Stressed brain, diseased heart: A review on the pathophysiologic mechanisms of neurocardiology

doi:10.1016/j.ijcard.2012.03.165

International Journal of Cardiology

Volume 166, Issue 1, 5 June 2013, Pages 30-37

https://doi.org/10.1016/j.ijcard.2012.03.165 Get rights and content

Abstract

Cardiovascular diseases are traditionally related to well known risk factors like dyslipidemia, smoking, diabetes and hypertension. More recently, stress, anxiety and depression have been proposed as risk factors for cardiovascular diseases including heart failure, ischemic disease, hypertension and arrhythmias. Interestingly, this association has been established largely on the basis of epidemiological data, due to insufficient knowledge on the underlying pathophysiologic mechanisms. This review will revisit evidence on the interaction between the cardiovascular and nervous systems, highlighting the perspective on how the central nervous system is involved in the pathogenesis of cardiovascular diseases. Such knowledge is likely to be of relevance for the development of better strategies to treat patients in a holistic perspective.

Introduction

Cardiovascular diseases (CVD) are the leading cause of death worldwide, being responsible for almost 32% of all deaths in women and 27% in men in 2004 and expected to kill 23.4 million people by 2030 if current trends remain [1]. While elevated blood levels of cholesterol, hypertension, diabetes mellitus and smoking are well-known risk-factors for CVD [2], understanding how other factors contribute to this burden is essential to develop new strategies to combat and/or prevent it. Among these, the central nervous system (CNS), in particular the stress response seems to be of relevance in the pathogenesis of CVD.

This review focuses on neurocardiology, highlighting the effects of central circuits over the control of cardiovascular system and on how peripheral mediators acting on specific brain regions influence neurocardiac conditions.

Section snippets

Neurocardiology: the facts

Psychiatric and neurologic diseases are positively associated with CVD. Epidemiological data clearly suggests that depression is an independent risk factor for myocardial infarction (AMI) and heart diseases in general [3], [4]. Prospective studies with depressed individuals showed that a history of a major depressive episode was associated with a higher risk of AMI, even after correction for major coronary risk factors [5], [6], [7]. Of interest, the same was observed for both men and women [7]

The relevance of stress in neurocardiology

Stress is a state of threatened homeostasis. For re-establishment of the equilibrium a repertoire of physiologic and behavioral responses is rapidly mobilized, constituting the adaptive stress response [19]. The adverse consequences of stress result from the inability of the individual to cope with the stressful stimuli or from maladaptive responses that may restore the homeostasis in short-term but may impose damage at different body systems in the long-term. It is a common belief that daily

Neuronal networks implicated in cardiovascular regulation: the effects of stress

Cardiovascular regulation by CNS has been widely discussed in the literature. Cardiovascular function is regulated by the autonomic nervous system, which encompasses two major divisions: the sympathetic and the parasympathetic system; the appropriate balance (autonomic tone) between the two is fundamental to the pathophysiology of CVD.

The organization of the autonomic nervous system (Fig. 1) is complex (for a review see [27]). It is widely recognized that regulation of cardiac function is

The role of the sympathetic system

As previously mentioned, chronic activation of the sympathetic system and/or decreased parasympathetic (vagal) is a remarkable feature of CVD [46], [47], [48]. In fact the sympathetic system contributes to endothelial dysfunction, hypertension and atherosclerosis; promotes insulin resistance and dyslipidemia; induces left ventricular hypertrophy; increases the incidence of arrhythmia; and promotes renal dysfunction by stimulating sodium and fluid retention, glomerulosclerosis and the activation

The renin–angiotensin–adosterone system

The RAAS has an important role in maintaining circulatory homeostasis. Angiotensin II stimulates aldosterone release by the adrenal cortex, leading to an increase of sodium and water reabsorption in the kidney, thus influencing blood pressure levels [59]. Therefore, it is not surprising that RAAS activation plays a central role in the development of hypertension and in the pathogenesis of HF. In fact, its pharmacological inhibition is one of the most successful strategies in the treatment of

Hypothalamus–pituitary–adrenal axis

The HPA axis is generally considered one of the principal effectors of stress response through the release of glucocorticoid hormones (GC; mainly cortisol in humans and corticosterone in rodents). These hormones contribute to restore homeostasis and to promote coping strategies to the initial insult through a series of actions both in the periphery and in the brain. GC promote gluconeogenesis, increasing the accessibility of energy to the exercising muscle; enhance cardiovascular tone; decrease

The crosstalk between the nervous and the adipose tissues

Classic risk factors for CVD tend to coexist in the same individual, thus exponentially increasing the risk of ischemic heart disease and other adverse outcomes. The existence of such clustering suggests a common pathophysiological mechanism for all these metabolic conditions and led to the proposal, in the 80s, of Syndrome X [more recently coined as metabolic syndrome (MSynd)]: “a state of insulin resistance that results in hypertriglyceridemia, low high-density lipoprotein (HDL)-cholesterol

Brain activation and stress induces myocytolysis

Until this point we have been discussing how brain injuries and chronic stress increase the risk of CVD by the deregulation of complex physiologic systems promoting hypertension, dyslipidemia, diabetes and atherosclerosis. What remains to be discussed is whether the brain–heart interaction may be more direct, by acting on the myocyte.

The most striking example of this direct interaction is the Takotsubo cardiomyopathy (or “stress cardiomyopathy”) that consists of a transient left ventricular

The periphery modulates brain areas implicated in CVD

As previously described, rodents submitted to CMS display alterations in autonomic parameters, like decreased HRV, suggesting an overactive sympathetic system that may impact on cardiovascular and metabolic functions. One would expect that once stress is over, the autonomic imbalance disappears and accompanies the improvement of the behavioral alterations seen in these animals. However, interesting data showed that recovery of depressive-like behavior in rats submitted to CMS protocol is not

Treatment options for stress-related CVD

When considering all evidence and mechanisms herein revisited, some considerations are worth mentioning regarding the treatment of patients with neuropsychiatric and/or cardiovascular diseases. We herein propose a shift in the therapeutic paradigm, considering processes “from the periphery to the brain and back”. In this sense, drugs that act not only in the periphery, but also in the CNS, can be of major interest. Although it is well established that chronic stress, depression and anxiety

Neurocardiology: final considerations

Recent data show that highly prevalent diseases like stress-related pathology and depression, long considered as brain disorders, are increasingly found to impose a heavy burden to the cardiovascular system. Even though the heart–brain interaction is known to be bidirectional, it seems, at this point, that regulation of the CNS over heart and vessels is more prevalent as shown by the increased risk of CVD in anxious, depressed, epileptic or stroke-victims patients. The study of the regulation

Acknowledgment

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

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ReviewStressed brain, diseased heart: A review on the pathophysiologic mechanisms of neurocardiology

Abstract

Introduction

Section snippets

Neurocardiology: the facts

The relevance of stress in neurocardiology

Neuronal networks implicated in cardiovascular regulation: the effects of stress

The role of the sympathetic system

The renin–angiotensin–adosterone system

Hypothalamus–pituitary–adrenal axis

The crosstalk between the nervous and the adipose tissues

Brain activation and stress induces myocytolysis

The periphery modulates brain areas implicated in CVD

Treatment options for stress-related CVD

Neurocardiology: final considerations

Acknowledgment

The global burden of disease: 2004 update

Global burden of cardiovascular diseases: part II: variations in cardiovascular disease by specific ethnic groups and geographic regions and prevention strategies

Circulation

Depression and heart disease: what do we know, and where are we headed?

Cleve Clin J Med

Depression and cardiac risk: present status and future directions

Postgrad Med J

Depression, psychotropic medication, and risk of myocardial infarction. Prospective data from the Baltimore ECA follow-up

Circulation

Symptoms of depression, acute myocardial infarction, and total mortality in a community sample

Circulation

Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans

Circulation

Depression as a predictor for coronary heart disease. a review and meta-analysis

Am J Prev Med

Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction

Circulation

Effects of depressive symptoms and coronary heart disease and their interactive associations on mortality in middle-aged adults: the Whitehall II cohort study

Heart

Clinical depression and risk of out-of-hospital cardiac arrest

Arch Intern Med

Depression and risk of sudden cardiac death and coronary heart disease in women: results from the Nurses Health Study

J Am Coll Cardiol

Depression worsens outcomes in elderly patients with heart failure: an analysis of 48,117 patients in a community setting

Eur J Heart Fail

Depression in heart failure a meta-analytic review of prevalence, intervention effects, and associations with clinical outcomes

J Am Coll Cardiol

Left insular stroke is associated with adverse cardiac outcome

Neurology

Insular infarcts and electrocardiographic changes at admission: results of the PRognostic of Insular CErebral infarctS Study (PRINCESS)

J Neurol

Sudden unexpected death in epilepsy: current knowledge and future directions

Lancet Neurol

EEG and ECG in sudden unexplained death in epilepsy

Epilepsia

Stress hormones: physiological stress and regulation of metabolism

Curr Opin Pharmacol

Voodoo death

Am Anthropol

Sudden cardiac death triggered by an earthquake

N Engl J Med

Association of psychosocial risk factors with risk of acute myocardial infarction in 11119 cases and 13648 controls from 52 countries (the INTERHEART study): case–control study

Lancet

Chronic mild stress (CMS) revisited: consistency and behavioural–neurobiological concordance in the effects of CMS

Neuropsychobiology

A trans-dimensional approach to the behavioral aspects of depression

Front Behav Neurosci

Cardiovascular alterations and autonomic imbalance in an experimental model of depression

Am J Physiol Regul Integr Comp Physiol

Stress, depression and cardiovascular dysregulation: a review of neurobiological mechanisms and the integration of research from preclinical disease models

Stress

Autonomic nervous system

Cortical modulation of the cardiovascular system

Prog Neurobiol

Effects of stroke localization on cardiac autonomic balance and sudden death

Stroke

Cardiac chronotropic organization of the rat insular cortex

Brain Res

Cerebrogenic cardiac arrhythmias: cortical lateralization and clinical significance

Clin Auton Res

Cerebral hemispheric lateralization in cardiac autonomic control

Arch Neurol

Autonomic consequences of cerebral hemisphere infarction

Stroke

Review
Stressed brain, diseased heart: A review on the pathophysiologic mechanisms of neurocardiology