Increase In Pulmonary Arterial Pressure Research Articles

Pulmonary hypertension – general considerations

Pulmonary hypertension (PH) defines an increase in mean pulmonary arterial pressure (PAPm) at a value equal to or greater than 25 mmHg, determined invasively by right cardiac catheterization. The hemodynamic de­fi­ni­tion of PH considers the combination of different he­mo­dy­na­mic parameters: mPAP, pulmonary wedge pressure (PWP), car­diac output (CO), diastolic pressure gradient (DPG) and pul­mo­nary vascular resistance (PVR). The cli­ni­cal cor­res­pon­dence of the haemodynamic definition, con­si­de­ring both the pathological aspect and the therapeutic ap­proach, clas­sifies the clinical conditions that associate PH in five cli­ni­cal groups. Worldwide data on the incidence of pulmonary hypertension are not systematically reported; data on PH prevalence in different aetiologies are not published in detail. PH epi­de­­mio­logy documentation becomes necessary in order to standardize diagnostic and therapeutic management prac­­tices, with particular interest in aligning the dif­feren­ces between different regions of the world, not only geo­gra­phi­cally but also economically. The only data on the survival rate of PH patients in Eastern Europe are published from the Czech Republic registry. The better survival in the throm­bo­em­bo­lic PH subgroup may be positively influenced by the availability of specific pharmacological therapy since 2007. The Portuguese registry reported in 2017 a survival rate at 1, 3 or 5 years of 95%, 77% and 71%, respectively, for new cases with different PH aetiologies, and the absence of statistically significant differences between different ae­tio­logy groups, but with a better prognosis for congenital heart disease related PH cases. For Romania, the National Pul­mo­na­ry Hypertension Register has centralized the data from the six national diagnostic and treatment centres by 2017. The PH pathophysiology is based on pulmonary vascular remodelling by endothelial cell proliferation, smooth muscle cell hypertrophy and perivascular inflammation.

Safflower injection inhibits pulmonary arterial remodeling in a monocrotaline-induced pulmonary arterial hypertension rat model.

Pulmonary arterial hypertension (PAH) is a group of diseases with an increase of pulmonary artery pressure (PAP) and pulmonary vascular resistance. Here, the effects of safflower injection, a preparation of Chinese herbs, was investigated in a monocrotaline (MCT)-induced PAH rat model. PAP, carotid artery pressure (CAP), and the right ventricular hypertrophy index (RVHI) increased in the PAH group, while safflower injection was able to inhibit this increase to similar levels as observed in the normal group. The arteriole wall of the lungs and cardiac muscle were thickened and edema was observed in the PAH group, while these pathologies were improved in the herb-treated group in a dose-dependent manner. MCT treatment induced proliferation of pulmonary artery smooth muscle cells (PASMCs), which was inhibited by safflower injection in a dose-dependent manner. Our experimental results demonstrated that safflower injection can regulate pulmonary arterial remodeling through affecting the expression of connective tissue growth factor, transforming growth factor-β, integrin, collagen or fibronectin, which subsequently affected the thicknesses of the arteriole walls of the lungs and cardiac muscle, and thereby benefits the control of PAH. This means safflower injection improved the abnormalities in PAP, CAP and RVHI, and pulmonary arterial remodeling through regulation of remodeling factors.

Non-invasive pulmonary artery pressure estimation by electrical impedance tomography in a controlled hypoxemia study in healthy subjects

Pulmonary hypertension is a hemodynamic disorder defined by an abnormal elevation of pulmonary artery pressure (PAP). Current options for measuring PAP are limited in clinical practice. The aim of this study was to evaluate if electrical impedance tomography (EIT), a radiation-free and non-invasive monitoring technique, can be used for the continuous, unsupervised and safe monitoring of PAP. In 30 healthy volunteers we induced gradual increases in systolic PAP (SPAP) by exposure to normobaric hypoxemia. At various stages of the protocol, the SPAP of the subjects was estimated by transthoracic echocardiography. In parallel, in the pulmonary vasculature, pulse wave velocity was estimated by EIT and calibrated to pressure units. Within-cohort agreement between both methods on SPAP estimation was assessed through Bland–Altman analysis and at subject level, with Pearson’s correlation coefficient. There was good agreement between the two methods (inter-method difference not significant (P > 0.05), bias ± standard deviation of − 0.1 ± 4.5 mmHg) independently of the degree of PAP, from baseline oxygen saturation levels to profound hypoxemia. At subject level, the median per-subject agreement was 0.7 ± 3.8 mmHg and Pearson’s correlation coefficient 0.87 (P < 0.05). Our results demonstrate the feasibility of accurately assessing changes in SPAP by EIT in healthy volunteers. If confirmed in a patient population, the non-invasive and unsupervised day-to-day monitoring of SPAP could facilitate the clinical management of patients with pulmonary hypertension.

The progression of pulmonary arterial hypertension induced by monocrotaline is characterized by lung nitrosative and oxidative stress, and impaired pulmonary artery reactivity

The time-course of pulmonary arterial hypertension in the monocrotaline (MCT) model was investigated. Male rats were divided into two groups: MCT (received a 60 mg/kg i.p. injection) and control (received saline). The MCT and control groups were further divided into three cohorts, based on the follow-up interval: 1, 2, and 3 weeks. Right ventricle (RV) catheterization was performed and RV hypertrophy (RVH) was estimated. The lungs were used for biochemical, histological, molecular, and immunohistochemical analysis, while pulmonary artery rings were used for vascular reactivity. MCT promoted lung perivascular edema, inflammatory cells exudation, greater neutrophils and lymphocytes profile, and arteriolar wall thickness, compared to CTR group. Increases in pulmonary artery pressure and in RVH were observed in the MCT 2- and 3-week groups. The first week was marked by the presence of nitrosative stress (50% moderate and 33% accentuated staining by nitrotyrosine). These alterations lead to an adaptation of NO production by NO synthase activity after 2 weeks. Oxidative stress was evident in the third week, probably by an imbalance between endothelin-1 receptors, resulting in extracellular matrix remodeling, endothelial dysfunction, and RVH. Also, it was found a reduced pulmonary arterial vasodilatory response to acetylcholine after 2 (55%) and 3 (45%) weeks in MCT groups. The relevance of this study is precisely to show that nitrosative and oxidative stress predominate in distinct time windows of the disease progression.

Contribution of peptidyl prolyl isomerase (Pin1) to development of pulmonary hypertension via pulmonary vascular endothelial cell dysfunction

Abstract Background Endothelial dysfunction is thought to be a major contributor to overall pathogenesis of vasculopathy seen in pulmonary hypertension (PH), which is manifested by the impaired release of nitric oxide (NO) generated through endothelial nitric oxide synthase (eNOS) in endothelial cells. Activation of human eNOS is regulated by phosphorylation at multiple sites including Thr33 and Ser114, which residues are followed by Pro. The peptidyl isomerase Pin1 specifically isomerizes the phospho-protein having Ser/Thr-Pro bond and regulates their activity. Pin1 is involved in proliferation, cell cycle, and apoptosis in cancer, by isomerizing some functional molecules such as JNK, JUN, cyclin D, BAX, etc. However, it is controversial whether direct interaction of Pin1 with eNOS and how eNOS activity is altered by Pin1, especially in PH. Purpose We aimed to clarify whether Pin1 contributes to the PH development using Pin1 knockout mice and Pin1 affects the expression of phosphorylated eNOS (p-eNOS) molecule and pulmonary arterial endothelial cell (PAEC) apoptosis. Methods and results Wild (WT) and Pin1-deficient mice (KO) were exposed to hypoxia (10% O2) or normoxia for 3 weeks to generate hypoxia-induced PH. Hypoxia-inducible factor (HIF1α) expression in lungs was significantly enhanced in WT-hypoxia (WH, n=6) and KO-hypoxia (KH, n=6), suggesting that hypoxic response was certainly occurred in these mice. Pulmonary arterial pressure did not elevate in KH compared with KO-normoxia (KN, n=6) and WT-normoxia (WN, n=6), it was significantly increased only in WH (P&amp;lt;0.01), indicating that KO did not develop PH by hypoxia. The gain of RV weight was parallel to the increase of pulmonary arterial pressure. Western blot showed that p-eNOS expression in lungs was significantly decreased in WH compared to WN, however, the expression was not different between KH and KN. It suggests that Pin1 plays a regulatory role in p-eNOS expression in hypoxic response. In cultured PAECs, the expression of p-eNOS and eNOS was markedly increased by siRNA-mediated Pin1 knockdown. Immunoprecipitation study showed the possibility of Pin1 binding to p-eNOS molecule. Apoptosis evaluated by caspase-3/7 activity by fluorescent assay and cleaved caspase-3 expression by Western blot was significantly increased by Pin1 overexpression in PAECs; however, it was significantly decreased by Pin1 knockdown. Moreover, the exaggeration of apoptosis induced by doxorubicin was markedly increased by Pin1 overexpression compared with control in PAECs; however, it was clearly suppressed by Pin1 knockdown. Conclusion This study suggests that endogenous Pin1 contributes to the development of PH partly via the dysfunction of PAECs, that is, by the interference with p-eNOS expression and by the increase of apoptosis inducibility to external stimuli. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI

Shift in transcriptional landscape of human right ventricle in chronic thromboembolic pulmonary arterial hypertension

Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a sub group of pulmonary hypertension (PH). CTEPH is characterized by the existence of thromboemboli and vascular remodeling in pulmonary vessels. The effect of increase in pulmonary artery pressures causes right ventricle (RV) hypertrophy and dilatation and finally leads to right heart failure and death. Surgical intervention in operable patients makes the CTEPH as an only curable and unique form of ph. Pulmonary endarterectomy (PEA) is the surgical procedure to remove the thromboembolic clots from the pulmonary vasculature, which restores RV function back to normal with significant improvements in cardiovascular magnetic resonance. Purpose The aim of this study is to use transcriptomic profiling to identify signaling pathways, master regulators, and potentially new biomarkers that specifically indicate the effect of PEA on the RV of patients with chronic thromboembolic pulmonary hypertension. Results RNA -sequencing (RNA-seq) was performed on RV biopsies obtained from CTEPH patients at PEA baseline (before PEA surgery) and the results were compared with those from RV biopsies obtained during follow-up evaluation. Bioinformatic analysis of RNA-seq data identified 2799 genes (n=14, −0.585 ≤ Log2 fold change ≥0.585, FDR ≤0.05) differentially regulated between the PEA baseline and follow-up sample groups. The great number of genes (2799) differentially expressed after PEA surgery in CTEPH patients confirms a major shift in the transcriptional landscape of RV in these patients. To further identify potential biomarker candidates from the large pool of 2799 differentially expressed genes (DEGs), extensive bioinformatic analysis of different data sets shortlisted 250 DEGs that were functionally associated with cardiovascular development or disease. The findings of this study reveal prominent transcriptional changes that occur in response to PEA. Gene ontology enrichment and pathway analysis confirmed altered regulation of hypoxia-inducible factor 1 (HIF-1) signaling, advanced glycation end products and their receptors (AGE-RAGE), mitogen-activated protein kinase (MAPK) signaling, hippo signaling, the Janus kinase/ signal transducers and activators of transcription (Jak-STAT) signaling pathway, and proteoglycans after PEA compared with before PEA. Conclusion Comparison of the results of RNA-seq analysis of RV biopsies of CTEPH patients, pre and post PEA, revealed a major shift in the transcriptional landscape of these patients after reducing the pressure overload of the RV by PEA. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): German Research Foundation (DFG)

Beta3-adrenergic stimulation restores endothelial mitochondrial dynamics and prevents pulmonary arterial hypertension

Abstract Background Endothelial dysfunction is one of the most important hallmarks of pulmonary arterial hypertension (PAH). This leads to anomalous production of vasoactive mediators that are responsible for a higher vascular tone and a subsequent increase in pulmonary artery pressure (PAP), and to an increased vascular permeability that favors perivascular inflammation and remodeling, thus worsening the disease. Therefore, preservation of the endothelial barrier could become a relevant therapeutic strategy. Purpose In previous studies, others and we have suggested the pharmacological activation of the β3-adrenergic receptor (AR) as a potential therapeutic strategy for pulmonary hypertension (PH) due to left heart disease. However, its potential use in other forms of PH remain unclear. The aim of the present study was to elucidate whether the β3-AR agonist mirabegron could preserve pulmonary endothelium function and be a potential new therapy in PAH. Methods For this purpose, we have evaluated the effect of mirabegron (2 and 10 mg/kg·day) in different animal models, including the monocrotaline and the hypoxia-induced PAH models in rats and mice, respectively. Additionally, we have used a transgenic mouse model with endothelial overexpression of human β3-AR in a knockout background, and performed in vitro experiments with human pulmonary artery endothelial cells (HPAECs) for mechanistic experiments. Results Our results show a dose dependent effect of mirabegron in reducing mean PAP and Right Ventricular Systolic Pressure in both mice and rats. In addition, the use of transgenic mice has allowed us to determine that pulmonary endothelial cells are key mediators of the beneficial role of β3-AR pathway in ameliorating PAH. Mechanistically, we have shown in vitro that activation of β3-AR with mirabegron protects HPAECs from hypoxia-induced ROS production and mitochondrial fragmentation by restoring mitochondrial fission/fusion dynamics. Conclusions This protective effect of mirabegron would lead to endothelium integrity and preserved pulmonary endothelial function, which are necessary for a correct vasodilation, avoiding increased permeability and remodeling. Altogether, the current study demonstrates a beneficial effect of the β3-AR agonist mirabegron that could open new therapeutic avenues in PAH. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Programa de Atracciόn de Talento, Comunidad de Madrid

Влияние положения Тренделенбурга и пневмоперитонеума на сердечно-сосудистую систему при робот-ассистированной радикальной простатэктомии.

Introduction. Prostate cancer remains one of the most common malignant neoplasms of the genitourinary system. Robot-assisted radical prostatectomy (RARP) is currently considered the most effective option for the treatment of this pathology. Special conditions of this operation, such as long-term stay of the patient in the Trendelenburg position and pneumoperitoneum, affect blood pressure, vascular resistance and inotropic function of the heart. The clinical significance of this effect remains poorly understood. The aim of the study was to systematize new information about hemodynamic disorders in patients with pneumoperitoneum in the Trendelenburg position in RARP. Materials and methods. The search for relevant studies published before may 2019 was conducted in the electronic databases PubMed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, Google Scholar using the keywords: «prostatectomy», «robotic surgery», «robotic assisted», «robotic laparoscopic radical prostatectomy», «pneumoperitoneum», «Trendelenburg position», «hemodynamics», «hemodynamic changes», «cardiac function», «cardiovascular function» without restrictions on the publication language. Forty one studies were identified, of which 15 were selected according to pre-defined inclusion criteria. Results. Most studies revealed an increase in arterial and central venous pressure in patients with pneumoperitoneum in the Trendelenburg position. Changes in stroke volume and cardiac output were multidirectional. There was also an increase in pulmonary artery pressure and filling pressure, a decrease in the aortic diameter and an increase in vascular resistance, a deterioration in central hemodynamic parameters, and increased microcirculation. Eleven studies did not show a negative effect of the Trendelenburg position and pneumoperitoneum on the cardiovascular system. The developed changes were easily controlled during anesthesia, and in the postoperative period, the indicators of the cardiovascular system returned to normal. In 4 studies, the negative impact of these factors was noted: the development of mitral valve dysfunction, a significant prolongation of the QT interval and an increase in blood pressure, and hemodynamic instability. Conclusions. The position of the Trendelenburg and pneumoperitoneum and in RARP are accompanied by hemodynamic disorders, most of which are controlled and reversible. Further studies with a longer follow-up period are needed to determine their clinical safety.

The selective PGI2 receptor agonist selexipag ameliorates Sugen 5416/hypoxia-induced pulmonary arterial hypertension in rats.

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by a progressive increase in pulmonary artery pressure due to an increase in vessel tone and occlusion of vessels. The endogenous vasodilator prostacyclin and its analogs are used as therapeutic agents for PAH. However, their pharmacological effects on occlusive vascular remodeling have not been elucidated yet. Selexipag is a recently approved, orally available and selective prostacyclin receptor agonist with a non-prostanoid structure. In this study, we investigated the pharmacological effects of selexipag on the pathology of chronic severe PAH in Sprague-Dawley and Fischer rat models in which PAH was induced by a combination of injection with the vascular endothelial growth factor receptor antagonist Sugen 5416 and exposure to hypoxia (SuHx). Oral administration of selexipag for three weeks significantly improved right ventricular systolic pressure and right ventricular (RV) hypertrophy in Sprague-Dawley SuHx rats. Selexipag attenuated the proportion of lung vessels with occlusive lesions and the medial wall thickness of lung arteries, corresponding to decreased numbers of Ki-67-positive cells and a reduced expression of collagen type 1 in remodeled vessels. Administration of selexipag to Fischer rats with SuHx-induced PAH reduced RV hypertrophy and mortality caused by RV failure. These effects were probably based on the potent prostacyclin receptor agonistic effect of selexipag on pulmonary vessels. Selexipag has been approved and is used in the clinical treatment of PAH worldwide. It is thought that these beneficial effects of prostacyclin receptor agonists on multiple aspects of PAH pathology contribute to the clinical outcomes in patients with PAH.

Clinical characteristics and therapeutic outcomes of pulmonary arterial hypertension secondary to congenital portosystemic shunts.

The aim of this retrospective study was to investigate the clinical characteristics and therapeutic outcomes of pulmonary arterial hypertension (PAH) secondary to congenital portosystemic shunts (CPSS). Thirty-three pediatric patients diagnosed in our institution with CPSS between 2012 and 2019 were enrolled in this study. The patients were divided into PAH and non-PAH groups. The PAH group included 15 patients who presented with unexplained PAH when CPSS was diagnosed. Two patients with microangiopathic hemolytic anemia died of right heart failure shortly after diagnosis. One patient received a liver transplant at the age of 4.3 years and showed a mild decrease in pulmonary artery pressure (PAP) 4 years after the operation. Seven patients underwent one-stage shunt closure at a median age of 2.8 years (1.4-13 years). Follow-up examinations, from 1.6 to 4.1 years after intervention, showed marked reduction of PAP in one patient and stabilization of PAH in six others. However, in one patient who underwent two-stage shunt closure, a marked increase in PAP was noted after partial ligation of the shunt. The remaining four patients received only pulmonary vasodilator therapy, and one of them died of right heart failure 12 years after the PAH diagnosis. The non-PAH group included 18 patients without evidence of PAH upon CPSS diagnosis. Shunt closure was carried out in eight of these patients, but one patient subsequently developed PAH after the resolution of hepatopulmonary syndrome.Conclusion: CPSS may be a more likely cause of unexplained PAH in pediatric patients than previously thought. Shunt closure or liver transplantation may prevent the progression of PAH, or even improve it for the majority of CPSS patients.

PULMONARY ARTERIAL PULSATILITY INDEX AS A PREDICTOR OF MORTALITY IN PULMONARY ARTERIAL HYPERTENSION

SESSION TITLE: Pulmonary Vascular Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Pulmonary arterial hypertension (PAH) is a condition characterized by an increase in pulmonary artery pressure (PAP) and right ventricular (RV) afterload, leading to RV failure and mortality. Right heart catheterization (RHC) remains the mainstay of diagnosis of pulmonary arterial hypertension and provides important prognostic information. The pulmonary arterial pulsatility index (PAPi), calculated as pulmonary arterial pulse pressure divided by right atrial pressure (RAP), has recently been suggested as a predictor of mortality in PAH. We aimed to determine whether the PAPi at diagnosis is associated with mortality in PAH. METHODS: We conducted a retrospective single-centre cohort study of incident patients ≥ 18 years old diagnosed with PAH by RHC between January 1, 2015 and April 31, 2019. PAPi was calculated as pulmonary arterial pulse pressure (systolic PAP – diastolic PAP) divided by RAP. The primary outcome was all-cause mortality. Cox regression analysis and Kaplan-Meier plots were used to assess the association between PAPi and mortality. RESULTS: There were 98 incident patients identified (mean age 59.6 ± 1.5 at diagnosis, 67% female). Mean PAP was 46 ± 1.2 mmHg, mean RAP was 9.6 ± 0.6 mmHg, and mean pulmonary vascular resistance was 9.1 ± 0.5 Wood Units. Twenty-five (26%) of patients received no initial therapy, 44 (45%) patients received initial oral monotherapy, 25 (26%) received dual oral combination therapy and 4 (4%) received triple therapy. Using the median PAPi value of 5.4, two groups were created. Baseline characteristics across groups (PAPi < 5.4 vs. ≥ 5.4) were primarily female (71% vs. 63%, p = 0.39); mean age 58 ± 2.2 years vs. 61 ± 2.2 years (p=0.31); mean body mass index 31.1 ± 1.4 kg/m2 vs. 28.0 ± 0.9 kg/m2 (p=0.06); and mean initial six minute walk distance 335 ± 20 m vs. 365 ± 20 m (p=0.29). There was no difference in the proportion of patients in New York Heart Association functional class I-II vs. III-IV between groups (p=0.69). Treatment strategy with no PAH therapy, monotherapy, dual therapy and triple therapy did not differ significantly between PAPi < 5.4 and PAPi ≥ 5.4 groups (22% vs. 29%, p=0.49; 51% vs. 38%, p=0.22; 24% vs. 26%, p=0.2; 2% vs. 6%, p = 0.31). There were 21 deaths during the follow-up period. In Cox regression modelling, those with PAPi ≥ 5.4 had a mortality hazard ratio, adjusted for age and sex, of 0.41 (95% CI 0.16-1.08, p=0.07). CONCLUSIONS: In this cohort, baseline PAPi ≥ 5.4 was associated with a trend toward lower all-cause mortality. A Canadian multicentre analysis is planned to help further validate whether PAPi predicts outcomes in a larger PAH population. CLINICAL IMPLICATIONS: PAPi is a useful prognostic variable in left heart failure and could also potentially be useful in PAH. Further studies are needed to compare PAPi with other invasive and non-invasive prognostic variables in PAH. DISCLOSURES: Industry sponsored clinical trial relationship with Johnson and Johnson Please note: $5001 - $20000 Added 06/13/2020 by Doug Helmersen, source=Web Response, value=Grant/Research Support Industry sponsored clinical trial relationship with United Therapeutics Please note: $5001 - $20000 Added 06/13/2020 by Doug Helmersen, source=Web Response, value=Grant/Research Support Industry sponsored clinical trial relationship with Bayer Please note: $20001 - $100000 Added 06/13/2020 by Doug Helmersen, source=Web Response, value=Grant/Research Support industry sponsored clinical trial relationship with Gilead Please note: $5001 - $20000 Added 06/13/2020 by Doug Helmersen, source=Web Response, value=Grant/Research Support Speaker/Speaker's Bureau relationship with Bayer Please note: $1001 - $5000 Added 06/13/2020 by Doug Helmersen, source=Web Response, value=Honoraria Investigator relationship with Bayer Pharmaceuticals Please note: $20001 - $100000 Added 06/11/2020 by Naushad Hirani, source=Web Response, value=Grant/Research Support Advisory Committee Member relationship with Actelion Canada Please note: $1001 - $5000 Added 06/11/2020 by Naushad Hirani, source=Web Response, value=Honoraria No relevant relationships by Jonathan Liu, source=Web Response No relevant relationships by Jordan Sugarman, source=Web Response No relevant relationships by Mitesh Thakrar, source=Web Response No relevant relationships by Rhea Varughese, source=Web Response Speaker/Speaker's Bureau relationship with Actelion Please note: $20001 - $100000 Added 04/04/2020 by Jason Weatherald, source=Web Response, value=Honoraria Consultant relationship with Actelion/Janssen Please note: $5001 - $20000 Added 04/04/2020 by Jason Weatherald, source=Web Response, value=Consulting fee Travel support relationship with Actelion/Janssen Please note: $1001 - $5000 Added 04/04/2020 by Jason Weatherald, source=Web Response, value=Travel Grant/Research relationship with Janssen Please note: $20001 - $100000 Added 04/04/2020 by Jason Weatherald, source=Web Response, value=Grant/Research Speaker/Speaker's Bureau relationship with Bayer Please note: $1001 - $5000 Added 04/04/2020 by Jason Weatherald, source=Web Response, value=Honoraria

Treatment of Swine Closed Head Injury with Perfluorocarbon NVX-428.

Pre-hospital treatment of traumatic brain injury (TBI) with co-existing polytrauma is complicated by requirements for intravenous fluid volume vs. hypotensive resuscitation. A low volume, small particle-size-oxygen-carrier perfluorocarbon emulsion NVX-428 (dodecafluoropentane emulsion; 2% w/v) could improve brain tissue with minimal additional fluid volume. This study examined whether the oxygen-carrier NVX-428 shows safety and efficacy for pre-hospital treatment of TBI. Anesthetized swine underwent fluid percussion injury TBI and received 1 mL/kg IV NVX-428 (TBI-NVX) at 15 min (T15) or normal saline (no-treatment) (TBI-NON). Similarly, uninjured swine received NVX-428 (SHAM-NVX) or normal saline (SHAM-NON). Animals were monitored and measurements were taken for physiological and neurological parameters before euthanasia at the six-hour mark (T360). Histopathological analysis was performed on paraffin embedded tissues. Physiological, biochemical and blood gas parameters were not different, with the exception of a significant but transient increase in mean pulmonary artery pressure observed in the TBI-experimental group immediately after drug administration. There were no initial differences in brain oxygenation at baseline, but over time oxygen decreased ~50% in both TBI groups. Histological brain injury scores were similar between TBI-NVX and TBI-NON, although a number of subcategories (spongiosis-ischemic/dead neurons-hemorrhage-edema) in TBI-NVX had a tendency for lower scores. The cerebellum showed significantly lower spongiosis and ischemic/dead neuron injury scores and a lower number of Fluoro-Jade-B-positive cerebellar-Purkinje-cells after NVX-428 treatment compared to controls. NVX-428 may assist in mitigating secondary cellular brain damage.

MR 4D flow-based mean pulmonary arterial pressure tracking in pulmonary hypertension

ObjectivesLongitudinal hemodynamic follow-up is important in the management of pulmonary hypertension (PH). This study aimed to evaluate the potential of MR 4-dimensional (4D) flow imaging to predict changes in the mean pulmonary arterial pressure (mPAP) during serial investigations.MethodsForty-four adult patients with PH or at risk of developing PH repeatedly underwent routine right heart catheterization (RHC) and near-term MR 4D flow imaging of the main pulmonary artery. The duration of vortical blood flow along the main pulmonary artery was evaluated from MR 4D velocity fields using prototype software and converted to an MR 4D flow imaging-based mPAP estimate (mPAPMR) by a previously established model. The relationship of differences between RHC-derived baseline and follow-up mPAP values (ΔmPAP) to corresponding differences in mPAPMR (ΔmPAPMR) was analyzed by means of regression and Bland-Altman analysis; the diagnostic performance of ΔmPAPMR in predicting mPAP increases or decreases was investigated by ROC analysis.ResultsAreas under the curve for the prediction of mPAP increases and decreases were 0.92 and 0.93, respectively. With the natural cutoff ΔmPAPMR = 0 mmHg, mPAP increases (decreases) were predicted with an accuracy, sensitivity, and specificity of 91% (91%), 85% (89%), and 94% (92%), respectively. For patients in whom 4D flow allowed a point estimate of mPAP (mPAP > 16 mmHg), ΔmPAPMR correlated strongly with ΔmPAP (r = 0.91) and estimated ΔmPAP bias-free with a standard deviation of 5.1 mmHg.ConclusionsMR 4D flow imaging allows accurate non-invasive prediction and quantification of mPAP changes in adult patients with PH or at risk of developing PH.Trial registrationClinicalTrials.gov identifier: NCT00575692 and NCT01725763Key Points• MR 4D flow imaging allows accurate non-invasive prediction of mean pulmonary arterial pressure increases and decreases in adult patients with or at risk of developing pulmonary hypertension.• In adult patients with mean pulmonary arterial pressure > 16 mmHg, MR 4D flow imaging allows estimation of longitudinal mean pulmonary arterial pressure changes without bias with a standard deviation of 5.1 mmHg.

Pulmonary hypertension or cardiology aerobatics

Pulmonary hypertension (PH) is a group of diseases with a hemodynamic pattern of progressive increase in pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP), which leads to right ventricular dysfunction and the development of right ventricular heart failure.

Qualidade de vida e variáveis cardiopulmonares em pacientes com hipertensão arterial pulmonar na cidade de Uruguaiana (RS)

A Hipertensão Pulmonar (HP) é definida como aumento na pressão arterial pulmonar média (PAPm) ≥ 25mmHg no repouso, resistência vascular pulmonar (RVP) superior a 4 Unidades Wood, ou quando o gradiente transpulmonar é superior a 10-12 mmHg. Ocasionando a dispneia, fadiga, descondicionamento físico e fraqueza muscular levando a piora da qualidade de vida. Dessa forma, o objetivo do estudo foi avaliar a qualidade de vida e as variáveis cardiopulmonares em pacientes com HP. Trata-se de uma série de casos de pacientes avaliados na Santa Casa de Caridade de Uruguaiana (RS) no período entre abril à junho de 2018. Após a consulta médica, foi aplicado o questionário de qualidade de vida Short Form 36 (SF-36). A seguir, foi conduzida à avaliação da força muscular respiratória (FMR). Após descanso de 30 minutos, os pacientes realizaram o teste de caminhada de 6 minutos (TC6). Foram incluídas duas pacientes no estudo, idade média de 39,5±2,12 anos, classe funcional I segundo a NYHA modificada para HP, as quais apresentaram valores dentro dos padrões de normalidade nos aspectos físicos e aspectos emocionais de acordo com o questionário SF-36 e em relação as variáveis cardiopulmonares (representadas pela FMR e pela TC6). Dessa forma, os domínios aspectos físicos e aspectos emocionais e as variáveis cardiopulmonares estavam dentro dos padrões de normalidade, uma vez que os casos destas pacientes encontravam-se em estágio inicial da doença.

The soluble guanylate cyclase stimulator riociguat is the first-line therapy for chronic thromboembolic pulmonary hypertension patients

Chronic thromboembolic pulmonary hypertension (CTEPH) is a precapillary type of pulmonary hypertension with chronic obstruction of large and medium branches of pulmonary arteries along with secondary alterations in pulmonary microcirculation, which cause progressive increases in pulmonary vascular resistance and pulmonary arterial pressure and ensuing severe right heart dysfunction and heart failure. Pulmonary thromboendarterectomy (PTE) is the treatment of choice for CTEPH; however, this procedure is available not for all patients. Although the surgery performed in the conditions of centers with advanced experience generally shows good results, up to 40% of patients are technically inoperable or PTE is associated with a high risk of complications. At present, riociguat, the only officially approved drug from the class of soluble guanylate cyclase stimulators, is considered as a first-line treatment for inoperable and residual forms of STEPH. Introduction of riociguat to clinical practice can be called a real breakthrough in the treatment of patients with STEPH who cannot undergo PTE or those with relapse or persistent STEPH after the surgery.

Hypoxia-induced pulmonary hypertension-Utilizing experiments of nature.

An increase in pulmonary artery pressure is a common observation in adult mammals exposed to global alveolar hypoxia. It is considered a maladaptive response that places an increased workload on the right ventricle. The mechanisms initiating and maintaining the elevated pressure are of considerable interest in understanding pulmonary vascular homeostasis. There is an expectation that identifying the key molecules in the integrated vascular response to hypoxia will inform potential drug targets. One strategy is to take advantage of experiments of nature, specifically, to understand the genetic basis for the inter-individual variation in the pulmonary vascular response to acute and chronic hypoxia. To date, detailed phenotyping of highlanders has focused on haematocrit and oxygen saturation rather than cardiovascular phenotypes. This review explores what we can learn from those studies with respect to the pulmonary circulation. LINKED ARTICLES: This article is part of a themed issue on Risk factors, comorbidities, and comedications in cardioprotection. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.1/issuetoc.

Effects of β‐adrenoceptor activation on haemodynamics during hypoxic stress in rats

What is the central question of this study? The acute hypoxic compensatory reaction is based on haemodynamic changes, and β-adrenoceptors are involved in haemodynamic regulation. What is the role of β-adrenoceptors in haemodynamics during hypoxic exposure? What is the main finding and its importance? Activation of β2 -adrenoceptors attenuates the increase in pulmonary artery pressure during hypoxic exposure. This compensatory reaction activated by β2 -adrenoceptors during hypoxic stress is very important to maintain the activities of normal life. The acute hypoxic compensatory reaction is accompanied by haemodynamic changes. We monitored the haemodynamic changes in rats undergoing acute hypoxic stress and applied antagonists of β-adrenoceptor (β-ARs) subtypes to reveal the regulatory role of β-ARs on haemodynamics. Sprague-Dawley rats were randomly divided into control, atenolol (β1 -AR antagonist), ICI118,551 (β2 -AR antagonist) and propranolol (non-selective β-AR antagonist) groups. Rats were continuously recorded for changes in haemodynamic indexes for 10min after administration. Then, a hypoxic ventilation experiment [15% O2 , 2200 m a.sl., 582 mmHg (0.765 Pa), 87.3 mmHg; Xining, China] was conducted, and the indexes were monitored for 5min after induction of hypoxia. Plasma catecholamine concentrations were also measured. We found that, during normoxia, the mean arterial pressure, heart rate, ascending aortic blood flow and pulmonary artery pressure were reduced in the propranolol and atenolol groups. Catecholamine concentrations were increased significantly in the atenolol group compared with the control group. During hypoxia, mean arterial pressure and total peripheral resistance were decreased in the control, propranolol and ICI118,551 groups. Pulmonary arterial pressure and pulmonary vascular resistance were increased in the propranolol and ICI118,551 groups. During hypoxia, catecholamine concentrations were increased significantly in the control group, but decreased in β-AR antagonist groups. In conclusion, the β2 -AR is involved in regulation of pulmonary haemodynamics in the acute hypoxic compensatory reaction, and the activation of β2 -ARs attenuates the increase in pulmonary arterial pressure during hypoxic stress. This compensatory reaction activated by β2 -ARs during hypoxic stress is very important to maintain activities of normal life.

Sleep-related breathing disorders and pulmonary hypertension.

Sleep-related breathing disorders (SBDs) include obstructive apnoea, central apnoea and sleep-related hypoventilation. These nocturnal events have the potential to increase pulmonary arterial pressure (PAP) during sleep but also in the waking state. "Pure" obstructive sleep apnoea syndrome (OSAS) is responsible for a small increase in PAP whose clinical impact has not been demonstrated. By contrast, in obesity hypoventilation syndrome (OHS) or overlap syndrome (the association of chronic obstructive pulmonary disease (COPD) with obstructive sleep apnoea (OSA)), nocturnal respiratory events contribute to the development of pulmonary hypertension (PH), which is often severe. In the latter circumstances, treatment of SBDs is essential in order to improve pulmonary haemodynamics.Patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) are at risk of developing SBDs. Obstructive and central apnoea, as well as a worsening of ventilation-perfusion mismatch, can be observed during sleep. There should be a strong suspicion of SBDs in such a patient population; however, the precise indications for sleep studies and the type of recording remain to be specified. The diagnosis of OSAS in patients with PAH or CTEPH should encourage treatment with continuous positive airway pressure (CPAP). The presence of isolated nocturnal hypoxaemia should also prompt the initiation of long-term oxygen therapy. These treatments are likely to avoid worsening of PH; however, it is prudent not to treat central apnoea and Cheyne-Stokes respiration (CSR) with adaptive servo-ventilation in patients with chronic right-heart failure because of a potential risk of serious adverse effects from such treatment.In this review we will consider the current knowledge of the consequences of SBDs on pulmonary haemodynamics in patients with and without chronic respiratory disease (group 3 of the clinical classification of PH) and the effect of treatments of respiratory events during sleep on PH. The prevalence and consequences of SBDs in PAH and CTEPH (groups 1 and 4 of the clinical classification of PH, respectively), as well as therapeutic options, will also be discussed.

Impaired pulmonary gas exchange efficiency, but normal pulmonary artery pressure increases, with hypoxia in men and women with a patent foramen ovale.

What is the central question of this study? Do individuals with a patent foramen ovale (PFO+ ) have a larger alveolar-to-arterial difference in ( ) than those without (PFO- ) and/or an exaggerated increase in pulmonary artery systolic pressure (PASP) in response to hypoxia? What is the main finding and its importance? PFO+ had a greater while breathing air, 16% and 14% O2 , but not 12% or 10% O2 . PASP increased equally in hypoxia between PFO+ and PFO- . These data suggest that PFO+ may not have an exaggerated acute increase in PASP in response to hypoxia. Patent foramen ovale (PFO) is present in 30-40% of the population and is a potential source of right-to-left shunt. Accordingly, those with a PFO (PFO+ ) may have a larger alveolar-to-arterial difference in ( ) than those without (PFO- ) in normoxia and with mild hypoxia. Likewise, PFO is associated with high-altitude pulmonary oedema, a condition known to have an exaggerated pulmonary pressure response to hypoxia. Thus, PFO+ may also have exaggerated pulmonary pressure increases in response to hypoxia. Therefore, the purposes of the present study were to systematically determine whether or not: (1) the was greater in PFO+ than in PFO- in normoxia and mild to severe hypoxia and (2) the increase in pulmonary artery systolic pressure (PASP) in response to hypoxia was greater in PFO+ than in PFO- . We measured arterial blood gases and PASP via ultrasound in healthy PFO+ (n=15) and PFO- (n=15) humans breathing air and 30min after breathing four levels of hypoxia (16%, 14%, 12%, 10% O2 , randomized and balanced order) at rest. The was significantly greater in PFO+ compared to PFO- while breathing air (2.1±0.7vs. 0.4±0.3Torr), 16% O2 (1.8±1.2vs. 0.7±0.8Torr) and 14% O2 (2.3±1.2vs. 0.7±0.6Torr), but not 12% or 10% O2 . We found no effect of PFO on PASP at any level of hypoxia. We conclude that PFO influences pulmonary gas exchange efficiency with mild hypoxia, but not the acute increase in PASP in response to hypoxia.