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

Heart-rate mediated blood pressure control in preterm fetal sheep under normal and hypoxic-ischemic conditions

Background: The understanding of hypoxemia-induced changes in baroreflex function is limited and may be studied in a fetal sheep experiment before, during, and after standardized hypoxic conditions. Methods: Preterm fetal lambs were instrumented at 102 d gestation (term: 146 d). At 106 d, intrauterine hypoxia–­ischemia was induced by 25¿min of umbilical cord occlusion (UCO). Baroreflex-related fluctuations were calculated at 30-min intervals during the first week after UCO by transfer function (cross-spectral) analysis between systolic blood pressure (SBP) and R–R interval fluctuations, estimated in the low-frequency (LF, 0.04–0.15 Hz) band. LF transfer gain (baroreflex sensitivity) and delay (s) reflect the baroreflex function. Results: Baseline did not differ in LF transfer gain and delay between controls and the UCO group. In controls, LF gain showed postnatal increase. By contrast, LF gain gradually decreased in the UCO group, resulting in significantly lower values 4–7 d after UCO. In the UCO group, LF delay increased and differed significantly from controls. Conclusion: Our results show that intrauterine hypoxia–ischemia results in reduced baroreflex sensitivity over a period of 7 d, indicating limited efficacy to buffer BP changes by adapting heart rate. Cardiovascular dysregulation may augment already present cerebral damage after systemic hypoxia–ischemia in the reperfusion period