Changes In Pulmonary Hemodynamics Research Articles

Impact of Age and of the Patent Ductus Arteriosus on Pulmonary Hemodynamics in Children with Complete Atrioventricular Septal Defect.

Complete atrioventricular septal defect (CAVSD) can lead to the development of pulmonary obstructive vascular disease due to high pulmonary blood flow and pressures. This study aimed to evaluate the changes in pulmonary hemodynamics with aging and with patent ductus arteriosus (PDA) in children with CAVSD. We retrospectively evaluated 137 children (94% with trisomy 21, median age of 195 (25-2963) days, 58.4% female) with CASVD referred to cardiac catheterization from January 2000 to December 2020. Those with associated congenital heart disease, except PDA, had been excluded. They were divided into three age terciles (T1, T2, and T3). Aging was directly associated with higher mean (T1: 34.2 ± 9.1; T2: 37.1 ± 5.8; T3: 42 ± 10.6 mmHg, p < 0.001) and diastolic (T1: 19.4 ± 5.3; T2 21.6 ± 5.0; T3: 26.0 ± 9.5 mmHg, P < 0.001) pulmonary arterial pressures, and with higher pulmonary vascular resistance (T1: 3.24 ± 1.69, T2: 3.47 ± 1.19; T3: 4.49 ± 3.91 Wu.m2, p = 0.023). This resulted in a loss of eligibility for anatomical correction, which became evident only after 300 days of age. PDA was associated with a higher mean (37.2 [35.9; 38.5] vs. 41.3 [37.5; 45.0] mmHg, p = 0.049) and diastolic (21.7 [20.7; 22.6] vs. 26.4 [24.1; 29.0] mmHg, p = 0.001) pulmonary pressure, and resistor-compliance time (0.28 [0.26; 0.29] vs. 0.36 [0.31; 0.40], p = 0.001) after adjusting for age and sex. In children with CAVSD, aging was associated with worsening of pulmonary vascular hemodynamics, particularly when PDA was associated, resulting in loss of eligibility for anatomical correction after 10 months of age as the first surgical option.

Effects of different nitric oxide synthases on pulmonary and systemic hemodynamics in hypoxic stress rat model.

Under hypoxia, exaggerated compensatory responses may lead to acute mountain sickness. The excessive vasodilatory effect of nitric oxide (NO) can lower the hypoxic pulmonary vasoconstriction (HPV) and peripheral blood pressure. While NO is catalyzed by various nitric oxide synthase (NOS) isoforms, the regulatory roles of these types in the hemodynamics of pulmonary and systemic circulation in living hypoxic animals remain unclear. Therefore, this study aims to investigate the regulatory effects of different NOS isoforms on pulmonary and systemic circulation in hypoxic rats by employing selective NOS inhibitors and continuously monitoring hemodynamic parameters of both pulmonary and systemic circulation. Forty healthy male Sprague-Dawley (SD) rats were randomly divided into four groups: Control group (NG-nitro-D-arginine methyl ester, D-NAME), L-NAME group (non-selective NOS inhibitor, NG-nitro-L-arginine methyl ester), AG group (inducible NOS inhibitor group, aminoguanidine), and 7-NI group (neurological NOS inhibitor, 7-nitroindazole). Hemodynamic parameters of rats were monitored for 10 min after inhibitor administration and 5 min after induction of hypoxia [15% O2, 2200 m a. sl., 582 mmHg (76.5 kPa), Xining, China] using the real-time dynamic monitoring model for pulmonary and systemic circulation hemodynamics invivo. Serum NO concentrations and blood gas analysis were measured. Under normoxia, mean arterial pressure and total peripheral vascular resistance were increased, and ascending aortic blood flow and serum NO concentration were decreased in the L-NAME and AG groups. During hypoxia, pulmonary arterial pressure and pulmonary vascular resistance were significantly increased in the L-NAME and AG groups. This compensatory mechanism activated by inducible NOS and endothelial NOS effectively counteracts the pulmonary hemodynamic changes induced by hypoxic stress. It plays a crucial role in alleviating hypoxia-induced pulmonary arterial hypertension.

Symposium review: high altitude travel with pulmonary vascular disease.

Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension are the main precapillary forms of pulmonary hypertension (PH) summarized as pulmonary vascular diseases (PVD). PVDs are characterized by exertional dyspnoea and oxygen desaturation, and reduced quality of life and survival. Medical therapies improve life expectancy and physical performance of PVD patients, of whom many wish to participate in professional work and recreational activities including traveling to high altitude. The exposure to the hypobaric hypoxic environment of mountain regions incurs the risk of high altitude adverse events (AEHA) due to severe hypoxaemia exacerbating symptoms and further increase in pulmonary artery pressure, which may lead to right heart decompensation. Recent prospective and randomized trials show that altitude-induced hypoxaemia, pulmonary haemodynamic changes and impairment of exercise performance in PVD patients are in the range found in healthy people. The vast majority of optimally treated stable PVD patients who do not require long-term oxygen therapy at low altitude can tolerate short-term exposure to moderate altitudes up to 2500m. PVD patients that reveal persistent severe resting hypoxaemia ( <80% for >30min) at 2500m respond well to supplemental oxygen therapy. Although there are no accurate predictors for AEHA, PVD patients with unfavourable risk profiles at low altitude, such as higher WHO functional class, lower exercise capacity with more pronounced exercise-induced desaturation and more severely impaired haemodynamics, are at increased risk of AEHA. Therefore, doctors with experience in PVD and high-altitude medicine should counsel PVD patients before any high-altitude sojourn. This review aims to summarize recent literature and clinical recommendations about PVD patients travelling to high altitude.

(336) - Changes in Right Ventricular Function and Pulmonary Hemodynamics During LVAD Support and Impact on Outcomes After LVAD Discontinuation: VAD Wean Registry Analysis

(336) - Changes in Right Ventricular Function and Pulmonary Hemodynamics During LVAD Support and Impact on Outcomes After LVAD Discontinuation: VAD Wean Registry Analysis

Pulmonary vasoconstriction plays a major role in the acute phase of pulmonary embolism in pigs

Abstract Background Pulmonary vascular resistance (PVR) increases in acute pulmonary embolism (PE) due to both mechanical obstruction and pulmonary vasoconstriction. Attenuation of adverse pulmonary vasoconstriction has shown promise as a treatment of acute PE in experimental studies. However, clinical trials have failed to replicate these beneficial effects in PE patients. Time may be a factor in this discrepancy between experimental and clinical studies. In experimental PE studies, PVR acutely increases and decreases within hours. Meanwhile in clinical trials, the time from symptom onset to study inclusion is often days, at which time PVR may already be decreased. Whether this decrease in PVR is due to reduced mechanical obstruction by endogenous fibrinolysis or attenuation of adverse pulmonary vasoconstriction is unknown. Purpose To investigate the contribution of the mechanical obstruction and pulmonary vasoconstriction to PVR in two days following PE in pigs. Methods In a controlled animal study, using an estabilished model of autologous PE in pigs (PE, n=12 ∼60 kg), changes in pulmonary hemodynamics and clot burden were evaluated. CT pulmonary angiograms were performed at baseline (BL), after acute PE and the following two days, quantifying clot burden using the Qanadli Obstruction Score. Hemodynamics were evaluated with real-time biventricular catheterization and systemic invasive pressures. To evaluate the vasoactive component, pulmonary vasodilators sildenafil (bolus 0.1 mg/kg) and oxygen (inspired fraction of oxygen 40%) were administered. Results Following PE, both mean PVR (Figure 1A) and pulmonary obstruction scores (Figure 1B) increased. PVR decreased at day one and remained unchanged at day two (Figure 1A). Meanwhile, mean obstruction score decreased slightly at day one but remained elevated throughout the study (Figure 1B). Vasodilatation induced by sildenafil and oxygen (SIL+OXY) decreased PVR at day zero but displayed no effect on the subsequent days (Figure 1A). Conclusion Pulmonary vasoconstriction and mechanical obstruction both contributed to the increase in PVR during the acute phase of PE. PVR decreased towards levels of baseline already day one and remained unchanged at day two. The contribution of pulmonary vasoconstriction decreased at day one and two, while the mechanical obstruction remained significantly increased. Accordingly, the effects of pulmonary vasodilators were only present in the acute phase of PE.Figure 1

Changes in Pulmonary Hemodynamics Resulted From Long-Term Mechanical Heart Support

Aim To study the dynamics of right ventricular function and pulmonary hemodynamics in patients with pulmonary hypertension during mechanical circulatory support of the heart.Material and methods A retrospective analysis was performed for 25 implantations of left ventricular assist device performed in the Meshalkin National Medical Research Center from 2006 through 2021. Mechanical assist devices were implanted in 21 men and 4 women (median age, 37.5 [29; 48] years). All patients had severe, NYHA functional class III-IV chronic heart failure refractory to the optimal drug therapy. Invasive measurements showed that mean pulmonary arterial pressure (MPAP) was 50 [44.5; 60] mm Hg, transpulmonary pressure gradient (TPG) was 16 [14; 19] mm Hg, and calculated pulmonary vascular resistance was 5.4 [4.9; 9] Wood units, which is an absolute contraindication (TPG &gt;15 mm Hg or pulmonary vascular resistance &gt;5 Wood units) for heart transplantation (HT).Results Duration of left ventricular support was from 17 to 948 days. For 12 (48 %) patients, the HT was performed at 180-948 days following the implantation of left ventricular assist device; 3 patients are presently waiting for HT; 10 patients died from various complications, 6 of them died during the hospital stage. Already during the early stage after the implantation of the mechanical assist device, pulmonary hemodynamics significantly improved. Thus, in one week, MPAP decreased from 50 [44.5; 60] mm Hg to 36 [33; 38] mm Hg (р=0.012) whereas pulmonary vascular resistance decreased from 5.4 [4.9; 9] to 2.9 [2.4; 3.6] Wood units (р=0.008). Follow-up showed further improvement of pulmonary hemodynamics; at 1 month, MPAP was 29 [27; 30] mm Hg and by the time of HT, MPAP was 2.0 [24.8; 26.3] mm Hg (р=0.01), i.e., reached a normal level, which made it possible to perform HT. Similar dynamics was observed for other variables that reflected pulmonary hemodynamics.Conclusion Mechanical support of the heart is able to alleviate manifestations of pulmonary hypertension in most patients with end-stage heart failure. It is necessary to develop an algorithm for identifying the category of patients with a high risk of progression of right ventricular failure.

Combined cardiopulmonary test and exercise Doppler echocardiography in systemic sclerosis

Abstract Background Cardiopulmonary exercise test (CPET) and exercise Doppler echocardiography (EDE) may be useful for the early detection of pulmonary hypertension in systemic sclerosis (SSc) Aim To assess the feasibility of CPET and EDE in detecting early changes in gas exchange and/or pulmonary hemodynamics in SSc Methods From 2016 to 2021, we evaluated 19 SSc patients (Group 1, age = 52.58±11.27, women 17 (89.5%)), and age 32.10±6.67, men 17 (89.4%) matched healthy controls (Group 2). Simultaneous CPET and EDE were performed. With CPET, we assessed peak oxygen uptake (VO2), peak respiratory quotient (RQ), respiratory equivalent ratio for carbonic gas (VE/VCO2), and maximal respiratory equivalent divided by maximal ventilatory ventilation (V̇E Max/VVM). With EDE, we assessed tricuspid regurgitant velocity (TRV) jet and pulmonary flow acceleration time (ACT) to derive systolic pulmonary arterial pressure (SPAP). Results Exercise duration was similar in the 2 groups (Group 1 = 9.2±2.93 vs Group 2 = 10.14±1.78 minutes). Among CPET parameters, SSc patients showed lower peak VO2 (Group 1 = 1.23±0.55 vs Group 2 = 2.45±0.7, p&amp;lt;0.001), similar RQ (1.10±0.10 vs 1.17±0.09;. p=0.036), VE/VCO2 (Group 1 = 31.90±3.65 vs Group 2 = 23.79±2.64, p&amp;lt;0.001) and V̇E Max/VVM (Group 1 = 1.93±0.60 vs Group 2 = 1.76±0.36, p=NS). With EDE, feasibility at peak stress was low for TRV (Group 1 = 42% vs Group 2 = 58%, p=NS), moderate for ACT (Group 1 = 53% vs Group 2 = 78%, p=NS) and high when at least one was technically adequate (Group 1 = 73% vs Group 2 = 100%, p&amp;lt;0.001). Rest TRV (Group 1 = 2.48±0.14 vs Group 2 = 2.08±0.12 m/s, p=0.033) and ACT (Group 1 = 100.14±10.63 vs Group 2 = 108.86±6.38 ms, p=0.482) showed similar values in the 2 groups (será que ficou similar?). During stress, TRV increased more markedly in SSc (Group 1 = 3.33±0.32 vs Group 2 = 2.34±0.09 m/s, p=0.004) and ACT decreased (Group 1 = 81.9±6.54 vs 73.39±5.18 ms, p=0.304), with estimated peak SPAP higher in SSc (Group 1 = 53.34±7.88 vs Group 2 = 43.33±5.49, p&amp;lt;0.001): see figure. Conclusion CPET and EDE offer complementary information on gas exchange and pulmonary hemodynamics in SSc and can detect early alterations missed by resting assessment. The success rate of EDE increases significantly with the combination of TRV and ACT. Funding Acknowledgement Type of funding sources: None.

Clinician's Corner: Counseling Patients with Pulmonary Vascular Disease Traveling to High Altitude

Ulrich, Silvia, Mona Lichtblau, Simon R. Schneider, Stéphanie Saxer, and Konrad E. Bloch, Clinician's corner: counseling patients with pulmonary vascular disease traveling to high altitude. High Alt Med Biol. 23:201-208, 2022.-Pulmonary vascular diseases (PVDs) with precapillary pulmonary hypertension (PH), such as pulmonary arterial or chronic thromboembolic PH, impair exercise performance and survival in patients. Vasodilators and other treatments improve quality of life and prognosis to an extent in patients who have PVDs as chronic disorders. Obviously, patients with PVD wish to participate in usual daily activities, including travel to popular settlements and mountainous regions located at high altitude. However, the pulmonary hemodynamic impairment due to PVD leads to blood and tissue hypoxia, particularly during exercise and sleep. It is thus of concern that alveolar hypoxia at higher altitude may exacerbate patients' symptoms and lead to decompensation. Current PH guidelines discourage high-altitude exposure for fear of altitude-related adverse health effects. However, several recent well-designed prospective and randomized trials show that despite altitude-induced hypoxemia, pulmonary hemodynamic changes and impairment of exercise performance in patients with PVD are similar to the responses in healthy people or in patients with mild chronic obstructive pulmonary disease. The vast majority of patients with PVD can tolerate short-term exposure to moderate altitudes up to 2,500 m. For the roughly 10% of patients with stable disease who develop severe hypoxemia when ascending to 2,500 m, they respond well to low-level supplemental oxygen support. The best low-altitude predictors for adverse health effects at high altitude are the known clinical risk factors for PVD such as symptoms, functional class, exercise capacity, and exertional oxygen desaturation, whereas hypoxia altitude simulation testing is of little additive value. In any case, patients should be instructed that altitude-related adverse health effects may be difficult to predict and that in case of worsening symptoms, immediate accompanied descent to lower altitude and oxygen therapy are required. Patients with severe hypoxemia near sea level may safely visit high-altitude regions up to 1,500-2,000 m while continuing oxygen therapy and avoiding strenuous exercise. All PH patients should be counseled before any high-altitude sojourn by doctors with experience in PVD and high-altitude medicine and have an action plan for the occurrence of severe hypoxemia and other altitude-related conditions such as acute mountain sickness.

Cardiorespiratory Adaptation to Short-Term Exposure to Altitude vs. Normobaric Hypoxia in Patients with Pulmonary Hypertension.

Prediction of adverse health effects at altitude or during air travel is relevant, particularly in pre-existing cardiopulmonary disease such as pulmonary arterial or chronic thromboembolic pulmonary hypertension (PAH/CTEPH, PH). A total of 21 stable PH-patients (64 ± 15 y, 10 female, 12/9 PAH/CTEPH) were examined by pulse oximetry, arterial blood gas analysis and echocardiography during exposure to normobaric hypoxia (NH) (FiO2 15% ≈ 2500 m simulated altitude, data partly published) at low altitude and, on a separate day, at hypobaric hypoxia (HH, 2500 m) within 20–30 min after arrival. We compared changes in blood oxygenation and estimated pulmonary artery pressure in lowlanders with PH during high altitude simulation testing (HAST, NH) with changes in response to HH. During NH, 4/21 desaturated to SpO2 < 85% corresponding to a positive HAST according to BTS-recommendations and 12 qualified for oxygen at altitude according to low SpO2 < 92% at baseline. At HH, 3/21 received oxygen due to safety criteria (SpO2 < 80% for >30 min), of which two were HAST-negative. During HH vs. NH, patients had a (mean ± SE) significantly lower PaCO2 4.4 ± 0.1 vs. 4.9 ± 0.1 kPa, mean difference (95% CI) −0.5 kPa (−0.7 to −0.3), PaO2 6.7 ± 0.2 vs. 8.1 ± 0.2 kPa, −1.3 kPa (−1.9 to −0.8) and higher tricuspid regurgitation pressure gradient 55 ± 4 vs. 45 ± 4 mmHg, 10 mmHg (3 to 17), all p < 0.05. No serious adverse events occurred. In patients with PH, short-term exposure to altitude of 2500 m induced more pronounced hypoxemia, hypocapnia and pulmonary hemodynamic changes compared to NH during HAST despite similar exposure times and PiO2. Therefore, the use of HAST to predict physiological changes at altitude remains questionable. (ClinicalTrials.gov: NCT03592927 and NCT03637153).

Y-Chromosome Gene, Uty, Protects Against Pulmonary Hypertension by Reducing Proinflammatory Chemokines.

Rationale: Idiopathic pulmonary arterial hypertension (PAH) is a terminal pulmonary vascular disease characterized by increased pressure, right ventricular failure, and death. PAH exhibits a striking sex bias and is up to four times more prevalent in females. Understanding the molecular basis behind sex differences could help uncover novel therapies. Objectives: We previously discovered that the Y chromosome is protective against hypoxia-induced experimental pulmonary hypertension (PH), which may contribute to sex differences in PAH. Here, we identify the gene responsible for Y-chromosome protection, investigate key downstream autosomal genes, and demonstrate a novel preclinical therapy. Methods: To test the effect of Y-chromosome genes on PH development, we knocked down each Y-chromosome gene expressed in the lung by means of intratracheal instillation of siRNA in gonadectomized male mice exposed to hypoxia and monitored changes in right ventricular and pulmonary artery hemodynamics. We compared the lung transcriptome of Uty knockdown mouse lungs to those of male and female PAH patient lungs to identify common downstream pathogenic chemokines and tested the effects of these chemokines on human pulmonary artery endothelial cells. We further inhibited the activity of these chemokines in two preclinical pulmonary hypertension models to test the therapeutic efficacy. Measurements and Main Results: Knockdown of the Y-chromosome gene Uty resulted in more severe PH measured by increased right ventricular pressure and decreased pulmonary artery acceleration time. RNA sequencing revealed an increase in proinflammatory chemokines Cxcl9 and Cxcl10 as a result of Uty knockdown. We found CXCL9 and CXCL10 significantly upregulated in human PAH lungs, with more robust upregulation in females with PAH. Treatment of human pulmonary artery endothelial cells with CXCL9 and CXCL10 triggered apoptosis. Inhibition of Cxcl9 and Cxcl10 expression in male Uty knockout mice and CXCL9 and CXCL10 activity in female rats significantly reduced PH severity. Conclusions:Uty is protective against PH. Reduction of Uty expression results in increased expression of proinflammatory chemokines Cxcl9 and Cxcl10, which trigger endothelial cell death and PH. Inhibition of CLXC9 and CXLC10 rescues PH development in multiple experimental models.

Pulmonary Artery Remodeling and Advanced Hemodynamics: Magnetic Resonance Imaging Biomarkers of Pulmonary Hypertension

Poorly characterized by non-invasive diagnostic imaging techniques, pulmonary hypertension (PHT) is commonly associated with changes in vascular hemodynamics and remodeling of pulmonary artery architecture. These disease phenotypes represent potential biomarkers of interest in clinical environment. In this retrospective clinical study, 33 patients with pulmonary hypertension and seventeen controls were recruited. Architectural remodeling was characterized using 3D-contrast enhanced angiogram via the measurement of pulmonary artery diameters, bifurcation distances, and angles. Hemodynamics were characterized using 4D-flow magnetic resonance imaging (MRI) via wall shear stress, kinetic energy, vorticity, and directional flow dynamics. Parameters were compared using independent samples student’s t-tests. Correlational analysis was performed using Pearson’s correlation. PHT patients demonstrated dilation in the main and right branch of the pulmonary artery (p &lt; 0.05). Furthermore, these patients also exhibited increases in bifurcation distances in the left and right pulmonary arteries (p &lt; 0.05). Wall shear stress, maximum kinetic energy, and energy loss were decreased in the pulmonary artery (p &lt; 0.001). Correlations were observed between peak velocities and right ventricle ejection fraction (r = 0.527, p &lt; 0.05). These findings suggest that pulmonary artery remodeling and hemodynamic changes may possess clinical utility as MRI biomarkers for PHT.

The Impact of Breathing Hypoxic Gas and Oxygen on Pulmonary Hemodynamics in Patients With Pulmonary Hypertension

BackgroundPure oxygen breathing (hyperoxia) may improve hemodynamics in patients with pulmonary hypertension (PH) and allows to calculate right-to-left shunt fraction (Qs/Qt), whereas breathing normobaric hypoxia may accelerate hypoxic pulmonary vasoconstriction (HPV). This study investigates how hyperoxia and hypoxia affect mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) in patients with PH and whether Qs/Qt influences the changes of mPAP and PVR.Study Design and MethodsAdults with pulmonary arterial or chronic thromboembolic PH (PAH/CTEPH) underwent repetitive hemodynamic and blood gas measurements during right heart catheterization (RHC) under normoxia [fractions of inspiratory oxygen (FiO2) 0.21], hypoxia (FiO2 0.15), and hyperoxia (FiO2 1.0) for at least 10 min.ResultsWe included 149 patients (79/70 PAH/CTEPH, 59% women, mean ± SD 60 ± 17 years). Multivariable regressions (mean change, CI) showed that hypoxia did not affect mPAP and cardiac index, but increased PVR [0.4 (0.1–0.7) WU, p = 0.021] due to decreased pulmonary artery wedge pressure [−0.54 (−0.92 to −0.162), p = 0.005]. Hyperoxia significantly decreased mPAP [−4.4 (−5.5 to −3.3) mmHg, p < 0.001] and PVR [−0.4 (−0.7 to −0.1) WU, p = 0.006] compared with normoxia. The Qs/Qt (14 ± 6%) was >10 in 75% of subjects but changes of mPAP and PVR under hyperoxia and hypoxia were independent of Qs/Qt.ConclusionAcute exposure to hypoxia did not relevantly alter pulmonary hemodynamics indicating a blunted HPV-response in PH. In contrast, hyperoxia remarkably reduced mPAP and PVR, indicating a preserved vasodilator response to oxygen and possibly supporting the oxygen therapy in patients with PH. A high proportion of patients with PH showed increased Qs/Qt, which, however, was not associated with changes in pulmonary hemodynamics in response to changes in FiO2.

Tricuspid valve repair and mechanical right ventricular support in rescue left ventricular assist device implantations: Still a relevant issue.

Right ventricular failure (RVF) remains the main cause of morbidity and mortality following the implantation of continuous flow (CF) left ventricular assist devices. Apart from the difficulties inherent in assessing right ventricular function, other factors that may confound the prediction of RVF intraoperative events include concomitant surgical procedures, postoperative changes in pulmonary hemodynamics, evolving mechanical circulatory support (MCS) technology, shifts in the target population, and device settings. In this commentary, the role of concomitant tricuspid valve repair, early planned temporary or durable MCS have been discussed. A focus on the current modifications in CF ventricular assist devices designed for the left ventricle to make them suitable for right ventricular support has been set.

Transcatheter radiofrequency pulmonary artery denervation in swine: the evaluation of lesion degree, hemodynamics and pulmonary hypertension inducibility

BackgroundMechanisms of positive effects of pulmonary artery (PA) denervation (PADN) remain poorly understood. The study aimed to evaluate pulmonary hemodynamic changes after PADN and their association with the extent of PA wall damage in an acute thromboxane A2 (TXA2)-induced pulmonary hypertension (PH) model in swine.MethodsIn this experimental sham-controlled study, 17 normotensive male white Landrace pigs (the mean weight 36.2 ± 4.5 kg) were included and randomly assigned to group I (n = 9)—PH modeling before and after PADN, group II (n = 4)—PADN only, or group III (n = 4)—PH modeling before and after a sham procedure. Radiofrequency (RF) PADN was performed in the PA trunk and at the proximal parts of the right and left PAs. PA wall lesions were characterized at the autopsy study using histological and the immunohistochemical examination.ResultsIn groups I and II, no statistically significant changes in the mean pulmonary arterial pressure nor systemic blood pressure were found after PADN (−0.8 ± 3.4 vs 4.3 ± 8.6 mmHg, P = 0.47; and 6.0 ± 15.9 vs -8.3 ± 7.5 mmHg, P = 0.1; correspondingly). There was a trend towards a lower diastolic pulmonary arterial pressure after PADN in group I when compared with group III during repeat PH induction (34.4 ± 2.9 vs 38.0 ± 0.8; P = 0.06). Despite the presence of severe PA wall damage at the RF application sites, S100 expression was preserved in the majority of PA specimens. The presence of high-grade PA lesions was associated with HR acceleration after PADN (ρ = 0.68, p = 0.03). No significant correlation was found between the grade of PA lesion severity and PA pressure after PADN with or without PH induction.ConclusionsExtended PADN does not affect PH induction using TXA2. Significant PA adventitia damage is associated with HR acceleration after PADN. Possible delayed effects of PADN on perivascular nerves and pulmonary hemodynamics require further research in chronic experiments.

Fetal pulmonary hemodynamics: Doppler reference values in low risk pregnancies

Objective To investigate fetal pulmonary hemodynamics in normal pregnancy using pulsed and color Doppler ultrasonography and to define Doppler reference ranges values in the whole fetal pulmonary circulation during different gestational ages. Materials and methods A prospective observational study was conducted to evaluate 190 healthy singleton pregnancies between 20 and 38 weeks of gestation, including 10 cases for each gestational age. The main pulmonary artery, right pulmonary artery, left pulmonary artery, ductus arteriosus and pulmonary veins waveforms were evaluated. The waveform profile was studied for each pulmonary vessel investigated. We calculated the normal distribution of data of 12 Doppler parameters, their values were expressed as 5th, 25th, 50th, 75th and 95th centile. Results We report several pulmonary hemodynamic changes with the progression of pregnancy. We focused on the hemodynamic values of the parameters most useful in clinical practice and that would better describe the hemodynamic events of this vascular district. Conclusion This study reports a complete description of the fetal pulmonary hemodynamics at different gestational ages. Many hemodynamic parameters show a typical change during gestation. The reference ranges described in this study may help in situations where is indicated to evaluate the pulmonary hemodynamics and to identify healthy fetuses from those affected by pathological conditions related mainly to fetal cardiovascular anomalies and/or feto-maternal pathologic conditions.

Pulmonary and Systemic Hemodynamics following Multielectrode Radiofrequency Catheter Renal Denervation in Acutely Induced Pulmonary Arterial Hypertension in Swine.

Objective We aimed to assess the effects of renal denervation (RDN) on systemic and pulmonary hemodynamics in a swine model of thromboxane A2- (TXA2-) induced pulmonary arterial hypertension (PAH). Methods The study protocol comprised two PAH inductions with a target mean pulmonary artery pressure (PAP) of 40 mmHg at baseline and following either the RDN or sham procedure. Ten Landrace pigs underwent the first PAH induction; then, nine animals were randomly allocated in 1 : 1 ratio to RDN or sham procedure; the second PAH induction was performed in eight animals (one animal died of pulmonary embolism during the first PAH induction, and one animal died after RDN). In the RDN group, ablation was performed in all available renal arteries, and balloon inflation within artery branches was performed in controls. An autopsy study of the renal arteries was performed. Results At baseline, the target mean PAP was achieved in all animals with 25.0 [20.1; 25.2] mcg of TXA2. The second PAH induction required the same mean TXA2 dose and infusion time. There was no statistically significant difference in the mean PAP at second PAH induction between the groups (39.0 ± 5.3 vs. 39.75 ± 0.5 mmHg, P > 0.05). In the RDN group, the second PAH induction resulted in a numerical but insignificant trend toward a decrease in the mean systemic blood pressure and systemic vascular resistance, when compared with the baseline induction (74 ± 18.7 vs. 90.25 ± 28.1 mmHg and 1995.3 ± 494.3 vs. 2433.7 ± 1176.7 dyn∗sec∗cm−5, P > 0.05, respectively). No difference in hemodynamic parameters was noted in the sham group between the first and second PAH induction. Autopsy demonstrated artery damage in both groups, but RDN resulted in more severe lesions. Conclusions According to our results, RDN does not result in significant acute pulmonary or systemic hemodynamic changes in the TXA2-induced PAH model. The potential chronic effects of RDN on PAH require further research.

Pharmacokinetics and pharmacodynamics of sildenafil in fetal lambs on extracorporeal support

BackgroundMaternal transplacental administration of sildenafil is being considered for a variety of fetal conditions. Clinical translation also requires evaluation of fetal safety in a higher species, such as the fetal lamb. Experiments with the pregnant ewe are curtailed by minimal transplacental transfer as well as limited access to the fetus. The EXTra-uterine Environment for Neonatal Development (EXTEND) model renders the isolated fetal lamb readily accessible and allows for direct fetal administration of sildenafil. MethodsFive fetal lambs were placed on extracorporeal support in the EXTEND device and received continuous intravenous (IV) sildenafil (0.3–0.5–0.7 mg/kg/24hr) for a duration of one to seven days. Plasma sildenafil concentrations were sampled at regular intervals to establish the pharmacokinetic profile using population pharmacokinetic modeling. Serial Doppler ultrasound examination, continuous non-invasive hemodynamic monitoring and blood gas analysis were done to evaluate the pharmacodynamic effects and fetal response. FindingsThe target concentration range (47–500 ng/mL) was attained with all doses. Sildenafil induced an immediate and temporary reduction of pulmonary vascular resistance, mean arterial pressure and circuit flow, without change in fetal lactate levels and acid-base status. The duration of the systemic effects increased with the dose. InterpretationImmediate temporary pulmonary vascular and systemic hemodynamic changes induced by sildenafil were biochemically well tolerated by fetal lambs on extracorporeal support, with the 0.5 mg/kg/24 h dose balancing rapid attainment of target concentrations with short-lived systemic effects. Research in contextNone. Search strategy before undertaking the studyA literature review was conducted searching online databases (Medline, Embase and Cochrane), using search terms: fetal OR prenatal OR antenatal AND sildenafil, without time-limit and excluding human studies. Where relevant, investigators were contacted in order to avoid duplication of work. Evidence before this studyPrenatal therapy with sildenafil, a phosphodiesterase-5 inhibitor with vasodilatory and anti-remodeling effects on vascular smooth muscle cells, has been considered for a variety of fetal conditions. One multicenter clinical trial investigating the benefit of sildenafil in severe intrauterine growth restriction (the STRIDER-trial) was halted early due to excess mortality in the sildenafil-exposed arm at one treatment site. Such findings demonstrate the importance of extensive preclinical safety assessment in relevant animal models. Transplacentally administered sildenafil leads to decreased pulmonary arterial muscularization, preventing or reducing the occurrence of pulmonary hypertension in rat and rabbit fetuses with diaphragmatic hernia (DH). Validation of these results in a higher and relevant animal model, e.g. fetal lambs, is the next step to advance clinical translation. We recently demonstrated that, in contrast to humans, transplacental transfer of sildenafil in sheep is minimal, precluding the in vivo study of fetal effects at target concentrations using the conventional pregnant ewe model. Added value of this studyWe therefore used the extracorporeal support model for fetal lambs, referred to as the EXTra-uterine Environment for Neonatal Development (EXTEND) system, bypassing placental and maternal metabolism, to investigate at what dose the target concentrations are reached, and what the fetal hemodynamic impact and response are. Fetal hemodynamic and metabolic tolerance to sildenafil are a crucial missing element on the road to clinical translation. This is therefore the first study investigating the pharmacokinetics, hemodynamic and biochemical effects of clinical-range concentrations of sildenafil in fetal lambs, free from placental and maternal interference. Implications of all the available evidenceWe demonstrated self-limiting pulmonary vasodilation, a decrease of both systemic arterial pressures and circuit flows, induced by clinical range concentrations of sildenafil, without the development of fetal acidosis. This paves the way for further investigation of prenatal sildenafil in fetal lambs on extracorporeal support. A dose of 0.5 mg/kg/24 h offered the best trade-off between rapid achievement of target concentrations and shortest duration of systemic effects. This is also the first study using the EXTEND as a model for pharmacotherapy during pregnancy.

Using pulmonary artery acceleration time to evaluate pulmonary hemodynamic changes on preterm infants with respiratory distress syndrome.

BackgroundPulmonary artery acceleration time (PAAT) is a reliable and non-invasive method for assessing pulmonary hemodynamics. To date, few studies have used PAAT to assess preterm infants, especially those with respiratory distress syndrome (RDS). This study aimed to assess changes in PAAT among preterm infants with RDS undergoing pulmonary surfactant (PS) therapy or not, and determine its potential effects on the pulmonary vascular disease (PVD) outcomes of preterm infants with RDS in the late postnatal period.MethodsThe risk of RDS was reviewed in 62 preterm infants with a gestational age of 26–31 weeks. The infants receiving PS therapy were allocated to the PS group, and the others were allocated to the control group. PAAT, right ventricular ejection time (RVET), and other ultrasonic parameters at 3 different time points after birth were studied and compared.ResultsInfants in the PS group had a significantly lower PAAT (52.7±5.9 vs. 59.6±8.7; P=0.001) and PAAT/RVET (0.30±0.03 vs. 0.33±0.03; P=0.001) than those in the control group at 36 weeks postmenstrual age (PMA). No significant increases in PAAT/RVET were detected at 3 different times for the PS group (P=0.117), but both PAAT and PAAT/RVET increased significantly with time after birth in the control group (P<0.001).ConclusionsPreterm infants with RDS might still have PVD in the late postnatal period and thus require long-term follow-up observation. PAAT appears to be a reliable non-invasive screening measure for evaluating pulmonary hemodynamics in preterm infants with RDS and late PVD.

Effect of Nocturnal Oxygen Therapy on Daytime Pulmonary Hemodynamics in Patients With Chronic Obstructive Pulmonary Disease Traveling to Altitude: A Randomized Controlled Trial.

IntroductionWe investigated whether nocturnal oxygen therapy (NOT) mitigates the increase of pulmonary artery pressure in patients during daytime with chronic obstructive pulmonary disease (COPD) traveling to altitude.MethodsPatients with COPD living below 800 m underwent examinations at 490 m and during two sojourns at 2,048 m (with a washout period of 2 weeks < 800 m between altitude sojourns). During nights at altitude, patients received either NOT (3 L/min) or placebo (ambient air 3 L/min) via nasal cannula according to a randomized crossover design. The main outcomes were the tricuspid regurgitation pressure gradient (TRPG) measured by echocardiography on the second day at altitude (under ambient air) and various other echocardiographic measures of the right and left heart function. Patients fulfilling predefined safety criteria were withdrawn from the study.ResultsTwenty-three COPD patients [70% Global Initiative for Chronic Obstructive Lung Disease (GOLD) II/30% GOLD III, mean ± SD age 66 ± 5 years, FEV1 54% ± 13% predicted] were included in the per-protocol analysis. TRPG significantly increased when patients traveled to altitude (from low altitude 21.7 ± 5.2 mmHg to 2,048 m placebo 27.4 ± 7.3 mmHg and 2,048 m NOT 27.8 ± 8.3 mmHg) difference between interventions (mean difference 0.4 mmHg, 95% CI −2.1 to 3.0, p = 0.736). The tricuspid annular plane systolic excursion was significantly higher after NOT vs. placebo [2.6 ± 0.6 vs. 2.3 ± 0.4 cm, mean difference (95% confidence interval) 0.3 (0.1 − 0.5) cm, p = 0.005]. During visits to 2,048 m until 24 h after descent, eight patients (26%) using placebo and one (4%) using NOT had to be withdrawn because of altitude-related adverse health effects (p < 0.001).ConclusionIn lowlanders with COPD remaining free of clinically relevant altitude-related adverse health effects, changes in daytime pulmonary hemodynamics during a stay at high altitude were trivial and not modified by NOT.Clinical Trial Registrationwww.ClinicalTrials.gov, identifier NCT02150590.

Dysbalance of ACE2 levels - a possible cause for severe COVID-19 outcome in COPD.

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) poses a serious threat to healthcare systems worldwide. Binding of the virus to angiotensin‐converting enzyme 2 (ACE2) is an important step in the infection mechanism. However, it is unknown if ACE2 expression in patients with chronic lung diseases (CLDs), such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary arterial hypertension (IPAH), or pulmonary fibrosis (PF), is changed as compared to controls. We used lung samples from patients with COPD (n = 28), IPAH (n = 10), and PF (n = 10) as well as healthy control donor (n = 10) tissue samples to investigate the expression of ACE2 and related cofactors that might influence the course of SARS‐CoV‐2 infection. Expression levels of the ACE2 receptor, the putative receptor CD147/BSG, and the viral entry cofactors TMPRSS2 (transmembrane serine protease 2), EZR, and FURIN were determined by quantitative PCR and in open‐access RNA sequencing datasets. Immunohistochemical and single‐cell RNA sequencing (scRNAseq) analyses were used for localization and coexpression, respectively. Soluble ACE2 (sACE2) plasma levels were analyzed by enzyme‐linked immunosorbent assay. In COPD as compared to donor, IPAH, and PF lung tissue, gene expression of ACE2, TMPRSS2, and EZR was significantly elevated, but circulating sACE2 levels were significantly reduced in COPD and PF plasma compared to healthy control and IPAH plasma samples. Lung tissue expressions of FURIN and CD147/BSG were downregulated in COPD. None of these changes were associated with changes in pulmonary hemodynamics. Histological analysis revealed coexpression of ACE2, TMPRSS2, and Ezrin in bronchial regions and epithelial cells. This was confirmed by scRNAseq analysis. There were no significant expression changes of the analyzed molecules in the lung tissue of IPAH and idiopathic PF as compared to control. In conclusion, we reveal increased ACE2 and TMPRSS2 expression in lung tissue with a concomitant decrease of protective sACE2 in COPD patients. These changes represent the possible risk factors for an increased susceptibility of COPD patients to SARS‐CoV‐2 infection.