Pulmonary Arterial Wall Research Articles

PULMONARY ARTERY WALL THICKNESS IN CHILDREN WITH FONTAN PHYSIOLOGY – AN OPTICAL COHERENCE TOMOGRAPHY CASE CONTROL STUDY

Fontan failure in patients with preserved ventricular function is not well understood. Loss of pulsatile flow in the pulmonary arteries leads to lack of shear stress, which is believed to result in endothelial dysfunction. This endothelial dysfunction may further promote vascular remodelling. Subsequent increased pulmonary vascular resistance is considered to be a potential contributing mechanism for Fontan failure. We sought to perform an in vivo case control study to evaluate structural changes in the pulmonary arteries of children with a Fontan circulation compared to those with a normal pulmonary circulation. Since May 2016, we have recruited patients undergoing cardiac catheterization at BC Children’s Hospital. The control group comprised of children with normal pulmonary circulation undergoing cardiac catheterization or invasive electrophysiology evaluation. We performed intravascular imaging of the pulmonary arteries using Optical Coherence Tomography (OCT, Abbott). For quantitative OCT image analyses, we identified a series of 10 cross-sectional frames that were each ≥0.5 mm apart along the vessel. Using digital planimetry, we measured lumen diameter (mm), lumen cross-sectional area (CSA, mm2), wall CSA (mm2), vessel CSA (lumen+wall CSA, mm2) and mean wall thickness (mm) for each frame. To standardize wall thickness by vessel size, we calculated wall CSA to vessel CSA ratios. We calculated median values across frames for each case. Between-group differences were assessed by Mann-Whitney U tests; associations by Spearman Rank correlation (Stata v. 14.0; p < 0.05). We quantitatively analysed OCT images of the pulmonary arteries in 10 children with a Fontan circulation (10.8±3.9yrs at OCT, 40% female) and 8 control children (10.5±4.2yrs at OCT, 75% female). Overall, there were no significant differences between groups in terms of wall thickness (overall median 0.11mm, interquartile range 0.10-0.15) or wall/vessel ratio (0.13, IQR 0.11-0.15). There was no association between wall thickness or wall/vessel ratio with age at OCT, age at Fontan completion, or time since Fontan completion. Median pulmonary artery pressure at time of OCT was 11.8mmHg (10.5-14.0), which was not associated with normalized wall thickness. OCT findings suggest that during childhood, pulmonary artery wall dimensions are normal in children with Fontan physiology and reassuring hemodynamic status. Further evaluation of vascular function and correlating structure with function in this population would be worthwhile. Serial evaluation of pulmonary artery structure and correlation with clinical course into adulthood is needed.

A genome-wide association analysis identifies PDE1A|DNAJC10 locus on chromosome 2 associated with idiopathic pulmonary arterial hypertension in a Japanese population

Pulmonary arterial hypertension (PAH) is a lethal disease that often affects the young. Although Bone Morphogenetic Protein Receptor Type 2 gene (BMPR2) mutations are related with idiopathic and heritable PAH, the low penetrance and variable expressivity in PAH suggest the existence of other genetic and/or environmental factors. In this study, we aimed to identify novel genetic factors associated with PAH, irrespective of BMPR2 mutation.We performed genome-wide association study (GWAS) in a Japanese population comprising 44 individuals with idiopathic and heritable PAH, and 2,993 controls.Seven loci identified in the genome-wide study were submitted to the validation study, and a novel susceptibility locus, PDE1A|DNAJC10, was identified that maps to 2q32.1 (rs71427857, P = 7.9 × 10-9, odds ratio in the validation study = 5.18; 95% CI 1.86 – 14.42). We also found the augmentation of PDE1A protein in distal remodeled pulmonary artery walls in idiopathic PAH patients.Given that phosphodiesterase 5 inhibitors are effective for the treatment of idiopathic and heritable PAH, our findings suggest that PDE1A could be a novel therapeutic target of PAH.

Baicalin attenuates chronic hypoxia-induced pulmonary hypertension via adenosine A2A receptor-induced SDF-1/CXCR4/PI3K/AKT signaling

BackgroundBaicalin, an important flavonoid in Scutellaria baicalensis Georgi extracts, exerts a variety of pharmacological effects. In this study, we explored the effects of baicalin on chronic hypoxia-induced pulmonary arterial hypertension (PAH) and investigated the mechanism underlying these effects. Moreover, we examined whether the inflammatory response was mediated by the A2A receptor (A2AR) and stromal cell-derived factor-1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-induced phosphatidyl inositol-3-kinase (PI3K) signaling in vivo.MethodsWe established a hypoxia-induced pulmonary hypertension (HPH) mouse model by subjecting wild-type (WT) and A2AR knockout (A2AR−/−) animals to chronic hypoxia, and we examined the effects of a 4-week treatment with baicalin or the A2AR agonist CGS21680 in these animals. Invasive hemodynamic parameters, the right ventricular hypertrophy index, pulmonary congestion, the pulmonary arterial remodeling index, blood gas parameters, A2AR expression, and the expression of SDF-1/CXCR4/PI3K/protein kinase B (PKB; AKT) signaling components were measured.ResultsCompared with WT mice, A2AR−/− mice exhibited increased right ventricular systolic pressure (RVSP), right ventricle-to-left ventricle plus septum [RV/(LV + S)] ratio, RV weight-to-body weight (RV/BW) ratio, and lung wet weight-to-body weight (Lung/BW) ratio in the absence of an altered mean carotid arterial pressure (mCAP). These changes were accompanied by increases in pulmonary artery wall area and thickness and reductions in arterial oxygen pressure (PaO2) and hydrogen ion concentration (pH). In the HPH model, A2AR−/− mice displayed increased CXCR4, SDF-1, phospho-PI3K, and phospho-AKT expression compared with WT mice. Treating WT and A2AR−/− HPH mice with baicalin or CGS21680 attenuated the hypoxia-induced increases in RVSP, RV/(LV + S) and Lung/BW, as well as pulmonary arterial remodeling. Additionally, baicalin or CGS21680 alone could reverse the hypoxia-induced increases in CXCR4, SDF-1, phospho-PI3K, and phospho-AKT expression. Moreover, baicalin improved the hypoxemia induced by 4 weeks of hypoxia. Finally, we found that A2AR levels in WT lung tissue were enhanced by hypoxia and that baicalin up-regulated A2AR expression in WT hypoxic mice.ConclusionsBaicalin exerts protective effects against clinical HPH, which are partly mediated through enhanced A2AR activity and down-regulated SDF-1/CXCR4-induced PI3K/AKT signaling. Therefore, the A2AR may be a promising target for baicalin in treating HPH.

Pulmonary arterial wall disease in COPD and interstitial lung diseases candidates for lung transplantation

BackgroundPulmonary hypertension (PH) associated with lung disease has the worst prognosis of all types of PH. Pulmonary arterial vasculopathy is an early event in the natural history of chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD). The present study characterized the alterations in the structure and function of the pulmonary arterial (PA) wall of COPD and ILD candidates for lung transplantation (LTx).MethodsA cohort of 73 patients, 63 pre-LTx (30 COPD, 33 ILD), and ten controls underwent simultaneous right heart catheterisation and intravascular ultrasound (IVUS). Total pulmonary resistance (TPR), capacitance (Cp), and the TPR-Cp relationship were assessed. PA stiffness and the relative area of wall thickness were estimated as pulse PA pressure/IVUS pulsatility and as [(external sectional area-intimal area)/external sectional area] × 100, respectively.ResultsTwenty-seven percent of patients had pulmonary arterial wedge pressure > 15 mmHg and were not analyzed. PA stiffness and the area of wall thickness were increased in comparison with controls, even in patients without PH (p < 0.05). ILD patients showed a significant higher PA stiffness, and lower Cp beyond mean PA pressure (mPAP) and lower area of wall thickness than COPD patients (p < 0.05). TPR-Cp relationship was shifted downward left for ILD patients.ConclusionsSignificant increase of PA stiffness and area of wall thickness were present even in patients without PH and can make the diagnosis of pulmonary vasculopathy at a preclinical stage in PH-lung disease candidates for LTx. ILD patients showed the worst PA stiffness and Cp with respect to COPD.

Upregulation of SRF Is Associated With Hypoxic Pulmonary Hypertension by Promoting Viability of Smooth Muscle Cells via Increasing Expression of Bcl-2.

The aim of study was to investigate the involvement of hypoxia-induced upregulation of serum response factor (SRF) and its downstream effector, B cell leukemia-2 (Bcl-2), in hypoxia-induced pulmonary hypertension (PH). Immunohistochemistry analysis and western blot analysis were used to detect the levels of SRF and Bcl-2 in rats exposed to hypoxia. Furthermore, the regulatory relationship between SRF and Bcl-2 was investigated in PASMCs using real-time PCR and western-blot analysis. We found that mPAP (mean pulmonary arterial pressure) and WA (the ratio of vascular wall area to external diameter) were increased after exposure to hypoxia, while LA (the ratio of vascular lumen area to total area) decreased after exposure to hypoxia. The immunohistochemistry analysis displayed a substantial increase in SRF and Bcl-2 in pulmonary arterial walls after 14 days of hypoxia. And the western blotting showed that SRF and Bcl-2 protein levels were much higher after 7 days of hypoxia and then remained at a high level. And then the levels of SRF and Bcl-2 in pulmonary artery smooth muscle cells (PASMCs) exposed to hypoxia were substantially suppressed following introduction of SRF siRNA, and the level of Bcl-2 was remarkably inhibited by Bcl-2 siRNA, while Bcl-2 siRNA had no effect on SRF level. Finally, SRF siRNA, and Bcl-2 siRNA significantly reduced viability of PASMCs exposed to hypoxia, and enhanced apoptosis of PASMCs exposed to hypoxia. These data validated that SRF responded to hypoxia, which subsequently was involved in pulmonary hypertension by abnormally promoting viability of PASMCs via modulating expression of Bcl-2. J. Cell. Biochem. 118: 2731-2738, 2017. © 2017 Wiley Periodicals, Inc.

Histone deacetylase inhibitors promote eNOS expression in vascular smooth muscle cells and suppress hypoxia-induced cell growth.

Hypoxia stimulates excessive growth of vascular smooth muscle cells (VSMCs) contributing to vascular remodelling. Recent studies have shown that histone deacetylase inhibitors (HDIs) suppress VSMC proliferation and activate eNOS expression. However, the effects of HDI on hypoxia‐induced VSMC growth and the role of activated eNOS in VSMCs are unclear. Using an EdU incorporation assay and flow cytometry analysis, we found that the HDIs, butyrate (Bur) and suberoylanilide hydroxamic acid (SAHA) significantly suppressed the proliferation of hypoxic VSMC lines and induced apoptosis. Remarkable induction of cleaved caspase 3, p21 expression and reduction of PCNA expression were also observed. Increased eNOS expression and enhanced NO secretion by hypoxic VSMC lines were detected using Bur or SAHA treatment. Knockdown of eNOS by siRNA transfection or exposure of hypoxic VSMCs to NO scavengers weakened the effects of Bur and SAHA on the growth of hypoxic VSMCs. In animal experiments, administration of Bur to Wistar rats exposed to hypobaric hypoxia for 28 days ameliorated the thickness and collagen deposition in pulmonary artery walls. Although the mean pulmonary arterial pressure (mPAP) was not obviously decreased with Bur in hypoxic rats, right ventricle hypertrophy index (RVHI) was decreased and the oxygen partial pressure of arterial blood was elevated. Furthermore, cell viability was decreased and eNOS and cleaved caspase 3 were induced in HDI‐treated rat pulmonary arterial SMCs. These findings imply that HDIs prevent hypoxia‐induced VSMC growth, in correlation with activated eNOS expression and activity in hypoxic VSMCs.

Capsaicin pretreatment reversed pulmonary arterial hypertension by alleviating inflammation via p38MAPK pathway

ABSTRACTPurpose/Aim: Pulmonary arterial hypertension (PAH) is a lethal disease associated with pulmonary vascular remodeling as well as inflammation. As a kind of tachykinin secreted by nerves and inflammatory cells, substance P (SP) has been proved to be involved in the progression of PAH. Capsaicin can deplete substance P and provide benefits in PAH. However, the mechanism is still unclear. In this article, we aim to illustrate the possible mechanism involved in the process of capsaicin alleviating PAH. Materials and Methods: A single injection of monocrotaline (MCT) to male Sprague–Dawley (SD) rats was conducted to induce PAH. Capsaicin pretreatment was administered three days before MCT injection to deplete substance P. P38mitogen-activated protein kinase (p38MAPK) activator or inhibitor was given intraperitoneally after MCT injection. After 28 days, hemodynamic studies were carried out, and right ventricular systolic pressure (RVSP), right ventricular (RV)/left ventricle plus septum (LV+S), RV/body weight (BW), and lung weight (LW)/BW were recorded and calculated. In addition, the pulmonary vascular remodeling (pulmonary arterial medial wall thickness, area, perivascualr fibrosis), pro-inflammatory cytokines, the common signal pathways, such as peroxisome proliferator-activated receptor gamma (PPARγ), extracellular signal-regulated kinases (Erk), protein kinase B (Akt), and p38MAPK were also detected. Results: Capsaicin pretreatment reversed PAH, including decreasing RVSP, RV/(LV+S), RV/BW, and LW/BW, and alleviating inflammation. Phosphorylated-p38 (p-p38) MAPK was up-regulated, which was partially reversed by capsaicin pretreatment. Interestingly, expression of Akt, Erk, and PPARγ was not altered by capsaicin pretreatment. Inhibition of p38MAPK provided the same benefits with capsaicin pretreatment, whereas it failed to provide additional improvement in the presence of capsaicin. Besides, p38MAPK activator abolished the effects of capsaicin pretreatment on PAH, suggesting a key role of p38MPAK pathway in the effects of capsaicin reversing PAH. Conclusions: Capsaicin pretreatment reversed PAH by alleviating inflammation via p38MAPK pathway.

Lipocalin-2 Promotes Endoplasmic Reticulum Stress and Proliferation by Augmenting Intracellular Iron in Human Pulmonary Arterial Smooth Muscle Cells.

Endoplasmic reticulum (ER) stress, a feature of many conditions associated with pulmonary hypertension (PH), is increasingly recognized as a common response to promote proliferation in the walls of pulmonary arteries. Increased expression of Lipocalin-2 in PH led us to test the hypothesis that Lipocalin-2, a protein known to sequester iron and regulate it intracellularly, might facilitate the ER stress and proliferation in pulmonary arterial smooth muscle cells (PASMCs). In this study, we observed greatly increased Lcn2 expression accompanied with increased ATF6 cleavage in a standard rat model of pulmonary hypertension induced by monocrotaline. In cultured human PASMCs, Lcn2 significantly promoted ER stress (determined by augmented cleavage and nuclear localization of ATF6, up-regulated transcription of GRP78 and NOGO, increased expression of SOD2, and mild augmented mitochondrial membrane potential) and proliferation (assessed by Ki67 staining and BrdU incorporation). Lcn2 promoted ER stress accompanied with augmented intracellular iron levels in human PASMCs. Treatment human PASMCs with FeSO4 induced the similar ER stress and proliferation response and iron chelator (deferoxamine) abrogated the ER stress and proliferation induced by Lcn2 in cultured human PASMCs. In conclusion, Lcn2 significantly promoted human PASMC ER stress and proliferation by augmenting intracellular iron. The up-regulation of Lcn2 probably involved in the pathogenesis and progression of PH.

Metabolic Reprogramming and Redox Signaling in Pulmonary Hypertension.

Pulmonary hypertension is a complex disease of the pulmonary vasculature, which in severe cases terminates in right heart failure. Complex remodeling of pulmonary arteries comprises the central issue of its pathology. This includes extensive proliferation, apoptotic resistance and inflammation. As such, the molecular and cellular features of pulmonary hypertension resemble hallmark characteristics of cancer cell behavior. The vascular remodeling derives from significant metabolic changes in resident cells, which we describe in detail. It affects not only cells of pulmonary artery wall, but also its immediate microenvironment involving cells of immune system (i.e., macrophages). Thus aberrant metabolism constitutes principle component of the cancer-like theory of pulmonary hypertension. The metabolic changes in pulmonary artery cells resemble the cancer associated Warburg effect, involving incomplete glucose oxidation through aerobic glycolysis with depressed mitochondrial catabolism enabling the fueling of anabolic reactions with amino acids, nucleotides and lipids to sustain proliferation. Macrophages also undergo overlapping but distinct metabolic reprogramming inducing specific activation or polarization states that enable their participation in the vascular remodeling process. Such metabolic synergy drives chronic inflammation further contributing to remodeling. Enhanced glycolytic flux together with suppressed mitochondrial bioenergetics promotes the accumulation of reducing equivalents, NAD(P)H. We discuss the enzymes and reactions involved. The reducing equivalents modulate the regulation of proteins using NAD(P)H as the transcriptional co-repressor C-terminal binding protein 1 cofactor and significantly impact redox status (through GSH, NAD(P)H oxidases, etc.), which together act to control the phenotype of the cells of pulmonary arteries. The altered mitochondrial metabolism changes its redox poise, which together with enhanced NAD(P)H oxidase activity and reduced enzymatic antioxidant activity promotes a pro-oxidative cellular status. Herein we discuss all described metabolic changes along with resultant alterations in redox status, which result in excessive proliferation, apoptotic resistance, and inflammation, further leading to pulmonary arterial wall remodeling and thus establishing pulmonary artery hypertension pathology.

Penetrating chest injury involving pulmonary artery: Challenges at emergency department

A case of penetrating chest trauma due to stab injury is described. At presentation to the emergency department (ED), he was hemodynamically unstable and only a small sutured left parasternal wound was noted. Extended focused assessment sonography in trauma revealed pericardial tamponade and left-sided hemothorax. He was shifted to the operating room immediately and rent in the anterior wall of the main pulmonary artery was closed. Timely diagnosis and the management strategy in ED resulted in successful outcome.

Tricuspid Valve Replacement in Infants and Children With Exclusively Autologous Tissue.

Tricuspid valve replacement has always been a challenge in the pediatric population, with high rates of mortality and morbidity. This article describes a new technique that we have used to replace the tricuspid valve with exclusively autologous tissues. The pulmonary autograft is used for tricuspid valve replacement. Pulmonary artery wall and autologous pericardium are utilized for right ventricular out flow tract reconstruction with the creation of a monocusp.

The role of MIF, cyclinD1 and ERK in the development of pulmonary hypertension in broilers

ABSTRACTPulmonary hypertension (PH) is a major disease in the broiler breeding industry. During PH, the pulmonary artery undergoes remodelling, which is caused by pulmonary vascular smooth muscle cell proliferation. CyclinD1 regulates cell proliferation. This study investigated the role of cyclinD1 in the development of PH in broilers, and which bioactivators and signalling pathway are involved in the pathological process. The PH group contained 3–4-week-old broilers with clinical PH, and the healthy group broilers from the same flock without PH. Histopathology indicated pulmonary arterial walls were thicker in the PH group compared with the healthy group. Target gene expressions of macrophage migration inhibitory factor (MIF), extracellular signal-regulated kinase (ERK), and cyclinD1 detected by quantitative real-time PCR were upregulated in the PH group compared with the healthy group. Immunohistochemistry showed MIF, phosphorylated ERK (p-ERK) and cyclinD1 were present on pulmonary vascular walls; MIF was present in the cytoplasm of arterial endothelial cells and smooth muscle cells; p-ERK and cyclinD1 were present in smooth muscle cell cytoplasm. Western blotting demonstrated that MIF, p-ERKand cyclinD1 levels were significantly higher (P < 0.01) in the PH group compared with the healthy group. In summary, increased MIF in PH broiler pulmonary arteries upregulated cyclinD1 via the ERK signalling pathway to induce pulmonary vascular smooth muscle cell proliferation, causing pulmonary artery remodelling and hypertension.

A Paradigm Shift Is Needed in the Field of Pulmonary Arterial Hypertension for Its Entrance Into the Precision Medicine Era.

Pulmonary arterial hypertension (PAH) is a complex disease leading to right ventricular (RV) failure and death, because of a proliferative vascular remodeling that obstructs the lumen of resistance pulmonary arteries (PA). Despite tremendous investments from the scientific community and industry over the past 20 years, the disease remains deadly.1 Currently approved therapies act mainly as vasodilators that cannot reverse the disease or improve survival, while they are offered at a prohibitive cost for many patients.1 Is the field in crisis? Kuhn2 described scientific crisis as a state where there is loss of confidence in the current paradigm while alternative, more attractive theories emerge and social pressures push toward a new outlook and proposed that these conditions promote a paradigm shift. The PAH community is losing confidence in the current paradigm, ie, the use of vasodilators as therapy for PAH, a disease in which vasoconstriction plays only a minor role. Yet, more drugs from the same families (endothelin receptor antagonists, activators of the NO/cGMP axis, or prostacyclin analogues) continue to be developed, tested, and approved. Although these drugs may also affect apoptotic and proliferation mechanisms, their primary mode of action is vasodilation. The proproliferative and antiapoptotic environment within the PA wall can be explained by a myriad of molecular abnormalities discovered in preclinical research, many of which show translational promise as targets for novel therapies.1 But none has been approved, and only a small fraction enters clinical trials.1 Translation to early-phase trials is a challenging stage in drug development, and many bottlenecks have been identified.1 Instead of intensifying efforts to develop novel drugs that target the foundation of PAH’s pathology, the development of vasodilators remains attractive for industry. Although vasoconstriction is not an important factor for most PAH patients, it contributes to a small degree …

Intermittent hypoxia during recovery from neonatal hyperoxic lung injury causes long-term impairment of alveolar development: A new rat model of BPD.

Bronchopulmonary dysplasia (BPD) is a chronic lung injury characterized by impaired alveologenesis that may persist into adulthood. Rat models of BPD using varying degrees of hyperoxia to produce injury either cause early mortality or spontaneously recover following removal of the inciting stimulus, thus limiting clinical relevance. We sought to refine an established rat model induced by exposure to 60% O2 from birth by following hyperoxia with intermittent hypoxia (IH). Rats exposed from birth to air or 60% O2 until day 14 were recovered in air with or without IH (FIO2 = 0.10 for 10 min every 6 h) until day 28 Animals exposed to 60% O2 and recovered in air had no evidence of abnormal lung morphology on day 28 or at 10-12 wk. In contrast, 60% O2-exposed animals recovered in IH had persistently increased mean chord length, more dysmorphic septal crests, and fewer peripheral arteries. Recovery in IH also increased pulmonary vascular resistance, Fulton index, and arterial wall thickness. IH-mediated abnormalities in lung structure (but not pulmonary hypertension) persisted when reexamined at 10-12 wk, accompanied by increased pulmonary vascular reactivity and decreased exercise tolerance. Increased mean chord length secondary to IH was prevented by treatment with a peroxynitrite decomposition catalyst [5,10,15,20-Tetrakis(4-sulfonatophenyl)-21H,23H-porphyrin iron (III) chloride, 30 mg/kg/day, days 14-28], an effect accompanied by fewer inflammatory cells. We conclude that IH during recovery from hyperoxia-induced injury prevents recovery of alveologenesis and leads to changes in lung and pulmonary vascular function lasting into adulthood, thus more closely mimicking contemporary BPD.

The application of autologous pulmonary artery in surgical correction of complicated aortic arch anomaly.

In the patients with longer-segment aortic arch hypoplasia or interruption with ventricular septal defect, surgery with homograft vessel or autologous pericardial patch to augment descending aortic arch will not result in adverse reactions caused by end-to-end anastomosis. In this study, we retrospectively analyzed primary experience of surgical correction of complicated aortic arch anomaly with autologous main pulmonary artery. From July 2010 to March 2016, the twenty-one cases of aortic arch complex anomalies were reconstructed with autologous main pulmonary artery. There were 5 patients with interrupted aortic arch and 16 patients with coarctation of aorta. In patients with interrupted aortic arch, anterior wall of main pulmonary artery was excised to form a conduit whose diameter varied according to the area of patient's body surface. Both ends of the conduit were anastomosed to aortic arch and descending aorta, respectively. In other patients with coarctation of aorta, aortic arch was augmented with tailored pulmonary artery patch in oval shape. The defect of main pulmonary artery was repaired with autologous pericardial patch. There was only one patient died of multiple organ failure postoperatively. The other twenty patients survived without any neurologic complications. Differences of blood pressure between upper and lower limbs were not significant in all cases. During follow-up period, the echocardiography for all patients in the third, sixth, twelfth, and twenty-fourth months showed that blood flow in the descending aortic arch was fluent and there was no obvious blood pressure gradient. Autologous main pulmonary artery can be used to repair complicated aortic arch anomalies completely without any anastomotic tension or bronchial obstruction postoperatively. This procedure is feasible and possesses predominant early and mid-term effects, and autologous main pulmonary artery can retain growth capacity during follow-up period. Of course, it is necessary to draw a definite conclusion of this technique during long-term follow-up period.

Effect of Tongxinluo on pulmonary hypertension and pulmonary vascular remodeling in rats exposed to a low pressure hypoxic environment

Ethnopharmacological relevanceTongxinluo (TXL), which is a Chinese medicine rooted from traditional used herbs, has been used in clinic to treat cardiovascular and cerebrovascular diseases. However, it remains unknown whether TXL alleviates low pressure hypoxic pulmonary hypertension. Aim of the studyHere, we aimed to observe the influence of TXL on pulmonary hypertension in a rat model that exposed to high altitude environment characterized by low pressure hypoxia. Materials and methodsA total of 32 male Sprague-Dawley rats were divided into four groups: control group (normal pressure and normoxia), pulmonary hypertension group (PAH, the parameter is equal to that in altitude 5000m), TXL group (rats living in environment equal to that at altitude of 5000m received TXL treatment), vardenafil group (VDNF, rats living in environment equal to that altitude of 5000m received vardenafil treatment). The high altitude environment was created in chamber by adjusting the inner pressure and oxygen content concomitantly. Before entering the chamber, the TXL group was given TXL (1.2gkg−1d−1) for 28 days, and the VDNF group was given VDNF (0.1gkg−1d−1) for 28 days. After 28 days, the mean pulmonary artery pressure (mPAP) and right ventricular pressure was measured using right heart catheterization. The weight of the right ventricle (RV), left ventricle (LV) and interventricular septum (IVS) was measured, and the right ventricular mass index was calculated. Lung tissue was subjected to hematoxylin and elastic fiber staining, and the medial wall thickness (MT), medial wall cross-sectional area (MA), MT%, and MA% were measured. Proliferative activity within the pulmonary arteries was quantified by Ki67staining. ResultsAfter 28 days, as compared with that in normal control group, animals living in the chamber (PAH group) showed a significant increase in mPAP( 47.5mmHg versus 18mmHg), RV/LV+IVS (0.45 versus 0.21) and MA% (78% versus 44%), respectively. Administration of TXL resulted in a significant decrease of 20mmHg in mPAP, returning of RV/LV+IVS to 0.27, and a 40% reduction in MT% compared with that in PAH group. In the VDNF group, RV/LV+IVS and MT% was 0.268 and 38.77, significantly lower than that in PAH group. While, mPAP increased by 12.5mmHg with treatment by VDNF. In contrast to the PAH group, alpha- Smooth Muscle Actin (α-SMA reduced by 19% in the TXL group (p=0.005) and 16% in the VDNF group (p=0.01). Ki67 expression in the VDNF group was significantly lower than the PAH group (P<0.01). Ki67 expression in the TXL group was significantly lower than the PAH group (P<0.01). Compared with the VDNF group, the indexes above reduced in the TXL group. Our results indicate that TXL significantly reduces pulmonary artery pressure, right ventricular hypertrophy, pulmonary small artery wall thickness, and luminal stenosis. In addition, smooth muscle proliferation markedly decreased and muscular artery decreased. However, TXL was unable to restore parameters to control levels. ConclusionsThe automatic-adjusted low pressure hypoxic chamber was capable of establishing a pulmonary hypertension rat model at an altitude of 5000m. Compared with VDNF, TXL decreased mPAP and right ventricular hypertrophy index (RVHI) in the pulmonary hypertension rat model, and prevented vascular remodeling by reducing small pulmonary artery thickening, smooth muscle thickening and proliferation. Thus, TXL may be a potential treatment for pulmonary hypertension.

Fever, abdominal distension, polyserositis

Objective To provide useful information for the diagnosis and differentiation through exploring the tumor with polyserositis as the initial symptom. Methods There was a case present with fever, poor spirit, abdominal distention and edema in Children′s Hospital of Hebei Province.The characteristics and results of physical examination were summarized and discussed according to the condition evolution phases.The possible etiological factors were analyzed.The treatment was adjusted.Further physical examination was improved.The final diagnosis was tracked. Results After getting admitted to hospital, the patient received CT scan and ultrasound examination for many times.The results suggested the pericardial effusion, pleural effusion, peritoneal effusion and cardiac insufficiency.The child had made a slight improvement through treatment.However, he had hemiparesis.Cerebral infarction was demonstrated through magnetic resonance imaging(MRI), magnetic resonance angiography(MRA), magnetic resonance venography(MRV). Ultrasound showed that there was more pericardial effusion, aortic root solid low echo mass, pulmonary arterial wall stiffness, left and right pulmonary artery blood flow speed increased.Neck and chest enhanced CT showed mediastinal lesions.Pathology examination results suggested myeloid sarcoma after referral to superior hospital. Conclusions When children had an unexplained polyserositis, more comprehensive analysis were needed.The illness condition should be explained with Monism as far as possible.Repeated inspections would be necessary when the pathogenesis was not clear.Careful watch for the tumor should be kept. Key words: Polyserositis; Heart failure; Cerebral infarction; Tumour

Postnatal growth restriction augments oxygen-induced pulmonary hypertension in a neonatal rat model of bronchopulmonary dysplasia

Prematurity and fetal growth restriction are risk factors for pulmonary hypertension (PH) in infants with bronchopulmonary dysplasia (BPD). Neonatal rats develop PH and vascular remodeling when exposed to hyperoxia. We hypothesize that postnatal growth restriction (PNGR) due to under-nutrition increases the severity of PH induced by hyperoxia in neonatal rats. Pups were randomized at birth to litters maintained in room air or 75% oxygen (hyperoxia), together with litters of normal milk intake (10 pups) or PNGR (17 pups). After 14 d, right ventricular hypertrophy (RVH) was assessed by Fulton's index (right ventricular weight/left ventricular plus septal weight) and PH by echocardiography. Lungs were analyzed by immunohistochemistry, morphometrics, western blotting, and metabolomics. Hyperoxia and PNGR each significantly increased pulmonary arterial pressure, RVH and pulmonary arterial medial wall thickness, and significantly decreased pulmonary vessel number. These changes were significantly augmented in pups exposed to both insults. Hyperoxia and PNGR both significantly decreased expression of proteins involved in lung development and vasodilation. PNGR induces right ventricular and pulmonary vascular remodeling and augments the effects of oxygen in neonatal rats. This may be a powerful tool to investigate the mechanisms that induce PH in low-birth-weight preterm infants with BPD.

Cardiopulmonary protective effects of the selective FXR agonist obeticholic acid in the rat model of monocrotaline-induced pulmonary hypertension

Farnesoid X receptor (FXR) activation by obeticholic acid (OCA) has been demonstrated to inhibit inflammation and fibrosis development and even induce fibrosis regression in liver, kidney and intestine in multiple disease models. OCA also inhibits liver fibrosis in nonalcoholic steatohepatitis patients. FXR activation has also been demonstrated to suppress the inflammatory response and to promote lung repair after lung injury.This study investigated the effects of OCA treatment (3, 10 or 30mg/kg, daily for 5days a week, for 7 and/or 28 days) on inflammation, tissue remodeling and fibrosis in the monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) rat model. Treatment with OCA attenuated MCT-induced increased pulmonary arterial wall thickness and right ventricular hypertrophy, by i) blunting pathogenic inflammatory mechanisms (downregulation of interleukin 6, IL-6, and monocyte chemoattractant protein-1, MCP-1) and ii) enhancing protective mechanisms counteracting fibrosis and endothelial/mesenchymal transition. MCT-injected rats also showed a marked decrease of pulmonary artery responsiveness to both endothelium-dependent and independent relaxant stimuli, such as acetylcholine and a nitric oxide donor, sodium nitroprusside. Administration of OCA (30mg/kg) normalized this decreased responsiveness. Accordingly, OCA treatment induced profound beneficial effects on lung histology. In particular, both OCA doses markedly reduced the MCT-induced medial wall thickness increase in small pulmonary arteries. To evaluate the objective functional improvement by OCA treatment of MCT-induced PAH, we performed a treadmill test and measured duration of exercise. MCT significantly reduced, and OCA normalized treadmill endurance. Results with OCA were similar, or even superior, to those obtained with tadalafil, a well-established treatment of PAH.In conclusion, OCA treatment demonstrates cardiopulmonary protective effects, modulating lung vascular remodeling, reducing right ventricular hypertrophy and significantly improving exercise capacity. Thus, OCA can restore the balance between relaxant and contractile pathways in the lung, promoting cardiopulmonary protective actions.

Non-invasive evaluation of pulmonary arterial blood flow and wall shear stress in pulmonary arterial hypertension with 3D phase contrast magnetic resonance imaging.

BackgroundRecently, time-resolved 3D phase contrast magnetic resonance imaging (4D-flow) allows flow dynamics in patients with pulmonary arterial hypertension to be measured. Abnormal flow dynamics, such as vortex blood flow pattern in the pulmonary artery (PA), may reflect progression of pulmonary arterial hypertension (PAH). Some reports suggested that abnormal blood flow parameters including wall shear stress (WSS) could be markers of PAH. However, it was not fully assessed clinical usefulness of these variables. We aimed to assess whether these flow dynamic parameters, such as vortex formation time (VFT) and WSS, were associated with right ventricular (RV) function.ResultsFifteen subjects, nine with PAH and six healthy volunteers, underwent 4D-flow. Differences of Blood flow patterns, blood flow velocities and WSS between PAH patients and healthy volunteers were evaluated. We also assessed the association between VFT, WSS and RV function in PAH patients. Both vortex blood flow patterns and early systolic retrograde flow in the main PA were observed in all patients with PAH. The PA flow velocities and WSS in patients with PAH were lower than those in healthy volunteers, but that blood flow volumes in the MPA, RPA and LPA and SV in the MPA were broadly comparable between the groups. The mean VFT was 35.0 ± 16.6 % of the cardiac cycle. The VFT significantly correlated with RV ejection fraction, RV end systolic volume, and RV end systolic volume index (RVEF = 75.1 + (−85.7)·VFT, p = 0.003, RVESV = 12.4 + 181.8·VFT, p = 0.037 and RVESVI = 10.6 + 114.8·VFT, p = 0.038, respectively) in PAH patients, whereas WSS did not correlate with RV function.ConclusionsWe confirmed that abnormal blood flow dynamics, including the vortex formation and the early onset of retrograde flow, low WSS in the PA were characteristics of PAH. The VFT may be associated with right ventricular dysfunction, whereas WSS was not. Our results suggest that 4D-flow is an effective means of detecting right heart failure as well as diagnosing PAH.Clinical trial registration URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi. Unique identifier: UMIN000011128Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-2755-7) contains supplementary material, which is available to authorized users.