Characteristics and Long-term Outcomes of Pulmonary Venoocclusive Disease Induced by Mitomycin C.

BACKGROUND: Pulmonary venoocclusive disease (PVOD) is an uncommon form of pulmonary hypertension (PH) predominantly characterized by pulmonary vein and capillary involvement. An association between chemotherapy, in particular mitomycin C (MMC), and PVOD has been reported. RESEARCH QUESTION: What are the characteristics of MMC-induced PVOD, and what is the prognosis for patients with MMC-induced PVOD? STUDY DESIGN AND METHODS: We report the clinical, functional, radiologic, and hemodynamic characteristics at diagnosis and outcomes of patients with PVOD from the French PH Registry after exposure to MMC. The results are expressed as the median (minimum-maximum). RESULTS: From June 2011 to December 2018, 17 incident cases of MMC-induced PVOD were identified. At diagnosis, these patients had severe clinical and functional impairment, with 12 patients having a New York Heart Association (NYHA) functional class of III or IV and a 6-min walk distance of 220 (0-465) m. Right heart catheterization confirmed severe precapillary PH with a mean pulmonary artery pressure of 38 (30-52) mm Hg, a cardiac index of 2.2 (1.5-4) L/(min × m2), and pulmonary vascular resistance of 8.3 (5.1-14.5) Wood units. The diffusing capacity of the lungs for carbon monoxide was markedly decreased at 31% (20%-51%) of the theoretical values associated with severe hypoxemia. MMC was withdrawn for all patients, and 14 patients received specific pulmonary arterial hypertension (PAH) therapies. Among these patients, mild but statistically insignificant improvements were observed in NYHA functional class (P = .10), 6-min walk distance (P = .09), and pulmonary vascular resistance (-4.7 Wood units; P = .052) at reassessment (median delay of 4.8 months). Three patients experienced pulmonary edema requiring the cessation or reduction of PAH treatment. The median overall survival was 20 months, and the 6-, 12-, and 24-month survival rates were 76%, 58%, and 18%, respectively. INTERPRETATION: PVOD after MMC treatment is a rare but life-threatening complication associated with a poor prognosis despite MMC withdrawal and PAH-specific therapy.

Inhibition of overexpressed Kv3.4 augments HPV in endotoxemic mice.

BACKGROUND: Hypoxic pulmonary vasoconstriction (HPV) is a reaction of the pulmonary vasculature upon hypoxia, diverting blood flow into ventilated areas to preserve oxygenation. It is impaired in endotoxemia or ARDS. Voltage gated potassium channels have been shown to play a key role in the regulation of HPV. The aim of the study was to identify a voltage gated potassium channel involved in dysregulated HPV during endotoxemia. METHODS: Lungs of male C57BL/6 mice with and without endotoxemia (n = 6 ea. group) were analyzed for Kv3.4 gene and protein expression. HPV was examined in isolated perfused lungs of mice with and without endotoxemia and with and without selective Kv3.4 blocker BDS-I (n = 7 ea. group). Pulmonary artery pressure (PAP) and pressure-flow curves were measured during normoxic (FiO2 0.21) and hypoxic (FiO2 0.01) ventilation. HPV was quantified as the increase in perfusion pressure in response to hypoxia in percent of baseline perfusion pressure (ΔPAP) in the presence and absence of BDS-I. RESULTS: Kv3.4 gene (3.2 ± 0.5-fold, p < 0.05) and protein (1.5 ± 0.1-fold p < 0.05) expression levels were increased in endotoxemic mouse lungs. Endotoxemia reduced HPV (∆PAP control: 121.2 ± 8.7% vs. LPS 19.5 ± 8.0%, means ± SEM) while inhibition of Kv3.4 with 50 nM BDS-I augmented HPV in endotoxemic but not in control lungs (∆PAP control BDS-I: 116.6 ± 16.0% vs. LPS BDS-I 84.4 ± 18.2%, means ± SEM). CONCLUSIONS: Kv3.4 gene and protein expressions are increased in endotoxemic mouse lungs. Selective inhibition of Kv3.4 augments HPV in lungs of endotoxemic mice, but not in lungs of control mice.

Do the remodeling effects of sacubitril/valsartan treatment depend upon heart failure duration?

AIMS: The angiotensin receptor and neprilysin inhibitor (ARNI) sacubitril/valsartan (LCZ696) is recommended for the treatment of patients with heart failure in New York Heart Association (NYHA) class II-III and left ventricular ejection fraction (LVEF) 35% or less. We examined the effects of sacubitril/valsartan on cardiac remodeling and their correlation with heart failure duration in patients enrolled in our heart failure clinic from March 2017 to December 2019. METHODS: Echocardiographic and clinical/laboratory data were collected at baseline and at 6-month and 12-month follow-up visits in 69 patients (age 67 ±â€Š12 years, disease duration 8.4 ±â€Š5.8 years, 93% men). RESULTS: At both time points, mean NYHA class, NT-proBNP level, LVEF, LV end-systolic volume, and estimated systolic pulmonary pressure significantly (P < 0.05) improved versus baseline, as did the proportion of patients with diastolic dysfunction grade 3 or functional mitral regurgitation grade 3-4. In the subgroup with mean disease duration less than 8.5 years (n = 40), there was a significant improvement in all variables at both time points; in this group, a recovery of right ventricular function was also seen at the 12-month follow-up. On the contrary, patients with heart failure duration of at least 8.5 years (n = 29) showed only a slight improvement in LVEF and mitral regurgitation at 12 months. There were no significant changes in renal function and/or potassium levels in all patients. CONCLUSION: In patients with a relatively short disease duration, sacubitril/valsartan was associated with a strong favorable remodeling of the left ventricle and improvement in pulmonary circulation.

l-Citrulline treatment alters the structure of the pulmonary circulation in hypoxic newborn pigs.

BACKGROUND: Dysregulated nitric oxide (NO) signaling contributes to chronic hypoxia (CH)-induced pulmonary hypertension (PH). NO signaling is improved and pulmonary vascular resistance (PVR) is reduced in CH piglets treated with the l-arginine-NO precursor, l-citrulline. We hypothesized that l-citrulline might cause structural changes in the pulmonary circulation that would contribute to the reduction in PVR and that the l-citrulline-induced structural changes would be accompanied by alterations in vascular endothelial growth factor (VEGF) signaling. METHODS: We evaluated small pulmonary arterial (PA) wall thickness, lung capillary density, and protein abundances of VEGF, VEGFR2, and phospho (p)-VEGFR2 in PA and peripheral lung samples of piglets raised in the lab in CH (10%-12% O2 ) from the day of life (DOL) 2 until DOL 11 to 12 or raised in room air (normoxia) by the vendor and studied on arrival to the lab on DOL 11 to 12. Some CH piglets were treated with oral l-citrulline (1-1.5 g/kg/d) starting on the third day of hypoxia. RESULTS: PA wall thickness was 32% less and lung capillary formation was nearly doubled in l-citrulline treated than untreated CH piglets. Both of these l-citrulline-induced structural changes in the pulmonary circulation were accompanied by altered amounts of VEGF protein but not by altered amounts of either VEGFR2 or p-VEGFR2 proteins. CONCLUSIONS: Alterations in the structure of the pulmonary circulation in CH piglets by l-citrulline are unlikely to be mediated by overall VEGF signaling. Nonetheless, l-citrulline- induced structural changes should reduce PVR and thereby contribute to the amelioration of CH-induced PH.

Serum Sirolimus Levels After Implantation of Third Generation Drug Eluting Cobalt Chromium Coronary Stent in Ductus Arteriosus in Neonates with Duct-Dependent Pulmonary Circulation.

Ductal stenting (DS) palliates duct-dependent lesions using coronary stents. Sirolimus-eluting stents have replaced bare-metal stents in coronary interventions. Concerns exist about sirolimus levels in neonates. Therapeutic immunosuppressive sirolimus level is 5-15 ng/ml. After neonatal DS, drug levels were assessed at 24 h, 7 days and monthly thereafter till they were undetectable. Clinical course, ductal patency till their final corrective surgery was analyzed. The exact quantity of sirolimus in each stent was known. Twelve neonates with median age of 5.5 days received sirolimus-eluting stents, one stent in nine and two in the rest. The lesions were pulmonary atresia intact ventricular septum(PAIVS) in four, univentricular lesions with pulmonary atresia in four, biventricular lesions with pulmonary atresia in three and right ventricular rhabdomyoma in one neonate. If single stents up to 22 mm length, 24-h drug levels were less than 5 ng/ml. Even though 24-h levels were above 5 ng/ml in patients with single longer stent or two stents, it reduced to very low levels by seventh day. Two hospital deaths included rhabdomyoma with complete heart block and post-valvotomy cardiac failure for PAIVS. Stent patency after valvotomy for PAIVS exceeded three years. Patency was retained for 8-27 months till their elective corrective surgery in others. Sirolimus levels were acceptable at 24 h in all neonates receiving single stent under 22 mm length. In patients needing two stents, drug levels were in immunosuppressive range at 24 h but reduced rapidly within 7 days. The palliation provided by sirolimus-eluting DS was sufficiently long to provide clinical benefit.

Perinatal Hypoxia-Inducible Factor Stabilization Preserves Lung Alveolar and Vascular Growth in Experimental Bronchopulmonary Dysplasia.

Rationale: Antenatal inflammation with placental dysfunction is strongly associated with high bronchopulmonary dysplasia (BPD) risk in preterm infants. Whether antenatal or postnatal HIF (hypoxia-inducible factor) augmentation can preserve lung structure and function and prevent pulmonary hypertension after intrauterine inflammation is controversial.Objectives: To determine whether antenatal or postnatal prolyl-hydroxylase inhibitor (PHi) therapy increases lung HIF expression, preserves lung growth and function, and prevents pulmonary hypertension in a rat model of chorioamnionitis-induced BPD caused by antenatal inflammation.Methods: Endotoxin (ETX) was administered to pregnant rats by intraamniotic injection at Embryonic Day 20, and pups were delivered by cesarean section at Embryonic Day 22. Selective PHi drugs, dimethyloxalylglycine or GSK360A, were administered into the amniotic space at Embryonic Day 20 or after birth by intraperitoneal injection for 2 weeks. Placentas and lung tissue were collected at birth for morphometric and Western blot measurements of HIF-1a, HIF-2a, VEGF (vascular endothelial growth factor), and eNOS (endothelial nitric oxide synthase) protein contents. At Day 14, lung function was assessed, and tissues were harvested to determine alveolarization by radial alveolar counts, pulmonary vessel density, and right ventricle hypertrophy (RVH).Measurements and Main Results: Antenatal PHi therapy preserves lung alveolar and vascular growth and lung function and prevents RVH after intrauterine ETX exposure. Antenatal administration of PHi markedly upregulates lung HIF-1a, HIF-2a, VEGF, and eNOS expression after ETX exposure.Conclusions: HIF augmentation improves lung structure and function, prevents RVH, and improves placental structure following antenatal ETX exposure. We speculate that antenatal or postnatal PHi therapy may provide novel strategies to prevent BPD due to antenatal inflammation.

Induction and Characterization of Pulmonary Hypertension in Mice using the Hypoxia/SU5416 Model.

Pulmonary Hypertension (PH) is a pathophysiological condition, defined by a mean pulmonary arterial pressure exceeding 25 mm Hg at rest, as assessed by right heart catheterization. A broad spectrum of diseases can lead to PH, differing in their etiology, histopathology, clinical presentation, prognosis, and response to treatment. Despite significant progress in the last years, PH remains an uncured disease. Understanding the underlying mechanisms can pave the way for the development of new therapies. Animal models are important research tools to achieve this goal. Currently, there are several models available for recapitulating PH. This protocol describes a two-hit mouse PH model. The stimuli for PH development are hypoxia and the injection of SU5416, a vascular endothelial growth factor (VEGF) receptor antagonist. Three weeks after initiation of Hypoxia/SU5416, animals develop pulmonary vascular remodeling imitating the histopathological changes observed in human PH (predominantly Group 1). Vascular remodeling in the pulmonary circulation results in the remodeling of the right ventricle (RV). The procedures for measuring RV pressures (using the open chest method), the morphometrical analyses of the RV (by dissecting and weighing both cardiac ventricles) and the histological assessments of the remodeling (both pulmonary by assessing vascular remodeling and cardiac by assessing RV cardiomyocyte hypertrophy and fibrosis) are described in detail. The advantages of this protocol are the possibility of the application both in wild type and in genetically modified mice, the relatively easy and low-cost implementation, and the quick development of the disease of interest (3 weeks). Limitations of this method are that mice do not develop a severe phenotype and PH is reversible upon return to normoxia. Prevention, as well as therapy studies, can easily be implemented in this model, without the necessity of advanced skills (as opposed to surgical rodent models).

Nicorandil, a KATP Channel Opener, Attenuates Ischemia-Reperfusion Injury in Isolated Rat Lungs.

PURPOSE: Nicorandil is a hybrid between nitrates and KATP channel opener activators. The aim of this study was to evaluate the nicorandil's effects on ischemia-reperfusion (IR) lung injury and examine the mechanism of its effects. METHODS: Isolated rat lungs were divided into 6 groups. In the sham group, the lungs were perfused and ventilated for 150 min. In the IR group, after perfusion and ventilation for 30 min, they were interrupted (ischemia) for 60 min, and then resumed for 60 min. In the nicorandil (N) + IR group, nicorandil 6 mg was added before ischemia (nicorandil concentration was 75 µg ml-1). In the glibenclamide + N + IR group, the L-NAME (Nω-Nitro-L-arginine methyl ester) + N + IR group and ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one) + N + IR group, glibenclamide 3 µM, L-NAME 100 µM, and ODQ 30 µM were added 5 min before nicorandil administration, respectively. We measured the coefficient of filtration (Kfc) of the lungs, total pulmonary vascular resistance, and the wet-to-dry lung weight ratio (WW/DW ratio). RESULTS: Kfc was significantly increased after 60 min reperfusion compared with baseline in the IR group, but no change in the sham group. An increase in Kfc was inhibited in the N + IR group compared with the IR group (0.92 ± 0.28 vs. 2.82 ± 0.68 ml min-1 mmHg-1 100 g-1; P < 0.01). Also, nicorandil attenuated WW/DW ratio was compared with IR group (8.3 ± 0.41 vs. 10.9 ± 2.5; P < 0.05). Nicorandil's inhibitory effect was blocked by glibenclamide and ODQ (P < 0.01), but not by L-NAME. CONCLUSIONS: Nicorandil attenuated IR injury in isolated rat lungs. This protective effect appears to involve its activation as KATP channel opener as well as that of the sGC-cGMP pathway.

Effect of low-dose dexamethasone on extra vascular lung water in patients following on-pump elective primary coronary artery bypass graft surgery.

Background: The primary objective was to compare the effect of a low-dose dexamethasone as against a saline placebo on extravascular lung water index (EVLWI) in patients undergoing elective primary coronary artery bypass surgery. The secondary endpoints were to assess the effect of dexamethasone on other volumetric parameters (pulmonary vascular permeability index, global end diastolic volume index, and intrathoracic blood volume index), Vasoactive Inotrope Scores, hemodynamic parameters and serum osmolality in both groups. Settings and Design: Prospective observational study performed at a single tertiary cardiac care center. Materials and Methods: Twenty patients were randomized to receive either dexamethasone (steroid group, n = 10) or placebo (nonsteroid group, n = 10) twice before the institution of cardiopulmonary bypass (CPB). EVLWI and other volumetric parameters were obtained with the help of VolumeView™ Combo Kit connected to EV 1000 clinical platform at predetermined intervals. Hemodynamic parameters, vasoactive-inotropic Scores, hematocrit values were recorded at the predetermined time intervals. Baseline and 1st postoperative day serum osmolality values were also obtained. Results: The two groups were evenly matched in terms of demographic and CPB data. Intra- and inter-group comparison of the baseline EVLWI including other volumetric and hemodynamic parameters with those recorded at subsequent intervals revealed no statistical difference and was similar. Generalized estimating equation model was obtained to compare the changes between the groups over the entire study period which showed that on an average the changes between the steroid and nonsteroid group in terms of all volumetric parameters were not statistically significant. Conclusions: There were no beneficial effects of low-dose dexamethasone on EVLWI or other volumetric parameters in patients subjected to on-pump primary coronary bypass surgery. Hemodynamic parameters were also not affected. Probably, the advanced hemodynamic monitoring aided in optimal fluid management in the nonsteroidal group impacting EVLW accumulation.

Inhaled prostacyclin for the prevention of increased pulmonary vascular resistance in cemented hip hemiarthroplasty-A randomised trial.

BACKGROUND: Bone cementation may cause pulmonary vasoconstriction and ventilation/perfusion abnormalities in patients undergoing cemented hip hemiarthroplasty. In this randomised trial, we tested the hypothesis that intra-operative inhalation of prostacyclin could attenuate the increase in pulmonary vascular resistance index (PVRI, primary endpoint) when compared to inhaled saline in this group of patients. METHODS: Twenty-two patients with displaced femoral neck fractures were allocated to receive inhaled aerosolised prostacyclin (20 ng/kg/min) (n = 11) or inhaled saline (NaCl, 9 mg/mL) (n = 11). All patients received total intravenous anaesthesia and were catheterised with radial and pulmonary artery fast response thermodilution catheters, for measurements of arterial and pulmonary arterial pressures, cardiac output, right ventricular ejection fraction and effective pulmonary arterial elastance. Haemodynamic measurements were performed after induction of anaesthesia, during surgery before and immediately after bone cementation and prosthesis insertion, 10 and 20 min after insertion and during skin closure. RESULTS: During the surgical procedure, PVRI increased both in the saline (44%, P < 0.001) and the prostacyclin (36%, P = 0.019) groups, with a less pronounced increase in the prostacyclin group (P = 0.031). Effective pulmonary arterial elastance increased both in the saline (44%, P < 0.001) and the prostacyclin groups (29%, P = 0.032), with a trend for a less pronounced increase in the prostacyclin group (P = 0.084). Right ventricular ejection fraction decreased significantly in both groups with no difference between the groups. CONCLUSION: Inhalation of prostacyclin attenuates the increase in pulmonary vascular resistance in patients undergoing cemented hip hemiarthroplasty and could potentially attenuate/prevent haemodynamic instability induced by an increase in right ventricular afterload seen in this procedure.

Pre-clinical assessment of a water-in-fluorocarbon emulsion for the treatment of pulmonary vascular diseases.

Hypoxic pulmonary vasoconstriction (HPV) is a well-characterized vascular response to low oxygen pressures and is involved in life-threatening conditions such as high-altitude pulmonary edema (HAPE) and pulmonary arterial hypertension (PAH). While the efficacy of oral therapies can be affected by drug metabolism, or dose-limiting systemic toxicity, inhaled treatment via pressured metered dose inhalers (pMDI) may be an effective, nontoxic, practical alternative. We hypothesized that a stable water-in-perfluorooctyl bromide (PFOB) emulsion that provides solubility in common pMDI propellants, engineered for intrapulmonary delivery of pulmonary vasodilators, reverses HPV during acute hypoxia (HX). Male Sprague Dawley rats received two 10-min bouts of HX (13% O2) with 20 min of room air and drug application between exposures. Treatment groups: intrapulmonary delivery (PUL) of (1) saline; (2) ambrisentan in saline (0.1 mg/kg); (3) empty emulsion; (4) emulsion encapsulating ambrisentan or sodium nitrite (NaNO2) (0.1 and 0.5 mg/kg each); and intravenous (5) ambrisentan (0.1 mg/kg) or (6) NaNO2 (0.5 mg/kg). Neither PUL of saline or empty emulsion, nor infusions of drugs prevented pulmonary artery pressure (PAP) elevation (32.6 ± 3.2, 31.5 ± 1.2, 29.3 ± 1.8, and 30.2 ± 2.5 mmHg, respectively). In contrast, PUL of aqueous ambrisentan and both drug emulsions reduced PAP by 20-30% during HX, compared to controls. IL6 expression in bronchoalveolar lavage fluid and whole lung 24 h post-PUL did not differ among cohorts. We demonstrate proof-of-concept for delivering pulmonary vasodilators via aerosolized water-in-PFOB emulsion. This concept opens a potentially feasible and effective route of treating pulmonary vascular pathologies via pMDI.

Treprostinil treatment decreases circulating platelet microvesicles and their procoagulant activity in pediatric pulmonary hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) results from pulmonary vascular disease and may eventually lead to right heart failure and death. Vasodilator therapy has greatly improved PAH prognosis. Circulating microvesicles are considered as surrogate markers of endothelial and hematopoietic cell activation. AIM: Thus, our purpose was to determine if MVs are upregulated in pediatric PAH such as reported in adult patients, and to analyze the impact of vasodilator therapies on MV count and function. PATIENTS: Population study consisted of 26 patients of median age 6.09 years, with Congenital Heart Disease (CHD) and elevated pulmonary vascular resistance (CHD-PAH) or idiopathic PAH (iPAH). RESULTS: Compared to healthy controls, all circulating MV subpopulations were found higher in untreated PAH patients. No significant differences of annexin-V+ total MV, endothelial, or leukocyte derived-MV counts were found between untreated patients and those receiving oral vasodilator therapies. Conversely, platelet MVs were significantly lower in the group treated with SC-treprostinil compared with both untreated PAH and oral therapy groups (P = 0.01), and exhibited a significant decrease of phospholipid procoagulant activity. Control samples treated in vitro with treprostinil at therapeutic concentrations showed as expected a significant decrease of platelet aggregation but also a reduced spontaneous MV generation. CONCLUSION: Our results suggest that treprostinil, besides vasodilation, might exert its beneficial effect through an inhibition of platelet activation, resulting in a decreased number and procoagulant activity of circulating MVs.

Vasculotide, an angiopoietin-1 mimetic, reduces pulmonary vascular leakage and preserves microcirculatory perfusion during cardiopulmonary bypass in rats.

BACKGROUND: Cardiopulmonary bypass (CPB) during cardiac surgery impairs microcirculatory perfusion and is paralleled by vascular leakage. The endothelial angiopoietin/Tie2 system controls microvascular leakage. This study investigated whether targeting Tie2 with the angiopoietin-1 mimetic vasculotide reduces vascular leakage and preserves microcirculatory perfusion in a rat CPB model. METHODS: Rats were subjected to 75 min of CPB after treatment with vasculotide or phosphate buffered solution as control or underwent a sham procedure. Microcirculatory perfusion and leakage were assessed with intravital microscopy (n=10 per group) and Evans blue dye extravasation (n=13 per group), respectively. Angiopoietin-1, -2, and Tie2 protein and gene expression were determined in plasma, kidney, and lung. RESULTS: CPB immediately impaired microcirculatory perfusion [5 (4-8) vs 10 (7-12) vessels per recording, P=0.002] in untreated CPB rats compared with sham, which persisted after weaning from CPB. CPB increased circulating angiopoeietin-1, -2, and soluble Tie2 concentrations and reduced Tie2 messenger ribonucleic acid (mRNA) expression in kidney and lung. Moreover, CPB increased Evans blue dye leakage in kidney [12 (8-25) vs 7 (1-12) µg g-1, P=0.04] and lung [and 23 (13-60) vs 6 (4-16) µg g-1, P=0.001] compared with sham. Vasculotide treatment preserved microcirculatory perfusion during and after CPB. Moreover, vasculotide treatment reduced Evans blue dye extravasation in lung compared with CPB control [18 (6-28) µg g-1vs 23 (13-60) µg g-1, P=0.04], but not in kidney [10 (3-23) vs 12 (8-25) µg g-1, P=0.38]. Vasculotide did not affect circulating or mRNA expression of angiopoietin-1, -2, and Tie2 concentrations compared with untreated CPB controls. CONCLUSIONS: Treatment with the angiopoietin-1 mimetic vasculotide reduced pulmonary vascular leakage and preserved microcirculatory perfusion during CPB in a rat model.

Exendin-4 improves cardiovascular function and survival in flow-induced pulmonary hypertension.

OBJECTIVES: Systemic left-to-right shunting causes pulmonary arteriopathy, leading to progressive cardiopulmonary failure and a poor prognosis. In this study, we examined the extraglycemic effect of a synthetic glucagon-like peptide, exendin-4, on pulmonary arteriopathy regression and cardiopulmonary function in nondiabetic rats. METHODS: Pulmonary hypertension (PH) was induced by monocrotaline (60 mg/kg, subcutaneous) injection followed by the creation of an aortocaval fistula. After 4 weeks, exendin-4 (1 µg/kg/day) was administered intraperitoneally for 3 consecutive weeks, followed by an assessment of cardiopulmonary function, pulmonary artery vasoreactivity, tissue and blood biochemistry, and lung histology. RESULTS: Exendin-4 significantly reduced right ventricle mass and pulmonary artery pressure, which improved right ventricle function and the survival rate in rats with PH. Tissue and blood interleukin-1ß levels decreased, whereas pulmonary artery cyclic adenosine monophosphate levels were restored by exendin-4. Smooth muscle-myosin heavy chain-II and α-smooth muscle actin protein levels increased in the pulmonary arteries of exendin-4-treated rats. Histology showed that exendin-4 decreased the main and intra-acinar pulmonary artery medial thickness. CONCLUSIONS: Exendin-4 treatment improved pulmonary artery function in flow-induced PH via its direct vasoactive properties, anti-inflammatory effects, and vascular smooth muscle cell phenotypic modulation. Mitigation of pulmonary arteriopathy further potentiated right ventricle performance and reduced overall mortality. These responses were associated with suppressed expression and activity of interleukin-1ß and its downstream signaling molecules. Glucagon-like peptide analogs may possess pleiotropic therapeutic potential in flow-induced PH.

Hemodynamic and gas exchange effects of inhaled iloprost in patients with COPD and pulmonary hypertension.

Studies have shown that vasodilators such as iloprost can be useful for treating pulmonary hypertension (PH). However, in patients with COPD, vasodilators may inhibit hypoxic pulmonary vasoconstriction and impair gas exchange. The efficacy and safety of iloprost inhalation was assessed in 67 patients with PH associated with COPD (COPD-PH), diagnosed by right heart catheterization. Of these, 37 patients had severe PH (mean pulmonary arterial pressure [mPAP] >35 mmHg or mPAP 25-35 mmHg with low cardiac index [<2.0 L⋅min-1⋅m-2]). All patients received a single 20 µg dose of iloprost via a nebulizer (4.4 µg delivered at the mouthpiece). No serious adverse events were reported. Hemodynamic and gas exchange parameters (arterial blood gas and shunt fraction [Qs/Qt]) were measured or calculated at baseline and 10 min after iloprost inhalation. mPAP decreased by 2.1 mmHg (95% CI, -3.3 to -1.0), pulmonary vascular resistance (PVR) decreased by 62.4 dyn⋅s⋅cm-5 (95% CI, -92.9 to -31.8), and cardiac output increased by 0.4 L⋅min-1 (95% CI, 0.2-0.5). There was a more significant decline in PVR in patients with severe COPD-PH than in those with nonsevere COPD-PH. Hypoxemia and intrapulmonary shunt were more extreme in patients with severe COPD-PH. However, there were no significant differences in arterial blood gas and Qs/Qt between patients with nonsevere and severe forms of COPD-PH. In conclusion, iloprost improved pulmonary hemodynamics without detrimental effects on arterial oxygenation in patients with COPD-PH, even in those with severe PH. These findings suggest that the short-term use of iloprost in patients with COPD-PH is effective and well tolerated.

Pulmonary hemodynamics and effects of phosphodiesterase type 5 inhibition in heart failure: a meta-analysis of randomized trials.

BACKGROUND: Previous studies suggested that phosphodiesterase 5 inhibitors (PDE5i) have a beneficial effect in patients with heart failure (HF), although the results were inconsistent. We performed a meta-analysis to evaluate the effect of PDE5i in HF patients, and investigated the relationship between PDE5i effects and pulmonary hemodynamics. METHOD: We searched PubMed, EMBASE and the Cochrane Library for randomized controlled trials (RCTs) that compared PDE5i with placebo in HF with reduced ejection fraction (HFrEF) or HF with preserved EF (HFpEF). PDE5i effects were interpolated according to baseline pulmonary arterial pressure (PAP) or according to changes in PAP after PDE5i treatment. RESULTS: Thirteen RCTs enrolling 898 HF patients, and two sub-analysis studies with different study outcomes, were included in the meta-analysis. Among patients with HFrEF, PDE5i improved peak VO2 (mean difference [MD], 3.76 mL/min/kg; 95% confidence interval [CI], 3.27 to 4.25; P < 0.00001), VE/VCO2 slope (MD, -6.04; 95% CI, -7.45 to -4.64; P < 0.00001), LVEF (MD, 4.30%; 95% CI, 2.18 to 6.42; P < 0.0001), and pulmonary vascular resistance (MD, -80.74 dyn·sec/cm5; 95% CI, -110.69 to -50.79; P < 0.00001). The effects of PDE5i in patients with HFpEF were heterogeneous. Meta-regression analyses indicated that the beneficial effect of PDE5i was related to the baseline PAP as well as the extent of PDE5i-mediated PAP decrease. CONCLUSION: PDE5i improved pulmonary hemodynamics and exercise capacity in patients with HFrEF, but not in HFpEF. The relationship between the benefits by PDE5i with the baseline PAP and the changes in PAP indicates the therapeutic potential of PDE5i in HF according to pulmonary hemodynamics.

The use of Macitentan in Fontan circulation: a case report.

BACKGROUND: The Fontan circulation, a result of a palliative procedure in patients with single systemic ventricles, is defined by chronically elevated pulmonary vascular resistance. When traditional heart failure therapies fail, pharmacological agents that reduce pulmonary artery pressures may be used. These include endothelial-receptor antagonists, prostanoids and phosphodiesterase type 5 inhibitors. We report the first use of macitentan, an endothelin-receptor antagonist, in a patient with a Fontan circulation. CASE PRESENTATION: We describe the case of a 50 year old female with tricuspid atresia and transposition of the great arteries. Following complex surgery as a child, she subsequently underwent a fenestrated modified atrial pulmonary Fontan operation which was later converted to a total cavopulmonary anastomosis Fontan circulation. Due to failure of various medications to relieve her worsening symptoms, she was commenced on macitentan in April 2016. Few months later, she demonstrated a significant symptomatic improvement and associated increase in her incremental shuttle walking test distance. CONCLUSIONS: Macitentan has slower receptor dissociation kinetics compared to other endothelin-receptor antagonists, leading to enhanced pharmacological activity with promising effects in patients with pulmonary arterial hypertension. The patient we report has shown considerable improvement in exercise capacity following introduction of this medication and thus we suggest further randomised trials to establish the role of different endothelin-receptor antagonists in the management of the Fontan circulation.

Endothelin inhibitors lower pulmonary vascular resistance and improve functional capacity in patients with Fontan circulation.

OBJECTIVES: To evaluate the effects of endothelin inhibitors (ERAs) on hemodynamic and functional parameters in patients post-Fontan procedure with high pulmonary vascular resistance (PVR). METHODS: Among our cohort of patients with Fontan circulation, 8 children, 8 adolescents, and 8 adults had PVR ≥2 WU*m2. These patients were treated with ERAs (minors with bosentan, adults with macitentan) and reevaluated after 6 months. Pre- and posttreatment hemodynamic variables were assessed by cardiac catheterization. Functional capacity was evaluated by cardiopulmonary exercise testing (CPET). Our primary endpoint was to obtain a reduction of PVR; the secondary endpoint was to obtain an improvement of functional capacity. RESULTS: Under treatment, New York Heart Association class improved for adolescents and adults. PVR decreased (P = .01) in all groups: in children from the median value 2.3 (interquartile range 2.0-3.1) to 1.9 (1.4-2.3) WU*m2, in adolescents from 2.3 (2.1-2.4) to 1.7 (1.4-1.8) WU*m2, and in adults from 2.8 (2.0-4.7) to 2.1 (1.8-2.8)WU*m2. In 71% of patients, PVR fell to less than 2 WU*m2. Cardiac index increased in adolescents from 2.6 (2.4-3.3) to 3.6 (3.4-4.3) L/min/m2, P = .04, and in adults from 2.1 (2.0-2.3) to 2.8 (2.3-4.7) L/min/m2, P = .03. CPET showed that only adolescents displayed a significant functional improvement. Anaerobic threshold improved from 17 (13-19) to 18 (13-20) mL/kg/min, P = .03; oxygen consumption and VO2 max increased from 1.3 (1.0-1.6) to 1.7 (1.1-1.9) L/min, P = .02 and from 25 (21-28) to 28 (26-31) L/min, P = .02, respectively. Oxygen pulse increased from 7.9 (5.7-10.4) to 11.2 (8.2-13.0) L/beat, P = .01. CONCLUSIONS: This is the first study that assesses by cardiac catheterization and CPET the effects of ERA in patients with Fontan circulation with increased PVR. These results suggest that ERAs might provide most pronounced hemodynamic and functional improvement in adults and adolescents.

In vitro and in vivo evaluation of dasatinib and imatinib on physiological parameters of pulmonary arterial hypertension.

PURPOSE: Pulmonary arterial hypertension (PAH) results from occlusion or vasoconstriction of pulmonary vessels, leading to progressive right ventricular failure. Dasatinib, a BCR-ABL1 tyrosine kinase inhibitor (TKI) approved for the treatment of chronic myelogenous leukemia, has been associated with PAH. In contrast, the BCR-ABL1 TKI imatinib has demonstrated anti-vasoproliferative properties and has been investigated as a potential treatment for PAH. Here we describe studies evaluating the effects of dasatinib and imatinib on cardiovascular and pulmonary functions to understand the reported differential consequences of the two TKIs in a clinical setting. METHODS: The direct effects of dasatinib and imatinib were explored in vivo to investigate possible mechanisms of dasatinib-induced PAH. In addition, effects of dasatinib and imatinib on PAH-related mediators were evaluated in vitro. RESULTS: In rats, both TKIs increased plasma nitric oxide (NO), did not induce PAH-related structural or molecular changes in PA or lungs, and did not alter hemodynamic lung function compared with positive controls. Similarly, in the pulmonary artery endothelial cells and smooth muscle cells co-culture model, imatinib and dasatinib increased NO and decreased endothelin-1 protein and mRNA. CONCLUSIONS: The results of these studies indicated that dasatinib did not induce physiological changes or molecular signatures consistent with PAH when compared to positive controls. Instead, dasatinib induced changes consistent with imatinib. Both dasatinib and imatinib induced biochemical and structural changes consistent with a protective effect for PAH. These data suggest that other factors of unclear etiology contributed to the development of PAH in patients treated with dasatinib.