Pathophysiologic mechanisms linking impaired cardiovascular health and neurologic dysfunction: The year in review

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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.



The complex interaction between the nervous system and cardiovascular (CV) health is well recognized. In addition to stroke, migraine, and other disorders, the focus has shifted to depression and related negative-affect states including anxiety, chronic stress, posttraumatic stress disorder, and social isolation. Although all of these conditions have been linked to poor CV health, the mechanisms responsible for this brain-cardiovascular interaction have been poorly understood until recently.

Figure 1. Neurologic and psychological disorders share some overlapping pathophysiologic mechanisms with vascular disorders. (5-HTTLPR = serotonin transporter-linked promoter region; EPCs = endothelial progenitor cells; HPA = hypothalamic-pituitary-adrenal)

At first, it appeared that the link between CV disease and such states as depression and anxiety was mediated by a clustering of shared risk conditions such as smoking, high low-density lipoprotein cholesterol, and obesity. As more research uncovered the pathophysiologic mechanisms underlying these negative-affect states, however, it became apparent that some of these mechanisms overlapped with those leading to vascular dysfunction (Figure 1). For instance, regulation of neurotransmitters such as serotonin is known to play a key role in mood dysfunction as well as in sleep and appetite, but only recently has this regulation been identified as an important component in moderating platelet function as well. Several other common pathways have been identified, including the hypothalamic-pituitary-adrenal (HPA) axis, endothelial progenitor cell (EPC) regulation, and inflammatory cell dysfunction. The role of genetic predisposition as a common factor leading to psychological and vascular dysfunction has been studied as well. In addition, research has recently expanded to examine other forms of central neurologic dysfunction besides mood, including stroke and migraine, and their connection with CV health.

This paper reviews a sample of the more recent advances in our understanding the pathophysiologic mechanisms underlying this complex brain-vascular interaction—including the roles of genetic predisposition, endothelial cell dysfunction, and endocrine dysregulation—and discusses future directions for research in this area.


Increasing evidence highlights the importance of genetic predisposition in both psychological dysfunction and CV disease. The importance of common genetic variability in these two conditions originated from studies of twins that established that both depression and coronary artery disease (CAD) tended to run in families. However, recent studies focused on identifying specific genes that may link depression/negative affect and CAD through various pathways related to platelet reactivity, inflammation, and autonomic nervous system regulation, among many others. A candidate gene study by McCaffery et al1 sought to identify specific genes influencing depressive symptoms in CAD patients. Genes were selected based on their role in biologic pathways involved in inflammation, platelet activation, and the HPA axis and sympathetic nervous system. Among the 59 genes analyzed, the strongest associations were between markers involved in endothelial dysfunction and platelet aggregation—specifically, the involvement of von Willebrand factor in platelet recruitment and of vascular cell adhesion molecule–1 in recruitment and adhesion of inflammatory cells to injured endothelium. Other recent studies have analyzed the role of various genes in mediating neurologic and CV dysfunction.

Serotonin: A multitude of cardiovascular effects

Serotonin (5-HT) is best known as a neurotransmitter involved in mood regulation, but it also directly affects endothelial cells and vascular smooth muscle. Human brain microvascular endothelial cells have 5-HT2A receptors, which are thought to be involved in blood-brain trafficking.2 Polymorphisms in this receptor have been associated with impaired glucose tolerance and type 2 diabetes.3

However, the role of serotonin within the CV system has only recently been realized. Along with its associated serotonin transporter (SERT), serotonin has been best studied within the CV system for its role in development of pulmonary hypertension via vasoconstricton. However, serotonin and SERT exhibit other effects on the CV system, including regulation of factors involved in vascular integrity, such as platelet activity, endothelial dysfunction, and smooth muscle cell and endothelial cell mitogenesis. Serotonin is stored peripherally in platelets and, when released at sites of endothelial damage, promotes platelet aggregation. Cardiomyocytes also are a source of serotonin within the heart, resulting in positive chronotropy, positive inotropy, and activation of mitogen activity.4

Serotonin also affects endothelium through effects on bone marrow production of EPCs. It has been shown in mice to increase the proliferative activity of hematopoietic stem cells in the bone marrow via 5-HT2 receptors.5 Serotonin is a mitogen for canine and bovine endothelial cells6 and has also been shown to enhance ex vivo expansion of CD34+ hematopoietic stem cells in mice.7 It also seems to have an effect on regulation of inflammatory cytokines by regulating different secretory pathways. Activity of several different serotonin receptors, including 5-HT2A, 5-HT4, and 5-HT7, inhibits tumor necrosis factor production in peripheral cells.8


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