HD was calculated as the natural log-transformed D_M of five ECG measurements (ventricular rate, QRS duration, corrected QT interval, R axis, and T axis) referenced to young individuals (age 19-29). ECG-HD increased with age (r = 0.28). Each standard deviation increment in ECG-HD was associated with a 48% higher unadjusted fracture risk (HR 1.48, 95% CI 1.37-1.58) and remained significant after adjustment for clinical risk factors, ECG diagnoses, and femoral neck BMD (aHR 1.28, 95% CI 1.15-1.42). ECG-HD was also associated with vertebral, nonvertebral, and hip fractures, and with mortality (aHR 1.44, 95% CI 1.18-1.74). ECG-HD, a measurement of entropy in the cardiac system, was associated with fracture risk and mortality in adults, independent of clinical risk factors, BMD, and ECG diagnoses.