The neurocircuitry of anxiety has been postulated to arise from the amygdala, the brain area that registers the emotional significance of environmental stimuli and stores emotional memories. The efferent pathways from the central nucleus of the amygdala travel to a multiplicity of critical brain structures, including the parabrachial nucleus (resulting in dyspnea and hyperventilation), the dorsomedial nucleus of the vagus nerve and nucleus ambiguous (activating the parasympathetic nervous system), and the lateral hypothalamus (resulting in SNS activation). Through reciprocal neuronal pathways connecting the amygdala to the medial prefrontal cortex, cognitive experience of the specific anxiety disorder differs, although fear symptoms may overlap. During panic attacks the fear is of imminent death; in social phobia, the fear is of embarassment; in postraumatic stress disorder, the traumatic memory is remembered or reexperienced; in obsessive-compulsive disorder, obsessional ideas recur and intrude; and in generalized anxiety disorder, anxiety is “free-floating” (i.e., not conditioned to specific situations or triggers).
Described in the past with terms such as cardiac neurosis, irritable heart syndrome, battle fatigue, and soldier’s heart, panic disorder is the anxiety disorder most often associated with cardiovascular symptoms of chest pain, tachycardia, and dyspnea. Discrete panic attacks can be induced in the laboratory setting, especially in patients with panic disorder, by a variety of stimuli: sodium lactate, caffeine, isoproterenol, serotonin receptor agonist m-chlorophenylpiperazine (m-CPP), cholecystokinin tetrapeptide (CCK4), inhalation of CO2-enriched air, and voluntary acute hyperventilation of room air. The common element among these disparate inducers may be their ability to stimulate the respiratory rate with the induction of an accompanying subjective sense of breathlessness.
Although some researchers have proposed that patients with panic disorder have only a heightened sensitivity to and develop a learned intolerance of tachypnea, the higher concordance rate of panic disorder observed in monozygotic as compared with dizygotic twins and evidence of altered respiratory rhythym during sleep provide proof of a genetic diathesis and a biological abnormality, respectively, underlying the phenotype of panic disorder.
Depression and Comorbid Medical Illness
Depression and Cardiovascular Disease: Clinical Samples
Anxiety Disorders and Cardiovascular Disease
Diminished Heart Rate Variability
Hypothalamic - Pituitary - Adrenocortical and Sympathomedullary Hyperactivity
Alterations in Platelet Receptors and/or Reactivity
Increased Secretion of Proinflammatory Cytokines
Treatment of Major Depression and Anxiety Disorders in Patients with Cardiovascular Disease
Effects of Mood and Anxiety Disorders: Future Directions for Research
A Focus on the Cardiovascular System
Although the neurobiology of specific anxiety disorders has not been explored as fully as that of unipolar depression, potential neurochemical, neuroendocrine, and neuroanatomic alterations have not only been identified but have been increasingly scrutinized. Patients with major depression or anxiety disorders may experience common symptoms (e.g., alterations in psychomotor activity, impairment of sleep, increased appetite, and reduced concentration). Moreover, there are several shared neurobiological findings between patients with certain common syndromal anxiety disorders and those with depression, although differences also exist. The neurobiology of patients with certain anxiety disorders is subsequently reviewed, with attention to mechanisms that contribute to the development of cardiovascular disease and/or cardiac-related mortality: HPA axis activity, sympathomedullary activity, diminished HRV, and alterations in platelet receptor number or function.
While limited and inconsistent evidence suggests that alterations of HPA axis activity occur across the anxiety disorder spectrum, altered HPA axis activity has been most consistently documented in individuals with posttraumatic stress disorder (PTSD). In nearly all controlled studies of PTSD patients, alterations of HPA axis hyperactivity have been documented, including elevations of cerebrospinal fluid (CSF) CRF concentrations and blunting of the ACTH response to CRF stimulation.
In comparison to control subjects, however, PTSD patients generally exhibit reduced plasma cortisol concentrations, diminished 24-h urinary cortisol concentrations, and a greater suppression of plasma cortisol concentrations in response to low doses (e.g., 0.5 mg) of dexamethasone. However the two studies that measured CSF CRF concentrations in PTSD found results identical to those repeatedly reported in depression: elevated CSF CRF concentrations. Whether patients with PTSD experience an increased (or decreased) relative risk of CVD is not known. Potential confounds in those studies include the very high rate of comorbid substance abuse and alcoholism as well as tobacco abuse in PTSD patients. Patients with panic disorder do not appear to exhibit alterations in HPA axis function consistently; scrutiny continues of patients with social phobia, generalized anxiety disorder, and obsessive-compulsive disorder.
Sympathomedullary function has been investigated intensively in patients with panic disorder. As was discussed previously, plasma concentrations of catecholamines are determined by the rate of release, local metabolic degradation, synaptic reuptake, and redistribution into other extravascular spaces. To examine systemic as well as regional sympathomedullary kinetics, investigators infuse intravenous trace amounts of radiolabeled NE and epinephrine (EPI). Arterial or “arterialized venous” samples of endogenous catecholamines are then obtained, and a “compartmental analysis” is performed to mathematically fit the data into a two-compartment (“whole-body” versus “cardiac” or “extravascular” versus “vascular”/plasma compartments) model. Whole-body NE “spillover” (the rate of NE appearance in plasma), a sensitive measure of systemic SNS activity, is similar under basal conditions in panic patients and control subjects and increases to a similar degree in both groups under laboratory mental stress. Panic patients do, however, exhibit significantly higher cardiac spillover rates of coronary sinus (cardiac-derived) EPI under basal conditions, increased whole-body EPI secretion during laboratory mental stress, and surges of EPI whole-body spillover during panic attacks. Such increases in EPI in panic patients presumably are due to “loading” of sympathetic neuronal stores by uptake from plasma during surges of EPI secretion during panic attacks. Further investigation of cardiac and/or systemic sympathomedullary activation during spontaneous or pharmacologically provoked panic attacks is needed to confirm these findings, along with prospective investigations of the cardiac-related risk of patients with panic disorder. However, multiple prospective cohort studies (which control for other accepted risk factors for IHD) report that increasing severity of anxiety is associated with an increased risk for developing elevated systolic blood pressure or hypertension. However, given the comorbidity between anxiety and depressive symptoms and syndromes, further studies are required to determine whether the evidence of increased risk for the development of CAD (or hypertension) in anxiety disorder patients is independent of the contribution of depression.
Another area awaiting investigation in patients with anxiety disorders is platelet receptor function, particularly the receptors most integral to thrombovascular repair and disease. Psychobiological studies of patients with panic disorder, in contrast to reports of patients with major depression, have not detected alterations of platelet 5-HT transporters and platelet 5-HT2 receptors. In comparison to control subjects, however, patients with panic attacks have been reported, like those with depression, to exhibit increased plasma concentrations of PF4 and β-TG, providing evidence of increased platelet secretion. Moreover, after treatment of panic patients with alprazolam, plasma concentrations of these alpha granule-specific proteins were reduced significantly. The presence of anxiety disorders has been hypothesized to trigger coronary events through atherosclerotic plaque rupture, coronary vasospasm, ventricular arrhythmias, or atrial arrhthymias. Panic-induced hyperventilation is a well-known precipitant of coronary spasm, which in turn may induce ventricular arrhythmias and MI.
Emergency room physicians and cardiologists are well acquainted with the challenges of evaluating patients with an acute onset of chest discomfort, combined with painful and overwhelming anxiety symptoms, which may or may not be associated with clinically significant cardiovascular disease (Table 91–6). The most compelling evidence regarding the association of anxiety disorders and cardiovascular dysfunction comes from reports of abnormal cardiac autonomic control. Examination of HRV in patients with anxiety disorders has revealed that patients with panic disorder and patients with generalized anxiety disorder exhibit reductions in high-frequency HRV. As was noted earlier, diminished HRV increases the risk of arrhythmias and sudden cardiac death. Indeed, patients with panic disorder or agoraphobia exhibit a higher density of PVCs in comparison to patients with other anxiety disorders and normal comparison subjects. Whether patients with panic disorder (or other anxiety disorders) exhibit increased rates of sudden cardiac death remains to be determined.
Although so-called mental disorders may produce effects on cardiovascular function, perhaps less well understood are the cardiovascular contributions to certain anxiety disorders. Whether cardiovascular abnormalities or dysfunction reliably produce symptoms of anxiety is an intriguing area of investigation (e.g., is worsening of CHF associated with an increased incidence of panic attacks?). In comparison to gender- and age-matched controls, individuals with cardiac arrhythmias exhibited significantly higher self-reported anxiety scores. Whether a causal biological mechanism exists between PVCs and anxiety symptoms or disorders or there is merely an association remains to be determined.
Certainly, the impact of anxiety disorders on the development of and worsening of CVD should be more completely discriminated from the contributions of depressive symptoms or syndromes. Such knowledge carries the promise of anxiety symptom reduction and improved quality of life and the potential for new treatment modalities to enhance cardiovascular function in patients with CVD who have comorbid anxiety disorders.
Revision date: June 21, 2011
Last revised: by Janet A. Staessen, MD, PhD