Christophe Tron

Ischemic preconditioning protects against coronary endothelial dysfunction induced by ischemia and reperfusion.

BACKGROUNDnRepetitive, brief periods of ischemia and reperfusion (preconditioning) increase the resistance of myocardial tissue to subsequent prolonged ischemic episodes and limit infarct size. We investigated whether preconditioning also protects against coronary endothelial dysfunction induced by ischemia and reperfusion.nnnMETHODS AND RESULTSnExperiments were performed in four groups of rats (n = 8 in each group): group 1 rats underwent sham surgery, group 2 rats were subjected to 20 minutes of left coronary artery occlusion without reperfusion, group 3 rats underwent 20 minutes of occlusion followed by 1 hour of reperfusion, and group 4 rats (preconditioning group) underwent the same protocol as group 3 rats, preceded by three cycles of 5 minutes of ischemia and 5 minutes of reperfusion. At the end of the experiments, coronary segments (internal diameter, 250 to 300 microns) were removed distal to the occlusion site and mounted in wire myographs for isometric tension recording. Relaxations induced by increasing concentrations of acetylcholine, the calcium ionophore A23187, or the nitric oxide (NO) donor SIN-1 were determined in arteries precontracted by serotonin. Basal NO release was estimated by measuring contractions to NG-nitro L-arginine methyl ester (L-NAME). In addition, we determined the effect of preconditioning on infarct size in two additional groups that were subjected to the same protocols as those of groups 3 and 4. In those animals, area at risk (India ink injection) and infarct size (triphenyltetrazolium stain) were determined by computerized analysis of enlarged sections after video acquisition. Preconditioning markedly limited infarct size (percent of area at risk: controls, 57 +/- 2; preconditioning, 2.2 +/- 0.6; P < .01). Ischemia (without or with reperfusion) or preconditioning did not affect the coronary responses to L-NAME, serotonin, A23187, or SIN-1. Ischemia without reperfusion did not modify the relaxations to acetylcholine (maximal relaxation: sham, 58 +/- 4%; ischemia, 56 +/- 7%; P = NS). In contrast, ischemia followed by reperfusion markedly impaired the response to acetylcholine (26 +/- 6%; P < .01 versus sham). This impaired response was restored by preconditioning (maximal relaxation: 59 +/- 9%; P = NS versus sham; P < .01 versus ischemia/reperfusion).nnnCONCLUSIONSnIn addition to protecting myocardial cells, preconditioning also protects coronary endothelial cells against ischemia/reperfusion injury.

Balloon angioplasty for the treatment of coronary in-stent restenosis : Immediate results and 6-month angiographic recurrent restenosis rate

OBJECTIVESnThe purpose of this prospective study was to evaluate the immediate results and the 6-month angiographic recurrent restenosis rate after balloon angioplasty for in-stent restenosis.nnnBACKGROUNDnDespite excellent immediate and mid-term results, 20% to 30% of patients with coronary stent implantation will present an angiographic restenosis and may require additional treatment. The optimal treatment for in-stent restenosis is still unclear.nnnMETHODSnQuantitative coronary angiography (QCA) analyses were performed before and after stent implantation, before and after balloon angioplasty for in-stent restenosis and on a 6-month systematic coronary angiogram to assess the recurrent angiographic restenosis rate.nnnRESULTSnBalloon angioplasty was performed in 52 patients presenting in-stent restenosis. In-stent restenosis was either diffuse (> or =10 mm) inside the stent (71%) or focal (29%). Mean stent length was 16+/-7 mm. Balloon diameter of 2.98+/-0.37 mm and maximal inflation pressure of 10+/-3 atm were used for balloon angioplasty. Angiographic success rate was 100% without any complication. Acute gain was lower after balloon angioplasty for in-stent restenosis than after stent implantation: 1.19+/-0.60 mm vs. 1.75+/-0.68 mm (p=0.0002). At 6-month follow-up, 60% of patients were asymptomatic and no patient died. Eighteen patients (35%) had repeat target vessel revascularization. Angiographic restenosis rate was 54%. Recurrent restenosis rate was higher when in-stent restenosis was diffuse: 63% vs. 31% when focal, p=0.046.nnnCONCLUSIONSnAlthough balloon angioplasty for in-stent restenosis can be safely and successfully performed, it leads to less immediate stenosis improvement than at time of stent implantation and carries a high recurrent angiographic restenosis rate at 6 months, in particular in diffuse in-stent restenosis lesions.

A new treatment for severe pulmonary embolism: percutaneous rheolytic thrombectomy.

BACKGROUNDnThe rheolytic thrombectomy catheter has been specially designed to remove intravascular thrombus from coronary and peripheral arteries. It demonstrates a practical application of Bernoullis principle relating to a low-pressure zone in the region of a high-velocity jet. In this device, this effect is created by direct high-pressure saline jets located at the tip. Thrombus is drawn into this region and, because of the large pressure difference, undergoes mechanical thrombolysis due to the powerful mixing forces. The resulting microparticles are aspirated through the same catheter and removed from the body.nnnMETHODS AND RESULTSnWe report the use of this device in two patients presenting with severe pulmonary embolism and contraindications to thrombolytic therapy. The two procedures were successfully performed with an excellent immediate angiographic result at the site of the rheolytic thrombectomy. In both cases, the clinical improvement was maintained at follow-up with the same good angiographic result and a decrease to a normal level of the systolic pulmonary pressure.nnnCONCLUSIONSnThis preliminary results suggest that this easy technical method may be useful in the treatment of life-threatening pulmonary embolism in patients with absolute contraindications to thrombolytic therapy. A larger cohort of patients is necessary to determine whether this treatment should be proposed as an alternative to the use of fibrinolytics in selected patients.

Frequency of Conduction Disturbances After Transcatheter Implantation of an Edwards Sapien Aortic Valve Prosthesis

We evaluated the incidence of conduction abnormalities and requirement for permanent pacemaker in patients undergoing transcatheter aortic valve implantation (TAVI) with the Edwards Sapien prosthesis. In 2009, >8,000 patients were treated with TAVI using 1 of the 2 commercialized models of bioprosthesis (Edwards Sapien, Edwards Lifesciences, Irvine, California; and CoreValve, Medtronic, Irvine, California). Occurrence of conduction abnormalities including complete atrioventricular block requiring permanent pacemaker has been reported after TAVI with the 2 models of valve, more frequently with the CoreValve. We analyzed standard 12-lead electrocardiograms of 69 consecutive patients in whom an Edwards Sapien prosthesis was successfully implanted. Electrocardiograms were examined before treatment, at day 1, and at 1-month follow-up. Heart rate, PR and QT intervals and QRS duration were measured and the presence of a first-, second-, or third-degree atrioventricular block was documented. There was a slight increase in heart rate and a discrete decrease in QT interval at day 1. These values had returned to baseline values at 1 month. There was no change in PR interval but a transitory increase in QRS duration was noted. Frequency of left bundle branch block increased from 14.5% at baseline to 27.5% at day 1 with a decreased incidence at day 30 (21.3%). Permanent pacemaker was required in only 3 patients (4.3%). In conclusion, in our experience, conductive disorders and requirement of a definitive pacemaker after implantation of an Edwards Sapien aortic bioprosthesis are infrequent. The physical properties of this prosthesis may explain this observation.

Role of endogenous endothelin in myocardial and coronary endothelial injury after ischaemia and reperfusion in rats: studies with bosentan, a mixed ETA-ETB antagonist

1 Previous studies suggested that endothelin‐1 (ET‐1) may play a role in myocardial ischaemia and reperfusion. This study was designed to test the effect of a new nonpeptide antagonist of endothelin ETA and ETB receptors, bosentan, on myocardial infarct size, ventricular arrhythmias, and coronary endothelial dysfunction after ischaemia and reperfusion. 2 Anaesthetized male Wistar rats were subjected to 20min ischaemia (left coronary artery occlusion) followed by 1 h (for the evaluation of coronary endothelial dysfunction) or 2 h (for the evaluation of infarct size) reperfusion, or 5 min ischaemia followed by 15 min reperfusion (for the evaluation of reperfusion arrhythmias). Vascular studies were performed on 1.5‐2 mm coronary segments (internal diameter 250–300 μm) removed distal to the site of occlusion and mounted in wire myographs for isometric tension recording. Area at risk and infarct size were determined by Indian ink injection and triphenyl tetrazolium staining, using computerized analysis of enlarged sections after colour video acquisition. 3 Bosentan, administered at a dose which virtually abolished the pressor response to big ET‐1 (3 mg kg−1, i.v. before ischaemia) did not affect heart rate, arterial pressure or the rate pressure product before ischaemia, during ischaemia and during reperfusion. Bosentan did not affect the incidence of reperfusion‐induced ventricular fibrillation (controls: 86%, n = 14; bosentan: 93%, n = 15), and did not modify infarct size (% of area at risk: controls: 63 ± 4, n = 10; bosentan: 60 ± 6, n = 8). Ischaemia followed by reperfusion markedly reduced the endothelium‐dependent relaxations to acetylcholine (maximal response: sham: 59 ± 4%, n = 9; ischaemia‐reperfusion: 26 ± 6%, n = 8; P < 0.01), characteristic of reperfusion‐induced endothelial dysfunction, and this dysfunction was not prevented by bosentan (maximal response to acetylcholine: 25 ± 5%, n = 9; P < 0.01 vs sham; P = NS vs ischaemia/reperfusion). 4 These experiments suggest that endogenous endothelin does not contribute to myocyte or coronary endothelial injury in this rat model of ischaemia and reperfusion.

Transcatheter aortic valve implantation: technical aspects, results and indications.

The development of the percutaneous heart valve (PHV) may become a primary therapeutic modality for the high risk and inoperable patients with critical symptomatic aortic stenosis. The first human percutaneous aortic valve implant was performed by our group in April 2002. To date, more than 500 Cribier-Edwards-PHV have been implanted worldwide using arterial trans-femoral or trans-apical approach. Data on the retrograde transfemoral approach is growing with more than 270 patients implanted as of October 2007. Procedural success rate is high (86%) and the 30-day mortality is 12%. Today, 2 patients are alive at a follow-up of more than 4 years. The same Cribier-Edwards-PHV can be implanted using trans-apical approach. In this procedure, PHV is introduced under direct vision into the left ventricle via a mini-thoracotomy. This obviates the concerns regarding vascular access in the presence of small caliber vessels and/or vascular occlusive disease. More than 200 patients have been treated with this approach. In the European experience 30-day mortality is 14%. There is intense interest in PHV technology, and there are multiple devices at various stages of development in animals and humans. The most developed is the CoreValve Revalving Technology. More than 350 patients have been treated with this technique. The immediate and mid-term results with this device are promising with a procedural success of 92% and a 30-day mortality of 15%. The future of this technology and its application is dependent on the continued collaboration between general internists, cardiologists, surgeons, engineers, and industry.

Myocardial and coronary endothelial protective effects of acetylcholine after myocardial ischaemia and reperfusion in rats: role of nitric oxide

1 Recent experiments suggest that acetylcholine (ACh) may exert myocardial protective effects during ischaemia (I) and reperfusion (R). The present study was designed (i) to assess whether ACh limits infarct size and protects coronary endothelial cells in a rat model of I and R, (ii) to evaluate the role of ATP‐sensitive potassium (KATP) channels and nitric oxide (NO) in the beneficial effect of ACh (iii) to evaluate whether the protective effect of ACh also extends to coronary endothelial cells and (iv) to assess whether ACh contributes to the beneficial effect of preconditioning. 2 Anaesthetized rats were subjected to 20 min I (left coronary artery occlusion) and 2 h of R. Infarct size was assessed by triphenyltetrazolium (TTC) staining and expressed as a % of the area at risk (India ink injection). Vascular studies were performed on 1.5–2 mm coronary segments (internal diameter 250–300 μm) removed distal to the site of occlusion and mounted in wire myographs. 3 ACh limited infarct size (from 59 ± 3 to 26 ± 5%, P < 0.01), and this was prevented by atropine (46 ± 7%; P < 0.05 vs ACh), but not by the inhibitor of KATP channels, glibenclamide (29 ± 8%). The inhibitor of NO synthesis NG‐nitro l‐arginine did not affect infarct size (54 ± 5%) but abolished the beneficial effect of ACh (59 ± 8%; P < 0.05 vs ACh), whereas the NO donor 3‐morpholinosydnonimine‐N‐ethylcarbamide (SIN‐1 limited infarct size to the same extent as ACh (28 ± 6%). Preconditioning also limited infarct size (5 ± 2%, P < 0.01 vs control), and this was not affected by atropine (6 ± 2%). I and R induced a significant decrease in the endothelium‐dependent relaxations of isolated coronary arteries to ACh (maximal response: sham: 58 ± 4; I/R: 25 ± 5%; P < 0.01) and this dysfunction was prevented by prior in vivo treatment with ACh (55 ± 7%; P < 0.01 vs I/R) or (SIN‐1 50 ± 5%; P < 0.05 vs I/R). 4 Thus, in the rat model, ACh is able to stimulate potent endogenous protective mechanisms during I and R, which are evident both at the level of myocardial and coronary endothelial cells, and appear entirely mediated through the production of NO. Pharmacological stimulation of this endogenous protective mechanism may constitute a new approach in the treatment of acute myocaridal ischaemia.

Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement: The Randomized BRAVO-3 Trial.

BACKGROUNDnAnticoagulation is required during transcatheter aortic valve replacement (TAVR) procedures. Although an optimal regimen has not been determined, heparin is mainly used. Direct thrombin inhibition with bivalirudin may be an effective alternative to heparin as the procedural anticoagulant agent in this setting.nnnOBJECTIVESnThe goal of this study was to determine whether bivalirudin offers an alternative to heparin as the procedural anticoagulant agent in patients undergoing TAVR.nnnMETHODSnA total of 802 patients with aortic stenosis were randomized to undergo transfemoral TAVR with bivalirudin versus unfractionated heparin during the procedure. The 2 primary endpoints were major bleeding within 48 h or before hospital discharge (whichever occurred first) and 30-day net adverse clinical events, defined as the combination of major adverse cardiovascular events (all-cause mortality, myocardial infarction, or stroke) and major bleeding.nnnRESULTSnAnticoagulation with bivalirudin versus heparin did not meet superiority because it did not result in significantly lower rates of major bleeding at 48 h (6.9% vs. 9.0%; relative risk: 0.77; 95% confidence interval [CI]: 0.48 to 1.23; p = 0.27) or net adverse cardiovascular events at 30 days (14.4% vs. 16.1%; relative risk: 0.89; 95% CI: 0.64 to 1.24; risk difference: -1.72; 95% CI: -6.70 to 3.25; p = 0.50); regarding the latter, the prespecified noninferiority hypothesis was met (pnoninferiority < 0.01). Rates of major adverse cardiovascular events at 48 h were not significantly different (3.5% vs. 4.8%; relative risk: 0.73; 95% CI: 0.37 to 1.43; p = 0.35). At 48 h, the bivalirudin group had significantly fewer myocardial infarctions but more acute kidney injury events than the heparin group; at 30 days, these differences were no longer significant.nnnCONCLUSIONSnIn this randomized trial of TAVR procedural pharmacotherapy, bivalirudin did not reduce rates of major bleeding at 48 h or net adverse cardiovascular events within 30 days compared with heparin. Although superiority was not shown, the noninferiority hypothesis was met with respect to the latter factor. Given the lower cost, heparin should remain the standard of care, and bivalirudin can be an alternative anticoagulant option in patients unable to receive heparin in TAVR. (International, Multi-center, Open-label, Randomized Controlled Trial in Patients Undergoing TAVR to Determine the Treatment Effect [Both Safety and Efficacy] of Using Bivalirudin Instead of UFH [BRAVO-2/3]; NCT01651780).

Multicenter Evaluation of Edwards SAPIEN Positioning During Transcatheter Aortic Valve Implantation With Correlates for Device Movement During Final Deployment

OBJECTIVESnThis study sought to evaluate the exact location of Edwards SAPIEN (Edwards Lifesciences, Irvine, California) devices in different stages of implantation and to quantify possible operator-independent device movement during final deployment.nnnBACKGROUNDnAccurate device positioning during transcatheter aortic valve implantation is crucial in order to achieve optimal results.nnnMETHODSnThis multicenter study consisted of 68 procedures with reliable pacemaker capture. Device positions were assessed using fluoroscopic images and the C-THV system (Paieon Medical, Rosh HaAyin, Israel).nnnRESULTSnThe location after implantation was significantly higher than in the final stage of rapid pacing: 16.7 ± 16.3% of device height below the plane of the lower sinus border versus 32.6 ± 13.8%, p < 0.0001. Operator-independent device-center upper movement during final deployment was 2 ± 1.43 mm, range: -1.3 to 4.6 mm. Device movement was asymmetrical, occurring more in the lower part of the device than in its upper part (3.2 ± 1.4 mm vs. 0.75 ± 1.5 mm, p < 0.001), resulting in device shortening. Multivariate analysis revealed that moderate and severe aortic valve calcification had 49% higher upward movement than mild calcification (p = 0.03), and aortic sinus volume was negatively correlated with movement size (r = -0.35, p = 0.005). This movement was independent of device version (SAPIEN vs. SAPIEN XT), procedural access (transfemoral vs. transapical), and interventricular septum width.nnnCONCLUSIONSnThe final Edwards SAPIEN position is mostly aortic in relation to the lower sinus border. There is an operator-independent upward movement of the device center during the final stage of implantation. Anticipated upward movement of the device should influence its positioning before final deployment.

Diagnostic Performance of Computed Tomography Coronary Angiography (from the Prospective National Multicenter Multivendor EVASCAN Study)

Computed tomographic coronary angiography (CTCA) has been proposed as a noninvasive test for significant coronary artery disease (CAD), but only limited data are available from prospective multicenter trials. The goal of this study was to establish the diagnostic accuracy of CTCA compared to coronary angiography (CA) in a large population of symptomatic patients with clinical indications for coronary imaging. This national, multicenter study was designed to prospectively evaluate stable patients able to undergo CTCA followed by conventional CA. Data from CTCA and CA were analyzed in a blinded fashion at central core laboratories. The main outcome was the evaluation of patient-, vessel-, and segment-based diagnostic performance of CTCA to detect or rule out significant CAD (≥50% luminal diameter reduction). Of 757 patients enrolled, 746 (mean age 61 ± 12 years, 71% men) were analyzed. They underwent CTCA followed by CA 1.7 ± 0.8 days later using a 64-detector scanner. The prevalence of significant CAD in native coronary vessels by CA was 54%. The rate of nonassessable segments by CTCA was 6%. In a patient-based analysis, sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios of CTCA were 91%, 50%, 68%, 83%, 1.82, and 0.18, respectively. The strongest predictors of false-negative results on CTCA were high estimated pretest probability of CAD (odds ratio [OR] 1.97, p <0.001), male gender (OR 1.5, pxa0<0.002), diabetes (OR 1.5, p <0.0001), and age (OR 1.2, p <0.0001). In conclusion, in this large multicenter study, CTCA identified significant CAD with high sensitivity. However, in routine clinical practice, each patient should be individually evaluated, and the pretest probability of obstructive CAD should be taken into account when deciding which method, CTCA or CA, to use to diagnose its presence and severity.