DITPA (3,5-Diiodothyropropionic Acid), a thyroid hormone analog to treat heart failure: phase II trial veterans affairs cooperative study.

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.

Effects of thyroidectomy, T4, and DITPA replacement on brain blood vessel density in adult rats.

In hypothyroid patients, altered microvascular structure and function may affect mood and cognitive function. We hypothesized that adult male hypothyroid rats will have significantly lower forebrain blood vessel densities (BVD) than euthyroid rats and that treatment with 3,5-diiothyroprionic acid (DITPA) (a thyroid hormone analog) or thyroxine (T(4)) will normalize BVDs. The euthyroid group received no thyroidectomy or treatment. The other three groups received thyroidectomies and pellets. The hypothyroid group received a placebo pellet, the DITPA group received an 80-mg DITPA-containing pellet, and the T(4) group received a 5.2-mg T(4) slow-release pellet for 6 wk. Body weights, cardiac function, and body temperatures were measured. A monoclonal antiplatelet endothelial cell adhesion antibody was used to visualize blood vessels. The euthyroid group averaged body weights of 548 +/- 54 g, while the hypothyroid group averaged a body weight of 332 +/- 19 g (P value < 0.001). Relative to the euthyroid group, the DITPA-treated group was significantly lighter (P value < 0.05), while the T(4)-treated group was comparable in body weight to the euthyroid group. The same trends were seen with body temperature and cardiac function with the largest difference between the euthyroid and hypothyroid groups. BVD in the euthyroid group was 147 +/- 12 blood vessels/mm(2) and in hypothyroid group 69 +/- 5 blood vessels/mm(2) (P = 0.013) but similar among the euthyroid, DITPA, and T(4) groups. These results show that hypothyroidism decreased BVD in adult rat forebrain regions. Moreover, DITPA and T(4) were efficacious in preventing effects of hypothyroidism on cardiac function and BVD.

Regulation of gene expression in rats with heart failure treated with the thyroid hormone analog 3,5-diiodothyropropionic acid (DITPA) and the combination of DITPA and captopril.

We have used an oligonucleotide microarray to identify genes that are affected by congestive heart failure and those influenced by treatment with DITPA and DITPA in combination with captopril using a rat postinfarction model. The most striking result when comparing heart failure to sham operation was that all of the mitochondrial and metabolic enzymes affected were down regulated. When comparing heart failure with DITPA treatment, most of the down regulated metabolic genes were returned toward normal. When comparing heart failure with heart failure animals treated with DITPA and captopril, metabolic enzymes were no longer significantly downregulated. DITPA treatment and the combination of DITPA and captopril show that the metabolic enzymes were no longer down regulated. This represents a substantial improvement in the energy- generating capacity of the heart. These results indicate that the actions of DITPA and the combination of DITPA and captopril in heart failure can be partially explained by differences in gene activation.

Thyroid hormone analog, diiodothyropropionic acid (DITPA), exerts beneficial effects on chamber and cellular remodeling in cardiomyopathic hamsters.

Diiodothyropropionic acid (DITPA) is a thyroid hormone analog that is currently in phase II clinical trials. However, there have not been any studies to comprehensively analyze its effect on myocyte morphology. In addition, long-term studies with DITPA have not been done. This study compares the effects of DITPA with L-thyroxine (T4) on chamber remodeling, cardiac function, cellular morphology, cardiac blood flow, and protein expression. Normal and cardiomyopathic hamsters were treated with T4 or DITPA for 2 months. At the end of the treatment, echos, hemodynamics, coronary blood flow, cell morphology, and protein expression data were collected. Both T4 and DITPA treatment reduced chamber diameter during diastole, suggesting attenuated chamber dilatation in cardiomyopathic hamsters. Wall thickness also tended to increase, which was supported by cell morphology data in which DITPA significantly increased cross-sectional growth of myocytes specifically in the minor dimension, which is oriented transmurally. T4 and DITPA also increased myocardial blood flow both at baseline and after maximal dilation. This suggests there was increased angiogenesis or reduced loss of arterioles. Both T4 and DITPA had beneficial effects on chamber remodeling, which was most likely due to beneficial changes in cell shape and improved vascular supply.

Grafting an acellular 3-dimensional collagen scaffold onto a non-transmural infarcted myocardium induces neo-angiogenesis and reduces cardiac remodeling.

BACKGROUND: This study was designed to determine whether tissue engineering could be used to reduce ventricular remodeling in a rat model of non-transmural, non-ST-elevation myocardial infarction. METHODS: We grafted an acellular 3-dimensional (3D) collagen type 1 scaffold (solid porous foam) onto infarcted myocardium in rats. Three weeks after grafting, the scaffold was integrated into the myocardium and retarded cardiac remodeling by reducing left ventricular (LV) dilation. The LV inner and outer diameters, measured at the equator at zero LV pressure, decreased (p < 0.05) from 11,040 +/- 212 to 9,144 +/- 135 microm, and 13,469 +/- 187 to 11,673 +/- 104 microm (N = 12), after scaffold transplantation onto infarcted myocardium. The scaffold also shifted the LV pressure-volume curve to the left toward control and induced neo-angiogenesis (700 +/- 25 vs 75 +/- 11 neo-vessels/cm2, N = 5, p < 0.05). These vessels (75 +/- 11%) ranged in diameter from 25 to 100 microm and connected to the native coronary vasculature. Systemic treatment with granulocyte-colony stimulating factor (G-CSF), 50 microg/kg/day for 5 days immediately after myocardial injury, increased (p < 0.05) neo-vascular density from 700 +/- 25 to 978 +/- 57 neo-vessels/cm2. CONCLUSIONS: A 3D collagen type 1 scaffold grafted onto an injured myocardium induced neo-vessel formation and reduced LV remodeling. Treatment with G-CSF further increased the number of vessels in the myocardium, possibly due to mobilization of bone marrow cells.

Thyroid hormone analogs for treatment of hypercholesterolemia and heart failure: past, present and future prospects.

Thyroid hormone has the unique properties of lowering cholesterol in hypothyroid individuals and improving cardiac performance. Beginning in the 1950s, extensive efforts were made to develop thyroid hormone analogs that could utilize the cholesterol-lowering property in euthyroid individuals without affecting the heart. These efforts culminated in the development of analogs that selectively bind to beta1-type nuclear thyroid hormone receptors (TRs), which are responsible for cholesterol-lowering activity, without activating alpha1-type receptors in the heart. beta1-Selective compounds may be useful in lowering cholesterol in euthyroid individuals who are intolerant to treatment with 'statins'. Screening of compounds for those that might be suitable for improving cardiac performance in heart failure led to the identification of 3,5-diiodothyropropionic acid (DITPA). DITPA binds to both alpha- and beta-type TRs with relatively low affinity. In postinfarction models of heart failure and in a pilot clinical study, DITPA increased cardiac performance without affecting heart rate. This compound also lowers cholesterol and may be a useful adjunct to standard heart failure therapy. Although there is both experimental and clinical evidence indicating that thyroid analogs act differently than thyroid hormones, the details of their mechanism of action have not been completely elucidated. A number of potential mechanisms are reviewed, including serum protein binding, tissue disposition, receptor binding, and gene activation. Clinical trials for thyroid hormone analogs are in prospect.

Oxidative stress and apoptosis in cardiomyocyte induced by high-dose alcohol.

Binge drinking of alcohol causes cardiac dysfunction in some people. The mechanism remains unclear. This study was designed to investigate high doses of alcohol-induced oxidative stress and apoptosis in cardiomyocytes and protective effects of antioxidants. Cardiomyocytes isolated from 1- to 2-day-old Sprague-Dawley rats were treated with ethanol at doses of 0 mM, 50 mM, 100 mM, and 200 mM for 24 hours. Vitamin E (1 mM) and vitamin C (0.2 mM) were added to medium 1 hour before addition of ethanol. Results showed typical apoptosis: chromatin condensation, membrane blebbing, shrinkage, and cytoplasm condensation. Apoptosis is concentration-dependent in the range of 0 to 100 mM ethanol (apoptosis rates were respectively 0.68%, 2.03%, and 9.66% at ethanol concentration of 0 mM, 50 mM, and 100 mM). Necrotic cells became greatly increased in the 200 mM ethanol-treated group. Intracellular production of reactive oxygen intermediates increased as mitochondrial membrane potential decreased after ethanol treatment. Cytochrome c was found to be greater in the cytosol of the ethanol-treated groups. Activity of caspase-3 was higher in ethanol-treated groups (P < 0.05). Both vitamin E and vitamin C inhibited oxidative stress and myocyte apoptosis in ethanol-treated groups (P < 0.05). In conclusion, our data indicated that acute high-dose ethanol treatment primarily induces cardiomyocyte apoptosis at concentration up to 100 mM while necrosis is predominate at 200 mM. The underlying mechanism appears to involve mitochondrial damage via an increase in oxidative stress and releasing cytochrome c, which activates caspases that initiate chromatin fragmentation and apoptosis. Antioxidants, to a large extent, inhibit oxidative stress and apoptosis induced by ethanol.

Regulation of gene expression in cardiomyocytes by thyroid hormone and thyroid hormone analogs 3,5-diiodothyropropionic acid and CGS 23425 [N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic acid].

The heart is an important target of thyroid hormone actions. Only a limited number of cardiac target genes have been identified, and little is known about their regulation by T(3) (3,3',5-triiodothyronine) and thyroid hormone analogs. We used an oligonucleotide microarray to identify novel cardiac genes regulated by T(3) and two thyroid hormone analogs, 3,5-diidodothyropropionic acid (DITPA) and CGS 23425 [N-[3,5-dimethyl-4-(4'-hydroxy-3'-isopropylphenoxy)-phenyl]-oxamic acid]. DITPA binds with lower affinity than T(3) to thyroid hormone receptor alpha1 and beta1 isoforms, whereas CGS 23425 binds selectively to beta1. Fluorescent-labeled cDNA was prepared from cultured heart cells maintained in medium stripped of thyroid hormone ("hypothyroid" control) or treated with T(3), DITPA, and CGS 23425 at concentrations 5 times their respective K(d) values for 48 h. The arrays were scanned and analyzed using an analysis of variance program. Sixty-four genes were identified that were >1.5 times up- or down-regulated by one of the treatments with P < 0.05. The genes regulated by T(3) and DITPA were nearly identical. Thirteen genes were differentially regulated by CGS 23425. Genes encoding contractile proteins, Ca(2+)-ATPase of sarcoplasmic reticulum and several proteins of mitochondrial oxidative phosphorylation, were up-regulated by T(3) and DITPA but not by CGS 23425. These results indicate that some, but not all, of the actions of thyroid hormone analogs can be explained by differences in gene activation.

Clinical and experimental studies on the use of 3,5-diiodothyropropionic acid, a thyroid hormone analogue, in heart failure.

Thyroid hormone has unique actions that make it a novel and possibly useful agent for treatment of heart failure. Because of potential adverse effects of thyroid hormone, however, there has been interest in developing analogues with fewer undesirable side effects. Screening of compounds structurally related to levothyroxine identified 3,5-diiodothyropropionic acid (DITPA) as an analogue with inotropic selectivity and low metabolic activity in hypothyroid rats. When DITPA was administered alone or in combination with captopril in rat and rabbit postinfarction models of heart failure, cardiac output was increased and left ventricular end-diastolic pressure (LV EDP) was decreased without increasing heart rate. A pilot clinical study was undertaken to evaluate the safety and efficacy of DITPA. In a dose-ranging study in 7 normal volunteers the drug was well tolerated. A double-blind comparison then was made of DITPA versus placebo in a group of 19 patients with moderately severe heart failure. Patients were randomly assigned to receive either 1.875 mg/kg of DITPA or placebo daily. After 2 weeks the drug was increased to 3.75 mg/kg daily for an additional 2 weeks. In heart failure patients receiving the drug for 4 weeks, cardiac index was increased (p = 0.04) and systemic vascular resistance index was decreased (p = 0.02). Total serum cholesterol (p = 0.013) and triglycerides (p = 0.005) also were decreased significantly. These results indicate that DITPA is well tolerated and could represent a useful new agent for treatment of congestive heart failure.

Pilot studies on the use of 3,5-diiodothyropropionic acid, a thyroid hormone analog, in the treatment of congestive heart failure.

After an initial safety study in 7 normal volunteers, a randomized double-blind comparison was made between 3,5-diiodothyropropionic acid (DITPA) and placebo in 19 patients with moderately severe congestive failure. In heart failure patients receiving the drug for 4 weeks, cardiac index was increased (p = 0.04) and systemic vascular resistance index was decreased (p = 0.02). Systolic cardiac function was unchanged but isovolumetric relaxation time was decreased significantly, suggesting improvement in diastolic function. Total serum cholesterol (p = 0.005) and triglycerides (p = 0.01) also were decreased significantly. DITPA could represent a useful new agent for treatment of congestive heart failure.