Vascular Bed-Specific HRV Patterns in Atherosclerosis are Prognostically Relevant for Major Adverse Cardiovascular Events

Background Autonomic function plays an important role in the progression of atherosclerotic disease due to its impact on vascular tone, heart rate, and systemic inflammation. However, the differential impact of the sympathetic and parasympathetic nervous systems on the progression of atherosclerosis within distinct vascular beds remains unknown.

Methods Data from the MyoVasc study (N=3,289; NCT04064450), a prospective cohort on cardiac disease and its interaction with vascular diseases, were used. Participants underwent standardized biannual deep clinical phenotyping at the study platform including sonography of the carotid arteries, Holter ECG, assessment of cardiovascular risk factors (CVRFs) and comorbidities. HRV metrics were derived from Holter ECGs. Worsening of atherosclerosis was defined as either the presence of asymptomatic organ damage or a new diagnosis of atherosclerotic events. Information on clinical outcome was obtained through follow-up visits, validation and independent adjudication of endpoints. 10-fold cross-validated elastic net logistic regressions identified separate HRV patterns for presence and progression of atherosclerosis, adjusted of age and sex. Linear regressions assessed clinical profile impact on HRV selections. Cox models analysed links between HRV and major adverse cardiovascular events (3-point MACE).

Results HRV was available for analysis in 1,001 participants (mean age 64.5±10.5 years; 35.4% women). Participants were classified into groups based on the presence of plaques in vascular beds, and the overlap between these groups was quantified. Overall, N=563 participants were categorized into the carotid group, where 56.5% had additional plaques in the coronary arteries and 15.6% in peripheral arteries. The coronary group included N=444 participants, with 81.7% exhibiting plaques in the carotid arteries and 18.5% in peripheral arteries. The group with peripheral atherosclerosis included N=128 individuals with 64.1% showing additional plaques in the coronary arteries and 78.6% in the carotid arteries. Nine HRV metrics were selected for carotid (AUC=0.80), eight for coronary (AUC=0.83), and six for peripheral (AUC=0.73) atherosclerosis. Carotid atherosclerosis shares the top selection, LF/HF, with coronary atherosclerosis. For peripheral SDANN is the top selection. A history of atrial fibrillation (β=0.447 [0.239; 0.656], p=0.00005) exhibited the strongest relationship with MADRR in the carotid group. In the coronary group, the association of chronic kidney disease (β=-0.497 [-0.784; -0.210], p=0.0007) with SDANN was the strongest. For the peripheral group, the correlation between chronic heart failure (β=-0.648 [-1.004; -0.291], p=0.0005) and SDNN was notably strong. LF/HF was associated with a significant increase in the risk of 3-point MACE (HRSD=0.616 [0.445; 0.855], p=0.0037) in participants with atherosclerosis. Ten HRV metrics were selected for a worsening of atherosclerosis (AUC=0.68) with TINN as the top metric. In this selection normalized LF was the strongest predictor for 3-point MACE (HRSD=0.714 [0.587; 0.868], p=0.0007).

Conclusion This study is the first to demonstrate distinct autonomic function patterns across the vascular beds of atherosclerosis and suggests a relationship between HRV and the incidence of 3-point MACE in a sample of individuals with atherosclerosis. These findings enhance the understanding of how autonomic function contributes to the pathophysiology of atherosclerosis.