Long-term follow-up of balloon-expandable valves according to the implantation strategy: insight from the DIRECTAVI trial.

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 (NCT02729519). 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 ≥ moderate aortic regurgitation). 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 balloon-expandable valve implantation, when feasible. CLINICAL TRIALS REGISTRATION NUMBER: NCT05140317.

Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing.

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.

In-Hospital and 1-Year Clinical Results from the French Registry Using Polymer-Free Sirolimus-Eluting Stents in Acute Coronary Syndrome and Stable Coronary Artery Disease.

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.

Heart rate reduction after genetic ablation of L-type Cav1.3 channels induces cardioprotection against ischemia-reperfusion injury.

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.

A prospective study comparing short versus standard dual antiplatelet therapy in patients with acute myocardial infarction: design and rationale of the TARGET-FIRST trial.

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.

Transcatheter aortic valve implantation in patients with uninterrupted vitamin K antagonists.

BACKGROUND: 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 transcatheter aortic valve implantation (TAVI). PURPOSE: The aim of this study was to evaluate the rate of major bleeding and vascular complications after TAVI performed in patients with uninterrupted VKA. METHODS: From January 2016 to October 2017, consecutive patients who underwent TAVI with uninterrupted VKA (International Normalized Ratio [INR] between 1.5 and 3.5) were prospectively included in a monocentric registry. TAVI was performed according to current guidelines and a 50 U/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 3 (VARC3) and the Bleeding Academic Research Consortium (BARC) definitions at a 30-day follow-up. RESULTS: A total of 88 patients were included with a median age of 84 years (81.8-87.0), 42% being female. The median society of thoracic surgeons 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 the time of implantation was 2.1 (1.8-2.6). The main VKA indication was atrial fibrillation. Transfemoral access was used in 88.6% of the patients. Major bleeding (BARC ≥ 3b) occurred in five patients (5.7%) and major vascular complications occurred in seven patients (8.0%). At 1 month follow-up, major bleeding (BARC ≥ 3) or vascular complications occurred in 10 patients (11.4%). In patients with major bleeding peripheral arterial disease (RR = 10.95; 95% confidence interval (CI) 1.63-73.75; p = 0.014) and carotid access (RR = 8.56; 95% CI 1.19-1.51; p = 0.033) were more common. INR > 2.5 was significantly associated with vascular complications (RR = 7.14; 95% CI 1.29-39.63; p = 0.025). At 30 days, mortality and stroke rates were 2.3% and 4.5%, respectively. CONCLUSION: TAVI with uninterrupted VKA treatment seems feasible and safe with a low risk of major bleeding and vascular complications in this first single-center experience. Particular caution is advocated in high body mass index patients and to keep INR < 2.5.

PPARß/δ priming enhances the anti-apoptotic and therapeutic properties of mesenchymal stromal cells in myocardial ischemia-reperfusion injury.

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 PPARß/δ (Peroxisome proliferator-activated receptors ß/δ) knockout mice that the acute cardioprotective properties of MSC during the first hour of reperfusion are PPARß/δ-dependent but not related to the anti-inflammatory effect of MSC. However, the role of the modulation of PPARß/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 PPARß/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 PPARß/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 PPARß/δ agonist GW0742 versus naïve MSC. In addition, PPARß/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 PPARß/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, PPARß/δ inhibition in MSC before their administration in post-ischemic hearts during reperfusion decreased their cardioprotective effects. CONCLUSION: Altogether these results revealed that PPARß/δ-primed MSC exhibit an increased resistance to oxidative stress and enhanced anti-apoptotic properties on cardiac cells in vitro. PPARß/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.

Clinical Outcomes in Patients Treated With Biodegradable-Polymer Biolimus-Eluting Stents and 6 Months of Dual-Antiplatelet Therapy: The French eBiomatrix 6-Month DAPT Registry.

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.

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).

PPARß/δ Is Required for Mesenchymal Stem Cell Cardioprotective Effects Independently of Their Anti-inflammatory Properties in Myocardial Ischemia-Reperfusion Injury.

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 PPARß/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 PPARß/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 (3.105, 6.105, and 24.105 cells/heart) and the dose of 6.105 MSC was found to be the optimal concentration. We showed that the cardioprotective effect of MSC was PPARß/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 PPARß/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 PPARß/δ-dependent but not related to their anti-inflammatory effects.

Use and outcomes of the PK Papyrus covered stent in France: SOS PK Papyrus Registry.

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 Injury After Balloon Predilatation Versus Direct Transcatheter Aortic Valve Replacement: Insights From the DIRECTAVI Trial.

Background Myocardial injury is associated with higher mortality after transcatheter aortic valve replacement (TAVR) and might be increased by prior balloon aortic valvuloplasty (BAV). We aimed to evaluate the impact of prior BAV versus direct prosthesis implantation on myocardial injury occurring after (TAVR) with balloon-expandable prostheses. Methods and Results The DIRECTAVI (Direct Transcatheter Aortic Valve Implantation) trial, an open-label randomized study, demonstrated noninferiority of TAVR without BAV (direct TAVR group) compared with systematic BAV (BAV group) with the Edwards SAPIEN 3 valve. High-sensitivity troponin was assessed before and the day after the procedure. Incidence of myocardial injury after the procedure (high-sensitivity troponin elevation >15× the upper reference limit [14 ng/L]) was the main end point. Impact of myocardial injury on 1-month adverse events (all-cause mortality, stroke, major bleeding, major vascular complications, transfusion, acute kidney injury, heart failure, pacemaker implantation, and aortic regurgitation) was evaluated. Preprocedure and postprocedure high-sensitivity troponin levels were available in 211 patients. The mean age of patients was 83 years (78-87 years), with 129 men (61.1%). Mean postprocedure high-sensitivity troponin was 124.9±81.4 ng/L in the direct TAVR group versus 170.4±127.7 ng/L in the BAV group (P=0.007). Myocardial injury occurred in 42 patients (19.9%), including 13 patients (12.2%) in the direct TAVR group and 29 (27.9%) in the BAV group (P=0.004). BAV increased by 2.8-fold (95% CI, 1.4-5.8) myocardial injury probability. Myocardial injury was associated with 1-month adverse events (P=0.03). Conclusions BAV increased the incidence and magnitude of myocardial injury after TAVR with new-generation balloon-expandable valves. Myocardial injury was associated with 1-month adverse events. These results argue in favor of direct SAPIEN 3 valve implantation. Registration URL: https://www.Clinicaltrials.gov; Unique identifier: NCT02729519.

Anti-apoptotic peptide for long term cardioprotection in a mouse model of myocardial ischemia-reperfusion injury.

Reperfusion therapy during myocardial infarction (MI) leads to side effects called ischemia-reperfusion (IR) injury for which no treatment exists. While most studies have targeted the intrinsic apoptotic pathway to prevent IR injury with no successful clinical translation, we evidenced recently the potent cardioprotective effect of the anti-apoptotic Tat-DAXXp (TD) peptide targeting the FAS-dependent extrinsic pathway. The aim of the present study was to evaluate TD long term cardioprotective effects against IR injury in a MI mouse model. TD peptide (1 mg/kg) was administered in mice subjected to MI (TD; n = 21), 5 min prior to reperfusion, and were clinically followed-up during 6 months after surgery. Plasma cTnI concentration evaluated 24 h post-MI was 70%-decreased in TD (n = 16) versus Ctrl (n = 20) mice (p***). Strain echocardiography highlighted a 24%-increase (p****) in the ejection fraction mean value in TD-treated (n = 12) versus Ctrl mice (n = 17) during the 6 month-period. Improved cardiac performance was associated to a 54%-decrease (p**) in left ventricular fibrosis at 6 months in TD (n = 16) versus Ctrl (n = 20). In conclusion, targeting the extrinsic pathway with TD peptide at the onset of reperfusion provided long-term cardioprotection in a mouse model of myocardial IR injury by improving post-MI cardiac performance and preventing cardiac remodeling.

Routine CYP2C19 Genotyping to Adjust Thienopyridine Treatment After Primary PCI for STEMI: Results of the GIANT Study.

OBJECTIVES: The aim of this study was to evaluate prospectively the clinical impact of routine transmission of CYP2C19 genotype in the management of acute ST-segment elevation myocardial infarction with primary percutaneous coronary intervention. BACKGROUND: Response to clopidogrel differs widely among patients, notably because of CYP2C19 genetic polymorphisms. METHODS: CYP2C19 genotype (6 alleles) was determined centrally and communicated within 4.1 ± 1.9 days of primary percutaneous coronary intervention in 1,445 patients with ST-segment elevation myocardial infarction recruited at 57 centers in France. CYP2C19 metabolic status was predicted from genotype and served to adjust thienopyridine treatment. The primary endpoint was differences in 12-month outcomes (death, myocardial infarction, and stent thrombosis) between patients with the wild-type genotype or gain-of-function allele (class 1, n = 1,118) and those with loss-of-function (LOF) alleles (class 2, n = 272) who received optimized thienopyridine treatment. RESULTS: Detection of LOF alleles resulted in adjustment of P2Y12 inhibition in 85% of patients, with significantly higher use of prasugrel or double-dose clopidogrel. The primary endpoint did not differ between class 1 and class 2 patients (3.31% vs. 3.04%, respectively; p = 0.82). In contrast, carriers of LOF alleles without treatment adjustment had significantly worse outcomes (15.6%; p < 0.05). Bleeding rates were not different between groups. CONCLUSIONS: In a real-world setting, a complete CYPC2C19 genotype can be mostly determined in <7 days using analysis of saliva deoxyribonucleic acid collected during the in-hospital phase among patients with ST-segment elevation myocardial infarction treated with primary percutaneous coronary intervention. Genotype information led to stronger platelet inhibition treatment in the vast majority of LOF allele carriers and to similar clinical outcomes as in patients carrying the wild-type genotype or gain-of-function allele. (Genotyping Infarct Patients to Adjust and Normalize Thienopyridine Treatment [GIANT]; NCT01134380).

Unrestricted use of polymer-free sirolimus eluting stents in routine clinical practice.

Stent designs with ultrathin struts may further increase the procedural success of challenging lesion subsets. The objective of this study was to assess the safety and efficacy of ultrathin strut, polymer-free sirolimus eluting stent (PF-SES) implantations in a large scale, unselected patient population.Adult patients underwent percutaneous coronary interventions (PCI) with a thin-strut PF-SES. Data from two all-comers observational studies having the same protocol (ClinicalTrials.gov Identifiers: NCT02629575 and NCT02905214) were pooled. The accumulated target lesion revascularization (TLR) rate at 9-12 months was the primary endpoint. All dual antiplatelet therapy strategies according to the applicable guidelines were permissible.In total, 7243 patients were prospectively enrolled for PCI with PF-SES in stable coronary artery disease or acute coronary syndrome (ACS). Major risk factors in the overall cohort were diabetes (37.3%), ST elevation myocardial infarction (18.1%) and non-ST myocardial infarction (24.6%). The follow-up rate was 88.6% in the overall population. The TLR rate in the overall cohort was 2.2% whereas definite/probable stent thrombosis (ST) occurred in 0.7%. In patients with in-stent restenosis lesions, the major adverse cardiac events rate was 6.4% whereas the corresponding rate for isolated left main coronary artery (LMCA) disease was highest with 6.7% followed by patients with culprit lesions in vein bypasses (VB, 7.1%). The mortality rate in patients treated in VB lesions was highest with 5.4%, followed by the isolated LMCA subgroup (3.4%) and ACS (2.6%).PCI with PF-SES in an unselected patient population, is associated with low clinical event and ST rates. Furthermore, PF-SES angioplasty in niche indications demonstrated favorable safety and efficacy outcomes with high procedural success rates.

Polymer-free sirolimus-eluting stent use in Europe and Asia: Ethnic differences in demographics and clinical outcomes.

BACKGROUND: The objective of this study was to assess regional and ethnic differences in an unselected patient population treated with polymer-free sirolimus-eluting stents (PF-SES) in Asia and Europe. METHODS: Two all-comers observational studies based on the same protocol (ClinicalTrials.gov Identifiers: NCT02629575 and NCT02905214) were combined for data analysis to assure sufficient statistical power. The primary endpoint was the accumulated target lesion revascularization (TLR) rate at 9-12 months. RESULTS: Of the total population of 7243 patients, 44.0% (3186) were recruited in the Mediterranean region and 32.0% (2317) in central Europe. The most prominent Asian region was South Korea (17.6%, 1274) followed by Malaysia (5.7%, 413). Major cardiovascular risk factors varied significantly across regions. The overall rates for accumulated TLR and MACE were low with 2.2% (140/6374) and 4.4% (279/6374), respectively. In ACS patients, there were no differences in terms of MACE, TLR, MI and accumulated mortality between the investigated regions. Moreover, dual antiplatelet therapy (DAPT) regimens were substantially longer in Asian countries even in patients with stable coronary artery disease as compared to those in Europe. CONCLUSIONS: PF-SES angioplasty is associated with low clinical event rates in all regions. Further reductions in clinical event rates seem to be associated with longer DAPT regimens.

A novel therapeutic peptide targeting myocardial reperfusion injury.

AIMS: Regulated cell death is a main contributor of myocardial ischaemia-reperfusion (IR) injury during acute myocardial infarction. In this context, targeting apoptosis could be a potent therapeutical strategy. In a previous study, we showed that DAXX (death-associated protein) was essential for transducing the FAS-dependent apoptotic signal during IR injury. The present study aims at evaluating the cardioprotective effects of a synthetic peptide inhibiting FAS:DAXX interaction. METHODS AND RESULTS: An interfering peptide was engineered and then coupled to the Tat cell penetrating peptide (Tat-DAXXp). Its internalization and anti-apoptotic properties were demonstrated in primary cardiomyocytes. Importantly, an intravenous bolus injection of Tat-DAXXp (1 mg/kg) 5 min before reperfusion in a murine myocardial IR model decreased infarct size by 48% after 24 h of reperfusion. In addition, Tat-DAXXp was still efficient after a 30-min delayed administration, and was completely degraded and eliminated within 24 h thereby reducing risks of potential side effects. Importantly, Tat-DAXXp reduced mouse early post-infarction mortality by 67%. Mechanistically, cardioprotection was supported by both anti-apoptotic and pro-survival effects, and an improvement of myocardial functional recovery as evidenced in ex vivo experiments. CONCLUSIONS: Our study demonstrates that a single dose of Tat-DAXXp injected intravenously at the onset of reperfusion leads to a strong cardioprotection in vivo by inhibiting IR injury validating Tat-DAXXp as a promising candidate for therapeutic application.