Is the autonomic dysfunction the missing link between panic disorder, hypertension and cardiovascular disease?

At first glance, it might be somewhat surprising to see an article dealing with panic disorders in a scientific journal primarily devoted to the pathophysiological and clinical aspects of the hypertensive state, such as the Journal of Hypertension [1]. However, there are a number of sound reasons that make this clinical entity of potential interest to the readership of the journal. First, several studies have documented that the prevalence of panic disorders is much greater in hypertensive than in normotensive people [2–4]. Furthermore, a noticeable fraction (approximately one-third) of patients suffering from resistant hypertension display several symptoms which are typical of the clinical picture of this disease [5–7]. Finally, panic disorders and panic attacks have been reported to be associated with symptoms of coronary artery disease, as well as with an increased incidence of cardiac dysrhythmias and sudden death [2,3–8]. In this issue of the journal, Lambert et al. [1] report on the results of a study aimed at investigating the behaviour of the neuroadrenergic cardiovascular function, as well as of the baroreflex cardiovascular control, in a group of patients suffering from panic disorder. Data were compared with those obtained in healthy individuals well matched with the previously mentioned group for a number of confounding variables (gender, body weight and blood pressure). The hypothesis tested by the investigators is a fascinating one, namely the possibility that a sympathetic overactivity and a related baroreflex dysfunction would be responsible for several of the clinical manifestations of the disease, including blood pressure elevation itself. Adrenergic overdrive in panic disorder: a fascinating but unconfirmed hypothesis As previously documented in other conditions at increased cardiovascular risk, such as essential hypertension and obesity [9,10], assessment of sympathetic function via measurement of circulating norepinephrine levels in panic disorders failed to provide a clearcut answer to the question of whether adrenergic activation does occur in this clinical syndrome [11–13]. However, in contrast to what sophisticated and sensitive approaches employed to investigate adrenergic function, such as the radiolabelled norepinephrine technique and microneurography, have shown in hypertension and in obesity [9,10] (i.e. a marked sympathetic activation), in panic disorders both norepinephrine spillover and muscle sympathetic nerve traffic values appear to be within the normal range [1,14]. Although, the results of the microneurographic study by Lambert et al. [1] appear to confirm previous data [11,13], they should be interpreted with some caution. First, in patients with panic disorder, the average sympathetic nerve traffic values, although not statistically different from those displayed by healthy subjects, appear to be approximately 30% higher. Thus, it cannot be ruled out that increasing the sample size would have yelded a statistically significant difference. Furthermore, it is also possible that sympathetic overactivity, rather than being a feature common to the whole group of patients suffering from this clinical syndrome, might be peculiar to a subgroup, which in turn might be more susceptible to the development of the hypertensive state and/or to other cardiovascular diseases. A further important consideration of the results of the study by Lambert et al. [1] refers to data having been collected in an event-free period (i.e. outside the panic attacks). It cannot be excluded that, during the acute episodes, these patients do display a state of sympathetic overactivity. This possibility seems to be indirectly confirmed by the finding that 24-h ambulatory blood pressure values in patients with panic disorder are within the normal range, while they undergo a marked and prolonged blood pressue increase, coupled with a pronounced tachycardic response, during panic attacks [15]. Whether these haemodynamic changes, which in other conditions and pathological states are often markers of adrenergic activation, are linked with and triggered by an increase in sympathetic nerve firing rate remains to be seen. Behaviour of the baroreflex function in panic disorder Lambert et al. [1] also investigated the patterns of the spontaneous baroreflex control of sympathetic as well as parasympathetic neural outflow in their patients. The results are intriguing because baroreflex control of heart rate, predominantly vagal in nature, appeared to be within the normal range, while baroreceptor control of peripheral sympathetic nerve traffic displayed a significant potentiation. What might be the pathophysiological implications of this finding? Two mutually exclusive hypotheses can be advanced. First, because an enhanced baroreflex sensitivity means there are greater adrenergic responses to blood pressure oscillations (which are potentiated in the early hyperventilatory phases of the panic attack), this dysfunction might be regarded as the mechanism promoting sympathetic activation and blood pressure increase during an acute episode of panic disorder. Alternatively, because an enhanced baroreflex control of sympathetic drive would imply greater sympathoinhibitory effects, it is possible that, during panic attacks, a baroreflex-mediated withdrawal triggered by the blood pressure increase does occur. This hypothesis would therefore suggest that the blood pressure elevation is not directly mediated by a neuroadrenergic activation during panic attacks and that other factors are therefore responsible for this haemodynamic change. Involvement of alternative reflex pathways From a theoretical viewpoint, an enhanced baroreflex modulation of sympathetic neural drive does not appear to be the only dysfunction characterizing the autonomic profile of patients with panic disorder. As shown in Figure 1, it may be that, during panic attacks, the hyperventilation-induced respiratory alkalosis causes a relative tissue hypoxia and thus triggers a peripheral chemoreceptor stimulation. In turn, this would lead to a marked sympathetic activation which, by acting on different cardiovascular districts (myocardium, coronary arteries, systemic circulation), might favour the development of cardiac dysrhythmias, ischaemic coronary heart disease and hypertension. Originally advanced a few years ago [7], this hypothesis, although so far never tested in ad-hoc studies, is worthy of future attention. If chemoreflex dysfunction was confirmed to be a feature of panic disorders, this alteration might indeed represent the link between this disease and the hypertensive state, characterized in a number of studies by an alteration in chemoreceptor control of neuroadrenergic cardiovascular drive [16–18].Fig. 1: Possible mechanisms responsible for chemoreceptor activation during a panic attack. The adverse cardiovascular consequences of the chemoreflex-dependent sympathetic activation are also shown.