A dose calculation algorithm with correction for proton-nucleus interactions in non-water materials for proton radiotherapy treatment planning.

In treatment planning for proton radiotherapy, the dose measured in water is applied to the patient dose calculation with density scaling by stopping power ratio [Formula: see text]. Since the body tissues are chemically different from water, this approximation may cause dose calculation errors, especially due to differences in nuclear interactions. We proposed and validated an algorithm for correcting these errors. The dose in water is decomposed into three constituents according to the physical interactions of protons in water: the dose from primary protons continuously slowing down by electromagnetic interactions, the dose from protons scattered by elastic and/or inelastic interactions, and the dose resulting from nonelastic interactions. The proportions of the three dose constituents differ between body tissues and water. We determine correction factors for the proportion of dose constituents with Monte Carlo simulations in various standard body tissues, and formulated them as functions of their [Formula: see text] for patient dose calculation. The influence of nuclear interactions on dose was assessed by comparing the Monte Carlo simulated dose and the uncorrected dose in common phantom materials. The influence around the Bragg peak amounted to -6% for polytetrafluoroethylene and 0.3% for polyethylene. The validity of the correction method was confirmed by comparing the simulated and corrected doses in the materials. The deviation was below 0.8% for all materials. The accuracy of the correction factors derived with Monte Carlo simulations was separately verified through irradiation experiments with a 235 MeV proton beam using common phantom materials. The corrected doses agreed with the measurements within 0.4% for all materials except graphite. The influence on tumor dose was assessed in a prostate case. The dose reduction in the tumor was below 0.5%. Our results verify that this algorithm is practical and accurate for proton radiotherapy treatment planning, and will also be useful in rapidly determining fluence correction factors for non-water phantom dosimetry.

Application of the pencil-beam redefinition algorithm in heterogeneous media for proton beam therapy.

In proton beam therapy, changes in the proton range due to lateral heterogeneity may cause serious errors in the dose distribution. In the present study, the pencilbeam redefinition algorithm (PBRA) was applied to proton beam therapy to address the problem of lateral density heterogeneity. In the calculation, the phase-space parameters were characterized for multiple range (i.e. proton energy) bins for given pencil beams. The particles that were included in each pencil beam were transported and redefined periodically until they had stopped. The redefined beams formed a detouring path that was different from that of the non-redefined pencil beams, and the path of each redefined beam was straight. The results calculated by the PBRA were compared with measured proton dose distributions in a heterogeneous slab phantom and an anthropomorphic phantom. Through the beam redefinition process, the PBRA was able to predict the measured proton-detouring effects. Therefore, the PBRA may allow improved calculation accuracy when dealing with lateral heterogeneities in proton therapy applications.

SU-E-T-488: Dose Calculation Model Using the Simplified Monte Carlo Method with an Initial Beam Model Adapted to a Beam-Wobbling System.

PURPOSE: We have developed an accurate dose calculation model based on a simplified Monte Carlo (SMC) method adapted to a beam-wobbling delivery system at National Cancer Center Hospital East (NCCHE). We used an initial beam model specific to the beam-wobbling system to reproduce accurately different dose distributions in two lateral directions (x- and y-directions) perpendicular to each other. METHODS: The SMC calculates a dose distribution by tracking individual protons. The SMC starts tracking protons at an entrance of a range compensator. Protons are generated in an initial phase space adapted to the wobbler system. Since two wobbling-magnets are located at separate places with different distances from the iso-center, different dose distributions are formed in x- and y-directions. We derived an initial phase space distribution for the beam-wobbling system using an analytical method. We used the SMC method with the initial beam model to calculate dose distributions accurately. To verify accuracy of the calculation method, we measured the dose distribution in a homogeneous phantom formed by 235 MeV protons passing through a L-shaped range compensator. We used a 2D-array of parallel-plate ionization chambers (2D Array seven29®) to measure dose distributions with a sampling period of 5 mm. RESULTS: The measured dose distribution in the x-direction was different from that in the y-direction. Our calculation model reproduces the measurement results well in both lateral directions. In addition, the calculation reproduced the dose increments in edge regions contributed by edge-scattered protons in collimator. It indicates the advantage of the SMC. CONCLUSIONS: A dose calculation model has been developed based on the simplified Monte Carlo method applied to a beam-wobbling system. By adapting the initial beam model to the wobbling system, the SMC method is found to reproduce observed different dose distributions in x- and y-directions well.

SU-E-J-31: Direct Point Dose Verification Using IGRT for Actual Beam Delivery.

PURPOSE: In radiation therapy, treatment planning for patients is performed using pre-acquired CT images. However, many patients with head-and-neck (H&N) cancer have tumor shrinkage and/or weight loss during their treatment course. Daily positional error of patients also causes unexpected deviations from the planning. Thus, it is essential to evaluate actual delivered dose for accurate clinical dosimetric consequence. In this study, actual delivered dose for an H&N site was determined by direct point dose measurement with metal-oxide-semiconductor field-effect transistor (MOSFET) detectors using IGRT procedure. We experimentally evaluated usefulness of the IGRT procedure for accurate irradiations. METHODS: Treatment processes from planning to beam delivery were performed for an H&N site of an anthropomorphic phantom. The MOSFET detectors were fixed inside the phantom in advance. Then, the anthropomorphic phantom was immobilized with a mould and mask and scanned by simulation-CT. Beam irradiation condition was field size of 12 cm × 12 cm, gantry angle of 0°, 90° and 330°, and 6 MV X-ray. Dose distribution was calculated with superposition algorithm with 2 mm calculation grid. Before the dose measurement, the anthropomorphic phantom was positioned using a localization system of mega-voltage cone-beam CT (MVCBCT). The MOSFET detectors were exposed five times according to a treatment plan. Measured doses with the MOSFET detectors were compared with calculated doses. RESULTS: Using the MVCBCT, the set-up of the anthropomorphic phantom was achieved within 1 mm in all directions of anterior/posterior, left/right, and superior/inferior. The calculated doses agreed well to the measured doses within ±3% even in evaluated region with high dose gradient. CONCLUSIONS: The actual delivered dose for an H&N site of an anthropomorphic phantom was evaluated experimentally with the MOSFET detectors. The IGRT procedure was useful for accurate irradiations.

Clinical implementation of a GPU-based simplified Monte Carlo method for a treatment planning system of proton beam therapy.

We implemented the simplified Monte Carlo (SMC) method on graphics processing unit (GPU) architecture under the computer-unified device architecture platform developed by NVIDIA. The GPU-based SMC was clinically applied for four patients with head and neck, lung, or prostate cancer. The results were compared to those obtained by a traditional CPU-based SMC with respect to the computation time and discrepancy. In the CPU- and GPU-based SMC calculations, the estimated mean statistical errors of the calculated doses in the planning target volume region were within 0.5% rms. The dose distributions calculated by the GPU- and CPU-based SMCs were similar, within statistical errors. The GPU-based SMC showed 12.30-16.00 times faster performance than the CPU-based SMC. The computation time per beam arrangement using the GPU-based SMC for the clinical cases ranged 9-67 s. The results demonstrate the successful application of the GPU-based SMC to a clinical proton treatment planning.

Possible contribution of hyalocytes to idiopathic epiretinal membrane formation and its contraction.

AIM: To address the cellular components and the contractile mechanisms of the idiopathic epiretinal membrane (ERM). METHODS: Ten surgically removed ERMs were fixed in 4% paraformaldehyde and analysed by whole-mount immunohistochemistry with anti-glial fibrillar acidic protein (GFAP) and alpha smooth-muscle actin (alphaSMA) antibodies. Type I collagen gel contraction assay, an established wound-healing assay in vitro, was performed using cultured bovine hyalocytes or normal human astrocytes (NHA) to evaluate the contractile property of the cells in the presence of tissue growth factor (TGF)-beta2. The expression of alphaSMA was also analysed by western blot analysis to examine myofibroblastic transdifferentiation of the cells. Vitreous-induced collagen gel contraction was also evaluated. RESULTS: All membranes were composed of alphaSMA immunopositive cells in contracted foci and GFAP immunopositive cells in the periphery. No apparent double positive cells were observed in any membranes examined. Cultured hyalocytes showed overexpression of alphaSMA and hypercontraction of collagen gels in response to TGF-beta2, while glial cells showed marginal change. The vitreous from ERM patients also caused overexpression of alphaSMA and hypercontraction of the gels embedding hyalocytes, which were almost completely inhibited in the presence of anti-TGF-beta2 neutralising antibody. CONCLUSIONS: Hyalocytes might be one of the critical components of ERM mediating its contractile property through the effect of TGF-beta2 in the vitreous fluid.

Residual internal limiting membrane in epiretinal membrane surgery.

BACKGROUND/AIM: To examine the degree of the residual internal limiting membrane (ILM) after epiretinal membrane (ERM) peeling. METHODS: Sixty-one eyes of 59 patients with ERM were enrolled. After ERM peeling, residual ILM was visualised with Brilliant Blue G (BBG). The residual ILM pattern was divided into three groups: (1) residual type (ILM mostly remained), (2) half type (approximately half of ILM remained), (3) no residual type (ILM mostly removed with ERM). If ILM remained, residual ILM was removed in all cases and histologically examined using the flat mount method in 10 cases. The correlation between the degree of ERM evaluated by preoperative best-corrected visual acuity (BCVA) and residual ILM pattern was also examined. RESULTS: Twenty-eight eyes (45.9%) were of the residual type. Three eyes (4.9%) were of the half type, and 30 eyes (49.2%) were of no residual type. The mean preoperative BCVA showed no significant correlation with the residual ILM pattern. Flat mount immunohistochemistry revealed many remnant cells, both glial fibrillar acidic protein positive and negative, on residual ILMs in all specimens examined. No recurrence that needed surgical treatment was observed. CONCLUSION: Residual ILM with remnant cells seems to be frequent after ERM removal. Intraoperative staining with BBG may be helpful in determining the extent of ILM removal.

Improved motion compensation in 3D-CT using respiratory-correlated segment reconstruction: diagnostic and radiotherapy applications.

Conventional respiratory-gated CT and four-dimensional CT (4DCT) are disadvantaged by their low temporal resolution, which results in the inclusion of anatomic motion-induced artefacts. These represent a significant source of error both in radiotherapy treatment planning for the thorax and upper abdomen and in diagnostic procedures. In particular, temporal resolution and image quality are vitally important to accurate diagnosis and the minimization of planning target volume margin due to respiratory motion. To improve both temporal resolution and signal-to-noise ratio (SNR), we developed a respiratory-correlated segment reconstruction method (RS) and adapted it to the Feldkamp-Davis-Kress algorithm (FDK) with a 256 multidetector row CT (256MDCT). The 256MDCT scans approximately 100 mm in the craniocaudal direction with a 0.5 mm slice thickness in one rotation. Data acquisition for the RS-FDK relies on the assistance of a respiratory sensing system operating in cine scan mode (continuous axial scan with the table stationary). We evaluated the RS-FDK for volume accuracy and image noise in a phantom study with the 256MDCT and compared results with those for a full scan (FS-FDK), which is usually employed in conventional 4DCT and in half scan (HS-FDK). Results showed that the RS-FDK gave a more accurate volume than the others and had the same SNR as the FS-FDK. In a subsequent animal study, we demonstrated a practical sorting process for projection data which was unaffected by variations in respiratory period, and found that the RS-FDK gave the clearest visualization among the three algorithms of the margins of the liver and pulmonary vessels. In summary, the RS-FDK algorithm provides multi-phase images with higher temporal resolution and better SNR. This method should prove useful when combined with new radiotherapeutic and diagnostic techniques.

Proteomic profiling and neurodegeneration in Alzheimer's disease.

Quantitative proteome analysis of Alzheimer's disease (AD) brains was performed using 2-D gels to identify disease specific changes in protein expression. The task of characterizing the proteome and its components is now practically achievable because of the development and integration of four important tools: protein, EST, and complete genome sequence databases, mass spectrometry, matching software for protein sequences and protein separation technology. Mass spectrometry (MS) instrumentation has undergone a tremendous change over the past decade, culminating in the development of highly sensitive, robust instruments that can reliably analyze biomolecules, particularly proteins and peptides; we identified 35 proteins from over 100 protein spots on a 2-D gel. Using this current technology, protein-expression profiling, which is actually a specialized form of mining, is an important principal application of proteomics. The information obtained has tremendous potential as a means of determining the pathogenesis, and detecting disease markers and potential targets for drug therapy in AD.

Oxidative stress causes abnormal accumulation of familial amyotrophic lateral sclerosis-related mutant SOD1 in transgenic Caenorhabditis elegans.

Mutations in the Cu/Zn superoxide dismutase (SOD1) genes are present in approximately 20% of families suffering from familial amyotrophic lateral sclerosis (FALS). Results from several transgenic studies in which FALS-related SOD1 mutations have been expressed have suggested that mutant SOD1 proteins induce cytotoxicity through a toxic gain of function, although the specific mechanism of this has not been fully clarified. To investigate the mechanism of toxicity induced by the mutant SOD1 associated with FALS, we generated transgenic Caenorhabditis elegans strains that contain wild-type and mutant human A4V, G37R and G93A SOD1 recombinant plasmids. The transgenic strains expressing mutant human SOD1 showed greater vulnerability to oxidative stress induced by 0.2 mM paraquat than a control that contained the wild-type human SOD1. In the absence of oxidative stress, mutant human SOD1 proteins were degraded more rapidly than the wild-type human SOD1 protein in C.elegans. In the presence of oxidative stress, however, this rapid degradation was inhibited, and the transgenic C.elegans co-expressing mutant human SOD1 and green fluorescent proteins (GFPs) in muscle tissues demonstrated discrete aggregates in the adult stage. These results suggest that oxidative damage inhibits the degradation of FALS-related mutant human SOD1 proteins, resulting in an aberrant accumulation of mutant proteins that might contribute to the cytotoxicity.

Potent and selective ET-A antagonists. 1. Syntheses and structure-activity relationships of N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives.

Modifications to the ET(A/B) mixed type compounds 1 (Ro. 46-2005) and 2 (bosentan) were performed. Introduction of a pyrimidine group into 1 resulted in a dramatic increase in affinity for the ET(A) receptor, and the subsequent optimization of substituents on the pyrimidine ring led us to the discovery of N-(6-(2-((5-bromo-2-pyrimidinyl)oxy)ethoxy)-5-(4-methylphenyl)-4-pyrimidinyl)-4-tert-butylbenzenesulfonamide (7k), which showed an extremely high affinity for the human cloned ET(A) receptor (K(i) = 0.0042 +/- 0.0038 nM) and an ET(A/B) receptor selectivity up to 29 000 (K(i) = 130 +/- 50 nM for the human cloned ET(B) receptor). The compound was designed on the hypothesis that the hydrogen atom of the hydroxyl group in 1 and 2 played a role not as a proton donor but as an acceptor in the possible hydrogen bonding with Tyr129. Since the incorporation of a pyrimidinyl group into the hydroxyethoxy side chain of the nonselective antagonist (1) dramatically enhanced both the ET(A) receptor affinity and selectivity, and since similar results were obtained from the benzene analogues, we put forward the hypothesis that a "pyrimidine binding pocket" might exist in the ET(A) receptor.

Potent and selective ET-A antagonists. 2. Discovery and evaluation of potent and water soluble N-(6-(2-(aryloxy)ethoxy)-4-pyrimidinyl)sulfonamide derivatives.

In the preceding article,(1) we outlined the discovery and structure-activity relationship of a potent and selective ET(A) receptor antagonist 1 and its related compounds. Metabolites of 1 having potent selective ET(A) receptor antagonist activity were identified. This study suggested the metabolic pathways of 1 were considerably affected by species. Consequently, structural modification of 1 intended to improve the complexity of the metabolic pathway, and water solubility was performed. The subsequent introduction of a hydroxyl group into the tert-butyl moiety of 1 led to the discovery of our new clinical candidate, 6b, which showed a higher water solubility, a uniform metabolic pathway among species, and very high affinity and selectivity for the human ET(A) receptor (K(i) for ET(A) receptor: 0.015 +/- 0.004 nM; for ET(B) receptor: 41 +/- 21 nM).

Dosimetry of pulsed clinical proton beams by a small ionization chamber.

Response of a micro volume (0.01 ml) ionization chamber has been studied with pulsed proton beams which are used for clinical purposes and has been compared with those of some JARP ionization chambers (0.6 ml). All chambers used had been calibrated by standard 60Co beams at the Electrotechnical Laboratory (ETL) and exposure calibration factors, Nx, were obtained on advance. Two methods are used to compensate the general recombination which occurs during pulsed beam irradiations: theoretical correction by a Boag's formulation and a modified two-voltage technique. An evaluation of absolute absorbed dose-to-water is performed on the basis of the protocol provided by ICRU report 59. The results imply that, to a first approximation, both chambers indicate the almost same result within 2% when unknown chamber-dependent parameters of the micro chamber are tentatively assumed to be identical to those of the JARP chamber for the calibration with 60Co beams. The about 1.5% discrepancy observed in the response of both chambers is not discussible due to presumably 1-2% uncertainty of the protocol of ICRU report 59 which does not include any chamber-dependent corrections for the perturbation effects in proton beams.

A case of frontotemporal dementia and parkinsonism of early onset with progressive supranuclear palsy-like features.

We report a patient with frontotemporal degeneration and parkinsonism with mental retardation. The patient was a 54-year-old man who had parkinsonism that resembled progressive supranuclear palsy, frontotemporal degeneration and myoclonus. His family included many affected members. Neuropathologically, there was degeneration of the frontal and temporal cortices, the basal ganglia, the brainstem and the cerebellum. Microscopically, neuronal loss was severe in the frontal and temporal cortex, the globus pallidus, substantia nigra, red nucleus and dentate nucleus. Fibrillary changes were found in neurons and glia that were immunostained for tau. Although we could not define the genetic abnormalities, we thought that this case might have involved frontotemporal dementia and parkinsonism linked to chromosome 17.

Multi-layer energy filter for realizing conformal irradiation in charged particle therapy.

A new type of filter for charged particle radiotherapy is developed to reduce unwanted dose transfer to the normal tissues around a tumor. The new filter can make a static irradiation field where the width of the spread-out Bragg peak (SOBP) is two-dimensionally adjusted. That makes the field conformal to the tumor three-dimensionally. The filter is made of many layers produced by using stereolithography. The layer has a miniaturized structure that has geometrical similarity to the conventional ridge filter. Shapes of cone and pyramid are also usable for the unit-cell constructing the layer. The spread of the field in the depth direction is decided by the thickness of the filter, or by the number of layers. The experimental result of the irradiation using the ridge-type construction shows a good agreement with an estimate by the Monte Carlo calculation. By combining this technique with intensity modulation that has lateral position dependence, the conformal irradiation can be achieved by a simple procedure.

Prevention of cerebral vasospasm by a novel endothelin receptor antagonist, TA-0201.

This study was designed to examine the preventive effect of a novel endothelin (ET)-receptor antagonist TA-0201 on the cerebral vasospasm in a canine double-hemorrhage model. TA-0201 (10(-9)-10(-7) M) inhibited ET-1-induced vasoconstriction in the isolated canine basilar artery without endothelium in a concentration-dependent manner. Its pA2 value was 9.2 (ET(A) antagonism). In a canine double-hemorrhage model, intravenous treatment with TA-0201 (3 mg/kg, twice a day for 7 days) ameliorated the basilar artery narrowing significantly on day 7 compared with that in nontreated dogs. The reductions of the basilar artery diameter were 26.1+/-3.9% and 40.5+/-4.1% with and without TA-0201 treatment, respectively (p<0.05). Histologic study on day 7 indicated that treatment with TA-0201 inhibited vessel-wall damage such as disintegration of endothelium architecture and degeneration of medial smooth-muscle cells. We conclude that intravenous treatment with TA-0201 prevents the development of cerebral vasospasm and accompanying pathologic changes of the vessel wall, probably through blockade of ET(A) receptors.

Characteristics of heterogeneity in the expression of vasoconstriction in response to N(G)-monomethyl-L-arginine in isolated canine arteries.

We characterized the contractile effect of a nitric oxide (NO) synthase inhibitor, N(G)-monomethyl-L-arginine (L-NMMA), in isolated canine arteries. L-NMMA induced a heterogenous response: potent vasoconstriction in the cerebral arteries, and weak or no vasoconstrictor responses in different peripheral arteries. The vasoconstriction of the cerebral artery was inhibited by L-arginine but not D-arginine. L-NMMA (1(-4) M) caused a 53% decrease in guanosine 3'5'-cyclic monophosphate (cGMP) levels in the cerebral artery, but it was not significant compared with that in peripheral arteries. The L-NMMA-induced vasoconstriction was inhibited by diltiazem and nicardipine, and the heterogeneity was mimicked by treatment with charybdotoxin, a Ca2+-activated K+ (BK(Ca)) channel blocker, channels which are regulated by NO/cGMP. Both L-NMMA and charybdotoxin caused a potent vasoconstriction in the mesenteric artery precontracted with 20 mM KCl. 1 H-[1,2,4]oxadiazolo[4,3-alpha] quinoxalin-1-one (ODQ) (10(-5) M), a selective guanylate cyclase inhibitor, caused vasoconstriction in the presence of nitroprusside in the endothelium-denuded basilar artery, but not in the endothelium-denuded mesenteric artery. In conclusion, LNMMA-induced heterogenous vasoconstriction was due to the different sensitivities of vascular smooth muscles to NO/cGMP. The heterogeneity may result from a difference in the basal state of ion channels such as the voltage-dependent Ca2+ channel and the BK(Ca) channel in vascular smooth muscles.

Effects of the endothelin ET(A) receptor antagonist, TA-0201, on pulmonary arteries isolated from hypoxic rats.

To investigate the roles of endothelin-1 in the pathogenesis of hypoxic pulmonary hypertension, we studied the effects of a selective endothelin ET(A) receptor antagonist, TA-0201 (N-(6-(2-(5-Bromopyrimidin-2-yloxy) ethoxy)-5-(4-methylphenyl) pyrimidin-4-yl)-4-(2-hydroxy-1,1-dimethylethyl) benzensulfonamide sodium salt sesquihydrate), on helical strips of pulmonary arteries isolated from hypoxia-induced pulmonary hypertensive rats as compared with those of normoxic rats. Endothelin-1-induced maximum contractions were significantly inhibited by exposure to hypoxia in the pulmonary arterial strips, but not in the mesenteric arterial strips. The hypoxia also induced right ventricular hypertrophy in rats. Addition of TA-0201 to the bath inhibited the endothelin-1-induced contraction of pulmonary arterial strips isolated from hypoxic rats more effectively than in those of normoxic rats. Oral administration of TA-0201 to hypoxic rats inhibited the hypoxia-induced right ventricular hypertrophy, and decreased the maximum contractile response to endothelin-1 in pulmonary arterial strips isolated from these rats. Those inhibitory effects induced by the oral administration of TA-0201 were not observed in the pulmonary arteries from normoxic rats or in the mesenteric arteries from both hypoxic and normoxic rats. These results suggest that endothelin-1 has important pathophysiological roles in hypoxia-induced pulmonary hypertension, and that TA-0201 may inhibit the endothelin-l-induced contraction through a change in the function of endothelin ET(A) receptor as well as competitive inhibition for endothelin ET(A) receptor.

Role of endothelin in deterioration of heart failure due to cardiomyopathy in hamsters: increase in endothelin-1 production in the heart and beneficial effect of endothelin-A receptor antagonist on survival and cardiac function.

BACKGROUND: We previously reported that chronic endothelin (ET) receptor blockade ameliorated the survival rate and cardiac hemodynamics in rats with chronic heart failure (CHF) due to myocardial infarction. However, it remains unclear whether ET-1 is involved in the pathophysiology of cardiomyopathy, which is one of the major causes of CHF. Accordingly, we investigated the production of ET-1 in the heart and the effect of chronic ETA receptor blockade on survival rate and cardiac function in the Bio 14.6 hamster, which is an idiopathic model of CHF caused by cardiomyopathy. METHODS AND RESULTS: We used 52-week-old Bio 14.6 cardiomyopathic hamsters and age-matched F1b normal hamsters. The expression of preproET-1 mRNA and the ET-1 level in the hearts were markedly higher in the cardiomyopathic hamsters than in the normal hamsters. The cardiomyopathic hamsters showed severe CHF, illustrated by lower left ventricular (LV) +dP/dt/Pmax and right ventricular (RV) +dP/dt/Pmax and by higher LV end-diastolic pressure (EDP), RVEDP, and central venous pressure compared with the normal hamsters. Long-term (9 weeks) treatment with an ETA antagonist (TA-0201, 1.3 mg. kg-1. d-1) markedly increased survival of cardiomyopathic hamsters (untreated, 16%; TA-0201-treated, 65.2%; P<0.001). After 6 weeks of treatment, LV +dP/dt/Pmax and RV +dP/dt/Pmax were significantly higher and LVEDP and RVEDP were lower in the TA-0201-treated group than in the untreated group, suggesting that chronic TA-0201 treatment effectively prevented deterioration of cardiac dysfunction. CONCLUSIONS: In the cardiomyopathic hamsters with CHF, the production of ET-1 in the heart was markedly increased, and chronic ETA receptor blockade greatly ameliorated survival and cardiac dysfunction. These results suggest that ET-1 plays an important role in the deterioration of CHF caused by cardiomyopathy, and ETA antagonists may exert therapeutic effects in CHF due to cardiomyopathy.