Nathan Messas

Endothelial Microparticles from Acute Coronary Syndrome Patients Induce Premature Coronary Artery Endothelial Cells Ageing and Thrombogenicity: Role of the Ang II/AT1 Receptor/NADPH Oxidase-mediated Activation of MAPKs and PI3-kinase Pathways.

Background: Microparticles (MPs) have emerged as a surrogate marker of endothelial dysfunction and cardiovascular risk. This study examined the potential of MPs from senescent endothelial cells (ECs) or from patients with acute coronary syndrome (ACS) to promote premature EC aging and thrombogenicity. Methods: Primary porcine coronary ECs were isolated from the left circumflex coronary artery. MPs were prepared from ECs and venous blood from patients with ACS (n=30) and from healthy volunteers (n=4) by sequential centrifugation. The level of endothelial senescence was assessed as senescence-associated &bgr;-galactosidase activity using flow cytometry, oxidative stress using the redox-sensitive probe dihydroethidium, tissue factor activity using an enzymatic Tenase assay, the level of target protein expression by Western blot analysis, platelet aggregation using an aggregometer, and shear stress using a cone-and-plate viscometer. Results: Senescence, as assessed by senescence-associated &bgr;-galactosidase activity, was induced by the passaging of porcine coronary artery ECs from passage P1 to P4, and was associated with a progressive shedding of procoagulant MPs. Exposure of P1 ECs to MPs shed from senescent P3 cells or circulating MPs from ACS patients induced increased senescence-associated &bgr;-galactosidase activity, oxidative stress, early phosphorylation of mitogen-activated protein kinases and Akt, and upregulation of p53, p21, and p16. Ex vivo, the prosenescent effect of circulating MPs from ACS patients was evidenced only under conditions of low shear stress. Depletion of endothelial-derived MPs from ACS patients reduced the induction of senescence. Prosenescent MPs promoted EC thrombogenicity through tissue factor upregulation, shedding of procoagulant MPs, endothelial nitric oxide synthase downregulation, and reduced nitric oxide–mediated inhibition of platelet aggregation. These MPs exhibited angiotensin-converting enzyme activity and upregulated AT1 receptors and angiotensin-converting enzyme in P1 ECs. Losartan, an AT1 receptor antagonist, and inhibitors of either mitogen-activated protein kinases or phosphoinositide 3-kinase prevented the MP-induced endothelial senescence. Conclusions: These findings indicate that endothelial-derived MPs from ACS patients induce premature endothelial senescence under atheroprone low shear stress and thrombogenicity through angiotensin II–induced redox-sensitive activation of mitogen-activated protein kinases and phosphoinositide 3-kinase/Akt. They further suggest that targeting endothelial-derived MP shedding and their bioactivity may be a promising therapeutic strategy to limit the development of an endothelial dysfunction post-ACS.

Impact of Malignancies in the Early and Late Time Course of Takotsubo Cardiomyopathy

BACKGROUND Although the relationship between malignancies and catecholamine-induced myocardial stunning remains largely speculative, it has been suggested that the presence of cancer may lower the threshold for stress stimuli and/or may aggravate cardiac adrenoreceptor sensitivity. We sought to investigate whether associations exist between a previous or current diagnosis of malignancy, diagnostic parameters during hospitalization and death in takotsubo. METHODSANDRESULTS The 154 takotsubo patients were retrospectively identified between May 2008 and December 2014. Previous history of malignancy was identified in 44 patients (28.5%). Cardiac arrest was present at admission in 13 patients (8.4%). Intra-aortic balloon pump was inserted in 16 patients (10.4%). In patients with malignancy, higher B-type natriuretic peptide (BNP), leukocyte and C-reactive protein (CRP) peaks could be observed during the hospital phase. Initial impairment of left ventricular ejection fraction was negatively related to BNP, leukocyte, and CRP peaks. At a median follow-up of 364 days, all-cause death occurred in 41 patients (26.6%) and cardiac death in 12 patients (7.7%). Multivariate Cox regression analysis identified malignancy (hazard ratio 4.77 (1.02-22.17), leukocyte peak and age as independent predictors of cardiac death. Malignancy (2.62 (1.26-5.44), leukocyte peak (1.05 (1.01-1.08) and initial cardiac arrest (6.68 (2.47-18.01) were identified as independent predictors of overall mortality. CONCLUSIONS In the present takotsubo patients, the prevalence of malignancy was high and may have affected cardiovascular outcomes through the activation of inflammatory and neurohormonal mechanisms. (Circ J 2016; 80: 2192-2198).

Out-of-hospital cardiac arrest survivors sent for emergency angiography: a clinical score for predicting acute myocardial infarction

Background: Out-of-hospital cardiac arrest (OHCA) remains a major public health issue. Emergency coronary angiography and percutaneous coronary intervention might improve survival, especially when cardiac arrest is caused by acute myocardial infarction (AMI). However, identifying patients with AMI after OHCA remains challenging. The aim of this study was to determine the clinical and ECG criteria in OHCA that may help to identify better the patients with AMI. Methods: Consecutive OHCA patients who underwent emergency coronary angiography in our centre between 2009 and 2013 were included in this retrospective single-centre observational study. Results: A total of 177 patients with complete datasets were included. Significant coronary artery disease was found in 71% of the patients, and 43% presented with AMI. The independent predictors of AMI were ST elevation in any lead including aVR (odds ratio (OR) 18.06; 95% confidence interval (CI) 6.6–49.38), chest pain before cardiac arrest (OR 4.05; 95% CI 1.55–10.54) and an initial shockable rhythm (OR 2.99; 95% CI 1.34–6.45). An additive score that included these three predictors yielded a sensitivity and a specificity for detecting AMI of 93% and 63%, respectively. Conclusions: These data suggest that fewer than half of patients with OHCA undergoing emergency coronary angiography present with AMI. The identification of OHCA patients with AMI might be improved by a simple score using post-resuscitation ECG and simple clinical criteria.

Impact of manual thrombectomy on myocardial reperfusion as assessed by ST-segment resolution in STEMI patients treated by primary PCI

BACKGROUND In STEMI patients treated by primary PCI, damage of the microvascular circulation caused by distal embolization of thrombotic material affects the quality of myocardial reperfusion. Important controversies remain concerning the usefulness of the manual thrombectomy to improve myocardial perfusion. The aim of this study is to evaluate the impact of manual thrombectomy on ST resolution as a surrogate of reperfusion extent. METHODS Two hundred and thirty-nine consecutive STEMI patients with an <12 hours onset of symptoms, were enrolled in an observational registry. Patients were divided into two cohorts according to the reperfusion strategy: manual thrombectomy before primary PCI (n=102) or conventional-PCI (n=137). The primary endpoint was the post procedural frequency of complete (>70%) resolution of ST segment elevation. RESULTS A complete resolution of ST segment elevation occurred in 51.4% of patients in the thrombectomy group and in 35,6% of those in the conventional-PCI group (P=0.018). Thrombectomy strategy was associated with a lower use of stents. Multivariate analysis identified manual thrombectomy (HR=2.08 IC 95% (1.01-4.26); P=0.046), inferior location and short ischemic delay (<180 min) as independent predictors of ST resolution. The cumulative Kaplan-Meier estimate of MACE was not significantly different between the two groups at one, three years follow-up. CONCLUSION In STEMI patients, manual thrombectomy improves myocardial reperfusion as assessed by the percentage of ST segment resolution and a lower use of stents. However, in this cohort of limited size, this strategy did not translate into an improved cardiovascular outcome at one year follow-up.

CT-ADP Point-of-Care Assay Predicts 30-Day Paravalvular Aortic Regurgitation and Bleeding Events following Transcatheter Aortic Valve Replacement

BACKGROUND Paravalvular aortic regurgitation (PVAR) remains a frequent postprocedural concern following transcatheter aortic valve replacement (TAVR). Persistence of flow turbulence results in the cleavage of high-molecular-weight von Willebrand multimers, primary haemostasis dysfunction and may favour bleedings. Recent data have emphasized the value of a point-of-care measure of von Willebrand factor-dependent platelet function (closure time [CT] adenosine diphosphate [ADP]) in the monitoring of immediate PVAR. This study examined whether CT-ADP could detect PVAR at 30 days and bleeding complications following TAVR. METHODS CT-ADP was assessed at baseline and the day after the procedure. At 30 days, significant PVAR was defined as a circumferential extent of regurgitation more than 10% by transthoracic echocardiography. Events at follow-up were assessed according to the Valve Academic Research Consortium-2 consensus classification. RESULTS Significant PVAR was diagnosed in 44 out of 219 patients (20.1%). Important reduction of CT-ADP could be found in patients without PVAR, contrasting with the lack of CT-ADP improvement in significant PVAR patients. By multivariate analysis, CT-ADP > 180 seconds (hazard ratio [HR]: 5.1, 95% confidence interval [CI]: 2.5-10.6; p < 0.001) and a self-expandable valve were the sole independent predictors of 30-day PVAR. At follow-up, postprocedural CT-ADP >180 seconds was identified as an independent predictor of major/life-threatening bleeding (HR: 1.7, 95% CI [1.0-3.1]; p = 0.049). Major/life-threatening bleedings were at their highest levels in patients with postprocedural CT-ADP > 180 seconds (35.2 vs. 18.8%; p = 0.013). CONCLUSION Postprocedural CT-ADP > 180 seconds is an independent predictor of significant PVAR 30 days after TAVR and may independently contribute to major/life-threatening bleedings.

Early and Late Atrial Arrhythmias After Lung Transplantation - Incidence, Predictive Factors and Impact on Mortality -

BACKGROUND Atrial arrhythmias (AAs) are frequent after lung transplantation (LT) and late postoperatively. Several predictive factors of early postoperative AAs after LT have been identified but those of late AAs remain unknown. Whether AA after LT affects mortality is still being debated. This study assessed in a large cohort of LT patients the incidence of AAs early and late after surgery, their predictive factors and their effect on mortality.Methods and Results:We studied 271 consecutive LT patients over 9 years. Mean follow-up was 2.9±2.4 years. 33% patients developed postoperative AAs. Age (odds ratio (OR) 2.35; confidence interval (CI) [1.31-4.24]; P=0.004) and chronic obstructive pulmonary disease (OR 2.13; CI [1.12-4.03]; P=0.02) were independent predictive factors of early AAs. Late AAs occurred 2.2±2.7 years after transplant in 8.8% of the patients. Pretransplant systolic pulmonary arterial pressure (PTsPAP) was the only independent predictive factor of late AA (OR 1.028; CI [1.001-1.056]; P=0.04). Double LT was associated with long-term freedom from atrial fibrillation (AF) but not from atrial flutter (AFL). Early and late AAs after surgery had no effect on mortality. Double LT was associated with better survival. CONCLUSIONS Early AA following LT is common in contrast with the low occurrence of late, often organized, AA. Early and late AAs do not affect mortality. PTsPAP is an independent predictor of late AA. Double LT protects against late AF but not AFL.

Antiplatelet Therapy in ACS Patients: Comparing Appropriate P2Y12 Inhibition by Clopidogrel to the Use of New P2Y12 Inhibitors

Aim: In percutaneous coronary intervention (PCI)-treated acute coronary syndrome (ACS) patients on clopidogrel therapy, high on-treatment platelet adenosine diphosphate (ADP) reactivity was observed in numerous studies, with significant increases in non-fatal myocardial infarction, definite/probable stent thrombosis, or cardiovascular mortality. Compared to clopidogrel, prasugrel and ticagrelor provide more potent platelet inhibition. Whether new P2Y12 inhibitors reduce thrombotic events in a similar manner compared to the rate observed with appropriate P2Y12 inhibition by clopidogrel must still be determined. This study sought to compare longterm outcomes between clopidogrel responders (platelet reactivity index [PRI] vasodilator-stimulated phosphoprotein [VASP] < 61%) and patients under prasugrel or ticagrelor therapy following PCI-treated ACS. Methods: 730 ACS patients undergoing urgent PCI were prospectively enrolled into two groups: clopidogrel responders (n = 448) and those under ticagrelor or prasugrel therapy (n = 282). The primary endpoint was a composite of cardiovascular death, myocardial infarction, stent thrombosis, and stroke; the secondary endpoint comprised major hemorrhagic events. Results: The median follow-up was 260 ± 186 days. Clopidogrel patients were older and more likely to present non-ST segment elevation myocardial infarction, cardiovascular risk factors, atrial fibrillation, or prior vascular disease. After propensity score matching, the primary endpoint was met in 7.1% of the clopidogrel group and 4.1% of the prasugrel/ticagrelor group (p = 0.43). Minor bleeding events were significantly reduced in the clopidogrel group (1.1% vs. 3%; p = 0.03). In a multivariate analysis, the antiplatelet treatment strategy was not an independent primary endpoint predictor. Conclusion: In PCI-treated ACS patients, clopidogrel therapy and PRI VASP < 61% were not associated with increased risks of thrombotic events compared to prasugrel or ticagrelor therapy.

Atrial arrhythmias in Takotsubo cardiomyopathy: incidence, predictive factors, and prognosis

Aims Takotsubo cardiomyopathy (TTC) is a stress-related transient cardiomyopathy. It is unclear whether TTC is associated with poorer prognosis when atrial arrhythmia (AA), atrial fibrillation or flutter, occurs. The purpose of this study was to assess the incidence of AA in patients with TTC, predictive factors of AA, and its association with mortality. Methods and results We studied 214 consecutive cases of TTC over 8 years. The study cohort was divided into two groups-those with newly diagnosed AA (AA-group) and those without (non-AA group). AA occurred in 24.8% of the patients. The AA group presented with lower left ventricular ejection fraction (LVEF) on admission and higher cardiac arrest rate. Admission and peak levels of troponin, B-type natriuretic peptide (BNP), C-reactive protein (CRP), and leucocytes were higher in the AA group. In-hospital, 30-day, cardiovascular, and all-cause mortality were significantly higher in the AA group. Independent predictors of newly diagnosed AA were troponin peak [odds ratio (OR) 1.03 (1.003-1.06); P = 0.029], CRP peak [OR 1.006 (1.001-1.01); P = 0.026], and LVEF on admission [OR 0.96 (0.93-0.99); P = 0.01]. Newly diagnosed AA was not predictive of mortality. The BNP peak [OR 1.00 (1.000-1.001); P = 0.022] and leucocytes peak [OR 1.095 (1.034-1.16); P = 0.002] were predictive factors of in-hospital mortality. LVEF upon discharge [OR 0.935 (0.899-0.972); P = 0.001] and leucocytes peak [OR 1.068 (1.000-1.139); P = 0.049] were predictive of cardiovascular death. Conclusion Newly diagnosed AA is frequently observed in patients presenting with TTC and is associated with poorer short- and long-term prognosis. Inflammation, myocardial damage, and LVEF are predictors of AA onset and cardiovascular mortality.

Impaired P2Y12 inhibition by clopidogrel in kidney transplant recipients: results from a cohort study

BackgroundCardiovascular complications represent a major cause of morbidity and mortality for patients who received kidney transplantation (KT). However, the impact of KT and chronic immunosuppression on platelet response to clopidogrel in patients undergoing coronary or peripheral revascularization procedures remains unclear. This cohort study compares platelet responsiveness to clopidogrel as assessed byvasodilator-stimulated phosphoprotein (VASP) phosphorylation.MethodsThe study population was divided between chronic kidney disease (CKD) patients who underwent KT (n = 36) and non-transplanted CKD patients (control group, n = 126). Patients were on maintenance antiplatelet therapy with clopidogrel 75 mg daily for at least 8 days. The mean platelet reactivity index (PRI) VASP values and the prevalence of high on-treatment platelet reactivity (HPR, defined as PRI VASP ≥61 %) were compared.ResultsThe mean PRI VASP value was significantly higher in the transplant group (60.1 ± 3 vs 51.2 ± 1.6 %; p=0.014). HPR was significantly more common in the transplant group on clopidogrel maintenance therapy (58 vs. 31 %; p = 0.011). KT was the only independent predictor of HPR (odds ratio: 2.6; 95 % confidence interval: 1.03–6.27, p = 0.03). The effect of treatment with calcineurin inhibitors on clopidogrel response could not be analyzed separately from the kidney transplant status.ConclusionsKT is associated with an increased prevalence of HPR. Our results suggest that plateletfunction tests may be clinically useful for the management of this specific population.

0376: Early and late atrial arrhythmias after lung transplantation: incidence, predictive factors and impact on mortality

Background Atrial arrhythmias (AA) are observed frequently early after lung transplant and also late after the surgery. Several predictive factors of post-operative AA after lung transplant have been already identified whereas those of late AA are still not known. Whether AA after lung transplant impacts mortality and the optimal strategy of rhythm management are still debated. The Purpose of the study was to assess in a large cohort of lung transplanted patients the incidence of AA early and late after surgery, their predictive factors and their impact on mortality. Methods and results We included 271 consecutive patients single or double lung-transplanted over a 9-years period in a large French center. We collected baseline clinical, surgery and post-operative data. The follow-up was 2,9±2,4 years. 33% patients developed post-operative AA. Age (HR=2,35; CI [1,31-4,24]) and chronic obstructive pulmonary disease (HR=1,028; CI [1,12-4,03]) were independant predictive factors of post-operative AA. Late AA occurred 2,2±2,7 years after transplant in 8.8% of the patients. Systolic pulmonary arterial pressure was the only independent predictive factor of late AA (HR=1,028; CI [1,001; 1,056]). Double lung transplant was associated with long term freedom from AF compared with single transplant (p=0,05) whereas the Kaplan-Meier curve for the development of late atrial flutter was similar in single and double lung transplant. Early and late AA after surgery showed no impact on mortality. Bilateral lung transplant was associated with a better survival. Conclusion Post-operative AA after lung transplantation are common with good outcome and contrast with the low occurrence of late organized AA. Double lung transplantation protects against AF but not AFL. Underlying electrophysiological mechanisms may explain these observations. Predictive factors of early and late AA after transplantation are different. Nevertheless these AA do not impact mortality after lung transplant (figure next page). Download : Download high-res image (108KB) Download : Download full-size image Abstract 0376 – Figure: Survival free of late AF and AFL by transplant