021: Clopidogrel low response and correlation between the different tests: light transmission aggregometry, VerifyNow-P2Y12 and V ASP

BackgroundClopidogrel low response correlates with poor prognosis after percutaneous coronary intervention (PCI). Many biological tests are currently available to test the clopidogrel response. However, the presence of any correlation between the different tests is today poorly reported.MethodsIn this prospective study, clopidogrel response was assessed in 100 consecutive patients. All patients were tested between 18h and 24h after a600mg clopidogrel loading dose using 3 different tests: light transmission aggregometry with 10μmol ADP (LTA, results expressed as platelet inhibition percentage), VerifyNow-P2Y12 (VN, results expressed as PRU) and vasodilatator stimulated phosphoprotein (VASP, results expressed as IRP). Patients under chronic clopidogrel therapy were excluded.ResultsThe mean platelet inhibition percentage, PRU value and IRP value were 38.5±13% by LTA, 178±89 PRU by VN and 52±21% by VASP. When results were analyzed as continuous variables, there was a good correlation between the different tests: LTA/VN (R2=0,642, p<0,001), LTA/VASP (R2=0,409, p<0,001) and VN/VASP (R2=0,616, p<0,001). However, when results were analyzed as pre-specified cut-off points to define patients as “low or good responders” (according to the literature: 50% for LTA, 235 PRU for VN and 50% IRP for VASP), only 47% of the patients were defined as “good” or “low responders” by the 3 tests. Altogether, 33% of the patients were defined as “low responders” by only 1 test, 20% by 2 tests and only 16% by the 3 tests.ConclusionIf the correlation between the different tests is good when results are analyzed as continuous variables, each individual is rarely (less than 50%) defined as “low or good responder” by all the 3 tests when recognized cut-off values are used. In that way, a sole test might not be sufficient to manage antiplatelet therapy in an individual patient

Impact of initial clinical presentation on clopidogrel low response

SummaryBackgroundLarge interindividual variability exists in clopidogrel response. Clopidogrel low response correlates with poor prognosis after percutaneous coronary intervention. Some authors also suggest intraindividual variability over time.AimTo assess the impact of initial clinical presentation on clopidogrel low response.MethodsIn this prospective study, clopidogrel response was assessed in 100 patients. Fifty patients presenting with acute coronary syndromes (ACS group) were compared with 50 patients with stable coronary artery disease matched 1:1 for age, sex, body mass index and diabetes (stable group). All patients were tested 18–24h after a 600mg loading dose of clopidogrel using the VerifyNow-P2Y12 test (results expressed as platelet reaction units [PRUs]). Patients under chronic clopidogrel therapy or treated with glycoprotein IIb/IIIa inhibitors, bivalirudin or thrombolytics were excluded.ResultsMean age was 61±12 years in each group; 28% of patients in each group were diabetic; mean body mass index was 27.6±5.6kg/m2 in the ACS group and 27.9±5.9kg/m2 in the stable group (p=0.80). Mean PRU values were 197±81 in the ACS group and 159±94 in the stable group (p=0.03). By multivariable analysis, the ACS group was significantly associated with a higher PRU value (p=0.02). There were significantly more clopidogrel low responders (PRU value>230) in the ACS group (38% vs. 18%; p=0.04).ConclusionOur study confirms that initial clinical presentation, especially ACS, is a strong predictor of clopidogrel low response; this suggests that the evolution of coronary artery disease for one patient influences the clopidogrel response over time. These results are in accordance with recent trials showing a benefit for more aggressive antiplatelet therapy in ACS patients

BBADIS-16-507-R1 1 Integrative network analysis reveals time-dependent molecular events underlying left ventricular remodeling in post-myocardial infarction patients

International audienceTo elucidate the time-resolved molecular events underlying the LV remodeling (LVR) process, we developed a large-scale network model that integrates the 24 molecular variables (plasma proteins and non-coding RNAs) collected in the REVE-2 study at four time points (baseline, 1month, 3months and 1year) after MI. The REVE-2 network model was built by extending the set of REVE-2 variables with their mechanistic context based on known molecular interactions (1310 nodes and 8639 edges). Changes in the molecular variables between the group of patients with high LVR (>20%) and low LVR (<20%) were used to identify active network modules within the clusters associated with progression of LVR, enabling assessment of time-resolved molecular changes. Although the majority of molecular changes occur at the baseline, two network modules specifically show an increasing number of active molecules throughout the post-MI follow up: one involved in muscle filament sliding, containing the major troponin forms and tropomyosin proteins, and the other associated with extracellular matrix disassembly, including matrix metalloproteinases, tissue inhibitors of metalloproteinases and laminin proteins. For the first time, integrative network analysis of molecular variables collected in REVE-2 patients with known molecular interactions allows insight into time-dependent mechanisms associated with LVR following MI, linking specific processes with LV structure alteration. In addition, the REVE-2 network model provides a shortlist of prioritized putative novel biomarker candidates for detection of LVR after MI event associated with a high risk of heart failure and is a valuable resource for further hypothesis generation

Angiotensin Converting Enzyme and Angiotensin II Type 1 Receptor Polymorphisms in Patients with Coronary Aneurysms

BACKGROUND: Conflicting results have been reported regarding the association of gene polymorphisms in the renin-angiotensin system (RAS) with different aspects of coronary artery disease (CAD), such as myocardial infarction, neointimal hyperplasia or coronary artery vasomotion. Since previous studies have linked angiotensin II to aneurysmal disease, our study hypothesis was that RAS gene polymorphisms may be associated with aneurysm remodeling in response to CAD. METHODS: The study population was selected from a series of 3862 consecutive patients who underwent coronary angiography in our institution. One hundred and thirteen consecutive patients with at least one coronary aneurysm (CA) were compared to 226 randomized control patients without CA. DNA was extracted from white blood cells. The angiotensin-converting enzyme (ACE) I/D and angiotensin type 1 receptor (AT1-R) A/C polymorphisms were detected using previously published techniques. RESULTS: The distributions of the three ACE genotypes were similar in both groups: CA: 13%, 46%, and 41% for II, ID, and DD respectively; controls: 18%, 41%, and 41% for II, ID, and DD respectively, p = 0.45. The distributions of the three AT1-R genotypes were also similar in both groups: CA: 54%, 41%, and 5% for AA, AC, and CC respectively; controls: 55%, 33%, and 12%, for AA, AC, and CC respectively, p = 0.08. CONCLUSION: Our results provide further information on the role of RAS polymorphisms on specific mechanisms implicated in CAD. Although an activated RAS may theoretically promote aneurysm formation, the 2 RAS polymorphisms analyzed in this study are not associated with this process in coronary arteries

Influence of diabetes mellitus on heart failure risk and outcome

Our aim is to summarize and discuss the recent literature linking diabetes mellitus with heart failure, and to address the issue of the optimal treatment for diabetic patients with heart failure. THE STUDIES LINKING DIABETES MELLITUS (DM) WITH HEART FAILURE (HF): The prevalence of diabetes mellitus in heart failure populations is close to 20% compared with 4 to 6% in control populations. Epidemiological studies have demonstrated an increased risk of heart failure in diabetics; moreover, in diabetic populations, poor glycemic control has been associated with an increased risk of heart failure. Various mechanisms may link diabetes mellitus to heart failure: firstly, associated comorbidities such as hypertension may play a role; secondly, diabetes accelerates the development of coronary atherosclerosis; thirdly, experimental and clinical studies support the existence of a specific diabetic cardiomyopathy related to microangiopathy, metabolic factors or myocardial fibrosis. Subgroup analyses of randomized trials demonstrate that diabetes is also an important prognostic factor in heart failure. In addition, it has been suggested that the deleterious impact of diabetes may be especially marked in patients with ischemic cardiomyopathy. TREATMENT OF HEART FAILURE IN DIABETIC PATIENTS: The knowledge of the diabetic status may help to define the optimal therapeutic strategy for heart failure patients. Cornerstone treatments such as ACE inhibitors or beta-blockers appear to be uniformly beneficial in diabetic and non diabetic populations. However, in ischemic cardiomyopathy, the choice of the revascularization technique may differ according to diabetic status. Finally, clinical studies are needed to determine whether improved metabolic control might favorably influence the outcome of diabetic heart failure patients

934-28 Sensitivity and Specificity of Angiographic Markers for Thrombus: A Prospective Comparison with Angioscopy

The limitations of angiography for the detection of intracoronary thrombus are well recognized. Between November 1991 and July 1994, we performed 402 angioscopy procedures in 225 vessels in 202 patients, with the Image-Cath (Baxter).We performed a prospective study in 190 of these patients, who had an interpretable angioscopy performed just before PTCA to determine the sensitivity and specificity of predetermined angiographic criteria that are considered to be indicative of the presence of intracoronary thrombus. Angiographically verified thrombus was used as the gold standard for comparison. Lesions were classified on angiography (2 orthogonal views) by independent observers. The presence of an intraluminal filling defect, of overhanging edges, of haziness, or of ulceration were noted. The characteristic ulceration was not mutually exclusive of the other 3 characteristics.Of 15 filling defects on angiography 14 (93%) had thrombus on angiography; in the 23 lesions with overhanging edges 19 (83%) had thrombus on angioscopy; in the 27 ulcerated lesions 21 (78%) had angioscopic thrombus; in the 6 lesions that were hazy on angiography 5 had angioscopic thrombus.AngioscopyThrombus+Thrombus-AngiographyThrombus+4512Thrombus-4093In our model, using 5 prespecified angiographic characteristics, angiography had high specificity (89%) but relatively low sensitivity (53%) for the detection of thrombus compared to angioscopy

Clinical score building from high-throughput proteomic data

International audienc

A common variant of endothelial nitric oxide synthase (Glu298Asp) is associated with collateral development in patients with chronic coronary occlusions

BACKGROUND: Experimental studies support an important role for endothelial nitric oxide synthase (eNOS) in the regulation of angiogenesis. In humans, a common polymorphism exists in the eNOS gene that results in the conversion of glutamate to aspartate for codon 298. In vitro and in vivo studies have suggested a decreased NOS activity in patients with the Asp(298 )variant. We hypothesized that a genetic-mediated decreased eNOS activity may limit collateral development in patients with chronic coronary occlusions. METHODS: We selected 291 consecutive patients who underwent coronary angiography and who had at least one chronic (>15 days) total coronary occlusion. Collateral development was graded angiographically using two different methods: the collateral flow grade and the recipient filling grade. Genomic DNA was extracted from white blood cells and genotyping was performed using previously published techniques. RESULTS: Collateral development was lower in patients carrying the Asp(298 )variant than in Glu-Glu homozygotes (collateral flow grade: 2.64 ± 0.08 and 2.89 ± 0.08, respectively, p = 0.04; recipient filling grade: 3.00 ± 0.08 and 3.24 ± 0.07, respectively, p = 0.04). By multivariable analysis, three variables were independently associated with the collateral flow grade: female gender, smoking, and the Asp(298 )variant (p = 0.03) while the Asp(298 )variant was the sole variable independently associated with the recipient filling grade (p = 0.03). CONCLUSION: Collateral development is lower in patients with the Asp(298 )variant. This may be explained by the decreased NOS activity in patients with the Asp(298 )variant. Further studies will have to determine whether increasing eNOS activity in humans is associated with coronary collateral development