Key words: Bipolar disorder � Major depression � Generalized anxiety disorder � Panic attack � Agoraphobia � Social phobia � Obsessive-compulsive disorder � Posttraumatic stress disorder � Heart disease
Correspondence: Prof. Carlo Faravelli, Dipartimento di Scienze Neurologiche e Psichiatriche, Università di Firenze, viale Morgagni 85, 50134 Firenze – Tel. +39 055 4298447 – E-mail: carlo.faravelli@unifi.it
Introduction
The relationship between heart diseases and psychiatric disorders has been widely studied: first, evaluating the incidence of psychiatric diagnosis in patients with cardiovascular diseases and, on the other hand, considering the risk of cardiovascular pathology in psychiatric patients.
This review focuses on of this second issue, and, in particular, on the possible increase of the risk of the occurrence of acute cardiac diseases in psychiatric patients (with affective and anxiety disorders) and of the mortality secondary to cardiovascular diseases.
All the studies reviewed concern the occurrence of cardiovascular diseases in patients with a psychiatric diagnosis according to the DSM-IV criteria (1) (2).
Methods
A literature search has been carried out in MEDLINE about heart disease and psychiatric disorders according to the following key words. Concerning the heart disease, the heart disease, heart failure, myocardial infarction and cardiovascular disease have been used as key-words combined with each psychiatric illness. Concerning the psychiatric disorders, the attention has been focused on mood disorders (major depression and bipolar disorder) and anxiety disorders (generalized anxiety disorder, panic disorder with and without agoraphobia, social phobia, obsessive-compulsive disorder, and posttraumatic stress disorder).
Researches about psychotropic drugs and psychiatric disorders have not been considered.
Affective disorders
Major depression
Patients with congestive heart failure (CHF) may have a high prevalence of depression, which may increase the risk of adverse outcome. Major depression is common in patients hospitalized with CHF and is independently associated with a poor prognosis (3) (4). Treatment and improvement of quality of life are strictly related to the prevalence and the relationship of depression to outcome of patients hospitalized with CHF.
For this reason, some studies investigated the relationship between heart failure and mood depression, in a perspective and in a retrospective way, trying to establish a possible link with the outcome.
Many studies investigated heart failure and depression both in special population (for example elderly people) and in community sample, and evaluating gender differences. On the other hand, many studies were conducted among hospitalized patients (3).
The majority of the studies used self administered questionnaires for depression at baseline and then a specific semi-structured interview (like SCID), in those who resulted positive to self administered test.
A 14 years follow up study was conducted in a community sample of 2501 individuals aged 65 years and older free of heart failure; it revealed that 132 women and 56 men scored as depressed at rating scale and that they were more likely to have hypertension, diabetes, and mobility-related functional limitations and were less likely to be male or married. At follow up those who were depressed tended to have a greater risk of heart failure (hazard ratio (HR) = 1.52), and the risk was significantly higher in women if compared to men. Concerning elderly people, depression is an independent risk factor for heart failure among women but not among men (5).
A study investigated 374 patients aged 18 years or older having New York Heart Association class II or greater CHF, an ejection fraction of 35% or less, or both, admitted to the cardiology service of one hospital. Patients with a Beck Depression Inventory (BDI) score of 10 or higher underwent a modified National Institute of Mental Health Diagnostic Interview Schedule to identify major depressive disorder. They assessed all-cause mortality and readmission rates 3 months and 1 year after depression. 35.3% had a BDI score of 10 or higher and 13.9% had major depressive disorder. Overall mortality was 7.9% at 3 months and 16.2% at 1 year. Major depression was associated with an increased and significantly higher mortality, readmission at 3 months and at 1 year and an higher risk of re-hospitalization at one year in depressed patients (odds ratio, 3.07; P = .005) (3).
Another study conducted among depressed elderly women observed that very often elderly depressed patients are admitted to a psychiatric hospital for a depression that is secondary to a serious medical illness and that patients who are at the first episode have an increased risk of morbidity and mortality (6).
Older patients hospitalized with congestive heart failure (CHF) had a diagnosis of major depression in 36.5%, (vs 25.5% of non CHF, p < 0.01). Compared with non depressed CHF patients, those with depression were more likely to have comorbid psychiatric disorders, severe medical illnesses, and severe functional impairment. CHF depressed patients used more outpatient and inpatients medical services, although this was largely due to the severity of their health problems. Patients often remained depressed for a prolonged period, and over 40% failed to remit during the year following discharge. Factors predicting slower remission included non health-related, stressful life events and low social support while physical health factors at baseline had little effect. The majority of depressed CHF patients did not receive treatment for their depression with either antidepressants or psychotherapy, and did not see mental health specialists any more frequently than did the non depressed ones (7).
Regarding to activity daily living, there is a strong and graded association between the severity of depressive symptoms at baseline and the rate of the combined end point of functional decline at six months.
After adjustment for demographic factors, medical history, baseline functional status and clinical severity, patients with 11 depressive symptoms or more, compared with those with less than depressive symptoms, had an 82% higher risk of either functional decline or death. A similar graded association was found for functional decline and death separately; however, after multivariate analysis, the association with mortality was less strong and no longer statistically significant.
Bipolar disorder
Cardiac dysfunctions in bipolar patients are not well investigated.
An increase of death has been noted for cardiovascular diseases in bipolar patients (8). This can be due to different factors: for example, the cholinergic and noradrenergic neurotrasmitters would be involved in both bipolar illness (9) and in hypertension (10), and this could increase the risk of cardiovascular disease in bipolar patients (8).
Rabb (11) suggests that recurrence in bipolar illness could have negatively influence in the cardiovascular system and predispose to disease.
There are some doubts about a direct correlation between these two pathologies and only a few systematic studies have been conducted in this field. Clinical reports are the most representative examples in literature.
However, there are clinical studies concerning mitral valve prolapse. Giannini and colleagues (12) found a prevalence in bipolar patients significantly more elevated than in unipolar patients and significantly greater than in the general population, while Ozeren and colleagues (13) found a low prevalence of this pathology in bipolar disorders. Both studies evaluated small samples (32 and 22 bipolar patients respectively).
Considering the risk factors for cardiac disease, it is important to notice that patients with major affective disorder had higher levels of plasma norepinephrine and higher pulse rates (tachycardia) than healthy control subjects, but their blood pressures were normal. These measurements were similar in manic, bipolar depressed, and unipolar patients (14).
Records of 366 bipolar patients are reviewed in relation to age of first psychiatric hospitalization. Late onset cases were matched to early onset cases and histories of vascular disease/risks and current cholesterol levels were compared. Vascular risks factors were greater and current cholesterol levels higher in the late onset group. Late onset mania was associated to greater vascular risk factors (15).
Anxiety disorders
Panic Disorder (PD)
Anxiety, particularly Panic Disorder (PD), seems common in cardiac patients. Golberg et al. (16) found a prevalence of 9.2% in a out patients population, moreover about 30% of the patients consulting in cardiology have been found to suffer with PD (17). Coryell et al. (18) found the risk for cardiovascular mortality among patients with probable Panic Disorder to be twice than expected from age, period and gender specific vital statistics for men. These results confirmed the previous findings (19) coming from the comparison between PD patients and surgical controls. All deaths among men with anxiety disorders were due to cardiovascular disease or suicide and all deaths among control men were due to other causes. PD patients, as a whole, were twice as likely as expected to die.
The high prevalence of PD among patients seen by cardiologists raises the question whether a specific relationship may exist between PD and some types of cardiac pathology.
In this sense, it is for instance interesting to notice that there is a high rate of co-occurrence between PD and mitral valve prolapse, but no convincing evidence of a cause-effect relationship or a common underlying mechanism has been found.
In a retrospective study examining the association between Panic Disorder and cardiovascular disorders in a random community center, Weissman and colleagues (20) found that participants with PD were at higher risk of reporting high blood pressure, heart attack, and stroke than the group of respondents with no psychiatric disorders. In particular, heart attacks were found to be secondary to respiratory panic attacks more likely than any other sub-type of panic attack (21). They hypothesized that persons with panic disorder could be less prudent in their diets, drinking, smoking or other health habits. However, other studies have shown an association between mental stress and myocardial ischaemia, independent of physical exertion (22).
Recent well conducted, prospective epidemiological studies confirmed the substantially increased risk of myocardial infarction and sudden death in patients with panic disorder (three to six fold increase). These patients seem to seat at the crossroads of cardiology and neuropsychiatry, and provide a clinical model for investigation of the relationship between stress and heart disease. The mechanism by which cardiac risk is increased in panic disorder is not known, but has been thought to involve activation of the sympathetic nerves of the heart, predisposing to ventricular arrhythmias, so that coronary artery spasm was thought to be the underlying mechanism of the ischaemia (23).
Patients with high levels of phobic anxiety were found to have a 3.77 relative risk of fatal coronary heart disease (CHD) (24), and may lead to physiologic worsening of that illness with more frequent episodes of chest pain (25). Moreover, phobia sub-scores were found to be the most significantly related to ischemic death. Still concerning phobia subscales, Kawachi and co-workers (26) found an increased risk for fatal CHD among participants with high levels of phobic anxiety and an higher risk of sudden cardiac death in men with low levels of anxiety.
Briefly, panic like anxiety is an independent risk factor for cardiovascular disease and, in particular, for cardiovascular death. In fact, sudden cardiac death is mainly attributable to ventricular arrhythmias in patients with CHD but can also occur in patients with structurally normal heart (27) (28).
Concerning cardiomyopathy (CMP), there is still a wide discussion. Kahn and co-workers (29) suggested a link between PD and idiopathic CMP in cardiac transplant candidates with end stage CMP speculating that increased sympathetic tone might be a common factor in the pathogenesis of both PD and CMP. But these findings have not been confirmed by Griez and co-workers (30).
The sympathetic tone seems to be involved even in the etiopathogenesis of essential hypertension. In this case it may contribute to left ventricular hypertrophy and to the commonly associated metabolic abnormalities of insulin resistance and hyperlipidaemia (31). Finally, in cardiac failure, the sympathetic nerves of the heart are preferentially stimulated. Noradrenaline released from the failing heart at rest in untreated patients is increased as much as 50 fold, similar to the level seen in the healthy heart during the near-maximal exercise. Activation of the cardiac sympathetic outflow provides adrenergic support to the failing myocardium, but a cost of arrythmia development and progressive myocardial deterioration.
There is gathering evidence that PD and mental stress are involved in “triggering” clinical cardiovascular events. The mechanisms involved are not entirely clear, but activation of the sympathetic nervous system seems to be of prime importance. Moreover, despite the interesting time of evidence suggesting a link between panic-like anxiety and cardiovascular diseases, it is too early to say that PD per se, is a risk factor for cardiovascular pathology, further investigations are necessary to improve the knowledge in this field.
Generalized Anxiety disorder (GAD)
A review of the international literature has not put in evidence any study regarding the prevalence of GAD in people who are affected by heart failure, but there are some results about the incidence of GAD in patients with heart failure showing a higher rate in this type of population (32). Among primary care patients (33), those with chronic medical illnesses, including heart failure, had low rates of lifetime (1.5% to 3.5%), and concurrent phobia and GAD were more common (10.4% to 12.4% current GAD), especially among depressed patients (25% to 54% current GAD). Depending on the type of medical illness or depression, 14% to 66% of primary care patients had at least one concurrent anxiety disorder (34).
There are also some studies regarding the prevalence of GAD in people having received a heart transplantation (35) (36) but there are not assessment before the transplantation.
On the basis of such literature it is not possible to say that GAD represents a risk factor for the development of heart failure but it is possible to say that people with heart failure more easily develop GAD and other psychiatric disorders.
Concerning coronary heart disease, in a review Kubzansky et al. (37) confirmed empirical evidence for a strong association between anxiety and coronary heart disease, with an increased risk in chronic anxiety patients of coronary heart disease depending also by health behaviors (e.g. smoking), promoting atherogenesis (e.g. via increased risk of hypertension) and triggering fatal coronary events, either through arrhythmia, plaque rupture, coronary vasospasm, or thrombosis [37].
Finally, anxiety appears to be associated with an abnormal cardiac autonomic control, which may indicate an increased risk of fatal ventricular arrhythmias (37).
Social Phobia (SP)
In the literature there are only a few studies concerning the possible correlation between social phobia and heart diseases. The majority are about the relationship of social phobia and some attitudes linked to an increased risk of cardiovascular pathology (e.g. smoking or alcohol abuse) (38)-(40). Only two studies concern social phobia and mitral valve prolapse: Chaleby et al. (41) found that the prevalence of echocardiogram evidence of mitral valve prolapse in social phobic patients was major than controls (8/30 vs 2/30). Benca et al. (42) also studied the response to the treatment with imipramina in patients with social phobia and mitral valve prolapse. Anyway, there are no studies concerning social phobia as a potential risk factor for cardiovascular diseases, neither studies regarding the increased risk of mortality after a cardiovascular accident among patients with diagnosis of social phobia in comparison to control subjects.
Obsessive-Compulsive disorder (OCD)
The findings concerning the relationship between cardiac disease and OCD a particularly rare in the literature. In a study comparing serum cholesterol levels of anxiety disorder patients, obsessive-compulsive disorder patients and normal control subjects (n = 60 in each group); OCD patients with any other anxiety disorder and OCD patients without any other anxiety disorder had more elevated cholesterol levels if compared with normal control subjects. These data support the assumption that elevation in cholesterol level is not a specific feature of panic disorder (as most assumed), but more generally associated with anxiety disorders. Increased cholesterol levels in patients with anxiety disorders and OCD may be of clinical relevance (43) especially because they are very important risk factors for cardiac diseases.
Males with anxiety disorders appear to have increased mortality due to circulatory system disease, and Type A behavior is a risk factor for coronary heart disease (CHD). In a study evaluating the incidence of type A behavior in anxious patients, the increased incidence of Type A behavior in male, but not in female, anxious patients suggested a mechanism for increased mortality due to circulatory disease in male anxiety patients (44).
Post traumatic stress disorder (PTSD)
The link between PTSD and cardiovascular diseases has not been deeply studied during the last decades. However, there are interesting findings concerning this relationship. It is nowadays excepted that the body’s principal adaptive responses to stress stimuli are mediated by an intricate stress system including the hypothalamic-pituitary-adrenocortical axis and the sympathoadrenal system. Dysregulation of the system, caused by the cumulative burden of repetitive or chronic environmental stress challenges contributes to the development of a variety of illnesses including hypertension and atherosclerosis. In particular, the neuroendocrinology of PTSD is noteworthy, being characterized in many adult victims by enhanced negative feedback sensitivity of glucocorticoid receptors in the stress response system, and lower than normal urinary and plasma cortisol levels. Adult patients with PTSD also exhibit exaggerated catecholamine responses to trauma-related stimuli (45). According to this biological point of view, in a study evaluating World War II Resistance veterans, these subjects scored highest on cardiovascular disease (CVD) risk factors (i.e., angina pectoris, type A behavior, life stressors, and vital exhaustion), except smoking. Fifty-six percent of these veterans were currently suffering from PTSD. They reported CVD risk factors, in particular type A behavior and vital exhaustion, more often than veterans without PTSD (46). As concern coronary artery disease, Pedersen (47) observed that some patients with coronary artery disease are at risk of developing post-traumatic stress disorder, although the prevalence varies considerably, and only some cardiac patients may develop post-traumatic stress that anyway could have a potential role in reinfarctions and mortality. It has also been observed a strict link between PTSD and myocardial infarction, Kutz (48) found, in a study examining the prevalence of post-traumatic stress disorder in a sample of 100 Israeli myocardial infarction (MI) patients, that chronic PTSD was diagnosed in 16% of these patients and acute (PTSD) in 9%. On the other hand, in a study conducted in twenty-three patients consecutively admitted for first myocardial infarction it was found that, after two years, 1 of 18 survivors had been suffering from a partial post-traumatic stress disorder (49). Finally, the electrocardiogram abnormalities among men with stress-related psychiatric disorders were studied and it was found that PTSD was associated with atrioventricular (AV) conduction defects (OR = 2.81, 95% CI = 1.03-7.66, p < 0.05) and infarctions (OR = 4.44, 95% CI = 1.20-16.43, p < 0.05). These findings suggest a possible role of psychological distress in arterial endothelial injury and coronary heart disease (CHD) and consequently in atrioventricular conduction defects and infarctions (50). Studies also show Posttraumatic Stress Disorder victims have higher circulating catecholamines and other sympathoadrenal-neuroendocrine bioactive agents implicated in arterial damagein CHD.
Conclusions
Anxiety and affective disorders seem common in patients with a cardiovascular disease, but the results are contradictory and not exaustive about the underlying mechanism of such a comorbidity. Unfortunately, several studies concerning affective disorders focus on psychiatric illness, especially depression, occurring after a heart disease, while the studies concerning anxiety disorders usually investigate the cardiac disease in anxiety patients.
Briefly, cardiovascular diseases occurring after a psychiatric disorder and the corresponding relationship have not been well investigated, excepted for the evaluation of role of the autonomic system dysregulation in both anxiety and affective disorders.
Moreover, the majority of these studies consider cardiac disorders and psychiatric illnesses in special population (elderly people or hospitalized patients) proposing results not applicable to the wide population of psychiatric patients (3).
On the other hand, psychiatric studies evaluate community samples are rare in the literature (51).
Besides the above limitations of the studies of the literature, it is evident that major depression and bipolar disorders are associated with an increased mortality for cardiovascular disease and an increase of death.
Similarly among patients with panic disorder the risk for cardiovascular mortality is twice than expected and several studies confirmed the substantially increased risk of myocardial infarction and sudden death in patients with panic disorder; anyway, anxiety disorders, and particularly panic disorder, are independent risk factors for cardiovascular disease and death.
There are no studies concerning GAD, social phobia and OCD as potential risk factors for cardiovascular disease, neither studies regarding the increased risk of mortality after a cardiovascular accident. However, in anxiety patients there is an increase of risk behaviors linked to cardiovascular disease like tobacco smoking and alcohol abuse, and higher cholesterol levels as risk factors. Moreover, it has been suggested that particular type of personality like obsessional neurosis and phobic anxiety are associated with a relative risk of fatal ischaemic disease (52).
Further investigations are necessary to improve the knowledge about the relationship between medical and psychiatric illnesses.
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