Fumio Sakamaki

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.

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.

Increased Plasma P-Selectin and Decreased Thrombomodulin in Pulmonary Arterial Hypertension Were Improved by Continuous Prostacyclin Therapy

BackgroundThrombosis 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 ResultsTo 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). ConclusionsDecreased 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.

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).

Plasma brain natriuretic peptide as a noninvasive marker for efficacy of pulmonary thromboendarterectomy

BACKGROUND Plasma brain natriuretic peptide (BNP), a cardiac hormone secreted mainly by the cardiac ventricles, has been shown to increase in proportion to the degree of cardiac overload. However, whether plasma BNP may serve as a marker for the efficacy of pulmonary thromboendarterectomy in patients with chronic thromboembolic pulmonary hypertension remains unknown. METHODS Plasma BNP level was measured in 34 patients with chronic thromboembolic pulmonary hypertension before and 1 month after pulmonary thromboendarterectomy. Right heart catheterization was also performed before and 1 month after the operation. RESULTS Preoperative plasma BNP level was significantly elevated in patients with chronic thromboembolic pulmonary hypertension compared with control patients (246 +/- 40 vs 13 +/- 2 pg/mL; p < 0.001; n = 34) and was positively correlated with total pulmonary resistance (r = 0.57; p < 0.001). After pulmonary thromboendarterectomy, plasma BNP level in survivors markedly decreased (220 +/- 31 to 54 +/- 9 pg/mL; p < 0.001; n = 32) in association with a reduction of total pulmonary resistance (15.6 +/- 1.0 to 4.5 +/- 0.3 Wood units; p < 0.001). The change in plasma BNP level was closely correlated with that in total pulmonary resistance (r = 0.63; p < 0.001). Importantly, a sustained elevation of plasma BNP (> or = 50 pg/mL) indicated the presence of residual pulmonary hypertension (> or = 5 Wood units) after operation (sensitivity = 73%; specificity = 81%). CONCLUSIONS Plasma BNP level was strongly associated with the severity of pulmonary hypertension in patients with chronic thromboembolic pulmonary hypertension and thereby may serve as a noninvasive marker for the efficacy of pulmonary thromboendarterectomy.

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.

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.

Analysis of comorbid factors that increase the COPD assessment test scores

BackgroundThe chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a concise health status measure for COPD. COPD patients have a variety of comorbidities, but little is known about their impact on quality of life. This study was designed to investigate comorbid factors that may contribute to high CAT scores.MethodsAn observational study at Keio University and affiliated hospitals enrolled 336 COPD patients and 67 non-COPD subjects. Health status was assessed by the CAT, the St. Georges Respiratory Questionnaire (SGRQ), and all components of the Medical Outcomes Study Short-Form 36-Item (SF-36) version 2, which is a generic measure of health. Comorbidities were identified based on patients’ reports, physicians’ records, and questionnaires, including the Frequency Scale for the Symptoms of Gastro-esophageal reflux disease (GERD) and the Hospital Anxiety and Depression Scale. Dual X-ray absorptiometry measurements of bone mineral density were performed.ResultsThe CAT showed moderate-good correlations with the SGRQ and all components of the SF-36. The presence of GERD, depression, arrhythmia, and anxiety was significantly associated with a high CAT score in the COPD patients.ConclusionsSymptomatic COPD patients have a high prevalence of comorbidities. A high CAT score should alert the clinician to a higher likelihood of certain comorbidities such as GERD and depression, because these diseases may co-exist unrecognized.Trial registrationClinical trial registered with UMIN (UMIN000003470).

A Case of Constrictive Pericarditis with Local Thickening of the Pericardium without Manifest Ventricular Interdependence

This is the first case report of postsurgical constrictive pericarditis confined to the left ventricle in which the majority of diagnosis tests were not indicative of the disease. A 50-year-old woman with a past history of mitral valve replacement was admitted for right heart failure. Cardiac catheterization showed impaired diastolic filling but lacked the characteristic ventricular interdependence recently reported to be specific for the disease, without manifest radiological appearance of pericardial thickening. However, a new technique using magnetic resonance tagging cine revealed pericardial adhesion, limited to the left ventricle, which was confirmed during pericardiectomy. After the surgery, right heart failure and diastolic filling abnormality disappeared with restoration of normal heart pressures.

Attenuation by intravenous 2-chloroadenosine of acute lung injury induced by live Escherichia coli or latex particles added to endotoxin in the neutropenic state

Although neutrophil depletion can reduce the level of acute lung injury (ALI) induced by Escherichia coli endotoxin, that induced by live E coli cannot be attenuated even in neutropenia. This suggests that live E coli cause ALI by way of an mechanism independent of circulating neutrophil. Tumor necrosis factor-alpha (TNF-alpha), which is released from monocytes and macrophages, is a proinflammatory cytokine that is recognized as a central mediator of several forms of inflammation. In this controlled experimental study, we examined the effects of an adenosine-receptor agonist, 2-chloroadenosine (2CA), that has suppressive effects on various cell types and TNF-alpha, on endotoxin plus latex particles, and on ALI induced by live E coli in the neutropenic state. We studied 42 guinea pigs rendered neutropenic by means of intraperitoneal cyclophosphamide administration. Experimental groups consisted of (1) a saline-solution control group; (2) an endotoxin (0.2 mg/kg)-treated group; (3) a group treated with endotoxin plus 2CA (10 micro g/kg); (4) a group treated with latex (2 x 10(9)/kg); (5) a group exposed to endotoxin and latex; (6) a group exposed to endotoxin, latex, and 2CA; (7) a group exposed to E coli (2 x 10(9)/kg); and (8) a group exposed to E coli and 2CA. The injection of endotoxin alone in neutropenic animals did not increase the indexes of ALI (lung tissue/plasma ratio [T/P] and lung wet weight/dry weight ratio [W/D], calculated with the use of iodine 125-labeled albumin). In contrast, these indexes were increased in the endotoxin-and-latex groups compared with those of the control group. ALI in the endotoxin-and-latex group was attenuated by intravenous 2CA. The intravenous injection of live E coli also caused increases in T/P, W/D, and plasma TNF-alpha, but thse were limited by 2CA. In summary, ALI induced by latex particles added to endotoxin and live E coli in the neutropenic state was attenuated by 2CA, suggesting a partial contribution of various cell types or humoral mediators as a neutrophil-independent pathway in its pathogenesis.