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Background— Traditional reperfusion options for patients with acute ST-segment elevation myocardial infarction (STEMI) presenting to non-primary percutaneous coronary intervention (PPCI)-capable hospitals generally include onsite fibrinolytics or emergency transfer for PPCI. A third option, involving interventionalist transfer, was examined in the REVERSE-STEMI study. Methods and Results— A total of 334 patients with acute STEMI who presented to 5 referral hospitals with angiographic facilities but without interventionalists qualified for PPCI were randomized to receive PPCI with either an interventionalist- (n=165) or a patient-transfer (n=169) strategy. The primary end point of door-to-balloon (D2B) time and secondary end points of left ventricular ejection fraction and major adverse cardiac events (MACE) at 1-year clinical follow-up were compared between the 2 groups. Compared with the patient-transfer strategy, the interventionalist-transfer strategy resulted in a significantly shortened D2B time (median, 92 minutes versus 141 minutes; P P P P =0.019). Multivariate Cox proportional hazards modeling revealed that the interventionalist-transfer strategy was an independent factor for reduced risk of composite MACE (hazard ratio, 0.63; 95% CI, 0.45 to 0.88; P =0.003). Conclusions— The interventionalist-transfer strategy for PPCI may be effective in improving the care of patients with STEMI presenting to a non-PPCI-capable hospital, particularly in a congested cosmopolitan region where patient transfers could be prolonged. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00713557.

BACKGROUND: This study sought to examine whether circulatory levels of endothelial dysfunction biomarkers [vascular cell adhesion molecule (sVCAM-1), intercellular adhesion molecule (sICAM-1), sE-selectin, von Willebrand factor (vWF), tissue plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI-1)] are associated with occurrence of late or very late stent thrombosis (ST) after percutaneous coronary intervention with sirolimus-eluting stent implantation, and to assess the possible influence of genetic variants of these proteins on ST. METHODS: Serum levels of sVCAM-1, sICAM-1, sE-selectin, vWF, t-PA and PAI-1 were measured, and polymorphisms of vWF (-1234C/T, -1185A/G and -1051G/A), t-PA (insertion/deletion) and PAI-1 genes (4G/5G) were determined in 41 patients who experienced at least one episode of late or very late ST. Eighty-two patients without ST randomly selected from the same study period served as controls. RESULTS: Serum levels of vWF, sVCAM-1 and sICAM-1 were significantly increased in patients with ST than in controls (all P

Background: ApoA-IV is associated with HDL in plasma but a large portion circulates lipid free. It has been shown to possess anti-inflammatory and anti-atherosclerotic effects. Methods and Results: We isolated HDL from plasma of type 2 diabetic patients and healthy controls, and found that apoA-IV of HDL from diabetic patients was significantly glycated by using Western blot and mass spectrometry. The glycation levels of apoA-IV were higher in diabetic patients than in controls, and were associated with the severity of coronary artery disease. Immunohistochemically, glycation sites co-localized with apoA-IV in atherosclerotic plaques from diabetic patients. In cell and animal studies, in vitro glycated apoA-IV protein promoted inflammatory reactions in human aortic endothelial cells and atherogenesis in apoE-KO mice as compared with control, whereas apoA-IV exhibited anti-inflammatory and anti-atherogenic effects. The pro-inflammatory action of glycated apoA-IV was mediated by receptor for glycation end products in endothelial cells. In microarray analysis and verification in endothelial cells, glycated apoA-IV but not apoA-IV, enhanced the expression of nuclear receptor NR4A3 greatly. Glycated apoA-IV-induced inflammatory reaction and atherogenic effect was significantly attenuated in endothelial cell with siRNA-NR4A3, native endothelial cells and macrophages from NR4A3-KO mice and in NR4A3-KO mice. Co-localization of NR4A3 with CD31 was observed in atherosclerotic plaque from diabetic patients. Moreover, glycated apoA-IV but not apoA-IV induced trans-activation of NR4A3 to the promoter of adhesion molecules (VCAM-1, ICAM-1 and E-selectin). ESI-Q-TOF-MS identified several glycation sites including K78, K189 and K328 in apoA-IV from diabetic patients, but not in controls. Mutated apoA-IV proteins (m-apoA-IV-K78A/K189A/K328A) were made. In vitro glycated m-apoA-IV displayed significantly attenuated activation of NR4A3 in endothelial cells and atherogenesis in apoE-KO mice, as compared with glycated apoA-IV. Conclusion: Glycation of apoA-IV is associated with the severity of coronary artery disease in diabetic patients and glycated apoA-IV protein promotes atherogenesis through nuclear receptor NR4A3 mediation.

Background: C1q/TNF-related protein (CTRP) 1 was initially identified as a paralog of adiponectin based on the similarity in C1q domain of these two proteins. However, vascular functions of CTRP1 remain largely undetermined. Here, we sought to investigate whether CTRP1 influences the pathogenesis of atherosclerosis. Methods and Results: We analyzed CTRP1 levels in sera of coronary artery disease (CAD) patients (n=451) and non-CAD controls (n=686), in coronary endarterectomy specimens (n=26) and non-atherosclerotic internal mammary arteries (n=32), and in peripheral blood mononuclear cells (PBMCs) from severe CAD patients (n=58) and non-CAD controls (n=25). CTRP1 levels were higher in sera, endarterectomy specimens and PBMCs from CAD patients compared with controls, and were related to CAD severity. Immunohistochemistry of human femoral arteries exhibited VE-cadherin loci-associated increased CTRP1 expression in atherosclerotic plaques. In cultured endothelial cells, CTRP1 stimulation resulted in reduced nitric oxide (NO) bioavailability and promotion of inflammatory reactions (increased production of inflammatory cytokines and induction of adhesion molecules). Intravital microscopy exhibited impaired endothelium-dependent arteriole dilation and enhanced leukocyte-endothelium interactions after injection of recombinant CTRP1, whereas improved arteriole dilation and decreased leukocyte-endothelium interactions were observed in CTRP1 knockout mice. Furthermore, we found that arginase 1 was significantly increased by CTRP1 in a dose-dependent fashion, thereby leading to eNOS-uncoupling and reactive oxygen species generation. Inhibition of arginase activity by synthetic chemicals markedly improved CTRP1-dependent endothelial dysfunction. Finally, intraperitoneal injection of recombinant CTRP1 promoted atherogenesis in apoE-/- mice. In contrast, proatherogenic effects were significantly attenuated in CTRP1-/-/apoE-/- double knockout mice. Conclusions: Our findings have demonstrated that CTRP1 is a pro-atherogenic adipokine, likely by modulating arginase 1 expression and enzyme activity. CTPP1 may represent a crucial therapeutic target in atherosclerosis.

To investigate the antianginal action of nitroglycerin and nifedipine, systemic and right heart pressures, cardiac output, oxygen consumption, and radionuclide left ventricular ejection fraction and volume were measured in 14 men with stable effort angina and a positive exercise electrocardiogram. Exercise tests were performed on a semiupright bicycle ergometer on no therapy and after intravenous nitroglycerin and sublingual nifedipine, which lowered mean arterial pressure by 20 mm Hg. Exercise tolerance improved from 50 +/- 4 to 61 +/- 5 W on nifedipine and to 79 +/- 4 W on nitroglycerin (p less than 0.01, nitroglycerin vs. nifedipine). At submaximal workloads, both drugs decreased arterial pressure and ventricular volumes, but heart rate was higher on nifedipine. At peak exercise on nitroglycerin (79 W), oxygen consumption, cardiac index, heart rate, and rate-pressure product were significantly increased over peak control and nifedipine values, while systolic pressure and end-diastolic volume were unchanged. Nitroglycerin reduced pulmonary wedge pressure more and systemic diastolic pressure less than nifedipine, so the coronary perfusion gradient was reduced by nifedipine and maintained by nitroglycerin. Also, there was less angina and ST-segment depression after nitroglycerin compared to control or nifedipine, and the left ventricular diastolic pressure-volume relationship was improved only by nitroglycerin. This suggests that the action of nitroglycerin in reducing ischemia is not only due to reduced myocardial oxygen demand, but that myocardial oxygen delivery may also be increased.

In a placebo-controlled, randomized, cross-over, double-blind study of 12 patients with stable exertional angina, we measured at rest and during bicycle exercise the effects of 20 mg of nifedipine administered sublingually on hemodynamics and systemic and regional oxygen extraction and metabolism. Nifedipine decreased systemic vascular resistance by 38% at rest (p less than .001) and by 28% during exercise (p less than .001). Cardiac output increased from 4.6 +/- 0.6 to 6.0 +/- 0.9 liters/min (p less than .001) at rest after nifedipine and from 10.6 +/- 3.7 to 11.8 +/- 3.4 liters/min (p less than .005) during exercise. After nifedipine, the arterial-mixed venous O2 content difference decreased from 4.7 +/- 0.6 to 3.5 +/- 0.5 ml/100 ml (p less than .001) at rest and from 10.5 +/- 1.7 to 8.8 +/- 1.6 ml/100 ml (p less than .001) during exercise. After nifedipine the arterial-iliac venous O2 content difference also decreased at rest, from 5.9 +/- 1.5 to 4.8 +/- 1.7 ml/100 ml (p = .06) but increased during exercise from 13.1 +/- 1.5 to 14.0 +/- 1.8 ml/100 ml (p less than .05). Oxygen consumption was not significantly altered at rest or during exercise. Nifedipine decreased mixed venous carbon dioxide tension (PCO2) during exercise from 53 +/- 3.5 to 50 +/- 4.0 mm Hg (p less than .05) but increased iliac venous PCO2 slightly from 61 +/- 4.6 to 63 +/- 5.2 mm Hg (p less than .01). Exercise pH was not significantly altered, but arterial lactate increased more after nifedipine (2.65 +/- 1.95 mmol/liter placebo, 3.54 +/- 2.74 mmol/liter nifedipine; p less than .05). Thus nifedipine produces similar changes in O2 extraction in mixed venous and iliac venous blood at rest but directionally opposite changes during exercise. The data support the hypothesis that nifedipine does not alter the distribution of cardiac output to the legs at rest, but during dynamic leg exercise reduces the redistribution of cardiac output to the legs. This probably results from the shunting of blood flow away from exercising muscles by the generalized vasodilatation of nifedipine.