An open-label, phase 2 study evaluating the efficacy and safety of the anti-IGF-1R antibody cixutumumab in patients with previously treated advanced or metastatic soft-tissue sarcoma or Ewing family of tumours.

BACKGROUND: Cixutumumab (IMC-A12), a fully human immunoglobulin G1 (IgG1) monoclonal antibody, exerts preclinical activity in several sarcoma models and may be effective for the treatment of these tumours. METHODS: In this open-label, multicentre, phase 2 study, patients with previously treated advanced or metastatic rhabdomyosarcoma, leiomyosarcoma, adipocytic sarcoma, synovial sarcoma or Ewing family of tumours received intravenous cixutumumab (10mg/kg) for 1h every other week until disease progression or discontinuation. The primary end-point was the progression-free survival rate (PFR), defined as stable disease or better at 12 weeks. In each tier of disease histology, Simon's optimum 2-stage design was applied (PFR at 12 weeks P0=20%, P1=40%, α=0.10, ß=0.10). Stage 1 enrolled 17 patients in each disease group/tier, with at least four patients with stable disease or better required at 12 weeks to proceed to stage 2. RESULTS: A total of 113 patients were enrolled; all tiers except adipocytic sarcoma were closed after stage 1 due to futility. The 12-week PFR was 12% for rhabdomyosarcoma (n=17), 14% for leiomyosarcoma (n=22), 32% for adipocytic sarcoma (n=37), 18% for synovial sarcoma (n=17) and 11% for Ewing family of tumours (n=18). Median progression-free survival (weeks) was 6.1 for rhabdomyosarcoma, 6.0 for leiomyosarcoma, 12.1 for adipocytic sarcoma, 6.4 for synovial sarcoma and 6.4 for Ewing family of tumours. Among all patients, the most frequent treatment-emergent adverse events (AEs) were nausea (26%), fatigue (23%), diarrhoea (23%) and hyperglycaemia (20%). CONCLUSIONS: Patients with adipocytic sarcoma may benefit from treatment with cixutumumab. Cixutumumab treatment was well tolerated, with limited gastrointestinal AEs, fatigue and hyperglycaemia.

Cryogenic EBSD on ice: preserving a stable surface in a low pressure SEM.

Naturally deformed ice contains subgrains with characteristic geometries that have recently been identified in etched surfaces using high-resolution light microscopy (LM). The probable slip systems responsible for these subgrain boundary types can be determined using electron backscattered diffraction (EBSD), providing the etch features imaged with reflected LM can be retained during EBSD data acquisition in a scanning electron microscope (SEM). Retention of the etch features requires that the ice surface is stable. Depending on the pressure and temperature, sublimation of ice can occur. The equilibrium temperature for a low pressure SEM operating at 1 × 10(-6) hPa is about -112°C and operating at higher temperatures causes sublimation. Although charging of uncoated ice samples is reduced by sublimation, important information contained in the etch features are removed as the surface sublimes. We developed a method for collecting EBSD data on stable ice surfaces in a low pressure SEM. We found that operating at temperatures of <-112°C reduced sublimation so that the original etch surface features were retained. Charging, which occurred at low pressures (<1.5 × 10(-6) to 2.8 × 10(-5) hPa) was reduced by defocusing the beam. At very low pressures (<1.5 × 10(-6) hPa) the spatial resolution with a defocused beam at 10 kV was about 3 µm in the x-direction at -150°C and 0.5 µm at -120°C, because at higher temperature charging was less and only a small defocus was needed to compensate it. Angular resolution was better than 0.7° after orientation averaging. Excellent agreement was obtained between LM etch features and EBSD mapped microstructures. First results are shown, which indicate subgrain boundary types comprised of basal (tilt and twist) and nonbasal dislocations (tilt boundaries).

Electron backscattered diffraction as a tool to quantify subgrains in deformed calcite.

In this work, we investigated processing methods to obtain subgrain sizes from electron backscattered diffraction data using samples of experimentally deformed calcite (CaCO(3)) polycrystals. The domain boundary hierarchy method, based on area measurements of domains enclosed by boundaries larger than a given misorientation angle, was applied to these calcite samples and was found to be limited by: (i) topological problems; (ii) undersampling of large grains; and (iii) artefacts caused by nonindexing. We tested two alternative methods that may reduce the problems: (i) the measured linear intercept hierarchy method, based on measurements of linear intercept between boundaries having larger misorientations than a given minimum angle; and (ii) the calculated linear intercept hierarchy method, based on the total length of boundaries having misorientations larger than a given minimum angle. The measured linear intercept hierarchy method was found to produce results more representative for the microstructure than the calculated linear intercept hierarchy method, because the calculated linear intercept hierarchy method has a significant uncertainty related to the grid-based nature of the measurements. Preliminary results on calcite suggest that the measured linear intercept hierarchy method is related, in a complex way, to deformation conditions such as stress, strain and temperature as well as to the characteristics of subgrain rotation and grain boundary migration processes.

Low-angle subgrain misorientations in deformed NaCl.

The development of subgrain boundary misorientations with strain in NaCl polycrystals has been investigated. At low strains, a power law relationship exists between strain and average misorientations. The accuracy of this relationship is assessed in terms of material and electron backscattered diffraction (EBSD) processing parameters and is found to hold for a material of constant grain size deformed in compression, providing EBSD mapping and processing conditions were similar. Average misorientations are strongly influenced by grain orientation, suggesting that the misorientation-strain relationship may also be texture dependent in materials with high plastic anisotropy. A slight grain size dependency of the average misorientations was observed.

Misorientation distributions in hot deformed NaCl using electron backscattered diffraction.

EBSD orientation mapping has been used to derive subgrain boundary misorientation distributions in a series of hot deformed and etched NaCl samples. The main objective of this study has been to examine the influence of data processing, noise caused by angular resolution limits and step size on the subgrain misorientation distributions in hot deformed NaCl. Processing of non-indexed EBSD patterns increased the average misorientations in etched NaCl. Noise contributed significantly to low angle misorientation peaks for step sizes less than the minimum subgrain size. Orientation data collected using a step size larger than the average subgrain size cumulated misorientations across individual subgrains and effectively measured an orientation gradient between steps. Orientation gradient distributions were not influenced by noise. Average misorientation values calculated from large step data correlated well with average misorientation from small step size data, Average misorientations showed a power law relationship with strain. Three types of substructures were identified using scanning electron microscopy and EBSD mapping, equiaxed subgrains, long subgrain boundaries and a core-mantle subgrain arrangement.

Prevention of abnormal sarcoplasmic reticulum calcium transport and protein expression in post-infarction heart failure using 3, 5-diiodothyropropionic acid (DITPA).

Heart failure of diverse causes is associated with abnormalities of sarcoplasmic reticulum (SR) Ca(2+)transport. The purpose of this study was to determine whether the thyroid hormone analogue, 3,5-diiodothyropropionic acid (DITPA), prevents abnormal Ca(2+)transport and expression of SR proteins associated with post-infarction heart failure. New Zealand White rabbits were randomly assigned to circumflex artery ligation or sham operation, and to DITPA administration (3.75 mg/kg/day) or no treatment in a two-by-two factorial design. After 3 weeks, echo-Doppler and LV hemodynamic measurements were performed. From ventricular tissue, single myocyte shortening and relaxation were determined, and Ca(2+)transport was measured in homogenates and SR-enriched microsomes. Levels of mRNA and protein content were determined for the SR Ca(2+)-ATPase (SERCA2a), phospholamban (PLB), cardiac ryanodine receptor (RyR-2) and calsequestrin. The administration of DITPA improved LV contraction and relaxation and improved myocyte shortening in infarcted animals. The improvements in LV and myocyte function were associated with increases in V(max)for SR Ca(2+)transport in both homogenates and microsomes. Also, DITPA prevented the decrease in LV protein density for SERCA2a, PLB and RyR-2 post-infarction, without measurable changes in mRNA levels. The thyroid hormone analogue, DITPA, improves LV, myocyte and SR function in infarcted hearts and prevents the downregulation of SR proteins associated with post-infarction heart failure. The specific effects of DITPA on post-infarction SR Ca(2+)transport and the expression of SR proteins make this compound a potentially useful therapeutic agent for LV systolic and/or diastolic dysfunction.

DITPA prevents the blunted contraction-frequency relationship in myocytes from infarcted hearts.

Loss of the positive force-frequency relationship is a characteristic finding in failing hearts. The mechanisms of this change are not well understood. Myocardial infarction (MI) was induced in rabbits to produce left ventricular (LV) dysfunction. Beginning 1 day after MI, a subgroup of rabbits received diiodothyropropionic acid (DITPA) (3.75 mg x kg(-1) x day(-1) sc) for 3 wk. We measured contractions, Ca(2+) transients, action potentials, and sarcoplasmic reticulum (SR) Ca(2+) content at different stimulation rates in single LV myocytes. The shortening-frequency relationship was markedly flattened in MI myocytes compared with control myocytes. In addition, Ca(2+) transients, action potentials, and contractions were prolonged. Myocytes from DITPA-treated MI rabbits had preserved inotropic responses to increased stimulation rate and normal duration of action potentials and Ca(2+) transients. SR Ca(2+) content increased significantly when stimulation rate was increased from 0.5 to 2.0 Hz in control myocytes but did not change significantly in MI myocytes. Myocytes from DITPA-treated MI rabbits had a greater frequency-dependent increase in SR Ca(2+) content compared with the untreated MI rabbits. Thus single myocytes from infarcted rabbit hearts have frequency-dependent abnormalities of contractility, Ca(2+) cycling, and action potential repolarization. The flattened contraction-frequency relationship can be partially explained by an attenuation of the normal enhancement of SR Ca(2+) content that occurs when stimulation rate is increased. Chronic DITPA administration after MI largely prevents the development of these abnormalities.

Pathophysiologic correlates of thromboembolism in nonvalvular atrial fibrillation: II. Dense spontaneous echocardiographic contrast (The Stroke Prevention in Atrial Fibrillation [SPAF-III] study).

We analyzed transesophageal echocardiograms from 772 participants in the Stroke Prevention in Atrial Fibrillation (SPAF-III) study, characterizing spontaneous echocardiographic contrast (SEC) in the left atrium or appendage as faint or dense. The association of dense SEC with stroke risk factors and anatomic, hemodynamic, and hemostatic parameters related to specific thromboembolic mechanisms was evaluated by multivariate analysis. Spontaneous echocardiographic contrast was present in 55% of patients and was dense in 13%. Age (odds ratio [OR] 2.4/decade, P <.001), constant atrial fibrillation (OR 6.9, P <.001), history of hypertension (OR 3. 2, P <.001), and current tobacco smoking (OR 2.6, P =.04) were independent clinical predictors of dense SEC. Multivariate analysis of clinical, echocardiographic, and hemostatic parameters yielded age as the sole independent clinical predictor of dense SEC (OR 2. 4/decade, P <.001). Other independent predictors were measures of left atrial/appendage flow dynamics, left atrial size (OR 2.4/cm diameter, M-mode, P <.001), atherosclerotic aortic plaque (OR 2.8, P =.002), and plasma fibrinogen >350 mg/dL (P <.001). Results were similar when SEC of any density was analyzed. In conclusion, SEC occurred in more than half of these patients with prospectively defined nonvalvular atrial fibrillation but was usually faint. Dense SEC was strongly associated with previously reported clinical predictors of stroke, linking them to thromboembolism through atrial stasis. Diverse pathophysiologic factors including atrial stasis, fibrinogen level, and aortic plaque influence SEC.

Warfarin safety and efficacy in patients with thoracic aortic plaque and atrial fibrillation. SPAF TEE Investigators. Stroke Prevention and Atrial Fibrillation. Transesophageal echocardiography.

Patients with atrial fibrillation and with documented aortic plaque who were assigned to adjusted-dose warfarin therapy (international normalized ratio 2.0 to 3.0) had an annual rate of cholesterol embolization of 0.7% (95% confidence interval [CI] 0.1% to 5.3%/patient-year). Warfarin-assigned patients with plaque had a lower rate of embolic events (5.9%/year; 95% CI 3.0 to 12) than those on combination low-dose warfarin (international normalized ratio <1.5) plus aspirin (17.3%/year; 95% CI 11 to 27; p = 0.01).

Left atrial diameter in nonvalvular atrial fibrillation: An echocardiographic study. Stroke Prevention in Atrial Fibrillation Investigators.

BACKGROUND: The left atrium (LA) is usually enlarged in patients with nonvalvular atrial fibrillation (AF), but factors associated with LA diameter are incompletely defined. METHODS AND RESULTS: This transthoracic echocardiographic cohort study includes 3465 participants with nonvalvular AF in 3 multicenter clinical trials. LA diameter determined by M-mode echocardiography was correlated with clinical and echocardiographic features by cross-sectional multivariate regression analyses. The mean LA diameter was 47 +/- 8 mm, on average 6 mm larger in those with AF at the time of echocardiography than in those with sinus rhythm (48 vs 42 mm, P <. 001). Patient age and body weight were independently predictive of LA diameter (P <.0001), but sex, body surface area, and body mass index were not. The estimated independent contribution of atrial rhythm to LA diameter was approximately 2.5 mm. Prolonged duration of AF, left ventricular dilatation and increased muscle mass, mitral regurgitation, annular calcification, and hypertension were additional independent predictors of LA diameter. CONCLUSIONS: Multiple factors appear to contribute to LA enlargement in patients with nonvalvular AF, including the presence and persistence of the dysrhythmia.

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.

A thyroid hormone analog stimulates angiogenesis in the post-infarcted rat heart.

In view of the evidence that thyroid hormone administration has angiogenic effects on the hypertrophic myocardium, we tested the hypothesis that the capillary supply in the hypertrophic myocardium surviving infarction would be improved by administration of the thyroid hormone analog, diiodothyroproprionic acid (DITPA). We administered DITPA (MI-DITPA) or saline (MI-saline), s.c., to rats for 10 days following experimental infarction of the left ventricle (LV). Morphometric methods were used to assess capillarity and myocyte cross-sectional area in three regions of the left ventricle: (1) border (next to the scar of infarction); (2) adjacent (next to the border); and (3) remote (interventricular septum). Infarct size ranged from 20-85% of the LV free-wall, and both groups had similar mean infarct size. Capillary length density (LV) was significantly higher in the remote region of the treated group than in the MI-saline rats. LV in the border region, which experienced the most marked increase in cardiocyte cross-sectional area, was not significantly lower than in the other regions, indicating a more marked angiogenic response. In hearts with large infarcts (> or = 40%) LV in the border region was higher in the DITPA group than in the non-treated rats. In the MI-DITPA group, cardiocyte size in the border region was positively correlated with that of the other regions, which contrasts with the negative correlations noted for the MI-saline rats. These data suggest that DITPA therapy (1) may improve maximal perfusion potential of the hypertrophied myocardium surviving a myocardial infarction, and (2) is selectively effective in the border region of hearts with large infarcts.

Enhanced vasorelaxation by overexpression of beta 2-adrenergic receptors in large arteries.

This study was designed to determine if adenoviral-mediated delivery of a transgene encoding the beta 2-adrenergic receptor (beta 2-AR) to the carotid arterial wall could result in alterations in in vivo vascular function. De-endothelialized rat carotid arteries were infused in vivo with 0.1 mg/ml elastase and adenovirus [6 x 10(9) plaque forming units (PFU)] containing either the marker gene beta-galactosidase (Adeno-beta-gal), DNA encoding the human beta 2-AR (Adeno-beta 2-AR), or no transgene. This low concentration of elastase increased the water permeability (5.2 +/- 0.6 v 1.9 +/- 0.4 x 10(-8) cm/s/mmHg, n = 4, P < 0.0001) without affecting either the vasomotor responsiveness or the morphology of the arterial wall. A transfection efficiency of 73% was achieved with Adeno-beta-gal (n = 3). beta-gal expression was associated with infrequent appearance of T and B lymphocytes, or neutrophil infiltration. Five days after infection with Adeno-beta 2-AR, the total beta-AR density increased six-fold (67.8 +/- 3.4 v 397.0 +/- 155.5 fmol/mg protein, n = 5, P < 0.01); isoproterenol-induced vasorelaxation at transmural pressures from 10-110/mmHg increased (P < 0.01) compared to arteries exposed to control virus (empty adenovirus), n = 4; and isoproterenol-stimulated cAMP production was increased by 65% (n = 5). Thus, adenoviral-mediated delivery of beta 2-ARs into large artery walls results in enhanced beta-AR-mediated vasorelaxation via augmentation in cAMP levels in vascular smooth muscle cells.

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.

Development of a thyroid hormone analogue for the treatment of congestive heart failure.

The possibility that thyroid hormone or a thyroid hormone analogue that improves cardiac performance might be useful in the treatment of heart failure has-been examined. In the rat postinfarction model of heart failure, treatment with low doses (1.5 micrograms/100 g) of thyroxine (T4) for 3 days produced a positive inotropic response, including an increase in left ventricular (LV) dP/dt and a decrease in LV end-diastolic pressure (LVEDP). When treatment with T4 was continued at the same or higher doses (3 to 15 micrograms/100 g) for 10-12 days, heart rate was increased and improvement in LVEDP was not sustained. To identify an analogue with a more favorable hemodynamic profile, single- and double-ring compounds related to T4 were screened for thyromimetic activity in heart cell cultures and for their ability to bind thyroid hormone receptors. One of the analogues selected, 3,5-diiodothyropropionic acid (DITPA), was found to have inotropic selectivity in hypothyroid rats. When administered (375 micrograms/100 g) to rats with ventricular dysfunction after myocardial infarction in combination with captopril, there was improvement of the resting and stressed cardiac index and LV filling pressure. Similar improvement in cardiac performance was obtained when DITPA was administered to rabbits after infarction. Thus a thyroid hormone analogue with inotropic selectivity may be a useful adjunct to other measures in the treatment of heart failure.

Left ventricular performance and remodeling in rabbits after myocardial infarction. Effects of a thyroid hormone analogue.

BACKGROUND: Because the rat postinfarction model differs from human heart failure with respect to the composition of myosin heavy chain (MHC) isoforms and other contractile proteins, alternative animal models are needed for the development of new treatments for human heart failure. The purpose of this study was threefold: (1) to test the feasibility of using the V3(beta,beta) rabbit postinfarction model for the study of heart failure by characterizing the effects of chronic coronary artery occlusion on the left ventricle; (2) to determine whether the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) produces improvements in left ventricular function; and (3) to determine the effects of myocardial infarction and treatment with DITPA on MHC protein isoforms. METHODS AND RESULTS: Male New Zealand White rabbits underwent proximal circumflex coronary artery ligation. After infarction, rabbits were treated with DITPA (3.75 mg/kg body wt) or placebo for 21 days and then underwent conscious and open-chest hemodynamic studies. In separate groups of rabbits, beta- and alpha-MHC isoforms were separated, and relative proportions were measured using gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis and laser densitometry. Infarction resulted in increased left ventricular end-diastolic pressure and prolonged left ventricular relaxation (tau) (P = .001 for both variables). Postinfarction treatment with DITPA decreased left ventricular end-diastolic pressure and tau (P = .002 and P = .001, respectively) and increased maximum positive and negative dP/dt (P = .002 and P = .016, respectively). Infarcted rabbits treated with DITPA had no significant changes in heart rate or left ventricular systolic pressure compared with untreated rabbits with infarction. There were no significant differences in heart rate, positive dP/dt, peak systolic pressure, or tau between sham-operated rabbits and sham-operated rabbits treated with DITPA. Although infarction resulted in increased left ventricular diameter, there were no effects of DITPA on left ventricular remodeling. Neither myocardial infarction nor treatment with DITPA altered the ratio of MHC isoforms. CONCLUSIONS: Rabbits that survive occlusion of the circumflex artery will develop myocardial dysfunction and left ventricular remodeling. Therapy with DITPA, a thyroid hormone analogue, produces improvement in ventricular performance and reduces end-diastolic pressure. The hemodynamic effects of DITPA were not associated with alterations of MHC isoforms. Whether DITPA represents the prototype of a previously undescribed class of agents for the treatment of heart failure will need to be determined by clinical trials.

Identification of simple substituted phenols with thyromimetic activity: cardiac effects of 3,5-diiodo-4-hydroxyphenylpropionic acid.

To define the minimal structural requirements for cardiac activity of thyroid hormone analogs, a series of substituted phenols were screened for their ability to bind bacterially expressed thyroid hormone receptors. Compounds with binding activity then were tested for their ability to induce expression of alpha-myosin heavy chain mRNA in primary cultures of fetal rat cardiomyocytes, a sensitive marker for potential inotropic activity. 3,5-Diiodo-4-hydroxyphenylpropionic acid (DIHPA) was found to bind specifically to bacterially expressed alpha-1 and beta-1 thyroid hormone receptors (Kaff approximately 1 to 2 x 10(5) M-1) and to induce alpha-myosin heavy chain (EC50 approximately 5 x 10(-7)). To assess the effects of DIHPA on cardiac performance in vivo, hemodynamic measurements were made in three groups of hypothyroid rats treated for 5 days with s.c. doses of DIHPA (15 mg/100 g), L-thyroxine (T4, 1.5 micrograms/100 g) or saline. Compared to controls, DIHPA and T4 produced increases in heart rate, left ventricular +dP/dtmax, -dP/dtmax, and isovolumic relaxation. In isometric papillary muscles preparations, DIHPA and T4 shortened time-to-peak tension and time-from-peak tension to 50% decline as compared with saline-treated controls. Muscles from both drug-treatment groups showed similar responses to graded doses of isoproterenol (10(-8) to 10(-3) M) and to variations in Ca++ concentration of the muscle bath (0.3125 to 3.75 x 10(-3) M). Thus, DIHPA is a novel thyromimetic compound with effects on myocardial function similar to those observed with T4.

Combination treatment with captopril and the thyroid hormone analogue 3,5-diiodothyropropionic acid. A new approach to improving left ventricular performance in heart failure.

BACKGROUND: An agent that improves left ventricular (LV) performance by non-cAMP-mediated mechanisms would be valuable in the treatment of chronic heart failure. We have shown earlier that the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) binds to nuclear receptors, alters transcription of T3-responsive genes, and increases +dP/dtmax in hypothyroid rats with substantially less effect on heart rate and metabolism than thyroid hormone, which makes it a selective cardiotonic agent. METHODS AND RESULTS: To determine whether DITPA might be useful in treating heart failure, we compared chronic treatment with normal saline, captopril (2 g/L), or the combination of DITPA (375 micrograms/100 g) and captopril (2 g/L) in Sprague-Dawley rats beginning 3 weeks after coronary artery ligation. Both DITPA/captopril and captopril treatment decreased LV end-diastolic pressure compared with controls (21 +/- 2 and 26 +/- 2 mm Hg, respectively, vs 34 +/- 3 mm Hg, P < .05 for each). The addition of DITPA to captopril produced a 36% increase in resting cardiac index (P < .05) and shifted the cardiac function curve upward and to the left, indicative of enhanced myocardial performance. Also, DITPA/captopril compared with captopril treatment or control produced an increase in the rate of LV relaxation, as manifested by a decrease in tau, the time constant of LV pressure decline (17.5 +/- 1.0 vs 22.2 +/- 1.7 milliseconds, P < .05) and a larger absolute value for -dP/dtmax (-4561 +/- 361 vs -3346 +/- 232 mm Hg/s, P < .05). These changes occurred without changes in heart rate, LV mass, LV systolic pressure, or peripheral resistance relative to captopril treatment (P > .05). CONCLUSIONS: The combination of DITPA and captopril improved cardiac output, increased -dP/dtmax, and increased the rate of LV relaxation to a greater extent than captopril treatment in the rat postinfarction model of heart failure. Use of a cardiotonic analogue of thyroid hormone represents a new approach to improving LV performance and may be a useful adjunct to afterload reduction for the treatment of heart failure.

Studies on the use of thyroid hormone and a thyroid hormone analogue in the treatment of congestive heart failure.

In heart failure, cardiac output is insufficient to meet the needs of the body for oxygen delivery. Available data suggest that alterations in thyroid hormone metabolism may contribute to defective myocardial performance. Accordingly, thyroid hormone or a thyroid hormone analogue that improves cardiac performance might be useful in the treatment of heart failure and has been studied. Experimental and theoretical results of these studies are reviewed and indicate that thyroid hormone increases cardiac output by a combination of effects on the heart and peripheral circulation, specifically by increasing myocardial contractile performance and decreasing venous compliance. In the rat postinfarction model of heart failure, treatment with low doses of thyroxine (1.5 micrograms/100 g) for 3 days produced a positive inotropic response, including an increase in rate of change of left ventricular pressure and a decrease in left ventricular end-diastolic pressure. These changes could be attributed to conversion to triiodothyronine, the active intracellular form of thyroid hormone. When treatment with thyroxine was continued at the same or higher doses (3 to 15 micrograms/100 g) for 10 to 12 days, heart rate increased and improvement in left ventricular end-diastolic pressure was not sustained. More favorable results were obtained with 3,5-diiodothyropropionic acid, a cardiotonic thyroid hormone analogue administered at doses of 375 microgram/100 g, given in combination with captopril. Thus, triiodothyronine or a thyroid hormone analogue may be a useful adjunct to other measures in the treatment of heart failure.

Cardiac effects of 3,5-diiodothyropropionic acid, a thyroid hormone analog with inotropic selectivity.

Thyroid hormone exerts a strong positive inotropic action on the heart and induces alpha-myosin heavy chain (MHC) gene expression. 3,5-Diiodothyropropionic acid (DITPA), a carboxylic acid analog with low metabolic activity, was observed to induce alpha-MHC mRNA in heart cell culture with EC50 approximately 5 x 10(-7) M. To determine if the compound has positive inotropic actions, the effects of DITPA and L-thyroxine on heart rate, left ventricular pressures, left ventricular dP/dt, myosin isoenzymes and hepatic alpha-glycerolphosphate dehydrogenase activity were compared in hypothyroid rats. Binding affinities of DITPA and triiodothyronine for bacterially expressed alpha-1 and beta-1 thyroid hormone receptors (TRs) also were determined. Over the dosage range of 150 to 1500 micrograms/100 g, DITPA produced increases in left ventricular dP/dt comparable to those obtained with L-thyroxine at dosages of 1.5 to 15 micrograms/100 g, but with significantly less tachycardia. The increase in alpha-MHC mRNA was about the same with both compounds whereas alpha-MHC protein content and GPDH activity increased less with DITPA. These differences could not be explained by preferential binding of DITPA to TR subtypes. Because heart rate is a major determinant of myocardial oxygen consumption, DITPA is able to achieve increased cardiac performance at lower myocardial oxygen costs.