Mechanisms underlying altered mood and cardiovascular dysfunction: the value of neurobiological and behavioral research with animal models

A bidirectional association between mood disorders and cardiovascular diseases has been described in humans, yet the precise neurobiological mechanisms that underlie this association are not fully understood. This article is focused on neurobiological processes and mediators in mood and cardiovascular disorders, with an emphasis on common mechanisms including stressor reactivity, neuroendocrine and neurohumoral changes, immune alterations, autonomic and cardiovascular dysregulation, and central neurotransmitter and neuropeptide dysfunction. A discussion of the utility of experimental investigations with rodent models, including those in rats and prairie voles (Microtus ochrogaster), is presented. Specific studies using these models are reviewed, focusing on the analysis of behavioral, physiological and neural mechanisms underlying depressive disorders and cardiovascular disease. Considered in combination with studies using human samples, the investigation of mechanisms underlying depressive behaviors and cardiovascular regulation using animal models will enhance our understanding of the association of depression and cardiovascular disease, and will promote the development of improved interventions for individuals with these detrimental disorders.     

Depression and cardiovascular disease: mechanisms of interaction.

This article explores the relationship between depression and cardiovascular disease from a mechanistic standpoint. Depression and cardiovascular disease are two of the most prevalent health problems in the United States and are the two leading causes of disability both in the United States and worldwide. Although depression is a known risk factor for the development of cardiovascular disease, as well as an independent predictor of poor prognosis following a cardiac event, the mechanistic relationship between the two remains unclear. Depression is associated with changes in an individual's health status that may influence the development and course of cardiovascular disease, including noncompliance with medical recommendations, as well as the presence of cardiovascular risk factors such as smoking and hypertension. In addition, depression is associated with physiologic changes, including nervous system activation, cardiac rhythm disturbances, systemic and localized inflammation, and hypercoagulability, that negatively influence the cardiovascular system. Further, stress may be an underlying trigger that leads to the development of both depression and cardiovascular disease. This article reviews seven potential mechanisms for the relationship between depression and cardiovascular disease and presents the available evidence surrounding each mechanism. Finally, future directions for research are discussed.     

Social isolation disrupts autonomic regulation of the heart and influences negative affective behaviors.

BACKGROUND: There is a documented association between affective disorders (e.g., depression and anxiety) and cardiovascular disease in humans. Chronic social stressors may play a mechanistic role in the development of behavioral and cardiac dysregulation. The current study investigated behavioral, cardiac, and autonomic responses to a chronic social stressor in prairie voles, a rodent species that displays social behaviors similar to humans. METHODS: Female prairie voles were exposed to 4 weeks of social isolation (n = 8) or pairing (control conditions; n = 7). Electrocardiographic parameters were recorded continuously during isolation, and behavioral tests were conducted during and following this period. RESULTS: Isolation induced a significant increase in resting heart rate, reduction in heart rate variability (standard deviation of normal-to-normal intervals and amplitude of respiratory sinus arrhythmia), and exaggerated cardiac responses during an acute resident-intruder paradigm. Isolation led also to both depression-like and anxiety-like behaviors in validated operational tests. These changes in response to social isolation showed predictable interrelations and were mediated by a disruption of autonomic balance including both sympathetic and parasympathetic (vagal) mechanisms. CONCLUSIONS: These findings indicate that social isolation induces behavioral, cardiac, and autonomic alterations related to those seen after other stressors and which are relevant to cardiovascular disease and affective disorders. This model may provide insight into the mechanisms that underlie these co-occurring conditions.     

Platelet activating factors in depression and coronary artery disease: A potential biomarker related to inflammatory mechanisms and neurodegeneration

The persistence of a depressive episode in coronary artery disease (CAD) patients not only heightens the risk of acute ischemic events, but it is also associated with accelerated cognitive decline. Antidepressant interventions for depression in CAD have only modest effects and novel approaches are limited by a poor understanding of etiological mechanisms. This review proposes that the platelet activating factor (PAF) family of lipids might be associated with the persistence of a depressive episode and related neurodegenerative pathology in CAD due to their association with leading etiological mechanisms for depression in CAD such as inflammation, oxidative and nitrosative stress, vascular endothelial dysfunction, and platelet reactivity. The evidence implicating PAFs in CAD, vascular pathology, and neurodegenerative processes is also presented. We also propose future directions for the investigation of PAFs as mediators of persistent depression. In summary, PAFs are implicated in leading mechanisms associated with depression in CAD. PAFs may therefore be associated with the persistence of depression in CAD and related to neurodegenerative and cognitive sequelae.     

Omega-3 fatty acids, homocysteine, and the increased risk of cardiovascular mortality in major depressive disorder

Depression is associated with elevated rates of cardiovascular morbidity and mortality. This elevation seems to be due to a significantly increased risk of coronary artery disease and myocardial infarction and, once the ischemic heart disease is established, sudden cardiac death. Recent data suggest that the increased rates of cardiovascular disease in patients with depression may be the result of one or more still-unrecognized underlying physiological factors that predispose a patient to both depression and cardiovascular disease. Two possibly related factors that may have a causal relation with both depressive disorders and cardiovascular disease are an omega-3 fatty acid deficiency and elevated homocysteine levels. We present the available data connecting cardiovascular disease, depression, omega-3 fatty acids, and homocysteine. In addition, we suggest research strategies and some preliminary treatment recommendations that may reduce the increased risk of cardiovascular mortality in patients with major depressive disorder.     

Restless legs syndrome and conditions associated with metabolic dysregulation, sympathoadrenal dysfunction, and cardiovascular disease risk: a systematic review

Restless legs syndrome (RLS) is a distressing sleep and sensorimotor disorder that affects a large percentage of adults in the western industrialized world and is associated with profound reductions in quality of life. However, the etiology of RLS remains incompletely understood. Enhanced understanding regarding both the antecedents and sequelae of RLS could shed new light on the pathogenesis of RLS. Evidence from an emerging body of literature suggests associations between RLS and diabetes, hypertension, obesity, and related conditions linked to sympathetic activation and metabolic dysregulation, raising the possibility that these factors may likewise play a significant role in the development and progression of RLS, and could help explain the recently documented associations between RLS and subsequent cardiovascular disease. However, the relation between RLS and these chronic conditions has received relatively little attention to date, although potential implications for the pathogenesis and treatment of RLS could be considerable. In this paper, we systematically review the recently published literature regarding the association of RLS to cardiovascular disease and related risk factors characterized by sympathoadrenal and metabolic dysregulation, discuss potential underlying mechanisms, and outline some possible directions for future research.     

Mood disorders: cardiovascular and diabetes comorbidity

PURPOSE OF REVIEW: Depression is often associated with medical comorbidity. New research quantifies patterns of mood disorder in illnesses such as cardiovascular disease and diabetes, evaluates the prognostic significance of mood symptoms, and seeks to identify common mechanisms for both mood and medical disease. This review provides recent findings on comorbidity, summarizes mechanistic hypotheses, and outlines developments in treatment and services. RECENT FINDINGS: Depression occurs in up to one-quarter of patients with cardiovascular disease and diabetes. Depressed patients with heart disease have poorer medical outcomes including increased risk of reinfarction and all-cause mortality. Patients with diabetes and depression have poorer glycemic control, more diabetes symptoms, and greater all-cause mortality. Depression is associated with both biological (hypothalamic-pituitary-adrenal axis dysregulation) and psychosocial processes (adherence, poorer diet, and exercise) that may mediate adverse medical outcomes. Antidepressant treatments are effective in treating depression in medically ill patients, but their impact on medical outcomes remains to be quantified. SUMMARY: Depression, cardiovascular disease, and diabetes are among the most common chronic illnesses affecting an aging population. Depression is treatable in patients with medical illnesses, and collaborative care models can yield better detection and depression treatment in primary care settings in which most patients with depression are seen.     

Psychophysiological biomarkers explaining the association between depression and prognosis in coronary artery patients: A critical review of the literature

This paper aims to provide an overview of the current state of affairs on psychophysiological factors that may explain the link between depression and adverse outcome in coronary artery disease (CAD) patients. Factors discussed include heart rate variability, inflammation, platelet function, hypothalamus-pituitary-adrenal axis activity, serotonin metabolism and polyunsaturated fatty acids. Evidence suggests the involvement of each of these factors in both depression and CAD, together contributing to the prospective association between depression and cardiac outcome. Unfortunately, the involvement of above factors has been evaluated mostly in isolation, despite their functional interrelations and associations with behavioral factors. Moreover, there may be specific relations between individual symptoms of depression and certain psychophysiological mechanisms, rather than with general depression, further complicating the notion of depression as a cardiotoxic factor. The relatively understudied complexity of the relation between depression and CAD may serve as an explanation for the finding that depression treatment does not or barely affect cardiac outcome. Future studies should focus on the network of psychophysiological (and behavioral) factors to elucidate their precise role and timing in depressed cardiac patients.     

Psychophysiological biomarkers explaining the association between depression and prognosis in coronary artery patients: A critical review of the literature

This paper aims to provide an overview of the current state of affairs on psychophysiological factors that may explain the link between depression and adverse outcome in coronary artery disease (CAD) patients. Factors discussed include heart rate variability, inflammation, platelet function, hypothalamus–pituitary–adrenal axis activity, serotonin metabolism and polyunsaturated fatty acids. Evidence suggests the involvement of each of these factors in both depression and CAD, together contributing to the prospective association between depression and cardiac outcome. Unfortunately, the involvement of above factors has been evaluated mostly in isolation, despite their functional interrelations and associations with behavioral factors. Moreover, there may be specific relations between individual symptoms of depression and certain psychophysiological mechanisms, rather than with general depression, further complicating the notion of depression as a cardiotoxic factor. The relatively understudied complexity of the relation between depression and CAD may serve as an explanation for the finding that depression treatment does not or barely affect cardiac outcome. Future studies should focus on the network of psychophysiological (and behavioral) factors to elucidate their precise role and timing in depressed cardiac patients.     

Depression in the medical setting: biopsychological interactions and treatment considerations

This article examines depression in 6 medical conditions: coronary artery disease (CAD), cancer, human immunodeficiency virus (HIV) infection, Parkinson's disease, pain, and the sex hormone changes of aging. Research is beginning to define specific biological and psychological mechanisms underlying the adverse interactions between depression and these medical conditions. Antidepressant medications, psychosocial therapies, and hormonal manipulations are effective in reducing depressive symptoms. Specific psychosocial interventions may increase longevity in CAD and cancer and may enhance quality of life in HIV infection. Newer antidepressants appear to be safer and better tolerated than older agents for medically ill patients, but do not appear to be as effective for neuropathic pain. Dopamine agonists may benefit depression associated with Parkinson's disease. Hormone replacement therapy may improve subsyndromal depressive symptoms in postmenopausal women and may enhance antidepressant response for older women with major depression.     

Sympathetic neural control of integrated cardiovascular function: insights from measurement of human sympathetic nerve activity

Sympathetic neural control of cardiovascular function is essential for normal regulation of blood pressure and tissue perfusion. In the present review we discuss sympathetic neural mechanisms in human cardiovascular physiology and pathophysiology, with a focus on evidence from direct recordings of sympathetic nerve activity using microneurography. Measurements of sympathetic nerve activity to skeletal muscle have provided extensive information regarding reflex control of blood pressure and blood flow in conditions ranging from rest to postural changes, exercise, and mental stress in populations ranging from healthy controls to patients with hypertension and heart failure. Measurements of skin sympathetic nerve activity have also provided important insights into neural control, but are often more difficult to interpret since the activity contains several types of nerve impulses with different functions. Although most studies have focused on group mean differences, we provide evidence that individual variability in sympathetic nerve activity is important to the ultimate understanding of these integrated physiological mechanisms.     

Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms

Depression increases the risk of cardiac mortality and morbidity in patients with coronary heart disease (CHD), but the mechanisms that underlie this association remain unclear. This review considers the evidence for several behavioral and physiological mechanisms that might explain how depression increases the risk for incident coronary disease and for subsequent cardiac morbidity and mortality. The candidate mechanisms include: (1). antidepressant cardiotoxicity; (2). association of depression with cardiac risk factors such as cigarette smoking, hypertension, diabetes, and reduced functional capacity; (3). association of depression with greater coronary disease severity; (4). nonadherence to cardiac prevention and treatment regimens; (5). lower heart rate variability (HRV) reflecting altered cardiac autonomic tone; (6). increased platelet aggregation; and (7). inflammatory processes. Despite recent advances in our understanding of these potential mechanisms, further research is needed to determine how depression increases risk for cardiac morbidity and mortality.     

The role of neutrophil gelatinase associated lipocalin (NGAL) as biological constituent linking depression and cardiovascular disease

Depression is more common in patients with cardiovascular disease than in the general population. Conversely, depression is a risk factor for developing cardiovascular disease. Comorbidity of these two pathologies worsens prognosis. Several mechanisms have been indicated in the link between cardiovascular disease and depression, including inflammation. Systemic inflammation can have long-lasting effects on the central nervous system, which could be associated with depression. NGAL is an inflammatory marker and elevated plasma levels are associated with both cardiovascular disease and depression. While patients with depression show elevated NGAL levels, in patients with comorbid heart failure, NGAL levels are significantly higher and associated with depression scores. Systemic inflammation evokes NGAL expression in the brain. This is considered a proinflammatory effect as it is involved in microglia activation and reactive astrocytosis. Animal studies support a direct link between NGAL and depression/anxiety associated behavior. In this review we focus on the role of NGAL in linking depression and cardiovascular disease.     

Is panic disorder associated with coronary artery disease? A critical review of the literature

OBJECTIVE: To critically review existing literature examining the relationship between panic disorder (PD) and coronary artery disease (CAD). We specifically sought answers to the following questions: (1) What is the prevalence of PD in CAD patients? (2) What is the directionality of the relationship between PD and CAD? (3) What mechanisms may mediate the link between PD and CAD? METHODS: Medline and Psychlit searches were conducted using the following search titles: "panic disorder and coronary artery disease", "panic disorder and coronary heart disease", and "panic disorder and cardiovascular disease" for the years 1980-1998. The above search was also repeated replacing "panic disorder" with "panic attacks" for the same period. RESULTS: The prevalence of PD in both cardiology out-patients and patients with documented CAD ranges from 10% to 50%. The association between PD and CAD appeared strongest in patients with atypical chest pain or symptoms that could not be fully explained by coronary status. There is some evidence linking phobic anxiety but not PD per se to CAD risk, but little evidence linking CAD to PD risk. Studies of the mechanisms linking PD to CAD are still in their infancy, but there is preliminary evidence linking PD to reduced heart rate variability (HRV) and myocardial ischemia, two pathophysiological mechanisms related to CAD. CONCLUSION: PD is prevalent in CAD patients, but it is unclear the extent to which PD confers risk for and/or exacerbates CAD. Prospective research is needed to more firmly establish PD as a distinct risk factor for the development and progression of CAD. However, because many of the symptoms of PD mimic those of CAD, differentiating these disorders and learning how they may influence each other is imperative for clinical practice.     

The Impact of Depression in Heart Disease

Depression and heart disease affect millions of people worldwide. Studies have shown that depression is a significant risk factor for new heart disease and that it increases morbidity and mortality in established heart disease. Many hypothesized and studied mechanisms have linked depression and heart disease, including serotonergic pathway and platelet dysfunction, inflammation, autonomic nervous system and hypothalamic-pituitary-adrenal axis imbalance, and psychosocial factors. Although the treatment of depression in cardiac patients has been shown to be safe and modestly efficacious, it has yet to translate into reduced cardiovascular morbidity and mortality. Understanding the impact and mechanisms behind the association of depression and heart disease may allow for the development of treatments aimed at altering the devastating consequences caused by these comorbid illnesses.     

Heart rate variability and markers of inflammation and coagulation in depressed patients with coronary heart disease

BACKGROUND: Depression is associated with an increased risk for cardiac morbidity and mortality in patients with coronary heart disease (CHD). Cardiac autonomic nervous system (ANS) dysregulation, proinflammatory processes, and procoagulant processes have been suggested as possible explanations. METHODS: Heart rate variability (HRV), an indicator of cardiac autonomic regulation, and markers of inflammation [C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha)] and coagulation (fibrinogen) were assessed in 44 depressed patients with CHD. RESULTS: Moderate, negative correlations were found between fibrinogen and four measures of HRV. IL-6 also negatively correlated with one measure of HRV (total power) and was marginally related to two others (very low frequency and low frequency power). Neither CRP nor TNF-alpha was significantly related to any measure of HRV. CONCLUSIONS: The finding that fibrinogen and IL-6 are moderately related to HRV suggests a link between these factors in depressed CHD patients. The relationship between ANS function and inflammatory and coagulant processes should be investigated in larger mechanistic studies of depression and cardiac morbidity and mortality.     

Depression is associated with flatter cortisol rhythms in patients with coronary artery disease

OBJECTIVE: Depression is associated with coronary heart disease, but the underlying mechanisms are not fully understood. Cortisol is involved in the development of coronary artery disease (CAD), but evidence directly linking depression with cortisol in patients with CAD is limited. This study evaluated cortisol output over the day in patients with suspected CAD in relation to depressive symptoms. METHODS: Eighty-eight patients who were being investigated for suspected CAD (defined by clinical symptoms plus positive exercise tests or myocardial perfusion scans) took eight saliva samples over the day and evening. Depressed mood was assessed with the Beck Depression Inventory. Actigraphy was used to define time of waking objectively. RESULTS: The cortisol awakening response and cortisol rhythm over the remainder of the day and evening were analyzed separately. Fifty-two (61.9%) patients were later found to have definite CAD on angiography, while the remainder did not. The cortisol slope over the day was flatter in more depressed patients with CAD (P<.001) but was not related to depression in patients without CAD (P=.68). This effect was due to the combination of lower cortisol early in the day and higher cortisol in the evening in more depressed CAD patients, independent of age, gender, medication, and times of waking and sleeping (P=.003). Additionally, cortisol measured on waking and 15 and 30 min after waking was greater in CAD than in non-CAD patients (P=.04), but was not related to depression. CONCLUSIONS: The flatter cortisol rhythms of more depressed CAD patients may contribute to the progression of coronary atherosclerosis.     

Relationship between lifetime smoking, smoking status at older age and human cognitive function

Cigarette smoking is a major risk factor for clinical cardiovascular disease and may also be associated with poorer cognitive functioning in older age. We measured lifetime cigarette smoking, smoking status and cognitive function in over 2,000 men and women from the general population aged over 50 years with subclinical atherosclerosis (ankle brachial pressure index相似文献   

Symbolic analysis detects alterations of cardiac autonomic modulation in congestive heart failure rats

Congestive heart failure (CHF) is associated with neurohumoral activation. Only very few studies have examined the progression of autonomic dysfunction in CHF in humans and scanty data are available in animal models of CHF. This study was performed to assess the changes in cardiac autonomic modulation during the progression of CHF in a rat model, using an innovative analysis of heart rate variability. Progression of cardiovascular autonomic dysfunction was assessed in a rat model of CHF induced by coronary artery ligation. Spectral and symbolic analyses were performed on heart period (approximated with pulse interval, PI) and systolic arterial pressure (SAP) signals, acquired ~ 2 and ~ 4 weeks after the surgical procedure. As CHF developed, symbolic analysis revealed a decrease of rhythmical physiological sympathetic modulation, as indicated by the reduction of the percentage of stable patterns. In addition, symbolic analysis revealed that runs of short–long–short and/or long–short–long PI values and high–low–high and/or low–high–low SAP values were more and more frequent as CHF progressed. On the contrary, spectral analysis of PI and SAP series was not able to detect any impairment of autonomic regulation. Indeed, low frequency and high frequency powers derived from both PI and SAP series were not significantly changed. These data indicate that the autonomic cardiovascular modulation is altered during the progression of CHF and that symbolic analysis seems to be more suitable than spectral analysis to describe alterations of heart period dynamics and of cardiovascular regulation in this animal model of CHF.     

Abnormal heart rate variability reflecting autonomic dysfunction in brainstem infarction

Objectives Brainstem infarctions frequently cause disturbances of cardiovascular and other autonomic functions, but the pathophysiologic mechanisms of these prognostically unfavourable complications are not well-known.
Material & methods In order to evaluate the effects of ischemic brainstem infarction on autonomic cardiac regulation, we analyzed the power spectrum of heart rate variability in 15 consecutive patients with brainstem infarction and in 15 age- and sex-matched healthy control subjects. The components of the power spectrum which reflect quantitatively both sympathetic and parasympathetic cardiovascular regulatory functions were measured from 24-hour electrocardiogram in the acute phase and at 1 month and 6 months after the infarction.
Results All the measured components of heart rate variability, i.e. total power (p < 0.01), very-low-frequency power (p < 0.001), low-frequency power (p < 0.01), and high-frequency power (p < 0.05), were significantly lower in the patients with medullary brainstem infarction than in the control subjects in the acute phase of the infarction. By 6 months, these abnormalities had been reversed. On the contrary, heart rate variability in pontine brainstem infarct patients did not differ significantly from that in the control subjects.
Conclusions These results suggest that brainstem infarction located in the medulla oblongata causes cardiovascular autonomic dysregulation manifesting as impaired heart rate variability. Medullary brainstem infarction seems to cause both sympathetic and parasympathetic dysfunction, which may contribute to the occurrence of cardiac complications in stroke.