Peter H. Spooner

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.

Echocardiographic changes after myocardial infarction in a model of left ventricular diastolic dysfunction

To determine the early and late effects of myocardial infarction on left ventricular (LV) diastolic function in the rabbit postinfarction model, male New Zealand White rabbits were randomly assigned to ligation of the circumflex artery or sham operation. Serial echocardiographic and Doppler studies were performed on both groups of animals at baseline and 1 h and 3 wk after surgery (n = 10 for each group) after verification of the reproducibility and repeatability of the measurements. At 1 h postinfarction, decreases in early mitral inflow velocity (E wave) and mitral inflow velocity with atrial contraction (A wave) and increases in the mean pulmonary venous systolic-to-diastolic ratio and A wave reversal velocities were observed, without changes in LV geometry. By 3 wk postinfarction, increases in the mitral E-to-A ratio (1.1 +/- 0.3 vs. 2.9 +/- 0.9, P < 0.001) and left atrial area (131 +/- 23 vs. 510 +/- 72 mm2, P < 0.001) and decreases in the pulmonary venous systolic-to-diastolic ratio (0.56 +/- 0.20 vs. 0.79 +/- 0.14, P = 0.008) were consistent with severe diastolic abnormalities (restricted physiology). The findings of this study demonstrate that coronary artery ligation in the rabbit provides a reproducible echocardiographic and Doppler model of LV diastolic dysfunction that is consistent with abnormalities found in humans with previous myocardial infarction, symptoms of heart failure, and preserved LV systolic function.To determine the early and late effects of myocardial infarction on left ventricular (LV) diastolic function in the rabbit postinfarction model, male New Zealand White rabbits were randomly assigned to ligation of the circumflex artery or sham operation. Serial echocardiographic and Doppler studies were performed on both groups of animals at baseline and 1 h and 3 wk after surgery ( n = 10 for each group) after verification of the reproducibility and repeatability of the measurements. At 1 h postinfarction, decreases in early mitral inflow velocity (E wave) and mitral inflow velocity with atrial contraction (A wave) and increases in the mean pulmonary venous systolic-to-diastolic ratio and A wave reversal velocities were observed, without changes in LV geometry. By 3 wk postinfarction, increases in the mitral E-to-A ratio (1.1 ± 0.3 vs. 2.9 ± 0.9, P < 0.001) and left atrial area (131 ± 23 vs. 510 ± 72 mm2, P < 0.001) and decreases in the pulmonary venous systolic-to-diastolic ratio (0.56 ± 0.20 vs. 0.79 ± 0.14, P = 0.008) were consistent with severe diastolic abnormalities (restricted physiology). The findings of this study demonstrate that coronary artery ligation in the rabbit provides a reproducible echocardiographic and Doppler model of LV diastolic dysfunction that is consistent with abnormalities found in humans with previous myocardial infarction, symptoms of heart failure, and preserved LV systolic function.

Thyroid hormone analog, DITPA, improves endothelial nitric oxide and beta-adrenergic mediated vasorelaxation after myocardial infarction.

This study was designed to determine if the thyroid hormone analog 3,5 diiodothyropropionic acid (DITPA), now in clinical trials for heart failure, alters endothelial function after myocardial infarction (MI). Three weeks after MI, adult Sprague–Dawley rats were randomly assigned to DITPA (375 μg/100 g subcutaneous) or no treatment of 3 weeks. In MI rats, left ventricular (LV) end-diastolic pressure and LV dP/dt decreased (P < 0.05). DITPA did not change MAP (87 ± 10 versus 90 ± 7 mm Hg) or LV end-diastolic pressure (23 ± 3 versus 19 ± 9 mm Hg) but did lower (P < 0.05) LV dP/dt (4633 ± 797 versus 3650 ± 1236 mm Hg/s). In aortic segments from MI rats, DITPA enhanced the acetylcholine dependent vasorelaxation (59 ± 11% at 10−4 M, P < 0.05) and isoproterenol induced vasorelaxation (57 ± 13% at 10−4 M, P < 0.05). The increases in vasorelaxation were blocked with l-NAME and restored with l-arginine. Treatment with DITPA increased (P < 0.05) eNOS protein content in aortic tissue from sham rats (3.8 ± 2.8 to 44.5 ± 7.1 integrated intensity units (II)/μg) and in MI rats (5.3 ± 3.4 to 28.3 ± 8.9 II/μg). In endothelial cells, 24 hours’ treatment with DITPA (10 μM) increased (P < 0.01) eNOS protein expression from 22.1 ± 4.8 to 52.7 ± 16.8 II/μg protein and DITPA (20 μM) increased eNOS to 49.1± 15.2 II/μg protein. The thyroid analog DITPA enhances endothelial nitric oxide and beta-adrenergic-mediated vasorelaxation by increasing nitric oxide in the vasculature.

Thyroid hormone and thyroid hormone analogues in the treatment of heart failure.

The thyroid hormone analogue DITPA is a promising potential new treatment for heart failure. Although the mechanism of action is incompletely determined, it is clear that DITPA improves systolic as well as diastolic function. It is also clear that the effects of DITPA are intrinsic to the muscle and not the result of changes in the structure or geometry of the left ventricle. On the basis of these experimental studies, we applied to the USA Food and Drug Administration for an Investigational New Drug application to study the use of DITPA in patients. These studies are currently in progress. While we await the outcome of these clinical trials, it is important to emphasize that even if the end-point is not a new drug to treat heart failure, our investigations are based on a systematic evaluation integrating biochemistry and physiology. We believe that this is the way to approach the problem of developmental pharmacology.

Increased intraventricular velocities: An unrecognized cause of systolic murmur in adults

OBJECTIVES The purpose of this study was to determine the frequency, clinical features and echocardiographic characteristics of increased intraventricular velocities (IIVs) in patients referred to the echocardiography laboratory for systolic murmur. BACKGROUND A subset of patients referred to the echocardiography laboratory for evaluation of a systolic murmur have IIVs in the absence of other recognized causes of systolic murmur. METHODS We prospectively studied echocardiograms from 108 consecutive patients referred for evaluation of a systolic murmur. Clinical data were obtained from patient examinations and medical records. RESULTS The sole explanation for systolic murmur was IIVs in 16.7% of referred patients. Compared with those without IIVs, patients with IIVs had a higher ejection fraction (EF) (58.7+/-7.8% vs. 51.1+/-12.5%, p < 0.001), percent fractional shortening (42.3+/-9.7% vs. 31.0+/-11.4%, p < 0.0001), left ventricular (LV) mass index (181+/-70 vs. 152+/-48 g/m2, p=0.046) and prevalence of hypertension (73.3% vs. 51.7%, p=0.043) and a lower prevalence of segmental wall motion abnormalities (2.2% vs. 39.3%, p < 0.001). CONCLUSIONS Increased intraventricular velocities are a common cause of systolic murmur in this group of patients and should be included in the differential diagnosis of systolic murmurs in adults. The association of IIVs with LV hypertrophy should be a clinical consideration when these murmurs are identified.