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
References (57)
- et al.
Declining incidence of sudden cardiac death from 1990–2010 in a general middle-aged and elderly population: the Rotterdam Study
Hear. Rhythm.
(2015) Identifying high-risk post-infarction patients by autonomic testing — below the tip of the iceberg
Int. J. Cardiol.
(2017)- et al.
Comparison of the usefulness of heart rate variability versus exercise stress testing for the detection of myocardial ischemia in patients without known coronary artery disease
Am. J. Cardiol.
(2015) - et al.
Heart rate variability as an index of sympathovagal interaction after acute myocardial infarction
Am. J. Cardiol.
(1987) - et al.
Decreased heart rate variability and its association with increased mortality after acute myocardial infarction
Am. J. Cardiol.
(1987) - et al.
The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors
Int. J. Cardiol.
(2010) - et al.
Posttraumatic stress disorder and impaired autonomic modulation in male twins
Biol. Psychiatry
(2013) - et al.
Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation
Clin. Psychol. Rev.
(1988) - et al.
A short questionnaire for the measurement of habitual physical activity in epidemiological studies
Am. J. Clin. Nutr.
(1982) - et al.
Description of complex time series by multipoles
Phys. A Stat. Mech. Its Appl.
(2002)
Noninvasive quantification of regional blood flow in the human heart using N-13 ammonia and dynamic positron emission tomographic imaging
J. Am. Coll. Cardiol.
Circadian rhythm in the cardiovascular system: Chronocardiology
Am. Heart J.
Circadian variation in cardiovascular events
Am. J. Hypertens.
Prognostic predictors and outcomes in patients with abnormal myocardial perfusion imaging and angiographically insignificant coronary artery disease
J. Nucl. Cardiol.
Role of adenosine in pathogenesis of anginal pain
Circulation.
Ischaemic heart disease and prodromes of sudden cardiac death. Is it possible to identify high risk groups for sudden cardiac death?
Br Hear. J.
The spectrum of epidemiology underlying sudden cardiac death
Circ. Res.
Sudden cardiac death risk stratification
Circ. Res.
Cardiac autonomic function and incident coronary heart disease: a population-based case-cohort study: the ARIC study
Am. J. Epidemiol.
Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction
Lancet.
Interaction of cardiovascular reflexes in circulatory control
Compr. Physiol.
A novel heart rate variability algorithm for the detection of myocardial ischemia: pilot data from a prospective clinical trial
Isr. Med. Assoc. J.
Heart rate variability
Eur. Heart J.
Low-frequency power of heart rate variability is not a measure of cardiac sympathetic tone but may be a measure of modulation of cardiac autonomic outflows by baroreflexes
Exp. Physiol.
Attenuated 24-h heart rate variability in apparently healthy subjects, subsequently suffering sudden cardiac death
Clin. Auton. Res.
Traditional and nonlinear heart rate variability are each independently associated with mortality after myocardial infarction
J. Cardiovasc. Electrophysiol.
Prognostic value of heart rate turbulence for risk assessment in patients with unstable angina and non-ST elevation myocardial infarction
Vasc. Health Risk Manag.
Heart rate variability density analysis (Dyx) and prediction of long-term mortality after acute myocardial infarction
Ann. Noninvasive Electrocardiol.
Cited by (8)
Cardiovascular pathophysiology from the cardioneural perspective and its clinical applications
2022, Trends in Cardiovascular MedicineCitation Excerpt :Non-linear HRV metrics, such as multiscale entropy, measure the amount of disorder in the system and indicate a breakdown in homeostasis due to either cardiovascular disease or psychological and mental health disturbances. Non-linear metrics from the Poincare plot may uniquely capture irregularities caused by periodic, disordered ANS activity bursts that occur with myocardial ischemia [37]. In addition to HRV, repolarization and myocardial contractility measurements can help evaluate the effects of psychological stress on ventricular sympathetic activation [38].
Heart rate variability, autonomic regulation and myocardial ischemia
2020, International Journal of CardiologyRelationship between dynamic electrocardiogram and CRP, IL-6, ET-1 expression in myocardial ischemia patients with coronary heart disease
2023, Cellular and Molecular BiologyToward a diagnostic CART model for Ischemic heart disease and idiopathic dilated cardiomyopathy based on heart rate total variability
2022, Medical and Biological Engineering and ComputingEarly life stress and autonomic response to acute mental stress in individuals with coronary heart disease
2022, Journal of Traumatic Stress