This is the first study to evaluate changes in postpartum pulmonary circulation in a novel pregnant rat model of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH).

Schistosomiasis is the most common parasitic disease associated with pulmonary hypertension. It induces remodelling via complex inflammatory processes, which eventually produce the clinical manifestation of pulmonary hypertension. The pulmonary hypertension shows clinical signs and symptoms that are not distinguishable from other forms of pulmonary arterial hypertension.

Pulmonary hypertension (PH) is common in infants with severe bronchopulmonary dysplasia (BPD) and increases the risk of death. The objectives of this preliminary study were to compare responses of pulmonary circulation parameters to 100% oxygen (O2 ) and inhaled nitric oxide (iNO) in infants with BPD and PH using echocardiography. Responses between fetal growth restriction (FGR) and appropriate for gestational age infants were compared. Ten infants <28 weeks GA at birth were assessed at ≥36 weeks corrected gestation. Baseline echocardiography1 was performed which was repeated (echocardiography2) after 30 minutes of O2 . After a gap of 2-3 hours, iNO was administered for 15 minutes and echocardiography3 was performed, followed by iNO weaning. The gestation and birthweight of the cohort were 25.9 ± 1.6 weeks and 612 ± 175 g. Assessments were performed at 38.7 ± 1.4 weeks corrected gestational age. Baseline time to peak velocity: right ventricular ejection time (TPV/RVETc) increased from 0.24 ± 0.02 to 0.27 ± 0.02 (O2 , p = .01) and 0.31 ± 0.03 (iNO, p < .001), indicating a decrease in pulmonary vascular resistance [PVR]. Baseline tricuspid annular plane systolic excursion (TAPSE) increased from 8.1 ± 0.6 mm to 9.3 ± 0.7 mm (O2 , p = .01) and 10.5 ± 1.1 mm (iNO, p = .0004), indicating improved ventricular systolic performance. Percentage change for all parameters was greater with iNO. Significant correlations between cardiac performance and PVR were noted. FGR infants noted higher baseline PVR (TPV/RVETc, 0.21 ± 0.02 vs. 0.25 ± 0.01, p = .002), lower ventricular performance (TAPSE, 7 ± 1.2 mm vs. 8.6 ± 6 mm, p = .003), and lower percentage change with O2 and iNO. A reactive component of pulmonary circulation provides real-time physiological information, which could rationalize treatment decisions.

Pulmonary vascular resistance (PVR) is traditionally used to describe pulmonary hemodynamic characteristics. However, it does not take into account pulmonary artery compliance (Ca) or pulsatile flow. The product of PVR and Ca is known as RC time. Previous studies assert that the PVR-Ca relationship is fixed and RC time is constant between health and disease states. We hypothesized that RC time was not constant in health and pulmonary vascular disease. Right heart catheterizations performed in Papworth Hospital over a 6 year period were analyzed. Subjects were divided into those with normal pulmonary hemodynamics (NPH group; n = 156) and pulmonary arterial hypertension (PAH group; n = 717). RC time and the right ventricle (RV) oscillatory power fraction were calculated. RC time for the NPH group (0.47 ± 0.13 sec) is significantly lower than the PAH group (0.56 ± 0.16 sec; P < 0.0001). The RV oscillatory power fraction is lower in the NPH group (P < 0.0001). RC time correlates inversely with the RV oscillatory power fraction in each group. We conclude, there is an inverse relationship between PVR and Ca, however, this relationship is not always fixed. Consequently, RC time is significantly lower in health compared to disease with elevated pulmonary artery pressures. PAH leads to a decrease in cardiac efficiency.

Adrenomedullin (AM) is a powerful pulmonary vasodilator with antimitogenic properties. We investigated the role of the AM receptor (AMR) and the calcitonin gene-related peptide type-1 receptor (CGRP1R) in regulating pulmonary vascular AM levels. The AMR antagonist hAM(22-52) (120 nmol/L) significantly elevated AM release compared with controls to 250% after 2 h in isolated rat lungs and to 830% after 4 h in pulmonary artery endothelial cells (PAEC). CGRP1R blockade had no effect. AMR blockade did not influence prepro-AM mRNA levels nor did inhibition of protein synthesis by cycloheximide (0.01 mg/mL) abolish the effect of the AMR antagonist. Radioligand-binding studies with PAEC membranes revealed a decrease by 44% of the AMR density in response to AMR antagonism. Altogether, the pulmonary vascular AMR represents not only a functionally active, but also a clearance receptor; its expression is constitutively stimulated by basal AM. This identifies a novel mechanism for controlling pulmonary AM levels.

In paired experiments, we exercised sheep at a constant rate of 4 mph on a treadmill and measured the hemodynamic effects of alpha receptor blockade (phentolamine 5 mg intravenously), beta receptor blockade (propranolol 1 mg intravenously), and combined alpha and beta receptor blockade. Beta blockade increased pulmonary vascular resistance (PVR) at rest and during steady-state exercise compared with control runs. PVR decreased slightly at rest with alpha blockade, but it was not different during exercise from that of control runs. Combined alpha and beta blockade restored PVR to that of control runs, showing that the vasoconstrictor effect of beta blockade was due to unopposed alpha receptor activation. In all sheep an early rapid decrease in PVR within the first 20 s of the onset of exercise was followed by a smaller, slower change over the next 40 to 240 s. The early decrease in PVR was unaffected by either alpha or beta receptor blockade, suggesting that it was due to recruitment of nonmuscular microvessels. We conclude that alpha and beta receptor activation occurs during exercise but that the net vasoactive effect is neutral. The changes in PVR during normal exercise are a combination of rapid recruitment of microvessels followed by slower vasodilation of resistance vessels.

Hypoxic pulmonary vasoconstriction (HPV) is a beneficial mechanism that diverts blood from hypoxic alveoli to better ventilated areas of the lung, but breathing hypoxic air causes the pulmonary circulation to become hypertensive. Responses to airway hypoxia are associated with depolarization of smooth muscle cells in the pulmonary arteries and reduced activity of K(+) channels. As Kv7 channels have been proposed to play a key role in regulating the smooth muscle membrane potential, we investigated their involvement in the development of HPV and hypoxia-induced pulmonary hypertension. Vascular effects of the selective Kv7 blocker, linopirdine, and Kv7 activator, flupirtine, were investigated in isolated, saline-perfused lungs from rats maintained for 3-5 days in an isobaric hypoxic chamber (FiO2 = 0.1) or room air. Linopirdine increased vascular resistance in lungs from normoxic, but not hypoxic rats. This effect was associated with reduced mRNA expression of the Kv7.4 channel α-subunit in hypoxic arteries, whereas Kv7.1 and Kv7.5 were unaffected. Flupirtine had no effect in normoxic lungs but reduced vascular resistance in hypoxic lungs. Moreover, oral dosing with flupirtine (30 mg/kg/day) prevented short-term in vivo hypoxia from increasing pulmonary vascular resistance and sensitizing the arteries to acute hypoxia. These findings suggest a protective role for Kv7.4 channels in the pulmonary circulation, limiting its reactivity to pressor agents and preventing hypoxia-induced pulmonary hypertension. They also provide further support for the therapeutic potential of Kv7 activators in pulmonary vascular disease.

Scientific theories take centuries to come into existence and they keep on evolving. Uncountable intellectual minds work on these theories; some fail to do anything about it; some add a little after tremendous efforts, and some people give remarkable and unforgettable contribution.As far as credit is concerned, the person who is able to prove the theory by his facts and who clears the maximum doubts by his observations, experimentations, facts and reasoning, gets the credit for that theory, and this should be done with honesty.The theory of pulmonary circulation took more than 2000 years to come into existence as we know it today. With the passage of time different people were given credit. Some say that it was given to Galen; some say it was Michael Servetus; others say that Realdus Columbus was the real discoverer; some gave the credit to Ibn Nafis, and finally people gave the credit to William Harvey. But after the rediscovery of Ibn Nafis' manuscript no.62243 titled Sharah al Tashreeh al Qanoon, or "Commentary on the anatomy of Canon of Avicenna" in 1924 AD in Europe, it became clear that Ibn Nafis had described the pulmonary circulation almost 300 years before Harvey, and the historians like Aldo Mieli, Max Mayrhoff, Edward Coppola etc. clearly state that Ibn Nafis is the real discoverer of the pulmonary circulation and that he should be given the credit for the discovery of the pulmonary circulation.

Lack of an experimental model of portopulmonary hypertension (POPH) has been a major obstacle in understanding of pathophysiological mechanisms underlying the disease.

Objective: To assess right ventricular (RV) function and RV-pulmonary arterial (PA) coupling by three-dimensions echocardiography and investigate the ability of RV-PA coupling to predict adverse clinical outcomes in patients with precapillary pulmonary hypertension (PH). Methods: We retrospectively collected a longitudinal cohort of 203 consecutive precapillary PH patients. RV volume, RV ejection fraction (RVEF), and RV longitudinal strain (RVLS) were quantitatively determined offline by 3D echocardiography. RV-PA coupling parameters including the RVEF/PA systolic pressure (PASP) ratio, pulmonary arterial compliance (PAC), and total pulmonary resistance (TPR) were recorded. Results: Over a median follow-up period of 20.9 months (interquartile range, 0.1-67.4 months), 87 (42.9%) of 203 patients experienced adverse clinical outcomes. With increasing World Health Organization functional class (WHO-FC), significant trends were observed in increasing RV volume, decreasing RVEF, and worsening RVLS. RV arterial coupling (RVAC) and PAC were lower and TPR was higher for WHO-FC III+IV than WHO-FC I or II. The RVEF/PASP ratio showed a significant correlation with RVLS. RVAC had a stronger correlation with the RVEF/PASP ratio than other indices. Multivariate Cox proportional-hazard analysis identified a lower 3D RVEF and worse RVLS as strong predictors of adverse clinical events. RVAC, TPR, and PAC had varying degrees of predictive value, with optimal cutoff values of 0.74, 11.64, and 1.18, respectively. Conclusions: Precapillary-PH with RV-PA uncoupling as expressed by a RVEF/PASP ratio <0.44 was associated with adverse clinical outcomes. PAC decreased and TPR increased with increasing WHO-FC, with TPR showing better independent predictive value.

The aim of the present study was to investigate the effect of nitric oxide inhalation (NOI) on cardiac troponin I (CTnI) levels and mean pulmonary arterial pressure (mPAP) in rabbits with acute massive pulmonary embolism (AMPE). Thirty rabbits were used as animal models for AMPE and received different treatments. A total of 4 h after successful modeling, the control group (CON, n=10) received conventional thrombolysis, whereas the treatment group (TRE, n=10) received conventional thrombolysis plus NOI. The experimental group (EXP, n=10) did not receive any treatments. Myocardial necrosis was pathologically confirmed in all 30 rabbits. In group EXP, the post-AMPE CTnI peak level was 0.42±0.12 µg/l, was achieved in 18.8±4.5 h and remained positive for 38.6±5.2 h (≥0.1 µg/l). These values were lower in group TRE when compared with those in groups CON and EXP (P<0.05). Group TRE exhibited significantly reduced mPAP at 24, 28, 32, and 34 h (P<0.05) when compared with group CON. AMPE-induced cardiac impairment was more severe in group EXP when compared with groups CON and TRE. The present findings indicated that the CTnI peak was significantly correlated with the corresponding mPAP. Furthermore, the results suggested NOI may reduce mPAP and CTnI peak levels, with protective effects against AMPE-induced myocardial damage in rabbits.

The cardiovascular effects of dotarizine in 10-min intravenous infusions were studied in thiopental-anesthetized dogs. The effects of dotarizine 0.024 mg/kg/min almost paralleled those of saline controls; 0.079 mg/kg/min dotarizine significantly raised the stroke index and ejection fraction, and, at a rate of 0.25 mg/kg/min, further effects appeared and were dose-dependent. Dotarizine produced arterial dilation in both systemic and pulmonary circulation: the total peripheral resistance dropped, and femoral artery flow rose; aortic and pulmonary artery mean and diastolic pressures declined, and systolic pressures remained almost stable. A trend of bradycardia and pulmonary artery pressure reduction persisted for 30 min. As compared with the reduced total peripheral resistance, aortic pressure fell only moderately because of rising cardiac output due to a higher ejection fraction and stroke volume. Cardiac preload tended to decline; contractility tended to increase. Cardiac performance remained stable while myocardial oxygen consumption tended to fall, as did the pressure-rate product and the tension time index. Dotarizine exerted direct cardiovascular effects similar to those of the 5-HT2-receptor antagonist ketanserin and, more generally, to calcium channel blockers rather than to alpha-adrenoceptor blockers.

General anesthesia (GA) can cause abnormal lung fluid redistribution. Pulmonary circulation transvascular fluid fluxes (JVA ) are attributed to changes in hydrostatic forces and erythrocyte volume (EV) regulation. Despite the very low hydraulic conductance of pulmonary microvasculature it is possible that GA may affect hydrostatic forces through changes in pulmonary vascular resistance (PVR), and EV through alteration of erythrocyte transmembrane ion fluxes ( ionJVA ). Furosemide (Fur) was also used because of its potential to affect pulmonary hydrostatic forces and ionJVA . A hypothesis was tested that JVA , with or without furosemide treatment, will not change with time during GA. Twenty dogs that underwent castration/ovariectomy were randomly assigned to Fur (n = 10) (4 mg/kg IV) or placebo treated group (Con, n = 10). Baseline arterial (BL) and mixed venous blood were sampled during GA just before treatment with Fur or placebo and then at 15, 30 and 45 min post-treatment. Cardiac output (Q) and pulmonary artery pressure (PAP) were measured. JVA and ionJVA were calculated from changes in plasma protein, hemoglobin, hematocrit, plasma and whole blood ions, and Q. Variables were analyzed using random intercept mixed model (P < 0.05). Data are expressed as means ± SE. Furosemide caused a significant volume depletion as evident from changes in plasma protein and hematocrit (P < 0.001). However; Q, PAP, and JVA were not affected by time or Fur, whereas erythrocyte fluid flux was affected by Fur (P = 0.03). Furosemide also affected erythrocyte transmembrane K+ and Cl-, and transvascular Cl- metabolism (P ≤ 0.05). No other erythrocyte transmembrane or transvascular ion fluxes were affected by time of GA or Fur. Our hypothesis was verified as JVA was not affected by GA or ion metabolism changes due to Fur treatment. Furosemide and 45 min of GA did not cause significant hydrostatic changes based on Q and PAP. Inhibition of Na+/K+/2Cl- cotransport caused by Fur treatment, which can alter EV regulation and JVA , was offset by the Jacobs Stewart cycle. The results of this study indicate that the Jacobs Stewart cycle/erythrocyte Cl- metabolism can also act as a safety factor for the stability of lung fluid redistribution preserving optimal diffusion distance across the blood gas barrier.

In an attempt to achieve post-inhalation self-regulated insulin release, we constructed a microparticle agglomerate of nano-sized liposomal particles, with the agglomeration facilitated by cross-linkages capable of cleavage by glucose. The particles exhibited a small aerodynamic diameter within the human respirable range, but a large geometric diameter that prevents macrophage uptake and clearance. Upon intratracheal instillation of the "glucose-sensitive" microparticle into the lungs of rats, hyperglycemic events triggered an acceleration of the release of insulin achieving normoglycemia shortly after "sensing" the elevated systemic glucose. This work is a demonstration of an inhalable particle with long residence times in the lungs capable of modulating insulin release based on systemic glucose levels.

Pulmonary hypertension (PH), a heterogeneous vascular disease, consists of subtypes with overlapping clinical phenotypes. MicroRNAs, small non-coding RNAs that negatively regulate gene expression, have emerged as regulators of PH pathogenesis. The muscle-specific micro RNA (miR)-204 is known to be depleted in diseased pulmonary artery smooth muscle cells (PASMCs), furthering proliferation and promoting PH. Alterations of circulating plasma miR-204 across the trans-pulmonary vascular bed might provide mechanistic insights into the observed intracellular depletion and may help distinguish PH subtypes. MiR-204 levels were quantified at sequential pulmonary vasculature sites in 91 patients with World Health Organization (WHO) Group I pulmonary arterial hypertension (PAH) (n = 47), Group II PH (n = 22), or no PH (n = 22). Blood from the right atrium/superior vena cava, pulmonary artery, and pulmonary capillary wedge was collected. Peripheral blood mononuclear cells (PBMCs) were isolated (n = 5/group). Excretion of miR-204 by PAH-PASMCs was also quantified in vitro. In Group I patients only, miR-204 concentration increased sequentially along the pulmonary vasculature (log fold-change slope = 0.22 [95% CI = 0.06-0.37], P = 0.008). PBMCs revealed insignificant miR-204 variations among PH groups ( P = 0.12). Cultured PAH-PAMSCs displayed a decrease of intracellular miR-204 ( P = 0.0004), and a converse increase of extracellular miR-204 ( P = 0.0018) versus control. The stepwise elevation of circulating miR-204 across the pulmonary vasculature in Group I, but not Group II, PH indicates differences in muscle-specific pathobiology between subtypes. Considering the known importance of miR-204 in PH, these findings may suggest pathologic excretion of miR-204 in Group I PAH by PASMCs, thereby accounting for decreased intracellular miR-204 concentration.

The current treatment algorithm for chronic thromboembolic pulmonary hypertension (CTEPH) as depicted in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines on the diagnosis and treatment of pulmonary hypertension (PH) includes a multimodal approach of combinations of pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA) and medical therapies to target major vessel pulmonary vascular lesions, and microvasculopathy. Today, BPA of >1700 patients has been reported in the literature from centers in Asia, the US, and also Europe; many more patients have been treated outside literature reports. As BPA becomes part of routine care of patients with CTEPH, benchmarks for safe and effective care delivery become increasingly important. In light of this development, the ESC Working Group on Pulmonary Circulation and Right Ventricular Function has decided to publish a document that helps standardize BPA to meet the need of uniformity in patient selection, procedural planning, technical approach, materials and devices, treatment goals, complications including their management, and patient follow-up, thus complementing the guidelines. Delphi methodology was utilized for statements that were not evidence based. First, an anatomical nomenclature and a description of vascular lesions are provided. Second, treatment goals and definitions of complete BPA are outlined. Third, definitions of complications are presented which may be the basis for a standardized reporting in studies involving BPA. The document is intended to serve as a companion to the official ESC/ERS guidelines.

Bone marrow stromal antigen 2 (BST-2) mediates various facets of cancer progression and metastasis. Here, we show that BST-2 is linked to poor survival in invasive breast cancer patients as its expression positively correlates with disease severity. However, the mechanisms that drive the pro-metastatic functions of BST-2 are not fully understood. Correlation of BST-2 expression and tumor aggressiveness was analyzed in human tissue samples. Migration, invasion, and competitive experimental metastasis assays were used to measure the cellular responses after silencing BST-2 expression. Using a mouse model of breast cancer, we show that BST-2 promotes metastasis independent of the primary tumor. Additional experiments show that suppression of BST-2 renders non-adherent cancer cells non-viable by sensitizing cells to anoikis. Embedment of cancer cells in basement membrane matrix reveals that silencing BTS-2 expression inhibits invadopodia formation, extracellular matrix degradation, and subsequent cell invasion. Competitive experimental pulmonary metastasis shows that silencing BST-2 reduces the numbers of viable circulating tumor cells (CTCs) and decreases the efficiency of lung colonization. Our data define a previously unknown function for BST-2 in the i) formation of invadopodia, ii) degradation of extracellular matrix, and iii) protection of CTCs from hemodynamic stress. We believe that physical (tractional forces) and biochemical (ECM type/composition) cues may control BST-2's role in cell survival and invadopodia formation. Collectively, our findings highlight BST-2 as a key factor that allows cancer cells to invade, survive in circulation, and at the metastatic site.

Adverse events in utero are associated with the occurrence of chronic diseases in adulthood. We previously demonstrated in mice that perinatal hypoxia resulted in altered pulmonary circulation in adulthood, with a decreased endothelium-dependent relaxation of pulmonary arteries, associated with long-term alterations in the nitric oxide (NO)/cyclic GMP pathway. The present study investigated whether inhaled NO (iNO) administered simultaneously to perinatal hypoxia could have potential beneficial effects on the adult pulmonary circulation. Indeed, iNO is the therapy of choice in humans presenting neonatal pulmonary hypertension. Long-term effects of neonatal iNO therapy on adult pulmonary circulation have not yet been investigated. Pregnant mice were placed in hypoxia (13% O2) with simultaneous administration of iNO 5 days before delivery until 5 days after birth. Pups were then raised in normoxia until adulthood. Perinatal iNO administration completely restored acetylcholine-induced relaxation, as well as endothelial nitric oxide synthase protein content, in isolated pulmonary arteries of adult mice born in hypoxia. Right ventricular hypertrophy observed in old mice born in hypoxia compared to controls was also prevented by perinatal iNO treatment. Therefore, simultaneous administration of iNO during perinatal hypoxic exposure seems able to prevent adverse effects of perinatal hypoxia on the adult pulmonary circulation.

While it is well established that the haemodynamic cause of hypoxic pulmonary hypertension is increased pulmonary vascular resistance, the molecular pathogenesis of the increased resistance remains incompletely understood. Macrophage migration inhibitory factor is a pleiotropic cytokine with endogenous tautomerase enzymatic activity as well as both intracellular and extracellular signalling functions. In several diseases, macrophage migration inhibitory factor has pro-inflammatory roles that are dependent upon signalling through the cell surface receptors CD74, CXCR2 and CXCR4. Macrophage migration inhibitory factor expression is increased in animal models of hypoxic pulmonary hypertension and macrophage migration inhibitory factor tautomerase inhibitors, which block some of the functions of macrophage migration inhibitory factor, and have been shown to attenuate hypoxic pulmonary hypertension in mice and monocrotaline-induced pulmonary hypertension in rats. However, because of the multiple pathways through which it acts, the integrated actions of macrophage migration inhibitory factor during the development of hypoxic pulmonary hypertension were unclear. We report here that isolated lungs from adult macrophage migration inhibitory factor knockout (MIF-/- ) mice maintained in normoxic conditions showed greater acute hypoxic vasoconstriction than the lungs of wild type mice (MIF+/+ ). Following exposure to hypoxia for three weeks, isolated lungs from MIF-/- mice had significantly higher pulmonary vascular resistance than those from MIF+/+ mice. The major mechanism underlying the greater increase in pulmonary vascular resistance in the hypoxic MIF-/- mice was reduction of the pulmonary vascular bed due to an impairment of the normal hypoxia-induced expansion of the alveolar capillary network. Taken together, these results demonstrate that macrophage migration inhibitory factor plays a central role in the development of the pulmonary vascular responses to chronic alveolar hypoxia.

Both systemic-pulmonary shunt and arterial duct stent could be the palliation of duct-dependent pulmonary circulation. We aimed to compare the safety and efficacy of the two approaches.