Introduction Mesenchymal Stromal Cells (MSC) have been widely used for their therapeutic properties in acute myocardial infarction (AMI) due to their pleiotropic properties. Despite promising results in animal studies and their safety and efficacy in phase I/II trials, inconsistencies have been reported in phase III trials. Recently, we have shown in a mouse model of ischemia-reperfusion (IR) that PPARβ/δ preconditioning of MSC allows to improve their therapeutic efficacy. Objective The present study aims at investigating the role of PPARβ/δ activation on human MSC to enhance their therapeutic properties in myocardial IR injury in a way of clinical translation. Method Cultured human adipose-derived MSC (ASC) were pretreated with 1μM of PPARβ/δ agonist GW0742 (ASC-Pr). ASC or ASC-Pr were challenged with various stresses including simulated oxidative and freezing/thawing stresses. Apoptosis was quantified in stressed ASC or ASC-Pr. The therapeutic properties of ASC and ASC-Pr were evaluated in vitro by co-culturing them with H9c2 cardiomyoblasts and Eahy926 human endothelial cells challenged with H2O2. Ex vivo and in vivo evaluation was obtained using mouse models of myocardial ischemia-reperfusion after cell administration during reperfusion and infarct size was measured using the TTC method. Results Apoptosis was decreased in ASC-Pr vs naïve ASC upon H2O2- or freezing/thawing induced stress showing an increased resistance of primed ASC. We observed also for ASC-Pr a more potent anti-apoptotic effect on both cardiomyocytes and endothelial cells in vitro than naïve ASC. Ex vivo, PPARβ/δ preconditioning allowed to reveal and increase the cardioprotective effect of naïve ASC perfused at a suboptimal dose (P<0.05; n=12 in each group). In vivo, ASC priming allowed to increase the cardioprotective effect not present in naïve condition (P=ns IR vs ASC and P*<0.05 IR vs ASC-Pr. Conclusion PPARβ/δ preconditioning enhanced the ASC resistance to apoptosis. The efficacy of ASC-based therapy was increased using this preconditioning protocol by increasing their anti-apoptotic effects on cardiomyocytes and endothelial cells. These results are of major interest to improve ASC efficacy for the cardioprotection of the myocardium in AMI patients.

BACKGROUND:Abbreviated antiplatelet therapy (APT) can reduce bleeding without increasing ischaemic harm in high bleeding risk (HBR) patients undergoing percutaneous coronary intervention (PCI). The impact of chronic kidney disease (CKD) on the safety and effectiveness of abbreviated APT remains unknown. AIMS:We aimed to investigate the comparative effectiveness of abbreviated (1 month) versus standard (≥3 months) APT in HBR patients with and without CKD. METHODS:This was a prespecified analysis from the MASTER DAPT trial, which randomised 4,579 HBR patients (1,428 [31%] with CKD) to abbreviated or standard APT. CKD was defined as an estimated glomerular filtration rate <60 mL/min/1.73 m2. Co-primary outcomes were net adverse clinical events (NACE; a composite of all-cause death, myocardial infarction [MI], stroke, and major bleeding), major adverse cardiac or cerebral events (MACCE; all-cause death, MI and stroke), and Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding at 11 months. RESULTS:NACE did not significantly differ with abbreviated and standard APT among CKD patients (hazard ratio [HR] 0.91, 95% confidence interval [CI]: 0.66-1.24) and non-CKD patients (HR 0.96, 95% CI: 0.73-1.27; pinteraction=0.78). Similarly, MACCE did not differ in CKD patients (HR 0.91, 95% CI: 0.64-1.27) and non-CKD patients (HR 1.09, 95% CI: 0.78-1.51; pinteraction=0.45). Abbreviated APT was associated with consistently lower BARC 2, 3, or 5 bleeding in both patients with CKD (HR 0.74, 95% CI: 0.52-1.07) and without it (HR 0.66, 95% CI: 0.51-0.85; pinteraction=0.59). CONCLUSIONS:Abbreviated APT was associated with similar NACE and MACCE rates and reduced bleeding compared with standard APT in HBR patients undergoing PCI, regardless of the presence or absence of CKD. (ClinicalTrials.gov: NCT03023020).

Background An appropriate duration of dual antiplatelet therapy after percutaneous coronary intervention for acute myocardial infarction that has been treated with guideline-recommended complete revascularization and a contemporary drug-eluting stent remains unclear.Methods We conducted a multicenter, open-label, randomized trial at 40 European sites. Adults with acute myocardial infarction who had undergone successful complete revascularization within 7 days after the infarction and had subsequently completed 1 month of dual antiplatelet therapy with no ischemic or major bleeding events were randomly assigned to transition to a P2Y12 inhibitor as monotherapy or to continue dual antiplatelet therapy for an additional 11 months. The primary outcome was a composite of death from any cause, myocardial infarction, stent thrombosis, stroke, or major bleeding (defined by the Bleeding Academic Research Consortium [BARC] as a bleeding event of type 3 or 5) at 11 months after randomization (tested for noninferiority with a margin of 1.25 percentage points). The main secondary outcome was BARC type 2, 3, or 5 bleeding (clinically relevant bleeding) at 11 months after randomization (tested for superiority).Results Among the 2246 enrolled patients, 1942 underwent randomization: 961 to receive P2Y12-inhibitor monotherapy and 981 to continue dual antiplatelet therapy. A primary-outcome event occurred in 20 patients (2.1%) in the P2Y12-inhibitor monotherapy group and in 21 patients (2.2%) in the dual antiplatelet therapy group (difference, -0.09 percentage points; 95% confidence interval [CI], -1.39 to 1.20; P=0.02 for noninferiority). BARC type 2, 3, or 5 bleeding occurred in 2.6% of the patients in the P2Y12-inhibitor monotherapy group and in 5.6% of those in the dual antiplatelet therapy group (hazard ratio, 0.46; 95% CI, 0.29 to 0.75; P=0.002 for superiority). Stent thrombosis was infrequent, and the incidence was similar in the two groups. The incidence of serious adverse events appeared to be similar in the two groups.Conclusions Among low-risk patients with acute myocardial infarction who had undergone early complete revascularization and had completed 1 month of dual antiplatelet therapy without complications, P2Y12-inhibitor monotherapy was noninferior to continued dual antiplatelet therapy with respect to the occurrence of adverse cardiovascular and cerebrovascular events and resulted in a lower incidence of bleeding events. (Funded by MicroPort [France]; TARGET-FIRST ClinicalTrials.gov number, NCT04753749.) In low-risk patients with MI and early complete revascularization, stopping aspirin after 1 month and continuing P2Y12 monotherapy was noninferior to dual antiplatelet therapy for ischemic outcomes and led to reduced bleeding at 1 year.

Introduction Mesenchymal stromal cells (MSC) have been widely used for their therapeutic properties in acute myocardial infarction (AMI) due to their pleiotropic properties. Despite promising results in animal studies and their safety and efficacy in phase I/II trials, inconsistencies have been reported in phase III trials. Recently, we have shown in a mouse model of ischemia-reperfusion (IR) that the cardioprotective effect of murine MSC administered during reperfusion was dependent on the presence of PPARβ/δ. Objective The present study aims at investigating the role of PPARβ/δ activation on human MSC to enhance their therapeutic properties in myocardial IR injury. Method Cultured human adipose-derived MSC (ASC) were pretreated with 1μM of PPARβ/δ agonist (GW0742) (ASC-ago). Apoptosis (DNA fragmentation) was quantified in ASC or ASC-ago challenged during 4hours with 350μM H2O2 and in H9c2 rat cardiomyoblasts and EAhy926 human endothelial cells challenged with H2O2 and co-cultured with ASC or ASC-ago. Also, ASC-ago were injected during the reperfusion phase in ex vivo and in vivo mouse model of myocardial IR injury and infarct size was measured using the TTC method. Results Apoptosis was decreased in ASC-ago versus naïve ASC upon H2O2-stress showing an increased resistance of primed ASC against oxidative stress. We observed also for ASC-ago an increased resistance against oxidative resistance and a more potent anti-apoptotic effect on both cardiomyocytes and endothelial cells in vitro than naïve ASC. Ex vivo, the reduction in infarct size was increased in the ASC-ago group compared to naïve ASC (P<0.05; n=12 in each group). In vivo, ASC priming allowed to increase the cardioprotective effect not present in naïve condition (P=ns IR versus ASC and P*<0.05 IR versus ASC-ago). Conclusion ASC preconditioning via PPARβ/δ agonist enhanced their resistance to oxidative stress and their anti-apoptotic effects on cardiac cells as well as their cardioprotective effect against IR injury both ex vivo and in vivo. These results are of major interest to improve ASC efficacy for the cardioprotection of the myocardium in AMI patients.

Background Safety and feasibility of transcatheter aortic valve replacement (TAVR) without balloon aortic valvuloplasty (BAV) using the SAPIEN 3 balloon-expandable device has been previously demonstrated. The impact on long-term valve hemodynamic performances and outcomes remains however unknown. We evaluate long-term clinical and hemodynamic results according to the implant strategy (direct TAVR vs BAV pre-TAVR) in patients included in the DIRECTAVI randomized trial Methods Clinical and echocardiographic follow-up until January 2023 was performed for all patients included in the DIRECTAVI trial since 2016 ( n = 228). The primary endpoint was incidence of moderate/severe hemodynamic valve deterioration (HVD), according to the Valve Academic Research defined Consortium-3 criteria (increase in mean gradient >10 mmHg resulting in a final mean gradient >20 mmHg, or new/worsening aortic regurgitation of 1 grade resulting in > Results Median follow-up was 3.8 (2.2-4.7) years. Mean age at follow-up was 87 +/- 6.7 years. No difference in incidence of HVD in the direct implantation group compared to the BAV group was found (incidence of 1.97 per 100 person-years and 1.45 per 100 person-years, respectively, P = 0.6). Prevalence of predicted prothesis-patient mismatch was low ( n = 13 [11.4%] in the direct TAVR group vs n = 15 [13.2%] in BAV group) and similar between both groups ( P = . 7). Major outcomes including death, stroke, hospitalization for heart failure and pacemaker implantation were similar between both groups, ( P = . 4, P = . 7, P = . 3, and P = . 3 respectively). Conclusion Direct implantation of the balloon-expandable device in TAVR was not associated with an increased risk of moderate/severe HVD or major outcomes up to 6-year follow-up. These results guarantee wide use of direct balloonexpandable valve implantation, when feasible.

Background:Acute myocardial infarction (AMI) is the major cause of cardiovascular mortality worldwide. Most ischemic episodes are triggered by an increase in heart rate, which induces an imbalance between myocardial oxygen delivery and consumption. Developing drugs that selectively reduce heart rate by inhibiting ion channels involved in heart rate control could provide more clinical benefits. The Cav1.3-mediated L-type Ca2+ current (ICav1.3) play important roles in the generation of heart rate. Therefore, they can constitute relevant targets for selective control of heart rate and cardioprotection during AMI. Objective:We aimed to investigate the relationship between heart rate and infarct size using mouse strains knockout for Cav1.3 (Cav1.3-/-) L-type calcium channel and of the cardiac G protein gated potassium channel (Girk4-/-) in association with the funny (f)-channel inhibitor ivabradine. Methods:Wild-type (WT), Cav1.3+/-, Cav1.3-/- and Girk4-/- mice were used as models of respectively normal heart rate, moderate heart rate reduction, bradycardia, and mild tachycardia, respectively. Mice underwent a surgical protocol of myocardial IR (40 min ischemia and 60 min reperfusion). Heart rate was recorded by one-lead surface ECG recording, and infarct size measured by triphenyl tetrazolium chloride staining. In addition, Cav1.3-/- and WT hearts perfused on a Langendorff system were subjected to the same ischemia-reperfusion protocol ex vivo, without or with atrial pacing, and the coronary flow was recorded. Results:Cav1.3-/- mice presented reduced infarct size (-29%), while Girk4-/- displayed increased infarct size (+30%) compared to WT mice. Consistently, heart rate reduction in Cav1.3+/- or by the f-channel blocker ivabradine was associated with significant decrease in infarct size (-27% and -32%, respectively) in comparison to WT mice. Conclusion:Our results show that decreasing heart rate allows to protect the myocardium against IR injury in vivo and reveal a close relationship between basal heart rate and IR injury. In addition, this study suggests that targeting Cav1.3 channels could constitute a relevant target for reducing infarct size, since maximal heart rate dependent cardioprotective effect is already observed in Cav1.3+/- mice.

Objectives. The aim of this postmarket clinical study was to assess the safety and efficacy of the latest generation polymer-free sirolimus-eluting stents (PF-SES) in an all-comers population comparing outcomes in stable coronary artery disease (CAD) versus acute coronary syndrome (ACS) in France. Background. The efficacy and safety of the first-generation PF-SES have already been demonstrated by randomized controlled trials and “all-comers” observational studies. Methods. For this all-comers observational, prospective, multicenter study, 1456 patients were recruited in 22 French centers. The primary endpoint was target lesion revascularization (TLR) rate at 12 months and secondary endpoints included major adverse cardiac events (MACE) and bleeding. Results. 895 patients had stable CAD and 561 had ACS. At 12 months, 2% of patients had a TLR, with similar rates between stable CAD and ACS (1.9% vs 2.2%, p = 0.7). The overall MACE rate was 5.2% with an expected higher rate in patients with ACS as compared to those with stable CAD (7.3% vs 3.9%, p = 0.007). The overall bleeding event rate was 4.5%, with similar rates in stable CAD as compared to ACS patients (3.8% vs 5.6%, p = 0.3). Dual antiplatelet therapy (DAPT) interruptions prior to the recommended duration occurred in 41.7% of patients with no increase in MACE rates as compared to patients who did not prematurely interrupt DAPT (3.9% vs 6.1%, p = 0.073). Conclusions. The latest generation PF-SES is associated with low clinical event rates in these all-comers patients. There was a high rate of prematurely terminated DAPT, without any effect on MACE at 12 months. This trial is registered with NCT03809715.

Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.

Based on the latest knowledge and technological advancements, it is still debatable whether a modern revascularisation approach in the setting of acute myocardial infarction (AMI), including complete revascularisation (in patients with significant non-culprit lesions) with newer-generation highly biocompatible drug-eluting stents, requires prolonged dual antiplatelet therapy (DAPT). TARGET-FIRST (ClinicalTrials.gov: NCT04753749) is a prospective, open-label, multicentre, randomised controlled study comparing short (one month) DAPT versus standard (12 months) DAPT in a population of patients with non-ST/ST-segment elevation myocardial infarction, completely revascularised at index or staged procedure (within 7 days), using Firehawk, an abluminal in-groove biodegradable polymer rapamycin-eluting stent. The study will be conducted at approximately 50 sites in Europe. After a mandatory 30-40 days of DAPT with aspirin and P2Y12 inhibitors (preferably potent P2Y12 inhibitors), patients are randomised (1:1) to 1) immediate discontinuation of DAPT followed by P2Y12 inhibitor monotherapy (experimental arm), or 2) continued DAPT with the same regimen (control arm), up until 12 months. With a final sample size of 2,246 patients, the study is powered to evaluate the primary endpoint (non-inferiority of short antiplatelet therapy in completely revascularised patients) for net adverse clinical and cerebral events. If the primary endpoint is met, the study is powered to assess the main secondary endpoint (superiority of short DAPT in terms of major or clinically relevant non-major bleeding). TARGET-FIRST is the first randomised clinical trial to investigate the optimisation of antiplatelet therapy in patients with AMI after achieving complete revascularisation with an abluminal in-groove biodegradable polymer rapamycin-eluting stent implantation.

EDITORIAL article Front. Cardiovasc. Med., 08 August 2023Sec. Cardiovascular Pharmacology and Drug Discovery Volume 10 - 2023 | https://doi.org/10.3389/fcvm.2023.1260800

Abstract Background The randomized DIRECTAVI trial demonstrated safety and feasibility of transcatheter aortic valve implantation (TAVI) without balloon aortic valvuloplasty (BAV) using SAPIEN 3 balloon-expandable devices. Purpose To evaluate long-term clinical and hemodynamic results according to the implant strategy (direct TAVI versus BAV) with the SAPIEN 3 balloon-expandable device in patients included in the DIRECTAVI trial. Methods All patients included in the DIRECTAVI trial since 2016 were offered a clinical and echocardiographic follow-up until January 2023. We applied Valve Academic Research Consortium (VARC-3) criteria to define moderate/severe hemodynamic valve deterioration (HVD) as an increase in mean gradient ≥10 mm Hg resulting with a final mean gradient ≥20 mm Hg, or new/worsening aortic regurgitation (AR) of 1 grade resulting in ≥moderate AR. Survival until moderate/severe HVD between the 2 groups was the primary end-point and overall survival between direct TAVI and BAV were compared using logrank tests. Major clinical outcomes at latest follow-up were also assessed using Chi² or Fisher’s tests. Results Among 250 patients included in DIRECTAVI, 228 patients were followed-up during 4.5 ± 1.1 years. Mean age at follow-up was 87 ± 6.7 years. Incidence rates of moderate/severe HVD were similar in the 2 groups (1.45 versus 1.97 per 100 person-years, p=0.6) (Figure). Incidence rates for death were similar between groups (9.19 and 7.34 events per 100 persons-years for BAV and direct TAVI, respectively, p=0.4). No clinically significant differences in outcomes were observed at the latest follow-up, including major stroke (4.4% for BAV versus 2.6% for direct TAVI, p=0.7), hospitalizations for heart failure (15.8% for BAV group and 11.4% for direct TAVI group, p=0.3), permanent pacemaker implantation (37.7% for BAV and 31.6% for direct TAVI, p=0.3). Moderate/severe patient-prosthesis mismatch was also similar between groups (p=0.6). Conclusion Compared to systematic BAV, direct implantation of the SAPIEN 3 device was not associated with an increased risk of moderate/severe valve deterioration or adverse clinical events up to 6-year follow-up. These results encourage wide use of this simplified strategy with balloon-expandable devices, when possible.Survival without valve deterioration

Bridging of vitamin K antagonist (VKA) with heparin is usually not promoted during interventional or surgical procedures related to increased risk of bleeding and thrombotic events but this strategy has not been evaluated during TAVI. The aim of this study was to evaluate the rate of major bleeding and vascular complications after TAVI performed in patients with uninterrupted VKA. From January 2016 to October 2017, consecutive patients who underwent TAVI with uninterrupted VKA (INR between 1.5 and 3.5) were prospectively included in a monocentric registry. TAVI were performed according to current guidelines and a 50UI/kg bolus of heparin was injected at the beginning of the procedure for all patients. Vascular and bleeding complications were assessed using the Valve Academic Research Consortium 2 (VARC2) and the Bleeding Academic Research Consortium (BARC) definitions at 30 day follow-up. A total of 88 patients were included with a median age of 84 years [81.8–87], 42% being female, the median STS score was 5.1 [4.1–7.5], the median CHADS2-VASc was 5.5 [5–6] and 60.2% had a chronic kidney failure. Median INR at time of implantation was at 2.1 [1.8–2.6]. VKA were used for atrial fibrillation (89.8%), mechanic mitral prosthesis (5.7%) or venous thromboembolic disease (4.5%). Trans femoral access was used in 88.6% of the patients. Major bleeding (BARC ≥3b) occurred in 5 patients (5,7%) and major vascular complications occurred in 7 patients (8%). Peripheral arterial disease (RR = 10.95; 95% CI: 1.63 to 73.75; p=0.014) and carotid access (RR=8.56; 95% CI: 1.19 to 61.51; p=0.033) were significantly associated with major bleeding. INR >2.5 was significantly associated with vascular complications (RR=7.14; 95% CI: 1.29 to 39.63; p=0.025). In multivariate analysis, Body mass index (OR=1.26; 95% CI: 1.02 to 1.57; p=0.032) and INR >2.5 (OR=18.91; 95% CI: 1.62 to 221.26; p=0.010) were independent factor significantly associated with vascular complications or major bleeding. Mortality rate at 30 days follow-up was 2.3%, there was no myocardial infarction and stroke rate was 4.5%. Figure 1. Study flowchart TAVI with uninterrupted VKA treatment seems to be feasible and safe with low risk of bleeding and vascular complications in this first single centre experience. Particular caution is advocated in low BMI patients and to keep INR<2.5.

BACKGROUND:Dual-antiplatelet treatment (DAPT) has conventionally been prescribed for 1 year after percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation. Recent evidence suggests that a duration of only 6 months may be equally safe and effective when using contemporary DES options. OBJECTIVE:The aim of this study was to assess clinical outcomes in patients treated with the BioMatrix biodegradable-polymer coated biolimus-eluting stent (BP-BES; Biosensors International) who received only 6 months of DAPT. METHODS:This prospective "all-comers" registry enrolled 2038 patients in France. Following PCI, DAPT was started for a recommended period of 6 months. Patients were followed up at 6 and 24 months. The primary endpoint of major adverse cardiac and cerebrovascular event (MACCE) was a composite of all-cause death, cerebrovascular accidents, non-fatal myocardial infarction, or clinically driven target-vessel revascularization. Secondary endpoints included stent thrombosis (ST) and major bleeding (MB). RESULTS:The mean age of the study population was 67 ± 10.5 years and 77% of patients were male. Follow-up data were available in 96.9% and 95.3% of patients at 6 and 24 months, respectively. At 6 months, the incidences of MACCE, ST, and MB were 3.1%, 0.3%, and 0.4%, respectively. At 24 months, 21.2% of patients were still on DAPT and the cumulative incidences of MACCE, ST, and MB were 9.7%, 0.54%, and 0.79%, respectively. CONCLUSIONS:In this unselected population of patients undergoing PCI with a BP-BES, a 6-month duration of DAPT after implantation is safe and effective.

The Biolimus A9 polymer-free Biofreedom stent was shown to be superior to bare metal stents in terms of efficacy and safety in the randomized controlled clinical trial LEADERS FREE in high bleeding risk (HBR) patients treated by one-month DAPT. To assess prospectively the two-year clinical outcomes in a real-world population treated by coronary angioplasty with Biofreedom stents. 1502 patients (74% men, mean age 72 years) were enrolled in 26 French centers. 756 (50.33%) patients presented at least one criterion of HBR. Multi-lesion procedure was performed in 30% of patients with implantation of 1.56 stent/patient. Patients were followed by phone contact at 3, 12 and 24 months. The primary endpoint (device-oriented) was composed of cardiovascular death, myocardial infarction or clinically driven target lesion revascularization at 12 months. The secondary patient-oriented end point was a composite of all-cause death, any stroke, any myocardial infarction and any revascularization at 12 and 24 months. Further secondary endpoints were BARC 3 to 5 bleeding, or stent thrombosis. At 3-month and 12-month follow-up the primary composite end point was observed in 32 (2.14%) and 84 (6.2%) patients, respectively, including cardiovascular death in 17 (1.14%) and 24 (1.69%), myocardial infarction in 8 (0.54%) and 12 (0.85%), and clinical driven target lesion revascularization in 12 (0.85%) and 59 (4.51%) patients. Stent thrombosis occurred in 6 (0.4%) and 14 (1.02%) patients at three months and one year, and stroke was observed in 8 (0.54%) and in 13 (0.93%). Bleeding BARC 3 to 5 was observed in 17 (1.14%) and 32 (2.31%) at 3 and 12 months. Two-year follow up is currently ongoing. This prospective registry confirms the excellent safety and efficacy profile of the Biolimus A9 polymer-free Biofreedom stent in a real-world population of patients with ischemic heart disease treated by angioplasty.

Abstract Background Mesenchymal Stromal Cells (MSC) have been widely used for their therapeutic properties in many clinical applications including myocardial infarction. Despite promising preclinical results and evidences of safety and efficacy in phases I/ II, inconsistencies in phase III trials have been reported. In a previous study, we have shown using MSC derived from the bone marrow of PPARβ/δ (Peroxisome proliferator-activated receptors β/δ) knockout mice that the acute cardioprotective properties of MSC during the first hour of reperfusion are PPARβ/δ-dependent but not related to the anti-inflammatory effect of MSC. However, the role of the modulation of PPARβ/δ expression on MSC cardioprotective and anti-apoptotic properties has never been investigated. Objectives The aim of this study was to investigate the role of PPARβ/δ modulation (inhibition or activation) in MSC therapeutic properties in vitro and ex vivo in an experimental model of myocardial infarction. Methods and results Naïve MSC and MSC pharmacologically activated or inhibited for PPARβ/δ were challenged with H2O2. Through specific DNA fragmentation quantification and qRT-PCR experiments, we evidenced in vitro an increased resistance to oxidative stress in MSC pre-treated by the PPARβ/δ agonist GW0742 versus naïve MSC. In addition, PPARβ/δ-priming allowed to reveal the anti-apoptotic effect of MSC on cardiomyocytes and endothelial cells in vitro. When injected during reperfusion, in an ex vivo heart model of myocardial infarction, 3.75 × 105 PPARβ/δ-primed MSC/heart provided the same cardioprotective efficiency than 7.5 × 105 naïve MSC, identified as the optimal dose in our experimental model. This enhanced short-term cardioprotective effect was associated with an increase in both anti-apoptotic effects and the number of MSC detected in the left ventricular wall at 1 h of reperfusion. By contrast, PPARβ/δ inhibition in MSC before their administration in post-ischemic hearts during reperfusion decreased their cardioprotective effects. Conclusion Altogether these results revealed that PPARβ/δ-primed MSC exhibit an increased resistance to oxidative stress and enhanced anti-apoptotic properties on cardiac cells in vitro. PPARβ/δ-priming appears as an innovative strategy to enhance the cardioprotective effects of MSC and to decrease the therapeutic injected doses. These results could be of major interest to improve MSC efficacy for the cardioprotection of injured myocardium in AMI patients.

: Objectives. To evaluate prospectively the clinical impact of routine transmission of CYP2C19 genotype in the management of acute ST-elevation myocardial infarction (STEMI) with primary PCI. Background. Response to clopidogrel widely differ between patients, notably because of CYP2C19 genetic polymorphisms. Methods. CYP2C19 genotype (6 alleles) was determined centrally and communicated within ± 1.9 days of primary PCI in 1,445 STEMI patients recruited in in CYP2C19 metabolic status was predicted and served to adjust The primary endpoint was differences in 12-month (death, myocardial infarction and stent thrombosis) between with genotype or gain-of-function 1118) and patients with loss-of-function (LOF) allele N= who received thienopyridine the vast majority of LOF carriers and to similar clinical outcomes than in patients carrying a wild genotype or a gain-of-function allele. abstract Previous retrospective studies have shown an association between CYP2C19 loss of function (LOF) allele, present in up to 30 % of patients, and a higher risk of MACE after acute coronary syndrome or percutaneous intervention. The present study showed the feasibility of routine CYP2C19 genotyping in a cohort of all-comer STEMI patients treated with primary PCI. This technique allowed appropriate treatment adjustment in a vast majority of LOF patients with a significantly beneficial impact on the one-year rate of clinical composite endpoint compared to unadjusted LOF patients and no differences compared to patients with a wild or gain of function genotype. our results suggest that CYP2C19 genotype can be

Objectives To evaluate the rate of procedural success and long-term outcomes of the PK Papyrus (PKP) covered stent (CS). Background CS are essential in the treatment of coronary artery perforation (CAP). They have also been used to treat coronary artery aneurysms. Limited evidence is available on clinical outcomes with the PKP. Methods This was a multicenter, observational, retrospective, and prospective study. Consecutive patients undergoing intentional PKP implantation in 22 centers in France were included. The primary endpoint was the rate of procedural success. Secondary endpoints included rates of death, myocardial infarction (MI), target lesion revascularization (TLR), in-stent restenosis (ISR), and stent thrombosis (ST). Results Data from 130 patients were analyzed (mean age 72.5 +/- 10.5 years; 71% men). The main indication for PKP was CAP, in 84 patients (65%). Delivery success was achieved in 95% and procedural success in 91%. During the in-hospital stay, 15 patients died (12%) and 7 (5%) presented with ST. Data from 127 patients were available at 19.2 +/- 12.8 month follow-up. Thirty-three patients died (26%), 15 (12%) had an MI and 21 (17%) presented with TLR. TLR was due to ISR in 12 patients (9%), 10 had definite ST (8%) and 1 patient for stent under-expansion. Conclusions The principal indication for PKP was CAP. PKP had high rates of delivery and procedural success. At long-term follow-up, there was a high rate of TLR, mainly due to ISR and ST. These results are consistent with previously reported data in these clinical settings.

Myocardial infarction ranks first for the mortality worldwide. Because the adult heart is unable to regenerate, fibrosis develops to compensate for the loss of contractile tissue after infarction, leading to cardiac remodeling and heart failure. Adult mesenchymal stem cells (MSC) regenerative properties, as well as their safety and efficacy, have been demonstrated in preclinical models. However, in clinical trials, their beneficial effects are controversial. In an experimental model of arthritis, we have previously shown that PPARβ / δ deficiency enhanced the therapeutic effect of MSC. The aim of the present study was to compare the therapeutic effects of wild-type MSC (MSC) and MSC deficient for PPARβ / δ (KO MSC) perfused in an ex vivo mouse model of ischemia-reperfusion (IR) injury. For this purpose, hearts from C57BL/6J mice were subjected ex vivo to 30 min ischemia followed by 1-h reperfusion. MSC and KO MSC were injected into the Langendorff system during reperfusion. After 1 h of reperfusion, the TTC method was used to assess infarct size. Coronary effluents collected in basal condition (before ischemia) and after ischemia at 1 h of reperfusion were analyzed for their cytokine profiles. The dose-response curve for the cardioprotection was established ex vivo using different doses of MSC (3.10 5 , 6.10 5 , and 24.10 5 cells / heart) and the dose of 6.10 5 MSC was found to be the optimal concentration. We showed that the cardioprotective effect of MSC was PPARβ / δ-dependent since it was lost using KO MSC. Moreover, cytokine profiling of the coronary effluents collected in the eluates after 60 min of reperfusion revealed that MSC treatment decreases CXCL1 chemokine and interleukin-6 release compared with untreated hearts. This anti-inflammatory effect of MSC was also observed when hearts were treated with PPARβ / δ-deficient MSC. In conclusion, our study revealed that the acute cardioprotective properties of MSC in an ex vivo model of IR injury, assessed by a decreased infarct size at 1 h of reperfusion, are PPARβ / δ-dependent but not related to their anti-inflammatory effects.