Vagal impairment and cardiovascular risk in those with zero to low coronary artery calcification scores: the Multi-Ethnic Study of Atherosclerosis.

Coronary artery calcification (CAC) is the most reliable noninvasive predictor of major adverse cardiovascular events (MACEs). Individuals with no detectable or minimal CAC (Agatston score 1-100) are considered at the lowest risk. However, MACE does occur in these groups. This study evaluated whether quantification of cardiac vagal activity by heart rate fragmentation (HRF) improved MACE risk prediction beyond CAC imaging. Our study population is a cohort of the Multi-Ethnic Study of Atherosclerosis (MESA). Cox regression models were used to assess the association between HRF, derived from polysomnographic ECGs, and incident MACE in the overall cohort with concurrent polysomnographic ECG and CAC data, and three nonoverlapping subgroups: "very-low-risk" (CAC = 0), "low-risk" (0 < CAC < 100), and "elevated-risk" (CAC ≥ 100). Over a median (1st; 3rd quartiles) follow-up period of 8.9 (8.4; 9.4) yr, there were 164, 29, 47, and 88 incident MACEs in the overall cohort ( = 1,354), very-low-risk ( = 495), low-risk ( = 422), and higher-risk ( = 437) subgroups, respectively. A one standard deviation increment in HRF was associated with a 22% (3%-44%) and a 60% (16%-122%) increase in the rate of MACE in the overall cohort and those without detectable CAC, respectively. Neither the Framingham nor the MESA-CAC index was predictive of MACE in the lowest-risk subgroup until nearly a decade of follow-up. From a physiologic perspective, our results suggest that vagal dysfunction precedes the onset of overt cardiovascular disease (CVD). From a translational perspective, they indicate that HRF enhances risk stratification, especially in populations traditionally classified as very-low risk. This study is the first to show that cardiac parasympathetic function, assessed via heart rate fragmentation (HRF), is independently associated with major adverse cardiovascular events (MACEs) in individuals traditionally considered low-risk due to nondetectable or minimal coronary artery calcification (CAC). HRF outperforms both the Framingham and MESA-CAC risk scores in the lowest-risk subgroup over the short term (<10 yr).