Effects of diesel exhaust particles on macrophage polarization.

BACKGROUND: Exposure to diesel exhaust particles (DEP) has long been associated with increased cardiovascular morbidity and mortality. The development of DEP toxicity seems to be linked to inflammation in which macrophages play a critical role. Macrophages can be polarized into proinflammatory M1 or anti-inflammatory M2 macrophages. The aim of this study was to identify the role of inflammation in DEP-induced toxicity by assessing the effects of DEP on macrophage polarization. METHODS: Monocyte-derived macrophages (Mϕ) were stimulated with interferon γ and lipopolysaccharide or interleukin (IL)-4 to obtain M1 and M2 subtypes, respectively. To test the polarization capacity of DEP, Mϕ cells were exposed to DEP and compared to Mϕ, M1, and M2. We also studied the effects of DEP on already-polarized M1 or M2. The M1 markers assessed were tumor necrosis factor α (TNF-α) and IL-1ß, while the M2 markers were the mannose receptor C type 1 (MRC-1) and transglutaminase 2 (TGM2). RESULTS: Western blots revealed a 31 kDa band corresponding to pro-IL-1ß, but only in M1-polarized macrophages. In M1, we also observed an upregulation of TNF-α messenger RNA (mRNA) expression. MRC-1 and TGM2 mRNA expression were only significantly enhanced in M2. DEP had no effect on any of the M1/M2 markers assessed. Moreover, DEP were not able to modify the phenotype of already-polarized M1 or M2. CONCLUSION: Mϕ incubation with DEP did not have any effect on macrophage polarization, at least on the markers assessed in this study, namely, TNF-α/IL-1ß for M1, and MRC-1/TGM2 for M2. Hence, these data argue against an important role of inflammation in DEP-induced vascular toxicity.

[Implementation of reperfusion therapy in ST segment elevation myocardial infarction (STEMI). A policy statement from the Belgian Society of Cardiology and its working group of acute cardiology and interventional cardiology]. / Mise en pratique du traitement de reperfusion dans les infarctus du myocarde avec élévation du segment ST (STEMI). Recommandations actualisées de la Société Belge de Cardiologie et de ses groupes de travail: le Groupe Interdisciplinaire de Cardiologie Aiguë (BIWAC) et le Groupe de Cardiologie Interventionnelle (BWGIC).

Myocardial infarction remains a major healthcare problem. Reperfusion therapy has been shown to influence favourably short- and long-term patient survival. The authors reviewed the data of early recognition of STEMI (ST Elevation Myocardial Infarction), the reperfusion modalities including a flowchart management, as proposed by the Belgian working groups (BIWAC and BWGIC), and the lessons learned from European and American registries. Primary PCI often remains the treatment of choice. A national policy is still required to implement the guidelines and improve clinical practice for our STEMI patients.

[Implementation of reperfusion therapy in ST segment elevation myocardial infarction (STEMI). A policy statement from the Belgian Society of Cardiology and its working group of acute cardiology and interventional cardiology]. / Mise en pratique du traitement de reperfusion dans les infarctus du myocarde avec élévation du segment ST.

Myocardial infarction remains a major healthcare problem. Reperfusion therapy has been shown to influence favourably short- and long-term patient survival. The authors reviewed the data of early recognition of STEMI (ST Elevation Myocardial Infarction), the reperfusion modalities including a flowchart management, as proposed by the Belgian working groups (BIWAC and BWGIC), and the lessons learned from European and American registries. Primary PCI often remains the treatment of choice. A national policy is still required to implement the guidelines and improve clinical practice for our STEMI patients.

Acute effect of sidestream cigarette smoke extract on vascular endothelial function.

Acute exposure to passive smoking adversely affects vascular function by promoting oxidative stress and endothelial dysfunction. However, it is not known whether tobacco sidestream (SS) smoke has a greater deleterious effect on the endothelium than non-tobacco SS smoke and whether these effects are related to nicotinic endothelial stimulation. To test these hypotheses, endothelial-dependent relaxation and superoxide anion production were assessed in isolated rat aortas incubated with tobacco SS smoke, non-tobacco SS smoke, or pure nicotine. Tobacco SS smoke decreased the maximal relaxation to acetylcholine (Ach) from 79 +/- 6% to 57 +/- 7.3% (% inhibition of phenylephrine-induced plateau, P < 0.001) and increased superoxide anion production from 31 +/- 9.7 to 116 +/- 24 count/10 sec/mg (P < 0.01, lucigenin-enhanced chemiluminescence technique). The non-tobacco SS smoke extract had no significant effect on the response to Ach but increased superoxide anion production in the aortic wall to 133 +/- 2 count/10 sec/mg (P < 0.001). Furthermore, concentration-response curves to Ach and superoxide production remained unaltered with nicotine (0.001, 0.01, or 0.1 mM). In conclusion, despite similar increases in vascular wall superoxide production with tobacco and non-tobacco SS smoke, only the tobacco SS smoke extracts affected endothelium-dependent vasorelaxation. Nicotine alone does not reproduce the effects seen with tobacco SS smoke, suggesting that the acute endothelial toxicity of passive smoking cannot simply be ascribed to a nicotine-dependent mechanism.

[The cardiology department]. / Le Service de Cardiologie.

Cardiology was present since the very beginning of the Erasme hospital. The Department of Cardiology was created in 1979. This department is made of a hospitalization unit (54 beds), a coronary care unit (12 beds) and a large technical unit. Clinical activity has increased tremendously and this had led to an important research activity in the fields of cardio-respiratory and metabolic adaptation to exercise, particularly after cardiac transplantation, of cardiovascular epidemiology, of clinical pharmacology and in pulmonary as well as systemic hypertension.

[Unstable atheromatous plaque. Physiopathology and therapeutic approach to coronary insufficiency]. / Plaque athéromateuse instable. Physiopathologie et approche thérapeutique de l'insuffisance coronaire.

Plaque disruption promoted by local inflammation and oxidative stress seems to be the triggering mechanisms of acute coronary syndromes. Oxidized low-density lipoproteins (LDL) play a key role in the inflammatory process. Within the inflammatory region, angiotensin-converting enzyme (ACE) accumulation has been described, leading to enhanced production of angiotensin II which stimulates adhesion molecule formation and increases oxidative stress. According to recent clinical trials, drugs like statins or ACE inhibitors seem promising and could stabilize the plaque, probably by attenuation of the inflammatory process. Finally, as thrombus formation also plays a role in these acute coronary syndromes, another approach is the use of antithrombotic therapy.

Early alterations of myocardial blood flow reserve in heart transplant recipients with angiographically normal coronary arteries.

BACKGROUND: The evaluation of the coronary reserve provides valuable information on the status of coronary vessels. Therefore, we studied with positron emission tomography (PET) and 13N-ammonia the myocardial blood flow (MBF) reserve in heart transplant recipients free of allograft rejection and with angiographically normal coronary arteries early after heart transplantation (HTx). The MBF reserve was calculated as the ratio between MBF after dipyridamole injection and basal MBF normalized for the rate-pressure product. METHODS: Patients were studied within 3 months (group A, n = 12) or more than 9 months (group B, n = 12) after HTx. Five patients have been studied both during the early and late period after HTx. Results were compared to those obtained in 7 normal volunteers (NL). RESULTS: Group A recipients had a significantly lower dipyridamole MBF (in ml/min/100 gr of tissue) than that of group B recipients (142+/-34 vs 195+/-59, p<0.05). This resulted in a significant decrease in MBF reserve early after HTx (group A: 1.82+/- 0.33) and a restoration to normal values thereafter (group B: 2.52+/- 0.53 vs NL: 2.62+/-0.51, p = ns). Separate analysis of 5 patients studied twice is consistent with these results. CONCLUSION: This study shows that in heart transplant recipients free of allograft rejection and with normal coronary angiography, MBF reserve is impaired early after HTx. Restoration within one year suggests that this abnormality does not represent an early stage of cardiac allograft vasculopathy.

Absence of L-arginine effect on coronary hypersensitivity to serotonin in cardiac transplant recipients.

Coronary hypersensitivity to serotonin promotes platelet aggregation and, therefore, the progression of the atherosclerotic process. This abnormality occurs in the early stages of coronary atherosclerosis when the responses to bradykinin are still preserved. To determine whether such changes also occur early after cardiac transplantation, intracoronary injections of bradykinin and serotonin were performed in 7 control patients, in 19 patients with dyslipidemia, and in 15 cardiac transplant recipients (1 year after operation). Coronary angiography was normal in the 3 groups. In the segments where serotonin effects were the most pronounced, the diameter changes were measured by quantitative angiography. Bradykinin (60, 200, and 600 ng) increased in the same way as the coronary diameters in the 3 groups; in contrast, serotonin elicited vasodilation only in the control group (7+/-3%, percentage of baseline) and vasoconstriction in the hyperlipidemic group (-9+/-2%) and in transplant recipients (-15+/-3%). After intracoronary infusion of L-arginine (40 mg/min for 14 minutes), serotonin-induced constriction was attenuated in the hyperlipidemic group but not in transplant recipients. Thus, the response to bradykinin is preserved in the early stages of graft vasculopathy. However, in contrast to patients with hyperlipidemia, the absence of an L-arginine effect on the responses to serotonin suggests the involvement of mechanisms other than a decrease in endothelium-derived nitric oxide availability. Immune processes promoting the release of endothelium-derived contracting factors such as endothelin and/or superoxide anion may play a role.

Absence of nitrate tolerance after long-term treatment with ramipril: an endothelium-dependent mechanism.

To determine whether nitrate tolerance is attenuated on aortas isolated from rats treated in the long term with an angiotensin-converting enzyme (ACE) inhibitor, five groups of rats were studied in parallel. Group 1 received ramipril, 1 mg/ kg/day, p.o., for 6 weeks; group 2 received ramipril at the same dose for 4 weeks, and the last 2 weeks, a cotreatment with ramipril plus HOE 140 (a bradykinin B2 antagonist, 500 microg/ kg/day, s.c. injections); group 3 received losartan, 2 mg/kg/day, p.o., for 6 weeks; group 4 received losartan at the same dose, and the last 2 weeks, a cotreatment with losartan plus HOE 140; and group 5 served as control. Rings of thoracic aorta from these groups were studied in organ baths. After nitroglycerin preincubation (10 microM for 30 min) in vitro, the dose-response curves to nitroglycerin were significantly shifted to the right in the control group but not in group 1. This protective effect was partially present in group 3; it was completely abolished in groups 2 and 4. In groups 1 and 3, it also was abolished after nitric oxide synthase (cNOS) inhibition (L-NMMA incubation) or removal of the endothelium. Superoxide anion accumulation (assessed by lucigenin chemiluminescence) was increased by nitroglycerin incubation in the control group but not in groups 1 and 3. After in vivo exposure to nitroglycerin (50 mg/kg subcutaneously twice daily for 4 days), this protection against nitrate tolerance also was observed in groups 1 and 3. Thus long-term ACE inhibition prevents nitrate tolerance by an endothelium-dependent mechanism involving mainly an enhanced NO availability via B2-kinin receptor. This effect on the cNOS pathway seems to attenuate the superoxide anion accumulation induced by nitroglycerin exposure (probably via a downregulation of oxidative enzyme).

[Vascular endothelium: target organ of cardiovascular pathologies]. / L'endothélium vasculaire: organe cible des pathologies cardio-vasculaires.

The endothelium plays an essential role in regulation of vascular tone. It has vasodilator, antiaggregating, anti-thrombotic and anti-inflammatory properties. In the case of endothelial dysfunction (induced by hypercholesterolaemia, hypertension and/or diabetes), all of these properties are reversed; it becomes thrombogenic, it secretes vasoconstrictor substances promoting platelet aggregation and penetration of white blood cells into the vessel wall. This endothelial dysfunction then allows the development of the atheromatous lesion. The therapeutic approach must be based on restoration of the normal physiological properties of the endothelium.

Unstable atherosclerotic plaque. Pathophysiology and therapeutic guidelines.

Plaque disruption promoted by local inflammation and oxidative stress seem to be the triggering mechanisms of acute coronary syndromes. Oxidized low-density lipoproteins (LDL) play a key role in this inflammatory process. Within the inflammatory region, angiotensin-converting enzyme (ACE) accumulation has been described, leading to enhanced production of local angiotensin II which stimulates adhesion molecule expression and increases oxidative stress (leading to excessive degradation of EDNO). According to recent clinical trials, drugs like statins or ACE inhibitors seem promising and could stabilize the plaque, probably by attenuation of the inflammatory process. Finally, as thrombus formation also plays a role in these acute coronary syndromes, another approach may be the use of antithrombotic therapy.

Assessment of coronary flow reserve by transesophageal echocardiography in cardiac transplant recipients.

This study investigated the feasibility of dipyridamole Doppler transesophageal echocardiography to assess coronary flow reserve in 26 patients with orthotopic heart transplantation and compared it with positron emission tomography. We found an 85% success rate in obtaining Doppler flow signals in the proximal left anterior descending coronary artery. Our data also showed that the correlation between transesophageal echocardiography and dipyridamole N-13 ammonia positron emission tomography increases when respective resting rate-pressure products are taken into account. However, comparison between the two methods should be made with caution because coronary flow reserve derived from transesophageal echocardiography tends to be higher than that obtained with positron emission tomography.

Endothelial function of internal mammary artery in patients with coronary artery disease and in cardiac transplant recipients.

The objective of this study was to examine the endothelial function of internal mammary artery in patients with coronary artery disease and in heart transplant recipients. Therefore the response of this artery to increasing concentrations of acetylcholine (1, 10, 20 microg/min for 2.5 minutes each) was assessed in 6 patients in a control group, 16 patients with coronary artery disease (CAD group) matched for risk factors with 16 heart graft recipients (who underwent transplantation for nonischemic heart failure), and 12 patients with coronary artery disease and peripheral vascular disease (PVD group). Diameters of proximal and middle segments of internal mammary artery were measured by quantitative angiography. The responses to the first concentration of acetylcholine were attenuated in these three groups compared with the control group. At the highest concentration of acetylcholine the diameter increase was similar in the control and CAD groups, whereas the responses remained significantly impaired in the transplant and PVD groups. However, after selective infusion of L-arginine (30 mg/min for 11 minutes), the precursor of endothelium-derived nitric oxide, was performed, the responses to acetylcholine were restored in these two latter groups. Endothelin plasma levels were significantly enhanced in the PVD group, which exhibited the most severe impairment in acetylcholine-induced vasodilation. Thus some patients with CAD, mainly those with advanced atherosclerosis, and cardiac transplant recipients exhibit internal mammary artery endothelial dysfunction, and this abnormality seems reversible.

Ramipril prevents endothelial dysfunction induced by oxidized low-density lipoproteins: a bradykinin-dependent mechanism.

We wished to determine whether the acute toxic effects of oxidized LDL are attenuated in aortas isolated from rats chronically treated with an angiotensin-converting enzyme (ACE) inhibitor. In aortic rings incubated with human oxidized LDL (300 microg/mL), the endothelium-dependent relaxations to acetylcholine were attenuated, but not those to A23187 and to nitroprusside. This toxic effect of oxidized LDL was completely prevented in preparations coincubated with oxidized LDL and the nitric oxide (NO) precursor L-arginine (0.3 mmol/L). In aortas isolated from rats orally treated for 6 weeks with 10 mg/kg ramipril (group 1) or 1 mg/kg ramipril (group 2), this toxic effect of oxidized LDL was also markedly attenuated. In contrast, in aortas isolated from rats cotreated with ramipril (10 mg/kg) for 6 weeks and subcutaneous injections of Hoe 140 (a B2 kinin antagonist), 500 microg/kg per day for the last 2 weeks (group 3) or from rats orally treated for 6 weeks with losartan (an AT1-type angiotensin II receptor antagonist), 20 mg/kg (group 4), the inhibitory effect of oxidized LDL on acetylcholine-induced relaxations was similar to that observed in the control group (group 5). Moreover, long-term treatment with ramipril increased relaxations to acetylcholine in groups 1 and 2 and also relaxations to A23187 and aortic cGMP content in group 1, suggesting an enhanced NO availability. Thus, the protective effect of long-term ACE inhibition against the acute vascular toxicity of oxidized LDL is bradykinin dependent and seems to involve a facilitation of NO release via endothelial B2 kinin receptors.

Prevention by selenium supplementation of cyclosporin-A-induced vascular toxicity.

OBJECTIVE: The aim was to determine whether selenium supplementation, an important component of glutathione peroxidase, might attenuate cyclosporin (Cx)-induced vascular toxicity. METHODS: Four groups of rats were treated in parallel: the first group was supplemented with selenium (sodium selenite, 0.5 mg.kg-1) orally (p.o.) for 5 weeks and the same dose of selenium plus Cx 20 mg.kg-1 (i.m.) during the 6th week; group 2 received Cx only (20 mg.kg-1 i.m. for 1 week); group 3 was supplemented with selenium (0.5 mg.kg-1 p.o., for 6 weeks) and group 4 served as control. Thoracic aortas isolated from these various groups were studied in organ baths. RESULTS: In comparison with the control group, selenium supplementation did not modify acetylcholine (Ach)- and nitroprusside-induced relaxations. In group 2, endothelium-dependent relaxations (Ach) were markedly impaired and endothelium-independent relaxations (nitroprusside) were shifted to the right; with selenium supplementation (group 1), the responses to Ach were partially restored whereas the rightward shift of the concentration-response curves to nitroprusside persisted. Incubation with superoxide dismutase (SOD, 150 IU.ml-1) or selenium (1 microgram.ml-1) (but not with selenium plus an inhibitor of the glutathione redox cycle) improved the relaxations to Ach in group 2. CONCLUSIONS: The vascular toxicity of Cx seems related to generation of oxygen-derived radicals promoting EDRF destruction and is attenuated by selenium supplementation.

Coronary vasomotility and myocardial blood flow early after heart transplantation.

Serotonin constricts coronary arteries with endothelial dysfunction, a common abnormality in cardiac transplant recipients. To assess whether endothelial dysfunction is associated with myocardial blood flow (MBF) abnormalities, 24 patients were studied 1 to 12 months after transplantation. Serotonin in increasing doses (1, 10, and 20 micrograms/min for 2.5 min each) was infused into the coronary circulation. Diameters were measured by quantitative angiography. Fourteen patients (group A) had a pronounced artery constriction (diameter reduction > 40%), while in 10 other patients (group B), such a constriction was never reached. No patient had evidence of rejection and all had angiographically normal coronary arteries. MBF was measured at rest and after intravenous dipyridamole with dynamic nitrogen-13 ammonia positron emission tomography (PET). The resting MBF was higher in group A than in group B (94 +/- 12 vs 74 +/- 15 ml/min/100 g of tissue; p < 0.05). During dipyridamole, MBF was not significantly different (191 +/- 53 vs 184 +/- 64 ml/min/100 g; p = NS). Coronary flow reserve (the ratio of perfusion after dipyridamole to perfusion at rest) was significantly lower in group A than in group B (2.08 +/- 0.54 vs 2.66 +/- 0.57; p < 0.05). Thus, coronary hypersensitivity to serotonin in cardiac transplant recipients is associated with elevated resting MBF and reduced coronary flow reserve. Immune mechanisms inducing endothelial injuries and inflammation-related hyperemia may account for these abnormalities.