The Problem
Both cardiovascular diseases (CVD) and mental disorders are major public health issues, which lead to increased disability and mortality. CVD are the worldwide leading cause of death and are responsible for around four million deaths each year in Europe. Mental disorders also demonstrate high lifetime prevalence. For ex-ample, the National Comorbidity Survey (NCS), a population-based study in the USA, revealed that as many as 48.7% of the respondents re-port at least one lifetime disorder, with the most frequent being substance abuse/dependence (35.4%), followed by anxiety (19.2%) and mood disorders (14.7%)[1]
reported in European populations[2 3]. A recent WHO projection concluded, that by 2030, uni-polar depressive disorders and ischemic heart disease will be among the three leading causes of disease burden worldwide[4].
In addition, there is evidence indicating that CVD and mental disorders co-occur more fre-quently than would be expected by chance[5].
The association between mental disorders and CVD
It is well documented that the prevalence of de-pression is increased among patients with vari-ous manifestations of coronary artery diseases (CAD)[6].
1. Department of Medicine, Internal Medicine
2. Department of Psychiatry, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
CORRESPONDENCE
Peter Vollenweider, Service de Médecine Interne, BH 10-624,
CHUV 1011 Lausanne, Switzerland
Phone: +41 21 314 09 63 Fax: +41 21 314 08 71 E-mail:
peter.vollenweider@chuv.ch
ACKNOWLEDGEMENTS
The CoLaus/PsyCoLaus study is supported by research grants from the Swiss National Science Foundation (grants no: 33CSCO-122661 and 3200B0–105993), from GlaxoSmithKline and the Faculty of Biology and Medicine of Lausanne, Switzerland. The authors also express their grati-tude to the participants in the Lausanne CoLaus study.
ISSN 2042-4884
ABSTRACT
Cardiovascular diseases (CVD), their well-established risk factors (CVRF) and mental disorders are common and co-occur more frequently than would be expected by chance. However, potential causal mechanisms underlying their association still need to be elucidated. Several non-mutually exclusive hypotheses have been suggested to explain this association: a) mental disorders could increase vulnerability to CVD through poor health behaviour including smoking, unbalanced diet,
the development of mental disorders; or c) mental disorders and CVD/CVRF could share risk factors such as common metabolic processes or common genes. Disentangling some of these mechanisms will require studying the temporal relationship of the appearance of CVD and mental disorders.
Herein we review the existing epidemiological evidence of an association between these two types
CoLaus/PsyCoLaus study cohort, a population-based in Lausanne, Switzerland designed to address some of these questions.
Cardiovascular Diseases and Mental Disorders:
Bidirectional Risk Factors?
Peter Vollenweider MD
1, Gérard Waeber MD
1, François Bastardot
1& Martin Preisig MD
2Received 17/12/2010, Reviewed 30/12/2010, Accepted 17/01/2011
DOI: 10.5083/ejcm.20424884.23
Similarly, depression can occur from 20% up to
stroke, with poststroke depression occurring in up to 30% of the patients[7]. The development of psychiatric symptoms is associated with a poor functional prognosis and a negative impact on the patient’s quality of life. Conversely, in pop-ulation-based prospective studies, individuals with depression or depressive symptoms have increased cardiovascular morbidity and mortal-ity[8]. However, the large majority of these epi-demiological studies rely on depression scales or self-rating questionnaires for depression rather than diagnostic interviews and did not
mental disorders such as anxiety and substance use disorders.
As these studies could not or only partially ad-just for the presence of CVRF other than depres-sion, the question of whether or not depression is an independent risk factor for CVD is still not resolved. In addition, not only depression but
in patients with CAD [9]. Potential mechanisms involved in this association of CVD and mental disorders have only been partially elucidated. Several non-mutually exclusive hypotheses have been suggested to explain this association: a) mental disorders could increase vulnerability to CVD; b) CVD or their treatment could favour the development of mental disorders and c) CVD/CVRF could share common pathogenic processes.
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Potential mechanisms underlying increased vulnerability to CVD in individuals with mental disorders
Several mechanisms have been postulated, starting with the fact that subjects with mental disorders may display damaging health behaviours. For example, depression and anxiety disorders are as-sociated with poor health behaviour such as smoking or unbal-anced diet. In addition, depressed patients are less compliant with medical therapy[10], which could contribute to an increased risk of CVD in individuals treated for high blood pressure, dyslipidaemia or diabetes.
Furthermore, hormonal factors have also been suggested to play a role. In particular, the hypothalamic-pituitary-adrenocortical axis (HPA) and the sympatho-medullary system are two primary com-ponents of the stress response and could mediate the association between depressive or anxiety disorder and the subsequent devel-opment of CVD. Administration of corticosteroids induces hyper-cholesterolemia, hypertriglyceridemia and hypertension leading to endothelial dysfunction.
Therefore, HPA hyperactivity, which has been frequently observed in patients with depression or anxiety disorders, could contribute to increased vulnerability to CVD in these individuals. Similarly, depression and anxiety disorders are associated with dysregula-tion of the sympathoadrenal system, hence elevated
norepineph-heart, blood vessels and platelets. Likewise, decreased parasympa-thetic tone in depression is associated with decreased heart rate variability, a possible risk factor for arrhythmia and cardiovascular mortality[11].
Finally, antidepressants drug used for the treatment for mood and anxiety disorders are also suspected to be involved in the
occur-cardiovascular system by in particular by potentially increasing ar-rhythmias [12].
Potential mechanisms underlying increased vulnerability to mental disorders in individuals with CVRF /CVD
CVRF such as hypertension, cigarette smoking, hypercholesterol-emia and diabetes are risk factors for the incidence of late-onset depression or “vascular depression”, related probably to subcortical brain lesions[13]. Depression could also be a consequence of
spe -ticular propranolol has been shown to be associated with higher frequency of anti-depressant prescription[14], but this has not been
artery disease and in particular myocardial infarction (MI) and
de-of chronic illness on mood.
However, as the prevalence of depression does not correlate with the degree of cardiac dysfunction, this hypothesis can be ques-tioned[6]. Finally, it has been suggested that CAD may contribute to
Shared common pathophysiological processes
Several common pathophysiological processes have also been suggested to explain the association between depression and -tion activity, metabolic abnormalities linked to reduced intake of essential fatty acids, sleep disturbances, migraine and common genetic variants. These mechanisms could either act as common pathophysiological process underlying the development of CVD and mental disorders or an intermediate process within the poten-tially bi-directional causal relationship between CVD and mental disorders.
-ticipates centrally in all stages of the atherosclerotic process from the very early adhesion of monocytes to endothelial cells to athero-sclerotic plaque growth progression and rupture. Furthermore, in large-scale epidemiological studies, CRP, tumour necrosis factor-α
cardiovascular events. However, it is not clear whether some of the
mediators of the atherosclerotic disease.
Accumulated evidence also suggests that there is a chronic
low-[15]. Moreover, treat-ments including the cytokine interferon-α lead to depression in up to 50% of patients[15]. Moreover, CRP has been found to be high-er in patients with bipolar-I disordhigh-er during acute mania and the depressive phase than in healthy controls[16]. Currently, available
disorders are largely cross-sectional and therefore the direction of
the development of CAD and depression, it is possible that genetic
depression.
Disturbed sleep is another risk factor that could predispose to both mental disorders (in particular mood and anxiety disorders) and CVD or mediate the association between the two types of patholo-gy. Circadian rhythm disturbances were found in both unipolar and bipolar mood disorders, although the direction of causality remains unclear[17]
(REM) sleep period and decreased sleep intensity are potential bio-logical markers of mood disorders, whereas sleep deprivation has
shown to be one of the major risk factors for CVD and metabolic disease, with a four-fold increased risk of fatal cardiovascular events in severe OSA patients[18]. Recent studies also documented an asso-ciation between poor sleep and increased plasma-levels of IL-6 and
that may explain the association between disturbed sleep and CVD.
Persistent pain (more than three months) is another clinical charac-teristic that has shown to be associated with mental disorders and CVD. Indeed several studies documented associations between chronic pain and anxiety or depressive disorders.
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A recent study has also demonstrated an association between back pain, coronary heart events and mortality in elderly women. It has been hypothesised that pain could be an intermediate factor con-tributing to reduced mobility, polypharmacy, obesity/malnutrition or sleep disturbances or a third factor underlying the association between CVRF/CVD and mental disorders. It is also possible that
and heart disease. CAD mortality is positively associated with low plasma levels of omega-3 fatty acids[19] and omega-3 fatty acids -bined incidence of death, nonfatal MI and stroke.
Similarly, several studies suggest a negative association between high plasma levels of omega-3 fatty acids and the prevalence of major depression, post-partum depression and suicidal ide-ation[20]. CAD patients with depression also revealed lower plasma levels of omega-3 fatty acids than CAD patients without depres-sion[21]. Regarding the role of genetic variants contributing to these pathologies, to our knowledge there is only twin study that considered depressive symptoms and CAD jointly[22]. It revealed a correlation across heritabilities of 0.42, suggesting that nearly 20% of variability in depressive symptoms and CAD was attributable to common genetic factors. Although there is no genome-wide asso-ciation (GWAS) or linkage study which jointly included depression and CAD phenotypes, yet, research focusing either on depression or CAD has provided some preliminary evidence of overlapping signals for the two types of pathology suggesting the potential for common candidate genes.
Regarding potential candidates genes, polymorphisms involved in the above processes which could underlie both mental disorders and CVD/CVRF are of particular interest, e.g. polymorphisms
re-for example. Both mental disorders and CAD are “complex” traits, meaning that the causal pathways are likely to involve multiple -ment interaction.
Limitations of existing studies
Existing studies investigating potential associations between men -tions including in particular:
1) the use of clinical rather than epidemiological samples 2) the lack of a comparison group
3) the application of psychiatric scales rather than structured diagnostic interviews
4) the assessment of the incidence of CVRF/CVD by self reports rather than clinical and biological information,
5) the lack of simultaneous assessments of both CVD and risk
6) the use of cross-sectional designs which leads to the problem-atic distinction between cause and consequence. These limitations
-tions between mental disorders and CVRF/CVD.
The CoLaus/PsyCoLaus study
In order to prospectively study the complex mechanisms under-lying eth association between mental disorders and CVD or risk factors, we have built the CoLaus/PsyCoLaus cohort study in Lau-sanne, Switzerland. This cohort is the follow-up of a cross sectional population-based study including 6738 participants aged 35-75 and assessed between 2003 and 2006 for prevalence and determi-nants of cardiovascular risk factors (CoLaus) and a psychiatric arm including 3719 subjects aged 35-66 years (PsyCoLaus). These stud-ies have been described in detail previously[23 24]. In summary in the CoLaus study all subjects underwent a detailed cardiovascular assessment including the measurement of a large panel of
biologi-DNA chip.
All subjects in the PsyCoLaus study underwent a comprehensive psychiatric assessment based on a semi-structured diagnostic in-terview (Diagnostic Inin-terview for Genetic studies: DIGS[25]). In the current follow-up, which started in 2009 all subjects are re-contact-ed for a new cardiovascular and psychiatric assessment. In addition to the repetition of measures done at baseline, we are collecting -ders, physical activity, diet and cognitive function in elderly sub-jects. The prospective design together with the combined physical and psychiatric investigation in a population-based sample over-comes most of the limitations of previous research and therefore provides a unique opportunity to study the dynamic interplay be-tween CVD/CVRF and mental disorders.
CONCLUSIONS
CVD and mental disorders are prevalent disorders with a major health burden and co-occur more frequently than expected by chance. A better understanding of the mechanistic links underlying
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