Preclinical research in cardiac repair

In medical research, animal models serve as surrogates for human disease which has both advantages and disadvantages. Importantly, it prevents human suffering. Further advantages are mainly financial, since animal studies are cheaper and less time consuming than clinical research and logistical, since animals are more easily accessible compared to healthy volunteers or patients. Also, the (genetic) propinquity of animals, diminishes the ‘noise’ within one study leading to a decline in the number of study subjects required to find significant results. On the other hand, one should consider the translatability of a uniform collection of animals towards a diverse patient population, threatening external validity of preclinical studies. In the first part of this thesis, hypotheses for future clinical and preclinical studies on cardiac repair are formed, including i) cell therapy effectuates a significant effect on cardiac function in large animal MI models; ii) allogeneic cell therapy is associated with a similar magnitude of effect as autologous cell therapy; iii) the pig MI model for cardiac cell therapy serves as relevant model for human disease. Furthermore lessons were learned about the importance of internal and external validity in view of successful progression on the translational axis from bench to bedside, and solving the issue of publication bias. Internal validity is jeopardized by several forms of bias, like selection bias, performance bias and detection bias. Risk of bias with regard to internal validity is easily reduced by randomization, allocation concealment (i.e. blinding of the operator) and blinded outcome assessment. In the second part of this thesis, several methodological studies regarding animal models and outcome measurement in cardiac regenerative medicine are presented. Methods described in these chapters may serve as protocols for future testing of cardiac regenerative therapies in a preclinical setting. In our opinion, upfront validation and publication of methodology contributes to standardized research, and reduction and refinement of animal studies. Based on the described methodology, and theconsiderations in the first part of this thesis, a randomized blinded placebo controlled preclinical study was conducted in order to test the efficacy of fetal human cardiomyocyte progenitor cells (CMPCs) in a pig model of MI.