Pulmonary Vascular Response Research Articles

Cardiopulmonary and cerebrovascular acclimatization in children and adults at 3800m.

Maturational differences exist in cardiopulmonary and cerebrovascular function at sea-level, but the impact of maturation on acclimatization responses to high altitude is unknown. Ten children (9.8±2.5years) and 10 adults (34.7±7.1years) were assessed at sea-level (BL), 3000m and twice over 4days at 3800m (B1, B4). Measurements included minute ventilation ( ), end-tidal partial pressures of oxygen ( ) and carbon dioxide, echocardiographic assessment of pulmonary artery systolic pressure (PASP) and stroke volume (SV) and ultrasound assessment of blood flow through the internal carotid and vertebral arteries was performed to calculate global cerebral blood flow (gCBF). At 3000m, was increased from BL by 19.6±19.1% (P=0.031) in children, but not in adults (P=0.835); SV was reduced in children (-11±13%, P=0.020) but not adults (P=0.827), which was compensated for by a larger increase in heart rate in children (+26 beatsmin-1 vs. +13 beatsmin-1 , P=0.019). Between B1 and B4, adults increased by 38.5±34.7% (P=0.006), while did not increase further in children. The rise in PASP was not different between groups; however, ∆PASP from BL was related to ∆ in adults (R2 =0.288, P=0.022), but not children. At BL, gCBF was 43% higher in children than adults (P=0.017), and this difference was maintained at high altitude, with a similar pattern and magnitude of change in gCBF between groups (P=0.845). Despite increasing in children but not adults at a lower altitude, the pulmonary vascular and cerebrovascular responses to prolonged hypoxia are similar between children and adults. KEY POINTS: Children have different ventilatory and metabolic requirements from adults, which may present differently in the pulmonary and cerebral vasculature upon ascent to high altitude. Children (ages 7-14) and adults (ages 23-44) were brought from sea level to high altitude (3000 to 3800m) and changes in ventilation, pulmonary artery systolic pressure (PASP) and cerebral blood flow (CBF) were assessed over 1 week. Significant increases in ventilation and decreases in left ventricle stroke volume were observed at a lower altitude in children than adults. PASP and CBF increased by a similar relative amount between children and adults at 3800m. These results help us better understand age-related differences in compensatory responses to prolonged hypoxia in children, despite similar changes in pulmonary artery pressure and CBF between children and adults.

Prevalence and implications of exercise pulmonary hypertension in chronic thromboembolic pulmonary disease

Abstract Introduction Recent international statement on chronic thromboembolic pulmonary hypertension proposed the definition of chronic thromboembolic pulmonary disease (CTEPD) and advocated further research regarding its clinical characteristic, natural history, and therapeutic strategy. Exercise pulmonary hypertension (Ex-PH) has been considered a mild degree of pulmonary hypertension (PH) among patients with normal pulmonary hemodynamics at rest. However, the clinical significance of Ex-PH in CTEPD remains unknown. Purpose In the patients with CTEPD, we aimed to verify 1) the prevalence and clinical profiles of Ex-PH, 2) effect of BPA on pulmonary vascular response after exercise in Ex-PH, 3) long-term clinical outcomes of conservative management in non-Ex-PH. Methods We retrospectively reviewed 26 patients with CTEPD (median age 65 years, 38% male), who underwent cardiopulmonary exercise test with right heart catheterization (CPET-RHC). The definitions of CTEPD are the following 1) pulmonary artery occlusion due to organic thrombus confirmed by imaging studies after ≥3 months of anticoagulation, 2) mPAP<25 mmHg and PAWP≤15 mmHg at rest. PQslope was plotted using multipoint plots. Ex-PH was defined by PQ slope>3.0, and the patients were divided into Ex-PH and non-Ex PH groups. Clinical profiles and long-term outcomes were compared between two groups. The patients in Ex-PH groupunderwent CPET-RHC 6–12 months after balloon pulmonary angioplasty (BPA). In Non-Ex-PH group, serial measurements of echocardiography were performed. Results Overall, 5 and 21 patients were categorized as CTEPD with PH (mPAP 21–24mmHg) and without PH (mPAP≤20mmHg), and 14 and 12 were categorized Ex-PH and non-Ex-PH groups, respectively. Although all 5 patients with CTEPD with PH were classified as Ex-PH group (Figure 1), there was no significant difference in baseline hemodynamics at rest between Ex-PH and non-Ex-PH groups (mPAP: 19.5 [18.4–20.6] vs. 17.7 [16.6–18.9] mmHg, PVR: 2.2 [1.7–2.7] vs. 2.3 [1.9–2.8] wood units, P>0.05, respectively). PQ slope was significantly higher in Ex-PH group (4.6 [3.2–6.0] vs. 1.31 [0.2–2.8], p=0.002). There were no differences in respiratory function test, blood gas analysis, and 6-minute walk distance between two groups. There were no major adverse events such as all-cause mortality and hospitalization for PH in overall cohort. Among Ex-PH group, BPA decreased PQslope (4.8 [3.6–6.4] to 2.3 [1.9–3.0], p<0.05). Among no-Ex-PH group, there was no significant change in tricuspid regurgitation pressure gradient (28 [17–33] to 27 [21–36] mmHg, p>0.05) over the 997 [651–1451] days. Conclusion Ex-PH was common in patients with CTEPD, and there were no clinical profiles differentiating Ex-PH from non-Ex-PH, except parameters of CPET-RHC. BPA improved an abnormal pulmonary vascular response to exercise in Ex-PH. The conservative management in non-Ex-PH was feasible. Randomized clinical trials will be needed to further investigate this treatment strategy. Funding Acknowledgement Type of funding sources: None.

Effects of exogenous hydrogen sulfide on pulmonary hypertension in rabbits with endotoxic shock

Objective: To investigate the effects of exogenous hydrogen sulfide (H2S) on pulmonary vascular reactivity induced by endotoxic shock (ES) in rabbits. Methods: In this experiment, the model of endotoxic shock (ES) was induced by injection of lipopolysaccharides (LPS) to New Zealand big eared white rabbit through jugular vein (8 mg/0.8 ml/kg), the intervention was performed by H2S donor(sodium hydrosulfide, NaHS) which was injected intraperitoneally (28 μmol/kg) 15 min in advance. New Zealand rabbits were randomly divided into 4 groups(n=8):control group, LPS group, LPS+NaHS group and NaHS group. The changes of mean arterial pressure (MAP) and mean pulmonary arterial pressure (MPAP) were detected. The tension of pulmonary artery ring (PARs) was detected byin vitro vascular ring technique. The ultrastructure of pulmonary artery wall and pulmonary artery endothelial cells were observed by light microscope and scanning electron microscope. Results: ①MAP was decreased while MPAP was increased in rabbits after LPS injection, and ES animal model was established successfully. Compared with LPS group, mPAP of rabbit in LPS+NaHS group was decreased significantly (all P＜0.05). ②Compared with normal control group, pulmonary artery of rabbits in LPS group had an increased contractile response to phenylephrine (PE) and a decreased relaxation response to acetylcholine (ACh) (both P＜0.01); Compared with LPS group, pulmonary artery of rabbits in LPS+NaHS group had a decreased contractile response to PE and an increased relaxation response to ACh (both P＜0.05). ③Under light microscope, the structure of vascular endothelial cells was continuous in the normal control group, the elastic fibers were intact in the subcutaneous layer, and the smooth muscle layer was arranged neatly. LPS can shed some of the pulmonary artery endothelial cells, break the subcutaneous elastic fibers, and disorder the smooth muscle layer structure. Compared with LPS group, the injury of pulmonary artery wall in LPS+NaHS group was ameliorated. The morphology of pulmonary artery wall was normal in NaHS group. It is showed that some endothelial cells of pulmonary artery were missing in LPS group by Scanning electron microscopy. The morphology of pulmonary artery endothelial cells in LPS+NaHS group was similar to that in the control group: slightly widened intercellular space was observed, and no cell exfoliation was observed. Conclusion: These results suggest that exogenous H2S can protect pulmonary artery endothelial cells and regulate the reactivity changes of pulmonary artery during ES, which may be one of the mechanisms reducing PAH in ES rabbits.

Exercise and hypoxia unmask pulmonary vascular disease and right ventricular dysfunction in a 10- to 12-week-old swine model of neonatal oxidative injury.

Prematurely born young adults who experienced neonatal oxidative injury (NOI) of the lungs have increased incidence of cardiovascular disease. Here, we investigated the long‐term effects of NOI on cardiopulmonary function in piglets at the age of 10–12 weeks. To induce NOI, term‐born piglets (1.81 ± 0.06 kg) were exposed to hypoxia (10–12% FiO2), within 2 days after birth, and maintained for 4 weeks or until symptoms of heart failure developed (range 16–28 days), while SHAM piglets were normoxia raised. Following recovery (>5 weeks), NOI piglets were surgically instrumented to measure haemodynamics during hypoxic challenge testing (HCT) and exercise with modulation of the nitric‐oxide system. During exercise, NOI piglets showed a normal increase in cardiac index, but an exaggerated increase in pulmonary artery pressure and a blunted increase in left atrial pressure – suggesting left atrial under‐filling – consistent with an elevated pulmonary vascular resistance (PVR), which correlated with the duration of hypoxia exposure. Moreover, hypoxia duration correlated inversely with stroke volume (SV) during exercise. Nitric oxide synthase inhibition and HCT resulted in an exaggerated increase in PVR, while the PVR reduction by phosphodiesterase‐5 inhibition was enhanced in NOI compared to SHAM piglets. Finally, within the NOI piglet group, prolonged duration of hypoxia was associated with a better maintenance of SV during HCT, likely due to the increase in RV mass. In conclusion, duration of neonatal hypoxia appears an important determinant of alterations in cardiopulmonary function that persist further into life. These changes encompass both pulmonary vascular and cardiac responses to hypoxia and exercise. Key points Children who suffered from neonatal oxidative injury, such as very preterm born infants, have increased risk of cardiopulmonary disease later in life.Risk stratification requires knowledge of the mechanistic underpinning and the time course of progression into cardiopulmonary disease.Exercise and hypoxic challenge testing showed that 10‐ to 12‐week‐old swine that previously experienced neonatal oxidative injury had increased pulmonary vascular resistance and nitric oxide dependency.Duration of neonatal oxidative injury was a determinant of structural and functional cardiopulmonary remodelling later in life.Remodelling of the right ventricle, as a result of prolonged neonatal oxidative injury, resulted in worse performance during exercise, but enabled better performance during the hypoxic challenge test.Increased nitric oxide dependency together with age‐ or comorbidity‐related endothelial dysfunction may contribute to predisposition to pulmonary hypertension later in life.

Priming of Cardiopulmonary Bypass with Human Albumin Decreases Endothelial Dysfunction after Pulmonary Ischemia-Reperfusion in an Animal Model.

The routine use of mechanical circulatory support during lung transplantation (LTx) is still controversial. The use of prophylactic human albumin (HA) or hypertonic sodium lactate (HSL) prime in mechanical circulatory support during LTx could prevent ischemia–reperfusion (IR) injuries and pulmonary endothelial dysfunction and thus prevent the development of pulmonary graft dysfunction. The objective was to investigate the impact of cardiopulmonary bypass (CPB) priming with HA and HSL compared to a CPB prime with Gelofusine (GF) on pulmonary endothelial dysfunction in a lung IR rat model. Rats were assigned to four groups: IR-CPB-GF group, IR-CPB-HA group, IR-CPB-HSL group and a sham group. The study of pulmonary vascular reactivity by wire myograph was the primary outcome. Glycocalyx degradation (syndecan-1 and heparan) was also assessed by ELISA and electron microscopy, systemic and pulmonary inflammation by ELISA (IL-1β, IL-10, and TNF-α) and immunohistochemistry. Clinical parameters were evaluated. We employed a CPB model with three different primings, permitting femoral–femoral assistance with left pulmonary hilum ischemia for IR. Pulmonary endothelium-dependent relaxation to acetylcholine was significantly decreased in the IR-CPB-GF group (11.9 ± 6.2%) compared to the IR-CPB-HA group (52.8 ± 5.2%, p < 0.0001), the IR-CPB-HSL group (57.7 ± 6.3%, p < 0.0001) and the sham group (80.8 ± 6.5%, p < 0.0001). We did not observe any difference between the groups concerning glycocalyx degradation, and systemic or tissular inflammation. The IR-CPB-HSL group needed more vascular filling and developed significantly more pulmonary edema than the IR-CPB-GF group and the IR-CPB-HA group. Using HA as a prime in CPB during Ltx could decrease pulmonary endothelial dysfunction’s IR-mediated effects. No effects of HA were found on inflammation.

Effect of selective dopamine D3 and D4 receptor agonists on trunk pulmonary artery vascular reactivity from control and monocrotaline-treated rats.

Dopamine D1-like and D2-like receptors are expressed in the pulmonary arteries, however there is a little information about their effect on vascular tone in pulmonary circulation, even the vascular effect of activation of the dopamine D3 and D4 subtypes in physiological and pathological conditions such as pulmonary hypertension is unknown. The objective of this study was to evaluate the vascular response of trunk pulmonary artery rings from saline and monocrotaline-treated rats in the presence of selective dopamine receptor agonists. In trunk pulmonary artery rings with intact and denuded endothelium, cumulative concentration-response curves were performed for phenylephrine, acetylcholine, and dopamine receptor agonists (apomorphine-D2-like, SKF38393-D1, quinpirole-D2/D3, 7-OH-DPATD3, and PD168077-D4) alone and in the presence of corresponding selective dopamine receptor antagonists (SCH23390-D1, raclopride-D2/D3, U99194 maleate-D3, and L-745,870-D4). Contractile and relaxant effects generated during the activation with phenylephrine and acetylcholine, respectively, were significantly reduced in intact and denuded endothelium trunk pulmonary artery rings from monocrotaline rats in comparison with control rats. All dopamine receptor agonists, except the 7-OH-DPAT, produced significant vascular relaxation in intact trunk pulmonary artery rings precontracted with phenylephrine in both experimental groups. Also, the vascular relaxation of SKF38393, and particularly apomorphine and PD168077 was significant in denuded endothelium trunk pulmonary artery rings from control and monocrotaline groups. Furthermore, the vasorelaxation induced by these dopamine agonists was significantly reduced in pulmonary preparations from monocrotaline-treated rats in comparison to that recorded in preparations from control rats. The effect of dopamine receptor agonists decreased significantly in the presence of the corresponding antagonist in both experimental groups. The results support that dopamine D4 receptor agonist induces significant vascular relaxation, whereas dopamine D3 receptor agonist induces vasoconstriction in intact and denuded endothelium trunk pulmonary artery rings in control and monocrotaline-induced pulmonary arterial hypertension rats.

Hemodynamic assessment of congenital heart malformations with left to right shunt

Cardiac catheterization with direct measurements of pressure and saturation in cardiac chambers and great vessels and calculation of systemic and pulmonary blood &amp;#64258; ow, pulmonary and systemic resistance, and pulmonary vascular reactivity are the gold standard for assessing the hemodynamics of congenital heart malformations with a left to right shunt in both children and adults. They are the basis for determining the indications for surgical or interventional treatment. Assessment of the blood &amp;#64258; ow according to Fick&amp;rsquo;s principle and the resistance according to Ohm&amp;lsquo;s law are the theoretical basis of hemodynamic calculations. The steps in assessing hemodynamics in a patient with a left-to-right shunt are presented consequently: pulmonary to systemic blood &amp;#64258; ow ratio, calculation of pulmonary vascular resistance (PVR) in case of pulmonary hypertension (PHy), and assessment of pulmonary vascular reactivity and their clinical signi&amp;#64257; cance as well. Special attention is paid to the assessment of hemodynamics and indications for closure in elderly patients with atrial septal defect (ASD) and left ventricular dysfunction. The limitations and sources of errors in hemodynamic calculations are presented.

Maladaptive Pulmonary Vascular Responses to Chronic Sustained and Chronic Intermittent Hypoxia in Rat.

Chronic sustained hypoxia (CSH), as found in individuals living at a high altitude or in patients suffering respiratory disorders, initiates physiological adaptations such as carotid body stimulation to maintain oxygen levels, but has deleterious effects such as pulmonary hypertension (PH). Obstructive sleep apnea (OSA), a respiratory disorder of increasing prevalence, is characterized by a situation of chronic intermittent hypoxia (CIH). OSA is associated with the development of systemic hypertension and cardiovascular pathologies, due to carotid body and sympathetic overactivation. There is growing evidence that CIH can also compromise the pulmonary circulation, causing pulmonary hypertension in OSA patients and animal models. The aim of this work was to compare hemodynamics, vascular contractility, and L-arginine-NO metabolism in two models of PH in rats, associated with CSH and CIH exposure. We demonstrate that whereas CSH and CIH cause several common effects such as an increased hematocrit, weight loss, and an increase in pulmonary artery pressure (PAP), compared to CIH, CSH seems to have more of an effect on the pulmonary circulation, whereas the effects of CIH are apparently more targeted on the systemic circulation. The results suggest that the endothelial dysfunction evident in pulmonary arteries with both hypoxia protocols are not due to an increase in methylated arginines in these arteries, although an increase in plasma SDMA could contribute to the apparent loss of basal NO-dependent vasodilation and, therefore, the increase in PAP that results from CIH.

Abstract 6991: Impaired Systemic Oxygen Extraction Relates to Reduced Exercise Capacity in Post-COVID-19 Long Hauler Syndrome

Introduction: Following acute coronavirus 2019 (COVID-19) disease, at least 10% of patients report some form of residual limitation, most commonly dyspnea and fatigue. These COVID-19 “long haulers” experience symptoms that are largely unexplained by pulmonary function testing (PFT), echocardiogram and chest computed tomography (CT). Using invasive cardiopulmonary exercise testing, this pilot study characterized exercise limitation in 5 patients with persistent symptoms 1 year following mild COVID-19 illness. Methods: Following written informed consent, data were obtained in accordance with an IRB-approved protocol entailing placement of radial and pulmonary arterial catheters for pressure monitoring and blood sampling prior to and during maximum upright incremental exercise. Rest and exercise pulmonary hemodynamics, ventilation and gas exchange were recorded. Aerobic exercise capacity was estimated by peak O 2 consumption (VO 2 ). Results: All patients had normal biventricular and valvular function on resting echocardiogram, no evident parenchymal lung disease on CT, and normal PFTs. Resting mean pulmonary arterial pressure was ≤20 mmHg for all patients with pulmonary vascular resistance &lt;3 Woods units. At maximum exercise, all patients exhibited normal respiratory, cardiac output (% predicted), and total pulmonary vascular resistance responses, but demonstrated clearly depressed aerobic capacity (peak VO 2 &lt;80% predicted). Reduced peak VO 2 was associated with impaired systemic O 2 extraction as indicated by an arterial-venous O 2 content difference (adjusted for hemoglobin) of &lt;80% ( Figure 1 ). Conclusion: This case series provides preliminary evidence that reduced peak aerobic capacity among long haulers is primarily attributable to a peripheral (i.e., impaired systemic O 2 extraction), rather than central cardiopulmonary, limitation. These results suggest that systemic microcirculatory dysfunction contributes to exercise limitation.

A computational model of contributors to pulmonary hypertensive disease: impacts of whole lung and focal disease distributions.

Pulmonary hypertension has multiple etiologies and so can be difficult to diagnose, prognose, and treat. Diagnosis is typically made via invasive hemodynamic measurements in the main pulmonary artery and is based on observed elevation of mean pulmonary artery pressure. This static mean pressure enables diagnosis, but does not easily allow assessment of the severity of pulmonary hypertension, nor the etiology of the disease, which may impact treatment. Assessment of the dynamic properties of pressure and flow data obtained from catheterization potentially allows more meaningful assessment of the strain on the right heart and may help to distinguish between disease phenotypes. However, mechanistic understanding of how the distribution of disease in the lung leading to pulmonary hypertension impacts the dynamics of blood flow in the main pulmonary artery and/or the pulmonary capillaries is lacking. We present a computational model of the pulmonary vasculature, parameterized to characteristic features of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension to help understand how the two conditions differ in terms of pulmonary vascular response to disease. Our model incorporates key features known to contribute to pulmonary vascular function in health and disease, including anatomical structure and multiple contributions from gravity. The model suggests that dynamic measurements obtained from catheterization potentially distinguish between distal and proximal vasculopathy typical of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. However, the model suggests a non-linear relationship between these data and vascular structural changes typical of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension which may impede analysis of these metrics to distinguish between cohorts.

VP35.13: Pulmonary vascular response to oxygen in growth‐restricted fetuses

VP35.13: Pulmonary vascular response to oxygen in growth‐restricted fetuses

EXERCISE HEMODYNAMICS TO REVEAL LATENT PULMONARY VASCULAR ABNORMALITIES AMONG CHRONIC THROMBOEMBOLIC DISEASE PATIENTS

BACKGROUND Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by persistent and organized pulmonary thrombi and pulmonary hypertension (PH). Right heart catheterization (RHC) is the gold standard for diagnosis of PH, defined by a resting mean pulmonary artery pressure (mPAP) > 20 mmHg. Chronic organized thrombi, in the absence of PH at rest is termed chronic thromboembolic disease (CTED). Pulmonary endarterectomy (PEA) is indicated for CTEPH, however PEA is not routinely endorsed for CTED. Exercise is increasingly employed as a provocative maneuver during RHC to elicit abnormalities of pulmonary vascular and cardiac physiology in patients without PH at rest who are at risk of pulmonary vascular disease. Exercise RHC may expose abnormalities of pulsatile or resistive pulmonary vascular afterload in CTED patients and may potentially identify a subset of CTED patients who benefit from PEA surgery. We describe the proportion of CTED patients with latent pulmonary vascular hemodynamic abnormalities and their hemodynamic characteristics. METHODS AND RESULTS Consecutive patients with a resting mPAP ≤ 20 mmHg and CTED who completed an exercise hemodynamic study between November 2016 and September 2020 were included. We defined exercise abnormalities of pulmonary resistive load as mPAP/CO > 3 WU and exercise abnormalities of pulsatile load as the ratio of pulmonary pulse pressure to pulmonary artery wedge pressure (PP/PAWP) > 2.5. Thirty-seven CTED patients (32% female, 55±15 years) were analyzed. Resting hemodynamics for the entire cohort and exercise hemodynamics for patients with and without latent pulmonary vascular abnormalities are shown (Table 1). Twenty-two patients (59%) demonstrated latent pulmonary vascular abnormalities; 12 had an elevated pulsatile load (PP/PAWP 5.3±4.5), 5 had an elevated resistive load (mPAP/CO 3.7±0.7 WU) and 5 had both (mPAP/CO 3.7±0.5 WU, PP/PAWP 7.3±3.6). Patients with latent pulmonary vascular abnormalities exercised to lower work-rates (P=0.03) and had lower exercise PAWP (P=0.02). They were also characterized by higher pulmonary vascular resistance (P < 0.001) and impaired pulmonary artery compliance (P < 0.001) compared to patients without latent pulmonary vascular abnormalities. CONCLUSION Patients with CTED and resting mPAP ≤ 20mmHg, exercise demonstrated latent abnormal pulmonary vascular responses in over 50% of patients. These patients predominantly demonstrated abnormalities of pulsatile afterload relative to resistive afterload. Further study is required to understand if these patients benefit from PEA surgery. Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by persistent and organized pulmonary thrombi and pulmonary hypertension (PH). Right heart catheterization (RHC) is the gold standard for diagnosis of PH, defined by a resting mean pulmonary artery pressure (mPAP) > 20 mmHg. Chronic organized thrombi, in the absence of PH at rest is termed chronic thromboembolic disease (CTED). Pulmonary endarterectomy (PEA) is indicated for CTEPH, however PEA is not routinely endorsed for CTED. Exercise is increasingly employed as a provocative maneuver during RHC to elicit abnormalities of pulmonary vascular and cardiac physiology in patients without PH at rest who are at risk of pulmonary vascular disease. Exercise RHC may expose abnormalities of pulsatile or resistive pulmonary vascular afterload in CTED patients and may potentially identify a subset of CTED patients who benefit from PEA surgery. We describe the proportion of CTED patients with latent pulmonary vascular hemodynamic abnormalities and their hemodynamic characteristics. Consecutive patients with a resting mPAP ≤ 20 mmHg and CTED who completed an exercise hemodynamic study between November 2016 and September 2020 were included. We defined exercise abnormalities of pulmonary resistive load as mPAP/CO > 3 WU and exercise abnormalities of pulsatile load as the ratio of pulmonary pulse pressure to pulmonary artery wedge pressure (PP/PAWP) > 2.5. Thirty-seven CTED patients (32% female, 55±15 years) were analyzed. Resting hemodynamics for the entire cohort and exercise hemodynamics for patients with and without latent pulmonary vascular abnormalities are shown (Table 1). Twenty-two patients (59%) demonstrated latent pulmonary vascular abnormalities; 12 had an elevated pulsatile load (PP/PAWP 5.3±4.5), 5 had an elevated resistive load (mPAP/CO 3.7±0.7 WU) and 5 had both (mPAP/CO 3.7±0.5 WU, PP/PAWP 7.3±3.6). Patients with latent pulmonary vascular abnormalities exercised to lower work-rates (P=0.03) and had lower exercise PAWP (P=0.02). They were also characterized by higher pulmonary vascular resistance (P < 0.001) and impaired pulmonary artery compliance (P < 0.001) compared to patients without latent pulmonary vascular abnormalities. Patients with CTED and resting mPAP ≤ 20mmHg, exercise demonstrated latent abnormal pulmonary vascular responses in over 50% of patients. These patients predominantly demonstrated abnormalities of pulsatile afterload relative to resistive afterload. Further study is required to understand if these patients benefit from PEA surgery.

Ubiquinol ameliorates endothelial dysfunction and increases expression of miRNA-34a in a rat model of pulmonary hypertension

Introduction: In this research, we evaluate the effect of intravenously administrated solubilized ubiquinol on 4-week monocrotalin-induced pulmonary hypertension (PH) in rats.&#x0D; Materials and methods: To reproduce the model, some male Wistar rats were subcutaneously injected with alcohol solution of monocrotaline60 mg/kg and the rest – with alcohol solution (Control). Those with monocrotaline (MCT) were divided into 3 groups. They underwent intravenous administration of 1% ubiquinol solution 30 mg/kg (MCT-Ubiquinol), the vehicle (MCT-Vehicle) and saline (MCT-saline) three times on days 7, 14 and 21, depending on the group. The hemodynamic parameters were measured in anesthetized rats on day 29. Right ventricle hypertrophy, pulmonary arteries reactivity and expression of miRNA-21 and miRNA-34a were estimated after euthanasia.&#x0D; Results and discussion: All MCT-groups demonstrated an increase in right ventricle systolic pressure and hypertrophy in comparison with the control group. An increase in lung weight was shown in MCT-Vehicle and MCT-Saline; however, the MCT-Ubiquinol indicators did not differ from those of the Control. There was an increased vasodilatation response to acetylcholine at concentrations of 1*10-6M and 1*10-5M in MCT-Ubiquinol in contrast to the other two MCT-groups. A significantly lower level of expression of miRNA-34a was observed in MCT-Ubiquinol.&#x0D; Conclusion: Our findings suggest that a triple ubiquinol injection influences pulmonary changes and endothelium-depended vasodilatation, which contributes to pulmonary vascular tone and reactivity. A decrease in miRNA-34a expression in MCT-Ubiquinol group demonstrates the ubiquinol anti-inflammatory properties.

Implication of Blood Rheology and Pulmonary Hemodynamics on Exercise-Induced Hypoxemia at Sea Level and Altitude in Athletes.

This study aimed to investigate the changes in blood viscosity, pulmonary hemodynamics, nitric oxide (NO) production, and maximal oxygen uptake (V˙O2max) during a maximal incremental test conducted in normoxia and during exposure to moderate altitude (2,400m) in athletes exhibiting exercise-induced hypoxemia at sea level (EIH). Nine endurance athletes with EIH and eight without EIH (NEIH) performed a maximal incremental test under three conditions: sea level, 1 day after arrival in hypoxia, and 5 days after arrival in hypoxia (H5) at 2,400m. Gas exchange and oxygen peripheral saturation (SpO2) were continuously monitored. Cardiac output, pulmonary arterial pressure, and total pulmonary vascular resistance were assessed by echocardiography. Venous blood was sampled before and 3min after exercise cessation to analyze blood viscosity and NO end-products. At sea level, athletes with EIH exhibited an increase in blood viscosity and NO levels during exercise while NEIH athletes showed no change. Pulmonary hemodynamics and aerobic performance were not different between the two groups. No between-group differences in blood viscosity, pulmonary hemodynamics, and V˙O2max were found at 1 day after arrival in hypoxia. At H5, lower total pulmonary vascular resistance and greater NO concentration were reported in response to exercise in EIH compared with NEIH athletes. EIH athletes had greater cardiac output and lower SpO2 at maximal exercise in H5, but no between-group differences occurred regarding blood viscosity and V˙O2max. The pulmonary vascular response observed at H5 in EIH athletes may be involved in the greater cardiac output of EIH group and counterbalanced the drop in SpO2 in order to achieve similar V˙O2max than NEIH athletes.

Honeymoon Period in Newborn Rats With CDH Is Associated With Changes in the VEGF Signaling Pathway.

Background: Patients with congenital diaphragmatic hernia (CDH) have a short postnatal period of ventilatory stability called the honeymoon period, after which changes in pulmonary vascular reactivity result in pulmonary hypertension. However, the mechanisms involved are still unknown. The aim of this study was to evaluate mechanical ventilation's effect in the honeymoon period on VEGF, VEGFR-1/2 and eNOS expression on experimental CDH in rats.Materials and Methods: Neonates whose mothers were not exposed to nitrofen formed the control groups (C) and neonates with left-sided defects formed the CDH groups (CDH). Both were subdivided into non-ventilated and ventilated for 30, 60, and 90 min (n = 7 each). The left lungs (n = 4) were evaluated by immunohistochemistry of the pulmonary vasculature (media wall thickness), VEGF, VEGFR-1/2 and eNOS. Western blotting (n = 3) was performed to quantify the expression of VEGF, VEGFR-1/2 and eNOS.Results: CDH had lower biometric parameters than C. Regarding the pulmonary vasculature, C showed a reduction in media wall thickness with ventilation, while CDH presented reduction with 30 min and an increase with the progression of the ventilatory time (honeymoon period). CDH and C groups showed different patterns of VEGF, VEGFR-1/2 and eNOS expressions. The receptors and eNOS findings were significant by immunohistochemistry but not by western blotting, while VEGF was significant by western blotting but not by immunohistochemistry.Conclusion: VEGF, its receptors and eNOS were altered in CDH after mechanical ventilation. These results suggest that the VEGF-NO pathway plays an important role in the honeymoon period of experimental CDH.

Sphingosine Kinase 1 Regulates the Pulmonary Vascular Immune Response.

The aberrant proliferation of pulmonary artery smooth muscle (PASMCs) cells is a defining characteristic of pulmonary arterial hypertension (PAH) and leads to increased vascular resistance, elevated pulmonary pressure, and right heart failure. The sphingosine kinase 1 (SPHK1)/sphingosine-1 phosphate/sphingosine-1 phosphate receptor 2 pathway promotes vascular remodeling and induces PAH. The aim of this study was to identify genes and cellular processes that are modulated by over-expression of SPHK1 in human PASMCs (hPASMCs). RNA was purified and submitted for RNA sequencing to identify differentially expressed genes. Using a corrected p-value threshold of <0.05, there were 294 genes significantly up-regulated while 179 were significantly down-regulated. Predicted effects of these differentially expressed genes were evaluated using the freeware tool Enrichr to assess general gene set over-representation (enrichment) and ingenuity pathway analysis (IPA™) for upstream regulator predictions. We found a strong change in genes that regulated the cellular immune response. IL6, STAT1, and PARP9 were elevated in response to SPHK1 over-expression in hPASMCs. The gene set enrichment mapped to a few immune-modulatory signaling networks, including IFNG. Furthermore, PARP9 and STAT1 protein were elevated in primary hPASMCs isolated from PAH patients. In conclusion, these data suggest a role of Sphk1 regulates pulmonary vascular immune response in PAH.

Carbonic anhydrase inhibition improves pulmonary artery reactivity and nitric oxide-mediated relaxation in sugen-hypoxia model of pulmonary hypertension.

Pulmonary hypertension (PH) is a serious disease with pulmonary arterial fibrotic remodeling and limited responsiveness to vasodilators. Our data suggest that mild acidosis induced by carbonic anhydrase inhibition could ameliorate PH, but the vascular mechanisms are unclear. We tested the hypothesis that carbonic anhydrase inhibition ameliorates PH by improving pulmonary vascular reactivity and relaxation mechanisms. Male Sprague-Dawley rats were either control normoxic (Nx), or injected with Sugen 5416 (20 mg/kg, sc) and subjected to hypoxia (9% O2) (Su+Hx), or Su+Hx treated with acetazolamide (ACTZ, 100 mg/kg/day, in drinking water). After measuring the hemodynamics, right ventricular hypertrophy was assessed by Fulton's Index; vascular function was measured in pulmonary artery, aorta, and mesenteric arteries; and pulmonary arteriolar remodeling was assessed in lung sections. Right ventricular systolic pressure and Fulton's Index were increased in Su+Hx and reduced in Su+Hx + ACTZ rats. Pulmonary artery contraction to KCl and phenylephrine were reduced in Su+Hx and improved in Su+Hx + ACTZ. Acetylcholine (ACh)-induced relaxation and nitrate/nitrite production were reduced in pulmonary artery of Su+Hx and improved in Su+Hx + ACTZ. ACh relaxation was blocked by nitric oxide (NO) synthase and guanylate cyclase inhibitors, supporting a role of NO-cGMP. Sodium nitroprusside (SNP)-induced relaxation was reduced in pulmonary artery of Su+Hx, and ACTZ enhanced relaxation to SNP. Contraction/relaxation were not different in aorta or mesenteric arteries of all groups. Pulmonary arterioles showed wall thickening in Su+Hx that was ameliorated in Su+Hx + ACTZ. Thus, amelioration of pulmonary hemodynamics during carbonic anhydrase inhibition involves improved pulmonary artery reactivity and NO-mediated relaxation and may enhance responsiveness to vasodilator therapies in PH.

Impact of COVID-19 on exercise pathophysiology: a combined cardiopulmonary and echocardiographic exercise study.

Survivors from COVID-19 pneumonia can present with persisting multisystem involvement (lung, pulmonary vessels, heart, muscle, red blood cells) that may negatively affect exercise capacity. We sought to determine the extent and the determinants of exercise limitation in patients with COVID-19 at the time of hospital discharge. Eighteen consecutive patients with COVID-19 and 1:1 age-, sex-, and body mass index-matched controls underwent: spirometry, echocardiography, cardiopulmonary exercise test and exercise echocardiography for the study of pulmonary circulation. Arterial blood was sampled at rest and during exercise in patients with COVID-19. Patients with COVID-19 lie roughly on the same oxygen consumption isophlets than controls both at rest and during submaximal exercise, thanks to supernormal cardiac output (P < 0.05). Oxygen consumption at peak exercise was reduced by 30% in COVID-19 (P < 0.001), due to a peripheral extraction limit. In addition, within COVID-19 patients, hemoglobin content was associated with peak oxygen consumption (R2 = 0.46, P = 0.002). Respiratory reserve was not exhausted (median [IRQ], 0.59 [0.15]) in spite of moderate reduction of forced vital capacity (79 ± 40%). Pulmonary artery pressure increase during exercise was not different between patients and controls. Ventilatory equivalents for carbon dioxide were higher in patients with COVID-19 than in controls (39.5 [8.5] vs. 29.5 [8.8], P < 0.001), and such an increase was mainly explained by increased chemosensitivity. When recovering from COVID-19, patients present with reduced exercise capacity and augmented exercise hyperventilation. Peripheral factors, including anemia and reduced oxygen extraction by peripheral muscles were the major determinants of deranged exercise physiology. Pulmonary vascular function seemed unaffected, despite restrictive lung changes.NEW & NOTEWORTHY At the time of hospital discharge, patients with COVID-19 present with reduced functional capacity and exercise hyperventilation. Peripheral factors, namely reduced oxygen extraction (myopathy) and anemia, which are not fully compensated by a supernormal cardiac output response, account for exercise limitation before exhaustion of the respiratory reserve. Enhanced chemoreflex sensitivity, rather increased dead space, mainly accounts for exercise hyperventilation. The pulmonary vascular response to exercise circulation of survived patients with COVID-19 does not present major pathological changes.

Influence of iron manipulation on hypoxic pulmonary vasoconstriction and pulmonary reactivity during ascent and acclimatization to 5050m.

Iron acts as a cofactor in the stabilization of the hypoxic-inducible factor family, and plays an influential role in the modulation of hypoxic pulmonary vasoconstriction. It is uncertain whether iron regulation is altered in lowlanders during either (1) ascent to high altitude, or (2) following partial acclimatization, when compared to high-altitude adapted Sherpa. During ascent to 5050m, the rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders; however, upon arrival to 5050m, PASP levels were comparable in both groups, but the reduction in iron bioavailability was more prevalent in lowlanders compared to Sherpa. Following partial acclimatization to 5050m, there were differential influences of iron status manipulation (via iron infusion or chelation) at rest and during exercise between lowlanders and Sherpa on the pulmonary vasculature. To examine the adaptational role of iron bioavailability on the pulmonary vascular responses to acute and chronic hypobaric hypoxia, the haematological and cardiopulmonary profile of lowlanders and Sherpa were determined during: (1) a 9-day ascent to 5050m (20 lowlanders; 12 Sherpa), and (2) following partial acclimatization (11±4days) to 5050m (18 lowlanders; 20 Sherpa), where both groups received an i.v. infusion of either iron (iron (iii)-hydroxide sucrose) or an iron chelator (desferrioxamine). During ascent, there were reductions in iron status in both lowlanders and Sherpa; however, Sherpa appeared to demonstrate a more efficient capacity to mobilize stored iron, compared to lowlanders, when expressed as a Δhepcidin per unit change in either body iron or the soluble transferrin receptor index, between 3400-5050m (P=0.016 and P=0.029, respectively). The rise in pulmonary artery systolic pressure (PASP) was blunted in Sherpa, compared to lowlanders during ascent; however, PASP was comparable in both groups upon arrival to 5050m. Following partial acclimatization, despite Sherpa demonstrating a blunted hypoxic ventilatory response and greater resting hypoxaemia, they had similar hypoxic pulmonary vasoconstriction when compared to lowlanders at rest. Iron-infusion attenuated PASP in both groups at rest (P=0.005), while chelation did not exaggerate PASP in either group at rest or during exaggerated hypoxaemia ( =67mmHg). During exercise at 25% peak wattage, PASP was only consistently elevated in Sherpa, which persisted following both iron infusion or chelation. These findings provide new evidence on the complex interplay of iron regulation on pulmonary vascular regulation during acclimatization and adaptation to high altitude.

Hemodynamic function of the right ventricular-pulmonary vascular-left atrial unit: normal responses to exercise in healthy adults

With each heartbeat, the right ventricle (RV) inputs blood into the pulmonary vascular (PV) compartment, which conducts blood through the lungs at low pressure and concurrently fills the left atrium (LA) for output to the systemic circulation. This overall hemodynamic function of the integrated RV-PV-LA unit is determined by complex interactions between the components that vary over the cardiac cycle but are often assessed in terms of mean pressure and flow. Exercise challenges these hemodynamic interactions as cardiac filling increases, stroke volume augments, and cycle length decreases, with PV pressures ultimately increasing in association with cardiac output. Recent cardiopulmonary exercise hemodynamic studies have enriched the available data from healthy adults, yielded insight into the underlying mechanisms that modify the PV pressure-flow relationship, and better delineated the normal limits of healthy responses to exercise. This review will examine hemodynamic function of the RV-PV-LA unit using the two-element Windkessel model for the pulmonary circulation. It will focus on acute PV and LA responses that accommodate increased RV output during exercise, including PV recruitment and distension and LA reservoir expansion, and the integrated mean pressure-flow response to exercise in healthy adults. Finally, it will consider how these responses may be impacted by age-related remodeling and modified by sex-related cardiopulmonary differences. Studying the determinants and recognizing the normal limits of PV pressure-flow relations during exercise will improve our understanding of cardiopulmonary mechanisms that facilitate or limit exercise.