Research Project
8645700
DESCRIPTION (provided by applicant): Long-term survival from myocardial infarction (MI) has improved with the use of 2-adrenergic blockers (BB) and angiotensin converting enzyme inhibitors (ACEi). Acute survival from myocardial infarction (MI) has also improved in recent years due to advances in early intervention. Nonetheless, current therapy is inadequate with many patients eventually progressing to dilated heart failure. After MI, patients develop low thyroid hormone (TH) levels and growing evidence suggests they may benefit from TH treatment. After MI, there is a rapid reduction in TH function which appears to be due to increased myocardial expression of the D3 deiodinase. D3 converts T4 to inactive rT3 and T3 to inactive T2. MI-related mortality increases as THs decline and rT3 levels increase. Additionally, hypothyroidism alone can lead to dilated heart failure while promoting a maladaptive change in myocyte shape and increased interstitial collagen. Interestingly, both of these maladaptive mechanisms play an important role in post-MI remodeling of the non-infarcted myocardium and progression to dilated failure. New data from rats shows that TH treatment of MI improved left ventricular function without elevating heart rate and led to a remarkable change in myocyte shape and reduced chamber diameter/posterior wall thickness ratio. These changes should prevent or attenuate progression to dilated heart failure. This proposal will test the hypothesis that low thyroid function resulting from MI is maladaptive and TH treatment will arrest progression of chamber dilatation and failure by induction of a beneficial change in myocyte shape, reduction of interstitial fibrosis, and stimulation of microvascular growth in the non-infarcted myocardium.Signaling networks underlying these cellular changes will also be investigated. Each aim is designed to provide critical, clinically- relevant information about post-MI thyroid hormone treatment effects on cell and tissue remodeling, LV function, and long-term outcome that is not currently available. Much of the information to be obtained cannot be collected from human trials for ethical reasons. For instance, the effects of thyroid hormone treatment alone and in the background of standard therapy (ACE inhibitors, 2-blockers) will be examined. These animal data should provide important insight for interpretation of their clinical results and should also be of predictive value in planning future long-term treatment studies.
