Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations

Derek J. Hausenloy 0 1 2 3 4 5 6 7 8 9 10 11 Gary Baxter 0 1 2 3 4 5 6 7 8 9 10 11 Robert Bell 0 1 2 3 4 5 6 7 8 9 10 11 Hans Erik Btker 0 1 2 3 4 5 6 7 8 9 10 11 Sean M. Davidson 0 1 2 3 4 5 6 7 8 9 10 11 James Downey 0 1 2 3 4 5 6 7 8 9 10 11 Gerd Heusch 0 1 2 3 4 5 6 7 8 9 10 11 Masafumi Kitakaze 0 1 2 3 4 5 6 7 8 9 10 11 Sandrine Lecour 0 1 2 3 4 5 6 7 8 9 10 11 Robert Mentzer 0 1 2 3 4 5 6 7 8 9 10 11 Mihaela M. Mocanu 0 1 2 3 4 5 6 7 8 9 10 11 Michel Ovize 0 1 2 3 4 5 6 7 8 9 10 11 Rainer Schulz 0 1 2 3 4 5 6 7 8 9 10 11 Richard Shannon 0 1 2 3 4 5 6 7 8 9 10 11 Malcolm Walker 0 1 2 3 4 5 6 7 8 9 10 11 Gail Walkinshaw 0 1 2 3 4 5 6 7 8 9 10 11 Derek M. Yellon 0 1 2 3 4 5 6 7 8 9 10 11 0 G. Walkinshaw FibroGen, Inc., 409 Illinois Street, San Francisco, CA 94158, USA 1 G. Baxter Welsh School of Pharmacy, Cardiff University , King Edward VII Avenue, Cardiff CF10 3NB, UK 2 R. Shannon Department of Medicine, Penn Medicine, University of Pennsylvania , Philadelphia, PA, USA 3 D. J. Hausenloy R. Bell S. M. Davidson M. M. Mocanu M. Walker D. M. Yellon (&) The Hatter Cardiovascular Institute, University College London Hospitals and Medical School , 67 Chenies Mews, London WC1E 6HX, UK 4 Report of the UCL-Hatter Cardiovascular Institute 6th International Cardioprotection Workshop together with the Working Group of Cellular Biology of the Heart of the European Society of Cardiology 5 M. Ovize Hopital L. Pradel, Hospices Civils de Lyon, 59, Blvd. Pinel, 69394 Lyon Cedex 03, France 6 R. Mentzer School of Medicine, Wayne State University , Detroit, MI, USA 7 S. Lecour Hatter Institute for Cardiology Research, University of Cape Town , Cape Town, South Africa 8 M. Kitakaze Cardiovascular Division of Medicine, National Cardiovascular Centre , Suita, Osaka, Japan 9 G. Heusch R. Schulz Institute of Pathophysiology , Zentrum fur Innere Medizin, Universitatsklinikum Essen , Hufelandstrae 55, 45122 Essen, Germany 10 J. Downey University of South Alabama College of Medicine , Mobile, AL 36688, USA 11 H. E. Btker Department of Cardiology, Aarhus University Hospital , Skejby Sygehus, Aarhus, Denmark Ischemic heart disease (IHD) is the leading cause of death worldwide. Novel cardioprotective strategies are therefore required to improve clinical outcomes in patients with IHD. Although a large number of novel cardioprotective strategies have been discovered in the research laboratory, their translation to the clinical setting has been largely disappointing. The reason for this failure M. Marber, London, UK, served as guest editor for the manuscript and was responsible for all editorial decisions, including the selection of reviewers. The policy applies to all manuscripts with authors from the editor's institution. - Ischemic heart disease (IHD) is the leading cause of death worldwide. As such, novel therapeutic strategies for protecting the heart against ischemiareperfusion injury (IRI) are urgently needed to: reduce myocardial injury, preserve cardiac function, prevent the development of heart failure, and improve clinical outcomes in patients with IHD [42, 66]. However, a major obstacle to this process has been the inability to successfully translate novel cardioprotective strategies discovered in the research laboratory setting directly into the clinical arena [38]. This important issue was the main topic of discussion of the 6th Hatter Institute International Workshop on Cardioprotection, which was held this year in Mauritius, an Island in which diabetes and associated IHD are major contributors to overall morbidity and mortality. It was organized together with the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. The main agenda of this International Workshop was to discuss and formulate a set of recommendations for the design and execution of future studies on cardioprotection in both the research laboratory and the clinical setting, in order to facilitate the translation of future novel cardioprotective strategies for patient benefit. One crucial aspect of this endeavour was to recognise the limitations in the design and execution of current experimental laboratory and clinical cardioprotection studies, a feature which was also highlighted by the NHLI Working Group in 2004 [7]. Inadequacy of the animal models of IRI It is well accepted that the majority of animal models of IRI currently used to investigate novel cardioprotective strategies are inadequate representations of the clinical setting [7, 33, 36, 56], given the size and age of the animals used as well as their lack of co-morbidities and co-treatments. Ideally, one would have to prove efficacy of a certain cardioprotective intervention in animal experiments by the reduction in myocardial infarct (MI) size and/or improvement of prognosis under all mimicked clinical circumstances; however, this is unrealistic and it was agreed that the following recommendations should be proposed. Species The response of the heart to IRI and cardioprotective strategies will vary depending on the species used. Often small animal MI models have been used to investigate cardioprotection, since knockout and/or silencing of target proteins is possible in these models. However, more expensive, large animal (canine, porcine, primate) MI models are needed to confirm results of small animal experiments before clinical testing, since the temporal and spatial development of MI as well as certain signalling pathways in small animals differ from that in larger mammals and humans [21, 53, 55]. Therefore, small animal MI models may be used for preliminary screening of a novel cardioprotective strategy, as long as the latter is also demonstrated to be efficacious in at least one large animal MI model. Age Patients with IHD usually present between the ages of 55 and 65 years, whereas many experimental studies use young adult rats and mice (aged 34 months) which are equivalent to the human age of 710 years [6]. Several studies have reported that with age the myocardium can become resistant to various cardioprotective strategies including ischemic preconditioning [48] and postconditioning [5, 44]. Therefore, it is essential to demonstrate that any novel cardioprotective strategy is effective in suitably aged animal hearts. The easiest and most convenient species for such experiments are mice and rats in which the human age of 5565 years corresponds to about 2124 months of age [6]. Sex Both male and female patients suffer from IHD, yet most preclinical cardioprotective studies are restricted to using male animals only. Several studies suggest that gender can impact on the myocardial sensitivity to different cardioprotective strategies [15, 56]. Therefore, it is necessary to establish whether or not a novel cardioprotective strategy is effective in both male and female animals. Co-morbidities Patients with IHD are likely to have a number of co-morbid conditions at the time of presentation, many of which can influenc (...truncated)