Alain Furber

Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial.

AIM This open-label, randomized, and multicentre trial tested the hypothesis that, on a background of aspirin, continuing clopidogrel would be superior to stopping clopidogrel at 12 months following drug-eluting stent (DES) implantation. METHODS AND RESULTS Patients (N = 1799) who had undergone placement of ≥1 DES for stable coronary artery disease or acute coronary syndrome were included in 58 French sites (January 2009-January 2013). Patients (N = 1385) free of major cardiovascular/cerebrovascular events or major bleeding and on aspirin and clopidogrel 12 months after stenting were eligible for randomization (1:1) between continuing clopidogrel 75 mg daily (extended-dual antiplatelet therapy, DAPT, group) or discontinuing clopidogrel (aspirin group). The primary outcome was net adverse clinical events defined as the composite of death, myocardial infarction, stroke, or major bleeding. Follow-up was planned from a minimum of 6 to a maximum of 36 months after randomization. Owing to slow recruitment, the study was stopped after enrolment of 1385 of a planned 1966 patients. Median follow-up after stenting was 33.4 months. The primary outcome occurred in 40 patients (5.8%) in the extended-DAPT group and 52 in the aspirin group (7.5%; hazard ratio 0.75, 95% confidence interval 0.50-1.28; P = 0.17). Rates of death were 2.3% in the extended-DAPT group and 3.5% in the aspirin group (HR 0.65, 95% CI 0.34-1.22; P = 0.18). Rates of major bleeding were identical (2.0%, P = 0.95). CONCLUSIONS Extended DAPT did not achieve superiority in reducing net adverse clinical events compared to 12 months of DAPT after DES placement. The power of the OPTIDUAL trial was however low and reduced by premature termination of enrolment. CLINICALTRIALSGOV NUMBER NCT00822536.

Incomplete Resolution of ST-Segment Elevation Is a Marker of Transient Microcirculatory Dysfunction After Stenting for Acute Myocardial Infarction

Background—Incomplete ST-segment resolution (STR) after successful primary angioplasty for acute myocardial infarction (AMI) is associated with a poor prognosis. We used intracoronary Doppler velocimetry to investigate whether incomplete STR after primary angioplasty is a marker of severe microcirculatory dysfunction. Methods and Results—Fifty patients with ≤12-hour AMI underwent successful primary angioplasty and systematic stenting with a Doppler guidewire. Patients with incomplete (<50%) STR 60 minutes after TIMI 3 flow was restored had flow velocity features suggestive of severe microcirculatory dysfunction, including a higher incidence of early systolic retrograde flow (41% versus 9%, P =0.007) and lower coronary flow velocity reserve (CVR, 1.3 versus 1.6, P <0.001). CVR improved immediately after stenting in patients with ≥50% STR but not in patients with <50% STR. There was a significant correlation between STR and poststent CVR. At 3 months, CVR was similar in patients with <50% and ≥50% STR. However, left ventriculography indicated lower global (42% versus 55%, P =0.001) and regional (16% versus 20%, P =0.03) left ventricular ejection fractions and 201Tl rest-redistribution scintigraphy indicated a larger infarct size (34% versus 16% 201Tl defect, P =0.007) in patients with <50% STR. Conclusions—After successful primary angioplasty with systematic stenting, <50% STR is a marker of severe albeit transient microcirculatory dysfunction in patients with AMI and is associated with more extensive myocardial damage.

The French Randomized Optimal Stenting Trial: A Prospective Evaluation of Provisional Stenting Guided by Coronary Velocity Reserve and Quantitative Coronary Angiography

OBJECTIVES We sought to make a prospective comparison of systematic stenting with provisional stenting guided by Doppler measurements of coronary velocity reserve and quantitative coronary angiography. BACKGROUND Despite the increasing use of stents during percutaneous transluminal coronary angioplasty, it is unclear whether systematic stenting is superior to a strategy of provisional stenting in which stents are placed only in patients with unsatisfactory results or as a bail-out procedure. METHODS Two hundred fifty-one patients undergoing elective coronary angioplasty were randomly assigned either to provisional stenting (group 1, in which stenting was performed if postangioplasty coronary velocity reserve was <2.2 and/or residual stenosis > or =35% or as bail-out) or to systematic stenting (group 2). The primary end point was the six-month angiographic minimal lumen diameter (MLD). Major adverse cardiac events were secondary end points (death, acute myocardial infarction and target lesion revascularization). RESULTS Stenting was performed in 48.4% of patients in group 1 and 100% of patients in group 2 (p<0.01). Six months after angioplasty, the MLD did not differ between groups (1.90+/-0.79 mm vs. 1.99+/-0.70 mm, p = 0.39), as was the rate of binary restenosis (27.1% vs. 21.4%, p = 0.37). Among patients with restenosis, 13/32 (40.6%) in group 1 but 100% (25/25) in group 2 had in-stent restenosis (p<0.01). Target lesion revascularization (15.1% vs. 14.4% in groups 1 and 2 respectively, p = 0.89) and major adverse cardiac events (15.1% vs. 16.0%, p = 0.85) were not significantly different. CONCLUSIONS Systematic stenting does not provide superior angiographic results at six months as compared with provisional stenting.

Apolipoprotein A-I Is a Potential Mediator of Remote Ischemic Preconditioning

Background Remote ischemic preconditioning (RIPC) has emerged as an attractive strategy in clinical settings. Despite convincing evidence of the critical role played by circulating humoral mediators, their actual identities remain unknown. In this study, we aimed to identify RIPC-induced humoral mediators using a proteomic approach. Methods and Results Rats were exposed to 10-min limb ischemia followed by 5- (RIPC 5′) or 10-min (RIPC 10′) reperfusion prior to blood sampling. The control group only underwent blood sampling. Plasma samples were analyzed using surface-enhanced laser desorption and ionization - time of flight - mass spectrometry (SELDI-TOF-MS). Three protein peaks were selected for their significant increase in RIPC 10′. They were identified and confirmed as apolipoprotein A-I (ApoA-I). Additional rats were exposed to myocardial ischemia-reperfusion (I/R) and assigned to one of the following groups RIPC+myocardial infarction (MI) (10-min limb ischemia followed by 10-min reperfusion initiated 20 minutes prior to myocardial I/R), ApoA-I+MI (10 mg/kg ApoA-I injection 10 minutes before myocardial I/R), and MI (no further intervention). In comparison with untreated MI rats, RIPC reduced infarct size (52.2±3.7% in RIPC+MI vs. 64.9±2.6% in MI; p<0.05). Similarly, ApoA-I injection decreased infarct size (50.9±3.8%; p<0.05 vs. MI). Conclusions RIPC was associated with a plasmatic increase in ApoA-I. Furthermore, ApoA-I injection before myocardial I/R recapitulated the cardioprotection offered by RIPC in rats. This data suggests that ApoA-I may be a protective blood-borne factor involved in the RIPC mechanism.

Coronary Blood Flow Assessment After Successful Angioplasty for Acute Myocardial Infarction Predicts the Risk of Long-Term Cardiac Events

Background—Analysis of coronary flow velocity (CFV) in the recanalized infarct-related coronary artery (IRA) with a Doppler guidewire is useful for predicting recovery of regional left ventricular function, in-hospital complications, and survival. We postulated that the CFV pattern after IRA reperfusion for acute myocardial infarction (AMI) would predict long-term adverse cardiac events. Methods and Results—Sixty-eight consecutive patients with a first AMI underwent CFV measurement with a Doppler guidewire after successful reopening of the IRA by coronary angioplasty. At the end of follow-up, 3.8±1.7 years after AMI, 44 of the 65 surviving patients (67.7%) were free of long-term cardiac events. Univariate analysis showed that the following factors were predictive of an end point combining cardiac death, recurrent MI, and congestive heart failure: hypertension, age ≥65 years, time from onset of chest pain to PTCA ≥6 hours, peak creatine kinase >4000 IU/L, ejection fraction ≤50%, proximal left anterior descending artery occlusion, resting average peak velocity ≤10 cm/s, average systolic peak velocity ≤5 cm/s, a rapid diastolic deceleration time (≤600 ms), and early retrograde systolic flow. In the final multivariate model, only age ≥65 years (OR, 3.6; 95% CI, 1.1 to 11.8; P=0.03), time to PTCA ≥6 hours (OR, 2.9; 95% CI, 1.0 to 8.3; P=0.04), and a rapid diastolic deceleration time (OR, 5.4; 95% CI, 1.5 to 19.3; P=0.01) were independent predictors. Conclusions—The CFV pattern appears to be an accurate predictor of long-term cardiac events in patients having undergone successful reopening of the IRA after AMI, identifying a subset of at-risk patients.

Regional assessment of wall curvature and wall stress in left ventricle with magnetic resonance imaging

Left ventricular functional abnormalities are associated with regional increases of wall stress and modifications of wall curvature. This study describes the integration of the short-axis and long-axis wall curvatures for determining peak systolic wall stress. Quantification was realized with cine magnetic resonance imaging (MRI) from the location of the endocardial and epicardial borders of the left ventricle on pairs of consecutive short-axis sections. Fifteen normal volunteers were subjected to cine MRI, and different methods of calculating peak systolic wall stress were compared. A short-axis analysis showed a 55 +/- 13% increase of the circumferential mean of the peak systolic wall stress between apical and basal sections. Regarding the curvature, no significant increase of wall stress was observed except on the septal wall (31 +/- 18%). Short-axis studies proved to be insufficient for determining the regional variations of left ventricular wall stress and for providing normal reference values for the location of abnormal regions in patients.

No post-conditioning in the human heart with thrombolysis in myocardial infarction flow 2-3 on admission.

AIMS Proof-of-concept evidence suggests that mechanical ischaemic post-conditioning (PostC) reduces infarct size when applied immediately after culprit coronary artery re-opening in ST-elevation myocardial infarction (STEMI) patients with thrombolysis in myocardial infarction 0-1 (TIMI 0-1) flow grade at admission. Whether PostC might also be protective in patients with a TIMI 2-3 flow grade on admission (corresponding to a delayed application of the post-conditioning algorithm) remains undetermined. METHODS AND RESULTS In this multi-centre, randomized, single-blinded, controlled study, STEMI patients with a 2-3 TIMI coronary flow grade at admission underwent direct stenting of the culprit lesion, followed (PostC group) or not (control group) by four cycles of (1 min inflation/1 min deflation) of the angioplasty balloon to trigger post-conditioning. Infarct size was assessed both by cardiac magnetic resonance at Day 5 (primary endpoint) and cardiac enzymes release (secondary endpoint). Ninety-nine patients were prospectively enrolled. Baseline characteristics were comparable between control and PostC groups. Despite comparable size of area at risk (AAR) (38 ± 12 vs. 38 ± 13% of the LV circumference, respectively, P = 0.89) and similar time from onset to intervention (249 ± 148 vs. 263 ± 209 min, respectively, P = 0.93) in the two groups, PostC did not significantly reduce cardiac magnetic resonance infarct size (23 ± 17 and 21 ± 18 g in the treated vs. control group, respectively, P = 0.64). Similar results were found when using creatine kinase and troponin I release, even after adjustment for the size of the AAR. CONCLUSION This study shows that infarct size reduction by mechanical ischaemic PostC is lost when applied to patients with a TIMI 2-3 flow grade at admission. This indicates that the timing of the protective intervention with respect to the onset of reperfusion is a key factor for preventing lethal reperfusion injury in STEMI patients. CLINICAL TRIAL NUMBER NCT01483755.

Three-dimensional coronary artery mr imaging using prospective real-time respiratory navigator and linear phase shift processing : Comparison with conventional coronary angiography

Respiratory gating with navigator echo is a recent technique to detect diaphragm position in 3D magnetic resonance (MR) coronary angiography. The purpose of our study was to image proximal coronary arteries and to detect significant stenoses in patients with coronary artery diseases and to compare with contrast enhanced angiography results. Twenty patients with coronary artery diseases who were referred for conventional angiography underwent magnetic resonance angiography (MRA). Three-dimensional gradient echo volumes were acquired using cardiac and respiratory gating and fat suppression. Using reformatted oblique planes and maximum intensity projection technique, visualization coronary segments and detection of significant coronary stenoses were made. Eighty-three coronary segments were analyzed. The sensitivity and specificity were 65% and 93%, respectively. The corresponding positive and negative predictive values were 69% and 91%. This study shows the ability to image correctly coronary arteries and to identify proximal stenoses, but image quality need to be improved for an efficiency detection of coronary artery stenoses in clinical practice.

Myocardial reperfusion injury management: erythropoietin compared with postconditioning

Ischemic postconditioning (IPost) and erythropoietin (EPO) have been shown to attenuate myocardial reperfusion injury using similar signaling pathways. The aim of this study was to examine whether EPO is as effective as IPost in decreasing postischemic myocardial injury in both Langendorff-isolated-heart and in vivo ischemia-reperfusion rat models. Rat hearts were subjected to 25 min ischemia, followed by 30 min or 2 h of reperfusion in the isolated-heart study. Rats underwent 45 min ischemia, followed by 24 h of reperfusion in the in vivo study. In both studies, the control group (n=12; ischemia-reperfusion only) was compared with IPost (n=16; 3 cycles of 10 s reperfusion/10 s ischemia) and EPO (n=12; 1,000 IU/kg) at the onset of reperfusion. The following resulted. First, in the isolated hearts, IPost or EPO significantly improved postischemic recovery of left ventricular developed pressure. EPO induced better left ventricular developed pressure than IPost at 30 min of reperfusion (73.18+/-10.23 vs. 48.11+/-7.92 mmHg, P<0.05). After 2 h of reperfusion, the infarct size was significantly lower in EPO-treated hearts compared with IPost and control hearts (14.36+/-0.60%, 19.11+/-0.84%, and 36.21+/-4.20% of the left ventricle, respectively; P<0.05). GSK-3beta phosphorylation, at 30 min of reperfusion, was significantly higher with EPO compared with IPost hearts. Phosphatidylinositol 3-kinase and ERK1/2 inhibitors abolished both EPO- and IPost-mediated cardioprotection. Second, in vivo, IPost and EPO induced an infarct size reduction compared with control (40.5+/-3.6% and 28.9+/-3.1%, respectively, vs. 53.7+/-4.3% of the area at risk; P<0.05). Again, EPO decreased significantly more infarct size and transmurality than IPost (P<0.05). In conclusion, with the use of our protocols, EPO showed better protective effects than IPost against reperfusion injury through higher phosphorylation of GSK-3beta.

Role of hypoxia inducible factor-1α in remote limb ischemic preconditioning

Remote ischemic preconditioning (RIPC) has emerged as a feasible and attractive therapeutic procedure for heart protection against ischemia/reperfusion (I/R) injury. However, its molecular mechanisms remain poorly understood. Hypoxia inducible factor-1α (HIF-1α) is a transcription factor that plays a key role in the cellular adaptation to hypoxia and ischemia. This studys aim was to test whether RIPC-induced cardioprotection requires HIF-1α upregulation to be effective. In the first study, wild-type mice and mice heterozygous for HIF1a (gene encoding the HIF-1α protein) were subjected to RIPC immediately before myocardial infarction (MI). RIPC resulted in a robust HIF-1α activation in the limb and acute cardioprotection in wild-type mice. RIPC-induced cardioprotection was preserved in heterozygous mice, despite the low HIF-1α expression in their limbs. In the second study, the role of HIF-1α in RIPC was evaluated using cadmium (Cd), a pharmacological HIF-1α inhibitor. Rats were subjected to MI (MI group) or to RIPC immediately prior to MI (R-MI group). Cd was injected 18 0min before RIPC (Cd-R-MI group). RIPC induced robust HIF-1α activation in rat limbs and significantly reduced infarct size (IS). Despite Cds inhibition of HIF-1α activation, RIPC-induced cardioprotection was preserved in the Cd-R-MI group. RIPC applied immediately prior to MI increased HIF-1α expression and attenuated IS in rats and wild-type mice. However, RIPC-induced cardioprotection was preserved in partially HIF1a-deficient mice and in rats pretreated with Cd. When considered together, these results suggest that HIF-1α upregulation is unnecessary in acute RIPC.