Anne-Marie Koop

2 45 Limitations This study comes with some limitations that should be discussed. 1) We studied a relatively small number of animals. The clear distinction in phenotype and major differences in function, morphology and biology however underline that our study had sufficient power. 2) The definition of RVF is a recurring subject of debate. The lack of a generally accepted definition for RVF is hampering studies addressing the progression from beneficial RV-adaptation to maladaptive RV-responses or RVF. We sought for a clinical relevant definition of RVF and used clinical signs of heart failure in the PAB rats. However, since RV failure is not a distinct entity but rather a continuum of progressive disease states, our clinical definition of RV failure, dichotomizing rats in a group with or without clinical RV failure in an effort to study differences throughout the process of RV failure, may be artificial. However, because of the analogywith the clinical presentation in patients, we considered this approach as a clinical relevant definition of RVF. 3) The observational approach of this studyyielded several associations between clinical RVF and biological/genetic changes, but obviously, does not prove causal relationships. Nevertheless, the identification of these associations allows for focused studies to delineate the mechanistic role of these changes in RVF. CONCLUSION The rat model of chronic ‘tight’ pulmonary artery banding leads to various degrees of RVF, including severe RVF with clinical symptoms in about half of the animals, characterized by progressive deterioration of diastolic function, a hypoxia-prone cellular environment in the RV myocardium, increased intrinsic protective response to oxidative stress and suppressed myocardial metabolism. This model represents clinical RVF due to increased pressure load and allows for unraveling of the mechanisms involved in the progression from RV adaptation to RV failure and the effect of intervention on these mechanisms. ACKNOWLEDGEMENTS The authors are greatly indebted to Michel Weij, who performed the pulmonary artery banding surgeries. We would also like to thank Bibiche Boersma and Martin Dokter for excellent technical assistance and Andre Zandvoort and Annemieke Smit-van Oosten for valuable help with the animal experiments. FINANCIAL SUPPORT This study was supported by the Sebald foundation and the Netherlands Heart Foundation [grant#: 2007T068]