Low vagally-mediated heart rate variability and increased susceptibility to ventricular arrhythmias in rats bred for high anxiety
Introduction
Converging evidence from both epidemiological and experimental studies indicates that there is a bidirectional association between anxiety disorders and cardiovascular disease [1], [2]. Patients suffering from anxiety disorders are at higher risk of morbidity and mortality related to heart disease [3], [4], [5], and cardiovascular disease may induce anxiety [6], [7]. Despite this, the mechanisms that underlie these associations are far from being completely understood.
Alterations of the autonomic neural control of cardiac function may play a mediating role in the link between anxiety disorders and cardiac pathophysiology. Basal and stress-induced changes in the autonomic modulation of heart rate (HR) have been described in humans with anxiety disorders [8], and they are also common in heart disease [9]. In particular, the notion that anxious individuals are often characterized by a relatively low vagal component of heart rate variability (HRV) has long-standing support in the literature [9], [10], [11].
Research into the study of cardiac autonomic modulation that characterizes anxiety in its state, trait and psychopathological forms may provide insights into the mechanisms underlying its comorbidity with cardiovascular disorders. Traditionally, preclinical research has focused on the study of autonomic correlates of stress-evoked anxiety. Specifically, animals displaying anxiety-like states in response to psychological stressors have been shown to be characterized by a cardiac autonomic imbalance in the sympathetic direction, as indexed by HRV indexes [12], [13]. On the other hand, the investigation of cardiac autonomic function in animal models of trait anxiety has been conducted only sporadically and provided preliminary evidence of an altered autonomic regulation of HR in subjects with high levels of trait anxiety [14], [15].
Given these considerations, the principal objective of this study was to characterize in detail the autonomic neural modulation of HR in two Wistar rat lines selectively bred for either high (HAB) or low (LAB) anxiety-related behavior. The HAB/LAB rats have been proved to display robust, consistent and reliable differences in their level of baseline anxiety (for a review see [16], [17]). In addition, this rat model has been particularly useful for unveiling the neurobiological, neuroendocrine and physiological correlates of high trait anxiety [18], [19], [20]. Therefore, the use of these psychogenetically selected rats offers, in our view, a valid and reliable methodological approach for investigating the autonomic correlates of extremes in anxiety-related behavior.
In the current study we tested the hypothesis that high levels of trait anxiety in rats would be associated to specific features of autonomic neural modulation of HR that would support the use of this rat model for the study of the mechanisms mediating anxiety and cardiovascular disorder comorbidity. Sympathetic and parasympathetic (vagal) influences on the heart were assessed during resting and stress conditions via time- and frequency-domain analysis of HRV. Pharmacological autonomic manipulations were conducted i) to assess the relative contribution of sympathetic and vagal components, using beta-adrenoceptor and muscarinic receptor antagonists, respectively, and ii) to investigate susceptibility to cardiac arrhythmias following pharmacological stimulation of β-adrenoreceptors. Finally, cardiac structural analysis was performed in order to verify whether given autonomic features were related to specific gross characteristics of the heart.
Section snippets
Ethics statement and animals
The experimental protocol described here was approved by the Veterinarian Animal Care and Use Committee of Parma University, and carried out in accordance with the European Community Council Directives of 22 September 2010 (2010/63/UE).
Experiments were carried out on 5-month-old male Wistar rats (380–420 g body weight) selectively bred for either high (HAB) or low (LAB) anxiety-related behavior in the elevated plus-maze test [16]. The animals were obtained from the animal facilities of the
Anxiety-related behavior
The elevated plus-maze test was conducted as a validation criterion for the relative anxiety phenotype of HAB and LAB rats. HAB rats were more anxious than LAB rats as reflected by a lower percentage of time spent on open arms (HAB = 2.1 ± 1.1% vs. LAB = 64.8 ± 1.1% of total time, t = − 15.4, p < 0.01) and a lower percentage of open arm entries than LABs (HAB = 18.3 ± 7.8% vs. LAB = 55.1 ± 2.1% of total entries, t = − 4.6, p < 0.01). In addition, the average latency time to enter an open arm was longer in HABs compared
Discussion
The purpose of this study was to characterize cardiac autonomic regulation in a unique model of trait-anxiety, the HAB/LAB rats. Our major novel finding is that HAB rats show signs of i) impaired cardiac autonomic modulation (low vagally-mediated HRV), ii) poor adaptive HR responsiveness to stressful stimuli, and iii) increased susceptibility to arrhythmias compared to LAB counterparts. These findings are consistent with the view that high levels of anxiety-related behavior in rats are
Acknowledgments
Funding for this study was provided by a grant from the University of Parma (FIL 2012).
References (42)
- et al.
Anxiety and depression after acute myocardial infarction
Heart Lung
(1996) - et al.
Heart rate and heart rate variability in panic, social anxiety, obsessive–compulsive, and generalized anxiety disorders at baseline and in response to relaxation and hyperventilation
Int J Psychophysiol
(2013) - et al.
The role of vagal function in the risk for cardiovascular disease and mortality
Biol Psychol
(2007) - et al.
Selective breeding for infant rat separation-induced ultrasonic vocalizations: developmental precursors of passive and active coping styles
Behav Brain Res
(2007) - et al.
Neurobiological correlates of high (HAB) versus low anxiety-related behavior (LAB): differential Fos expression in HAB and LAB rats
Biol Psychiatry
(2004) - et al.
Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat
J Neurosci Methods
(1985) - et al.
Electrode positioning for reliable telemetry ECG recordings during social stress in unrestrained rats
Physiol Behav
(1996) - et al.
Behavioral and electrocardiographic responses to social stress in male rats
Physiol Behav
(1994) - et al.
Maternal separation decreases adult hippocampal cell proliferation and impairs cognitive performance but has little effect on stress sensitivity and anxiety in adult Wistar rats
Behav Brain Res
(2011) - et al.
Heart rate variability: a measure of cardiac autonomic tone
Am Heart J
(1994)
The Lambeth Conventions (II): Guidelines for the study of animal and human ventricular and supraventricular arrhythmias
Pharmacol Ther
Cardiac vagal tone: a physiological index of stress
Neurosci Biobehav Rev
Anxiety and autonomic flexibility: a cardiovascular approach
Biol Psychol
The effects of stress–anxiety and coping styles on heart rate variability
Int J Psychophysiol
“The rust of life”: impact of anxiety on cardiac patients
Am J Crit Care
Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy
Circulation
Phobic anxiety and risk of coronary heart disease and sudden cardiac death among women
Circulation
Tension and anxiety and the prediction of the 10-year incidence of coronary heart disease, atrial fibrillation, and total mortality: the Framingham Offspring Study
Psychosom Med
Anxiety predicts mortality and morbidity after coronary artery and valve surgery—a 4-year follow-up study
Psychosom Med
Association of anxiety and depression with all-cause mortality in individuals with coronary heart disease
J Am Heart Assoc
Anxiety and autonomic flexibility: a cardiovascular approach
Biol Psychol
Cited by (24)
Enhanced Myocardial Adenylyl Cyclase Activity Alters Heart-Brain Communication
2023, JACC: Clinical ElectrophysiologySelective breeding of rats for high (HAB) and low (LAB) anxiety-related behaviour: A unique model for comorbid depression and social dysfunctions
2023, Neuroscience and Biobehavioral ReviewsLow vagal tone in two rat models of psychopathology involving high or low corticosterone stress responses
2019, PsychoneuroendocrinologyHeart Rate Variability as a Translational Biomarker for Emotional and Cognitive Deficits
2019, Handbook of Behavioral NeuroscienceReduced NPY Y1 receptor hippocampal expression and signs of decreased vagal modulation of heart rate in mice
2017, Physiology and Behavior