Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Incidence et facteurs prédictifs de la néphropathie de contraste chez les patients revascularisés en urgence par angioplastie pour infarctus du myocarde au CHU de Tours

TOURS-BU Médecine (372612103) / SudocSudocFranceF

Véronique en roulotte / Jacques Isorni

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Prognostic value of programmed ventricular stimulation in Brugada syndrome according to clinical presentation: An updated meta-analysis of worldwide published data

International audienc

Comparative Analysis of Methods to Induce Myocardial Infarction in a Closed-Chest Rabbit Model

Objective. To develop a rabbit model of closed-chest catheter-induced myocardial infarction. Background. Limitations of rodent and large animal models justify the search for clinically relevant alternatives. Methods. Microcatheterization of the heart was performed in 47 anesthetized 3-4 kg New Zealand rabbits to test five techniques of myocardial ischemia: free coils (n=4), interlocking coils (n=4), thrombogenic gelatin sponge (n=4), balloon occlusion (n=4), and alcohol injection (n=8). In order to limit ventricular fibrillation, an antiarrhythmic protocol was implemented, with beta-blockers/amiodarone before and xylocaine infusion during the procedure. Clinical, angiographic, and echographic data were gathered. End points included demonstration of vessel occlusion (TIMI flow grades 0 and 1 on the angiogram), impairment of left ventricular function at 2 weeks after procedure (by echocardiography), and pathologically confirmed myocardial infarction. Results. The best arterial access was determined to be through the right carotid artery. The internal mammary guiding catheter 4-Fr was selected as the optimal device for selective intracoronary injection. Free coils deployed prematurely and tended to prolapse into the aorta. Interlocking coils did not deploy completely and failed to provide reliable results. Gelatin sponge was difficult to handle, adhered to the catheter, and could not be clearly visualized by fluoroscopy. Balloon occlusion yielded inconsistent results. Alcohol injection was the most efficient and reproducible method for inducing myocardial infarction (4 out of 6 animals), the extent of which could be fine-tuned by using a coaxial balloon catheter as a microcatheter (0.52 mm) to achieve a superselective injection of 0.2 mL of alcohol. This approach resulted in a 20% decrease in LVEF and infarcted myocardium was confirmed histologically. Conclusions. By following a stepwise approach, a minimally invasive, effective, and reproducible rabbit model of catheter-induced myocardial infarction has been developed which addresses the limitations of rodent experiments while avoiding the logistical and cost issues associated with large animal models

Prognostic value of programmed ventricular stimulation in Brugada syndrome according to clinical presentation: An updated meta-analysis of worldwide published data

International audienc

A novel way to manage trastuzumab cardiotoxicity

International audiencePurpose: Trastuzumab is the most widely prescribed anti-HER2 humanized monoclonal antibody. Cardiac toxicity is the only limiting toxicity of trastuzumab and it is of particular concern in patients with complete response, since the drug needs to be stopped, with a risk of disease relapse. To date, no pharmacological data on trastuzumab cardiotoxicity in patients have been made available. Here, we provide proof of concept, demonstrating that it was possible to prevent trastuzumab-induced cardiotoxicity by modifying the drug administration schedule.Methods: In this paper, we report the case of a patient with metastatic breast cancer responding to trastuzumab, who developed severe cardiac toxicity twice using a 3-weekly regimen. Considering preclinical pharmacological data on trastuzumab cardiotoxicity, we hypothesized that a weekly schedule of trastuzumab with lower peaks of serum concentration could be safe while remaining efficient. With the patient's consent, we started a weekly combination of carboplatin (AUC2) and trastuzumab (2 mg/kg) with close monitoring of trastuzumab concentrations.Results: We successfully controlled the disease for an additional 6 months with relevant trough concentrations of trastuzumab of around 50 mg/L. Another important aspect is that, with this weekly schedule, we observed no cardiac toxicity, and the left ventricular ejection fraction remained stabilized, at over 50%.Conclusions: Trastuzumab is the most widely prescribed anti-HER2 monoclonal antibody for the treatment of HER2 metastatic breast cancer, and it is the only drug that has been approved for the treatment of localized HER2 breast cancer, 1-year treatment being required after surgery. In case of cardiac toxicity, particularly in women over 60 years of age, a weekly regimen with lower peaks of concentration could be an alternative to the standard 3-weekly regimen