Fabrice Ivanes

Should Atrial Fibrillation Patients With Only 1 Nongender-Related CHA2DS2-VASc Risk Factor Be Anticoagulated?

Background and Purpose— There is some uncertainty about treating patients with atrial fibrillation (AF) with 1 nongender-related (NGR) stroke risk factor (CHA2DS2-VASc [ie, congestive heart failure, hypertension, age (≥75 years; 2 points), diabetes, stroke/transient ischemic attack (2 points), vascular disease, age (65–74 years), sex (female)] score of 1 in males and 2 in females) with oral anticoagulation (OAC). Methods— We investigated adverse outcomes and calculated the net clinical benefit of OAC use in a community-based cohort of unselected AF patients with 0 compared with 1 NGR stroke risk factor (CHA2DS2-VASc 0 versus 1 in males; and 1 versus 2 in females). Among 8962 patients with AF, 2208 (25%) had 0 or 1 NGR stroke risk factors, of which 45% were not prescribed OAC. Results— During a follow-up of 1028±1189 days (median, 495; interquartile range, 5–1882 days), the yearly rate of the combined end point of stroke/systemic embolism in nonanticoagulated AF patients with 1 NGR stroke risk factor was 2.09% (95% confidence interval, 1.37–3.18). This corresponded to an adjusted hazard ratio of 2.82 (95% confidence interval, 1.32–6.04) relative to the group with 0 NGR stroke risk factor. When the benefit of ischemic stroke reduction was balanced against the increased risk of intracranial hemorrhage among patients with 1 NGR stroke risk factor, the net clinical benefit was positive in favor of OAC use versus no antithrombotic therapy or antiplatelet therapy use. The net clinical benefit was negative for antiplatelet therapy use versus no antithrombotic therapy. Conclusions— Among AF patients with 1 NGR stroke risk factor (ie, CHA2DS2-VASc 1 in males or 2 in females), OAC use as indicated according to the guidelines was associated with a positive net clinical benefit for the prevention of stroke and thromboembolic events.

Postconditioning in Acute Myocardial Infarction Patients

Reperfusion therapy is the indispensable treatment of acute myocardial infarction (AMI) and must be applied as soon as possible to attenuate the ischemic insult. Evidence indicates that reperfusion is responsible for additional myocardial damage likely involving opening of the mitochondrial permeability transition pore. Ischemic postconditioning is a new way to dramatically reduce the lethal reperfusion injury. Several clinical studies using angioplasty postconditioning now support its protective effects in patients with an AMI. An interesting alternative is pharmacological postconditioning, which could be applied to a much larger number of patients. The mitochondrial permeability transition pore inhibitor cyclosporine A has been shown to generate a comparable protection in AMI patients. Future large-scale trials are needed to determine whether postconditioning may improve clinical outcome in ST-segment elevation MI patients.

Postconditioning: from experimental proof to clinical concept.

The therapeutic strategies for acute myocardial infarction in the last decade have, among other therapeutic targets, focused on myocardial reperfusion injury, which accounts for a significant part of the final infarct size. Although several experiments in the last 20 years have reported that pharmacological interventions at reperfusion might reduce myocardial reperfusion injury, this could not be consistently confirmed in animal models or human studies. An alternative to chemical modifiers, postconditioning (brief repeated periods of ischemia applied at the onset of reperfusion) is the first method proven to be efficient in different animal models and to be confirmed in a recent human study. This simple method, applied in the first minute of reperfusion, reduces the final infarct size by 30–50%. This review will focus on the postconditioning technique and show how the data from different animal models and experimental settings have advanced our understanding of both the mechanisms and the definition of an accurate protocol that is easily applicable in human patients in the setting of acute myocardial infarction.

Hypoxia/Reoxygenation Inhibits P2Y11 Receptor Expression and Its Immunosuppressive Activity in Human Dendritic Cells

High concentrations of extracellular ATP (eATP) resulting from cell damage may be found during an ischemia/reperfusion (I/R) episode at the site of injury. eATP activates purinergic receptors in dendritic cells (DCs) and may inhibit inflammation. This immunosuppressive activity could be of interest in the field of I/R, which is an inflammatory condition involved in myocardial infarction, stroke, and solid organ transplantation. However, the specific purinergic receptor responsible for this effect remains to be identified. In this study, we report that eATP induced maturation of human monocyte-derived DCs. Additionally, eATP inhibited IL-12 production whereas IL-10 levels remained unchanged in activated DCs. These effects were prevented by the P2Y11R antagonist NF340. Interestingly, a 5-h hypoxia prevented the effects of eATP on cytokine production whereas a 1-h hypoxia did not affect the eATP-mediated decrease of IL-12 and IL-6. We showed a time-dependent downregulation of P2Y11R at both mRNA and protein levels that was prevented by knocking down hypoxia-inducible factor-1α. In this study, we showed an immunosuppressive role of P2Y11R in human DCs. Additionally, we demonstrated that the time-dependent downregulation of P2Y11R by hypoxia orientates DCs toward a proinflammatory phenotype that may be involved in post-I/R injuries as observed after organ transplantation.

Predictive factors of contrast-induced nephropathy in patients undergoing primary coronary angioplasty

BACKGROUND Contrast-induced nephropathy (CIN) severely impacts patient morbidity and mortality, especially in patients with ST-segment elevation myocardial infarction treated by primary coronary angioplasty, whose renal function is often unknown at the time of contrast exposure. AIM We sought the incidence and factors predictive of CIN in patients treated by primary coronary angioplasty in our hospital; we also questioned the relevance of Mehrans risk score in this population. METHODS We considered all patients admitted for primary coronary angioplasty between January 2010 and December 2011, and included 322 patients with complete data on renal function. CIN was defined as a relative (≥25%) or absolute (≥44 μmol/L) increase in serum creatinine following contrast medium administration. We compared patients with or without CIN, to identify predictive factors, and investigated the effectiveness of Mehrans score using a receiver operating characteristic (ROC) curve, Youdens index and a likelihood ratio test. RESULTS The incidence of CIN was 9.1%. A multivariable analysis identified two independent risk factors for CIN: impaired glomerular filtration rate and cardiogenic shock at admission (P<0.05). An elevated Mehrans score was associated with increased incidence of CIN, but statistical analysis revealed this score to have poor sensitivity, especially in high-risk patients. Youdens index was very low and the area under the ROC curve was 0.59 in our population. CONCLUSION Renal failure and cardiogenic shock at admission were independent predictors of CIN in our acute myocardial infarction population. Mehrans score added little to the discrimination of patients undergoing primary coronary angioplasty, particularly high-risk individuals.

Effect of Active Smoking on Comparative Efficacy of Antithrombotic Therapy in Patients With Atrial Fibrillation : The Loire Valley Atrial Fibrillation Project

BACKGROUND Active smoking is associated with elevated thrombotic risk. Smoking status has recently been incorporated into the SAMe-TT2R2 (sex female, age < 60 years, medical history [more than two comorbidities], treatment [interacting drugs, eg, amiodarone for rhythm control], tobacco use [doubled], race [doubled]) score that can help predict poor international normalized ratio control in patients with atrial fibrillation (AF) treated with vitamin K antagonists (VKAs). The clinical benefit of antiplatelet therapy (APT) has been seen primarily in smokers. We hypothesized that active smoking may differently influence the risks of stroke and bleeding in patients with AF treated with VKAs or with APT. METHODS We examined the clinical course of 7,809 consecutive patients with AF seen between 2000 and 2010. Outcomes in patients who were active smokers were compared with those in other patients. RESULTS Among 7,809 patients with AF, 1,034 (13%) were active smokers. APT was prescribed on an individual basis for 2,761 patients (35%) and VKAs for 4,534 (57%). After a follow-up of 929 ± 1,082 days (median = 463 days, interquartile range = 1,564 days), smoking was not independently associated with a higher risk of stroke/thromboembolic event in patients with AF (hazard ratio [HR], 0.95; 95% CI, 0.78-1.22; P = .66). On multivariate analysis, smoking was independently associated with a worse prognosis for the risk of severe bleeding (HR, 1.23; 95% CI, 1.01-1.49; P = .04) and for the risk of major Bleeding Academic Research Consortium bleeding (HR, 1.40; 95% CI, 1.02-1.90; P = .03). Smoking was independently associated with a higher risk of bleeding in patients treated with VKAs (HR, 1.32; 95% CI, 1.04-1.67; P = .02), whereas the risk was nonsignificant in patients treated with APT (HR, 1.28; 95% CI, 0.94-1.74; P = .11). CONCLUSIONS In AF, there was a higher risk of severe bleeding in smokers, mainly in those treated with VKAs.

Antithrombotic management in patients with atrial fibrillation undergoing coronary stent implantation: What is the impact of guideline adherence?

AIMS Patients with atrial fibrillation (AF) who undergo percutaneous coronary intervention (PCI) and stenting require triple antithrombotic therapy according to current ESC guidelines. The purpose of this study was to assess guideline implementation and predictive factors of the prognosis related to ESC guideline adherence. METHODS AND RESULTS We enrolled consecutive AF patients referred for PCI with stent from 2011 to 2014. Among 371 patients (72% male; mean age 76 ± 11) followed up for 505 ± 372 days (median 391, interquartile range 550 days), 118 (45%) undergoing elective coronary stenting and 41 (31%) among those with acute coronary syndrome were guideline adherent. Oral anticoagulation (OAC) before hospitalization was the only factor independently associated with guideline adherence (OR, 0.45; 95% CI 0.26-0.77; p=0.003). OAC underuse and antiplatelet therapy (APT) underuse were independently associated with increased risks of death (OR 5.55; 95% CI 2.42-13.47; p<0.0001 and OR 5.56; 95% CI, 2.17-14.65; p=0.0004, respectively) and major adverse cardiac events (MACE) (OR 4.18; 95% CI 2.05-8.79; p<0.0001 and OR 4.81; 95% CI, 2.09-11.18; p=0.0002, respectively). CONCLUSION Guidelines for antithrombotic therapy in patients with AF who undergo PCI and stent implantation are still poorly followed in clinical practice. OAC and APT underuse were both associated with an increased risk of death and MACE in this population.

Revisiting myocardial necrosis biomarkers: assessment of the effect of conditioning therapies on infarct size by kinetic modelling

Infarct size is a major predictor of subsequent cardiovascular events following ST-segment elevation myocardial infarction (STEMI) and is frequently used in clinical trials focused on cardioprotection. Approximately assessed through serial blood sampling, it can be accurately measured by imaging techniques, e.g. cardiac magnetic resonance imaging, which is the actual gold standard for infarct size determination but with limited availability in daily practice. We developed a mathematical biomarker kinetic model based on pharmacokinetic compartment models to easily and accurately estimate infarct size using individual data from five clinical trials evaluating the impact of conditioning therapies in STEMI between 2005 and 2013. Serial blood sampling was available in all studies with data regarding creatine kinase (CK), CK specific of cardiomyocytes (CK-MB) and cardiac troponin I. Our model allowed an accurate estimation of biomarker release as a surrogate marker of infarct size and a powerful assessment of conditioning treatments. This biomarker kinetic modelling approach identified CK-MB as the most accurate biomarker in determining infarct size and supports the development of limited sampling strategies that estimate total biomarker amount released with a lower number of samples. It will certainly be a useful add-on to future studies in the field of STEMI and cardioprotection.

Polymorphism in programmed cell death 1 gene is strongly associated with lung and kidney allograft survival in recipients from CMV-positive donors

BACKGROUND Cytomegalovirus (CMV) has a role in chronic rejection and graft loss in kidney transplant (KTx) and lung transplant (LTx) recipients. In addition, donor CMV seropositivity is an independent risk factor for renal graft loss. The anti-CMV response might modulate this risk. Expression of programmed cell death 1 (PD-1), a receptor involved in viral-specific T-cell exhaustion, is influenced by a single nucleotide polymorphism called PD-1.3 (wild-type allele G, variant allele A). METHODS We performed a retrospective study to assess the impact of PD-1.3 on graft outcome in donor CMV seropositive (D+) and donor CMV seronegative (D-) KTx and LTx. We also performed a case-control study to evaluate the anti-CMVpp65 response according to genotype. RESULTS PD-1.3 was determined in 1,119 KTx and 181 LTx. In 481 D+ KTx, A allele carriers (24%) experienced significantly less graft failure compared with GG carriers (p = 0.001). Multivariate analysis showed that this association was independent of donor and recipient age, acute rejection episodes, and number of human leukocyte antigen mismatches (hazard ratio, 0.381; 95% confidence interval, 0.209-0.696; p = 0.002). Analysis in 85 D+ LTx showed similar results: A allele carriers had better survival (hazard ratio, 0.302; 95% confidence interval, 0.128-0.716; p = 0.006) and greater 6-month forced expiratory volume (71% ± 17% vs 54% ± 16%, p = 0.001). In D- recipients, PD-1.3 did not affect KTx or LTx outcome. Finally, AA recipients had a stronger anti-CMVpp65 T-cell response than matched GG recipients (p = 0.003). CONCLUSIONS The A variant allele in PD-1.3 single nucleotide polymorphism improved graft survival in kidney and lung transplant recipients receiving grafts from CMV-positive donors.

Performing diagnostic coronary angiography to evaluate high-risk cardiac donors: A French nationwide cohort study

BACKGROUND Allograft shortage might be overcome by the use of hearts from expanded-criteria donors (ECD) but their estimated high-risk of coronary artery disease (CAD) results in a limited utilization of these hearts for transplantation. We aimed to determine if performing coronary angiography (CA) in ECD enhances cardiac procurement and to develop a predictive model estimating their probability of absence of CAD. METHODS We retrospectively used the French National Transplant Registry CRISTAL and considered all donors aged 45 to 70 with ≥ 1 organ harvested between March 2012 and June 2014 to derive a high-risk donor population. Of 515 donors with ≥ 1 CAD risk factor and no obvious contraindication for cardiac procurement, 230 underwent CA. Coefficients estimated by multivariate logistic regression models were used to evaluate the impact of CA on procurement and build the predictive model. RESULTS Among CA donors, 133 had CAD, 53 (23%) with at least one stenosis ≥ 50%. Predictors of cardiac graft offer were female gender, age below 60, no cardiac arrest, no intravenous adrenaline/dobutamine requirement and no treated hypercholesterolemia. CA increased the probability of procurement by 9% (p = 0.028). Female gender, non-vascular cause of death, absence of diabetes and BMI ≥ 25 kg/m2 (p < 0.05) were associated with a normal CA and used for the prediction model. The area under the ROC curve of the model was 0.70. Specificity for the highest quartile was 82%. CONCLUSION Performing CA in ECD enhances cardiac procurement. When CA is not feasible, we defined a clinical score allowing accurate estimation of normal CA probability.