Cardiovascular autonomic neuropathy defined by indices of heart rate variability is associated with cardiovascular disease: a longitudinal cohort study of participants with type 1 diabetes

Background: To describe longitudinal prevalence and risk factors associated with cardiovascular autonomic neuropathy (CAN), defined by heart rate variability (HRV) indices, and evaluate the impact of CAN on cardiovascular disease (CVD), in adults with type 1 diabetes (T1D) from the Epidemiology of Diabetes Interventions and Complications (EDIC) study. Methods: Standard resting electrocardiogram (ECG) recordings were obtained annually in 997 participants (mean ± SD age 56.2 ± 6.8 years; T1D duration 34.7 ± 7.9 years; 48% female) between 2015 and 2022. The standard deviation of normally conducted R-R intervals (SDNN) and root mean square of successive differences between normal-to-normal R-R intervals (rMSSD) were used to define CAN using previously validated cut-offs in this cohort from gold-standard cardiovascular reflex tests (CARTs). Generalized estimating equation models were used to evaluate the association of ECG-derived CAN with individual risk factors over repeated time points. Kaplan-Meier estimates were used to describe the cumulative incidence of the first occurrence of any-CVD and of MACE by ECG-derived CAN status, and Cox proportional hazards regression models were used to estimate the effect of ECG-derived CAN adjusted for age and HbA1c. Results: The prevalence of ECG-derived CAN (~ 64%) was stable. Higher pulse rate (OR [95% CI] 1.08 [1.07,1.10] per 1 bpm) and HbA1c (1.43 [1.29,1.58] per 1%) were the most significant risk factors for CAN, followed by older age, male sex, higher albumin excretion rate, and hypertension history. The cumulative incidence of first occurrence of any-CVD over 7 years of follow-up was significantly higher in participants with vs. without CAN (HR [95% CI] any-CVD 2.37 [1.43,3.94]), which remained significant adjusting for mean HbA1c and age, but was attenuated with further adjustment for other factors. Conclusions: The prevalence of and risk factors for standard resting ECG-derived CAN were similar to previously reported estimates from CARTs. CVD risk was significantly higher in those with vs. without CAN. These data support future studies examining the diagnostic utility of HRV indices at the point of care for risk stratification. Trial registration: clinicaltrials.gov NCT00360815 and NCT00360893.