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

Study of excitation transfer Li(3D → 3P) occurring in optical collisions with rare gas atoms experimentally

By selective optical excitation of collision pairs and observation of the reemitted fluorescence information is obtained on the role of the molecular channels involved in inelelastic collisions. As an example case we have studied experimentally the Li($\rm 3D\rightarrow3P$) excitation transfer in Li(3D)X systems with $X=\rm Ne$, Ar by means of the optical collision process ${\rm Li(2P)} + X + h \nu \rightarrow {\rm Li}X(3{\rm D}\Lambda)\rightarrow {\rm Li(3P, 3D)} + X$ where ${\rm Li}X(3{\rm D}\Lambda)$ collision molecules dissociate into Li(3P, 3D) atoms following laser excitation $h\nu$ of ${\rm Li(2P)}+X$ pairs. For this purpose we measured the Li 3P/3D population ratio by the fluorescence from these levels as function of the laser detuning $\Delta\nu$ from the Li(2P-3D) transition and the rare gas pressure, and determined from this the 3P/3D excitation ratio $B(\Delta\nu)$ for single collision conditions. The experiments were performed using two step cw laser excitation of gaseous mixtures ${\rm Li}+X$ at temperatures around 600 K in the detuning range $|\Delta\nu|\leq 100$ cm-1. The $B(\Delta\nu)$ profiles obtained display strong blue-red wing asymmetries both for $\rm Li^*Ne$ and $\rm Li^*Ar$. This reflects different dissociation probabilities from the ${\rm 3D}\Sigma$ or ${\rm 3D}(\Pi,\Delta)$ states that are initially prepared by blue wing or red wing excitation, respectively. The results are qualitatively discussed in terms of new ab initio potentials for the two systems

Cardioprotection by Remote Ischemic Preconditioning is Blocked in the Aged Rat Heart in Vivo

Objectives: In animal studies, remote ischemic preconditioning (RIPC) is a powerful tool to protect the heart from ischemia and reperfusion injury. Unfortunately, this effect was not seen consistently in recent large clinical trials. Aging was shown to be a confounding factor for the effect of direct preconditioning in experimental studies, but whether aging also can influence the effect of RIPC and thus be responsible for the contradictory clinical effect is unknown. The aim of this study was to investigate whether the cardioprotective effect of RIPC was abolished by aging. Design: Randomized, prospective, blinded laboratory investigation. Setting: Experimental laboratory. Participants: Male Wistar rats. Interventions: Anesthetized young (Y, 2-3 months) and aged (A, 22-24 months) male Wistar rats were randomized to 4 groups (n = 6 per group). Control animals (Y-Con and A-Con) were not treated further; RIPC groups (Y-RIPC and A-RIPC) received 4 cycles of 5 minutes of bilateral hind limb ischemia interspersed with 5 minutes reperfusion before myocardial ischemia and reperfusion. All animals underwent 25 minutes of regional myocardial ischemia and 120 minutes of reperfusion. At the end of reperfusion, infarct size was determined by Tit staining. Measurements and Main Results: In the control group of young rats, infarct size was 56 +/- 9% of the area at risk. RIPC reduced infarct size to 31 +/- 9% (p <0.05 v Y-Con). Cardioprotection by RIPC was abolished completely in the aged rat heart (A-RIPC: 62 +/- 8%, A-Con: 63 +/- 4%; ns). Conclusions: The results of the authors' study showed that cardioprotection induced by remote ischemic preconditioning was blocked in the aged rat heart. (C) 2017 Elsevier Inc. All rights reserve