Bridging Gaps in Cardiac Repair: Looking back to think ahead

Abstract

This thesis contains research focusing on enhancing cardiac repair after injury and the need for increased translatability of preclinical findings. In Part 1, the research focuses on the search for endogenous pathways for intrinsic cardiomyocyte proliferation. The Wnt pathway is known to be active in both cardiac development and disease. An overview and research protocol are provided, to understand these processes in more detail. Through large screens and validation studies we have also looked into novel pathways/transcription factors driving cardiomyocyte differentiation and proliferation. In Part 2 & 3, we focussed on new methods of hypothesis generation in cell therapy research. We use meta-analyses in preclinical and clinical settings to answer unsolved questions regarding determinants of efficacy of cell therapy, choice of animal model and the potential influence of sham procedures on clinical trials. Using meta-analysis as a starting point, we went back into the lab to validate multiple of these interesting findings. Interestingly, our work suggests that the regular comedication for myocardial infarction (prescribed to patients, suffering from this disease) might affect the majority of our assays both in vitro and in vivo, so should be taken into account. Furthermore, the choices made for the type of animal model influence most primary outcomes and are factors to take into account when designing your preclinical study. We also came up with a new model to define response to cell therapy in the clinical setting and have generated new hypotheses regarding sham procedures in cell therapy research. Interestingly, the application of placebo therapy particularly also boosted a reparative response in patients compared to patients who did not receive this administration. Finally, we also looked into methodology for meta-analysis, specifically the use of funnel plots and standardized mean differences. Through analysis of empirical datasets and illustrative simulations, we showed that the standardized mean difference and its standard error are an unsuitable combination for funnel plots, which unfortunately have been used in the past. Researchers who have done so, should reconsider their conclusions based on this assay. The research described in this thesis will likely have a major impact on the cardiovascular research field, mainly in optimizing current preclinical models and analysis methods.