Letter by Pingitore et al Regarding Article, “DITPA (3,5-Diiodothyropropionic Acid), a Thyroid Hormone Analog to Treat Heart Failure: Phase II Trial Veterans Affairs Cooperative Study”
To the Editor:
Treatment with thyroid hormone (TH) or TH analogs represents a novel therapeutic challenge in cardiac patients with nonthyroidal illness. Actually, many observational studies in humans have shown a negative prognostic impact of low l-triiodothyronine (T3) syndrome in cardiac disease.1 Also, experimental animal data have shown the beneficial effects of TH and TH analogs on cardiac remodeling and function in dilated cardiomyopathy, hypertension, and myocardial infarction without increasing heart rate above control values.1 Moreover, a rat study showed that hypothyroidism alone can eventually lead to heart failure.2
In the placebo-controlled study by Goldman et al,3 the TH analogue 3,5-diiodothyropropionic acid (DITPA) was administered to patients with congestive heart failure. No improvement on outcome or symptoms was observed, but rather fatigue was more frequent in the DITPA group. Importantly, weight loss and reduction in serum cholesterol were also observed in the DITPA group. Nevertheless, DITPA induced an increase in both cardiac index and heart rate, which was associated with a reduction in systemic vascular resistance. Comprehensive interpretation of overall results is, however, difficult because of the lack of reported single parameters as measured after treatment.
The rationale of using DITPA was to avoid the detrimental effects of exogenously administered TH, such as increased heart rate and body metabolism, which, as the authors stated, can overshadow its beneficial and therapeutic effects.3 Although the rationale behind the study appears logical, the results showed the appearance of the aforementioned adverse effects. In particular, weight loss, increased heart rate, fatigue, and suppression of thyroid stimulating hormone are well-known signs and symptoms of thyrotoxicosis.
In the few reported studies on heart failure patients and nonthyroidal illness treated with TH (either T3 or l-thyroxine) and at different dosages, administration modality (intravenous or orally), and time of treatment, no side effects have ever been observed.1 In particular, in the recent study by our group,4 an increase in cardiac index was observed after substitutive, 3-day l-T3 infusion, and heart rate was actually reduced. This improvement in cardiac performance was not associated with an increase in myocardial O2 consumption, nor was there an increase in total cardiac work. The modality of the therapeutic approach is likely the key point in the treatment of cardiac patients with nonthyroidal illness. The strategy of maintaining long-term normal TH and TSH is likely a better end point than maintaining long-term suppression of TSH. At present, much of the experimental evidence on the beneficial effects of TH treatment is after acute myocardial infarction, when there appears to be rapid induction of a low thyroid state in the heart.5 Accordingly, we recently started a Phase II, randomized, double-blind, placebo-controlled study with long-term substitutive l-T3 treatment targeting restoration and maintenance of normal circulating levels of T3, l-thyroxine, and TSH in patients with acute myocardial infarction and low T3 syndrome. The principal aim of the study is to evaluate the safety and feasibility of TH treatment and its effect on cardiac performance and remodeling as assessed by cardiac magnetic resonance.
Tang YD, Kuzman JA, Said S, Anderson BE, Wang X, Gerdes AM. Low thyroid function leads to cardiac atrophy with chamber dilatation, impaired myocardial blood flow, loss of arterioles, and severe systolic dysfunction. Circulation. 2005; 112: 3122–3130.
Goldman S, McCarren M, Morkin E, Ladenson PW, Edson R, Warren S, Ohm J, Thai H, Churby L, Barnhill J, O'Brien T, Anand I, Warner A, Hattler B, Dunlap M, Erikson J, Shih MC, Lavori P. DITPA (3,5-diiodothyropropionic acid), a thyroid hormone analog to treat heart failure: Phase II trial Veterans Affairs cooperative study. Circulation. 2009; 119: 3093–3100.
Pingitore A, Galli E, Barison A, Iervasi A, Scarlattini M, Nucci D, L'Abbate A, Mariotti R, Iervasi G. Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low T3 syndrome: a randomized, placebo-controlled study. J Clin Endocrinol Metab. 2008; 93: 1351–1358.