Coronary microvascular dysfunction is associated with impaired cognitive function: the Cerebral-Coronary Connection study (C3 study)

Background It remains unknown whether the presence of coronary microcirculatory dysfunction (CMD) correlates with its equivalent conditionin the brain, cerebral small vessel disease (CSVD). The cerebral-coronary connection (C3), a prospective blinded study, investigatedthe prevalence of CMD in patients with coronary artery disease (CAD) and its association with CSVD and cognitive function. Methodsand results Patients with documented CAD fulfilling inclusion criteria underwent physiological assessment of epicardial vessels and the microcirculation using intracoronary pressure and Doppler. Coronary microcirculation-related indices included coronary flow reserve (CFR) and hyperaemic microvascular resistance. Brain magnetic resonance imaging, transcranial Doppler (TCD), and neurocognitive examination were performed. Overall, 67 patients were included in the study (mean age 66 years, 73% female). Patients with abnormal CFR (<2.0) (55.2%) showed higher burden of white-matter hyperintensities: 43.2 vs. 20.0% (P=0.044). After statistical adjustment, low CFR was associated with lower grey matter volume (P=0.024) and with parameters of white-matter microstructural damage in diffusion-tensor imaging (lower fractional anisotropy and higher mean diffusivity, P=0.029 and P=0.032, respectively). Low CFR was associated with higher resistive (P=0.027) and pulsatility (P=0.043) values on TCD, and worse neurocognitive test scores (lower mini mental state examination, P=0.025, and slower Trail Making Test A, P=0.034). Conclusions Coronary microcirculatory dysfunction is frequent in patients with CAD and correlates with CSVD, abnormal cerebral flow haemodynamics, and significant cognitive impairment. These findings support the hypothesis that microvascular dysfunction in the heart and the brain are part of a single pathological process affecting microcirculation in patients with CAD.Depto. de Psicobiología y Metodología en Ciencias del ComportamientoFac. de PsicologíaTRUEpu

Extracellular signal-regulated kinase plays an essential role in endothelin-1-induced homotypic adhesion of human neutrophil granulocytes

1. Endothelin-1 (ET-1) stimulates integrin-dependent adhesion of neutrophil granulocytes to endothelial cells, one of the early key events in acute inflammation. However, the signalling pathway(s) of ET-1-stimulated neutrophil adhesive responses has not been elucidated. Previous studies indicated that extracellular signal-regulated kinase (ERK) activation could mediate rapid responses of neutrophil granulocytes to various stimuli. In this study, we investigated the role of ERK signalling in human neutrophil granulocytes challenged with ET-1. 2. ET-1 rapidly down-regulated the expression of L-selectin and up-regulated the expression of CD11b/CD18 on the neutrophil surface. Concomitantly, ET-1 induced homotypic adhesion (aggregation) of neutrophils, that was blocked by a monoclonal antibody to CD18. 3. ET-1, through ET(A) receptors, evoked activation of Ras and subsequent phosphorylation of Raf-1, mitogen-activated protein kinase kinase (MAPK/ERK kinase) and ERK 1/2. ERK activation by ET-1 was rapid, concordant with the kinetics of ET-1-stimulated neutrophil aggregation. 4. Neutrophil responses to ET-1 were markedly attenuated by the MAPK/ERK kinase inhibitor PD98059, whereas inhibitors of p38 MAPK, tyrosine kinases and phosphatidylinositol 3-kinase had no detectable effects. We have observed a tight correlation between neutrophil ERK activation and homotypic adhesion. 5. These data indicate an essential role for ERK in mediating ET-1-stimulated adhesive responses of human neutrophil granulocytes

Endothelin-1 enhances neutrophil adhesion to human coronary artery endothelial cells: role of ET(A) receptors and platelet-activating factor

1. The potent coronary vasoconstrictor, endothelin-1 (ET-1) may also regulate neutrophil traffic into tissues. The aim of the present study was to characterize the endothelin receptors responsible and to investigate the underlying mechanisms. 2. ET-1 (1 nM–1 μM) markedly enhanced attachment of human neutrophils to lipopolysaccharide-, and to a lesser extent, to ET-1-activated human coronary artery endothelial cells (HCAEC). This can partially be blocked by monoclonal antibodies against E-selectin, L-selectin or CD18, whereas combination of the three antibodies inhibited adhesion by ∼83%. Increases in neutrophil adhesion evoked by ET-1 were also blocked by the platelet-activating factor (PAF) antagonists, BN 52021 (50 μM) and WEB 286 (10 μM). 3. ET-1 downregulated the expression of L-selectin and upregulated expression of CD11b/CD18 and CD45 on the neutrophil surface and induced gelatinase release with EC(50) values of ∼2 nM. These actions of ET-1 were almost completely prevented by the ET(A) receptor antagonist FR 139317 (1 μM) and the ET(A)/ET(B) receptor antagonist bosentan (10 μM), whereas the ET(B) receptor antagonist BQ 788 (1 μM) had no effect. ET-1 slightly increased the expression of E-selectin and ICAM-1 on HCAEC, that was prevented by BQ 788, but not by FR 139317. 4. Receptor binding studies indicated the presence of ET(B) receptors (K(D): 40 pM) on phosphoramidon-treated HCAEC and the predominant expression of ET(A) receptors (K(D): 38 pM) on neutrophils. 5. These results indicate that promotion by ET-1 of neutrophil adhesion to HCAEC is predominantly mediated through activation of ET(A) receptors on neutrophils and subsequent generation of PAF