Abstract
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.
Highlights
This study describes a novel noninvasive biomarker of cardiovascular (CV) risk based on heart rate dynamics
The present investigation was designed to test the association of quantitative measures of heart rate fragmentation (HRF), a newly defined property of shortterm sino-atrial rhythm dynamics, with adverse CV outcomes in Multi-Ethnic Study of Atherosclerosis (MESA), a large ongoing multicenter study of individuals recruited from the general community
The key findings of this study were that: (1) increased HRF was significantly associated with risk of incident cardiovascular event (CVE) and CV mortality; (2) measures of fragmentation added value to Framingham and MESA risk prediction indices; and (3) traditional metrics of short-term heart rate variability (HRV) as well as a nonlinear index (DFA α1) were not associated with incident CVEs or CV death
Summary
This study describes a novel noninvasive biomarker of cardiovascular (CV) risk based on heart rate dynamics. In healthy adults at rest and during sleep, the highest frequency at which the sino-atrial node (SAN) rate fluctuates varies between ∼0.15 and 0.40 Hz (Figures 1A1–A4). These oscillations, referred to as respiratory sinus arrhythmia, are due to vagally-mediated coupling between the SAN and breathing. An increased density of reversals in HR acceleration sign, not consistent with short-term parasympathetic control, can be observed (Figures 1B1–B4). This dynamical biomarker of electrophysiologic instability has recently been identified and termed heart rate fragmentation (HRF) (Costa et al, 2017a). We hypothesized that HRF may be a dynamical biomarker of adverse cardiovascular events (CVEs)
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