Pulmonary Arterial Blood Pressure Research Articles

Echocardiographic assessment of cardiovascular involvements in children with cystic fibrosis

BackgroundOver the past four decades, numerous case reports and clinical studies have highlighted the presence of heart disease in individuals with cystic fibrosis. Given the limited information in this field and the imperative to identify early changes during childhood, our study aims to explore cardiac dysfunction in patients with cystic fibrosis using echocardiography. MethodsIn this case-control study, we examined echocardiographic findings from thirty-three patients with cystic fibrosis and sixty healthy children. Demographic information for both groups was recorded, and the disease severity in patients was assessed using the Schawachman criterion. M-mode, Doppler flow velocity, and Tissue Doppler Imaging echocardiography were performed for all participants, with subsequent data analysis using SPSS 24. ResultsOur study encompassed thirty-three CF patients and sixty healthy children. The estimated pulmonary artery blood pressure (systolic and mean) in patients with cystic fibrosis was significantly higher than in the control group (P < 0.05). Additionally, the mean trans-tricuspid peak early to late diastolic flow velocity (E/A) was significantly lower in the case group than the control group (P < 0.05), along with a significantly lower mean tricuspid valve deceleration time (DT) (P < 0.05). Similarly, the mean TAPSE in the case group was notably lower than in the control group (P < 0.05). No significant difference in Mean left ventricular Ejection Fraction (EF) and Fractional Shortening (FS) existed between the two groups (P > 0.05). Furthermore, Trans-mitral peak early to late diastolic flow velocity (E/A) in the case group was significantly lower than in the control group (P < 0.05), and the mean mitral valve DT in the case group was also significantly lower (P < 0.05). ConclusionOur study findings indicate the presence of some degree of right ventricular dysfunction in children with cystic fibrosis. This finding may have implications for the development or modification of clinical guidelines for managing cystic fibrosis in children. Further investigations are recommended to elucidate the underlying mechanisms and contributing factors, providing valuable insights for clinical management.

Proteomic analysis of the serum in dogs with pulmonary hypertension secondary to myxomatous mitral valve disease: the preliminary study.

Pulmonary hypertension (PH) is a common complication in dogs with myxomatous mitral valve disease (MMVD), characterized by elevated blood pressure in pulmonary artery. Echocardiography is a reliable technique for PH diagnosis in veterinary medicine. However, it is limited to use as an early detection method. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has found extensive application in the discovery of serum protein biomarkers for various diseases. The objective of this study was to identify serum proteins in healthy control dogs and MMVD dogs both with and without PH using LC-MS/MS. In this research, a total of 81 small-breed dogs participated, and they were categorized into three groups: the control (n = 28), MMVD (n = 24) and MMVD+PH (n = 29) groups. Serum samples were collected and analyzed by LC-MS/MS. Differentially expressed proteins were identified, and the upregulated and downregulated proteins in MMVD+PH group including Myomesin 1 (MYOM1) and Histone deacetylase 7 (HDAC7), Pleckstrin homology domain containing M3 (PLEKHM3), Diacylglycerol lipase alpha (DAGLA) and Tubulin tyrosine ligase like 6 (TTLL6) were selected as proteins of interest in MMVD dogs with PH. Different types of proteins have been identified in healthy dogs and MMVD dogs with and without PH. Additional studies are needed to investigate the potential of these proteins as biomarkers for PH in dogs with MMVD.

Management of a child with portopulmonal hypertension due to cavernous transformation of the portal vein and sple- norenal anastomosis

A clinical case of the development of portopulmonary hypertension in a child after splenorenal anastomosis is presented. The surgical intervention was performed to correct the congenital malformation — cavernous transformation of the portal vein, which led to portal hypertension and varicose veins of the esophagus and stomach. In the long-term postoperative period, pulmonary arterial hypertension, hypersplenism with bilinear cytopenia, and moderate liver failure developed. Combined therapy provided a temporary improvement of the patient status, therefore, during subsequent surgery, the size of the anastomosis was changed. This led to a sustained decrease in pulmonary artery blood pressure and clinical improvement in the boy’s condition.

Анализ роли нейтрофилов в развитии воспаления в монокроталининдуцированной легочной артериальной гипертензии

Pulmonary arterial hypertension (PAH) is a clinical syndrome with dismal outcome. This disease is associated with endothelial dysfunction or damage, pulmonary vascular remodeling, and increased vascular resistance and pulmonary artery blood pressure. All this provokes right ventricular failure and pulmonary edema, which leads to premature death of patients. PAH is accompanied by the inflammatory process deve­lopment, one of the main causes of which is the increased production of reactive oxygen and chlorine species by stimulated neutrophils. The purpose of our study was to study the role of these cells in the oxidative stress formation in experimental model of PAH. The studies were conducted on outbred white rats. Modeling of PAH was carried out by subcutaneous administration of a monocrotaline solution at a dose of 60 mg/kg. The control group consisted of 10 healthy animals. After monocrotaline injection, PAH animals were divided into 4 groups: 10 rats in the 2-week group, 10 rats in the 4-week group, 14 rats in the 6-week group, and 20 rats in the 8-week group. After collecting peripheral blood and isolating neutrophils, reactive oxygen and chlorine species production, secretory degranulation and the unbound calcium ions concentration in the cytosol were determined using spectral analysis methods. The results were compared with corresponding data obtained for 10 healthy animals. It has been established that the development of PAH in rats over 8 weeks is accompanied by neutrophil priming and oxidative stress formation as a result of “respiratory burst” mechanisms modification. Changes in reactive oxygen and chlorine species production, disruption of Ca2+-dependent intracellular signaling involving cyclooxygenase 1/2 and phosphatidylinositol 3-kinase, and increased secretion of myeloperoxidase from neutrophils were revealed.

Study of the Relationship between Pulmonary Artery Pressure and Heart Valve Vibration Sound Based on Mock Loop.

The vibration of the heart valves' closure is an important component of the heart sound and contains important information about the mechanical activity of a heart. Stenosis of the distal pulmonary artery can lead to pulmonary hypertension (PH). Therefore, in this paper, the relationship between the vibration sound of heart valves and the pulmonary artery blood pressure was investigated to contribute to the noninvasive detection of PH. In this paper, a lumped parameter circuit platform of pulmonary circulation was first set to guide the establishment of a mock loop of circulation. By adjusting the distal vascular resistance of the pulmonary artery, six different pulmonary arterial pressure states were achieved. In the experiment, pulmonary artery blood pressure, right ventricular blood pressure, and the vibration sound of the pulmonary valve and tricuspid valve were measured synchronously. Features of the time domain and frequency domain of two valves' vibration sound were extracted. By conducting a significance analysis of the inter-group features, it was found that the amplitude, energy and frequency features of vibration sounds changed significantly. Finally, the continuously varied pulmonary arterial blood pressure and valves' vibration sound were obtained by continuously adjusting the resistance of the distal pulmonary artery. A backward propagation neural network and deep learning model were used, respectively, to estimate the features of pulmonary arterial blood pressure, pulmonary artery systolic blood pressure, the maximum rising rate of pulmonary artery blood pressure and the maximum falling rate of pulmonary artery blood pressure by the vibration sound of the pulmonary and tricuspid valves. The results showed that the pulmonary artery pressure parameters can be well estimated by valve vibration sounds.

A topological data analysis study on murine pulmonary arterial trees with pulmonary hypertension

Pulmonary hypertension (PH), defined by a mean pulmonary arterial blood pressure above 20 mmHg in the main pulmonary artery, is a cardiovascular disease impacting the pulmonary vasculature. PH is accompanied by chronic vascular remodeling, wherein vessels become stiffer, large vessels dilate, and smaller vessels constrict. Some types of PH, including hypoxia-induced PH (HPH), also lead to microvascular rarefaction. This study analyzes the change in pulmonary arterial morphometry in the presence of HPH using novel methods from topological data analysis (TDA). We employ persistent homology to quantify arterial morphometry for control and HPH mice characterizing normalized arterial trees extracted from micro-computed tomography (micro-CT) images. We normalize generated trees using three pruning algorithms before comparing the topology of control and HPH trees.This proof-of-concept study shows that the pruning method affects the spatial tree statistics and complexity. We find that HPH trees are stiffer than control trees but have more branches and a higher depth. Relative directional complexities are lower in HPH animals in the right, ventral, and posterior directions. For the radius pruned trees, this difference is more significant at lower perfusion pressures enabling analysis of remodeling of larger vessels. At higher pressures, the arterial networks include more distal vessels. Results show that the right, ventral, and posterior relative directional complexities increase in HPH trees, indicating the remodeling of distal vessels in these directions. Strahler order pruning enables us to generate trees of comparable size, and results, at all pressure, show that HPH trees have lower complexity than the control trees.Our analysis is based on data from 6 animals (3 control and 3 HPH mice), and even though our analysis is performed in a small dataset, this study provides a framework and proof-of-concept for analyzing properties of biological trees using tools from Topological Data Analysis (TDA). Findings derived from this study bring us a step closer to extracting relevant information for quantifying remodeling in HPH.

The sine transform is the sine qua non of the pulmonary and systemic pressure relationship.

Assessment of therapeutic interventions in patients with pulmonary arterial hypertension (PAH) suffers from several commonly encountered limitations: (1) patient studies are often too small and short-term to provide definitive conclusions, (2) there is a lack of a universal set of metrics to adequately assess therapy and (3) while clinical treatments focus on management of symptoms, there remain many cases of early loss of life in a seemingly arbitrary distribution. Here we provide a unified approach to assess right and left pressure relationships in PAH and pulmonary hypertension (PH) patients by developing linear models informed by the observation of Suga and Sugawa that pressure generation in the ventricle (right or left) approximately follows a single lobe of a sinusoid. We sought to identify a set of cardiovascular variables that either linearly or via a sine transformation related to systolic pulmonary arterial pressure (PAPs) and systemic systolic blood pressure (SBP). Importantly, both right and left cardiovascular variables are included in each linear model. Using non-invasively obtained cardiovascular magnetic resonance (CMR) image metrics the approach was successfully applied to model PAPs in PAH patients with an r2 of 0.89 (p < 0.05) and SBP with an r2 of 0.74 (p < 0.05). Further, the approach clarified the relationships that exist between PAPs and SBP separately for PAH and PH patients, and these relationships were used to distinguish PAH vs. PH patients with good accuracy (68%, p < 0.05). An important feature of the linear models is that they demonstrate that right and left ventricular conditions interact to generate PAPs and SBP in PAH patients, even in the absence of left-sided disease. The models predicted a theoretical right ventricular pulsatile reserve that in PAH patients was shown to be predictive of the 6 min walk distance (r2 = 0.45, p < 0.05). The linear models indicate a physically plausible mode of interaction between right and left ventricles and provides a means of assessing right and left cardiac status as they relate to PAPs and SBP. The linear models have potential to allow assessment of the detailed physiologic effects of therapy in PAH and PH patients and may thus permit cross-over of knowledge between PH and PAH clinical trials.

Galectin-3 Expression Promotes Pulmonary Hypertension Through Multiple Mechanisms

Pulmonary Hypertension is a progressive vascular disease resulting from the tapering of pulmonary arteries causing high pulmonary arterial blood pressure and ultimately right ventricular failure. A defining characteristic of Pulmonary Hypertension is the excessive remodeling of pulmonary arteries that includes increased proliferation, vascular fibrosis and inflammation. There is no outward cure for Pulmonary Hypertension nor are there interventions that effectively impede or reverse pulmonary arterial remodeling, and pulmonary vascular research over the past several decades has sought to identify novel molecular mechanisms to target for therapeutic benefit. Galectin-3 is a carbohydrate binding lectin that is unique for its chimeric structure, comprised of an N-terminal oligomerization domain and a C-terminal carbohydrate-recognition domain. Galectin-3 is a regulator of modifications in cell behavior that contribute to aberrant pulmonary arterial remodeling including cell proliferation, inflammation, and fibrosis, but its role in Pulmonary Hypertension is poorly understood. In this review, we define Galectin-3 and summarize specific topics regarding the role of Galectin-3 expression in the development of Pulmonary Hypertension by providing evidence which supports the ability of Galectin-3 to influence reactive oxygen species production, NADPH enzyme expression, vascular inflammation and vascular fibrosis, all phenomena which contribute to pulmonary arterial remodeling and the development of Pulmonary Hypertension.

Assessment of Inhaled Treprostinil Palmitil, Inhaled and Intravenous Treprostinil, and Oral Selexipag in a Sugen/Hypoxia Rat Model of Pulmonary Arterial Hypertension.

Treprostinil palmitil (TP), a long-acting inhaled pulmonary vasodilator prodrug of treprostinil (TRE), has beneficial effects in a Sugen5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) that compare favorably to the oral phosphodiesterase 5 inhibitor (PDE5) sildenafil. In this study in male Sprague-Dawley rats, a dry powder formulation of TP (TPIP) was compared with inhaled and intravenous TRE and oral selexipag to evaluate inhibition of hemodynamic and pathologic changes in the lungs and heart induced by Su/Hx challenge. Su (20 mg/kg) was injected subcutaneously followed by 3 weeks of Hx (10% O2/balance N2) and then initiation of test article administration over 5 weeks with room air breathing. Hemodynamics and histopathology were measured at the end of the study. Su/Hx challenge approximately doubled the mean pulmonary arterial blood pressure (mPAP) and the Fulton index, decreased cardiac output (CO), doubled the wall thickness and muscularization of the small (10-50 μm) and medium (51-100 μm) sized pulmonary arteries, and increased the percentage of obliterated pulmonary blood vessels. Even though inhaled TRE (65 μg/kg, 4× daily), intravenous TRE (810 ng/kg/min), and oral selexipag (30 mg/kg, twice daily) provided some beneficial effects against the Su/Hx challenge, the overall benefit was generally greater with TPIP at high dose (117 μg/kg, once daily). These results demonstrate that TPIP compares favorably to inhaled and intravenous TRE and oral selexipag with respect to inhibition of the pathophysiological changes induced by Su/Hx challenge in rats. SIGNIFICANCE STATEMENT: Treprostinil palmitil (TP) is a long-acting pulmonary vasodilator prodrug of treprostinil (TRE) formulated for inhaled administration by dry powder [treprostinil palmitil inhalation powder (TPIP)]. Comparison of the activity of TPIP, inhaled and intravenous TRE, and oral selexipag in a Sugen5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension demonstrated that each of these drugs exert protection against the hemodynamic and histopathological changes induced by the Su/Hx challenge, with the greatest effect on these changes produced by TPIP.

Impact of reductive tricuspid ring annuloplasty on right ventricular size, geometry and strain in an ovine model of functional tricuspid regurgitation.

OBJECTIVESReductive ring annuloplasty of the tricuspid annulus represents the contemporary surgical approach to functional tricuspid regurgitation (FTR). We set out to investigate the influence of moderate reductive tricuspid ring annuloplasty on tricuspid regurgitation and right ventricular (RV) size, geometry and strain in an ovine model of chronic FTR.METHODSEight healthy Dorsett male sheep (62.8 + 2kg) underwent a left thoracotomy for placement and tightening of pulmonary artery band to at least double proximal pulmonary artery blood pressure. After 8 weeks of recovery, animals underwent sternotomy, epicardial echocardiography and sonomicrometry crystal implantation. Six crystals were placed around tricuspid annulus and 13 on RV free wall epicardium along 3 parallels defining 3 wall regions (basal, mid and lower) and 1 on the RV apex. All animals underwent beating heart implantation of 26 mm MC3 annuloplasty ring during a second cardiopulmonary bypass run after baseline data acquisition. Simultaneous haemodynamic, sonomicrometry and echocardiography data were acquired at Baseline and after reductive tricuspid ring annuloplasty.RESULTSImplantation of reductive ring annuloplasty resulted in 47 ± 7% annular area reduction (996 ± 152 mm vs 516 ± 52 mm2, P = 0.0002) and significantly decreased RV end-diastolic volume (185 ± 27 vs 165 ± 30 ml, P = 0.02). Tricuspid ring annuloplasty effectively reduced FTR grade (3.75 ± 0.6 vs 0.3 ± 0.5, P = 0.00004) and had little influence on RV function, cross-sectional area, radius of curvature or free wall regional strains.CONCLUSIONSIn adult sheep with 8 weeks of pulmonary artery banding and FTR, tricuspid annulus reduction of 47% with prosthetic ring annuloplasty effectively abolished FTR while maintaining regional RV function and strain patterns.

The role of serial right heart catheterization in risk stratification and management of pulmonary arterial hypertension

Introduction Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial blood pressure secondary to increased pulmonary vascular resistance. Despite the advances in medical therapy, PAH continues to be a significant cause of morbidity and mortality. Areas covered Invasive hemodynamic assessment by performing a right heart catheterization (RHC) remains the gold standard to confirm the diagnosis and further management of PAH. The RHC also helps to determine the severity of RV dysfunction and can be used to test for pulmonary vasoreactivity. After diagnosis and initiation of therapy, many PAH centers continue to perform RHC at regular intervals to monitor for disease progression and alter management. In this review, we discuss the importance of risk stratification in PAH, the role of RHC in the evaluation and treatment of these patients and compare non-invasive risk assessment tools to that of RHC. Expert opinion RHC is useful for diagnosis of PAH, assessing the risk of mortality and morbidity, directing the escalation and de-escalation of therapy, and monitoring for disease progression. In the current era of improved non-invasive cardiac hemodynamic assessment, the role for routine follow-up serial RHC in patients with PAH needs to be reassessed in future studies. With the availability of non-invasive risk assessment tools such as REVEAL Lite 2, it may be reasonable to reconsider the role of annual or protocoled RHC, and instead, move to an “as needed” and individual basis.

Characterization of the spontaneous right ventricular hypertrophy and evolution to heart failure in Wistar Kyoto rat strain

Heart failure is a pathological condition that remains as a major cause of morbi‐mortality in the world, and several cellular mechanisms involved in the development of heart failure remain unknown. In this study it was characterized a spontaneous experimental model of right ventricular hypertrophy from Wistar Kyoto rat strain and monocrotaline injection as a factor to induce the development of heart failure. Morphological and functional cardiovascular parameters, and atrial natriuretic factor (ANF) in serum were measured to determine criteria to be considered as a model of heart failure. Male WK rats 2 months old were assigned to 3 experimental groups (n=8 each group): control, right ventricular hypertrophy + saline (RVH+S) and right ventricular hypertrophy + monocrotaline (RVH+MCT). RVH was diagnosed through no invasive electrocardiographic record in awake animals, and one dose of monocrotaline (60 mg/Kg, ip) was injected. After 3 weeks, cardiovascular parameters were recorded (systemic and pulmonary systolic arterial blood pressure, heart rate), and arterial blood from aorta was taken and the heart was removed and analyzed. Total heart, right ventricle, left ventricle weights (g), and right ventricle free wall (in mm) were significantly different in the RVH+S (1.3±0.02, 0.40±14.11, 0.58±13, 2.86±0.19) and the RVH+MCT (1.6±0.09, 0.53±17.5, 0.67±18.94, 4±0.32) groups in comparison with the control group (0.99±0.04, 0.22±4.0, 0.55±14.38, 2.13±0.05), P&gt;0.001 for all parameters, except for LV weight in the RVH+S group. The systemic arterial blood pressure analysis demonstrates absence of significant difference between groups, however, right ventricular pressure (RVP in mm Hg) in the RVH+S (42±2.53), and RVH+MCT (78±4.22), was significantly increased in comparison with the control group (22±1.16), P&lt;0.001. ANF levels in serum were higher in the RVH+S and RVH+MCT experimental groups in comparison with the control group (537±11.04, 557±7.7 and 473±10.65 in pg/ml, respectively; P&lt;0.01). The results suggest that a sub‐strain from WK rats develop right ventricular hypertrophy spontaneously and with the administration of monocrotaline, severe right and left ventricular hypertrophy was developed, changes associated to an increase in levels of atrial natriuretic peptide suggesting heart failure, then could be a useful experimental model of heart failure where right ventricular hypertrophy is a central pathologic mechanism.

Nasal and tracheobronchial nitric oxide production and its influence on oxygenation in horses undergoing total intravenous anaesthesia

BackgroundThe present study aimed to investigate the effect of endotracheal intubation on nasal and tracheal endogenous NO concentrations, gas exchange and oxygenation in horses undergoing general anaesthesia. In many species a major part of physiological nitric oxide (NO) production takes place in the nasopharynx. Inhaled NO acts as a pulmonary vasodilator and regulates lung perfusion and endotracheal intubation bypasses the nasopharynx. Six horses were randomly assigned to either the “intubated” (INT) or the “non-intubated” (nINT) treatment group. Horses were premedicated with dexmedetomidine (5 μg/kg IV). Anaesthesia was induced with 2.5 mg/kg ketamine and 0.05 mg/kg diazepam IV, and it was maintained by administration of a triple-drip (100 mg/kg/h guaifenesin, 4 mg/kg/h ketamine, 7 μg/kg/h dexmedetomidine). The horses were spontaneously breathing room air. Heart rate, cardiac output, arterial blood pressure, pulmonary arterial blood pressures and respiratory rate were recorded during a 100-min anaesthesia period. Arterial, venous and mixed venous blood samples were taken every 10 minutes and analysed for partial pressure of oxygen (PO2) and carbon dioxide (PCO2), oxygen saturation and haemoglobin content. Standard oxygenation indices were calculated. Nasal and tracheal endogenous NO concentration was determined by chemiluminescence.ResultsCardiovascular variables, respiratory rate, PO2, PCO2, oxygen saturation, haemoglobin content, CaO2, O2ER, P(a-ET)CO2 and Qs/Qt did not differ significantly between the two treatment groups. The P(A-a)O2 was significantly higher in INT (6.1 ± 0.3 kPa) compared to nINT (4.9 ± 0.1 kPa) (p = 0.045), respectively. The nasal (8.0 ± 6.2 ppb) and tracheal (13.0 ± 6.3 ppb) endogenous NO concentration differed significantly in INT (p = 0.036), but not in nINT (nasal: 16.9 ± 9.0 ppb; tracheal: 18.5 ± 9.5 ppb) (p = 0.215).ConclusionEndotracheal intubation reduces the nasal and tracheal endogenous NO concentration. The influence on pulmonary gas exchange and oxygenation is negligible in horses breathing room air.

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.

Treprostinil palmitil inhibits the hemodynamic and histopathological changes in the pulmonary vasculature and heart in an animal model of pulmonary arterial hypertension

Treprostinil palmitil (TP) is a long-acting inhaled pulmonary vasodilator prodrug of treprostinil (TRE). In this study, TP was delivered by inhalation (treprostinil palmitil inhalation suspension, TPIS) in a rat Sugen 5416 (Su)/hypoxia (Hx) model of pulmonary arterial hypertension (PAH) to evaluate its effects on hemodynamics, pulmonary vascular remodeling, and cardiac performance and histopathology. Male Sprague-Dawley rats received Su (20 mg/kg, s.c), three weeks of Hx (10% O2) and 5 or 10 weeks of normoxia (Nx). TPIS was given during the 5–10 week Nx period after the Su/Hx challenge. Su/Hx increased the mean pulmonary arterial blood pressure (mPAP) and right heart size (Fulton index), reduced cardiac output (CO), stroke volume (SV) and heart rate (HR), and increased the thickness and muscularization of the pulmonary arteries along with obliteration of small pulmonary vessels. In both the 8- and 13-week experiments, TPIS at inhaled doses ranging from 39.6 to 134.1 μg/kg, QD, dose-dependently improved pulmonary vascular hemodynamics, reduced the increase in right heart size, enhanced cardiac performance, and attenuated most of the histological changes induced by the Su/Hx challenge. The PDE5 inhibitor sildenafil, administered at an oral dose of 50 mg/kg, BID for 10 weeks, was not as effective as TPIS. These results in Su/Hx challenged rats demonstrate that inhaled TPIS may have superior effects to oral sildenafil. We speculate that the improvement of the pathobiology in this PAH model induced by TPIS involves effects on pulmonary vascular remodeling due to the local effects of TRE in the lungs.

Fibroblast growth factors: the keepers of endothelial normalcy.

Endothelial cells (ECs) under physiologic and pathologic conditions are capable of substantial plasticity that includes the endothelial-mesenchymal transition (EndMT). Notably, in the hypoxic pulmonary circulation EndMT likely drives increases in the pulmonary arterial blood pressure, leading to pulmonary arterial hypertension (PAH). However, it is unclear whether suppressing EndMT can prevent PAH development or mitigate established disease. In this issue of the JCI, Woo et al. generated mice with EC-specific deletion of FGFR1 and -2 and mice with EC-specific expression of a constitutively active FGFR1 to determine the role of FGF signaling in PAH. Mice with FGFR1/2 deletion in ECs that were exposed to hypoxic conditions developed extensive EndMT and more severe PAH than control mice. Animals with the constitutively active endothelial FGFR were protected from hypoxia-induced EndMT and PAH development. These findings suggest that FGF signaling may promote vascular resilience and prevent hypoxia-induced development of EndMT and PAH.

Targeting JP2: A New Treatment for Pulmonary Hypertension.

Pulmonary hypertension (PH) is a disease with a complex etiology and high mortality rate. Abnormal pulmonary vasoconstriction and pulmonary vascular remodeling lead to an increase in mean pulmonary arterial blood pressure for which, and there is currently no cure. Junctophilin-2 (JP2) is beneficial for the assembly of junctional membrane complexes, the structural basis for excitation-contraction coupling that tethers the plasma membrane to the sarcoplasmic reticulum/endoplasmic reticulum and is involved in maintaining intracellular calcium concentration homeostasis and normal muscle contraction function. Recent studies have shown that JP2 maintains normal contraction and relaxation of vascular smooth muscle. In some experimental studies of drug treatments for PH, JP2 expression was increased, which improved pulmonary vascular remodeling and right ventricular function. Based on JP2 research to date, this paper summarizes the current understanding of JP2 protein structure, function, and related heart diseases and mechanisms and analyzes the feasibility and possible therapeutic strategies for targeting JP2 in PH.

Identification of the molecular mechanisms underlying brisket disease in Holstein heifers via microbiota and metabolome analyses

Brisket disease (BD) is common among Holstein heifers in high-altitude environments, and this disease may result in serious economic loss. At present, no effective treatment is available for brisket disease. In this study, liver and cecum samples were collected from five heifers with BD and five healthy heifers (HH) for analyses of the metabolome and microbiota. The mean pulmonary arterial pressure and systolic blood pressure were significantly higher in BD heifers, whereas the average breathing rate, blood oxygen saturation, and glucose level were significantly lower in BD group than in the HH group. Further, 16S rDNA data showed that the abundance of Firmicutes was significantly lower and that of Bacteroidetes was significantly higher in BD group than in the HH group. At the genus level, the BD group heifers harbored fewer Ruminococcaceae and Lachnospiraceae than the HH group. Several metabolites, including beta-d-fructose, d-ribose, 1,4-beta-d-glucan, sucrose, and glucose-6-phosphate were present at low levels in BD heifers. Moreover, the mean pulmonary arterial pressure was negatively correlated with beta-d-fructose (r = − 0.74; P = 0.013), d-ribose (r = − 0.72; P = 0.018), and acetyl-tyrosine-ethyl-ester (r = − 0.71; P = 0.022). We also found that mean pulmonary arterial pressure was negatively correlated with most of the genera, including those in the families of Lachnospiraceae and Ruminococcaceae. In summary, the decreased levels of metabolites and microbial genera might affect BD by limiting the energy supply. This study may help us better understand the role of the microbiota in BD and provide new insights into the management of feeding to decrease the rate of BD in Holstein dairy cows in the Qinghai-Tibetan plateau.

Pulmonary Artery Pressure and Variations in Arterial Blood Pressure During the Induction Period of General Anesthesia in Elderly Patients.

To determine the correlation of old age, pulmonary artery pressure (PAP) and mean arterial blood pressure (MABP) during anesthetic induction in elderly patients. Prospective cohort study. Central Hospital affiliated to Chongqing Medical University from September 2016 to September 2019. A total of 75 elderly patients with pulmonary hypertension, who underwent surgery under general anesthesia, were inducted. Each 25 patients were allocated into 65-74 years, 75-84 years, and ≥85 years groups. PAP was invasively measured using a right heart floating catheter before induction, while MAP was measured using an invasive radial artery catheter at one minute before and within five minutes after anesthetic induction. PAP and PAMP, both increased with age (p <0.001). MAP at one minute before induction significantly increased with aging, while MAP measured at 1, 3 and 5 minutes after anesthetic induction, exhibited tendencies of significant decrease with aging (p <0.05). The correlation analysis results revealed that mean MAP during anesthesia induction was significantly associated with PASP before induction (r = -0.384 and -0.532 for Kendall and Spearman correlation analyses; both p<0.05). Increased PAP may be involved in the association between with aging and increased risk of hypotension during induction. Key Words: General anesthesia, Hypotension, Pulmonary arterial blood pressure, Old age.

Galectin-3 Promotes ROS, Inflammation, and Vascular Fibrosis in Pulmonary Arterial Hypertension.

Pulmonary Arterial Hypertension (PAH) is a progressive vascular disease arising from the narrowing of pulmonary arteries (PA) resulting in high pulmonary arterial blood pressure and ultimately right ventricular (RV) failure. A defining characteristic of PAH is the excessive remodeling of PA that includes increased proliferation, inflammation, and fibrosis. There is no cure for PAH nor interventions that effectively impede or reverse PA remodeling, and research over the past several decades has sought to identify novel molecular mechanisms of therapeutic benefit. Galectin-3 (Gal-3; Mac-2) is a carbohydrate-binding lectin that is remarkable for its chimeric structure, comprised of an N-terminal oligomerization domain and a C-terminal carbohydrate-recognition domain. Gal-3 is a regulator of changes in cell behavior that contribute to aberrant PA remodeling including cell proliferation, inflammation, and fibrosis, but its role in PAH is poorly understood. Herein, we summarize the recent literature on the role of Gal-3 in the development of PAH and provide experimental evidence supporting the ability of Gal-3 to influence reactive oxygen species (ROS) production, NOX enzyme expression, inflammation, and fibrosis, which contributes to PA remodeling. Finally, we address the clinical significance of Gal-3 as a target in the development of therapeutic agents as a treatment for PAH.