Abstract Background The dual antiplatelet therapy (DAPT) duration is a matter of great interest among cardiologists. Because of the conflicting evidences and the necessity to balance the reduction in major cardiac events (MACE) occurrence and the risk of major bleedings after an acute coronary syndrome (ACS), there is a general consensus on prolonging DAPT on an individual basis. There is less consensus on which parameters are to be evaluated. Nowadays tests of platelet reactivity are not included in the decision-making. Few data are available on the prognostic value of aspirin response tests that are sensitive to other mediators of platelet adhesion and aggregation in vivo under flow conditions. Purpose To demonstrate the role of the Platelet Function Analyzer (PFA-100) Collagen/Epinephrine (CEPI) cartridge, which is very sensitive to von Willebrand factor (VWF) levels, an emerging vascular risk factor, in risk stratification in ACS patients undergoing percutaneous coronary intervention (PCI). Methods We measured platelet reactivity by PFA-100 CEPI cartridges in a prospective cohort of 928 patients admitted for ACS between January 2006 to December 2009 and urgently treated by PCI at day 6±1 after admission. All the patients were treated with aspirin and clopidogrel according to current standard of that time. Results High platelet reactivity (HPR) defined as PFA-100 values <190”was found in 307 (33%) patients. No significant differences were found in demographic, angiographic and biochemical characteristics of both populations (PFA-100 <190” and PFA-100>190”). At a mean follow up of 5±1 years patients with HPR had a significant increase in cardiac death: 12.3% vs 2.6% (hazard ratio 6.05; 95% confidence interval: 3.34–10.95; p<0.0001) and recurrence of myocardial infarction (MI): 49% vs 17% (hazard ratio 4,29; 95% confidence interval: 3,27–5,64; p<0.0001). The trend in events incidence in our cohort of patients, in line with recent evidences, was maintained beyond the first year of follow-up Conclusions Using a multivariable Cox-proportional hazard model, HPR was found to be an independent predictor of MACE. These results indicate that PFA-100 CEPI cartridge, which correlates well with VWF levels, may be a useful point-of-care test to stratify the cardiovascular risk after an ACS. This also underlines the additional value of this test in the decision-making about the correct extension of DAPT.

OBJECTIVES We investigated the main biomolecular features in the evolution of aortic stenosis, focusing on advanced lesions. BACKGROUND “Degenerative” aortic valve stenosis shares risk factors and inflammatory similarities with atherosclerosis. METHODS We compared nonrheumatic stenotic aortic valves from 26 patients undergoing surgical valve replacement (group A) and 14 surgical control patients (group B). We performed semiquantitative histological and immunohistochemical analyses on valve leaflets to measure inflammation, sclerosis, calcium, neoangiogenesis, and intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression. We assessed heat shock protein 60 (hsp60) gene expression as an index of cellular stress and C-reactive protein, erythrocyte sedimentation rate, and fibrinogen as systemic inflammatory markers. RESULTS In group A valves, we found a prevalence of calcium nodules surrounded by activated inflammatory infiltrates, neovessels, and abundant ICAM-1, VCAM-1, and hsp60 gene expression. Specimens from group B were negative for all of these markers, except 2 of 14 positivity for hsp60. The presence of active inflammatory infiltrates correlated with an abundance of thin neovessels (p 0.01) and hsp60 gene expression (p 0.01), whereas neoangiogenesis correlated with inflammation (p 0.04), calcium (p 0.01), and hsp60 gene expression (p 0.04). CONCLUSIONS “Degenerative” aortic valve stenosis appears to be a chronic inflammatory process associated with atherosclerotic risk factors. The coexistence of neoangiogenesis, T-lymphocyte infiltration, adhesion molecules, and hsp60 gene expression indicates an active immunomediated process in the final phases of the disease. (J Am Coll Cardiol 2004;43:1670–6) © 2004 by the American College of Cardiology Foundation

Major advances in Human Genome research could significantly change the clinical medical practice, providing new possibilities for both diagnosing and treating common pathologies. Many genetic tests are now commercially available for predicting future risk of common disorders. However, genetic testing has potential benefits but also limitations for the patients, and it should not be used to 'screen' the general population. Diagnostic assays for a predisposition of both venous and arterial thrombosis are among the most requested genetic tests in molecular diagnostics laboratories. However, there is considerable uncertainty as to how this information should be utilized in patient management. Both the medical community and the patients need to obtain accurate information concerning the appropriate use of genetic testing. The purpose of this article is to discuss the usefulness and the practical applications of thrombotic genetic testing in order to define which patients should be tested for both venous and arterial thrombotic risk as well as to have an acceptable cost/benefit ratio and to prevent patients' anxiety.

INTRODUCTION:An increasing amount of evidence indicates that platelet reactivity, despite a standard anti-thrombotic therapy, is a potential risk factor for recurrent myocardial ischemia in patients with coronary artery disease. We now hypothesize that this condition, measured by collagen-epinephrine (CEPI) or collagen-ADP (CADP) closure times (CT) by Platelet Function Analyzer (PFA-100), may predict the recurrence of coronary events after percutaneous coronary intervention (PCI). MATERIALS AND METHODS:CEPI and CADP-CT were measured 30+/-8 h after PCI in 175 consecutive patients admitted with a diagnosis of stable angina (n=94) or acute coronary syndromes (n=81) and prospectively followed up for a mean period of 6 months. We stratified the patients in accordance to both the CEPI-CT ( 190 s), reflecting the intensity of cycloxygenase inhibition by aspirin and the distribution into quartiles for CADP-CT. RESULTS:CEPI-CT<190 s as well as CADP-CT<82 s were associated with a higher rate of clinical recurrence (hazard ratio 8.5, p<0.001 and 22.9, p<0.001, respectively). Multivariate analysis after adjustment for other risk factors confirmed that the lowest CADP-CT quartile significantly correlates with the risk of recurrent coronary events (hazard ratio 36.5, p<0.01), as well as CEPI-CT<190 s (hazard ratio 6.7, p=0.01). CONCLUSIONS:An enhanced platelet function after PCI when measured under high shear rates by PFA-100 is an independent predictor of a worst clinical outcome, even during a short term follow-up and may help in patients risk stratification.

Neutrophil and mononuclear cell functional changes represent a hallmark of inflammation during cardiopulmonary bypass and cardiovascular surgery. Knowledge of mechanisms underlying monocyte functional modulation in coronary blood may be useful to develop protective interventions that can limit ischemia/reperfusion injury.

BACKGROUND:Cardiopulmonary bypass induces a systemic inflammatory response that may contribute to clinical morbidity. Gaseous nitric oxide at relatively low concentrations may elicit peripheral anti-inflammatory effects in addition to a reduction of pulmonary resistances. We examined the effects of 20 ppm of inhaled nitric oxide administered for 8 hours during and after cardiopulmonary bypass.METHODS AND RESULTS:Twenty-nine consecutive patients undergoing aortic valve replacement combined with aortocoronary bypass were randomly allocated to either 20 ppm of inhaled nitric oxide (n = 14) or no additional inhalatory treatment (n = 15). Blood samples for total creatine kinase, creatine kinase MB fraction, and troponin I measurements were collected at 4, 12, 24, and 48 hours postsurgery. In addition, we collected perioperative blood samples for measurements of circulating nitric oxide by-products and brain natriuretic peptide. Soluble P-selectin was analyzed in blood samples withdrawn from the coronary sinus before and after aortic clamping. The area under the curve of creatine kinase MB fraction (P =.03), total creatine kinase (P =.04), and troponin I (P =.04) levels were significantly decreased in the nitric oxide-treated patients. Moreover, in the same group we observed blunted P-selectin and brain natriuretic peptide release (P =.01 and P =.02, respectively). Nitric oxide inhalation consistently enhanced nitric oxide metabolite levels (P =.01).CONCLUSIONS:Nitric oxide, when administered as a gas at low concentration, is able to blunt the release of markers of myocardial injury and to antagonize the left ventricular subclinical dysfunction during and immediately after cardiopulmonary bypass. The organ protection could be mediated, at least in part, by its anti-inflammatory properties.

Gastrobronchial fistula and anastomotic esophagogastric stenosis after esophagectomy for esophageal carcinoma

Background: Cardiovascular surgery with cardiopulmonary bypass (CPB) induces systemic inflammation and postoperative complications depending on pro- and anti-inflammatory mechanisms. Activated polymorphonuclear cells and monocytes may be responsible for morbidity associated with CPB. Knowledge of the monocyte functional state in particular may help to develop protective interventions.Methods: Samples were drawn from venous peripheral blood (basal condition, at 4 and 24 h after CPB) and coronary blood (before and after cardioplegic arrest) of 14 patients undergoing cardiac surgery. The following phenotypic and functional parameters of the monocyte population were studied by flow cytometry: surface molecules expression (CD18, CD11a, CD11b, CD14, CD15, CD45, HLA-DR, and Toll-like receptor [TLR]-4), myeloperoxidase (MPO) content, and intracellular cytokine production (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, IL-6, and IL-8).Results: Cardiac surgery with CPB induced down-modulation of surface molecules expression on peripheral monocytes, especially at 24 h after CPB, for CD18, CD11a, and CD11b (P < 0.003) and for the CD15 adhesive cluster (P = 0.0028) and HLA-DR (P < 0.001). At 4 h after CPB, downregulation was observed for CD14 (P = 0.004), CD45 (P = 0.014), and CD15 (P = 0.0056). A loss of MPO was detected in venous peripheral (at 24 h after CPB, P = 0.01) or coronary (at reperfusion, P < 0.02) blood. The CD15 cluster complex exhibited a down-modulation in coronary blood (at reperfusion, P = 0.0003). Spontaneous intracellular production of IL-1beta, IL-6, and IL-8 decreased at 24 h after CPB (P < 0.05).Conclusions: The down-modulation of integrins and adhesive receptor expression and the loss of MPO suggest a strong activation and shedding reaction of circulating monocyte after CPB, further exacerbated by contact with coronary ischemic vessels. The changes of differentiation antigens may reflect the appearance of a partially immature population immediately after CPB. The reduced proinflammatory cytokine production, observed at 24 h after CPB, suggests a functional polarization of circulating monocytes. (C) 2003 Wiley-Liss, Inc.

Objective: Biological and prosthestic rings are available for supporting mitral valve repair (MVR). Contrasting data are reported on the durability of pericardial ring annuloplasty. This retrospective study was undertaken to assess the durability of MVR for degenerative regurgitation with posterior annuloplasty performed with glutaraldehyde-treated autologous pericardium. Methods: From August 1995 through December 2000, 133 patients underwent mitral repair for degenerative regurgitation (86 men, age 62.9 +/- 11.5 years). Thirty patients (22.6%) underwent combined coronary artery bypass graft and fourteen (10.5%) underwent tricuspid annuloplasty. Associated aortic disease, previous cardiac surgery and endocarditis were considered exclusion criteria. Results: Seventy-seven patients (57.9%) received a Carpentier-Edwards ring and 56 received (42.1%) an autologous pericardium ring. Thirty-day mortality was 3.8%. Mean follow-up, 98.3% complete, was of 35.6 +/- 18.7 months. Five-year freedom from reoperation and recurrence of mitral regurgitation greater than or equal to 3 + /4 + was significantly higher in the prosthetic ring group (90.1% - CL90%: 81.9-98.3%) compared with the pericardial ring group (62.6% - CL90%: 43.1-82.1%; P = 0.027). Prosthetic ring implantation (P = 0.004; RR = 0.11) and preoperative New York Heart Association (NYHA) class less than or equal to 11 (P = 0.011; RR = 0.16) were independently related to a lower risk of reoperation and recurrence of mitral regurgitation greater than or equal to 3 + /4 +, by multivariate analysis. Five-year overall survival was 91.4% (CL90%: 87.9.7-95%). A higher preoperative left ventricular end-diastolic diameter (P = 0.006; RR = 1.17) and the severity of associated coronary artery disease (P = 0.021; RR = 2.00) were independent predictive factors for poor survival by multivariate analysis. Conclusions: Posterior pericardial annuloplasty can jeopardize reproducibility and durability of MVR for degenerative regurgitation. (C) 2003 Published by Elsevier Science B.V.

Polymorphonuclear cells (PMNs) play a central role in the inflammatory response following cardiac surgery with cardiopulmonary bypass (CPB). PMNs activation after bypass surgery is responsible for post-operative morbidity, so rendering the knowledge of their functional state relevant to develop cardioprotective interventions. At present, flow cytometry is an indispensable tool to asses neutrophil phenotype and function. In our study, the evaluation of integrins and activatory molecules, selectin ligands and intracellular content of myeloperoxidase (MPO), has been carried out during open heart surgery with CPB. PMNs exhibited a down modulation of integrins, associated with a decreased level of CD15. Moreover, an up regulation of CD66b and a loss of MPO, were observed. Our data indicate that the PMNs activation is associated with a down modulation of adhesive receptors on circulating leukocytes.

Off-pump coronary artery bypass graft (CABG) surgery may reduce the inflammatory response and the neuronal damage associated with conventional CABG on cardio-pulmonary bypass. The purpose of this study was to explore the protective effect of off-pump surgery by assessing plasma inflammatory and neuronal injury markers. Forty-one patients with coronary artery disease undergoing elective CABG were examined: 21 on-pump (Group I) and 20 off-pump (Group II). The perioperative release of interleukin-2 receptor (IL-2r), IL-6, tumor necrosis factor-alpha, S-100 protein (S-100) and neuron-specific enolase (NSE) were measured. Postoperative peak values of NSE (p B /0.001) and S-100 (p B /0.05) were significantly lower in Group II. IL-6 showed significantly lower values in off-pump patients (p B /0.001). A significant correlation was found between NSE and IL-6 (p B /0.001). In conclusion, off-pump surgery reduces the inflammatory response as well as the perioperative release of neuronal damage markers. Correlation between inflammatory activation and neuronal markers may suggest a link between inflammation and release of markers of neuronal clinical and subclinical injury.

Because of its high diffusing capacity through the alveolar-blood barrier and its high selectivity for the pulmonary vasculature, inhaled nitric oxide (NO) has been recently shown to be a viable and efficient approach to restore pulmonary NO deficiency.The most relevant applications of inhaled NO are in infants with primary pulmonary hypertension or hypoxia. In these patients, inhaled NO improves gas exchange and ventilation-perfusion matching, reduces the length of hospitalization and is without severe detrimental effects. The use of inhaled NO has also been extended to adults with pulmonary hypertension and the acute respiratory distress syndrome. In addition, recent clinical evidence supported by data from animal models, shows beneficial extra-pulmonary effects of inhaled NO, including protection against myocardial ischaemia-reperfusion injury.