| Heart failure is a major problem in clinical cardiology. The 1 and 5 year survival rate of patients is 80% and 40%, respectively. Chronic left ventricular (LV) overload following myocardial infarction (MI) is the most common cause of pathological ventricular hypertrophy and remodeling leading to congestive heart failure. The disease is multi-factorial and although numerous signal-transduction pathways have been implicated in pathological hypertrophy, the mechanisms underlying the progression to failure are still unclear. Ventricular gene expression, myocyte morphology and contractile function are to a large extent dependent on the cellular actions of thyroid hormone (TH). Cardiac TH signaling is constant under normal conditions, but results from various research lines suggest that cardiac TH signaling is impaired in pathological hypertrophy through multiple mechanisms. New data from our work shows for the first time that cardiac TH action is greatly reduced in heart failure and associated with the induction of the TH-degrading enzyme Deiodinase type 3 (D3) in the hypertrophic cardiomyocyte. Impaired TH action would provide an explanation for the induction of the fetal gene program that characterizes the failing heart, since this also characterizes the TH-deficient heart. Furthermore, exercise training, which is therapeutic in the management of heart failure and reverses the fetal gene program, was recently shown to induce improvement of TH-signaling. We therefore hypothesize that impaired TH-signaling plays a causal role in the pathogenesis of heart failure following MI and that induction of D3 is a critical factor in this proces. Furthermore, that the beneficial effects of exercise training are at least in part dependent on alleviating this impairment of TH signaling. The aims of this study are to provide an analysis of the changes in cardiac TH signaling and action during the course of LV remodeling following MI, as well as during mitigation of remodeling induced by exercise training. Also, this study will test for the first time the causality of altered TH action in the progression of pathological hypertrophy to heart failure following MI. A model of post-MI LV remodeling and failure will be used in normal mice and in an established transgenic line with increased cardiac TH signaling. Functional and morphological parameters will be obtained by non-invasive and invasive techniques over the course of eight weeks following MI and these will be correlated with analyses of cardiac gene-expression and TH-metabolism using standard techniques. Ventricular transfection of a new TH-indicator probe will be used to measure the actual in vivo transcriptional activity of TH in cardiomyocytes in the live animal. RNAi-based knock-down of the Dio3 gene using viral transfection will test the proposed critical role of the D3 enzyme. Effects of exercise training on TH-signaling and gene expression in post-MI mice will be studied using treadmill running. The project will yield a comprehensive view of the involvement of altered TH signaling in the pathogenesis of ventricular remodeling and heart failure following myocardial infarction, as well as in the beneficial effects of exercise training on the development of heart failure. It is expected that these studies will identify potential therapeutic targets for early intervention. Objectives 1. To identify the changes in cardiac TH signaling over the course of LV remodeling and failure following MI, and to correlate these with changes in essential cardiac gene expression and ventricular function. 2. To test the relevance of impaired TH signaling for the development of pathological remodeling and the progression to heart failure by preventing the induction of D3 activity or by selectively increasing cardiac TH action. 3. To identify the effects of exercise training on TH signaling and the development of pathological remodeling following MI. Relevance for cardiovascular diseases Chronic left ventricular (LV) overload following myocardial infarction (MI) is the most common cause of pathological ventricular hypertrophy and remodeling leading to congestive heart failure. The disease is recognized as multi-factorial, but the mechanisms underlying failure are still not understood. The project will yield, for the first time, a comprehensive analysis of all processes related to the hypothesized role of impaired TH signaling in a well-defined model of LV remodeling and failure following MI. It will indicate whether TH signaling is indeed a critical factor and as such a target for therapeutic intervention. Apart from induction of D3 activity, whose role will be tested in this study, other factors and/or processes responsible for altered TH action that may be identified in the project, may provide such targets. The project will also enhance our understanding of the beneficial effects of exercise training on LV remodelling after MI, in particular with respect to the possible role of TH signaling in this form of therapy. |
