Alterations in heart rate variability are associated with abnormal myocardial perfusion

https://doi.org/10.1016/j.ijcard.2020.01.069Get rights and content

Highlights

  • Low heart rate variability is associated with abnormal stress myocardial perfusion and low coronary flow reserve

  • Autonomic differences in those with abnormal myocardial perfusion occur in the early morning hours

  • Heart rate variability may be helpful in risk stratification of those in whom ischemic heart disease is suspected

Abstract

Background

Abnormalities in the autonomic nervous system may occur in ischemic heart disease, but the mechanisms by which they are linked are not fully defined. The risk of cardiac events is increased during morning hours. Studying the contributions of autonomic mechanisms may yield insights into risk stratification and treatment. We hypothesize that autonomic dysfunction, measured by decreased heart rate variability (HRV), associates with abnormal stress myocardial perfusion imaging (MPI).

Methods

We performed a cross-sectional study of the association between abnormal myocardial stress perfusion with HRV using 276 middle-aged veteran twins without known ischemic heart disease. The primary independent variable was cardiac autonomic regulation measured with 24-hour electrocardiogram (ECG) monitoring, using linear and non-linear (multipole density, or Dyx) HRV metrics. The primary outcome was abnormal perfusion (>5% affected myocardium) during adenosine stress on [13N]-ammonia myocardial perfusion imaging with positron emission tomography.

Results

The mean (SD) age was 53 (3) years and 55 (20%) had abnormal perfusion. HRV (by Dyx) was reduced during morning hours in subjects with abnormal perfusion. At 7 AM, each standard deviation (SD) decrease in Dyx was associated a 4.8 (95% CI, 1.5 — 15.8) odds ratio (OR) for abnormal MPI. With Dyx < 2.0, the 7 AM OR for abnormal MPI was 11.8 (95% CI, 1.2 — 111.4).

Conclusions

Autonomic dysfunction, measured by non-linear HRV in the morning hours, was associated with an increased OR of abnormal MPI. These results suggest a potentially important role of ECG-based biomarkers in risk stratification for individuals with suspected ischemic heart disease.

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)

  • G.D. Hutchins et al.

    Noninvasive quantification of regional blood flow in the human heart using N-13 ammonia and dynamic positron emission tomographic imaging

    J. Am. Coll. Cardiol.

    (1990)
  • Y.F. Guo et al.

    Circadian rhythm in the cardiovascular system: Chronocardiology

    Am. Heart J.

    (2003)
  • J.E. Muller

    Circadian variation in cardiovascular events

    Am. J. Hypertens.

    (1999)
  • F. Alqaisi et al.

    Prognostic predictors and outcomes in patients with abnormal myocardial perfusion imaging and angiographically insignificant coronary artery disease

    J. Nucl. Cardiol.

    (2008)
  • F. Crea et al.

    Role of adenosine in pathogenesis of anginal pain

    Circulation.

    (1990)
  • J.K. Madsen

    Ischaemic heart disease and prodromes of sudden cardiac death. Is it possible to identify high risk groups for sudden cardiac death?

    Br Hear. J.

    (1985)
  • M. Hayashi et al.

    The spectrum of epidemiology underlying sudden cardiac death

    Circ. Res.

    (2015)
  • M.W. Deyell et al.

    Sudden cardiac death risk stratification

    Circ. Res.

    (2015)
  • D. Liao et al.

    Cardiac autonomic function and incident coronary heart disease: a population-based case-cohort study: the ARIC study

    Am. J. Epidemiol.

    (1997)
  • M.T. La Rovere et al.

    Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction

    Lancet.

    (1998)
  • F.M. Abboud et al.

    Interaction of cardiovascular reflexes in circulatory control

    Compr. Physiol.

    (2011)
  • D. Oieru et al.

    A novel heart rate variability algorithm for the detection of myocardial ischemia: pilot data from a prospective clinical trial

    Isr. Med. Assoc. J.

    (2015)
  • Task Force of the ESC and NAS

    Heart rate variability

    Eur. Heart J.

    (1996)
  • D.S. Goldstein et al.

    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.

    (2011)
  • H. Mølgaard et al.

    Attenuated 24-h heart rate variability in apparently healthy subjects, subsequently suffering sudden cardiac death

    Clin. Auton. Res.

    (1991)
  • P.K. Stein et al.

    Traditional and nonlinear heart rate variability are each independently associated with mortality after myocardial infarction

    J. Cardiovasc. Electrophysiol.

    (2005)
  • P.R.E. Harris et al.

    Prognostic value of heart rate turbulence for risk assessment in patients with unstable angina and non-ST elevation myocardial infarction

    Vasc. Health Risk Manag.

    (2013)
  • R.M. Jørgensen et al.

    Heart rate variability density analysis (Dyx) and prediction of long-term mortality after acute myocardial infarction

    Ann. Noninvasive Electrocardiol.

    (2016)
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