Elsevier

Physiology & Behavior

Volume 128, 10 April 2014, Pages 16-25
Physiology & Behavior

Low vagally-mediated heart rate variability and increased susceptibility to ventricular arrhythmias in rats bred for high anxiety

https://doi.org/10.1016/j.physbeh.2014.01.033Get rights and content

Highlights

  • Anxiety-cardiovascular comorbidity is a relevant clinical issue.

  • Cardiac autonomic modulation is investigated in a rat model of trait anxiety.

  • A negative relationship between cardiac vagal tone and trait anxiety is documented.

  • Low vagal tone is associated with signs of increased arrhythmogenic susceptibility.

Abstract

In humans, there is a documented association between anxiety disorders and cardiovascular disease. Putative underlying mechanisms may include an impairment of the autonomic nervous system control of cardiac function. The primary objective of the present study was to characterize cardiac autonomic modulation and susceptibility to arrhythmias in genetic lines of rats that differ largely in their anxiety level. To reach this goal, electrocardiographic recordings were performed in high-anxiety behavior (HAB, n = 10) and low-anxiety behavior (LAB, n = 10) rats at rest, during stressful stimuli and under autonomic pharmacological manipulations, and analyzed by means of time- and frequency-domain indexes of heart rate variability. During resting conditions, HAB rats displayed a reduced heart rate variability, mostly in terms of lower parasympathetic (vagal) modulation compared to LAB rats. In HAB rats, this relatively low cardiac vagal control was associated with smaller heart rate responsiveness to acute stressors compared to LAB counterparts. In addition, beta-adrenergic pharmacological stimulation induced a larger incidence of ventricular tachyarrhythmias in HABs compared to LABs. At sacrifice, a moderate increase in heart-body weight ratio was observed in HAB rats. We conclude that high levels of anxiety-related behavior in rats are associated with signs of i) impaired autonomic modulation of heart rate (low vagally-mediated heart rate variability), ii) poor adaptive heart rate responsiveness to stressful stimuli, iii) increased arrhythmia susceptibility, and iv) cardiac hypertrophy. These results highlight the utility of the HAB/LAB model for investigating the mechanistic basis of the comorbidity between anxiety disorders and cardiovascular disease.

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).

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