Heart Rate Fragmentation as a Novel Biomarker of Adverse Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis

Madalena D. Costa, Susan Redline, Roger B. Davis, Susan R. Heckbert, Elsayed Z. Soliman, Ary L. Goldberger

Background: A major objective of precision medicine is the elucidation of non-invasive biomarkers of cardiovascular (CV) risk. Recently, we introduced a new dynamical marker of sino-atrial instability, termed heart rate fragmentation (HRF), which outperformed traditional and nonlinear heart rate variability metrics in separating ostensibly healthy subjects from patients with coronary artery disease. Accordingly, we hypothesized that HRF may be a dynamical biomarker of adverse cardiovascular events (CVEs). Methods: This study employed data from a cohort of participants in the Multi-Ethnic Study of Atherosclerosis (MESA), a prospective study of sub-clinical heart disease. Interbeat interval time series (n = 1963), derived from the electrocardiographic channel of the polysomnogram study, were analyzed using the newly introduced metrics of fragmentation, as well as traditional heart rate variability (HRV) indices and the short-term detrended fluctuation analysis exponent. Cox regression analysis was used to assess the association between HR dynamic indices and CV outcomes in unadjusted and adjusted models. Results: The mean (± SD) follow-up time was 2.97 ± 0.63 years. In adjusted models, higher fragmentation was significantly associated with incident CVEs (number of events; hazard ratio [95% confidence interval]: n = 72, 1.43 [1.16-1.76]) and CV death (n = 21; 1.65 [1.15-2.36]). The traditional HRV and the fractal indices were not associated with CVEs or CV death. The most discriminatory fragmentation indices added significant value to Framingham and MESA CV risk indices in all analyses. Conclusion: Our findings show that HRF has promise as a non-invasive, automatable biomarker of CV risk. The basic mechanisms underlying fragmentation remain to be delineated. Its association with incident outcomes raises the possibility of connections to degenerative changes in the multisystem network controlling SAN function.