High Prevalence of Geriatric Conditions Among Older Adults With Cardiovascular Disease.

As the population ages, the global cardiovascular disease burden will continue to increase, particularly among older adults. Increases in life expectancy and better cardiovascular care have significantly reshaped the epidemiology of cardiovascular disease and have created new patient profiles. The combination of older age, multiple comorbidities, polypharmacy, frailty, and adverse noncardiovascular outcomes is challenging our routine clinical practice in this field. In this review, we examine noncardiovascular factors that statistically interact in a relevant way with health status and quality of life in older people with cardiovascular disease. We focused on specific geriatric conditions (multimorbidity, polypharmacy, geriatric syndromes, and frailty) that are responsible for a major risk of functional decline and have an important impact on the overall prognosis in this patient population.

Cardiovascular outcomes in patients with cancer during a 5-year follow-up: Results from a French administrative database.

BACKGROUND: Limited data are available regarding the optimal management and prognosis of patients with cancer who develop an acute myocardial infarction. AIM: The objective of this study was to analyse the characteristics and outcomes of patients according to cancer and myocardial infarction occurrence. METHODS: Based on the French administrative hospital discharge database, the study collected information for all consecutive patients seen in French hospitals in 2013, excluding those with a history of myocardial infarction. The population was divided into two groups according to their history of cancer. We studied the following outcomes: all-cause and cardiovascular mortality; acute myocardial infarction; and ischaemic stroke. Data were collected after a 5-year follow-up. RESULTS: Between 2013 and 2019, 3,381,472 patients were seen in French hospitals; among them, 3,323,757 had no history of myocardial infarction. Patients with a history of cancer (n=497,593) had higher incidences of all-cause mortality (17.82%/year vs 3.79%/year), cardiovascular mortality (1.61%/year vs 1.17%/year), myocardial infarction (0.82%/year vs 0.61%/year) and ischaemic stroke (0.91%/year vs 0.62%/year) compared with patients without cancer (n=2,826,164). After performing an adjusted competing-risk analysis, the cumulative incidence of acute myocardial infarction, cardiovascular death and ischaemic stroke incidence was found to be lower in patients with a history of cancer, whereas death of non-cardiac origin was more prevalent in patients with a history of cancer. CONCLUSIONS: In this observational study, we have shown that patients with cancer have a higher incidence of all-cause mortality, cardiovascular mortality and myocardial infarction. However, multivariable analysis showed a lower cumulative incidence of these events.

Low levels of low-density lipoprotein cholesterol, intracerebral haemorrhage, and other safety issues: is there still a matter of debate?

Although some observational studies suggest a potential association of low levels of low-density lipoprotein cholesterol (LDL-C) with intracerebral haemorrhage (ICH), these analyses have issues of confounding where other factors (e.g. older age, frailty) that likely explain the findings, and the number of events was very low. More recent results from randomized clinical trials have not found an increased risk in ICH, most notably trials using PCSK9 inhibitors that achieve very low levels of LDL-C, but also in the long-term follow-up of the IMPROVE-IT trial. Also, other statin-associated safety issues, including new onset diabetes and the cancer risk should not be the reason of statin discontinuation, especially for the former, the benefits highly outweigh the risk (even 5×), and for the latter, there is no confirmed link suggesting any increased risk, in opposite, data exist suggesting benefits of statin therapy in cancer prevention. Furthermore, use of intensive lipid-lowering strategies with statins and non-statin drugs leads to decrease of ischaemic major adverse cardiac events, without safety concern, in a large population of patients with atherosclerotic cardiovascular disease (ASCVD). These data should promote the concept 'the earlier, the lower, the longer, the better' for the lipid management of patients with ASCVD. While few uncertainties remain in several populations that have been underrepresented in clinical trials (African American and Asian patients, low weight individuals), the most recent data with intensive LDL-C lowering with PCSK9 inhibitors are reassuring that the benefit outweighs any possible risk.

P2x4 receptor promotes mammary cancer progression by sustaining autophagy and associated mesenchymal transition.

Metastatic progression is a major burden for breast cancer patients and is associated with the ability of cancer cells to overcome stressful conditions, such as nutrients deprivation and hypoxia, and to gain invasive properties. Autophagy and epithelial-to-mesenchymal transition are critical contributors to these processes. Here, we show that the P2X4 purinergic receptor is upregulated in breast cancer biopsies from patients and it is primarily localised in endolysosomes. We demonstrate that P2X4 enhanced invasion in vitro, as well as mammary tumour growth and metastasis in vivo. The pro-malignant role of P2X4 was mediated by the regulation of lysosome acidity, the promotion of autophagy and cell survival. Furthermore, the autophagic activity was associated with epithelial-to-mesenchymal transition (EMT), and this role of P2X4 was even more pronounced under metabolic challenges. Pharmacological and gene silencing of P2X4 inhibited both autophagy and EMT, whereas its rescue in knocked-down cells led to the restoration of the aggressive phenotype. Together, our results demonstrate a previously unappreciated role for P2X4 in regulating lysosomal functions and fate, promoting breast cancer progression and aggressiveness.

Regadenoson versus dipyridamole: Evaluation of stress myocardial blood flow response on a CZT-SPECT camera.

BACKGROUND: Regadenoson is a selective adenosine receptor agonist. It is currently unclear if the level of hyperemia differs between stress agents. We compared Myocardial Blood Flow (MBF) and Myocardial Flow Reserve (MFR) response on CZT-SPECT Myocardial Perfusion Imaging (MPI) to evaluate if dipyridamole and regadenoson could induce the same level of hyperemia. METHODS: 228 patients with dynamic CZT-SPECT MPI were retrospectively analyzed (66 patients stressed with regadenoson and 162 with dipyridamole) in terms of MBF and MFR. To rule out confounding factors, two groups of 41 patients were matched for clinical characteristics in a sub-analysis, excluding high cardiovascular risk patients. RESULTS: Overall stress MBF was higher in regadenoson patients (1.71 ± 0.73 vs. 1.44 ± 0.55 mL·min-1·g-1 for regadenoson and dipyridamole, respectively, p < .05). However, when confounding factors were ruled out, stress MBF (1.57 ± 0.56 vs. 1.61 ± 0.62 mL·min-1·g-1 for dipyridamole and regadenoson, respectively, p = .88) and MFR (2.62 ± 0.77 vs. 2.46 ± 0.76 for dipyridamole and regadenoson, respectively, p = .40) were not different between regadenoson and dipyridamole. CONCLUSIONS: Our results suggest that dipyridamole and regadenoson induce equivalent hyperemia in dynamic SPECT with similar stress MBF and MFR in comparable patients.

Fractional Flow Reserve to Guide Treatment of Patients With Multivessel Coronary Artery Disease.

BACKGROUND: There is limited evidence that fractional flow reserve (FFR) is effective in guiding therapeutic strategy in multivessel coronary artery disease (CAD) beyond prespecified percutaneous coronary intervention or coronary graft surgery candidates. OBJECTIVES: The FUTURE (FUnctional Testing Underlying coronary REvascularization) trial aimed to evaluate whether a treatment strategy based on FFR was superior to a traditional strategy without FFR in the treatment of multivessel CAD. METHODS: The FUTURE trial is a prospective, randomized, open-label superiority trial. Multivessel CAD candidates were randomly assigned (1:1) to treatment strategy based on FFR in all stenotic (≥50%) coronary arteries or to a traditional strategy without FFR. In the FFR group, revascularization (percutaneous coronary intervention or surgery) was indicated for FFR ≤0.80 lesions. The primary endpoint was a composite of major adverse cardiac or cerebrovascular events at 1 year. RESULTS: The trial was stopped prematurely by the data safety and monitoring board after a safety analysis and 927 patients were enrolled. At 1-year follow-up, by intention to treat, there were no significant differences in major adverse cardiac or cerebrovascular events rates between groups (14.6% in the FFR group vs 14.4% in the control group; hazard ratio: 0.97; 95% confidence interval: 0.69-1.36; P = 0.85). The difference in all-cause mortality was nonsignificant, 3.7% in the FFR group versus 1.5% in the control group (hazard ratio: 2.34; 95% confidence interval: 0.97-5.18; P = 0.06), and this was confirmed with a 24 months' extended follow-up. FFR significantly reduced the proportion of revascularized patients, with more patients referred to exclusively medical treatment (P = 0.02). CONCLUSIONS: In patients with multivessel CAD, we did not find evidence that an FFR-guided treatment strategy reduced the risk of ischemic cardiovascular events or death at 1-year follow-up. (Functional Testing Underlying Coronary Revascularisation; NCT01881555).

Plasma and genetic determinants of soluble TREM-1 and major adverse cardiovascular events in a prospective cohort of acute myocardial infarction patients. Results from the FAST-MI 2010 study.

INTRODUCTION: Triggering receptor expressing on myeloid cells (TREM)-1 is involved in the pathophysiology of ischemic heart disease. Plasma soluble TREM-1 levels (sTREM-1) has been associated with increased risk of major adverse cardiovascular events (MACE) in acute myocardial infarction (AMI) patients. However, the causative link between TREM-1 and MACE remains unknown and requires further investigation before developing potential therapeutic approaches. METHODS AND RESULTS: Using the serum and DNA data bank from the prospective, nationwide French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction (FAST-MI 2010, N = 1293), we studied the association of plasma levels of sTREM-1 with 9 common genetic variants at the TREM1 locus and their relationship with recurrent MACE over a 3-year follow up. Plasma levels of sTREM-1 were associated with an increased risk of MACEs (death, recurrent MI or stroke) (adjusted HR = 1.86, 95%CI = 1.06-3.26 and HR = 1.11, 95%CI = 0.61-2.02 respectively for tertiles 3 and 2 versus tertile 1, P < 0.001). The study of common variants identified two major genetic determinants of sTREM-1 (rs4714449: beta = -0.11, Padd = 7.85 × 10-5 and rs3804276: beta = 0.18, Padd = 2.65 × 10-11) with a potential role on maintenance and/or differentiation of hematopoietic stem cells. However, associated variants only explained 4% of sTREM-1 variance (P = 2.74 × 10-14). Moreover, the rs4714449 variant, individually and in haplotype, was not significantly associated with MACE (HR = 0.61, 95%CI: 0.35-1.05, P = 0.07). CONCLUSIONS: Despite its relationship with increased risk of death, recurrent MI and stroke, genetic determinants of plasma levels of sTREM-1 were not found to be causal prognostic factors in patients with acute myocardial infarction.

Outcomes in patients with acute myocardial infarction and history of illicit drug use: a French nationwide analysis.

AIMS: Several reports suggest that illicit drug use may be a major cause of acute myocardial infarction (AMI) independently of smoking habits and associated with a poorer prognosis. The aim of our study was to evaluate the impact of illicit drug use on (i) the risk of AMI and (ii) its prognosis. METHODS AND RESULTS: This French longitudinal cohort study was based on the administrative hospital-discharge database from the entire population. First, we collected data for all patients admitted in hospital in 2013 with at least 5 years of follow-up to identify potential predictors of AMI. In a second phase, we collected data for all patients admitted with AMI from January 2010 to December 2018. We identified patients with a history of illicit drug use (cannabis, cocaine, or opioid). These patients were matched with patients without illicit drug use to assess their prognosis. In 2013, 3 381 472 patients were hospitalized with a mean follow-up of 4.7 ± 1.8 years. In multivariable analysis, among all drugs under evaluation, only cannabis use was significantly associated with a higher risk of AMI [HR 1.32 (95% CI 1.09-1.59), P = 0.004]. Between January 2010 and December 2018, we then identified 738 899 AMI patients. Among these patients, 3827 (0.5%) had a known history of illicit drug use. These patients were younger, most often male and had less comorbidities. After 1:1 propensity score matching, during a mean follow-up of 1.9 ± 2.3 years, there was no significant difference between patients without illicit drug use and patients with illicit drug use regarding all-cause death, cardiovascular death, stroke, or heart failure. CONCLUSION: In a large and systematic nationwide analysis, cannabis use was an independent risk factor for the incidence of AMI. However, the prognosis of illicit drug users presenting with AMI was similar to patients without illicit drug use.

Metabolically healthy obesity and cardiovascular events: A nationwide cohort study.

AIM: To evaluate the associations between metabolically healthy obesity (MHO) and different types of incident cardiovascular events in a contemporary population. MATERIALS AND METHODS: All patients discharged from French hospitals in 2013 with at least 5 years of follow-up and without a history of major adverse cardiovascular event (MACE; myocardial infarction, heart failure [HF], ischaemic stroke or cardiovascular death [MACE-HF]) or underweight/malnutrition were identified. They were categorized by phenotypes defined by obesity and three metabolic abnormalities (diabetes, hypertension and hyperlipidaemia). Hazard ratios (HRs) for cardiovascular events during follow-up were adjusted on age, sex and smoking status at baseline. RESULTS: In total, 2 873 039 individuals were included in the analysis, among whom 272 838 (9.5%) had obesity. During a mean follow-up of 4.9 years, when pooling men and women, individuals with MHO had a higher risk of MACE-HF (multivariate-adjusted HR 1.22, 95% confidence interval [CI]: 1.19-1.24), new-onset HF (HR 1.34, 95% CI 1.31-1.37) and atrial fibrillation (AF; HR 1.33, 95% CI 1.30-1.37) compared with individuals with no obesity and zero metabolic abnormalities. By contrast, risks were not higher for myocardial infarction (HR 0.92, 95% CI 0.87-0.98), ischaemic stroke (HR 0.93, 95% CI 0.88-0.98) and cardiovascular death (HR 0.99, 95% CI 0.93-1.04). MHO in men was associated with a higher risk of clinical events compared with metabolically healthy men of normal weight (HR 1.12-1.80), while women with MHO had a lower risk for most events than metabolically healthy women of normal weight (HR 0.49-0.99). CONCLUSIONS: In a large and contemporary analysis of patients seen in French hospitals, individuals with MHO did not have a higher risk of myocardial infarction, ischaemic stroke or cardiovascular death than metabolically healthy individuals with no obesity. By contrast, they had a higher risk of new-onset HF and new-onset AF. However, notable differences were observed in men and women in the sex-stratified analysis.

ST-segment elevation myocardial infarction: Management and association with prognosis during the COVID-19 pandemic in France.

BACKGROUND: Systems of care have been challenged to control progression of the COVID-19 pandemic. Whether this has been associated with delayed reperfusion and worse outcomes in French patients with ST-segment elevation myocardial infarction (STEMI) is unknown. AIM: To compare the rate of STEMI admissions, treatment delays, and outcomes between the first peak of the COVID-19 pandemic in France and the equivalent period in 2019. METHODS: In this nationwide French survey, data from consecutive STEMI patients from 65 centres referred for urgent revascularization between 1 March and 31 May 2020, and between 1 March and 31 May 2019, were analysed. The primary outcome was a composite of in-hospital death or non-fatal mechanical complications of acute myocardial infarction. RESULTS: A total of 6306 patients were included. During the pandemic peak, a 13.9±6.6% (P=0.003) decrease in STEMI admissions per week was observed. Delays between symptom onset and percutaneous coronary intervention were longer in 2020 versus 2019 (270 [interquartile range 150-705] vs 245 [140-646]min; P=0.013), driven by the increase in time from symptom onset to first medical contact (121 [60-360] vs 150 [62-420]min; P=0.002). During 2020, a greater number of mechanical complications was observed (0.9% vs 1.7%; P=0.029) leading to a significant difference in the primary outcome (112 patients [5.6%] in 2019 vs 129 [7.6%] in 2020; P=0.018). No significant difference was observed in rates of orotracheal intubation, in-hospital cardiac arrest, ventricular arrhythmias and cardiogenic shock. CONCLUSIONS: During the first peak of the COVID-19 pandemic in France, there was a decrease in STEMI admissions, associated with longer ischaemic time, exclusively driven by an increase in patient-related delays and an increase in mechanical complications. These findings suggest the need to encourage the population to seek medical help in case of symptoms.

NSTE-ACS ESC Guidelines Recommend Prasugrel as the Preferred P2Y12 Inhibitor: A Contrarian View.

In the 2020 European Society of Cardiology guidelines on non-ST-segment elevation acute coronary syndromes (NSTE-ACS), the experts proposed to put an end to the equipoise of ticagrelor and prasugrel in addition to aspirin in patients with NSTE-ACS who proceed to percutaneous coronary intervention (PCI). They gave a strong level of recommendation (IIa) in favor of prasugrel over ticagrelor in these patients. We challenge this proposition, which was mainly driven by the results of ISAR-REACT 5, an open-label prospective head-to-head study of a prasugrel-based strategy compared with a ticagrelor-based strategy in patients with ACS undergoing PCI. In addition to the methodological concerns regarding the ISAR-REACT 5 study, we also question this decision in light of the ISAR-REACT 5 diabetes mellitus subgroup analysis and previous studies and meta-analysis that showed no difference between ticagrelor and prasugrel in patients with ACS. Although we agree with the "one size does not fit all" concept for antiplatelet regimens in patients with ACS who proceed to PCI, we believe that the decision to strongly favor prasugrel was premature and not supported enough by the ISAR-REACT 5 results. In our opinion, equipoise remains between the ticagrelor- and prasugrel-based strategies and more data are needed to settle the debate.

SAFEHEART risk-equation and cholesterol-year-score are powerful predictors of cardiovascular events in French patients with familial hypercholesterolemia.

BACKGROUND AND AIMS: Patients with heterozygous familial hypercholesterolemia (HeFH) present elevated cardiovascular (CV) risk. Current CV risk stratification algorithms developed for the general population are not adapted for heFH patients. It is therefore of singular importance to develop and validate CV prediction tools, which are dedicated to the HeFH population. METHODS: Our first objective was to validate the Spanish SAFEHEART-risk equation (RE) in the French HeFH cohort (REFERCHOL), and the second to compare SAFEHEART-RE with the low-density-lipoprotein-cholesterol (LDL-C)-year-score for the prediction of CV events in the HeFH French population. RESULTS: We included HeFH (n = 1473) patients with a genetic or clinical diagnosis (DLCN score ≥8). Among them, 512 patients with a 5-year follow-up were included to validate the 5 year-CV-RE. A total of 152 events (10.3%) occurred in the entire population of 1473 patients during a mean follow-up of 3.9 years. Over the five-year follow-up, non-fatal CV events occurred in 103 patients (20.2%). Almost all the parameters used in the SAFEHEART-RE were confirmed as strong predictors of CV events in the REFERCHOL cohort. The C-statistic revealed a satisfactory performance of both the SAFEHEART-RE and LDL-C-year-scores in predicting CV events for all the patients (primary and secondary prevention) (C-index 0.77 and 0.70, respectively) as well as for those in primary prevention at inclusion (C-index 0.78 and 0.77, respectively). CONCLUSIONS: This analysis represents the first external validation of the SAFEHEART-RE and demonstrated that both SAFEHEART-RE and the LDL-C-year-score are good predictors of CV events in primary prevention HeFH patients.

Futility Risk Model for Predicting Outcome After Transcatheter Aortic Valve Implantation.

Risk-benefit assessment for transcatheter aortic valve implantation (TAVI) is still a matter of debate. We aimed to identify patients with a bad outcome within 1 year after TAVI, and to develop a Futile TAVI Simple score (FTS). Based on the administrative hospital-discharge database, all consecutive patients treated with percutaneous TAVI in France between 2010 and 2018 were included. A prediction model was derived and validated for 1-year all-cause death after TAVI (considered as futility) by using split-sample validation: 20,443 patients were included in the analysis (mean age 83 ± 7 years). 7,039 deaths were recorded (yearly incidence rate 15.5%), among which 3,702 (53%) occurred in first year after TAVI procedure. In the derivation cohort (n = 10,221), the final logistic regression model included male sex, history of hospital stay with heart failure, history of pulmonary oedema, atrial fibrillation, previous stroke, vascular disease, renal disease, liver disease, pulmonary disease, anaemia, history of cancer, metastasis, depression and denutrition. The area under the curve (AUC) for the FTS was 0.674 (95%CI 0.660 to 0.687) in the derivation cohort and 0.651 (95%CI 0.637 to 0.665) in the validation cohort (n = 10,222). The Hosmer-Lemeshow test had a p-value of 0.87 suggesting an accurate calibration. The FTS score outperformed EuroSCORE II, Charlson comorbidity index and frailty index for identifying futility. Based on FTS score, 7% of these patients were categorized at high risk with a 1-year mortality at 43%. In conclusion, the FTS score, established from a large nationwide cohort of patients treated with TAVI, may provide a relevant tool for optimizing healthcare decision.

Long-term outcomes after acute myocardial infarction in patients with familial hypercholesterolemia: The French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction program.

BACKGROUND: Patients with familial hypercholesterolemia (FH) are prone to develop acute myocardial infarction (AMI) at a younger age. OBJECTIVES: The aim of the present study was to assess 5-year outcomes after AMI according to the presence of FH in a large multicenter cohort of patients. METHODS: The French registry of Acute ST-elevation and non-ST-elevation Myocardial Infarction consists of nationwide surveys recruiting patients over a 1- to 2-month period every 5 years. Patients recruited in 2005 and 2010 were followed up to 5 years. RESULTS: Of 5147 patients discharged alive and in whom FH status could be assessed, 2.8% had probable/definite FH, using an adapted Dutch Lipid Clinic score. They were 12 years younger, on average, than non-FH patients. Before adjustment, their 5-year survival and event-free survival did not differ from non-FH patients. After adjustment, however, both mortality (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.15-2.89; P = .011) and the combined endpoint of death, AMI, or stroke (HR 2.22, 95% CI: 1.51-3.26; P < .001) were higher in FH patients. The higher risk in FH patients was also present in patients receiving high-intensity lipid-lowering therapy at discharge: adjusted HR for mortality 2.29, 95% CI: 1.18 to 4.47, P = .015; HR for cardiovascular events 2.57, 95% CI: 1.48 to 4.48, P = .001. Concordant results were observed in propensity score-marched cohorts. CONCLUSIONS: The risk of long-term mortality and cardiovascular events is twice as high in FH than in non-FH patients, when adjusted on baseline characteristics, even for those receiving high-intensity lipid-lowering therapy. Additional therapeutic measures are needed in these patients.

In-hospital outcomes and 5-year mortality following an acute myocardial infarction in patients with a history of cancer: Results from the French registry on Acute ST-elevation or non-ST-elevation myocardial infarction (FAST-MI) 2005 cohort.

BACKGROUND: Cancer and acute myocardial infarction (AMI) have important prognostic consequences. Treatment of some cancers may affect coronary artery disease, myocardial function and/or AMI management. Whether the early and long-term mortality of patients with AMI differ according to their history of cancer remains questionable. AIMS: To determine in-hospital outcomes and 5-year mortality following AMI according to patient history of cancer. METHODS: The FAST-MI registry is a nationwide French survey collecting data on characteristics, management and outcomes of 3670 consecutive patients admitted for AMI during October 2005. RESULTS: Overall, 246/3664 patients (6.7%) admitted for an AMI (47.6% with ST-segment elevation myocardial infarction [STEMI]; 52.4% with non-STEMI [NSTEMI]) had a history of cancer. In-hospital mortality was not significantly different for patients with versus without a history of cancer, overall (adjusted odds ratio [OR]: 1.15, 95% confidence interval [CI]: 0.68-1.94; P=0.61) and in patients with STEMI (adjusted OR: 1.37, 95% CI: 0.69-2.71; P=0.37) or NSTEMI (adjusted OR: 0.97, 95% CI: 0.41-2.28; P=0.95). All-cause mortality at 5 years was higher among patients with a history of cancer (adjusted hazard ratio [HR]: 1.36, 95% CI: 1.08-1.69; P=0.008), whereas 5-year cardiovascular mortality did not differ (adjusted HR: 1.17, 95% CI: 0.89-1.53; P=0.25), regardless of whether the patients had STEMI or NSTEMI. Similar results were found in populations matched on a propensity score including baseline characteristics and early management. CONCLUSION: A history of cancer, per se, does not appear to be a risk factor for increased in-hospital mortality or long-term cardiovascular mortality in patients admitted for AMI.

Stimulation of P2Y11 receptor protects human cardiomyocytes against Hypoxia/Reoxygenation injury and involves PKCε signaling pathway.

Sterile inflammation is a key determinant of myocardial reperfusion injuries. It participates in infarct size determination in acute myocardial infarction and graft rejection following heart transplantation. We previously showed that P2Y11 exerted an immunosuppressive role in human dendritic cells, modulated cardiofibroblasts' response to ischemia/reperfusion in vitro and delayed graft rejection in an allogeneic heterotopic heart transplantation model. We sought to investigate a possible role of P2Y11 in the cellular response of cardiomyocytes to ischemia/reperfusion. We subjected human AC16 cardiomyocytes to 5 h hypoxia/1 h reoxygenation (H/R). P2Y11R (P2Y11 receptor) selective agonist NF546 and/or antagonist NF340 were added at the onset of reoxygenation. Cellular damages were assessed by LDH release, MTT assay and intracellular ATP level; intracellular signaling pathways were explored. The role of P2Y11R in mitochondria-derived ROS production and mitochondrial respiration was investigated. In vitro H/R injuries were significantly reduced by P2Y11R stimulation at reoxygenation. This protection was suppressed with P2Y11R antagonism. P2Y11R stimulation following H2O2-induced oxidative stress reduced mitochondria-derived ROS production and damages through PKCε signaling pathway activation. Our results suggest a novel protective role of P2Y11 in cardiomyocytes against reperfusion injuries. Pharmacological post-conditioning targeting P2Y11R could therefore contribute to improve myocardial ischemia/reperfusion outcomes in acute myocardial infarction and cardiac transplantation.

Effects of remote ischemic conditioning on kidney injury in at-risk patients undergoing elective coronary angiography (PREPARE study): a multicenter, randomized clinical trial.

The ability of remote ischemic preconditioning (RIPC) to prevent contrast-induced nephropathy (CIN) following percutaneous coronary angiography in at-risk patients is controversial. No evidence exists regarding potential RIPC positive effects on renal function and clinical outcomes in the long-term. The PREPARE study was a randomized, prospective, multicenter, and double-blinded trial. A total of 222 patients scheduled for coronary angiography and/or percutaneous transluminal coronary angioplasty with an estimated glomerular filtration rate (eGFR) < 40 mL/min/1.73 m2, or eGFR between 40 and 60 mL/min/1.73 m2 and two further risk factors were allocated to RIPC or control groups. Preventive measures were applied to all patients, including continuous intravenous saline infusion, withdrawal of nephrotoxic drugs, and limited volume of contrast medium. The primary endpoint, namely incidence of CIN, was 3.8% in the control group and 5.1% in the RIPC group (p = 0.74). The secondary endpoints, i.e., changes in serum creatinine and eGFR levels from baseline to 48 hours and from baseline to 12 months following contrast medium exposure, did not differ between both groups. The incidences of all major clinical events at 12 months were similar in both groups. In this population at risk of CIN, preventive strategies were associated with low CIN incidence. RIPC impacted neither the CIN incidence nor both the renal function and clinical outcomes at 1-year follow-up.

Stimulation of murine P2Y11-like purinoreceptor protects against hypoxia/reoxygenation injury and decreases heart graft rejection lesions.

OBJECTIVE: Myocardial ischemia reperfusion is a major cause of cell injury during cardiac transplantation and is responsible for increased graft rejection. Several in vitro studies demonstrated the protective effect of P2Y11-like purinoreceptor stimulation in the context of myocardial ischemia/reperfusion. In this study, we hypothesized a possible cardioprotective role of P2Y11R stimulation against ischemia/reperfusion lesions and validated its clinical effect in vivo in a heart transplantation model. METHODS: We subjected H9c2 rat cardiomyocyte-derived cell line to 5 hours of hypoxia and 1 hour of reoxygenation. P2Y11R selective agonist NF546 and antagonist NF340 were added at the onset of reoxygenation. Cell injuries were assessed by microculture tetrazolium reduction and intracellular adenosine triphosphate level. Clinical effect of P2Y11R stimulation was further investigated in vivo. Hearts from BALB/c mice were transplanted intra-abdominally into allogenic C57BL/6 mice (n = 104). Recipient mice were injected with P2Y11R agonist. Mice in the sham group were injected with saline solution. In the control group, hearts from C57BL/6 were transplanted into syngeneic C57BL/6 mice. Rejection lesions were investigated using histology and immunohistochemistry at days 3, 5, and 7 after transplantation. We measured caspase activities to quantify apoptosis. Production of proinflammatory and anti-inflammatory cytokines was investigated. RESULTS: P2Y11R stimulation at the onset of reoxygenation significantly reduced in vitro hypoxia/reoxygenation injuries. This protection was suppressed with P2Y11R antagonist. In vivo, cardiac allograft survival was significantly prolonged after P2Y11R stimulation. Rejection lesions, classified according to the International Society of Heart Lung Transplantation guidelines and quantified using the mean number of inflammatory cells per field, were significantly reduced in the treated group. At day 5 after transplantation, P2Y11R agonist pretreated allografts also demonstrated less apoptotic lesions. CONCLUSIONS: Our data suggest a novel cardioprotective role of P2Y11R at the onset of reoxygenation/reperfusion against reperfusion injuries. Pharmacologic conditioning using P2Y11 agonist may be beneficial after cardiac transplantation in improving myocardial ischemia/reperfusion outcomes and decreasing graft rejection lesions.

Dual Antiplatelet Therapy Combining Aspirin and Ticagrelor for Intracranial Stenting Procedures: A Retrospective Single Center Study of 154 Consecutive Patients With Unruptured Aneurysms.

BACKGROUND: Dual antiplatelet therapy (DAPT) associating aspirin + clopidogrel is commonly utilized in neurovascular interventions despite unpredictable clopidogrel efficacy with 4% to 50% of patients considered nonresponders. Ticagrelor is an antiplatelet agent with low resistance rates but unknown efficacy and safety in neurovascular patients. OBJECTIVE: To evaluate frequency of ischemic and hemorrhagic events in patients treated with aspirin and ticagrelor when associated with perioperative heparin bolus for unruptured aneurysms treated with intracranial stents. METHODS: One hundred fifty-four consecutive patients with unruptured intracranial aneurysms treated by stent procedures (113 = flow diverter stent [FDS], 41 = stent-assisted coiling) were retrospectively analyzed. All patients received aspirin and ticagrelor without platelet function testing. Patients were separated in 2 groups following perioperative heparin dose: group I = 70 U/kg; group II = 50 U/kg. FDS versus stent-assisted coiling procedures were also separately analyzed. RESULTS: Nine patients (5.8%) presented symptomatic neurological complications poststenting (3 ischemic, 6 hemorrhagic): 8 patients received 70 U/kg of heparin (11.1%) and 1 patient received 50 U/kg (1.2%; P < .009). Four patients died (2.6%) during the 3-mo follow-up period-all deaths were correlated to intracranial hemorrhage: 3 at group I and 1 at group II (P < .251). No difference in complications or death was observed considering separately FDS and stent-assisted coiling procedures. CONCLUSION: This study did not find more neurological complications than in previous neurointerventional reports using DAPT with aspirin + ticagrelor or aspirin + clopidogrel. Overall number of neurological complications was lower when a lower dose of heparin was administered. Neurovascular studies comparing clopidogrel to ticagrelor and different doses of heparin are necessary to demonstrate which association is more efficient with lower complication rates.

Overview of Systematic Reviews and Meta-analyses on Systemic Adverse Events Associated With Intravitreal Anti-Vascular Endothelial Growth Factor Medication Use.

Importance: The systemic safety of intravitreal anti-vascular endothelial growth factor (anti-VEGF) medications is still a matter of debate. Objective: This overview of systematic reviews evaluates systemic adverse events associated with intravitreal anti-VEGF treatments in patients with neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion. Design, Evidence, and Reporting: This systematic search of PubMed and the Cochrane Central Register of Controlled Trials database includes meta-analyses and systematic reviews. We describe the summary measures of association between anti-VEGF treatments and outcomes reported in each systematic review. Main Outcomes and Measures: The quality of the systematic reviews was assessed with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist and A Measurement Tool to Assess Systematic Reviews (AMSTAR) checklist, version 1. Findings: We retrieved 21 systematic reviews published between January 1, 2011, and June 30, 2016. Of these, 11 analyzed systemic adverse events as the primary outcome. The median (interquartile range) PRISMA and AMSTAR scores were 23 of 27 (15-27) and 8 of 11 (5-11), respectively, but 5 reviews (25%) scored below 20 and 7, respectively. All reviews used an objective scale to assess methodological risk of bias in their included studies, the Cochrane Risk of Bias Tool being the most commonly used (16 reviews [76%]). Anti-VEGF treatments did not increase the risk of systemic adverse events when compared with control regimens; similarly, there was no increase in systematic adverse events when treatment was given on a monthly schedule vs an as-needed regimen. Compared with ranibizumab, bevacizumab did not appear to be associated with an increase in the risk of systemic adverse events in the most recent and exhaustive reviews. Compared with control treatments, ranibizumab may be associated with an increase in the risk of nonocular hemorrhage in patients with age-related macular degeneration. Conclusions and Relevance: This overview of reviews and meta-analyses suggest that anti-VEGF treatments do not increase the risk of systemic adverse events, but that caution might be advisable in older patients with age-related macular degeneration who may be at higher risk of hemorrhagic events when receiving ranibizumab.