Cardiovascular autonomic dysfunction precedes cardiovascular disease and all-cause mortality: 11-year follow-up of the ADDITION-PRO study

Background Cardiovascular autonomic dysfunction remains a silent complication in people at high risk of diabetes. We aim to determine the impact of week-long heart rate variability (HRV) on the risk of cardiovascular events and mortality in this population.

Week-long HRV and mean heart rate (mHR) were measured in 1,627 participants from the ADDITION-PRO study between 2009-2011. As measurement for HRV, we calculated a proxy for standard deviation of normal heartbeat (SDNN) both weekly, daily and hourly. Data on cardiovascular events (CVD) and all-cause mortality were obtained from Danish patient registers until 2021. We fitted poisson regression to determine incidence rate ratios (IRR) for major adverse cardiovascular events (MACE) (myocardial infarction, stroke, cardiovascular death), heart failure, and all-cause mortality.

Mean (SD) age was 66 years (7), and 47 % were women. The population had a mean (SD) week-long SDNN of 139.0 (32.3) ms. Week-long HRV index SDNN showed an IRR of 0.82 (CI: 0.69; 0.97), 0.76 (CI: 0.58; 0.99), and 0.79 (CI: 0.66; 0.94) per SD for MACE, heart failure, and all-cause mortality, respectively. The risk for MACE, heart failure, and all-cause mortality was higher at SDNN values below 120ms. SDNN measurements taken from 6:00-7:00 AM showed the strongest association with the risk of MACE. Lower SDNN was consistently associated with higher all-cause mortality risk across all hours of the day. Adjustment for concurrent physical acceleration and heart rate did not materially change the magnitude of these associations. Night-time heart rate was associated with a higher risk of MACE, heart failure and all-cause mortality.

Cardiovascular autonomic dysfunction, measured by week-long HRV, is associated with higher risk of CVD, heart failure and all-cause mortality. Certain time frames of the day for HRV and heart rate under free-living conditions showed higher risk of CVD. Hence, long-term HRV and the diurnal response are linked with CVD risk among people with high risk of diabetes. Studies exploring the benefit of HRV modifications in CVD prevention are warranted. Competing Interest Statement ELG reports the following general conflicts of interest: ELG has received speaker honoraria or consultancy fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Novo Nordisk, Lundbeck Pharma and Organon. He is an investigator in clinical studies sponsored by AstraZeneca, Idorsia or Bayer and has received unrestricted research grants from Boehringer Ingelheim. DV has received research grants from Bayer A/S, Sanofi Aventis, Novo Nordisk A/S, and Boehringer Ingelheim and holds shares in Novo Nordisk A/S. The remaining authors declare no conflicts of interest related to this manuscript. Funding Statement JFRS, DRW, AS, and LB are employed at Steno Diabetes Center Aarhus, and CSH is employed at Steno Diabetes Center Copenhagen. Both institutions are partly funded by a donation from the Novo Nordisk Foundation. The funders had no role in the design of the study. JRS, DRW and STA are supported by EFSD/Sanofi European Diabetes Research Programme in diabetes associated with cardiovascular disease. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethical approval for the ADDITION PRO study was obtained from the scientific ethics committee of the Central Denmark Region (Reference No. 20000183). The study was conducted in accordance with the Helsinki Declaration, and all participants provided oral and written informed consent for participation and for linkage of their data with national registers. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability The data that support the findings of this study are available from the Danish Data Protection Agency and Danish Health Data Agency (j‑No: 2012‑58‑0004 and FSEID‑00002001) but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of the Danish Data Protection Agency and Dan‑ ish Health Data Agency (j‑No: 2012‑58‑0004 and FSEID‑00002001). Abbreviations - CVD - Cardiovascular disease - MACE - Three-point major adverse cardiovascular events - ECG - Electrocardiogram - HRV - Heart rate variability - rHR - Resting heart rate - SDNN - The standard deviation of normal-to-normal R-R intervals - mHR - Mean heart rate - IRR - Incidence rate ratio - PAEE - Physical activity energy expenditure