Pilot Studies on the Use of 3,5-Diiodothyropropionic Acid, a Thyroid Hormone Analog, in the Treatment of Congestive Heart Failure

Morkin, Eugene; Pennock, Gregory D.; Spooner, Peter H.; Bahl, Joseph J.; Fox, Katherine Underhill; Goldman, Steven

doi:10.1159/000063110

Cited by 40 publications

(15 citation statements)

References 16 publications

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“…However, Spooner et al (26) reported that DITPA alone did not alter the hemodynamics significantly with the only effect being a decrease in ϩdP/dt. Morkin et al (20) showed DITPA improved diastolic function with systolic cardiac function unchanged. As shown here in rats, a previous study in our laboratory showed no detectible hemodynamic changes in cardiomyopathic hamsters after treatment with DITPA, which was also administered by subcutaneous pellets (13).…”

Section: Discussionmentioning

confidence: 98%

Thyroid hormone analog 3,5-diiodothyropropionic acid promotes healthy vasculature in the adult myocardium independent of thyroid effects on cardiac function

Liu¹,

Wang²,

Redetzke³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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Liu Y, Wang D, Redetzke RA, Sherer BA, Gerdes AM. Thyroid hormone analog 3,5-diiodothyropropionic acid promotes healthy vasculature in the adult myocardium independent of thyroid effects on cardiac function. Am J Physiol Heart Circ Physiol 296: H1551-H1557, 2009. First published March 13, 2009; doi:10.1152/ajpheart.01293.2008Patients with hypothyroidism are at a higher risk for coronary vascular disease. Patients with diabetes and related vascular complications also have an increased incidence of low thyroid function. While thyroid hormones (THs) may be key regulators of a healthy vasculature, potential undesirable side effects hinder their use in the treatment of vascular disorders. TH analogs such as 3,5-diiodothyropropionic acid (DITPA) may provide a safer treatment option. However, the relative potency of DITPA on vascular growth, cardiac function, and metabolism is poorly understood. We hypothesized that the vascular growth-promoting effects of DITPA can be obtained with a minimum effect on cardiac function. Thyroidectomized Sprague-Dawley rats were given slow-release pellets with either thyroxine (T4, 2.7 or 5.2 mg) or DITPA (80 mg) for 6 wk and were compared with placebo. Heart mass, body mass, body temperature, serum THs, cardiac function (echocardiograms and hemodynamics), and myocardial arteriolar density were determined. Hypothyroidism led to reductions in cardiac function, heart mass, body temperature, and myocardial arterioles. High-dose T4 prevented arteriolar loss and the development of hypothyroidism. Low-dose T4 partially prevented the reduction in cardiac function but had minimal effects on arteriolar loss. In contrast, DITPA treatment prevented myocardial arteriolar loss but not the progression of hypothyroid-induced changes in cardiac function. The results suggested that DITPA can promote a healthy vasculature independently from its thyroid-related metabolic effects. Drugs in this class may provide new therapeutic options for patients with vascular disease.hypothyroidism; myocardial arterioles; vascular disease HYPOTHYROIDISM HAS BEEN LINKED to a variety of cardiovascular diseases, such as myocardial infarction (9), coronary atherosclerosis (5), and congestive heart failure (2). Thyroid hormone (TH) supplementation can increase cardiac contractility (16), promote cardiac hypertrophy (7), and induce vasodilatation (22). Tomanek et al. (29) have shown that THs are proangiogenic and can stimulate angiogenesis and arteriolar growth in normal hearts. We have shown that TH treatment of rats during an induction of hypothyroidism prevents the associated loss of arterioles (15). These beneficial effects of THs make them potentially attractive for the use of treating various cardiovascular diseases. However, concerns have been raised about the potential undesirable adverse effects such as increased heart rate and metabolism.It has been shown that the TH analog 3,5-diiodothyropropionic acid (DITPA) has inotropic selectivity (23) due partly to the enhanced release of sarcoplasmic reticulum calcium (11) ...

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Section: Discussionmentioning

confidence: 98%

Thyroid hormone analog 3,5-diiodothyropropionic acid promotes healthy vasculature in the adult myocardium independent of thyroid effects on cardiac function

Liu¹,

Wang²,

Redetzke³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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show abstract

“…22 Our efforts led to the discovery that DITPA improves left ventricular function both in animal models 3,4 and in a preliminary study of patients with heart failure, with no change in heart rate. 5 This led to the design of the present phase II safety and efficacy study of DITPA.…”

Section: Discussionmentioning

confidence: 99%

“…5 Herein, we report the first randomized, placebo-controlled phase II trial designed to evaluate the safety of and provide preliminary data on the potential efficacy of DITPA in patients with stable CHF.…”

Section: Clinical Perspective On P 3100mentioning

confidence: 99%

DITPA (3,5-Diiodothyropropionic Acid), a Thyroid Hormone Analog to Treat Heart Failure

et al. 2009

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Background— In animal studies and a pilot trial in patients with congestive heart failure, the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA) had beneficial hemodynamic effects. Methods and Results— This was a phase II multicenter, randomized, placebo-controlled, double-blind trial of New York Heart Association class II to IV congestive heart failure patients randomized (2:1) to DITPA or placebo and treated for 6 months. The study enrolled 86 patients (n=57 to DITPA, n=29 to placebo). The primary objective was to assess the effect of DITPA on a composite congestive heart failure end point that classifies patients as improved, worsened, or unchanged based on symptom changes and morbidity/mortality. DITPA was poorly tolerated, which obscured the interpretation of congestive heart failure-specific effects. Fatigue and gastrointestinal complaints, in particular, were more frequent in the DITPA group. DITPA increased cardiac index (by 18%) and decreased systemic vascular resistance (by 11%), serum cholesterol (−20%), low-density lipoprotein cholesterol (−30%), and body weight (−11 lb). Thyroid-stimulating hormone was suppressed in patients given DITPA, which reflects its thyromimetic effect; however, no symptoms or signs of potential hypothyroidism or thyrotoxicosis were seen. Conclusions— DITPA improved some hemodynamic and metabolic parameters, but there was no evidence for symptomatic benefit in congestive heart failure.

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“…A direct association of serum thyroid hormone levels with an α-to βMHC switch during cardiac hypertrophy has not been found; however, defects in the expression levels of thyroid receptors (TRα1, TRβ1 and TRα2) have been documented [58]. Treatment of animals with T4 or thyromimetic agent, DITPA, (diiodothyropropionic acid) reversed the myosin isoform switch as well as contractile dysfunctions associated with hypertrophy and heart failure, suggesting that a defect in thyroidhormone signaling may, in part, contribute to the MHC isoform distribution accompanied with the failing heart [108,117]. By promoter analysis of the αMHC gene, a number of negative regulatory DNA elements and their cognate binding factors have been identified.…”

Section: Cardiac Hypertrophymentioning

confidence: 99%

Factors controlling cardiac myosin-isoform shift during hypertrophy and heart failure

Gupta

2007

Journal of Molecular and Cellular Cardiology

190

171

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Pilot Studies on the Use of 3,5-Diiodothyropropionic Acid, a Thyroid Hormone Analog, in the Treatment of Congestive Heart Failure

Cited by 40 publications

References 16 publications

Thyroid hormone analog 3,5-diiodothyropropionic acid promotes healthy vasculature in the adult myocardium independent of thyroid effects on cardiac function

Thyroid hormone analog 3,5-diiodothyropropionic acid promotes healthy vasculature in the adult myocardium independent of thyroid effects on cardiac function

DITPA (3,5-Diiodothyropropionic Acid), a Thyroid Hormone Analog to Treat Heart Failure

Factors controlling cardiac myosin-isoform shift during hypertrophy and heart failure

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