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Background: Elderly patients are at elevated risk of both ischemic and bleeding complications after an acute coronary syndrome and display higher on-clopidogrel platelet reactivity compared with younger patients. Prasugrel 5 mg provides more predictable platelet inhibition compared with clopidogrel in the elderly, suggesting the possibility of reducing ischemic events without increasing bleeding., Methods: In a multicenter, randomized, open-label, blinded end point trial, we compared a once-daily maintenance dose of prasugrel 5 mg with the standard clopidogrel 75 mg in patients >74 years of age with acute coronary syndrome undergoing percutaneous coronary intervention. The primary end point was the composite of mortality, myocardial infarction, disabling stroke, and rehospitalization for cardiovascular causes or bleeding within 1 year. The study was designed to demonstrate superiority of prasugrel 5 mg over clopidogrel 75 mg., Results: Enrollment was interrupted, according to prespecified criteria, after a planned interim analysis, when 1443 patients (40% women; mean age, 80 years) had been enrolled with a median follow-up of 12 months, because of futility for efficacy. The primary end point occurred in 121 patients (17%) with prasugrel and 121 (16.6%) with clopidogrel (hazard ratio, 1.007; 95% confidence interval, 0.78-1.30; P =0.955). Definite/probable stent thrombosis rates were 0.7% with prasugrel versus 1.9% with clopidogrel (odds ratio, 0.36; 95% confidence interval, 0.13-1.00; P =0.06). Bleeding Academic Research Consortium types 2 and greater rates were 4.1% with prasugrel versus 2.7% with clopidogrel (odds ratio, 1.52; 95% confidence interval, 0.85-3.16; P =0.18)., Conclusions: The present study in elderly patients with acute coronary syndromes showed no difference in the primary end point between reduced-dose prasugrel and standard-dose clopidogrel. However, the study should be interpreted in light of the premature termination of the trial., Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01777503., (© 2018 American Heart Association, Inc.)

Rationale: Endothelial progenitor cells (EPCs) are present in the systemic circulation and home to sites of ischemic injury where they promote neoangiogenesis. β2-Adrenergic receptor (β2AR) plays a critical role in vascular tone regulation and neoangiogenesis., Objective: We aimed to evaluate the role of β2AR on EPCs' function., Methods and Results: We firstly performed in vitro analysis showing the expression of β2AR on EPCs. Stimulation of wild-type EPCs with β-agonist isoproterenol induced a significant increase of Flk-1 expression on EPCs as assessed by fluorescence-activated cell sorter. Moreover, β2AR stimulation induced a significant increase of cell proliferation, improved the EPCs migratory activity, and enhanced the EPCs' ability to promote endothelial cell network formation in vitro. Then, we performed in vivo studies in animals model of hindlimb ischemia. Consistent with our in vitro results, in vivo EPCs' treatment resulted in an improvement of impaired angiogenic phenotype in β2AR KO mice after induction of ischemia, whereas no significant amelioration was observed when β2AR knock out (KO) EPCs were injected. Indeed, wild-type-derived EPCs' injection resulted in a significantly higher blood flow restoration in ischemic hindlimb and higher capillaries density at histological analysis as compared with not treated or β2AR KO EPC-treated mice., Conclusions: The present study provides the first evidence that EPCs express a functional β2AR. Moreover, β2AR stimulation results in EPCs proliferation, migration, and differentiation, enhancing their angiogenic ability, both in vitro and in vivo, leading to an improved response to ischemic injury in animal models of hindlimb ischemia.

The present clinical case shows that assessment of longitudinal strain in the coronary care unit using speckle tracking echocardiography can help to quantify myocardial damage in the context of acute coronary syndromes and detect changes otherwise not visible with semi-quantitative evaluation of wall motion.

Objectives: The purpose of this study was to evaluate the role of genetic variants within the coagulation factor II receptor (F2R) in the occurrence of coronary heart disease (CHD)., Methods and Results: Four SNPs (-1738 G/A, 2860 G/A, 2930 T/C, and 9113 C/A) and an ins/del polymorphism -506-/GGCCGCGGGAAGC (D/I), replicating a consensus sequence for Ets-1 transcription factor, and their related haplotypes were tested for association to CHD in 1600 hypertensive patients divided in 2 groups according to presence (cases, n=559) and absence (controls, n=1041) of CHD. Allele I at -506 locus was associated with increased risk of CHD under additive, dominant, and recessive models of inheritance (all P<0.01). Three haplotypes carrying I allele were consistently associated with an increased risk of CHD (all P<0.05). Patients homozygous for the C allele at the 2930 locus also showed an increased risk of CHD (P<0.05). To test the functionality of -506 locus, nuclear extracts were incubated with -506D and -506I sequences by EMSA and F2R promoter activity (F2R-A) were assessed in HUVECs transfected with vectors carrying -506D and -506I sequences and exposed to hypoxia. Presence of the -506I sequence was associated with a 26% reduction of affinity binding to nuclear proteins and to blunted F2R-A in response to hypoxia as compared with the -506D sequence (all P<0.05)., Conclusions: F2R genetic variants may influence the natural history of CHD in patients at high risk of cardiovascular events.

Beta2-adrenergic receptors (beta2ARs) are widely expressed, although their physiological relevance in many tissues is not yet fully understood. In vascular endothelial cells, they regulate NO release and vessel tone. Here we provide novel evidence that beta2ARs can regulate neoangiogenesis in response to chronic ischemia. We used in vivo adenoviral-mediated gene transfer of the human beta2AR to the endothelium of the rat femoral artery and increased beta2AR signaling resulting in ameliorated angiographic blood flow and hindlimb perfusion after chronic ischemia. Histological analysis confirmed that beta2AR overexpression also produced benefits on capillary density. The same maneuver partially rescued impaired angiogenesis in spontaneously hypertensive rats (SHR), whereas gene delivery of the G-protein-coupling defective mutant Ile164 beta2AR failed to provide ameliorations. Stimulation of endogenous and overexpressed beta2AR on endothelial cells in vitro was found to regulate cell number by inducing proliferation and [3H]-thymidine incorporation through means of extracellular receptor-activated kinase and vascular endothelial growth factor. The beta2AR also has novel effects on endothelial cell number through stimulation of proapoptosis and antiapoptosis pathways involving p38 mitogen-activated protein kinase and PI3-kinase/Akt activation. Therefore, beta2ARs play a critical role in endothelial cell proliferation and function including revascularization, suggesting a novel and physiologically relevant role in neoangiogenesis in response to ischemia.

Background: Adrenergic regulation of coronary vasomotion is balanced between alpha1-adrenergic-mediated (alpha1-AR) constriction and beta2-adrenergic-mediated (beta2-AR) relaxation. This study aimed at assessing the role of beta2-ARs in normal, mildly atherosclerotic, and stenotic human coronary arteries., Methods and Results: During intracoronary (IC) infusion of increasing doses of the beta2-AR agonist salbutamol (0.15, 0.3, and 0.6 mug/min) and the endothelial vasodilator acetylcholine (1, 3, and 10 microg/min), we measured (1) changes in lumen diameter (LD) by quantitative coronary angiography in 34 normal, 55 mildly atherosclerotic, and 42 stenotic coronary artery segments and (2) changes in average peak velocity (APV) and coronary blood flow (CBF) with the use of Doppler flow wire in 11 normal, 10 mildly atherosclerotic, and 11 stenotic coronary arteries. In 6 of 11 stenotic coronary arteries, the protocol was repeated after an IC bolus (12 microg/kg) of the alpha-adrenergic blocker phentolamine. In 6 of 11 normal coronary arteries, the protocol was repeated after an IC infusion (60 micromol/min) of N(G)-monomethyl-L-arginine (L-NMMA), a nitric oxide inhibitor. Neither salbutamol IC infusion nor acetylcholine significantly changed heart rate or blood pressure, whereas L-NMMA slightly increased blood pressure. In normal coronary arteries, salbutamol increased LD (LD max %: 11+/-2, P<0.05), APV (APV max %: 53+/-17, P<0.05), and CBF (CBF max %: 57+/-17, P<0.05), whereas L-NMMA caused a blunted APV (APV max %: 27+/-6, P<0.05) and CBF (CBF max %: 29+/-6, P<0.05) response to salbutamol. In mildly atherosclerotic coronary arteries, the salbutamol increase in LD (LD max %: 10+/-2, P<0.05), APV (APV max %: 33+/-12, P<0.05), and CBF (CBF max %: 37+/-12, P<0.05) was preserved. In stenotic coronary arteries, salbutamol induced a paradoxical reduction in LD (LD max %: -6+/-2, P<0.05), APV (APV max %: -15+/-9, P<0.05), and CBF (CBF max %: -15+/-6, P<0.05), which was no longer observed after phentolamine. Acetylcholine increased LD (LD max %: 14+/-3, P<0.05), APV (APV max %: 61+/-20, P<0.05), and CBF (CBF max %: 67+/-19, P<0.05) in normal coronary arteries. In mildly atherosclerotic coronary arteries, acetylcholine induced a significant reduction in LD (LD max %: -15+/-2, P<0.05) and no changes in APV (APV max %: -6+/-13, P=NS) and CBF (CBF max %: -10+/-13, P=NS). In stenotic coronary arteries, acetylcholine significantly reduced LD (LD max %: -15+/-3, P<0.05), APV (APV max %: -15+/-9, P<0.05), and CBF (CBF max %: -15+/-6, P<0.05)., Conclusions: In severely atherosclerotic coronary arteries, beta2-adrenergic vasodilatation is impaired, and this might contribute to alter the vasomotor balance, further precipitating myocardial ischemia during sympathetic activation.