Distal Pulmonary Artery Research Articles

Abstract MP155: Oxidized Lipids Diet Causes Pulmonary Hypertension Through T-cell Dependent Endothelial Cell Apoptosis

Background: Pulmonary hypertension (PH) is a fatal disease characterized by an increased mean pulmonary arterial pressure above 25mmHg. This increased pressure is, at least in part, due to thickening of the distal pulmonary arteries. Recently, numerous studies demonstrated an increased plasma concentration of oxidized lipids in PH and in diseases where secondary PH developed. Furthermore, 15-hydroxyeicosatetraenoic acid (15-HETE) an oxidized lipid and a major metabolite of arachidonic acid in the lung, has been implicated in dysregulation of major biological pathways in PH. However, the mechanisms involved in the causal role of 15-HETE in pulmonary hypertension development are not known. Methods and Results: To study the role of 15-HETE in PH development, we fed C57BL6/J mice a diet supplemented with 15-HETE for 3 weeks with no other insults. After 3 weeks on the diet with added 15-HETE, C57BL6/J mice had increased concentrations of not only 15-HETE but also of other oxidized lipids (5-, 11- and 12-HETE) in plasma and lung, and they developed PH. RNA-seq analysis revealed the activation of pathways involved in antigen processing and presentation, and with evidence of T cell mediated cytotoxicity in lungs of mice fed 15-HETE. Transcriptomic profiling of lung tissues obtained from patients with pulmonary arterial hypertension (PAH) demonstrated activation of pathways similar to those seen mice. In mice fed a 15-HETE diet, there was an increase in the number of CD8/CD69 double positive cells, as well as an increase in pulmonary arterial endothelial cell (PAEC) apoptosis. Furthermore, PAEC exposed to 15-HETE were more prone to apoptosis when exposed to CD8 cells. Adding Tg6F, an apoA-I mimetic peptide to the 15-HETE diet prevented and rescued PH in C57BL6/J mice, in part, by inhibiting PAEC apoptosis. Conclusions: 15-HETE diet induced PH in C57Bl6/J mice by triggering PAEC death in a T-cell dependent mechanism. The apoA-I mimetic peptide Tg6F was able to prevent and rescue PH induced by 15-HETE.

Can sonographic assessment of pulmonary vascular reactivity following maternal hyperoxygenation predict neonatal pulmonary hypertension? (HOTPOT study protocol)

BackgroundPersistent pulmonary hypertension of the newborn (PPHN) is a condition that occurs in 0.5–7 per 1000 live births and can result in significant cardiovascular instability in the newborn. It occurs when there is a failure of the normal circulatory transition in the early newborn period. Recent studies have shown that fetal pulmonary vasculature reacts to maternal hyperoxygenation (MH). The aim of the study is to assess if the in-utero response to MH can predict pulmonary hypertension in the early newborn period. MethodsWe will perform a prospective cohort study. It will evaluate the use of fetal echocardiographic Doppler assessment of the pulmonary vasculature prior to and following MH to predict fetuses that may develop pulmonary hypertension in the neonatal period. The study will be undertaken in the Rotunda Hospital, Dublin, Ireland. A fetal ultrasound and echocardiography will be performed on fetuses in the third trimester. Blood flow velocity waveforms will be recorded during periods of fetal quiescence. Pulsatility index (PI), Resistance index (RI), Peak systolic (PSV) and end diastolic velocity (EDV), time-averaged velocity (TAV), acceleration time (AT), and ejection time (ET) will be measured within the fetal distal pulmonary artery (PA). The acceleration-to-ejection time ratio (AT: ET) will be used to assess pulmonary vascular resistance (PVR). Doppler measurements will be taken at baseline and repeated immediately following MH for 10 min (O2 100% v/v inhalational gas) at a rate of 12L/min via a partial non-rebreather mask. Doppler waveform measurements from the umbilical artery (UAD), middle cerebral artery (MCA) ductus arteriosus (DA), aortic isthmus (AoI) and ductus venosus (DV) will also be obtained. After birth, a comprehensive neonatal functional echocardiogram will be performed within the first 24 hours of life. DiscussionThis study proposes to validate methods described to date in investigating the fetal pulmonary vascular response to MH, with expansion of the study subjects to include fetuses at risk of PPHN. Evaluation of the different at-risk subgroups will be informative in relation to the fetal circulatory adaptation close to term. Prediction of neonatal pulmonary hypertension may help guide the pharmacological and neonatal ICU strategies that optimise postnatal survival.

Extracellular vesicles influence the pulmonary arterial extracellular matrix in congenital diaphragmatic hernia.

Abnormal pulmonary vasculature directly affects the development and progression of congenital diaphragmatic hernia (CDH)-associated pulmonary hypertension (PH). Though overarching structural and cellular changes in CDH-affected pulmonary arteries have been documented, the precise role of the extracellular matrix (ECM) in the pulmonary artery (PA) pathophysiology remains undefined. Here, we quantify the structural, compositional, and mechanical CDH-induced changes in the main and distal PA ECM and investigate the efficacy of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) as a therapy to ameliorate pathological vascular ECM changes. Pregnant Sprague-Dawley rodents were administered nitrofen to induce CDH-affected pulmonary vasculature in the offspring. A portion of CDH-affected pups was treated with intravenous infusion of MSC-EVs (1 × 1010 /mL) upon birth. A suite of histological, mechanical, and transmission electron microscopic analyses were utilized to characterize the PA ECM. The CDH model main PA presented significantly altered characteristics-including greater vessel thickness, greater lysyl oxidase (LOX) expression, and a relatively lower ultimate tensile strength of 13.6 MPa compared to control tissue (25.1 MPa), suggesting that CDH incurs ECM structural disorganization. MSC-EV treatment demonstrated the potential to reverse CDH-related changes, particularly through rapid inhibition of ECM remodeling enzymes (LOX and MMP-9). Additionally, MSC-EV treatment bolstered structural aspects of the PA ECM and mitigated pathological disorganization as exhibited by increased medial wall thickness and stiffness that, while not significantly altered, trends away from CDH-affected tissue. These data demonstrate notable ECM remodeling in the CDH pulmonary vasculature, along with the capacity of MSC-EVs to attenuate pathological ECM remodeling, identifying MSC-EVs as a potentially efficacious therapeutic for CDH-associated pulmonary hypertension.

Pulmonary vessel casting in a rat model of monocrotaline-mediated pulmonary hypertension.

Pulmonary hypertension is a chronic vascular disease characterized by pulmonary vasoconstriction and pulmonary arterial remodeling. Pulmonary arterial remodeling is mainly due to small pulmonary arterial wall thickening and lumen occlusion. Previous studies have described intravascular changes in lung sections using histopathology, but few were able to obtain a fine detailed image of the pulmonary vascular system. In this study, we used Microfil compounds to cast the pulmonary arteries in a rat model of monocrotaline-induced pulmonary hypertension. High-quality images that enabled quantification of distal pulmonary arterial branching based on the number of vessel bifurcations/junctions were demonstrated in this model. The branch and junction counts of distal pulmonary arteries significantly decreased in the monocrotaline group compared to the control group, and this effect was inversely proportional to the mean pulmonary artery pressure observed in each group. The patterns of pulmonary vasculature and the methods for pulmonary vessel casting are presented to provide a basis for future studies of pulmonary arterial remodeling due to pulmonary hypertension and other lung diseases that involve the remodeling of vasculature.

Advances in Hemodynamic Monitoring in Heart Failure Patients

Abnormal hemodynamics are associated with poor clinical outcomes in patients with heart failure. Given the invasiveness and unfeasibility of routine right heart catheterization, non-invasive methodologies to monitor hemodynamics are needed. The CardioMEMS™ device is a recently developed technology that enables remote monitoring of pulmonary artery pressures via an implanted sensor located in the distal left pulmonary artery. Along with the CardioMEMS™, a remote dielectric system might be another promising device that reports indirect intra-thoracic filling pressures associated with pulmonary congestion. In patients with advanced heart failure who require left ventricular assist devices, non-invasive hemodynamic monitoring is particularly necessary, given the increased procedural risks of invasive assessments. The HeartWare ventricular assist device flow waveform is a variable under active investigation that might also provide an estimation of filling pressures. This methodology is expected to lead to the development of a smart pump that can adjust its own settings, including the pump speed, automatically by monitoring the hemodynamics.

Chrysin Alleviates Monocrotaline-Induced Pulmonary Hypertension in Rats Through Regulation of Intracellular Calcium Homeostasis in Pulmonary Arterial Smooth Muscle Cells.

Chrysin (CH) is the main ingredient of many medicinal plants. Our previous study showed that CH could suppress hypoxia-induced pulmonary arterial smooth muscle cells proliferation and alleviate chronic hypoxia-induced pulmonary hypertension by targeting store-operated Ca entry (SOCE)-[Ca]i pathway. In this study, we investigated the effect of CH on monocrotaline-induced pulmonary hypertension (MCTPH) and the mechanism behind it. Results show that, in MCTPH model rats, (1) CH significantly reduced the enhancement of right ventricular pressure, right ventricular hypertrophy, and pulmonary vascular remodeling; (2) CH markedly suppressed the promotion of SOCE and [Ca]i in pulmonary arterial smooth muscle cells; and (3) CH obviously inhibited the MCT-upregulated proliferating cell nuclear antigen, TRPC1, TRPC4, and TRPC6 expression in distal pulmonary arteries. These results demonstrate that CH likely alleviates MCTPH by targeting TRPC1,4,6-SOCE-[Ca]i pathway.

Pulmonary ductal coarctation and left pulmonary artery interruption; pathology and role of neural crest and second heart field during development.

ObjectivesIn congenital heart malformations with pulmonary stenosis to atresia an abnormal lateral ductus arteriosus to left pulmonary artery connection can lead to a localised narrowing (pulmonary ductal coarctation) or even interruption We investigated embryonic remodelling and pathogenesis of this area.Material and methodsNormal development was studied in WntCre reporter mice (E10.0–12.5) for neural crest cells and Nkx2.5 immunostaining for second heart field cells. Data were compared to stage matched human embryos and a VEGF120/120 mutant mouse strain developing pulmonary atresia.ResultsNormal mouse and human embryos showed that the mid-pharyngeal endothelial plexus, connected side-ways to the 6th pharyngeal arch artery. The ventral segment formed the proximal pulmonary artery. The dorsal segment (future DA) was solely surrounded by neural crest cells. The ventral segment had a dual outer lining with neural crest and second heart field cells, while the distal pulmonary artery was covered by none of these cells. The asymmetric contribution of second heart field to the future pulmonary trunk on the left side of the aortic sac (so-called pulmonary push) was evident. The ventral segment became incorporated into the pulmonary trunk leading to a separate connection of the left and right pulmonary arteries. The VEGF120/120 embryos showed a stunted pulmonary push and a variety of vascular anomalies.SummarySide-way connection of the DA to the left pulmonary artery is a congenital anomaly. The primary problem is a stunted development of the pulmonary push leading to pulmonary stenosis/atresia and a subsequent lack of proper incorporation of the ventral segment into the aortic sac. Clinically, the aberrant smooth muscle tissue of the ductus arteriosus should be addressed to prohibit development of severe pulmonary ductal coarctation or even interruption of the left pulmonary artery.

Three-dimensional imaging of pulmonary arterial vasa vasorum using optical coherence tomography in patients after bidirectional Glenn and Fontan procedures.

We evaluated pulmonary arterial (PA) vasa vasorum (VV) in Fontan candidate patients with a novel three-dimensional (3D) imaging technique using optical coherence tomography (OCT). This prospective study assessed the development of adventitial VV in the distal PA of 10 patients with bidirectional Glenn circulation (BDG group, 1.6 ± 0.3 years) and Fontan circulation (Fontan group, 3.3 ± 0.3 years), and in 20 children with normal PA haemodynamics and morphology (Control group, 1.5 ± 0.3 years). We assessed the PA VV with two-dimensional (2D) cross-sectional, multi-planar reconstruction (MPR), and volume rendering (VR) imaging. VV development was evaluated by the VV area/volume ratio, defined as the VV area/volume divided by the adventitial area/volume. Compared to the control group, the observed VV number and diameter on 3D images of MPR and VR were significantly higher, and curved and torturous-shaped VV were more frequently observed in the BDG and Fontan groups (P < 0.001, all). The median VV volume ratio was significantly greater in the BDG than in the control group (3.38% vs. 0.61%; P < 0.001). Although the VV volume ratio decreased significantly after the Fontan procedure (2.64%, P = 0.005 vs. BDG), the ratio remained higher than in the control group (P < 0.001 vs. control). 3D OCT imaging is a novel method that can be used to evaluate adventitial PA VV and may provide pathophysiological insight into the role of the PA VV in these patients.

Role of Na+/H+ Exchanger 1 in Regulating Resistance to Apoptosis in Pulmonary Arterial Smooth Muscle Cells

Vascular remodeling within the pulmonary arterioles is a key component of pulmonary arterial hypertension (PAH). In a rat model of severe PAH, the SU5416‐Hypoxia (SuHx) model, pulmonary arterial smooth muscle cells (PASMCs) demonstrate resistance to apoptosis and contribute to vascular remodeling. Na+/H+ exchange (NHE) is increased in SuHx PASMCs; however, few studies have elucidated the functional role of NHE in these cells. Previous studies have shown a link between NHE and the expression of CHOP, a critical mediator of apoptosis. Therefore, we tested the hypothesis that altering NHE1 expression and or activity is sufficient to modulate apoptosis in PASMCs. PASMCs were isolated from distal pulmonary arteries dissected from vehicle‐treated, male, Wistar rats or rats exposed to hypoxia after an injection of SU5416 (SuHx rats). PASMCs were treated with vehicle, a combination of a pharmacologic inhibitor of NHE (EIPA) and hydrogen peroxide (H2O2), an apoptosis‐inducing agent, or either EIPA or H2O2 alone. Apoptosis was measured via Hoechst staining. In other experiments, control PASMCs were infected with a viral construct to overexpress wild‐type NHE1 (AdNHE1), a translocation‐disabled NHE1 mutant (AdE266I), or green fluorescent protein (AdGFP) as a control. NHE activity was measured via the ammonium‐pulse technique. SuHx PASMCs exhibited decreased CHOP expression and minimal apoptosis rates in response to H2O2 when compared to control PASMCs. EIPA had no effect on unstimulated apoptosis in control cells, but induced apoptosis in SuHx PASMCs at baseline and sensitized the cells to H2O2. AdNHE1, but not AdE266I, increased NHE1 activity. Interestingly, both AdNHE1 and AdE266I conferred a resistance to H2O2‐induced apoptosis when compared to the AdGFP‐infected cells. Overall, these findings suggest that increased NHE1 may be responsible for attenuating apoptotic responses in SuHx PASMCs and that increasing NHE1 levels in normal PASMCs is sufficient to promote increased survival via an ion‐translocation‐independent function.Support or Funding InformationSupported by NIH grants HL073859, HL126514 and HL084762

Targeted Angiogenesis Gene Expression Profiling of Patients with Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by organized thrombi in the pulmonary arteries leading to right heart failure and death. Impaired angiogenesis and systemic inflammation could be involved in the pathophysiology of this disease. The aim of this study was to determine the angiogenic expression profile in patients with CTEPH. We studied pulmonary endarterectomy specimens from 5 CTEPH patients, distal pulmonary arteries specimens from 5 CTEPH patients undergoing transplantation (CTEPH TP) and distal pulmonary arteries specimens from 5 controls undergoing lobectomy for low-stage cancer without metastasis enrolled at Marie Lannelongue Hospital. We also analyzed Pulmonary endothelial cells (PECs) isolated by enzymatic digestion from all subjects, comparing them to PECs from patients with idiopathic pulmonary hypertension (iPAH). Angiogenic proteomic profiling of specimens and PECs was performed using Human angiogenesis qPCR array from Anygenes according to manufacturer instructions (198 biomarkers). Gene expression analyses revealed that several angiogenic molecules (such as VEGFA) and receptors (such as VEGFR2) are decreased in fibrotic CTEPH thrombi (CTEPH) and to a greater extent in distal pulmonary arteries specimen (CTEPH TP) as compared to controls (Figure 1A). Endothelial cells isolated from thrombi (CTEPH) and distal pulmonary arteries specimen (CTEPH TP) have distinct angiogenic profiles from iPAH and controls (Figure 1B). These results suggest a downregulation of angiogenesis in endothelial cells from patients with CTEPH as compared to controls. Downregulation of genes involved in angiogenesis and dysfunctional PECs in CTEPH thrombi may underlie thrombus persistence.

Surgical treatment of pinch-off syndrome: A hybrid technique combining cone-beam computed tomography-guided targeting and surgical removal of catheter remnant

Abstract Pinch-off syndrome is a rare complication associated with central venous catheters in which the tip of the catheter breaks off, usually in the cardiac chamber or pulmonary artery. Because the catheter tip can induce embolization, it is essential to remove it in these cases. An interventional technique is usually preferred over surgical removal due to the risk of surgery in pediatric patients. However, we present here the successful removal of a catheter tip from the distal pulmonary artery using a hybrid technique combining cone-beam computed tomography-guided targeting with surgical removal.

Acute peripheral pulmonary embolism attributed to autoimmune haemolytic anaemia: a case report

BackgroundPE (pulmonary embolism) is a life-threatening complication rarely seen in the AIHA (autoimmune haemolytic anaemia) patients. Herein we reported a rare and serious AIHA-PE patient characterised by extensive peripheral pulmonary embolism on CTPA.Case presentationA 59-year-old woman presented to our ED (emergency department) complaining of acute chest pain and dyspnea. During her presentation in ED she experienced a sudden syncope and soon developed CA (cardiac arrest). Laboratory studies showed a increase of CK-MB,troponin T,myoglobin and D-dimer. Computed tomography pulmonary angiography (CTPA) showed no large central or segment pulmonary emboli but increased RV (right ventricle)size,enlarged main pulmonary artery and invisible peripheral pulmonary artery. She was diagnosed with acute PE and alteplase was delivered intravenously. After thrombolytic therapy she remained hypotension and developed worsening anaemia. Detailed examination for anaemia revealed AIHA. She was discharged in a stable condition after 5 weeks with methylprednisolone and warfarin. Hb, D-dimer and transthoracic echocardiography showed complete recovery at 3-months follow up.ConclusionPE attributed to AIHA is characterized by subsegment and distal pulmonary artery embolism which is easily neglected but always life-threatening. This case also highlights the PE as a secondary diagnosis should be evaluated comprehensively in order to identify the underlying pathogenesis.

Lumped-Parameter Circuit Platform for Simulating Typical Cases of Pulmonary Hypertensions from Point of Hemodynamics

Pulmonary hypertension (PH) presents unusual hemodynamic states characterized by abnormal high blood pressure in pulmonary artery. The objective of this study is to simulate how the hemodynamics develops in typical PH cases without treatment. A lumped-parameter circuit platform of human circulation system is set up to simulate hemodynamic abnormalities of PH in different etiologies and pathogenesis. Four typical cases are considered, which are distal pulmonary artery stenosis, left ventricular diastolic dysfunction, ventricular septal defect, and mitral stenosis. The authors propose regulation laws for chambers and vessels to adapt the abnormal hemodynamic conditions for each PH case. The occurrence and development of each PH case are simulated over time using the lumped-parameter circuit platform. The blood pressure, blood flow, pressure-volume relations for chambers and vessels are numerically calculated for each case of PH progression. The model results could be a quite helpful to understand the hemodynamic mechanism of typical PHs.Graphical

Reconstruction surgery case report: ex vivo surgery and auto lung transplantation for pulmonary artery sarcoma

This is a report on the lung autotransplant techniques for the treatment of intimal sarcoma of pulmonary artery (PA). A 58-year-old man was diagnosed with PA sarcoma occluding the right main PA and peripherally extending into the right interlobar PA. First, the tumor was completely removed by pulmonary endarterectomy combined with right pneumonectomy under cardiopulmonary bypass. A following ex vivo evaluation of the explanted right lung revealed that the right lower PA was intraluminally intact, so the right lower lobe was used for reimplantation after being flushed with cold organ preservation solution on a back table. The patient was safely weaned from cardiopulmonary bypass following transplantation. His early post-transplant course was uneventful. He died of tumor recurrence at the distal left PA and liver and bone metastasis 14 months after surgery.

Chrysin Alleviates Chronic Hypoxia-Induced Pulmonary Hypertension by Reducing Intracellular Calcium Concentration in Pulmonary Arterial Smooth Muscle Cells.

Chrysin (CH), the main ingredient of many medicinal plants, has been reported to be a very potent flavonoid possessing a large number of pharmacological activities. Recent studies have shown that CH significantly improves hemodynamic parameters such as right ventricular pressure, right ventricular hypertrophy, and pulmonary vascular remodeling in a rat model of chronic hypoxia-induced pulmonary hypertension (CHPH). These improvements are through the inhibition of NOX4 expression, reactive oxygen species and malondialdehyde production, pulmonary arterial smooth muscle cell (PASMC) proliferation, and collagen accumulation. In this study, we investigated another mechanism by which CH alleviates CHPH by regulating intracellular calcium concentrations ([Ca]i) in PASMCs, as well as the underlying signaling pathway. The results show that (1) in CHPH model rats, CH substantially attenuated elevated right ventricular pressure, right ventricular hypertrophy, and pulmonary vascular remodeling; (2) in cultured rat distal PASMCs, CH inhibited the hypoxia-triggered promotion of cell proliferation, store-operated Ca entry and [Ca]i; and (3) CH significantly suppressed the hypoxia-upregulated HIF-1α, BMP4, TRPC1, and TRPC6 expression in distal pulmonary arteries (PAs) and cultured rat distal PASMCs. These results indicate that CH likely exerts its CHPH protective activity by regulating [Ca]i, which may result from the downregulation of HIF-1α, BMP4, TRPC1, and TRPC in PASMCs.

Hepatopulmonary syndrome has low prevalence of pulmonary vascular abnormalities on chest computed tomography.

Hepatopulmonary syndrome (HPS) is defined as an arterial oxygenation defect induced by intrapulmonary vascular dilatations associated with hepatic disease. This study aimed to assess the prevalence of type 1 and 2 pulmonary vascular abnormalities on chest computed tomography (CT) in patients with cirrhosis and HPS and to characterize intra- and interobserver reliability. Two thoracic radiologists retrospectively evaluated chest CT scans from 38 cirrhosis patients with HPS. They classified the pulmonary vascular abnormalities as type 1 (multiple dilated distal pulmonary arteries), type 2(nodular dilatation or individual pulmonary arterial malformation), or absence of abnormality. Furthermore, they measured the diameters of the central pulmonary arteries and subsegmental pulmonary arteries and bronchi. We analyzed the prevalence, intraobserver reliability, and interobserver reliability of abnormal CT findings related to HPS, and the correlation of these findings with partial arterial oxygen pressure (PaO2). The overall prevalence of pulmonary vascular abnormalities was 28.9% (95% confidence intervals: 15.4%, 45.9%). Moreover, 26.3% of patients had type 1 abnormality (13.4%, 43.1%) and 2.6% of patients had type 2 abnormality (0.0%, 13.8%). The intraobserver reliability kappa value was 0.666 (0.40, 0.91) and the interobserver kappa value was 0.443 (0.12, 0.77). There was no correlation between pulmonary vascular abnormalities on CT and PaO2 values. The prevalence of pulmonary vascular abnormalities on chest CT of patients with cirrhosis and HPS is low and not correlated with PaO2. These findings question the usefulness of chest CT for the evaluation of patients with cirrhosis and HPS.

Factors associated with perioperative mortality in children and adolescents operated for tetralogy of Fallot: A sub-Saharan experience.

Patients with tetralogy of Fallot are now surviving to adulthood with timely surgical intervention. However, many patients in low-income countries have no access to surgical intervention. This paper reports the surgical access and perioperative mortality in a sub-Saharan center that was mainly dependent on visiting teams. We reviewed records of patients operated from January 2009 to December 2014. We examined perioperative outcomes, primarily focusing on factors associated with perioperative mortality. During this period, 62 patients underwent surgery. Fifty-seven (91.9%) underwent primary repair, while 5 (6.5%) underwent palliative shunt surgery. Of the five patients with shunt surgery, four ultimately underwent total repair. Eight (12.9%) patients died during the perioperative period. Factors associated with perioperative mortality include repeated preoperative phlebotomy procedures (P < .001), repeated runs and long cardiopulmonary bypass time (P < .001), and aortic cross-clamp time (P < .001), narrow pulmonary artery (PA) valve annulus diameter (P = .022), narrow distal main PA diameter (P = .039), narrow left branch PA diameter (P = .049), and narrow right PA diameter (P = .039). Of these factors, cardiopulmonary bypass time/aortic cross-clamp time and pulmonary valve annulus diameter less than three SD were independently associated with perioperative mortality. In this series of consecutive patients operated by a variety of humanitarian surgical teams, cardiopulmonary bypass time/aortic cross-clamp time, and pulmonary valve annulus diameter less than three SD were independently associated with perioperative mortality risk. As some of these factors are modifiable, we suggest that they should be considered during patient selection and at the time of surgical intervention.

Multicenter Preclinical Validation of BET Inhibition for the Treatment of Pulmonary Arterial Hypertension.

Rationale: Pulmonary arterial hypertension (PAH) is a degenerative arteriopathy that leads to right ventricular (RV) failure. BRD4 (bromodomain-containing protein 4), a member of the BET (bromodomain and extra-terminal motif) family, has been identified as a critical epigenetic driver for cardiovascular diseases.Objectives: To explore the therapeutic potential in PAH of RVX208, a clinically available BET inhibitor.Methods: Microvascular endothelial cells, smooth muscle cells isolated from distal pulmonary arteries of patients with PAH, rats with Sugen5416 + hypoxia- or monocrotaline + shunt-induced PAH, and rats with RV pressure overload induced by pulmonary artery banding were treated with RVX208 in three independent laboratories.Measurements and Main Results: BRD4 is upregulated in the remodeled pulmonary vasculature of patients with PAH, where it regulates FoxM1 and PLK1, proteins implicated in the DNA damage response. RVX208 normalized the hyperproliferative, apoptosis-resistant, and inflammatory phenotype of microvascular endothelial cells and smooth muscle cells isolated from patients with PAH. Oral treatment with RVX208 reversed vascular remodeling and improved pulmonary hemodynamics in two independent trials in Sugen5416 + hypoxia-PAH and in monocrotaline + shunt-PAH. RVX208 could be combined safely with contemporary PAH standard of care. RVX208 treatment also supported the pressure-loaded RV in pulmonary artery banding rats.Conclusions: RVX208, a clinically available BET inhibitor, modulates proproliferative, prosurvival, and proinflammatory pathways, potentially through interactions with FoxM1 and PLK1. This reversed the PAH phenotype in isolated PAH microvascular endothelial cells and smooth muscle cells in vitro, and in diverse PAH rat models. RVX208 also supported the pressure-loaded RV in vivo. Together, these data support the establishment of a clinical trial with RVX208 in patients with PAH.

Multiscale Modeling of Superior Cavopulmonary Circulation: Hemi-Fontan and Bidirectional Glenn Are Equivalent

Superior cavopulmonary circulation (SCPC) can be achieved by either the Hemi-Fontan (hF) or Bidirectional Glenn (bG) connection. Debate remains as to which results in best hemodynamic results. Adopting patient-specific multiscale computational modeling, we examined both the local dynamics and global physiology to determine if surgical choice can lead to different hemodynamic outcomes. Six patients (age: 3-6 months) underwent cardiac magnetic resonance imaging and catheterization prior to SCPC surgery. For each patient: (1) a finite 3-dimensional (3D) volume model of the preoperative anatomy was constructed to include detailed definition of the distal branch pulmonary arteries, (2) virtual hF and bG operations were performed to create 2 SCPC 3D models, and (3) a specific lumped network representing each patient's entire cardiovascular circulation was developed from clinical data. Using a previously validated multiscale algorithm that couples the 3D models with lumped network, both local flow dynamics, that is, power loss, and global systemic physiology can be quantified. In 2 patients whose preoperative imaging demonstrated significant left pulmonary artery (LPA) stenosis, we performed virtual pulmonary arterioplasty to assess its effect. In one patient, the hF model showed higher power loss (107%) than the bG, while in 3, the power losses were higher in the bG models (18-35%). In the remaining 2 patients, the power loss differences were minor. Despite these variations, for all patients, there were no significant differences between the hF and bG models in hemodynamic or physiological outcomes, including cardiac output, superior vena cava pressure, right-left pulmonary flow distribution, and systemic oxygen delivery. In the 2 patients with LPA stenosis, arterioplasty led to better LPA flow (5-8%) while halving the power loss, but without important improvements in SVC pressure or cardiac output. Despite power loss differences, both hF and bG result in similar SCPC hemodynamics and physiology outcome. This suggests that for SCPC, the pre-existing patient-specific physiology and condition, such as pulmonary vascular resistance, are more deterministic in the hemodynamic performance than the type of surgical palliation. Multiscale modeling can be a decision-assist tool to assess whether an extensive LPA reconstruction is needed at the time of SCPC for LPA stenosis.

The small molecule macrophage migration inhibitory factor antagonist MIF098, inhibits pulmonary hypertension associated with murine SLE

Pulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE), with unclear etiopathogenesis. We evaluated the role of macrophage migration inhibitory factor (MIF), which has been implicated in idiopathic pulmonary hypertension (PH), in SLE-associated PAH. Circulating MIF was measured in SLE patients, SLE-PAH patients, and healthy donors. In situ pulmonary artery MIF protein expression was determined in spontaneous SLE mice (MRL/lpr) and hypoxia-induced C57BL/6J mice. Daily MIF098 was administered to C57BL/6J mice, and these mice were maintained in a hypoxic chamber for 4 weeks. The right ventricular systolic pressure (RVSP) and pathological characteristics of the pulmonary artery (PA), such as hyperproliferation, muscularization, and fibrosis were then measured in each group of mice. Data were also obtained in vitro using pulmonary smooth muscle cells (PASMC) challenged with platelet-derived growth factor (PDGF)-BB or 1% O2 hypoxia. As a result, circulating MIF was elevated in SLE-PAH patients compared with SLE patients or healthy donors. Higher RVSP SLE mice produced more MIF protein than lower RVSP SLE mice in the pulmonary artery. MIF098 decreased RVSP and inhibited distal pulmonary artery hyperproliferation, muscularization, and collagen deposition in hypoxia challenged mice. In addition, MIF098 inhibited PASMC proliferation and migration by regulating mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/ERK1/2) signal- and cell-cycle-related proteins. MIF098 also reduced collagen synthesis by inhibiting the TGFβ1/Smad2/Smad3 pathway in cell-based experiments. In conclusion, MIF may serve as a biomarker and a therapeutic target of SLE-associated PAH. Pharmacologic MIF antagonism may be an effective means to ameliorate SLE-PAH.