Decrease In Mean Pulmonary Artery Pressure Research Articles

N-terminal pro–B-type natriuretic peptide for monitoring after balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension

Balloon pulmonary angioplasty (BPA) is an emerging interventional treatment option for chronic thromboembolic pulmonary hypertension (CTEPH). The non-invasive monitoring of CTEPH patients is a clinical challenge. In this study we examined changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients undergoing BPA for inoperable CTEPH and related them to peri-procedural success. In this study we analyzed a total of 51 consecutive patients who underwent BPA treatment and completed a 6-month follow-up (6-MFU) between March 2014 and March 2017. Serum samples for NT-proBNP measurement were collected before every BPA and at 6-MFU. The 51 patients underwent 265 interventions involving angioplasty of a total of 410 vessels. The 6-month survival rate was 96.1%. The baseline (BL) mean pulmonary artery pressure (PAP) was 39.5 ± 12.1 mm Hg, pulmonary vascular resistance (PVR) was 515.8 ± 219.2 dynes/s/cm5 and the median NT-proBNP level was 820 (153 to 1,871.5) ng/liter. At BL, World Health Organization functional class (FC) was ≥III in 96.1% of the patients, whereas, at 6-MFU, 11.8% were in WHO FC ≥III. At 6-MFU, mean PAP (32.6 ± 12.6 mm Hg; p < 0.001), PVR (396.9 ± 182.6 dynes/s/cm5; p < 0.001) and NT-proBNP (159.3 [84.4 to 464.3] ng/liter; p < 0.001) levels were reduced. The decrease in NT-proBNP levels correlated with the decrease in mean PAP (rrs = 0.43, p = 0.002) and PVR (rrs = 0.50, p = 0.001). A reduction in the NT-proBNP level of 46% indicated a decrease in mean PAP of ≥25% (area under the curve [AUC] = 0.71) and a reduction of 61% indicated a decrease in PVR of ≥35% (AUC 0.77). Our results demonstrate that NT-proBNP levels decrease after BPA, providing valuable evidence of procedural success. NT-proBNP measurement allows identification of patients who are BPA non-responders and may thus be a valuable adjunct in therapy monitoring.

59-Year-Old Woman With Fatigue, Dyspnea, and Lower Extremity Edema

59-Year-Old Woman With Fatigue, Dyspnea, and Lower Extremity Edema

Angiotensin-converting enzyme 2 activation ameliorates pulmonary endothelial dysfunction in rats with pulmonary arterial hypertension through mediating phosphorylation of endothelial nitric oxide synthase

This study aims to investigate the effect of angiotensin-converting enzyme 2 (ACE2) activation on pulmonary endothelial function in the process of preventing pulmonary arterial hypertension (PAH) in rat models and to explore the underlying mechanisms. Specific pathogen free rats were randomly divided into five groups including control group, PAH group, PAH + Resorcinolnaphthalein (Res) group (ACE2 activation), PAH + Res + MLN4760 group (ACE2 inhibition), and PAH + Res + L-NAME group (endothelial nitric oxide synthase [eNOS] inhibition). Rat PAH model was constructed using combined left pneumonectomy with a single dose of monocrotaline injection 1 week after the surgery, and the rats were then given corresponding reagents. Hemodynamics, endothelial function, and pathologic changes were evaluated 3 weeks after monocrotaline injection. The concentration of nitric oxide (NO), expression of eNOS, and phosphorylation of eNOS at Ser1177 and Thr495 in the lung tissues from rats were also investigated.The Res-induced activation of ACE2 led to decreased mean pulmonary arterial pressure (mPAP) and pulmonary artery remodeling in the PAH + Res group comparing with the PAH rats (P < .05). In addition, the reduction in mPAP induced by acetylcholine (Ach) was augmented in PAH + Res group (P < .05), but this was not observed under the treatment with sodium nitroprusside (SNP) (P > .05). The ratio of decrease in mPAP caused by Ach to that caused by SNP (Ach/SNP) was also increased (P < .05) in ACE2-activated rats. However, the protective effects of ACE2 activation on PAH were counteracted by co-administration of MLN4760, an ACE2 antagonist (all P > .05). The mechanistic study showed that the concentration of NO in the lung tissues was downregulated in the PAH group but upregulated in the PAH + Res group (P < .05), whereas the NO concentration in the PAH + Res + MLN4760 group was not obviously different from that in the PAH group (P > .05). Regarding the factors regulating NO release, we found that the eNOS was upregulated in the PAH group, and Res did not affect the expression of eNOS. The phosphorylation of eNOS at Ser1177 was increased but at Thr495 was reduced after Res injection, when compared with the PAH group (P < .05). As expected, co-injection of MLN4760 eliminated these differences (P > .05). The reduction in mPAP induced by Ach was attenuated in the PAH + Res + L-NAME group compared with the PAH + Res group (P < .05), but this was not observed in rats treated with SNP (P > .05). The Ach/SNP ratio of decline in mPAP was also decreased in the PAH + Res + L-NAME group (P < .05). Activation of ACE2 had a protective role in the development of PAH via improving the function of pulmonary arterial endothelium. This effect was potentially mediated by promoted NO release as a consequence of increased phosphorylation of eNOS at Ser1177 and dephosphorylation of eNOS at Thr495.

Reversal of right ventricular remodeling by dichloroacetate is related to inhibition of mitochondria-dependent apoptosis.

Most patients with pulmonary arterial hypertension die from right ventricular failure (RVF). Right ventricular (RV) myocardial apoptosis has an important role in RVF and is regulated by the mitochondria. Dichloroacetate (DCA) can improve cardiac function in RVF, but whether it can regulate myocardial apoptosis via mitochondria is still unknown. In this study, we investigated the effects of DCA on myocardial mitochondria, the mitochondrial apoptosis and other aspects of RV remodeling, including fibrosis and capillary rarefaction. RVF was induced in rats by a single s.c. injection of monocrotaline. After 4 weeks, DCA treatment was started with i.p. injection of 50, 150 or 2007 mg kg(-1) per day during 14 days. Compared with saline-treated RVF animals, treatment with DCA resulted in decreased mean pulmonary arterial pressure and total pulmonary resistance (TPR), and increased cardiac output. The expression of pyruvate dehydrogenase kinase was suppressed, while pyruvate dehydrogenase expression was upregulated with DCA application. DCA treatment was also associated with restored RV mitochondrial function and a reduction in RV hypertrophy, fibrosis, capillary rarefaction and apoptosis. Mitochondria-dependent apoptosis was involved in DCA regulation of RV. The absent correlation between TPR and main parameters in RV suggests that the effects of DCA in the two organ systems are independent. We conclude that DCA improves cardiac function in experimental RVF partly by reversing RV remodeling, restoring mitochondrial function and regulating mitochondria-dependent apoptosis. The study shows that a fear for increased RV apoptosis with DCA treatment is unnecessary and suggests a potential role of DCA in the treatment of RVF.

Abstract 14360: Gene Transfer of Sarco/Endoplasmic reticulum Ca2+-ATPase 2a Restores Pulmonary Artery Endothelial Catechol-O-Methyltransferase Activity to Decrease Norepinephrine Levels in Pulmonary Hypertension

Elevated levels of norepinephrine (NE) may occur in pulmonary hypertension (PH), in part, when activity of catechol- O -methyltransferase (COMT) is decreased. COMT is expressed by pulmonary artery endothelial cells (PAEC), degrades NE, and is negatively regulated by aldosterone (ALDO) and cytosolic Ca 2+ . Expression of the cardiac isoform of the sarco/endoplasmic Ca 2+ -ATPase (SERCA2a) modulates ALDO and cytosolic Ca 2+ and is downregulated in pulmonary arteries in PH. We hypothesized that gene transfer of SERCA2a to pulmonary arteries would prevent the decrease in COMT activity and lower NE levels. Accordingly, human PAEC were infected with an adenovirus encoding SERCA2a to increase expression 4.2-fold (p&lt;0.01) or control virus and exposed to ALDO (10 -7 mol/L), which decreases COMT activity by 59.2 ± 6.2% (p&lt;0.01). Compared to controls, SERCA2a overexpression in PAEC had no effect on COMT mRNA or protein levels but increased COMT activity by 148.8 ± 14.5% (p&lt;0.01) by decreasing cytosolic Ca 2+ levels by 38.2 ± 6.7% (p&lt;0.05). This resulted in a decrease in NE levels in the medium (229.4 ± 20.6 vs. 139.9 ± 14.8 vs. pg/mg protein, p&lt;0.01) and collagen I expression. To examine the in vivo relevance of SERCA2a gene transfer on COMT activity, the rat monocrotaline model of PH was treated with inhaled adeno-associated virus 1 carrying SERCA2a (AAV1.SERCA2a). There was no difference in COMT expression in AAVI.SERCA2a-treated or saline control PH-rats; however, lung COMT activity was increased 139.8 ± 8.2% (p&lt;0.01) while lung levels of NE (366.7 ± 38.6 vs. 504 ± 30.2 pg/ml/mg, p&lt;0.01), serum ALDO, and pulmonary artery collagen 1 were decreased by AAV1.SERCA2a. In the pig pulmonary vein banding model of PH, inhaled AAV1.SERCA2a gene therapy decreased mean pulmonary artery pressure (54 ± 20 vs. 29 ± 5 mmHg, p&lt;0.03); increased COMT activity by 121.1 ± 6.2% (p&lt;0.05); and decreased levels of ALDO by 43.3 ± 4.6% (p&lt;0.03), NE by 43.3 ± 4.6% (p&lt;0.03), and collagen I in remodeled vessels. Taken together, these data indicate that gene therapy with inhaled AAV1.SERCA2a increases COMT activity by decreasing intracellular Ca 2+ , thereby decreasing NE levels. This extends the actions of SERCA2a beyond pulmonary vascular remodeling in PH to modulating levels of circulating catecholamines.

PP.21.23

Objective: Evaluate the data of right heart catheterization (RHC) and echocardiography (ECHO) at baseline and their dynamics during 12-week treatment with bosentan in patients with idiopathic pulmonary hypertension (IPH). Design and method: The study included 42 patients (39 women and 4 men, II-IV FC (WHO)) with a verified diagnosis IPH. All patients underwent acute pharmacological testing (aPhT) with iNO during RHC. Patients with negative vasoreactivity response (n = 22) recieved pathogenetic therapy with bosentan and standard therapy of heart failure. The starting dose was 62,5 mg twice per day for 1 month, followed by titration to dose 125 mg twice/day. Dose titration was carried out under the control of blood pressure, heart rate, liver enzymes monthly. Evaluating the effectiveness of treatment was carried out according to RHC and ECHO. Results: The therapy increased exercise tolerance according to 6MWT: initially 363,2 ± 80,4m. and during 3 months of therapy 427,8 ± 69,9 m. (p < 0,05). There was improvement of hemodynamic parameters according to RHC: decreased mean pulmonary artery pressure of 8,8mmHg (p < 0,05), pulmonary vascular resistance of 602,6din*s/sm5 (p < 0,05); cardiac index increased by 0,6 l /min*m2 (p < 0,05) at the same time there have been no significant reduction in systolic pulmonary artery pressure (initially 102,4 mmHg, on the treatment 96,4 mmHg (p > 0,05)). According to echocardiography there was a significant positive dynamic: reduced antero-posterior size of the right ventricle (delta = -0,23sm), area of the right atrium (delta = -1,6sm2); increased end-diastolic size of left ventricule (delta = +0,3sm). Conclusions: The patients had positive dynamics in the form of increased exercise tolerance, improvement data of RHC and echocardiography during 12 weeks of bosentan therapy.

Effects of different inspired oxygen fractions on sildenafil-induced pulmonary anti-hypertensive effects in a sheep model of acute pulmonary embolism.

Sildenafil is a pulmonary anti-hypertensive agent whose action could be modified by different fractions of inspired oxygen (FiO2). We compared the effects of pure oxygen (FiO2 > 90%) or room air (21% FiO2) on the cardiopulmonary actions of sildenafil in sheep with acute pulmonary embolism (APE). Thirty-two anesthetized, mechanically ventilated sheep (34.9 ± 5.4 kg), were randomly distributed into four groups (n = 8 per group): FiO2 > 90% without intervention; APE induced by microspheres with FiO2 > 90%, followed 30 min later by placebo (Emb90); or APE followed 30 min later by intravenous sildenafil (0.7 mg/kg over 30 min) with FiO2 > 90% (Emb + Sild90) or 21% FiO2 (Emb + Sild21) [Corrected]. Variables were recorded until 30 min after the end of treatment administration. Microsphere injection increased (P < 0.05) mean pulmonary artery pressure (MPAP) in all embolized groups (111-140% higher than that of baseline). Compared with values recorded 30 min after induction of APE (E30), sildenafil induced greater decreases in MPAP in the Emb + Sil90 group than in the Emb + Sil21 group (23% and 14% lower than E30, respectively). Hypotension (mean arterial pressure < 60 mm Hg) was precipitated by sildenafil due to systemic vasodilation in the Emb + Sil21 group. Embolization lowered the PaO2/FiO2 ratio and increased venous admixture, but sildenafil did not alter the oxygenation impairment induced by APE. Sildenafil induces a more consistent pulmonary anti-hypertensive effect and causes less interference with the systemic circulation with the concomitant use of pure oxygen than that with room air in the APE setting.

Peripheral Pulmonary Artery Stenosis as a Cause of Pulmonary Hypertension in Adults

Peripheral pulmonary artery stenosis (PPAS) is an underrecognized condition in the adult population. PPAS can lead to pulmonary hypertension but is likely misdiagnosed as either idiopathic pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. We retrospectively identified adult patients with PPAS either in its isolated form or related to other congenital defects from January 1998 to September 2012. We reviewed the patients' clinical data by using our hospital electronic medical records and/or their paper charts. We identified 6 adult patients with PPAS with an age range of 16-56 years (1 woman and the rest men). Presenting signs and symptoms were thoracic murmurs, progressive dyspnea, and syncope. Three patients had Williams-Beuren syndrome. Pulmonary angiography showed that PPAS was predominantly located in main branches or lobar pulmonary arteries in 5 patients, while in 1 patient the arterial narrowing was at the level of the segmental pulmonary arteries. Right heart catheterization showed a mean pulmonary artery pressure (PAP) ranging from 35 to 60 mmHg. Balloon dilation was performed in all patients, predominantly in the lobar arteries, and it caused a decrease in mean PAP that ranged from 16% to 46% in 5 patients. In 1 patient the mean PAP did not decrease. All but 1 patient had follow-up echocardiograms at 1 year that showed stable echocardiographic findings. Pulmonary hypertension due to PPAS continues to presents a diagnostic challenge. Therefore, a high index of suspicion during the initial evaluation of pulmonary hypertension is essential for its prompt diagnosis and adequate treatment.

Efficacy of rotational thrombectomy on the mortality of patients with massive and submassive pulmonary embolism.

Pulmonary embolism (PE) associated with hemodynamic instability has exceedingly high mortality. We describe our experience using percutaneous mechanical thrombectomy (PMT) in patients with massive PE (MPE) and submassive PE (SPE). Thirty-six patients (16 males and 20 females; mean age, 51.4 ± 6.6 years) with massive and submassive PE were treated with PMT. All patients exhibited acute symptoms and computed tomography evidence of large thrombus burden and evidence of right ventricular (RV) dysfunction and/or failure. An Aspirex® percutaneous aspiration device was used in all patients. Clinical outcomes, hemodynamic recovery, RV and pulmonary artery pressures (PAP), blood gas changes, thrombus clearance, and complications were evaluated. Treatment of 36 patients resulted in complete thrombus clearance (≥ 90%) in 83.3% of the patients (n = 30) and near-complete (50% to 90%) clearance in 13.8%. Measurements before and after treatment showed a decrease in mean PAP (53 ± 5.8 mmHg versus 25.6 ± 6.3 mmHg in MPE group [p < 0.01] and 46 ± 7.7 versus 22 ± 3.6 in SPE group [p < 0.01]). One patient died from refractory shock. No cardiovascular deaths or recurrent PE were documented during clinical follow-up but one patient demonstrated evidence of mild cor pulmonale. This study demonstrates safety and effectiveness of percutaneous mechanical aspiration thrombectomy in patients with massive and submassive PE with a large thrombus burden.

A new era of therapeutic strategies for chronic thromboembolic pulmonary hypertension by two different interventional therapies; pulmonary endarterectomy and percutaneous transluminal pulmonary angioplasty.

BackgroundPulmonary endarterectomy (PEA) is established for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). Recently, percutaneous transluminal pulmonary angioplasty (PTPA) has been added for peripheral-type CTEPH, whose lesions exist in segmental, subsegmental, and more distal pulmonary arteries. A shift in clinical practice of interventional therapies occurred in 2009 (first mainly PEA, later PTPA). We examined the latest clinical outcomes of patients with CTEPH.Methods and ResultsThis study retrospectively included 136 patients with CTEPH. Twenty-nine were treated only with drug (Drug-group), and the other 107 underwent interventional therapies (Interventions-group) (39 underwent PEA [PEA-group] and 68 underwent PTPA [PTPA-group]). Total 213 PTPA sessions (failures, 0%; mortality rate, 1.47%) was performed in the PTPA-group (complications: reperfusion pulmonary edema, 7.0%; hemosputum or hemoptysis, 5.6%; vessel dissection, 2.3%; wiring perforation, 0.9%). Although baseline hemodynamic parameters were significantly more severe in the Interventions-group, the outcome after the diagnosis was much better in the Interventions-group than in the Drug-group (98% vs. 64% 5-year survival, p<0.0001). Hemodynamic improvement in the PEA-group was a 46% decrease in mean pulmonary arterial pressure (PAP) and a 49% decrease in total pulmonary resistance (TPR) (follow-up period; 74.7±32.3 months), while those in the PTPA-group were a 40% decrease in mean PAP and a 49% decrease in TPR (follow-up period; 17.4±9.3 months). The 2-year survival rate in the Drug-group was 82.0%, and the 2-year survival rate, occurrence of right heart failure, and re-vascularization rate in the PEA-group were 97.4%, 2.6%, and 2.8%, and those in the PTPA-group were 98.5%, 2.9%, and 2.9%, respectively.ConclusionThe patients who underwent interventional therapies had better results than those treated only with drugs. The availability of both of these operative and catheter-based interventional therapies leads us to expect the dawn of a new era of therapeutic strategies for CTEPH.

Comparison of pharmacological activity of macitentan and bosentan in preclinical models of systemic and pulmonary hypertension

AimsThe endothelin (ET) system is a tissular system, as the production of ET isoforms is mostly autocrine or paracrine. Macitentan is a novel dual ETA/ETB receptor antagonist with enhanced tissue distribution and sustained receptor binding properties designed to achieve a more efficacious ET receptor blockade. To determine if these features translate into improved efficacy in vivo, a study was designed in which rats with either systemic or pulmonary hypertension and equipped with telemetry were given macitentan on top of maximally effective doses of another dual ETA/ETB receptor antagonist, bosentan, which does not display sustained receptor occupancy and shows less tissue distribution. Main methodsAfter establishing dose–response curves of both compounds in conscious, hypertensive Dahl salt-sensitive and pulmonary hypertensive bleomycin-treated rats, macitentan was administered on top of the maximal effective dose of bosentan. Key findingsIn hypertensive rats, macitentan 30mg/kg further decreased mean arterial blood pressure (MAP) by 19mmHg when given on top of bosentan 100mg/kg (n=9, p<0.01 vs. vehicle). Conversely, bosentan given on top of macitentan failed to induce an additional MAP decrease. In pulmonary hypertensive rats, macitentan 30mg/kg further decreased mean pulmonary artery pressure (MPAP) by 4mmHg on top of bosentan (n=8, p<0.01 vs. vehicle), whereas a maximal effective dose of bosentan given on top of macitentan did not cause any additional MPAP decrease. SignificanceThe add-on effect of macitentan on top of bosentan in two pathological models confirms that this novel compound can achieve a superior blockade of ET receptors and provides evidence for greater maximal efficacy.

Adrenomedullin alleviates pulmonary artery collagen accumulation in rats with pulmonary hypertension induced by high blood flow

Collagen accumulation is one of the important pathologic changes in the development of pulmonary hypertension. Previous research showed that adrenomedullin (ADM) mitigates the development of pulmonary hypertension. The present study explored the role of ADM in the development of pulmonary artery collagen accumulation induced by high pulmonary blood flow, by investigating the effect of ADM [1.5μg/(kgh)] subcutaneously administered by mini-osmotic pump on pulmonary hemodynamics, pulmonary vascular structure and pulmonary artery collagen accumulation and synthesis in rats with high pulmonary blood flow induced by aortocaval shunting. The results showed that ADM significantly decreased mean pulmonary artery pressure (mPAP) and the ratio of right ventricular mass to left ventricular plus septal mass [RV/(LV+SP)], attenuated the muscularization of small pulmonary vessels and relative medial thickness (RMT) of pulmonary arteries in rats with high pulmonary blood flow. Meanwhile, ADM ameliorated pulmonary artery collagen deposition represented by a decrease in lung tissue hydroxyproline, collagens I and III content and pulmonary artery collagens I and III expression, reduced collagen synthesis represented by a decrease in lung tissue procollagens I and III mRNA expression. The results suggest that ADM plays a protective role in the development of pulmonary hypertension induced by high blood flow, by inhibiting pulmonary procollagen synthesis and alleviating pulmonary artery collagen accumulation.

Balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension

ObjectiveTo examine the effect of balloon pulmonary angioplasty (BPA) on chronic thromboembolic pulmonary hypertension (CTEPH) in patients with inoperable disease or persistent pulmonary hypertension after pulmonary endarterectomy.DesignObservational cohort study.SettingReferred patients...

Pulmonary Hypertension Secondary to Left-Heart Failure Involves Peroxynitrite-Induced Downregulation of PTEN in the Lung

Pulmonary hypertension (PH) that occurs after left-heart failure (LHF), classified as Group 2 PH, involves progressive pulmonary vascular remodeling induced by smooth muscle cell (SMC) proliferation. However, mechanisms involved in the activation of SMCs remain unknown. The objective of this study was to determine the involvement of peroxynitrite and phosphatase-and-tensin homolog on chromosome 10 (PTEN) in vascular SMC proliferation and remodeling in the LHF-induced PH (LHF-PH). LHF was induced by permanent ligation of left anterior descending coronary artery in rats for 4 weeks. MRI, ultrasound, and hemodynamic measurements were performed to confirm LHF and PH. Histopathology, Western blot, and real-time polymerase chain reaction analyses were used to identify key molecular signatures. Therapeutic intervention was demonstrated using an antiproliferative compound, HO-3867. LHF-PH was confirmed by significant elevation of pulmonary artery pressure (mean pulmonary artery pressure/mm Hg: 35.9±1.8 versus 14.8±2.0, control; P<0.001) and vascular remodeling. HO-3867 treatment decreased mean pulmonary artery pressure to 22.6±0.8 mm Hg (P<0.001). Substantially higher levels of peroxynitrite and significant loss of PTEN expression were observed in the lungs of LHF rats when compared with control. In vitro studies using human pulmonary artery SMCs implicated peroxynitrite-mediated downregulation of PTEN expression as a key mechanism of SMC proliferation. The results further established that HO-3867 attenuated LHF-PH by decreasing oxidative stress and increasing PTEN expression in the lung. In conclusion, peroxynitrite and peroxynitrite-mediated PTEN inactivation seem to be key mediators of lung microvascular remodeling associated with PH secondary to LHF.

Reversal of pulmonary hypertension in children after adenoidectomy or adenotonsillectomy

IntroductionAdenotonsillar hypertrophy is a common condition in pediatric patients with upper respiratory airways complaints, and pulmonary arterial hypertension (PAH) may be one complication of that condition. ObjectivesTo study the occurrence of PAH (mean pulmonary artery pressure higher than or equal to 25mmHg) in a group of children with adenotonsillar hypertrophy and upper respiratory complaints (snoring or oral breathing), and to verify the pulmonary arterial pressure (PAP) changes after adenotonsillectomy. Study designCase–control prospective study. SettingsStudy conducted at São Lucas Hospital, approaching both public and private sector. Subject and methodsThirty-three pediatric patients with adenotonsillar hypertrophy and evidence of obstructive upper airways complaints were treated with adenotonsillectomy. All 33 patients underwent echocardiogram before and after the surgery with determination of the pulmonary arterial pressure (PAP), through either the tricuspid regurgitation or artery linear flow acceleration time estimation. Similar determinations were performed in 10 normal non operated controls. ResultsPulmonary hypertension was verified 12 (36%) of the 33 patients with adenotonsillar hypertrophy. Adenoidectomy or adenotonsillectomy was associated to a significant 27% decrease in mean PAP (27±2.8 to 20±5.1mmHg, p<0.001) and to a non significant 26% decrease in systolic PAP (35±6.2mmHg to 25±0.5mmHg, p=0.243). The PAP values in children with no pulmonary hypertension were not changed after the surgery. ConclusionsIn children with pulmonary hypertension associated to adenotonsillar hypertrophy, the adenotonsillectomy decreased PAP to normal values in all patients.

Cyclooxygenase‐2 inhibition and thromboxane A2 receptor antagonism attenuate hypoxic pulmonary vasoconstriction in a porcine model

Hypoxic pulmonary vasoconstriction (HPV) causes pulmonary hypertension that may lead to right heart failure. We hypothesized that the COX-2 inhibitor nimesulide and the thromboxane A(2) receptor antagonist daltroban would attenuate HPV. Haemodynamic measurements and blood sampling were performed in 18 anaesthetized, mechanically ventilated pigs, with mean ± SEM weights of 31.3 ± 0.6 kg, in normoxia (F(i)O(2)~0.21) and hypoxia (F(i)O(2)~0.10), before and 5, 15 and 45 min after initiation of right atrial infusion of nimesulide (n = 6) or daltroban (n = 6), respectively, and in six control pigs. Compared with normoxia, hypoxia (n = 18) increased mean pulmonary artery pressure by 15.8 ± 0.8 mmHg (P < 0.001), pulmonary vascular resistance (PVR) by 2.7 ± 0.3 WU (P < 0.05) and mean right atrial pressure by 2.3 ± 0.3 mmHg (P < 0.001). In the control pigs, mean pulmonary artery pressure, PVR and mean right atrial pressure remained stable (P = ns) throughout 45 min hypoxia, compared with hypoxia baseline. Nimesulide decreased mean pulmonary artery pressure by 3.7 ± 1.3 mmHg after 45 min (P < 0.013), as well as PVR by 0.8 ± 0.2 WU (P < 0.05), levelling off after 15 min. Daltroban transiently increased (P < 0.001) mean pulmonary artery pressure and mean right atrial pressure by 7.2 ± 1.2 and 2.7 ± 0.4 mmHg, respectively, but they returned to hypoxia baseline (P = ns) within 5 min. Daltroban then decreased mean pulmonary artery pressure to after 45 min be 4.2 ± 1.6 mmHg lower (P < 0.005) than at hypoxia baseline. COX-2 inhibition and thromboxane A(2) receptor antagonism attenuate HPV by decreasing mean pulmonary artery pressure by approximately 10-11%, as measured 45 min after initiation of nimesulide or daltroban infusion respectively.

Vardenafil in Pulmonary Arterial Hypertension

Although the phosphodiesterase type 5 inhibitors sildenafil and tadalafil have demonstrated efficacy in patients with pulmonary arterial hypertension (PAH), monotherapy with these agents has not been conclusively shown to reduce clinical worsening events.To evaluate the safety and efficacy of the phosphodiesterase type 5 inhibitor vardenafil in Chinese patients with PAH.In a randomized, double-blind, placebo-controlled study, 66 patients with PAH were randomized 2:1 to vardenafil (5 mg once daily for 4 wk then 5 mg twice daily; n = 44) or placebo (n = 22) for 12 weeks. Patients completing this phase were then treated with open-label vardenafil (5 mg twice daily) for a further 12 weeks.At Week 12, the mean placebo-corrected 6-minute walking distance was increased with vardenafil (69 m; P < 0.001), and this improvement was maintained for at least 24 weeks. Vardenafil also increased the mean placebo-corrected cardiac index (0.39 L·min(-1)·m(-2); P = 0.005) and decreased mean pulmonary arterial pressure and pulmonary vascular resistance (-5.3 mm Hg, P = 0.047; -4.7 Wood U, P = 0.003; respectively) at Week 12. Four patients in the placebo group (20%) and one in the vardenafil group (2.3%) had clinical worsening events (hazard ratio 0.105; 95% confidence interval, 0.012-0.938; P = 0.044). Vardenafil was associated with only mild and transient adverse events.Vardenafil is effective and well tolerated in patients with PAH at a dose of 5 mg twice daily.

Haemodynamic effects of rolofylline in the treatment of patients with heart failure and impaired renal function

The direct effects of adenosine A1 receptor antagonists on haemodynamic parameters in patients with acute heart failure (HF) remain largely unknown. We evaluated the haemodynamic effects of the AA(1)RA rolofylline in 59 HF patients with concomitant renal impairment (estimated creatinine clearance 20-80 mL/min). Placebo or rolofylline 30 mg was administered as a 4 h infusion followed by intravenous (i.v.) loop diuretic administration. Haemodynamic measurements were carried out hourly up to 8 h post-dosing by pulmonary artery catheterization. Urine output, fractional excretion of sodium, potassium, urea, and uric acid, and blood urea nitrogen (BUN) and creatinine levels were also measured. In both groups, the changes from baseline in all haemodynamic indices except mean pulmonary artery pressure (PAP) were not clinically significant. Mean [95% confidence interval (CI)] PAP showed a placebo-adjusted decrease with rolofylline of -1.5 (-4.1, 1.1)mmHg at Hour 4 and -3.5 mmHg (95% CI: -6.2, -0.2) at Hour 8. There was a significant increase with rolofylline in diuresis [placebo-corrected mean (95% CI) change of 68 (20, 116)mL/h at Hour 2-4 and 103 (21, 185)mL/h at Hour 4-8] and in fractional excretion of sodium, potassium, and uric acid. Placebo-corrected changes in plasma levels of creatinine and BUN with rolofylline were non-significant. Single administration of rolofylline in patients with HF and impaired renal function produced a slight decrease in mean PAP and consistently increased diuresis and natriuresis without compromising renal function, both before and after administration of i.v. loop diuretics.

Sildenafil attenuates pulmonary arterial pressure but does not improve oxygenation during ARDS

ObjectivePulmonary hypertension is a characteristic feature of acute respiratory distress syndrome (ARDS) and contributes to mortality. Administration of sildenafil in ambulatory patients with pulmonary hypertension improves oxygenation and ameliorates pulmonary hypertension. Our aim was to determine whether sildenafil is beneficial for patients with ARDS.DesignProspective, open-label, multicenter, interventional cohort study.SettingMedical-surgical ICU of two university hospitals.PatientsTen consecutive patients meeting the NAECC criteria for ARDS.InterventionsA single dose of 50 mg sildenafil citrate administered via a nasogastric tube.Main resultsAdministration of sildenafil in patients with ARDS decreased mean pulmonary arterial pressure from 25 to 22 mmHg (P = 0.022) and pulmonary artery occlusion pressure from 16 to 13 mmHg (P = 0.049). Systemic mean arterial pressures were markedly decreased from 81 to 75 mmHg (P = 0.005). Sildenafil did not improve pulmonary arterial oxygen tension, but resulted in a further increase in the shunt fraction.ConclusionAlthough sildenafil reduced pulmonary arterial pressures during ARDS, the increased shunt fraction and decreased arterial oxygenation render it unsuitable for the treatment of patients with ARDS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00134-010-1754-3) contains supplementary material, which is available to authorized users.

Acute hemodynamic effects of inhaled nitroglycerine, intravenous nitroglycerine, and their combination with intravenous dobutamine in patients with secondary pulmonary hypertension

The presence of pulmonary artery hypertension (PAH) affects the prognosis of patients; therefore, it is important to treat it. The aim of this study is to compare the acute hemodynamic effects of inhaled nitroglycerine (iNTG), intravenous nitroglycerine (IV NTG) alone and their combination with intravenous dobutamine (IV DOB) during the early postoperative period, in patients with PAH undergoing mitral valve or double valve replacement surgery. In the study, 40 patients with secondary PAH were administered iNTG 2.5 microg/kg/min, IV NTG 2.5 microg/kg/min, a combination of iNTG 2.5 microg/kg/min + IV DOB 10 microg/kg/min, and IV NTG 2.5 microg/kg/min + IV DOB 10 microg/kg/min for 10 minutes each following valve replacement surgery, in random order. The hemodynamic parameters were recorded before (T0) and immediately after the intervention. (T1). iNTG effectively decreased mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance index (PVRI), and the PVR / SVR ratio, without affecting arterial pressures, systemic vascular resistance or mixed venous oxygen saturation (SvO2). IV NTG produced both systemic and pulmonary vasodilation along with a significant fall in SvO2. The combination of iNTG and IV DOB caused a significant decrease in mPAP and PVRI, with no significant change in SVRI, PVR / SVR ratio, and SvO2. A combination of IV NTG + IV DOB caused both pulmonary and systemic vasodilatation with a significant decrease in SvO2. None of the drugs caused any significant change in the cardiac index. All drugs were of similar efficacy in reducing the pulmonary vascular resistance index. Only iNTG produced selective pulmonary vasodilatation, while IV NTG and its combination with IV dobutamine had a significant concomitant systemic vasodilatory effect.