Time-course of ventilation, arterial and pulmonary CO(2) tension during CO (2) increase in humans.

A change of ventilation (VE), PaCO( 2 ) (arterial CO( 2 ) tension) and PvCO( 2 ) (pulmonary arterial CO( 2 ) tension) with time was not evaluated precisely during exercise or CO( 2 ) rebreathing in humans. In this study, changes of these variables with time were fitted to exponential curves {y = Exp ( x/ T + A ) + k} and compared. When exercise pulmonary hemodynamics was examined in 15 cardiac patients to decide therapies, we asked the patients to undergo CO( 2 ) rebreathing using air with supplementation of consumed O( 2 ). Arterial and pulmonary blood was drawn every minute. During exercise, T was 28.2 ± 8.4 and 26.8 ± 12.4, and A was 0.80 ± 0.50 and 0.50 ± 0.90 in VE and PvCO( 2 ), respectively, with no statistical differences. During CO( 2 ) rebreathing, T was 18.6 ± 5.8, 41.8 ± 38.0 and 21.6 ± 9.7 and A was 0.39 ± 0.67, 1.64 ± 1.35 and 0.17 ± 0.83 in VE, PaCO( 2 ) and PvCO( 2 ), respectively, with statistical difference of PaCO( 2 ) from other variables, suggesting that VE and PvCO( 2 ) showed same mode of change according to time but PaCO( 2 ) did not.

Histopathological multiple recanalized lesion is critical element of outcome after pulmonary thromboendarterectomy.

Pulmonary thromboendarterectomy (PEA) is a curative therapy for chronic thromboembolic pulmonary hypertension (CTEPH), but the postoperative mortality remains unsatisfactory (4-10%). Residual pulmonary hypertension is the most common cause of perioperative death. Although PEA specimens seem to contain lesions responsible for hemodynamic improvement, relevant histopathological findings have still to be identified.The aim of this study was to identify histopathological findings that predict postoperative residual pulmonary hypertension after PEA.PEA specimens obtained from 51 consecutive patients with CTEPH were histopathologically assessed. The patient characteristics and disease location were reviewed by medical records. The associations with residual pulmonary hypertension were analyzed.The mean values of preoperative and postoperative vascular resistance (PVR) were 1142 ± 454 and 496 ± 368 dynes•sec/cm(-5), respectively. Twenty of 51 patients (39%), including 2 patients who died, continued to have residual pulmonary hypertension (PVR ≥ 500 dynes•sec/cm(-5)). Statistical tests indicated that male, proximal disease type and the presence of histopathological multiple recanalized thrombus were associated with good surgical outcome (PVR < 500 dynes•sec/cm(-5)). The positive and negative predictive values for surgical outcome estimated by the presence of multiple recanalized lesions were higher than the values estimated by proximal disease type (85% and 88% versus 73% and 71%, respectively). Moreover, the number of multiple recanalize lesions was significantly correlated to the reduction in PVR (P = 0.03).The presence of histopathological multiple recanalized lesions was significantly associated with a decrease in PVR after PEA. Histopathological study may be a potent diagnostic strategy for accurately predicting surgical outcome in the early perioperative period.

A simple method to predict impaired right ventricular performance and disease severity in chronic pulmonary hypertension using strain rate imaging.

BACKGROUND: The evaluation of right ventricular (RV) function is clinically important in pulmonary hypertension (PH) because of prognostic implications. Conventional echocardiography has been used to predict adverse outcomes in chronic PH, but there were certain limitations arising from the complexity of RV anatomy. We used strain rate imaging (SRI) to evaluate RV function in PH patients. METHODS: Study population consisted of 50 patients (mean age 46 ± 13 years; 39 females) with chronic PH who underwent echocardiography including SRI within 24h of right heart catheterization. Mean value of peak systolic longitudinal strain obtained from basal and mid RV free wall were calculated. Reduced RV systolic contraction (fractional area change <32%) and cardiac index (CI) <2.0 L/min/m(2) were defined as impaired RV performance. RESULTS: Pulmonary vascular resistance (PVR) averaged 1195 ± 522 dyn · s · cm(-5). RV strain correlated closely with pulmonary artery systolic pressure (r = 0.53; p < 0.001) and PVR (r = 0.68; p < 0.001). RV strain best correlated with CI (r = -0.70; p < 0.001) among the invasive variables. After adjusting for various parameters that could influence the CI, this correlation remained robust (r = -0.63, p < 0.001). In a multivariate model, RV strain (odds ratio 1.65; 95% confidential interval 1.06-2.57; p = 0.028) was independently associated with impairment of RV performance. A cutoff value of -15.5% discriminated cases of impaired RV performance from those of preserved RV performance with a sensitivity of 100%, specificity of 84% and accuracy of 92%. CONCLUSIONS: RV strain correlates well with hemodynamic variables indicative of disease severity and help identify the cases of impaired RV performance in PH patients.

Value of estimated right ventricular filling pressure in predicting cardiac events in chronic pulmonary arterial hypertension.

BACKGROUND: Right ventricular (RV) filling pressure can be estimated using tissue Doppler imaging (TDI) from the tricuspid lateral annulus, but few data are available on the usefulness of Doppler-derived RV filling pressure in predicting the prognosis of chronic pulmonary arterial hypertension (PAH). METHODS: In 50 consecutive patients with PAH, TDI was performed within 24 hours of right-sided catheterization to measure early diastolic myocardial velocity at the tricuspid lateral annulus (E(a)) and early diastolic tricuspid inflow (E). The tricuspid E/E(a) ratio was calculated and compared with the invasive hemodynamic variables. Cardiac events were defined as cardiac death or rehospitalization due to RV failure. RESULTS: Mean right atrial pressure (RAP) averaged 6 +/- 5 mm Hg (range, 1-25 mm Hg). E/E(a) correlated positively with mean RAP (r = 0.80, P < .001), irrespective of RV systolic function. We divided patients into group A with cardiac events (n = 19) and group B without events (n = 31) in a mean follow-up period of 14 months. Plasma brain natriuretic peptide level and E/E(a) were significantly higher in group A than in group B (349 +/- 310 pg/dL vs 129 +/- 136 pg/dL, P = .001; 7.0 +/- 3.2 vs 4.5 +/- 1.9, P = .004, respectively), whereas mean pulmonary artery pressure did not differ significantly. In a multivariate model, E/E(a) remained predictive for cardiac events (hazard ratio 1.227; 95% confidence interval, 1.042-1.444; P = .014). An E/E(a) cutoff value of 6.8 discriminated cases with cardiac events with a sensitivity of 42% and specificity of 97% (area under the curve 0.71). CONCLUSION: The tricuspid E/E(a) ratio provides a reliable estimation of RV filling pressure and predicts cardiac events in patients with PAH.

Noninvasive estimation of pulmonary vascular resistance by Doppler echocardiography in patients with pulmonary arterial hypertension.

Pulmonary vascular resistance (PVR) is an important hemodynamic variable in the management of patients with pulmonary hypertension. To establish a method of estimating PVR in patients with pulmonary arterial hypertension (PAH), Doppler echocardiography was performed within 24 hours of right heart catheterization in 43 patients with PAH (idiopathic PAH, n = 20; chronic thromboembolic pulmonary hypertension, n = 9; congenital heart disease, n = 9; and others). Correlations between invasive PVR and Doppler variables of pulmonary artery flow and tricuspid regurgitation were examined. Mean invasive PVR was 1,294 +/- 680 dyne s cm(-5). Linear regression analysis revealed significant correlations with invasive PVR for the time-velocity integral (TVI; r = -0.63, p = 0.009) of right ventricular outflow and peak tricuspid regurgitant pressure gradient (TRPG; r = 0.77, p <0.001). The TRPG/TVI ratio, which approximated the ratio of pulmonary artery pressure to pulmonary blood flow, showed an improved correlation coefficient of 0.82 (PVR = 187 + TRPG/TVI x 118, p <0.001). After excluding 5 patients with an intracardiac shunt, 26 of the remaining 38 patients (68%) met the hemodynamic criteria in international guidelines for the selection of lung transplantation candidates and were defined as the poor-prognosis group. A TRPG/TVI >7.6 showed 85% sensitivity and 92% specificity for identifying patients in the poor-prognosis group. In conclusion, TRPG/TVI provides a reliable estimation of PVR over a wide range in patients with PAH with various underlying causes.

Usefulness of three-dimensional echocardiography in assessing right ventricular function in patients with primary pulmonary hypertension.

Although right ventricular (RV) function is an important determinant of morbidity and mortality in patients with primary pulmonary hypertension (PPH), there have been no clinically validated quantification methods to date. The first derivative of RV pressure (dP/dt) is a good index of contractility, but it depends on preload. dP/dt divided by end-diastolic volume (EDV), that is, dP/dt/EDV, on the other hand, is an index of contractility relatively independent of preload. However, the measurement of accurate RV EDV is difficult because of RV complex geometry. Real-time three-dimensional (3D) echocardiography allows us to measure ventricular volume irrespective of its shape. To investigate the clinical feasibility and significance of 3D echocardiography in evaluating RV function in patients with PPH by measuring RV EDV and dP/dt/EDV, 13 patients with PPH (41+/-20 years, four men) underwent echocardiography, a 6-min walk distance (mWD) test and blood sampling within 1 week of invasive hemodynamic measurements. RV dP/dt was estimated from a continuous wave Doppler-determined tricuspid regurgitant velocity. RV EDV was measured by both two-dimensional (2D) biplane Simpson method (EDV(2D)) and real-time 3D echocardiography (EDV(3D)). RV dP/dt/EDV was calculated using EDV(2D) and EDV(3D). EDV(3D) showed better correlations than EDV(2D) with the invasive and non-invasive parameters of RV function, suggesting the validity of volume measurement by 3D echocardiography. RV dP/dt/EDV(3D) correlated well with disease severity, whereas dP/dt and dP/dt/EDV(2D) did not. In patients with PPH, 3D-echocardiography-determined RV dP/dt/EDV and EDV seem to be potential markers of disease severity.

Association of serum lipocalin-type prostaglandin D synthase levels with subclinical atherosclerosis in untreated asymptomatic subjects.

Recent studies suggest that lipocalin-type prostaglandin (PG) D synthase (L-PGDS), which converts PGH2 to PGD2, is implicated in the pathogenesis of atherosclerosis. However, clinical evidence for the association between serum L-PGDS levels and atherosclerosis has not been reported. In this study, we measured the serum L-PGDS concentration using sandwich enzyme-linked immunosorbent assay (ELISA) and investigated the association with traditional cardiovascular risk factors and surrogate atherosclerotic indices, such as the maximum score of the intima-media complex thickness of the carotid artery (C-IMT(max)) and the brachial-ankle pulse wave velocity (ba-PWV), in 500 non-treated asymptomatic subjects. The serum concentration of L-PGDS was 0.56+/-0.01 (mean+/-SEM, range 0.25-1.27, median 0.54) mg/L. Serum L-PGDS levels increased with age and were higher in men than in women. Serum L-PGDS was higher in subjects with hypertension and increased with increasing numbers of the traditional atherosclerotic risk factors. When the subjects were divided into four groups according to the levels of serum L-PGDS, the age-adjusted values of C-IMT(max) and ba-PWV were significantly increased in subjects with higher serum L-PGDS levels (quartile 3 and quartile 4) compared to those in the lowest quartile (quartile 1), for both genders. Multiple regression analysis including risk factors revealed that serum L-PGDS was an independent determinant for ba-PWV (beta=0.130, p<0.001). Serum L-PGDS tended to associate with C-IMT(max) but was not statistically significant (beta=0.084, p=0.075). In conclusion, our results suggest that an increase in serum L-PGDS concentration is associated with the progression of atherosclerosis.

Patterns of the interventricular septal motion can predict conditions of patients with pulmonary hypertension.

OBJECTIVES: We sought to investigate the clinical and hemodynamic implications of interventricular septal motion in patients with pulmonary hypertension. BACKGROUND: In patients with pulmonary hypertension, we have noticed two types of peculiar motions of the interventricular septum by M-mode echocardiography: marked early systolic anterior motion (type A) and marked early diastolic posterior motion (type B). METHODS: We performed echocardiography on 32 patients (age 42 +/- 13 years) with pulmonary hypertension within 1 week of cardiac catheterization. Type A was found in 14 patients (group A) and type B was found in 18 patients (group B). RESULTS: There was no difference between two groups in left ventricular eccentricity index at early diastole (2.4 +/- 0.6 vs 2.1 +/- 0.7) and mean pulmonary arterial pressure (54 +/- 10 vs 53 +/- 13 mm Hg). However, New York Heart Association functional class (2.7 +/- 0.4 vs 2.2 +/- 0.3) and serum levels of brain natriuretic peptide (271 +/- 155 vs 74 +/- 55 pg/mL) were significantly higher and cardiac index (1.7 +/- 0.3 vs 2.3 +/- 0.4 L/min/m(2)) was significantly lower in group A (P < .001). Simultaneous recordings of both ventricular pressures showed that right ventricular pressure was higher than left ventricular pressure during whole diastole in group A, but in group B, during only early diastole. By multiple linear regression analysis, type A motion independently predicted low cardiac index. CONCLUSIONS: Interventricular septal motion could predict patients' conditions. Patients with type A motion were more morbid clinically and hemodynamically than patients with type B motion.

Long-term trial of bosentan monotherapy for pulmonary arterial hypertension in Japanese patients.

OBJECTIVE: To determine the efficacy and safety of long-term bosentan monotherapy in Japanese patients with pulmonary arterial hypertension (PAH). RESEARCH DESIGN AND METHODS: The present study was an extension to a 12-week open-label trial of bosentan in which 21 Japanese patients with PAH received bosentan, 125 mg twice daily. Of the 21 patients in the initial trial, 20 elected to participate in the long-term study and to continue to receive bosentan for up to 3 years. MAIN OUTCOME MEASURES: The primary efficacy measure was comparison of World Health Organization (WHO) functional class for pulmonary arterial hypertension following long-term (> 2.5 years) therapy compared with baseline (prior to initiation of bosentan). Secondary outcomes included time from initiation of bosentan therapy to clinical worsening and safety assessments. RESULTS: Bosentan treatment was continued for a median of 2.7 years (range 0.4-3.0 years); 12 patients received bosentan monotherapy for at least 2.5 years. Following long-term treatment, improvement of WHO functional class compared with baseline was observed in 9/12 patients (75.0%) and in 3/12 patients (25.0%) the functional class remained stable; no patient experienced a worsening of WHO functional class compared with baseline. Overall, long-term treatment with bosentan was well tolerated. CONCLUSIONS: Long-term treatment with bosentan is well tolerated and is associated with sustained clinical improvement in Japanese patients with PAH. Bosentan, therefore, represents a valuable treatment option for Japanese patients with this devastating disease.

Long-term recovery of exercise ability after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

BACKGROUND: The exercise capacity of patients with thromboembolic pulmonary hypertension was investigated to clarify the long-term effects of pulmonary endarterectomy. This capacity was assessed by measuring cardiopulmonary factors during cardiopulmonary exercise testing at the maximal level of exercise and a 6-minute walk test at the submaximal level. Their survival rate was also determined. METHODS: We conducted a retrospective review of the clinical records of 102 patients who underwent pulmonary endarterectomy (63 women; median age, 53 years). RESULTS: Eight (7.8%) hospital mortalities were encountered. Three late mortalities due to fulminant hepatitis, breast cancer, and pneumonia in a patient under steroid therapy were unrelated to pulmonary endarterectomy. The actual survival rate including hospital mortalities was 90.9% at 3 years and 84.0% at 5 years. All hemodynamic measurements significantly improved and reached a plateau 1-month after endarterectomy. The cardiopulmonary exercise test at the maximal exercise level revealed that peak oxygen uptake (V(O2)) baseline was 13.8 +/- 3.2 mL/min/kg, and at 1-month was 16.2 +/- 4.2 mL/min/kg (p = 0.0015) and ventilatory response to carbon dioxide production (V(E)-V(CO2)) slope baseline was 46.5 +/- 8.4 mL/min/kg, and at 1-month was 39.9 +/- 7.4 (p = 0.0006), which gradually and significantly improved during the first year after endarterectomy (peak V(O2), 19.9 +/- 3.9 mL/min/kg [p < 0.0001] and V(E)-V(CO2) slope, 33.2 +/- 5.4 mL/min/kg [p <0.0001]). The 6-minute walk test, which reflects the systemic response at the submaximal level of functional capacity, showed that the walking distance gradually and significantly increased for up to 1 year after endarterectomy (baseline, 358 +/- 102 meters [m]; at 1-month, 433 +/- 105 m; and at 1-year, 490 +/- 80 m [p < 0.0001]) and then reached a plateau. CONCLUSIONS: After pulmonary endarterectomy, the hemodynamic recovery occurred immediately, and the patients' exercise capacity improved during the year. The 6-minute walk test was a good indicator to assess the recovery of exercise capacity.

A case of alpha-thalassemia-2 associated with pulmonary infarction.

Pulmonary infarction is an entity of medical significance that develops concurrently in beta-thalassemia but not in alpha-thalassemia. The reason for this difference is yet to be elucidated. We have evaluated a 21-year-old male alpha-thalassemia-2 patient who had profound microcytic anemia and pulmonary infarction. Analysis of the alpha-globin gene revealed -alpha3.7/alpha alpha genotype. His mother also had the same heterozygous gene deletion, though she had neither anemia nor pulmonary infarction. Since the patient had no other predisposition to pulmonary infarction, it is suggested that there is a close etiologic relationship between morphologic abnormality of the erythrocytes caused by alpha-thalassemia-2 and development of pulmonary infarction.

Japanese single-center experience of surgery for chronic thromboembolic pulmonary hypertension.

BACKGROUND: We review the outcome of surgery for chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: Between 1995 and 2004, 88 patients underwent surgery for CTEPH. Mean pulmonary artery pressure and pulmonary vascular resistance were 46 mm Hg (range, 23 to 70 mm Hg) and 986 dynes.sec(-1).cm(-5) (298 to 2,231 dynes.sec(-1).cm(-5)). The pulmonary artery lesion was proximally located in 51 patients, subsegmental in 34 patients, and peripheral in 3 patients. Pulmonary endarterectomy was performed using cycles of 15-minute intermittent circulatory arrest followed by 10-minute reperfusion at 16 degrees C to 18 degrees C. RESULTS: The median durations of circulatory arrest, cardiopulmonary bypass, and surgery were 58, 217, and 355 minutes, respectively. Percutaneous extracorporeal membrane oxygenation was used in 8 patients (9.1%) who had difficulty being weaning from cardiopulmonary bypass. Three recent patients for whom this was performed promptly were weaned and survived. There were 7 hospital deaths (8.0%, including 6 30-day deaths) from pulmonary bleeding in 2 patients, residual pulmonary hypertension in 3, rupture of bulla in 1, and empyema in 1. In the 81 survivors, mean pulmonary artery pressure and pulmonary vascular resistance fell significantly after surgery (p < 0.0001, each case). Age more than 60 years was a risk factor for hospital mortality on multivariate analysis. Although distal pulmonary artery disease including subsegmental and peripheral lesions was not a significant risk factor for mortality, it did influence patient recovery: the frequency of percutaneous extracorporeal membrane oxygenation was higher and hemodynamic improvement less pronounced in patients with distal disease. The actuarial survival rate was 90.7% at 3 years and 86.4% at 5 years. None of the patients have suffered recurrence. The event-free rate was 97.1% at 3 years and 93.5% at 5 years. Of the 68 patients surviving for more than 1 year after surgery, 67.6% were successfully weaned from home oxygen therapy and 13.2% required only occasional use of oxygen. CONCLUSIONS: Pulmonary endarterectomy can be safely performed with relatively low mortality and favorable prognosis with long-term survival, although it should be performed carefully for patients with distal disease.

Increased plasma monocyte chemoattractant protein-1 level in idiopathic pulmonary arterial hypertension.

OBJECTIVE: Monocyte chemoattractant protein-1 (MCP-1), a pro-inflammatory chemokine, has potent chemoattractant activity for monocytes/macrophages. We sought to investigate the clinical significance of MCP-1 in idiopathic pulmonary arterial hypertension (IPAH). METHODS: This study included 28 patients with IPAH, seven patients with pulmonary arterial hypertension (PAH) related to collagen vascular disease, and 13 healthy subjects. Plasma MCP-1 levels were measured together with serum IL-6 and tumour necrosis factor-alpha (TNF-alpha) levels. RESULTS: Circulating levels of MCP-1, IL-6 and TNF-alpha were significantly higher in patients with IPAH than in healthy controls, although they were lower than in patients with PAH related to collagen vascular disease. Plasma MCP-1 did not significantly correlate with any haemodynamic variables. However, plasma MCP-1 levels correlated negatively with the disease duration (time from symptom onset). CONCLUSIONS: Plasma MCP-1 levels were elevated in patients with IPAH, and this elevation was particularly marked in the early stage of disease. Taking into account the chemoattractant activity of MCP-1, these results imply a contribution of MCP-1 to the development of pulmonary hypertension.

Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is clinically characterized by a sustained elevation in mean pulmonary artery pressure leading to significant morbidity and mortality. The disorder is typically sporadic, and in such cases the term idiopathic PAH (IPAH) is used. However, cases that occur within families (familial PAH (FPAH)) display similar clinical and histopathological features, suggesting a common etiology. Heterozygous mutations of a type II member of the TGF-beta cell signaling superfamily known as BMPR2 on chromosome 2q33 have been identified in many kindreds with FPAH, yet display both reduced penetrance and sex bias. This report presents the compilation of data for 144 distinct mutations that alter the coding sequence of the BMPR2 gene identified in 210 independent PAH subjects. This large data set characterizes the extent of sequence variation and reveals that the majority (71%) of mutations in FPAH and IPAH comprise nonsense, frameshift, and splice-site defects, and gene rearrangements. These predict premature termination of the transcript with likely loss through the process of nonsense-mediated decay (NMD). A total of 44 missense mutations were identified that substitute amino acid residues at highly conserved sites within recognized functional domains of the mature receptor. We assess this category of mutations in the context of their heterogeneous effects on cell signaling when assayed by in vitro cell-based systems. Disease-causing mutation hot-spots within BMPR2 are summarized. Taken together, these observations are likely to aid in the development of targeted mutation detection strategies relevant for patient management. Finally, we examine the age- and sex-dependent reduced penetrance of BMPR2 mutations by reviewing bmpr2 animal models and the requirement for additional genetic and/or environmental modifiers of disease. In conclusion, these data provide compelling genetic evidence that haploinsufficiency is the predominant molecular mechanism underlying disease predisposition, and support the concept of a critical threshold of signaling activity below which disease may be precipitated.

Flow-independent myocardial ischemia induced by endothelin-1: an NADH fluorescence analysis.

The endothelin-1 (ET-1) is known to cause myocardial ischemia; however, whether this effect is entirely dependent on vasoconstriction is uncertain. The aim of this study was to characterize the myocardial ischemia after the intracoronary administration of endothelin-1, and compare it with that induced by coronary stenosis. In the left anterior descending coronary artery of 15 dogs, a mild inflow reduction (30%) was produced for 10 minutes using intracoronary endothelin-1 (46 +/- 33 pmol/min) or coronary stenosis. The hearts were rapidly cross-sectioned at short axial plane and freeze-clamped within 120 milliseconds using a specially developed device to visualize and quantify the area of ischemia (%IA) with NADH fluorescence photography. The %IA was larger in the endothelin-1 group than in the stenosis group (66 +/- 23 versus 18 +/- 18, P = 0.0005); furthermore, the ischemia was transmural in the ET-1 group, but limited to subendocardium in the stenosis group. ET-1 increased the coronary arterial resistance especially in subepicardial region and produced smaller ischemic foci in microcirculation. The mechanism of larger ischemia produced by ET-1 might depend on pro-ischemic effects on myocytes and vasoconstriction of the coronary microcirculation, predominantly in the subepicardium in vivo.

A long-acting prostacyclin agonist with thromboxane inhibitory activity for pulmonary hypertension.

RATIONALE: The balance between prostacyclin and thromboxane plays an important role in the regulation of pulmonary vascular tone. Recently, we developed ONO-1301, a novel, long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. OBJECTIVES: We investigated whether modulation of prostacyclin/thromboxane balance by ONO-1301 ameliorates monocrotaline-induced pulmonary hypertension in rats. METHODS: After subcutaneous injection of monocrotaline or vehicle, rats were randomized to receive repeated subcutaneous administration of ONO-1301 or vehicle twice per day for 3 wk. MEASUREMENTS AND MAIN RESULTS: There was significant development of pulmonary hypertension 3 wk after monocrotaline injection. Treatment with ONO-1301 significantly attenuated the increases in right ventricular systolic pressure and ratio of right ventricular weight to body weight in monocrotaline rats. Furthermore, ONO-1301 significantly attenuated the increase in medial wall thickness of peripheral pulmonary arteries in monocrotaline rats. The half-life of plasma ONO-1301 concentration after a single subcutaneous administration was approximately 5.6 h. A single administration of ONO-1301 increased plasma cyclic adenosine 3', 5'-monophosphate level, which lasted at least up to 8 h. Treatment with ONO-1301 significantly decreased plasma 11-dehydro-thromboxane B2, a metabolite of thromboxane, in monocrotaline rats. Finally, Kaplan-Meier survival curves demonstrated that repeated administration of ONO-1301 improved survival rate in monocrotaline rats compared with vehicle administration (80 vs. 30% in 6-wk survival). CONCLUSIONS: Subcutaneous administration of a novel prostacyclin agonist (ONO-1301) markedly attenuated monocrotaline-induced pulmonary hypertension and improved survival in rats. The beneficial effects of ONO-1301 may occur through its long-lasting stimulation of cyclic adenosine 3', 5'-monophosphate and inhibition of thromboxane synthase.

Descriptive patterns of severe chronic pulmonary hypertension by chest radiography.

BACKGROUND: To find chest roentgenographic (CXR) features to help differentiate two representative diseases with severe chronic pulmonary hypertension (PH). STUDY SUBJECTS: Thirty-six consecutive patients with chronic thromboembolic PH (CTEPH), 38 with primary PH (PPH), and 37 with left heart disease and PH. METHODS: CXRs were reviewed about 6 features (left 2nd arc protrusion, right descending pulmonary artery diameter (rPAD), cardiothoracic ratio (CTR), right 2nd arc width, avascular area and pleural abnormality). Hemodynamic data and the degree of tricuspid regurgitation (TR) on echocardiography were compared with CXR findings. RESULTS: The diagnostic pattern of CTEPH was the presence of one of two findings, an avascular area or marked rPAD (>20mm) together with pleuritic change. The diagnostic pattern of PPH was one of the two features; without pleuritic abnormality, marked left 2nd arc protrusion (>10mm) or moderate left 2nd arc protrusion (5-10mm) with marked rPAD (<20mm). The sensitivity for the diagnosis of CTEPH among the three diseases was 78% and specificity was 92%. The sensitivity for the diagnosis of PPH was 45% and specificity was 88%. CTR and right 2nd arc width were related to the degree of TR in CTEPH and PPH. CONCLUSIONS: Characteristic roentgenographic findings can help differentiate two frequent diseases associated with chronic pulmonary hypertension and reflect the severity of disease.

Relationships of nutrient intake and lifestyle-related factors to serum folate and plasma homocysteine concentrations in 30-69 year-old Japanese.

We studied non-hospitalized 30-69 y-old Japanese subjects to ascertain the influences of a 677C-T methylene-tetrahydrofolate reductase (MTHFR) genotype, nutritional intake and lifestyle-related factors on plasma homocysteine (Hcys) and serum folate concentrations. Hcys was higher and serum folate was lower in males than in females (p < .01). The Hcys concentration was higher in the VV group than in the AA and AV groups for both males and females. However, a relatively low serum folate concentration of 18 +/- 7 nmol/L was found in the entire male group as compared with 22 +/- 10 nmol/L in all females. In the female subjects, serum folate concentrations differed among MTHFR genotypes, being lowest in the VV group. In all male subjects, log folate intake per 1,000 kcal was a significant positive predictor of log serum folate concentration (p < 0.01), while in females the log vitamin C intake per standard body weight was a significant positive variable (p < 0.001) predicting the log serum folate concentration. Smokers had significantly lower serum folate concentrations, regardless of dietary folate intake. High folate and vitamin C consumptions, appears to be beneficial to normal and heterozygous MTHFR genotype subjects for maintaining serum folate concentrations. Even a 400 microg daily intake of folate might be less than what is needed, especially for homozygous MTHFR subjects and smokers, to maintain an adequate serum folate concentration.