Trends, Therapies and Translational Models in Human Heart Failure

Abstract

Heart failure affects more than 30 million people worldwide. Therapies for both congenital and acquired heart failure have greatly improved over the last decade but there is currently no means to replace the ultimate loss of cardiomyocytes in the failing heart. Similarly, our knowledge of the pathogenesis of heart failure is expanding but it is mainly derived from animal models, with incomplete translation to humans (patients). This is particularly so with cardiac regeneration, where the current dogma is that the human heart is an aplastic organ. In this thesis, we identify the increasing prevalence and growing disease burden of heart failure in adults with congenital heart disease. We then assess the benefits and limitations of surgical revascularisation in ischaemic cardiomyopathy, which is the most common form of acquired heart failure. At a molecular level, we describe some of the difficulties in translating animal models of heart failure to humans. We establish one means by which this can be achieved; via complementary gene-to-protein studies that utilise biorepositories of human cardiac tissue. Finally, we propose an in vitro (cellular) model of heart failure, establishing proof of concept that the human heart possesses an intrinsic regenerative capacity in both normal development and in ischaemic heart disease.