Norifumi Nakanishi

Plasma Brain Natriuretic Peptide Levels Increase in Proportion to the Extent of Right Ventricular Dysfunction in Pulmonary Hypertension

OBJECTIVES This study sought to investigate the influence of right ventricular (RV) hemodynamic variables and function on the secretion of brain natriuretic peptide (BNP) in patients with isolated RV overload. BACKGROUND Plasma BNP is known to increase in proportion to the degree of left ventricular (LV) overload. However, whether BNP secretion is also regulated in the presence of RV overload remains unknown. METHODS Plasma BNP and atrial natriuretic peptide (ANP) levels in the pulmonary artery were measured in 44 patients with RV overload: 18 with RV volume overload (RVVO) due to atrial septal defect and 26 with RV pressure overload (RVPO) due to primary or thromboembolic pulmonary hypertension. Right heart catheterization was performed in all patients. RV and LV ejection fraction, myocardial mass and volume of the four chambers were determined by using electron beam computed tomography. RESULTS Although both plasma BNP and ANP levels were significantly elevated in patients with RV overload compared with values in control subjects, plasma BNP and the BNP/ANP ratio were significantly higher in patients with RVPO than with RVVO (BNP 294 +/- 72 vs. 48 +/- 14 pg/ml; BNP/ANP 1.6 +/- 0.2 vs. 0.8 +/- 0.2, both p < 0.05). Plasma BNP correlated positively with mean pulmonary artery pressure (r = 0.73), total pulmonary resistance (r = 0.79), mean right atrial pressure (r = 0.79), RV end-diastolic pressure (r = 0.76) and RV myocardial mass (r = 0.71); it correlated negatively with cardiac output (r = -0.33) and RV ejection fraction (r = -0.71). Plasma BNP significantly decreased from 315 +/- 120 to 144 +/- 54 pg/ml with long-term vasodilator therapy (total pulmonary resistance decreased from 23 +/- 4 to 15 +/- 3 Wood U). CONCLUSIONS Plasma BNP increases in proportion to the extent of RV dysfunction in pulmonary hypertension.

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).

Effects of Adrenomedullin Inhalation on Hemodynamics and Exercise Capacity in Patients With Idiopathic Pulmonary Arterial Hypertension

Background—Adrenomedullin (AM) is a potent pulmonary vasodilator peptide. However, whether intratracheal delivery of aerosolized AM has beneficial effects in patients with idiopathic pulmonary arterial hypertension remains unknown. Accordingly, we investigated the effects of AM inhalation on pulmonary hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension. Methods and Results—Acute hemodynamic responses to inhalation of aerosolized AM (10 &mgr;g/kg body wt) were examined in 11 patients with idiopathic pulmonary arterial hypertension during cardiac catheterization. Cardiopulmonary exercise testing was performed immediately after inhalation of aerosolized AM or placebo. The work rate was increased by 15 W/min until the symptom-limited maximum, with breath-by-breath gas analysis. Inhalation of AM produced a 13% decrease in mean pulmonary arterial pressure (54±3 to 47±3 mm Hg, P <0.05) and a 22% decrease in pulmonary vascular resistance (12.6±1.5 to 9.8±1.3 Wood units, P <0.05). However, neither systemic arterial pressure nor heart rate was altered. Inhalation of AM significantly increased peak oxygen consumption during exercise (peak &OV0312;o2, 14.6±0.6 to 15.7±0.6 mL · kg−1 · min−1, P <0.05) and the ratio of change in oxygen uptake to that in work rate (&Dgr;&OV0312;o2/&Dgr;W ratio, 6.3±0.4 to 7.0±0.5 mL · min−1 · W−1, P <0.05). These parameters remained unchanged during placebo inhalation. Conclusions—Inhalation of AM may have beneficial effects on pulmonary hemodynamics and exercise capacity in patients with idiopathic pulmonary arterial hypertension.

Gene Transfer of Human Prostacyclin Synthase Ameliorates Monocrotaline-Induced Pulmonary Hypertension in Rats

BackgroundProstacyclin is a potent vasodilator that also inhibits platelet adhesion and cell growth. We investigated whether in vivo gene transfer of human prostacyclin synthase (PGIS) ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Methods and ResultsThe cDNA encoding PGIS was intratracheally transfected into the lungs of rats by the hemagglutinating virus of Japan–liposome method. Rats transfected with control vector lacking the PGIS gene served as controls. Three weeks after MCT injection, mean pulmonary arterial pressure and total pulmonary resistance had increased significantly; the increases were significantly attenuated in PGIS gene–transfected rats compared with controls [mean pulmonary arterial pressure, 31±1 versus 35±1 mm Hg (−12%); total pulmonary resistance, 0.087±0.01 versus 0.113±0.01 mm Hg · mL · min−1 · kg−1 (−23%), both P <0.05]. Systemic arterial pressure and heart rate were unaffected. Histologically, PGIS gene transfer inhibited the increase in medial wall thickness of peripheral pulmonary arteries that resulted from MCT injection. PGIS immunoreactivity was intense predominantly in the bronchial epithelium and alveolar cells. Lung tissue levels of 6-keto-PGF1&agr;, a stable metabolite of prostacyclin, were significantly increased for ≥1 week after transfer of PGIS gene. The Kaplan-Meier survival curves demonstrated that repeated transfer of PGIS gene every 2 weeks increased survival rate in MCT rats (log-rank test, P <0.01). ConclusionsIntratracheal transfer of the human PGIS gene augmented pulmonary prostacyclin synthesis, ameliorated MCT-induced pulmonary hypertension, and thereby improved survival in MCT rats.

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.

Right ventricular reverse remodelling after balloon pulmonary angioplasty

Balloon pulmonary angioplasty (BPA) has been reported to improve haemodynamics and functional capacity, with an acceptable risk, in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are not candidates for pulmonary endarterectomy. However, right ventricular (RV) function, an important predictor in CTEPH, remains to be elucidated. We aimed to examine the impact of BPA on RV remodelling and dysfunction relative to haemodynamic improvements in patients with inoperable CTEPH. 20 consecutive patients with inoperable CTEPH who underwent BPA with cardiovascular magnetic resonance before and after BPA were retrospectively studied. BPA led to significant amelioration of the mean pulmonary arterial pressure, cardiac index and pulmonary vascular resistance (PVR), without death or major complications. Furthermore, BPA significantly ameliorated right-sided heart failure symptoms and signs, and exercise capacity. Cardiovascular magnetic resonance revealed a marked improvement in RV end-diastolic and end-systolic volume index, with concomitant improvements in RV ejection fraction, mass and interventricular septal bowing after BPA. Changes in RV volumes strongly correlated with changes in cardiac index and PVR. BPA induced RV reverse remodelling and improved systolic dysfunction safely by ameliorating haemodynamics in patients with inoperable CTEPH. Evaluating RV function with cardiovascular magnetic resonance may be effective for noninvasively monitoring BPA efficacy. BPA safely ameliorates haemodynamics, leading to right ventricular reverse remodelling in inoperable CTEPH http://ow.ly/tQX2R

Characteristics of Pulmonary Artery Pressure Waveform for Differential Diagnosis of Chronic Pulmonary Thromboembolism and Primary Pulmonary Hypertension

OBJECTIVES The accurate diagnosis of chronic pulmonary thromboembolism (CPTE) is a prerequisite for life-saving surgical interventions. To help in the differential diagnosis of CPTE and primary pulmonary hypertension (PPH), we characterized the configuration of the pulmonary artery pressure waveform. BACKGROUND Because CPTE predominantly involves the proximal arteries, whereas PPH involves the peripheral arteries, we hypothesized that patients with CPTE would have stiff or high resistance proximal arteries, whereas those affected by PPH would have high resistance peripheral arteries. These differences in the primary lesions would make arterial pulsatility relative to mean pressure larger in CPTE than in PPH. METHODS In 34 patients with either CPTE (n = 22) or PPH (n = 12) whose pulmonary systolic pressure was > or = 50 mm Hg, we measured pulmonary artery pressure using a fluid-filled system that included a balloon-tipped flow-directed catheter. RESULTS To quantify the magnitude of pulsatility relative to mean pressure, we normalized pulse pressure by mean pressure, hereinafter referred to as fractional pulse pressure (PPf). PPf was markedly higher in CPTE than in PPH (mean [+/-SD] 1.41 +/- 0.20 and 0.80 +/- 0.18, respectively, p < 0.001) and was diagnostic in separating the two groups without overlap. Similarly, the coefficient of variation of pulmonary artery pressure also separated the two groups without overlap (0.45 +/- 0.06 and 0.25 +/- 0.06, respectively, p < 0.001). Fractional time to half the area under the pressure curve separated the two groups reasonably well (0.35 +/- 0.02 and 0.43 +/- 0.03, respectively, p < 0.001). CONCLUSIONS The analysis of pulsatility of pulmonary artery pressure is useful in the differential diagnosis of CPTE and PPH.