Endothelial Dysfunction and Platelet Activation in Major Depressive Disorder: Association with Brain Perfusion Abnormalities

Abstract Background: Major depressive disorder (MDD) has been consistently associated with vascular derangement affecting different territories and an important independent risk factor for cardiovascular disease (CVD). Subjects with depression are more likely to develop CVD and, on the other hand in patients with existing CVD, depression seems to be a marker of worse outcome. Depression may also constitute a risk marker for cerebrovascular complications such as stroke and, patients with neuro-vascular disease are at higher risk of depression. In fact, there is evidence suggesting that depressive patients exhibit abnormalities in regional cerebral blood flow (rCBF). Endothelial dysfunction (ED) defines different forms of abnormal activity of the endothelium, leading to an inflammatory and prothrombotic phenotype. ED is associated with several clinical conditions linked with higher cardiovascular risk among which, depression is included. Regardless that the association between MDD and ED has been recognized, studies aimed to understand the possible relationship of ED and hemostatic activation with rCBF are still under investigation. Aim: To demonstrate activation of the hemostatic system and systemic ED in patients with MDD and their relationship with abnormal rCBF. Methods: We studied 23 unipolar depressive patients: 17 females, (mean age 34 years). All patients fulfilled DSM-IV criteria for major depressive disorder with 21-item Hamilton depression rating scale ≥17 points. To assess platelet activation, plasma levels of soluble CD40L (sCD40L), regulated on activation normal T cells expressed and secreted (RANTES) and Neutrophil-Activating Peptide-2 (NAP-2) were measured by ELISA using commercial reagents and standards. ED was evaluated by measuring levels of circulating endothelial cells (CECs) and soluble plasma markers. CECs were isolated from peripheral blood by use of immunomagnetic beads coated with anti-CD146, stained for CD45 and Ulex Europaeus lectin and counted under fluorescence microscopy. Plasma levels of soluble intercellular cell adhesion molecule (sICAM), monocyte chemoattractant protein 1 (MCP-1), vascular endothelial growth factor (VEGF) and free brain-derived neurotrophic factor (BDNF), were measured by enzyme-linked immunosorbent assay (ELISA) using commercial reagents. Basal percental relative brain perfusion was assessed with 99mTc-ECD SPECT and regional analysis in Brodmann areas (BA) known as associated with MDD. Results: Patients with MDD showed significantly elevated number of CECs compared to the controls (p=0.0003). They also showed increased levels of sICAM, MCP-1 and VEGF as compared to the control group (p=0.029, p=0.047 and p=0.031, respectively). Platelet activation markers, NAP-2, RANTES and sCD40L were significantly elevated in the plasma of MDD patients (p<0.0001, p<0.0001 and p=0.0007, respectively). Soluble markers of ED, sICAM and VEGF, were also increased among patients (p=0.029; p=0.031, respectively). MCP-1 was slightly elevated regarding controls (p=0.047). Results are shown in Table 1.VEGF levels correlated positively with sCD40L (r: 0.53; p=0.03) and NAP-2 (r: 0.54; p=0.007) whereas BNDF levels correlated strongly with RANTES (r: 0.66; p=0.007), sCD40L (r: 0.85; p<0.0001) and NAP-2 (r: 0.88; p<0.0001). With respect to brain perfusion, all patients showed reduced regional brain perfusion mostly prefrontal. In patients with MDD there were significant positive correlations between the extent of hypoperfusion in Brodmann areas (BA) and markers of platelet activation: right BA28 with NAP-2 (r: 0.44; p=0.03); left BA40 with sP-selectin (r: 0.49; p=0.02) and right BA11 with BDNF levels (r: 0.49; p=0.02). Conclusions: Our data confirmed increased rates of endothelial damage and platelet activation in non-treated MDD patients. Furthermore, we found a positive association between regional brain perfusion and platelet activation. Together, our observations showed impairment of two fundamental hemostatic components, platelets and endothelial cells, in MDD patients, which may explain not only the increased risk of systemic vascular complications but also the association with the brain vasculature. These findings may allow to explore new treatments aimed at protecting the endothelium and targeting platelet activation, as a comprehensive approach in the disease management. Disclosures No relevant conflicts of interest to declare.