ADVERTISEMENT

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

July 1, 2010|Cleveland Clinic Journal of Medicine
Ki E. Park, MD;Carl J. Pepine, MD
Author and Disclosure Information

Ki E. Park, MD
Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL

Carl J. Pepine, MD
Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL

Correspondence: Carl J. Pepine, MD, Division of Cardiovascular Medicine, Department of Medicine, University of Florida College of Medicine, 1600 SW Archer Road, P.O. Box 100277, Gainesville, FL 32610–0277; ki.park@medicine.ufl.edu

Both authors reported that they have no financial relationships that pose a potential conflict of interest with this article.

 

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.

Focus on endothelial progenitor cells

EPCs from bone marrow and likely other sites (eg, spleen, perivascular omentum, liver, mesentery) play an important role in maintaining vascular integrity. The interaction between the bone marrow, nervous system, HPA axis, and progenitor cells, together with the effect of this interaction on vascular integrity, has become an area of increasing research. Specifically, the sympathetic nervous system has been identified as playing an important role in progenitor cell egress from the bone marrow. Mice with abnormal nerve conduction produce virtually no progenitor cells when treated with granulocyte colony-stimulating factor.21

Psychosocial factors influence activation of the sympathetic nervous system. An innovative recent study examined the effect of psychosocial determinants on bone marrow–derived progenitor cells; the psychosocial variables and progenitor cell counts were associated independently from traditional biological and behavioral risk factors.22 This is one of the first studies to examine the effect of psychosocial stressors on progenitor cells and should open the way for further research exploring this association and its effects on CV health.

Reprinted, with permission, from Neurology (Lee S-T, et al. Decreased number and function of endothelial progenitor cells in patients with migraine. Neurology 2008; 70:1510–1517).
Figure 2. Endothelial progenitor cell counts in headache patients. The counts were lowest in patients with migraine with aura, followed by migraine without aura, followed by tension headaches. Box plots show the median count (white lines), interquartile ranges (green boxes), 5% to 95% percentiles (whiskers), and outliers (dots). P values were calculated using a two-tailed Student t test.24
Another area of interest has been the ability of progenitor cells to aid in repair after neurologic damage following vascular insult. Two areas related to progenitor cells have been stroke and migraine, which is a risk factor for stroke as well as depression.23 Compared with patients with tension headaches, patients with migraines (with and without aura) had lower levels of EPCs, with the lowest levels observed in migraine patients with aura (Figure 2).24 The EPCs in patients with migraine with and without aura also showed reduced migratory capacity and increased senescence.24
Reprinted, with permission, from Stroke (Sobrino T, et al. The increase of circulating endothelial progenitor cells after acute ischemic stroke is associated with good outcome Stroke 2007; 38:2759–2764), Copyright © 2007 American Heart Association, Inc.
Figure 3. Temporal profile of number of circulating endothelial progenitor cells in stroke patients by stroke outcome at 3 months. Box plots show the median number (white lines) and interquartile ranges (boxes).25
Another study examined the relationship between EPCs and ischemic stroke, finding that an increase in circulating EPCs after acute ischemic stroke was associated with better outcomes and reduced infarct growth (Figure 3).25 This suggests that EPCs may play an important role in neurovascular repair after ischemic insult.
Reprinted, with permission, from Stroke (Jickling G, et al. Circulating endothelial progenitor cells and age-related white matter changes. Stroke 2009; 40:3191–3196), Copyright © 2009 American Heart Association, Inc.
Figure 4. Endothelial progenitor cell levels and age-related white matter change severity as measured by computed tomography.26
A different study evaluated EPC levels in individuals with age-related white matter changes.26 These white matter changes, measured on computed tomography or magnetic resonance imaging, correlate with microvascular pathology mainly within the elderly and are associated with increased risk of stroke and cognitive impairment such as dementia. In the study, circulating levels of EPCs were found to be significantly lower in patients with severe age-related white matter changes (Figure 4).26 This suggests that defects in endothelial repair are linked to small-vessel cerebrovascular disease.

Platelet activity

Platelets play a critical role in endothelial hemostasis. Alterations in platelet function have been hypothesized as a mechanism by which depression may lead to CV disease.27 A recent study analyzed the effects of persistent depressive symptoms on platelet activation in a cohort of spousal dementia caregivers.28 P-selectin, measured as an index of platelet activation, and depression, mainly in the subclinical range, were associated with elevated platelet reactivity and recovery. This may be one mechanism by which elderly caregivers are at risk of CV disease even without evidence of clinical depression.

Serotonin is also known for its effect on platelet function and vascular tone and is one of the main targets of antidepressant therapy. Several studies have analyzed the effect of depression treatment with SSRIs on platelet function. An initial analysis from the SADHART trial in 2003 found that in depressed patients treated with sertraline after acute coronary syndrome, reductions in platelet/endothelial activation occurred despite concurrent treatment with antiplatelet drugs, including aspirin and clopidogrel.29 This suggests that the antiplatelet properties of sertraline differ from those of aspirin and other antiplatelet therapies. A study by van Zyl et al30 yielded similar results with a different SSRI, citalopram, along with enhanced production of nitric oxide.

ADVERTISEMENT
ADVERTISEMENT
ADVERTISEMENT