Influence of leukotriene pathway polymorphisms on clinical responses to montelukast in Japanese patients with asthma.

WHAT IS KNOWN AND OBJECTIVE: Montelukast, a cysteinyl leukotriene receptor 1 antagonist, is safe and efficacious in patients with asthma. The mechanisms underlying the significant interpatient variability in response to montelukast are not clear but are believed to be, in part, because of genetic variability. METHODS: To examine the associations between polymorphisms in candidate genes in the leukotriene pathway and outcomes in patients with asthma on montelukast for 4-8 weeks, we evaluated the changes in peak expiratory flow (PEF), forced expiratory volume in 1 s (FEV(1·0) ) and patients' subjective symptom before and after montelukast treatment. DNA was collected from 252 Japanese participants. RESULTS AND DISCUSSION: Two single-nucleotide polymorphisms (SNPs) in the ALOX5 (rs2115819) and LTA4H (rs2660845) genes were successfully typed. There was no difference between members of the general population (n = 200) and patients (n = 52) in each genotype frequency. Significant associations were found between SNP genotypes in the LTA4H gene and changes in PEF and FEV(1·0) . The PEF and FEV(1·0) responses to montelukast in the A/A genotypes (n = 4) for the LTA4H SNP were significantly higher than those in the G allele carriers (A/G+G/G) (n = 17). WHAT IS NEW AND CONCLUSION: Despite the small sample size, our results suggest that genetic variation in leukotriene pathway candidate genes contributes to variability in clinical responses to montelukast in Japanese patients with asthma.

Health-related quality of life does not predict mortality in idiopathic pulmonary fibrosis.

BACKGROUND: Although health-related quality of life (HRQL) has recently been considered to be an important outcome in clinical trials of idiopathic pulmonary fibrosis (IPF), its relationship with survival is unknown. OBJECTIVE: To determine the prognostic significance of HRQL scores in IPF assessed with the SGRQ. DESIGN: Eighty-seven consecutive patients with IPF, who had undergone evaluations and completed the St. George's Respiratory Questionnaire (SGRQ) at diagnosis were included in this study, as is the general practice. Cox proportional hazards analyses were performed to examine the relationship between HRQL scores and survival. RESULTS: The mean observation period was 44.2 +/- 29.6 mo, in the course of which 54 patients (62.0%) died. Univariate analysis revealed that the activity scores in the SGRQ(HR: 1.016, 95% CI: 1.004-1.029, P = 0.01) were significantly predictive of survival, although the symptoms, impacts, and total scores were not significantly related to mortality from all causes. However, multivariate analysis revealed that only the forced vital capacity percent predicted was a significant predictor of survival, and that the activity score in the SGRQwas not significantly related to mortality. CONCLUSIONS: There was no significant relationship between HRQL evaluated with the SGRQ and the subsequent mortality in IPF. The present negative result might suggest that HRQL is measuring an aspect other than one from physiological and functional impairment or disability.

A simple assessment of dyspnoea as a prognostic indicator in idiopathic pulmonary fibrosis.

The prognosis in idiopathic pulmonary fibrosis (IPF) is poor. No therapy has been shown to prolong survival. The objective of this study was to examine the prognostic significance of dyspnoea in daily living at baseline in IPF using a simple assessment tool. 93 consecutive patients with IPF, who had undergone evaluation at diagnosis, were included. The level of dyspnoea was assessed using the modified Medical Research Council (MRC) scale. The relationship between data at baseline and survival was examined. A univariate Cox proportional-hazard model showed that forced vital capacity % predicted (hazard ratio (HR) 0.965, 95% CI 0.948-0.982; p<0.0001), diffusing capacity of the lung for carbon monoxide % predicted (HR 0.978, 95% CI 0.963-0.993; p = 0.0041), baseline arterial oxygen tension (HR 0.963, 95% CI 0.938-0.989; p = 0.0060) and modified MRC score (HR 2.402, 95% CI 1.495-3.858; p = 0.0003) were significantly predictive of survival. All variables of the 6-min walk test, including walk distance (HR 0.995, 95% CI 0.992-0.998; p = 0.0020), the lowest arterial oxygen saturation measured by pulse oximetry (S(p,O(2))) (HR 0.944, 95% CI 0.918-0.972; p<0.0001) and the Borg scale (HR 1.285, 95% CI 1.091-1.514; p = 0.0027), were also significant. With stepwise, multivariate Cox proportional analysis, the modified MRC score (HR 2.181, 95% CI 1.333-3.568; p = 0.0019) and the lowest S(p,O(2)) during the 6-min walk test (HR 0.952, 95% CI 0.924-0.981; p = 0.0014) were the most significant. Dyspnoea in daily living, assessed with the modified MRC scale at baseline, provides additional prognostic information for patients with IPF.

Risk factors of acute exacerbation of idiopathic pulmonary fibrosis.

BACKGROUND: Although acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a well known clinical condition, predicting risk factors remain unknown. We evaluated the frequency, risk factors and impact on survival of AE-IPF. METHODS: We retrospectively studied patients diagnosed with IPF based on the criteria of the ATS/ERS consensus statement and followed them for periods of more than 3 years except in dead cases. Initial characteristics including the level of dyspnoea, which was assessed with the modified Medical Research Council (MRC) scale, and decline of forced vital capacity (FVC) defined by at least 10% decline at 6 months, were evaluated as possible risk factors for AE. RESULTS: Seventy-four patients with IPF were studied. One-year, two-year, and three-year incidence of AE were 8.6%, 12.6%, and 23.9%, respectively. Multivariate analysis revealed that higher body mass index (BMI) [hazard ratio (HR), 1.20; 95% confidence interval (CI), 1.03-1.40], higher modified MRC scale [HR, 2.93; 95% CI, 1.46-5.85], and a decline in FVC at 6 mounths [HR, 0.97-2.60 (per mo); 95% CI, 1.01-7.45] were independent risk factors for AE-IPF. The causes of death were assessed to be AE in 20 of 57 expired patients. A stepwise multivariate Cox regression model evaluating AE-IPF, adjusted for %FVC and decline in FVC, demonstrated a statistically significant impact on overall survival [HR, 2.79; 95% CI, 1.59-4.88; p < 0.001]. CONCLUSION: These data suggest that initial high modified MRC scale, high BMI, and decline in FVC at 6 months were significant independent risk factors for AE-IPF. AE was an independent prognostic factor in IPF.

Factors in maintaining long-term improvements in health-related quality of life after pulmonary rehabilitation for COPD.

The purpose of this study was to reveal predictors for the long-term effects of pulmonary rehabilitation for chronic obstructive pulmonary disease (COPD) patients, in terms of health-related quality of life (HRQoL). We investigated the long-term effects of pulmonary rehabilitation in 53 COPD patients who had completed the outpatient program and could be evaluated continuously for 1 year. We also investigated factors related to long-term maintenance of HRQoL assessed by the St George's Respiratory Questionnaire (SGRQ). In the year following the program, the only items that retained a significant improvement compared with the pre-program levels were respiratory muscle strength and 6-min walking distance. Patients whose total SGRQ score showed improvements that were maintained above the minimal clinically important difference were placed in a maintained-improvements group (n = 18, 34.0%), and the others in a non-maintained group (n = 35, 66.0%). A comparison of the groups revealed that the maintained-improvements group had significantly lower forced vital capacity (FVC), inspiratory capacity (IC), and tidal volume (TV) at rest; higher PaCO(2); greater initial impairments in HRQoL; and more frequent attendance in a maintenance program. In a multiple logistic regression model, only PaCO(2) was identified as predictor for the maintenance of improvement in HRQoL over a long term. In conclusion, higher baseline PaCO(2) is predictor of maintained, long-term improvement in HRQoL after pulmonary rehabilitation. Frequent attendance in a maintenance program is another predictor.

Health-related quality of life in patients with idiopathic pulmonary fibrosis. What is the main contributing factor?

The prognosis of patients with idiopathic pulmonary fibrosis (IPF) is generally considered to be poor. As the disease progresses, patients invariably become severely limited in their activities. Therefore, evaluating the health-related quality of life (HRQoL) in IPF patients is considered to be important. However, there have been few studies of this kind to date. We applied the St. George's Respiratory Questionnaire (SGRQ) to 41 consecutive IPF patients and examined various physiological variables to identify factors that were correlated with the HRQoL. Total lung capacity, transfer factor, arterial partial pressure of oxygen at rest, the lowest oxygen saturation during exercise test, and the baseline dyspnoea index (BDI) score were significantly correlated with the total SGRQ score. A similar tendency was observed in each component. Conversely, peak oxygen uptake, known as one of the important factors that determines HRQoL in chronic obstructive pulmonary disease (COPD), did not correlate with any SGRQ scores. In stepwise multiple regression analysis, the BDI score was selected as the only factor significantly contributing to the total SGRQ score. Dyspnoea was the most important factor determining HRQoL in IPF. The types of other variables that correlated with the HRQoL in IPF patients were different from those in COPD.

Cyclophosphamide and low-dose prednisolone in idiopathic pulmonary fibrosis and fibrosing nonspecific interstitial pneumonia.

The present study compared the efficacy of cyclophosphamide combined with low-dose prednisolone in the treatment of idiopathic pulmonary fibrosis (IPF) with efficacy in idiopathic fibrosing nonspecific interstitial pneumonia fibrosing (NSIP). A total of 27 patients with IPF and 12 patients with fibrosing NSIP were included in this study. All patients had undergone surgical lung biopsy. The diagnoses were made based on clinical, radiological and pathological findings. All patients were treated with intermittent pulse therapy with methylprednisolone for 4 weeks, followed by cyclophosphamide with low-dose prednisolone. According to pulmonary function tests, four of 27 patients with IPF had improved, 22 remained unchanged, and one had worsened at the completion of pulse therapy. After 1 yr of combination therapy, four of 27 patients had improved, 14 remained unchanged, and nine had worsened. After pulse therapy, four of 12 patients with fibrosing NSIP had improved, and eight remained unchanged. After 1 yr of combination therapy, eight of 12 patients had improved, four remained unchanged, and none had worsened. Median survival of IPF patients was 4.1 yrs, which is significantly worse than that of fibrosing NSIP patients. In conclusion, patients with fibrosing nonspecific interstitial pneumonia had a more favourable response to combination therapy and a better survival than those with idiopathic pulmonary fibrosis.

[Aortitis syndrome associated with ulcerative colitis, preceded by pulmonary infarction involvement].

A 21-year-old woman with a 6-year history of ulcerative colitis admitted to our hospital with chest pain, cough and fever of unknown origin in August 1998. On admission, laboratory data showed positive inflammatory signs. A chest radiograph and chest computed tomogram (CT) revealed nodular shadows in the right upper lung field. Fifty days after admission, hypertension developed and a bruit was audible in the neck and the upper abdomen. Digital subtraction angiography showed stenosis in carotid, renal and right upper pulmonary arteries. On the basis of these results, a diagnosis of aortitis syndrome was made. Moreover, these findings indicated pulmonary infarction in the right upper lobe due to aortitis syndrome. Aortitis syndrome preceded by pulmonary infarction involvement is very rare. Autoimmune disorders may have been involved in this case because of the association with ulcerative colitis.

Effect of prolonged low-dose methylprednisolone therapy in acute exacerbation of idiopathic pulmonary fibrosis.

We report on a 74-year-old man with an acute exacerbation of idiopathic pulmonary fibrosis (IPF) who was successfully treated with prolonged low-dose methylprednisolone, initiated at a loading dose of 2 mg/kg, followed by 2 mg/kg per day for 14 days. The dose was then tapered. The exacerbation observed on the chest radiograph and high-resolution computed tomography was found to have abated after the treatment. This successful case suggests the feasibility of this methylprednisolone treatment protocol for patients with IPF accompanied by accelerated deterioration. Furthermore, this case suggests possible similarities between acute exacerbation of IPF and late acute respiratory distress syndrome, as the same treatment protocol was previously proved to be beneficial for patients with late acute respiratory distress syndrome.

Serial high resolution CT findings in nonspecific interstitial pneumonia/fibrosis.

PURPOSE: The purpose of this work was to evaluate the radiographic and serial high resolution CT (HRCT) findings in patients with nonspecific interstitial pneumonia/ fibrosis (NSIP). METHOD: We identified 15 patients with biopsy-proven NSIP. Radiography and initial and follow-up CT findings were reviewed. RESULTS: Predominant radiographic findings were bilateral infiltrates distributing in the middle and lower lung zones and decreased lung volumes. At initial CT, predominant patterns were peribronchovascular interstitial thickening (n = 6), parenchymal bands (n = 8), intralobular interstitial thickening (n = 12), and traction bronchiectasis (n = 14). Mixed pattern of ground-glass opacity and consolidation (n = 11) were predominant findings of increased lung opacity. At follow-up CT in 14 cases, the abnormalities had disappeared completely in 3, improved in 9, persisted in 1, and worsened in 1. CONCLUSION: The pulmonary abnormalities observed in NSIP on HRCT can disappear or be diminished in most cases after corticosteroid therapy. Intralobular interstitial thickening and traction bronchiectasis, which have been considered to be indicators of irreversible fibrosis, also show favorable responses.

The effectiveness of the visual analogue scale 8 in measuring health-related quality of life for COPD patients.

The Visual Analogue Scale 8 (VAS8), consisting of eight linear scales, has been developed to measure health-related quality of life (HRQoL) in chronic obstructive pulmonary disease (COPD) patients. The purpose of this study was to examine the validity and responsiveness of the VAS8. First, HRQoL was assessed in a cross-sectional study with the VAS8 and the St George's Respiratory Questionnaire (SGRQ) in 46 COPD patients. Relationships between the VAS8 and various physiological parameters were examined. Second, in a longitudinal study, changes in HRQoL scores after pulmonary rehabilitation were evaluated in 29 COPD patients. The total VAS8 scores showed a weak correlation with vital capacity and maximal inspiratory pressure and a moderately strong correlation with 6-min walking distance and dyspnoea rating. The total VAS8 score showed a significant correlation with each SGRQ score. Furthermore, almost every VAS8 and SGRQ score improved significantly after pulmonary rehabilitation. The change in the total VAS8 value showed a strong correlation with that of the SGRQ. The VAS8 is well-suited to assess HRQoL in COPD patients. Visual analogue scales are generally useful in measuring HRQoL in COPD patients, and the VAS8 is particularly beneficial because of its ease of use.

[Positive response to smoking challenge test in a case of acute eosinophilic pneumonia].

A 19-year-old man presented with an acute febrile illness and progressive dyspnea. He had begun smoking two weeks before admission. A chest X-ray film revealed Kerley B lines and diffuse infiltration in both lungs. Analysis of bronchoalveolar lavage fluid showed 21% eosinophils. The patient had no history of hypersensitivity to drugs, nor was there any evidence of infectious disease. Acute eosinophilic pneumonia was diagnosed, and his condition improved without steroid treatment. A smoking challenge test was performed. After the test, the patient's body temperature rose to 38.0 degrees C, computed tomograms of the chest showed increased density, and elevated eosinophil levels were again detected in bronchoalveolar lavage fluid. These findings supported the view that beginning to smoke can be a cause of acute eosinophilic pneumonia.

Assessment of myocardial fatty acid metabolic abnormalities in patients with idiopathic dilated cardiomyopathy using 123I BMIPP SPECT: correlation with clinicopathological findings and clinical course.

OBJECTIVE: To determine the clinical and prognostic value of identifying metabolic abnormalities of myocardial fatty acid metabolism in idiopathic dilated cardiomyopathy using iodine-123 beta-methyl-iodophenyl pentadecanoic acid (123I BMIPP). SETTING: Cardiac care division in national hospital. PATIENTS: 32 consecutive patients with idiopathic dilated cardiomyopathy in whom both 123I BMIPP and thallium-201 myocardial single photon emission computed tomography were performed. METHODS: The uptake of each tracer was scored visually from 0 (normal) to 3 (defect) in 17 segments (eight basal, eight midventricular, and one apical). A total score for all 17 segments was compared with clinicopathological variables. Prognostic value of mismatches between the two tracers were also evaluated. RESULTS: The 123I BMIPP total score was correlated with pulmonary capillary wedge pressure (r = 0.68, p < 0.001), left ventricular end diastolic pressure (r = 0.65, p < 0.001), percentage fractional shortening at six months' follow up (r = -0.58, p = 0. 001), myocyte diameter (r = 0.66, p < 0.001), and percentage area of interstitial fibrosis (r = 0.69, p < 0.001) measured by morphometry in the biopsy specimens. During a mean (SD) follow up of 20 (11) months, deterioration of the New York Heart Association functional class was observed in 11 of the 32 patients; four of these died. Segments with a greater decrease in 123I BMIPP than thallium-201 uptake (type B mismatching) were often observed in patients with deterioration (88/187, 29% v 58/357, 16%; p < 0.001). CONCLUSIONS: The extent of the abnormality of myocardial fatty acid metabolism in idiopathic dilated cardiomyopathy reflects the severity of haemodynamic deterioration and histopathological changes. Type B mismatching is one of the important prognostic indicators in idiopathic dilated cardiomyopathy.

[Irreversible airflow limitation in asthmatics].

To evaluate irreversible airflow limitation in asthmatics, we studied 168 patients admitted to our hospital with acute exacerbation of asthma. All patients were given intravenous methylprednisolone for at least 7 days to maximum 14 days and the best of PEF (% of predicted) was evaluated. In all subjects, the best of PEF showed significant correlations with both the patients' age (r = -0.411, p < 0.0001) and the duration of asthma (r = -0.494, p < 0.0001). A significant correlations between the best of PEF and the duration of asthma were also observed in both patients over 60 years old (r = -0.157, p < 0.0001) and non-smokers (r = -0.568, p < 0.0001). We conclude that asthma may develop irreversible airflow limitation in itself and the degree of impairment of lung function correlated with the duration of the disease.

[Preventive effect of pravastatin on restenosis following coronary angioplasty: prospective randomized trial].

This study investigated the preventive effect of pravastatin on restenosis following successful transluminal coronary angiography (PTCA) in 109 consecutive patients. Patients were randomly and prospectively assigned to the pravastatin group (group P, n = 57) or the control group (group C, n = 52). The former received 10 mg/day pravastatin from the day of PTCA for 3 months. Restenosis was defined as a > or = 50% diameter stenosis at follow-up angiography with a > or = 15% reduction in luminal diameter compared to post-PTCA. The effect of pravastatin was analyzed in association with 7 clinical and 15 angiographic factors. Follow-up rate, serum lipid levels (total cholesterol, triglyceride, and HDL-cholesterol), and clinical and angiographic backgrounds except age and angularity of the lesions were not significantly different between the two groups at PTCA. Three months later, total cholesterol decreased from 222.3 +/- 35.1 to 179.2 +/- 31.2 mg/dl in group P, but was unchanged in group C (from 226.0 +/- 33.7 to 211.7 +/- 30.9 mg/dl). The restenosis rate was not different between the two groups (35.6 vs 35.7% per patient, 32.0 vs 33.3% per lesion). Moreover, no relationship between restenosis rate and serum total cholesterol level at follow-up angiography was observed. Multivariate analysis, including 7 clinical and 15 angiographic factors, found neither pravastatin administration nor serum lipid levels were significantly correlated with decreased luminal diameter. Pravastatin (10 mg/day) did not reduce the incidence of restenosis after PTCA when administered from the day of PTCA for 3 months.

Histological abnormalities in a biopsy specimen obtained from the left ventricle without reduced function in a patient with right ventricular dysplasia.

Left ventricular histological examination was performed in a patient with right ventricular (RV) dysplasia. Although the left ventricle (LV) appeared to have a normal shape and function, the LV biopsy specimen revealed apparent myocyte hypertrophy and substantial fibrotic changes without fatty infiltration. It was not clear whether these considerable histological changes were part of right ventricular dysplasia or not. The present case indicates that even with normal LV shape and function in patients with right ventricular dysplasia, histological examination of LV may provide additional information on its pathogenesis and prognosis.

Acute left main coronary artery obstruction with myocardial infarction--reperfusion strategies, and the clinical and angiographic outcome.

We studied the clinical and angiographic outcomes in 8 patients with acute left main coronary artery obstruction. Intracoronary thrombolysis with 1.2 x 10(5) units of urokinase was performed in 3 patients during preparation for percutaneous transluminal coronary angioplasty (PTCA), and failed in all 3 cases. In 2 patients, the left main coronary artery was recanalized by intracoronary thrombolysis with 3.6 and 4.8 x 10(5) units of urokinase, respectively. PTCA was attempted either before or after intracoronary thrombolysis in 5 patients and achieved reperfusion in all 5 cases. However, 2 of the 8 patients had persistent high-grade residual stenosis 69% and 89% luminal reduction, respectively. Emergency coronary artery bypass grafting was successfully performed in these 2 patients, and both are currently alive. Although intraaortic balloon counterpulsation was performed in all 8 patients, 2 died acutely from pump failure in the catheterization laboratory. One patient died later due to congestive heart failure. The factors favoring survival were right coronary artery dominance and a well-developed collateral circulation. Our findings suggest that PTCA is a useful strategy for reperfusion following acute left main coronary artery occlusion. When PTCA cannot achieve sufficient revascularization, emergency coronary artery bypass grafting should be performed. To control pump failure, intraaortic balloon counterpulsation is insufficient in some cases and more aggressive measures may be required.

Emergency coronary angioplasty for acute myocardial infarction--factors affecting acute restenosis in catheterization laboratory and reocclusion during hospitalization.

A total of 107 consecutive patients with acute myocardial infarction underwent emergency coronary angioplasty (PTCA). Restoration of blood flow with TIMI grade III was established by emergency PTCA in 101 patients (94.4%). "Acute restenosis" was defined as a lesion that, when dilated to less than 50%, narrowed again to more than 75% luminar reduction 5 min after the balloon inflation. Acute restenosis occurred in 39 patients (39%). Multivariate analysis selected 3 factors associated significantly with an increased rate of acute restenosis: (1) dissection, (2) small balloon/artery diameter ratio and (3) low systolic blood pressure during PTCA. Reocclusion, which was defined as a total reobstruction of the lesion during hospitalization following emergency PTCA, was examined by predischarge coronary angiography. Acute restenosis correlated significantly with an increase in reocclusion rate. The incidence of documented reocclusion was 12%. Residual stenosis, multivessel disease and irregular dilation correlated significantly with an increased rate of reocclusion. The in-hospital and postdischarge mortalities were 5.6% and 2.1%, respectively. In summary, emergency PTCA produced a high angiographic success rate. Use of adequate balloon size and sufficient dilation correlated significantly with angiographic outcome in emergency PTCA. Patients with acute restenosis, high residual stenosis, irregular dilation, and multivessel disease would have a relatively high risk of reocclusion.

[A case of acute myocardial infarction due to simultaneous occlusion of the right coronary artery and left anterior descending coronary artery].

We reported a rare case of a 53-year-old man who experienced acute myocardial infarction due to simultaneous occlusion in the right coronary artery and the left anterior descending coronary artery. He also experienced thromboembolisms on several occasions. So anticoagulant therapy is necessary for patients with exceedingly poor LV function.

[Chronic intractable pericardial effusion associated with pulmonary hypertension: report of two cases].

We report two cases of chronic intractable pericardial effusion associated with pulmonary hypertension. Case 1. A 35-year-old women was admitted to our hospital because of dyspnea and edema. Chest X-ray examination showed enlargement of cardiac, and pulmonary artery shadow. An electrocardiogram with high voltage of R in V1 and deep S in V5 suggested right ventricular hypertrophy. Pericardial echo-free space with dilated right ventricle was demonstrated by echocardiography. Cardiac catheterization revealed an elevated pulmonary systolic pressure of 120 mmHg. No intracardiac shunt was calculated. A diagnosis of primary pulmonary hypertension was made. Pericardial drainage diminished pericardial effusion. Soon after discharge, however, pericardial effusion increased and the patient died. Case 2. A 65-year-old man was admitted because of dyspnea. The findings of chest X-ray and echocardiography were essentially the same as Case 1. Pericardial effusion disappeared after pericardiocentesis, but appeared again one month later. Cardiac catheterization demonstrated an elevated pulmonary systolic pressure of 73 mmHg. Pulmonary-capillary-wedge pressure was normal. Pulmonary arteriogram showed occlusion of the pulmonary artery trees. A diagnosis of chronic thromboembolic pulmonary hypertension was made. Although diuretics and vasodilators decreased pulmonary-artery pressure, pericardial effusion was unchanged. We compared these two cases with 11 control patients of pulmonary hypertension without pericardial effusion. Venous pressure was higher than that in the controls in Case 1, but not different in Case 2. Thus, venous pressure did not fully account for pericardial effusion. In summary, chronic pulmonary hypertension should be added to the list of conditions known to cause pericardial effusion. In these cases, echocardiography revealed important signs, and cardiac catheterization was essential for definite diagnosis. Pericardial effusion associated with pulmonary hypertension was refractory to diuretics and vasodilators.