Attenuation of hypercapnic carbon dioxide chemosensitivity after postinfarction exercise training: possible contribution to the improvement in exercise hyperventilation.

OBJECTIVE: To elucidate the responsible mechanisms of increased slope of minute ventilation relative to carbon dioxide production (VE/VCO(2)) during exercise after acute myocardial infarction without overt signs of heart failure, patients who had an acute myocardial infarction were examined after participating in a three month supervised exercise training programme. DESIGN: Exercise testing, hypercapnic CO(2) chemosensitivity measurement (rebreathing method), and pulmonary function test were repeated at entry and after three months in 50 acute myocardial infarction patients with neither symptoms nor signs of heart failure who completed the training programme. Ten patients who performed initial inhospital training served as controls. RESULTS: Age, peak oxygen uptake, left ventricular ejection fraction, CO(2) chemosensitivity, respiratory parameters (percentage of predicted normal vital capacity (%VC), forced expiratory volume in one second, and carbon monoxide transfer factor (%TLCO)) were all significantly correlated with VE/VCO(2) slope. Multivariate regression analysis showed that age (beta = 0.29, p = 0.01), %TLCO (beta = -0.27, p = 0.01), and CO(2) chemosensitivity (beta = 0.49, p < 0.001) were independent determinants of VE/VCO(2) slope. After three months, there was no significant change in these parameters in the control group. Peak oxygen uptake, %TLCO, and %VC and attenuation in CO(2) chemosensitivity increased significantly in the training group. The VE/VCO(2) slope decreased marginally (p = 0.11). The changes in VE/VCO(2) slope were correlated only with those in CO(2) chemosensitivity (r = 0.50, p < 0.001). CONCLUSION: After acute myocardial infarction, exercise hyperventilation is seen in association with aging, enhanced hypercapnic CO(2) chemosensitivity, and reduced TLCO, even in the absence of overt heart failure. The correlation of VE/VCO(2) attenuation after training with the reduction in CO(2) chemosensitivity suggests that exercise training may reduce increased VE/VCO(2) slope, at least partially by reducing CO(2) chemosensitivity.

Oral beraprost sodium improves exercise capacity and ventilatory efficiency in patients with primary or thromboembolic pulmonary hypertension.

OBJECTIVE: To investigate the effect of beraprost sodium, an orally active prostacyclin analogue, on exercise capacity and ventilatory efficiency in patients with primary pulmonary hypertension and chronic thromboembolic pulmonary hypertension. PATIENTS AND DESIGN: Symptom limited cardiopulmonary exercise testing was performed before and 3 (1) months (mean (SEM)) after beraprost treatment in 30 patients with precapillary pulmonary hypertension (14 with primary pulmonary hypertension and 16 with chronic thromboembolic pulmonary hypertension). RESULTS: Long term treatment with beraprost resulted in significant increases (mean (SEM)) in peak workload (87 (4) W to 97 (5) W, p < 0.001) and peak oxygen consumption (peak VO2, 14.9 (0.7) ml/kg/min to 16.8 (0.7) ml/kg/min, p < 0.001). Beraprost decreased the ventilatory response to carbon dioxide production during exercise (VE-VCO2 slope, 42 (2) to 37 (1), p < 0.001). No significant difference in the responses of these variables to beraprost treatment was observed between patients with primary pulmonary hypertension and chronic thromboembolic pulmonary hypertension. CONCLUSIONS: Oral administration of beraprost sodium may improve exercise capacity and ventilatory efficiency in patients with both primary and chronic thromboembolic pulmonary hypertension.

Pulmonary artery reflection for differentially diagnosing primary pulmonary hypertension and chronic pulmonary thromboembolism.

OBJECTIVES: The purpose of this investigation was to differentiate chronic pulmonary thromboembolism (CPTE) from primary pulmonary hypertension (PPH) by means of the indexes of pulmonary arterial reflection. BACKGROUND: These differences in the primary lesions would make pulmonary artery reflection occur earlier in CPTE than in PPH. Although the analysis of pulsatility of pulmonary arterial pressure is useful in the differential diagnosis of PPH and CPTE, it is not known whether the analysis of pulmonary artery reflection can differentiate CPTE from PPH. METHODS: Since CPTE predominantly involves the proximal arteries, whereas PPH involve the peripheral arteries, we hypothesized that patients with CPTE have a large augmentation index and a short inflection time. For this study, we enrolled 62 patients who had CPTE (31 patients) and PPH (31 patients). We measured pulmonary arterial pressure using a fluid filled system that included a balloon-tipped flow directed catheter. To quantify the pulmonary artery reflection, we used the augmentation index and inflection time. RESULTS: The augmentation index was markedly higher in CPTE than it was in PPH (27.4% +/- 15.2% [SD] and -25.1% +/- 26.9%, respectively, p < 0.001) and was diagnostic in separating the two groups. Inflection time separated the two groups reasonably well (97 +/- 20 ms and 210 +/- 49 ms, respectively, p < 0.001). CONCLUSIONS: The analysis of pulmonary arterial reflection is useful in the differential diagnosis of CPTE and PPH.

Acute and chronic effects of surgical thromboendarterectomy on exercise capacity and ventilatory efficiency in patients with chronic thromboembolic pulmonary hypertension.

OBJECTIVE: To assess acute and chronic effects of surgical thromboendarterectomy on exercise capacity and ventilatory efficiency in patients with chronic thromboembolic pulmonary hypertension (CTEPH). DESIGN: Cardiopulmonary exercise testing was performed in 20 patients with CTEPH before thromboendarterectomy (baseline), one month after (early phase), and four months after (late phase). Peak oxygen uptake (peak VO(2)) and the ventilatory response to carbon dioxide production (VE-VCO(2) slope) were measured for assessment of exercise capacity and ventilatory efficiency. Right heart catheterisation was performed in all patients before and one month after surgery. RESULTS: Baseline peak VO(2) decreased and VE-VCO(2) slope increased along with the increase in pulmonary vascular resistance in patients with CTEPH. After thromboendarterectomy, the VE-VCO(2) slope decreased greatly from baseline to the early phase (mean (SD), 50 (9) to 37 (7), p < 0.05) and reached a steady level thereafter. In contrast, a continued increase in peak VO(2) was noted from the early to the late phase (16.9 (4.1) to 21.1 (5.0) ml/kg/min, p < 0.05). The decrease in the VE-VCO(2) slope from baseline to the early phase, but not the increase in peak VO(2), correlated strongly with the decrease in pulmonary vascular resistance after surgery (r = 0.75, p < 0.01). CONCLUSIONS: Thromboendarterectomy may cause an immediate improvement in ventilatory efficiency, possibly through its beneficial haemodynamic effects. In contrast, exercise capacity may continue to improve towards the late phase, reflecting peripheral adaptation to exercise.

[Coagulation and fibrinolytic abnormality related to endothelial injury in pulmonary arterial hypertension].

It remains unclear whether a coagulation abnormality plays an important role in the clinical course in pulmonary arterial hypertension as well as vasoconstriction and vascular-wall remodeling, although several studies of pathological specimens and clinical studies demonstrating that anticoagulation prolongs life have suggested the importance of thrombosis. Several parameters for hemostasis related to endothelial injury are expected to reflect abnormal coagulation and fibrinolytic systems in pulmonary hypertension. Recently, we demonstrated that plasma level of soluble P-selectin was increased and that of thrombomodulin (TM) was decreased in patients with pulmonary arterial hypertension. The abnormal values of P-selectin and TM were improved by continuous prostacyclin infusion. Altered hemostasis may be important as a pathogenesis in pulmonary hypertension and adequate anti-coagulant therapy is expected.

Short-term oral administration of L-arginine improves hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension.

We sought to assess the effects of oral supplementation of L-arginine, the precursor of nitric oxide (NO), on hemodynamics and exercise capacity in patients with pulmonary hypertension. Acute hemodynamic responses to oral L-arginine (0.5 g/10 kg body weight) or placebo were examined in 19 patients with primary or precapillary secondary pulmonary hypertension. Cardiopulmonary exercise tests were performed to measure peak oxygen consumption (peak V O(2)) and the ventilatory response to carbon dioxide production (V E-V CO(2) slope) before and 1 wk after treatment with L-arginine (1.5 g/10 kg body weight/d) or placebo. Oral supplementation of L-arginine significantly increased plasma L-citrulline, which indicated enhancement of NO production. Supplemental L-arginine produced a 9% decrease in mean pulmonary arterial pressure (53 +/- 4 to 48 +/- 4 mm Hg, p < 0.05) and a 16% decrease in pulmonary vascular resistance (14.8 +/- 1.5 to 12.4 +/- 1.4 Wood units, p < 0.05). L-arginine modestly decreased mean systemic arterial pressure (92 +/- 4 to 87 +/- 3 mm Hg, p < 0.05). A 1-wk supplementation of L-arginine resulted in a slight increase in peak V O(2) (831 +/- 88 to 896 +/- 92 ml/min, p < 0.05) and a significant decrease in the V E- V CO(2) slope (43 +/- 4 to 37 +/- 3, p < 0.05) without significant systemic hypotension. Hemodynamics and exercise capacity remained unchanged during placebo administration. These results suggest that oral supplementation of L-arginine may have beneficial effects on hemodynamics and exercise capacity in patients with precapillary pulmonary hypertension.

[Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension].

BACKGROUND: Plasma brain natriuretic peptide (BNP) level increases in proportion to the degree of right ventricular dysfunction in pulmonary hypertension. We sought to assess the prognostic significance of plasma BNP in patients with primary pulmonary hypertension. METHODS AND RESULTS: Plasma BNP was measured in 60 patients with primary pulmonary hypertension at diagnostic catheterization, together with atrial natriuretic peptide, norepinephrine, and epinephrine. Measurements were repeated in 53 patients after a mean follow-up period of 3 months. Forty-nine of the patients received intravenous or oral prostacyclin. During a mean follow-up period of 24 months, 18 patients died of cardiopulmonary causes. According to multivariate analysis, baseline plasma BNP was an independent predictor of mortality. Patients with a supramedian level of baseline BNP (> or = 150 pg/ml) had a significantly lower survival rate than those with an inframedian level, according to Kaplan-Meier survival curves (p < 0.05). Plasma BNP in survivors decreased significantly during the follow-up (217 +/- 38 to 149 +/- 30 pg/ml, p < 0.05), whereas that in nonsurvivors increased (365 +/- 77 to 544 +/- 68 pg/ml, p < 0.05). Thus, survival was strikingly worse for patients with a supramedian value of follow-up BNP (> or = 180 pg/ml) than for those with an inframedian value (p < 0.0001). CONCLUSIONS: A high level of plasma BNP, and in particular, a further increase in plasma BNP during follow-up, may have a strong, independent association with increased mortality in patients with primary pulmonary hypertension.

Increased plasma P-selectin and decreased thrombomodulin in pulmonary arterial hypertension were improved by continuous prostacyclin therapy.

BACKGROUND: Thrombosis in situ related to endothelial cell injury may contribute to the development of pulmonary hypertension (PH). P-selectin, a leukocyte adhesion receptor present in endothelial cells and platelets, reflects endothelial injury and platelet activation, and thrombomodulin (TM), a receptor for thrombin and a major anticoagulant proteoglycan on the endothelial membrane, reflects the anticoagulant activity of the endothelium. METHODS AND RESULTS: To assess abnormal coagulation due to endothelial injury in patients with PH, plasma levels of soluble P-selectin and TM were measured in 32 patients with primary PH (PPH), 25 with secondary pulmonary arterial hypertension (sPAH), 31 with pulmonary venous hypertension (PVH), and 17 healthy subjects (Control). These measurements were repeated after continuous infusion of prostacyclin in 15 patients with PPH and 3 with sPAH. P-selectin levels in both the sPAH and PPH groups were significantly higher than those in the Control and PVH groups (P<0.05). Plasma TM level in the PPH group was significantly lower than those in the other groups (P<0.01). After prostacyclin therapy, the lower TM level was increased and the higher P-selectin level was decreased (P<0.05). CONCLUSIONS: Decreased TM and increased P-selectin in PPH and sPAH may reflect in situ thrombosis due to endothelial injury. Prostacyclin may act not only as a vasodilator but also as an agent that improves endothelial injury and altered hemostasis in pulmonary arterial injury.

Haemodynamic and hormonal effects of adrenomedullin in patients with pulmonary hypertension.

OBJECTIVE: To investigate whether infusion of adrenomedullin, a potent vasorelaxant peptide, has beneficial haemodynamic and hormonal effects in patients with pulmonary hypertension. PATIENTS AND DESIGN: The haemodynamic and hormonal responses to intravenous infusion of adrenomedullin (0.05 microgram/kg/min) or placebo were examined in 13 patients with precapillary pulmonary hypertension. RESULTS: Infusion of adrenomedullin produced a 44% increase in cardiac index (mean (SD) 1.8 (0.2) to 2.6 (0.3) l/min/m(2), p < 0. 05) and a 32% decrease in pulmonary vascular resistance (19.7 (1.4) to 13.4 (1.3) units, p < 0.05), with a 4% reduction in mean pulmonary arterial pressure (62 (4) to 59 (4) mm Hg, NS). Adrenomedullin also decreased mean systemic arterial pressure (81 (3) to 72 (4) mm Hg, p < 0.05) and increased heart rate (73 (4) to 79 (4) beats/min, p < 0.05). Adrenomedullin decreased plasma aldosterone (9.8 (2.5) to 7.1 (1.5) ng/dl, p < 0.05) without significant changes in plasma renin activity. Plasma atrial and brain natriuretic peptides tended to decrease with adrenomedullin, although these changes did not reach significance. The haemodynamic and hormonal variables remained unchanged during placebo infusion. CONCLUSIONS: Intravenous adrenomedullin has beneficial haemodynamic and hormonal effects in patients with precapillary pulmonary hypertension.

Plasma brain natriuretic peptide as a prognostic indicator in patients with primary pulmonary hypertension.

BACKGROUND: Plasma brain natriuretic peptide (BNP) level increases in proportion to the degree of right ventricular dysfunction in pulmonary hypertension. We sought to assess the prognostic significance of plasma BNP in patients with primary pulmonary hypertension (PPH). METHODS AND RESULTS: Plasma BNP was measured in 60 patients with PPH at diagnostic catheterization, together with atrial natriuretic peptide, norepinephrine, and epinephrine. Measurements were repeated in 53 patients after a mean follow-up period of 3 months. Forty-nine of the patients received intravenous or oral prostacyclin. During a mean follow-up period of 24 months, 18 patients died of cardiopulmonary causes. According to multivariate analysis, baseline plasma BNP was an independent predictor of mortality. Patients with a supramedian level of baseline BNP (>/=150 pg/mL) had a significantly lower survival rate than those with an inframedian level, according to Kaplan-Meier survival curves (P<0.05). Plasma BNP in survivors decreased significantly during the follow-up (217+/-38 to 149+/-30 pg/mL, P<0. 05), whereas that in nonsurvivors increased (365+/-77 to 544+/-68 pg/mL, P<0.05). Thus, survival was strikingly worse for patients with a supramedian value of follow-up BNP (>/=180 pg/mL) than for those with an inframedian value (P<0.0001). CONCLUSIONS: A high level of plasma BNP, and in particular, a further increase in plasma BNP during follow-up, may have a strong, independent association with increased mortality rates in patients with PPH.

Correlation between severity of pulmonary arterial hypertension and 123I-metaiodobenzylguanidine left ventricular imaging.

UNLABELLED: It remains unclear whether cardiac sympathetic nervous function is disturbed in patients with pulmonary arterial hypertension (PH) and how sympathetic dysfunction is related to PH. METHODS: In this study, (123)I-metaiodobenzylguanidine (MIBG) imaging of the heart, which reveals the sympathetic innervation of the left ventricle, was performed in 7 healthy volunteers without cardiopulmonary disease (control subjects); 55 patients with PH, including 27 with chronic thromboembolic pulmonary hypertension (CTEPH) of major vessels; and 28 patients with primary pulmonary hypertension (PPH). RESULTS: Cardiac (123)I-MIBG uptake, assessed as the heart-to-mediastinum activity ratio (H/M), was significantly lower in the CTEPH and PPH groups compared with that in the control group (P < 0.01). Myocardial MIBG turnover, expressed as the washout rate (WR [%]) from 15 to 240 min, was significantly higher in the CTEPH and PPH groups than that in the control group (P < 0.01). In the PPH group, H/M and WR values of MIBG correlated with the severity of pulmonary hypertension (represented by total pulmonary vascular resistance determined by right heart catheterization), the right ventricular ejection fraction determined by electron beam CT, and other variables but did not correlate well in the CTEPH group. In both groups, patients with H/M > or = 2.0 showed better cumulative survival than did those with H/M < 2.0 (P < 0.05). CONCLUSION: Patients with PH have significant left ventricular myocardial sympathetic nervous alteration. (123)I-MIBG imaging of the heart is useful for assessing the severity of pulmonary hypertension caused by PPH or CTEPH.

Haemodynamic correlates and prognostic significance of serum uric acid in adult patients with Eisenmenger syndrome.

OBJECTIVE: To assess haemodynamic correlates and prognostic significance of serum uric acid in adult patients with Eisenmenger syndrome. DESIGN: Retrospective observational study. SETTING: Tertiary referral centre. PATIENTS: 94 adult patients with Eisenmenger syndrome who were diagnosed between September 1982 and July 1998. MAIN OUTCOME MEASURES: Serum uric acid was measured in all patients, together with clinical and haemodynamic variables related to mortality. RESULTS: Serum uric acid was raised in patients with Eisenmenger syndrome compared with age and sex matched control subjects (7.0 v 4.7 mg/dl, p < 0.0001) and increased in proportion to the severity of New York Heart Association functional class. Serum uric acid was positively correlated with mean pulmonary arterial pressure (r = 0.30, p = 0.0052) and total pulmonary resistance index (r = 0.55, p < 0.0001), and negatively correlated with cardiac index (r = -0.50, p < 0.0001). During a mean follow up period of 97 months, 38 patients died of cardiopulmonary causes. Among various clinical, echocardiographic, and laboratory variables, serum uric acid remained predictive in multivariate analysis. Kaplan-Meier survival curves based on median serum uric acid showed that patients with high values had a significantly worse survival rate than those with low values (log-lank test: p = 0.0014 in male patients, p = 0.0034 in female patients). CONCLUSIONS: Serum uric acid increases in proportion to haemodynamic severity in adult patients with Eisenmenger syndrome and is independently associated with long term mortality.

Improvement in exercise capacity with nitric oxide inhalation in patients with precapillary pulmonary hypertension.

BACKGROUND: Patients with precapillary pulmonary hypertension (PH) exhibit a poor exercise capacity due to an impaired vasodilatory response of their pulmonary arteries. By causing the pulmonary artery to dilate, inhaled nitric oxide (NO) may allow an increase in exercise capacity in patients with PH. METHODS AND RESULTS: On 2 separate days, 3 days apart, 14 patients with precapillary PH (10 primary PH, 4 residual PH after correction of an intracardiac shunt; age, 40+/-12 years; mean pulmonary artery pressure, 60+/-23 mm Hg) performed exercise, with and without inhalation of 20 ppm NO, on a cycle ergometer. The work rate was increased 15 W/min until their symptom-limited maximum, with breath-by-breath gas analysis. Patients were randomly and blindly selected to inhale NO on either their first or second test. Peak exercise load and anaerobic threshold tended to increase, but not significantly. Peak oxygen consumption (f1.gif" BORDER="0">O(2)) and Deltaf1.gif" BORDER="0">O(2)/DeltaW ratio increased significantly, by 18% and 22%, respectively (peak f1.gif" BORDER="0">O(2), 13.6+/-3.6 to 16.0+/-4. 1 mL. kg(-1). min(-1); Deltaf1.gif" BORDER="0">O(2)/DeltaW ratio, 5. 8+/-2.4 to 7.1+/-2.3 mL. kg(-1). min(-1). W(-1); both P<0.01). Peak f1.gif" BORDER="0">O(2) increased >10% in 12 of the 14 patients. However, respiratory quotient at peak exercise decreased from 1. 22+/-0.15 to 1.09+/-0.15 (P<0.01). CONCLUSIONS: Inhaled NO substantially increases oxygen consumption at the same workload during exercise. This finding supports the possibility of ambulatory NO inhalation therapy in patients with precapillary PH.

Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Comparison with cardiopulmonary exercise testing.

The six-minute walk test is a submaximal exercise test that can be performed even by a patient with heart failure not tolerating maximal exercise testing. To elucidate the clinical significance and prognostic value of the six-minute walk test in patients with primary pulmonary hypertension (PPH), we sought (1) to assess the relation between distance walked during the six-minute walk test and exercise capacity determined by maximal cardiopulmonary exercise testing, and (2) to investigate the prognostic value of the six-minute walk test in comparison with other noninvasive parameters. The six-minute walk test was performed in 43 patients with PPH, together with echocardiography, right heart catheterization, and measurement of plasma epinephrine and norepinephrine. Symptom-limited cardiopulmonary exercise testing was performed in a subsample of patients (n = 27). Distance walked in 6 min was significantly shorter in patients with PPH than in age- and sex-matched healthy subjects (297 +/- 188 versus 655 +/- 91 m, p < 0. 001). The distance significantly decreased in proportion to the severity of New York Heart Association functional class. The distance walked correlated modestly with baseline cardiac output (r = 0.48, p < 0.05) and total pulmonary resistance (r = -0.49, p < 0. 05), but not significantly with mean pulmonary arterial pressure. In contrast, the distance walked correlated strongly with peak V O(2) (r = 0.70, p < 0.001), oxygen pulse (r = 0.57, p < 0.01), and V E-VCO(2) slope (r = -0.66, p < 0.001) determined by cardiopulmonary exercise testing. During a mean follow-up period of 21 +/- 16 mo, 12 patients died of cardiopulmonary causes. Among noninvasive parameters including clinical, echocardiographic, and neurohumoral parameters, only the distance walked in 6 min was independently related to mortality in PPH by multivariate analysis. Patients walking < 332 m had a significantly lower survival rate than those walking farther, assessed by Kaplan-Meier survival curves (log-rank test, p < 0.01). These results suggest that the six-minute walk test, a submaximal exercise test, reflects exercise capacity determined by maximal cardiopulmonary exercise testing in patients with PPH, and it is the distance walked in 6 min that has a strong, independent association with mortality.

Hemodynamic, renal, and hormonal effects of adrenomedullin infusion in patients with congestive heart failure.

BACKGROUND: Experimental studies have shown that adrenomedullin (AM) causes vasodilatation, diuresis, and a positive inotropic effect. In humans, however, whether infusion of AM has beneficial effects in congestive heart failure (CHF) remains unknown. METHODS AND RESULTS: Hemodynamic, renal, and hormonal responses to intravenous infusion of human AM (0.05 microg. kg(-1). min(-1)) were examined in 7 patients with CHF and 7 normal healthy subjects (NL). In NL group, AM significantly decreased mean arterial pressure (-16 mm Hg, P<0. 05) and increased heart rate (+12 bpm, P<0.05). In CHF group, AM also decreased mean arterial pressure (-8 mm Hg, P<0.05) and increased heart rate (+5 bpm, P<0.05), but to a much lesser degree (P<0.05 versus NL). AM markedly increased cardiac index (CHF, +49%; NL, +39%, P<0.05) while decreasing pulmonary capillary wedge pressure (CHF, -4 mm Hg; NL, -2 mm Hg, P<0.05). AM significantly decreased mean pulmonary arterial pressure only in CHF (-4 mm Hg, P<0.05). AM increased urine volume (CHF, +48%; NL, +62%, P<0.05) and urinary sodium excretion (CHF, +42%; NL, +75%, P<0.05). Only in CHF, plasma aldosterone significantly decreased during (-28%, P<0.05) and after (-36%, P<0.05) AM infusion. These parameters remained unchanged in 7 patients with CHF and 6 healthy subjects who received placebo. CONCLUSIONS: Intravenous infusion of AM has beneficial hemodynamic and renal effects in patients with CHF.

[Pulmonary thromboendarterectomy for chronic pulmonary thromboembolism in three patients with systemic lupus erythematosus and antiphospholipid syndrome].

Pulmonary hypertension (PH) is a serious and often fatal complication of systemic lupus erythematosus (SLE). Several potential mechanisms have been postulated for narrowing of vessels as a result of pulmonary vasculitis and pulmonary thromboembolism caused by antiphospholipid antibodies. Pulmonary thromboendarterectomy for chronic pulmonary thromboembolism is performed to alleviate pulmonary hypertension. We report three rare cases of SLE with antiphospholipid syndrome in patients who presented with PH secondary to chronic pulmonary thromboembolism. Pulmonary thromboendarterectomy was performed, and all patients remained well without deterioration of PH after surgery. Pulmonary thromboendarterectomy should be considered as an effective method of treatment for this disease.

Abnormality of left ventricular sympathetic nervous function assessed by (123)I-metaiodobenzylguanidine imaging in patients with COPD.

BACKGROUND: Cardiac and systemic autonomic nervous function may be impaired in patients with COPD. Few reports, however, have described sympathetic nervous function of the left ventricle (LV) in COPD patients. STUDY OBJECTIVE: To assess the LV sympathetic nervous function in patients with COPD using (123)I-metaiodobenzylguanidine (MIBG) imaging of the heart. DESIGN: Prospective comparison of (123)I-MIBG imaging results in COPD patients and normal subjects. PARTICIPANTS: Twenty-eight patients with COPD without manifest right ventricular overload and 7 volunteers without cardiopulmonary disease (control subjects). MEASUREMENTS: (123)I-MIBG imaging results and plasma norepinephrine concentration were compared between the COPD and control groups. In the COPD group, pulmonary function tests were performed and all subjects were interviewed about their symptoms. RESULTS: (123)I-MIBG uptake, assessed as the cardiac to mediastinal activity ratio in the delayed image, was significantly lower in the COPD group than in the control group (p < 0.05). (123)I-MIBG turnover, expressed as the washout rate (WR) of (123)I-MIBG from 15 to 240 min, was significantly higher in the COPD group than in the control group (p < 0.01). In the COPD group, patients with dyspnea showed lower cardiac to mediastinal activity ratios and higher WRs compared with patients who had mild dyspnea. The WR correlated negatively with the vital capacity/predicted value ratio, correlated negatively with the maximal voluntary ventilation volume/predicted value ratio, and correlated positively with the residual volume/total lung capacity ratio in the COPD group. The plasma norepinephrine concentration in COPD patients was higher than that in the control subjects. CONCLUSION: Patients with COPD have significant sympathetic nervous impairment of the LV myocardium as a result of generalized sympathetic overactivity.

Effect of orally active prostacyclin analogue on survival of outpatients with primary pulmonary hypertension.

OBJECTIVES: This study sought to investigate the effect of beraprost sodium (BPS), an orally active prostacyclin analogue, on the survival of outpatients with primary pulmonary hypertension (PPH). BACKGROUND: Continuous intravenous administration of epoprostenol (prostacyclin) has been shown to improve survival in PPH. However, the effect of oral BPS on survival in PPH remains unknown. METHODS: Fifty-eight consecutive patients with PPH who could be discharged after the first diagnostic catheterization for PPH were retrospectively divided into two groups: patients treated with BPS (BPS group, n = 24) and those without BPS (conventional group, n = 34). The baseline demographic and hemodynamic data did not significantly differ between the two. RESULTS: Twenty-seven patients died of cardiopulmonary causes in the conventional group during a mean follow-up period of 44 +/- 45 months. In contrast, only 4 patients died of cardiopulmonary causes in the BPS group during a mean follow-up period of 30 +/- 20 months. In a subsample (n = 15) of patients in the BPS group, mean pulmonary arterial pressure and total pulmonary resistance significantly decreased, respectively, by 13% and 25% during a mean follow-up period of 53 days. Among the variables previously known to be associated with the mortality in PPH, the absence of BPS therapy and the reduced cardiac output were independently related to the mortality by a multivariate Cox proportional hazards regression analysis (both p < 0.05). The Kaplan-Meier survival curves demonstrated that the one-, two- and three-year survival rates for the BPS group were 96%, 86% and 76%, respectively, as compared with 77%, 47% and 44%, respectively, in the conventional group (log-rank test, p < 0.05). CONCLUSIONS: The oral administration of BPS may have beneficial effects on the survival of outpatients with PPH as compared with conventional therapy alone.

Clinical and immunoregulatory effects of roxithromycin therapy for chronic respiratory tract infection.

The clinical and immunoregulatory effects of long-term macrolide antibiotic therapy for patients with chronic lower respiratory tract infections (CLRTI) were investigated. Clinical parameters and neutrophil chemotactic mediators in the epithelial lining fluid (ELF) of CLRTI patients (n = 10) were examined before and after 3 months oral administration of roxithromycin (RXM). The in vitro effects of RXM were also examined on the release of these mediators from alveolar macrophages (AM) and neutrophils. Arterial oxygen tension (p<0.05), vital capacity (VC) (p<0.001), %VC (p<0.05) and forced expiratory volume in one second (p<0.01) were improved after RXM treatment, but airway bacteria were not eradicated. Among the mediators, the levels of interleukin (IL)-8, neutrophil elastase (NE) and leukotriene B4 (LTB4) were higher in ELF than in plasma of CLRTI patients and they decreased after RXM treatment (n = 7, p<0.05 for each). RXM concentrations were significantly increased in the bronchoalveolar lavage cells of the treated patients. In in vitro experiments, RXM showed inhibitory effects on IL-8 release from AM and neutrophils. In conclusion, interleukin-8, neutrophil elastase and leukotriene B4 contribute to the neutrophilic inflammation in the airways of chronic lower respiratory tract infection patients and the clinical effects of roxithromycin may, in part, be attributable to the suppression of excess release of the chemotactic mediators from inflammatory cells.

Serum uric acid levels correlate with the severity and the mortality of primary pulmonary hypertension.

Serum uric acid (UA), the final product of purine degradation, has been proposed to be a marker for impaired oxidative metabolism and a possible predictor of mortality in patients with chronic heart failure. To elucidate whether serum UA correlates with the severity and the mortality of primary pulmonary hypertension (PPH), serum UA was assessed in 90 patients with PPH together with other clinical variables. Right heart catheterization was performed in all patients. Serum UA was significantly elevated in patients with PPH compared with age-matched control subjects (7.5 +/- 2.5 versus 4.9 +/- 1.2 mg/ml, p < 0.001). Serum UA negatively correlated with cardiac output (r = -0.52, p < 0.001) and positively correlated with total pulmonary resistance (r = 0.57, p < 0.001). Serum UA significantly decreased from 7.1 +/- 1.9 to 5.9 +/- 1.6 mg/dl with vasodilator therapy, associated with a reduction in total pulmonary resistance from 22 +/- 6 to 17 +/- 7 Wood units. During a mean follow-up period of 31 mo, 53 patients died of cardiopulmonary causes. Among noninvasive variables, serum UA was independently related to mortality by a multivariate Cox proportional-hazards analysis. The Kaplan-Meier survival curves according to the median value of serum UA demonstrated that patients with high serum UA had a significantly higher mortality rate than did those with low serum UA (log-rank test, p < 0.01). These results suggest that serum UA increases in proportion to the clinical severity of PPH and has independent association with long-term mortality of patients with PPH.