Pathophysiologic mechanisms linking impaired cardiovascular health and neurologic dysfunction: The year in review
ABSTRACT
The nervous system and cardiovascular system have long been known to interact. Only more recently, however, have the mechanisms driving this interaction become more clearly understood. Although many psychological disturbances, including depression and anxiety, are known to predict poor outcomes in patients with cardiovascular disease, other neurologic disturbances, such as migraine and stroke, have been connected to poor cardiovascular outcomes as well. Although these connections were traditionally thought to be due to shared risk factors, recent research has focused on pathophysiologic mechanisms underlying these interactions, including neuroendocrine dysregulation, genetic predisposition, and vascular dysfunction.
HORMONES, NEGATIVE AFFECT, AND CV DISEASE
Patients with CAD have different patterns of cortisol excretion compared with controls. A dysfunctional HPA axis has been implicated, leading to a failure in containing inflammatory activity.31 In healthy older patients without known CAD, heightened cortisol reactivity is associated with a greater extent of coronary artery calcification.32 Cynical hostility is also associated with CAD, but the mechanism is unclear. Higher levels of cynical hostility were associated with attenuation of the decreasing phase of the cortisol awakening response.33 Another recent study also found a higher cortisol awakening response and a larger ratio of total cholesterol to high-density lipoprotein cholesterol in response to stress in socially isolated men.34
Although cortisol is the most studied end product of the HPA axis, aldosterone is also released. Recent research has focused on the role of aldosterone in CV injury through its increase in superoxide generation and its upregulation of genes involved in inflammation, fibrosis, and atherosclerosis.35,36 Several studies have demonstrated the increased incidence of CV disease, including atrial fibrillation, stroke, and MI, among patients with primary hyperaldosteronism compared with patients with similar blood pressure elevations.37,38 Continued evidence supports the importance of the endocrine pathways in modulation of CV disease, and future research should continue to explore the role of various hormones in this interaction.
DIRECTIONS FOR FUTURE RESEARCH
Although advances have been made in understanding the pathophysiologic mechanisms involved in interactions between the nervous system and CV disease, many factors have yet to be completely understood. For example, the role of gender in the interaction between psychological distress and heart disease is an area of increasing discussion. CV disease is a significant cause of morbidity and mortality among women, who are also at increased risk of depression and anxiety as well as stroke and migraine. Recent literature supports the concept that significant biologic differences exist in the effect of stress and depression on men and women. A recent study in mice found that a lifelong increase in SERT function decreased constitutive cerebral metabolism in a number of brain regions, and that this effect was significant only in females.39 Gender differences also appear to exist in the efficacy of antidepressant therapy.11 Although these differences have been observed, it remains unclear whether they primarily are due to obvious hormonal differences or to differences in genetic predisposition.
Stem cell therapy—for stroke and perhaps even for migraine and other disorders—is another area of potential future research. In CV disease, bone marrow–derived EPCs have been used in the post-MI setting and for heart failure. Injured endothelium presents a similar target for endothelial repair with cell therapy in stroke and migraine as well. Continued research in these areas will provide new insights into this brain-vascular interaction and could help provide new directions for treatment in the future.
