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.
Insights from genetic analysis of SERT
These areas of recent research continue to highlight the importance of serotonin within the CV system, and its overlapping role in depression and other forms of psychological dysfunction underscores the importance of understanding its regulation.
The best-studied component of serotonin regulation is SERT, a sodium-dependent transporter that removes serotonin from outside the cell, bringing it back into the cell for repackaging. It is recognized as the site of action of the selective serotonin reuptake inhibitors (SSRIs).
Analysis of the serotonin transporter gene has traditionally focused on polymorphisms within the promoter region (5-HTTLPR). Two common alleles, the long (L) and short (S) variants, are the best characterized. The S variant is associated with a lower expression of SERT, leading to reduced uptake and release of serotonin. The SS genotype of SERT has been linked to major depressive disorder9 and to increased risk of subsequent cardiac events after myocardial infarction (MI).10
A study of the effects of environmental stress and gender on associations between depression and 5-HTTLPR found that this link varied according to gender and stressful life events.11 Specifically, women with the SS genotype, which leads to less transcriptional activity of 5-HTTLPR, tended to be more susceptible to depression under stressful life conditions. However, in men the LL genotype was associated with increased transcriptional activity and the same increased susceptibility to depression. 11 Expression of the LL genotype also resulted in upregulation of SERT, leading to higher MI risk.12
Another study investigated the relationship between genetic variability in two serotonin-related gene polymorphisms and found that the 5-HTTLPR gene polymorphism was associated with adverse cardiac events after coronary artery bypass graft surgery in combination with depression, specifically in patients with the L allele compared with SS.13
Humans who possess the L variant of the SERT protein have more rapid platelet serotonin uptake.14 Inhibitors of SERT have been shown to reduce platelet serotonin content, leading to disruption of thrombosis and increased bleeding due to inhibition of serotonin reuptake. A study in middle-aged men also found that genetic variability within SERT was associated with increased depressive symptoms and elevated levels of interleukin-6, a marker of inflammation.15 This indicates a common source of genetic vulnerability accounting for both depression and inflammation, and could help to explain the increased risk of CV disease in patients with depression.15
Mental stress–induced myocardial ischemia
The association between mental stress and activation of the sympathetic nervous system is well established. Stress leads to increases in blood pressure and heart rate. In patients with CAD, mental stress–induced myocardial ischemia (MSIMI) is a well-characterized phenomenon whereby ischemia is provoked by psychological stress. Sympathetic nervous system activation from stressful life events can increase vulnerability to CV outcomes such as MI, arrhythmias, and sudden cardiac death. MSIMI has been identified as a risk factor for poor outcomes in patients with known CAD. Proposed mechanisms include mismatch of myocardial blood supply and demand, as well as coronary spasm.
A recent study by Hassan et al evaluated associations of beta1-adrenergic receptor gene (ADBR1) polymorphisms with MSIMI in CAD patients.16 The researchers found a threefold increase in MSIMI in patients with a particular allele of the ADBR1 gene. This is the first report to highlight a specific genetic predisposition to susceptibility to MSIMI; it could help explain why some patients are at increased risk and also suggest targeting specific behavioral or pharmacologic therapies to reduce MSIMI.
ENDOTHELIAL DYSFUNCTION
Dysfunctional endothelium is important in the link between neurologic dysfunction and CV disease. Circulating EPCs have been recognized as playing an important role in maintaining vascular health. These cells originate in the bone marrow and may be identified by their surface markers and various functional characteristics. They have been shown to be a key part of the process involved in repair of biologic risk factor–mediated damage to endothelium and are reduced and/or dysfunctional in patients with CV risk factors such as tobacco use, diabetes, and hypertension. Low EPC levels have also been found in patients with cerebrovascular disease and are key in vascular neogenesis after ischemic insult.
Genetic effects on endothelium in migraine and stroke
A more recent area of interest in brain and cardiovascular health has been the role of EPCs in migraine, which is often debilitating. The association between migraine and increased risk of depression,17 as well as stroke and MI, has been well recognized. A recent study by MacClellan et al evaluated whether polymorphisms in genes regulating endothelial function and vascular tone influenced susceptibility to migraine and stroke in a large subset of young women.18 Analyzed genes included endothelin-1 (EDN), endothelin receptor type B (EDNRB), and nitric oxide synthase-3 (NOS3). Several polymorphisms within these genes were associated with stroke in white women but not in black women. However, the study did not show whether the association between migraine and stroke was mediated by the polymorphisms studied from the candidate genes. Others have found no association with EDNRB but found that the homozygous minor genotype (present in 5% of cases) of the EDNRA SNP rs2048894 showed association with migraine with aura (odds ratio [OR] = 1.61, 95% confidence interval [CI], 1.12–2.32; P = .010] when adjusted for gender and sample origin.19 Early age at onset (P = .011) in the pooled sample.19 Studies on larger samples will be needed to confirm these findings.
Depression may alter endothelial homeostasis
One mechanism by which depression may lead to increased CV disease risk is through effects on endothelial homeostasis. Several studies have found an association between depression and attenuated flow-mediated vasodilation. However, it has been postulated that this effect was mediated by atherosclerosis, as these studies were performed in older cohorts. To evaluate this association without the possibility of confounding severe atherosclerosis, a recent study evaluated this association in adolescent women with no known health problems.20 Regression analysis demonstrated a significant inverse relationship between depression and endothelial function as measured by pulse-wave amplitude. Most patients in this study had evidence of subclinical depression, suggesting that even those with mild symptoms can have endothelial dysfunction.20 These findings provide evidence to suggest that there may be some factors that underlie the vascular dysfunction associated with both depression and early subclinical atherosclerosis.
