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Boger RH, Endres HG, Schwedhelm E, Darius H, Atzler D, Luneburg N, von Stritzky B, Maas R, Thiem U, Benndorf RA, Diehm C (Institute of Clinical Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, Hamburg; Ruhr University Bochum; Vivantes Berlin-Neukolln Medical Center, Berlin; Sanofi-Aventis Pharma GmbH, Berlin; Institute of Clinical Pharmacology and Toxicology, University of Erlangen; Ruhr University Bochum, Herne; Klinikum Karlsbad-Langensteinbach, Affiliated Teaching Hospital of the Ruprecht-Karls-University of Heidelberg, Germany) Asymmetric dimethylarginine as an independent risk marker for mortality in ambulatory patients with peripheral arterial disease. J Intern Med 2010; 269: 349–361. Background. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis causing endothelial dysfunction, an early sign of atherogenesis. Symmetric dimethylarginine (SDMA) does not inhibit NO synthases. Peripheral arterial disease (PAD) is a systemic indication of atherosclerosis. Methods. We assessed the associations between both ADMA and SDMA blood levels and major cardiovascular and cerebrovascular events or death from any cause within a 5-year follow-up in the multicentre getABI trial. From a cohort of 6821 primary care patients, aged ≥65 years, all 1260 patients with prevalent PAD were compared with a random sample of 1187 non-PAD controls. A total of 11 544 patient-years were documented. Multivariate risks were calculated by Cox proportional hazard models, adjusting for PAD, renal dysfunction and other important cardiovascular risk factors. Results. We documented 390 deaths, 296 cardiovascular events and 98 cerebrovascular events. Increased ADMA levels in the 4th quartile were significantly associated with total mortality [hazard ratio (HR) 1.41; 95% CI 1.14–1.74] and with cardiovascular events (HR 1.32; 95% CI 1.03–1.69), but there was a nonsignificant association with cerebrovascular events (HR 1.50; 95% CI 0.98–2.29). Increased SDMA was only just significantly associated with mortality (HR 1.27; 95% CI 1.01–1.59). In PAD patients compared with non-PAD controls, only mean SDMA concentration was considerably increased (0.52 μmol L−1 vs. 0.48 μmol L−1; P

Myocardial ischemia and reperfusion injury (MI/R) can be related to leukocyte activation with subsequent release of cytokines and oxygen derived free radicals. Activation of the complement system has been implicated in the pathogenesis of myocardial ischemia and reperfusion injury. Inflammatory injury will subsequently result in cellular activation and protein synthesis. In the present study we analyzed the myocardial protein expression and its pattern following myocardial ischemia and reperfusion, with and without complement inhibition with the synthetic serine protease inhibitor Futhan/nafamstat mesilate (FUT-175) known to inhibit classical and alternative complement pathway in a rabbit model of myocardial ischemia and reperfusion (60 min I+180 min R). FUT-175 significantly reduced myocardial necrosis, i.e. creatine kinase release which were analyzed for the three groups (p

Although optimized antiplatelet medication has improved the clinical outcome after coronary stenting, vessel occlusion and restenosis still remain a relevant clinical problem. Platelets play a key role in this process. Therefore, the authors compared the platelet adhesion on different stent surface modifications (electropolished without coating or coated with carbon, carbon and additional heparin, silicon carbide, or heparin alone) to investigate their role in reducing platelet adhesion. All stents and additional stainless steel plates were incubated in heparinized whole blood with radiolabeled platelets. After washing the stents and plates four times, radioactivity caused by the adhesion of radiolabeled platelets was measured. The adhesion of radiolabeled platelets, compared to uncoated, electropolished stents, was reduced through silicon carbide coating to 58.6%, by carbon coating with additional heparin to 32.9%, and heparin coating alone to 7.7%. Stent coating with heparin is the most effective among the examined coatings in reducing platelet adhesion in vitro.

Beta-blocker therapy results in a functional benefit in patients with heart failure (CHF) due to idiopathic dilated cardiomyopathy (DCM). This study assessed if similar effects were observed in patients with ischemic heart disease (CAD), NYHA II–III after 6 months of therapy with metoprolol. Methods and results: Fifty-two patients with CHF secondary to DCM (26 patients) and CAD (26 patients) and a left ventricular ejection fraction (EF) < 40% were enrolled in the placebo-controlled study. The study medication was titrated over 6 weeks, the mean final dosage was 135 mg/day. Three patients died due to cardiogenic shock, two received placebo and one metoprolol. Eight patients did not complete the study due to non-compliance. Metoprolol significantly reduced heart rate at rest and after submaximal and maximal exercise. Vo2-max and Vo2-AT as well as the 6-min walk test improved significantly after metoprolol treatment. There was a significant increase in EF at rest (27.3–35.2%), submaximal (28.5–37.7%) and maximal exercise (28.7–40.9%) in the metoprolol-treated patients. No differences were found between patients with CAD and DCM. We also observed reduced left ventricular volumes. Conclusion: The additional therapy with metoprolol improved cardiac function and the cardiopulmonary exercise capacity in patients with CHF.

Smooth muscle cell (SMC) proliferation can result in luminal reduction of a vessel following balloon angioplasty. This study was designed (i) to determine if local administration of trapidil (triazolopyrimidine) into a vessel wall reduces neointima formation, and (ii) to explore the mechanism involved in the subsequent reduction in cell proliferation. Following balloon angioplasty in 40 anaesthetized New Zealand White rabbits, trapidil (50–200 mg) or its vehicle (saline) was injected into the dilated vessel wall of the right femoral artery. Experimental groups and time of investigation: (I) vehicle (2 weeks, n=3), (II) trapidil-100 mg (2 weeks, n=3), (III) vehicle (3 weeks, n=8), (IV) trapidil-50 mg (3 weeks, n=5); (V) trapidil-100 mg (3 weeks, n=9) or (V) trapidil-200 mg (3 weeks, n=7). After 2 weeks, there was a significant reduction of intimal hyperplasia (expressed as intima to media area ratio) in the trapidil group compared with vehicle (0.44±0.04 vs 0.93±0.04, *P

Background: Infective endocarditis is associated with significant morbidity and mortality, with valvular destruction, and with congestive heart failure. Embolic events are more common in patients with echocardiographically discernible vegetations, especially when vegetations are >10 mm in diameter. Hypothesis: The objective of the study was to follow vegetation morphology during native valve endocarditis, to compare it with the clinical course and antibiotic treatment chosen, and to evaluate whether the impact on vegetation size and complication rate of antibiotic regimens differed in patients with positive and negative blood cultures. Methods: The effect of different antibiotic regimes on vegetation size monitored by using transesophageal echocardiography was evaluated in 183 patients with echocardiographic evidence of infective endocarditis. A total of 223 vegetations attached to the aortic or mitral valves were detected using the transesophageal approach. The patients were followed for a mean of 76 weeks and underwent a minimum of two consecutive transesophageal echocardiographic examinations. Results: Treatment with different kinds of antibiotics corresponded with significant differences in vegetation size; vancomycin‐associated treatment was related to a 45% reduction, ampicillin to a 19% reduction, penicillin to a 5% reduction, penicillase‐resistant drugs to a 15% increase, and cephalosporin to a 40% increase in vegetation size. Multivariate analysis showed that penicillin, cephalosporin, and penicillase‐resistant drug treatments were associated with an increased embolic risk, vancomycin treatment with abscess formation, and cephalosporin medication with increased mortality. Plotting changes in vegetation size against the incidence of embolism and mortality, linear regression analysis suggested a 40–50% reduction in vegetation size, thereby greatly reducing the risk of embolism and mortality. Conclusion: Our study shows that different antibiotics have different effects on vegetation size. The highest complication rate was observed when vegetations significantly increased in size during antibiotic treatment. Especially in culture‐negati ve patients, monitoring vegetation size by means of transesophageal echocardiography may prove to be useful for estimating the efficacy of antibiotic treatment.

The purpose of the present study was to determine whether increased levels of platelet-activating factor (PAF) type activity can be detected in plasma from patients with septicemia and other diseases. A level of PAF below 0.5 ng/mL of plasma was considered normal. We found that plasma from a patient with adverse anaphylactoidic reaction to intravenous analgetics contained 2.1 ng PAF/mL. In seven patients with septicemia, including urosepsis, endocarditis and peritonitis, and with positive blood culture, increased plasma PAF levels (1-20 ng PAF/mL) were observed. Other patients with clinical indications of septicemia had negative blood cultures and/or increased levels of C-reactive protein (CRP). Yet, in the plasma from these patients, no increased PAF levels were detected under the assay conditions used. Two patients with allergic asthma, requiring treatment with steroids, had no measurable plasma PAF. In the plasma from a patient with idiopathic thrombocytopenic purpura (ITP) only an "endogenous" inhibitor of PAF induced platelet aggregation was initially observed. In spite of this, the patient responded to treatment with the PAF antagonist WEB 2086 with a dramatic increase in platelet count (Lohmann et al., Lancet ii, 1147, 1988). Thereafter, also increased PAF levels (3.3 ng PAF/mL) were detected in plasma, although some "endogenous" inhibitor of PAF was still present. In conclusion, increased PAF levels in plasma from patients support a role of PAF in certain human disease states, such as in anaphylactoid reaction, sepsis and septic shock. The type, relevance and specificity of endogenous inhibitors of PAF deserve further study.