Heart rate and QT interval variability: abnormal alpha-2 adrenergic function in patients with panic disorder
Introduction
Anxiety disorders are common and are reportedly associated with an increase in cardiovascular mortality (Coryell et al., 1986, Weissmann et al., 1990, Kawachi et al., 1994). Panic disorder is one such condition with pronounced autonomic symptoms such as palpitations, difficulty to breathe, heart pounding, tremulousness and fear of dying of a heart attack (Spitzer et al., 1987). Thus, the investigation of abnormal cardiovascular function in panic disorder is of particular interest. Several previous studies have shown that decreased beat-to-beat heart rate (HR) variability and increased QT interval variability are associated with increased cardiac mortality (Malik and Camm, 1990, Malliani et al., 1991, Atiga et al., 1998). Spectral power in the high frequency (HF: 0.15–0.5 Hz) band reflects respiratory sinus arrhythmia (RSA) and, thus, cardiac vagal activity. Low frequency (LF: 0.04–0.15 Hz) power is related to baroreceptor control and is dually mediated by vagal and sympathetic systems (Akselrod et al., 1981, Pomeranz et al., 1985). Decreased HR variability (HRV) is an important predictor of sudden cardiac death in patients with cardiac disease as well as normal subjects (Kleiger et al., 1987, Bigger et al., 1992, Molgaard et al., 1991). In several previous reports, we found a relative decrease in cardiac vagal function and an increase in sympathetic function in patients with panic disorder (Yeragani et al., 1990, Yeragani et al., 1992, Yeragani et al., 1993, Yeragani et al., 1994, Yeragani et al., 1995, Yeragani et al., 1998, Yeragani et al., 2000a, Radhakrishna and Yeragani, 2001).
A recent measure, beat-to-beat QT interval variability, appears to be a better indicator of cardiac sympathetic function as it appears to be influenced by sympathetic challenges such as a change from supine to standing posture and intravenous isoproterenol infusions in addition to mental stress (Negoescu et al., 1997, Dinca-Panaitescu et al., 1999, Yeragani et al., 2000b, Pohl et al., 2003). QT interval on the surface electrocardiogram (ECG) reflects time for repolarization, and several studies have shown a relationship between prolonged QTc and life-threatening arrhythmias (Jervell and Lange-Nelson, 1957, Schwartz and Wolf, 1978). Recent literature also implicated abnormal repolarization in serious ventricular arrhythmias (Binah and Rosen, 1992, Tomaselli et al., 1994). We have recently found that patients with panic disorder and depression have higher QT variability (Yeragani et al., 2000c), which is reportedly associated with symptomatic patients with cardiomyopathy and also sudden cardiac death (Berger et al., 1997, Atiga et al., 1998, Atiga et al., 2000). Isoproterenol, a beta-adrenergic agonist, increases QTvi (common logarithmic value of QT variance corrected for mean QT interval squared/HR variance corrected for mean HR squared) in humans. This increase is more significant in patients with panic disorder compared to the increase in normal controls (Pohl and Yeragani, 2001).
Increased sympathetic activity may play an important role in the pathophysiology of anxiety (Holmberg and Gershon, 1961, Redmond et al., 1976, Charney and Redmond, 1983). Yohimbine is an alpha-2 adrenergic antagonist that increases sympathetic outflow and clonidine, an apha-2 adrenergic agonist, has the opposite effect. In non-human primates and humans, yohimbine produces symptoms of anxiety, and in humans, it produces an increase in plasma norepinephrine (NE) and 3-methoxy-4-hydroxy phenylethylene-glycol (MHPG), and it also produces anxiety more frequently in patients with panic disorder compared to normal controls (Charney et al., 1982, Charney et al., 1984, Charney et al., 1989, Coplan et al., 1992, Charney and Redmond, 1983, Gurguis et al., 1997, Gurguis and Uhde, 1990). Thus, there is a remarkable consistency of the anxiogenic effects of yohimbine. We have previously reported a significantly increased responsiveness of patients with panic disorder to the adrenergic effects of yohimbine compared to normal controls on standing LF power of HR (Yeragani et al., 1992).
Clonidine has exactly the opposite pharmacological effect of yohimbine and has a central hypotensive effect (Srimal et al., 1977). Clonidine has an anxiolytic effect in patients with anxiety (Uhde et al., 1989). However, this anxiolytic effect is short-term and does not persist with long-term administration in patients with panic disorder. Several reports suggest that clonidine improves HR variability measures, especially increasing the HR high frequency (HF: 0.15–0.5 Hz) power in cardiac patients (Girgis et al., 1998). Clonidine significantly decreases HR and blood pressure (BP) oscillations, especially in the low frequency region (LF: 0.19–0.61 Hz in rats; in humans it is approx. 0.1 Hz) (Grichois et al., 1990, Elghozi et al., 1991). Similar effects of decreased LF power and increased HF power were reported during clonidine administration by other investigators (Girgis et al., 1998, Lazzeri et al., 1998a, Lazzeri et al., 1998b). We have recently shown that endurance exercise training for 8 weeks produces a highly significant decrease in LF power of HR and BP in rats (DiCarlo et al., 2002), which is most likely related to the sympatholytic effects of endurance exercise training. Thus, sympatholytic effects are associated with decreased LF oscillations of HR and BP. Though the finding is not directly related, it should also be noted that the alpha-2 adrenergic binding sites for clonidine were significantly lower in patients with anxiety compared to normal subjects (Cameron et al., 1990).
Uhde et al. (1986) have reported blunted growth hormone response to clonidine in panic disorder patients. Abelson et al., 1991, Abelson et al., 1992 have also found similar blunted growth hormone responses in patients with panic disorder as well as generalized anxiety disorder.
The aim of the present study was to evaluate the effects of yohimbine and clonidine on beat-to-beat HR and QT variability measures, which can be related to the alpha-2 adrenergic effects of these drugs. We specifically hypothesized that patients with panic disorder would have significantly increased responsiveness to yohimbine as well as to clonidine in regards to their QT variability measures, especially QTvi, compared to normal controls.
Section snippets
Subjects
Twelve normal controls (eight males and four females; age: 32±7 years) and 19 patients with panic disorder (eight males and 11 females; age: 34±7 years) participated in this study. We have used means and standard deviations (S.D.) throughout the text and tables. These studies were approved by the Institutional Review Board at Wright State University School of Medicine, Dayton, OH, USA. All subjects were healthy and informed consent was obtained prior to their participation in these studies. The
Results
Table 1, Table 2 show the HR and QT variability values of supine and standing postures for patients and controls for all three drug conditions with significant post-hoc differences. Table 3 shows the anxiety scores for all three conditions.
Table 4, Table 5 show the results of three-way ANOVA for supine and standing postures for QT and HR variability. A significant group effect or an interaction between the grouping factor and the drug condition relates to the differences between patients and
Discussion
To our knowledge, this is the first report on the effects of yohimbine and clonidine on beat-to-beat QT interval time series comparing patients with panic disorder to normal controls. The relative excess of males in the control group may not explain these findings, as there was no gender effect. We have concentrated on the effects of the study drugs mainly on QT variability, as QTvi may be a better indicator of cardiac sympathetic function than HR variability.
Acknowledgements
This work was supported by the NIMH Grant R0-1 MH50752 to Dr Vikram K. Yeragani.
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