Synthetic thyroid hormone and thyroid analogues for treatment of heart failure

Abstract Heart failure (HF) should be seen in a unique scenario of altered systemic homeostasis in which heart dysfunction, peripheral organ dysfunction, and derangement of the neuroendocrine and immune systems represent chronic crosstalking between stress stimuli, with continuous activation of the stress response. The thyroid hormone (TH) system is profoundly involved in cardiovascular and systemic homeostasis. In HF the most frequent alteration of TH metabolism is a low-triiodothyronine state, which may participate directly in progression of HF. Initial results show that TH replacement therapy in patients with HF improves cardiac performance, hemodynamic and exercise performance, and also induces deactivation of the neuroendocrine profile, as a result of the significant reduction in vasoconstrictor/sodium-retaining noradrenaline and aldosterone, and in the plasma levels of their counterpart, N-terminal pro B-type natriuretic peptide (NTproBNP). Depending on the pathophysiology of the HF, two strategies of TH replacement therapy are suggested: (1) the cardiosystemic strategy, which involves administration of synthetic T4 or T3, or (2) the cardioselective one, using TH analogues, in particular 3,5-diiodothyropropionic acid (DITPA). The rationale of these two approaches is based on the pathophysiology of HF progression, which is linked to the progressive impairment of systolic-diastolic cardiac function, but also to the systemic disturbance, which frequently progresses independently of deteriorating cardiac function.