Alterations in heart rate variability are associated with abnormal myocardial perfusion
Introduction
Almost half of sudden cardiac deaths occur in men and women without known ischemic heart disease (IHD) [, , , [1], [2], [3]]. Identification of those at higher risk may require evaluation of additional, non-traditional risk factors, such as autonomic dysfunction [, , , , [4], [5], [6], [7]]. The autonomic nervous system (ANS) is implicated, for example, in the regulation of cardiac electrophysiology, contractility, and coronary vasomotor tone, among other effects [, [8]]. Early identification of abnormalities in cardiac autonomic regulation may provide more insight into why certain individuals are at increased risk of sudden cardiac death.
Recent advances in electrocardiography (ECG) have led to the discovery of new risk markers for the identification of cardiovascular disease, which carry the advantages of being low cost and non-invasive performance [, [9],, [10]]. These include markers of ANS function as reflected by heart rate variability (HRV) [, [11]], a complex measure of the sinoatrial node responses to changes in autonomic outflow. HRV is dependent on multiple peripheral and central mechanisms that vary with physical position, psychological context, and the circadian rhythm [, [11],, [12]]. Autonomic dysfunction, as indicated by low HRV, is associated with IHD and major adverse cardiovascular events [, [7],, [13],, [14]], and predicts worse outcomes in patients with myocardial infarction and ischemic cardiomyopathy [, [15],, [16]], as well as in the general population [, [14],, [17]]. Low HRV is thought to be a measure of sympathovagal imbalance [, [18],, [19]]. Increased sympathetic tone and vagal withdrawal is implicated in the pathogenesis of cardiac diseases, and dysregulation of the autonomic feedback mechanisms between the heart and brain may play a key role in the pathogenesis of cardiac diseases [, [20],, [21]]. Prior studies have found a relationship between myocardial perfusion and HRV, but were limited by size and, more importantly, did not account for the context of HRV measurement, such as time of day, and are important to address before HRV can be considered a valid clinical tool [, [9],, [10]].
Our study evaluated the relationships between alterations in HRV and abnormalities in myocardial perfusion imaging (MPI) and coronary flow reserve (CFR) during pharmacological stress testing. The twin design reduces potential genetic and environmental confounding effects by evaluating differences within pairs [, [22]]. We tested the hypothesis that low HRV is associated with abnormal coronary blood flow regulation during pharmacologic stress tests, measured by >5% perfusion deficits on MPI and low CFR.
Section snippets
Study population
This cross-sectional study was designed to evaluate the relationship of abnormal stress MPI and CFR with autonomic function, measured hourly over the course of 24 h, in individuals without known IHD. Subjects were drawn from the Emory Twin Study [, [23],, [24]], which recruited middle-aged male twin pairs from the Vietnam Era Twin Registry [, [25]]. Pairs of twins were examined at the Emory University General Clinical Research Center, and all data collection occurred during a 24-hour admission
Baseline characteristics
From the original 526 individuals, 250 were excluded due to a combination of unusable Holter data (n = 197), known IHD (n = 94), beta blocker usage (n = 43), or incomplete PET data (n = 69) (Supplemental Table 2). The final sample consisted of 276 individuals. The mean age ± SD was 55 ± 3 years. The mean BMI was 29 ± 5 kg/m2. Comorbid conditions and cardiovascular risk factors were frequent in this sample of middle-aged veterans, including current/previous smoking (62%), hypertension (29%),
Discussion
The major finding of our study is that alterations in the morning variation of heart rate variability are associated with alterations of coronary blood flow regulation. The strongest association with abnormal MPI imaging was a low Dyx at 7 AM, with an additional association at 6 PM. The effects remained significant after rigorous adjustment with traditional risk factors and familial effects in the within-pair analysis. Our data supports the growing evidence of Dyx as a marker of cardiovascular
Conclusion
There is a circadian variation in autonomic control of HRV that is highly predictive of abnormal pharmacological stress MPI. The non-linear measure Dyx showed the strongest association, suggesting that decreased complexity is a representative feature of dysfunction of cardiac vasomotor regulation, which is likely involves autonomic mechanisms. These hypothesis-generating results should lead to further evaluation of the mechanisms underlying the relationship between autonomic control of HRV and
Author statement
These authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
CRediT authorship contribution statement
Anish S. Shah: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Software, Validation, Visualization, Writing - original draft, Writing - review & editing. Rachel Lampert: Investigation, Methodology, Project administration, Resources, Software, Supervision, Writing - review & editing. Jack Goldberg: Conceptualization, Methodology, Project administration, Software, Writing - review & editing. J. Douglas Bremner: Investigation, Project administration,
Declaration of competing interest
The authors report no relationships that could be construed as a conflict of interest.
Acknowledgements
The United States Department of Veterans Affairs has provided financial support for the development and maintenance of the VET (Vietnam Era Twin) Registry. Numerous organizations have provided invaluable assistance, including: VA Cooperative Study Program; Department of Defense; National Personnel Records Center, National Archives and Records Administration; the Internal Revenue Service; National Institutes of Health (NIH); National Opinion Research Center; National Research Council, National
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