Bioenergetic aspects of experimental heart failure

Abstract: Congestive heart failure (CHF) is a complex syndrome associated with high morbidity and mortality in spite of advances in pharmacological treatment during recent years. CHF is global health problem and will become an even more important health issue in the future since the incidence of CHF is predicted to increase worldwide in the next decades. Clearly, better therapeutic strategies are needed in order to decrease patents morbidity and mortality and alter the relentless progress of deterioration in cardiac function and structure through the process of cardiac remodeling. Future advance in the treatment of CHF will depend on how successful researchers will be in elucidating the basic mechanisms and in finding new targets for intervention. Significant part of the future insights will most probably come from relevant animal models, especially from genetically modified animals. Continuous improvement of our research tools is prerequisite for the future successes. The aims of this thesis were:· To develop a model for in vivo noninvasive assessment of cardiac energy metabolism with volume-selective 31P magnetic resonance spectroscopy (MRS) and to evaluate the myocardial bioenergetics during early postinfarct remodeling and developing heart failure in the rat.· To develop a model for in vivo noninvasive assessment of cardiac energy metabolism with volume-selective 31P MRS in the mouse and to evaluate feasibility of detection of bioenergetic abnormalities in the myocardium of the living mouse.· To investigate in vivo whether treatment with b-blockade improves myocardial energy metabolism in experimental myocardial infarction (MI) and developing heart failure.· To evaluate the effects of GH treatment on myocardial energy metabolism, function, neurohormonal activation and remodeling in experimental myocardial infarction and developing heart failure.Methods for volume-selective in vivo 31P MRS using Image Selected in Vivo Spectroscopy (ISIS) were developed and applied in rats with postinfarct heart failure and in transgenic mice overexpressing bovine growth hormone (GH) with cardiomyopathy. Effects of treatment with selective beta1-blockade and recombinant human GH on myocardial bioenergetics, function, morphology as well as on neurohormonal activation were evaluated in rat model of postinfarct heart failure using 31P MRS, echocardiography and standard biochemical methods high performance liquid chromatography and radio-assay methods.It is concluded that in vivo volume-selective 31P MRS may be successfully used for non-invasive and repeated evaluation of myocardial energy metabolism in small animals under physiological conditions. Disturbances in myocardial energy metabolism are present early after myocardial infarction and may be important mechanism in the pathophysiology of transition from compensated cardiac dysfunction to overt heart failure. Both, beta-blockade and GH as separate treatments initiated early in the postinfarct period are able to normalize disturbances in myocardial energy metabolism. Future studies should address the question whether these two therapeutical approaches could be combined to achieve synergistic effect. Although the treatment with GH have shown several beneficial effects on the heart, the use of this hormone in the treatment of patients with CHF and possibly with MI has to await confirmation from large clinical studies. The concept of beta-blockade in the treatment of CHF has been unequivocally proven in large clinical trials although the mechanisms of action of this therapy are insufficiently known. The results from this thesis provide the experimental evidence that one such mechanism may be mediated by improvement in myocardial energy metabolism.