Objective To ascertain the cross-sectional association between cardiovascular autonomic function and arterial stiffness across glucose metabolism status. Methods We performed a cross-sectional analysis of participants of The Maastricht Study without prior CVD. Cardiovascular autonomic function was based on heart rate variability (HRV) indices from 24-hour electrocardiogram recordings and summarized in Z-scores for time and frequency domains. Aortic and carotid stiffness were assessed by carotid-femoral pulse wave velocity (PWV) and carotid artery distensibility (CD), respectively. We used multiple linear regression to study the associations and adjusted for demographic and lifestyle factors and a range of cardiovascular risk factors. We tested the modification of the associations by glucose metabolism status. Results PWV and CD measures were available in 3671 and 1806 participants, respectively (median (25th; 75th percentile) age: 60 years (53; 66), 51% women, 20 % type 2 diabetes by design). Participants with lower HRV had higher aortic stiffness, as reflected by 2.8% (CI: 2.1; 3.4) and 2.8% (2.1; 3.5) higher PWV per standard deviation (SD) lower composite HRV time-domain and frequency domain Z-score, respectively. Similar trends were observed for carotid stiffness, reflected by 3.2% (1.4; 5.00) and 3.1% (1.2; 5.0) lower CD per SD lower composite HRV time-domain and frequency domain Z-score, respectively. Associations were stronger among people with prediabetes and type 2 diabetes compared to normal glucose metabolism (p-value for interaction for prediabetes: <0.05; and for type 2 diabetes ranging between: <0.05 - <0.10). Conclusion Cardiovascular autonomic dysfunction is associated with higher aortic and carotid stiffness, especially in people with dysglycemia. Thus, autonomic dysfunction may contribute to cardiovascular risk by affecting vascular stiffness.

The authors have declared no competing interest.

JRS, DRW, STA 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. JRS, DRW, and STA are supported by the EFSD/Sanofi European Diabetes Research Programme in diabetes associated with cardiovascular disease. The funders had no role in the design of the study. This study was supported by the European Regional Development Fund via OP-Zuid, the Province of Limburg, the Dutch Ministry of Economic Affairs (grant 31O.041), Stichting De Weijerhorst (Maastricht, The Netherlands), the Pearl String Initiative Diabetes (Amsterdam, The Netherlands), the Cardiovascular Center (CVC, Maastricht, the Netherlands), CARIM School for Cardiovascular Diseases (Maastricht, The Netherlands), CAPHRI Care and Public Health Research Institute (Maastricht, The Netherlands), NUTRIM School for Nutrition and Translational Research in Metabolism (Maastricht, the Netherlands), Stichting Annadal (Maastricht, The Netherlands), Health Foundation Limburg (Maastricht, The Netherlands), and by unrestricted grants from Janssen-Cilag B.V. (Tilburg, The Netherlands), Novo Nordisk Farma B.V. (Alphen aan den Rijn, the Netherlands), and Sanofi-Aventis Netherlands B.V. (Gouda, the Netherlands).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study has been approved by the institutional medical ethics committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG). All participants gave written informed consent.

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The data of this study derive from The Maastricht Study, but restrictions apply to the availability of these data, which were used under license for the current study. Data are, however, available from the authors upon reasonable request and with permission of The Maastricht Study management team.