Mechanisms Of Pulmonary Hypertension Research Articles

Inhibition of RUNX1 slows the progression of pulmonary hypertension by targeting CBX5.

Pulmonary artery smooth muscle cell (PASMC) dysfunction is the central pathogenic mechanism in pulmonary hypertension (PH). This study explored the mechanism of action of RUNX1, a potential therapeutic target for PH, in PASMCs. A PH mouse model was used to investigate the impacts of RUNX1 knockdown on hemodynamics, right ventricular hypertrophy (RVH), and pulmonary artery remodeling (HE staining). Isolated PASMCs were transfected with RUNX1- or CBX5-related vectors and then subjected to cell function assays. Immunoprecipitation was used to detect molecular binding and ubiquitination. RUNX1 knockdown reduced right ventricular systolic pressure, RVH, and pulmonary artery remodeling in mice with PH. Knockdown of RUNX1 or CBX5 suppressed proliferation, invasion, and migration and stimulated apoptosis in PASMCs under hypoxia. RUNX1 enhanced USP15 promoter activity. USP15 bound to CBX5 and reduced CBX5 ubiquitination, thereby promoting CBX5 expression. CBX5 overexpression promoted the proliferation and movement of hypoxic PASMCs with reduced RUNX1 expression and decreased their apoptosis. In conclusion, RUNX1 knockdown alleviates PH in mice and reduces hypoxia-induced PASMC dysfunction by inhibiting USP15 transcription, thereby promoting the ubiquitination and degradation of CBX5.

Abstract 2223 Multi-Omics Approaches to Discover Novel Mechanisms in Pulmonary Hypertension

Abstract 2223 Multi-Omics Approaches to Discover Novel Mechanisms in Pulmonary Hypertension

Impact of hyperoxia on the phenotype of pulmonary artery smooth muscle cells

Objective: To investigate the influence of varied oxygen (O2) concentration environments on the phenotypic transformation of pulmonary artery smooth muscle cells (PASMC) and the mechanism of pulmonary hypertension. Methods: Primary rat PASMC were isolated and cultured through the process of enzymatic digestion. Following identification, the stable passaged PASMC were subjected to a 6-hour incubation in sealed containers with normal O2 content (group C) and relative O2 content comprising 55% (group H55), 75% (group H75), and 95% (group H95). mRNA and protein expression of α-Actin (α-SMA), smooth muscle 22α (SM22α), osteopontin (OPN), and matrix metalloproteinase-2 (MMP-2) were measured using real-time quantitative PCR and western blot analysis. Results: The H55 group displayed no significant difference from the C group in terms of mRNA and relative protein expression levels for α-SMA, SM22α, OPN, and MMP-2 (all P>0.05). On the other hand, groups H75 and H95 exhibited a reduction in mRNA and relative protein expression of α-SMA and SM22α, along with an increase in mRNA and relative protein expression of OPN and MMP-2 when compared with both the C and H55 groups (all P<0.05). The H95 group showed a higher relative mRNA expression of MMP-2 as compared to the H75 group (P<0.05). Conclusions: Oxygen concentration environments of 75% or higher can serve as the foundation for the pathogenesis of pulmonary hypertension, essentially by inducing a phenotypic transformation in PASMC towards adopting a robust secretory function. This induction is contingent upon the concentration of oxygen present.

Mitochondria-derived Vesicle Packaging as a Novel Therapeutic Mechanism in Pulmonary Hypertension.

Increasing evidence suggests that mitochondrial dysfunction in pulmonary endothelial cells (ECs) plays a causative role in the initiation and progression of pulmonary hypertension (PH); how mitochondria become dysfunctional in PH remains elusive. Mitochondria-derived vesicles (MDVs) are small subcellular vesicles that excise from mitochondria. Whether MDV deregulation causes mitochondrial dysfunction in PH is unknown. The aim of this study was to determine MDV regulation in ECs and to elucidate how MDV deregulation in ECs leads to PH. MDV formation and mitochondrial morphology/dynamics were examined in ECs of EC-specific liver kinase B1 (LKB1) knockout mice (LKB1ec-/-), in monocrotaline-induced PH rats, and in lungs of patients with PH. Pulmonary ECs of patients with PH and hypoxia-treated pulmonary ECs exhibited increased mitochondrial fragmentation and disorganized mitochondrial ultrastructure characterized by electron lucent-swelling matrix compartments and concentric layering of the cristae network, together with defective MDV shedding. MDVs actively regulated mitochondrial membrane dynamics and mitochondrial ultrastructure via removing mitofission-related cargoes. The shedding of MDVs from parental mitochondria required LKB1-mediated mitochondrial recruitment of Rab9 GTPase. LKB1ec-/- mice spontaneously developed PH with decreased mitochondrial pools of Rab9 GTPase, defective MDV shedding, and disequilibrium of the mitochondrial fusion-fission cycle in pulmonary ECs. Aerosol intratracheal delivery of adeno-associated virus LKB1 reversed PH, together with improved MDV shedding and mitochondrial function in rats invivo. We conclude that LKB1 regulates MDV shedding and mitochondrial dynamics in pulmonary ECs by enhancing mitochondrial recruitment of Rab9 GTPase. Defects of LKB1-mediated MDV shedding from parental mitochondria instigate EC dysfunction and PH.

Stiff “Left Atrial” syndrome post-mustard procedure

Objectives: We describe the clinical course and management of two patients with post-capillary pulmonary hypertension due to diffuse pulmonary venous baffle calcification decades post-Mustard procedure. Background: From the late 1950s to the early 1990s, the definitive surgical repair for children with D-transposition of the great vessels (D-TGA) was an atrial switch procedure (either Senning or Mustard operation) which utilizes atrial-level baffles to shunt pulmonary venous blood to the morphologic right (systemic) ventricle and caval blood to the morphologic left (sub-pulmonary) ventricle. From a hemodynamic standpoint, baffle leaks and stenoses as well as precapillary pulmonary hypertension have all been described as both early and late complications [1]. Recently, delayed post-capillary pulmonary hypertension (in the absence of discrete baffle obstruction) decades post-atrial switch has also been described [2]. The underlying pathophysiology for this postcapillary pulmonary hypertension is unclear but is theorized to involve impaired diastology referable to the pulmonary venous baffle. Methods/Results: Using hemodynamic and imaging data, we describe two patients with extensive pulmonary venous baffle calcification and resultant pulmonary hypertension from the so-called “stiff left atrial (LA) syndrome.” This problem can be difficult to treat medically and is not amenable to catheter-based interventions. We hypothesize that this is an underlying mechanism for pulmonary hypertension in at least some post-Mustard and Senning patients. Conclusion: We describe the treatments and clinical course for each of these patients, and in particular describe how the surgical revision of the pulmonary venous baffle in one case led to the complete resolution of symptoms.

Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension.

Cancer therapies are being considered for treating rare noncancerous diseases like pulmonary hypertension (PH), but effective computational screening is lacking. Via transcriptomic differential dependency analyses leveraging parallels between cancer and PH, we mapped a landscape of cancer drug functions dependent upon rewiring of PH gene clusters. Bromodomain and extra-terminal motif (BET) protein inhibitors were predicted to rely upon several gene clusters inclusive of galectin-8 (LGALS8). Correspondingly, LGALS8 was found to mediate the BET inhibitor–dependent control of endothelial apoptosis, an essential role for PH in vivo. Separately, a piperlongumine analog’s actions were predicted to depend upon the iron-sulfur biogenesis gene ISCU. Correspondingly, the analog was found to inhibit ISCU glutathionylation, rescuing oxidative metabolism, decreasing endothelial apoptosis, and improving PH. Thus, we identified crucial drug-gene axes central to endothelial dysfunction and therapeutic priorities for PH. These results establish a wide-ranging, network dependency platform to redefine cancer drugs for use in noncancerous conditions.

Vitamin D Repletion Mitigates Oxidative Stress Induced Pulmonary Artery Remodeling in Sickle Cell Disease

The lung is a primary target of end organ pathology in patients with sickle cell disease (SCD). Pulmonary artery remodeling, a common feature at autopsy in SCD, is characteristic of the pulmonary hypertension of SCD. In an autopsy cohort of 20 patients with SCD, we found that pulmonary artery remodeling was a pathology of the young patient. Patients with severe remodeling had less than a 15% probability of surviving to 25 years of age, whereas those with milder remodeling had an 80% probability of living beyond 50. Therefore, we wanted to understand the mechanisms underpinning pulmonary artery remodeling.Using benchtop ion trap mass spectrometry on extracted pulmonary proteins from the autopsy study, we screened for oxidative “fingerprints” (protein modifications) that were specific for SCD. We found that the lungs from patients with SCD carried a profound oxidative burden. Oxidative modifications arising from the hydroxyl (∙OH), superoxide (∙O2-) peroxynitrite (ONOO-),and eosinophil peroxidase were all significantly elevated compared to samples prepared from identical lung blocks from unaffected controls at autopsy. However, of the oxidative modifications detected, only the signature from peroxynitrite, 3-nitro tyrosine, (3-NT) could differentiate those SCD patients with profound pulmonary artery remodeling from those with milder forms of this pathology. After adjusting for age, the 3-NT content was increased 16 fold in the severely remodeled pulmonary tissues. Using immunohistochemistry, we found that 3NT was exquisitely localized to remodeling vessels and areas of smooth muscle proliferation. We assayed plasma proteins from patients with SCD at steady state and found a consistently elevated 3-NT content when compared to control plasma. The 3-NT containing proteins in living patients correlated strongly with NT-proBNP, but inversely with plasma free hemoglobin at steady state.Peroxynitrite, a strong smooth muscle mitogen, is formed via the reaction of NO with ∙O2-, therefore we reasoned that the presence of the superoxide radical was transforming NO into ONOO-. Extracellular (EC) superoxides are neutralized by EC-superoxide dismutases (SODs) to preserve the vaso-regulatory effects of NO. EC-SOD is tethered to the outer membrane of cells to allow for diffusion of NO without superoxide attack. Using immunohistochemistry, electron microscopy, and linear-ion trap mass spectrometry with comparative proteomics on paraffin-free lung tissue we noted, that pulmonary EC-SOD was 60-fold depleted in the remodeling pulmonary vessels and endothelium in patients with SCD at autopsy. The plasma of patients at steady state, compared to unaffected controls, however, contained increased, but inactive EC-SOD indicating an SCD-specific release of EC-SOD from the outer membrane of endothelial surfaces and into the plasma compartment.Using an in vitro culture of human pulmonary endothelial cells, we quantified EC-SOD on the cell surface using ELISA. Plasma from patients with SCD significantly reduced the amount of EC-SOD detectable on the endothelial cells. Plasma from healthy control subjects was without effect.We, and many other groups have demonstrated that patients with SCD have compromised flow mediated dilation (FMD) - an NO mediated process. We found that both plasma EC-SOD and 3-NT content of plasma proteins inversely correlated with FMD in patients with SCD. However, high dose vitamin D repletion (100,000 units ergocalciferol weekly) improved FMD within 8 weeks and reduced both plasma EC-SOD and 3NT content of plasma proteins, thus restoring NO function. After an 8 week washout period of the ergocalciferol, FMD values, plasma EC-SOD, and plasma 3-NT content returned to baseline, pathological steady state levels.Furthermore, plasma from the 8 week ergocalciferol treated patients lost the ability to deplete EC-SOD from the endothelial cell surface in vitro, whereas after the washout, plasma from the same subject effectively removed EC-SOD from the endothelial cells.Taken together these data suggest a new mechanism of pulmonary hypertension in patients with SCD, one in which NO in the presence of superoxide radical promotes pulmonary artery remodeling and predicts an early death. Vitamin D, through an as yet undetermined mechanism, appears to restore NO function, and re-localize EC-SOD to the appropriate vascular compartment. DisclosuresKutlar:Sancilio & Co (OMEG-411-02): Other: Chair of Data and Safety Monitoring Board; BlueBird Bio: Other: Member of Data Monitoring Committee; Reprixys Pharmaceuticals Corporation (formerly known as Selexys Pharmaceuticals Corporation, which is not affiliated with Selexis S.A.): Research Funding; Novartis: Research Funding.

The expression and significance of heparinase, MMP‐9 in lung tissue of rat pulmonary hypertension model

Objective To investigate the relationship between heparinase and matrix metalloproteinase (MMP 9) and pulmonary hypertension by comparing their expression characteristics in pulmonary hypertension model rats and normal rats, and to study their possible mechanisms in pulmonary hypertension and pulmonary vascular structure reconstruction in rats. Methods Pulmonary hypertension model was established by single intraperitoneal injection of Monocrotaline. Twenty rats were randomly divided into normal control group and pulmonary hypertension model group (model group) with 10 rats in each group. Color Doppler ultrasonography was used to measure the changes of pulmonary artery peak velocity and inner diameter of pulmonary artery root. The changes of mean pulmonary artery pressure (mPAP), right ventricular hypertrophy index and mean carotid artery pressure (mCAP) were measured. HE staining was used to observe the pathological morphological changes of pulmonary vessels. The expression of heparinase and MMP 9 in the lung tissues of rats in the two groups was determined by immunohistochemical SABC method. Results The peak velocity of pulmonary artery, inner diameter of pulmonary artery root, mPAP, MMP 9 and right ventricular hypertrophy index in model group were significantly higher than those in control group (P<0.01). There was no significant difference in mean carotid pressure and heparinase expression between the two groups (P>0.05). Conclusion The establishment of pulmonary hypertension model by single intraperitoneal injection of Lilipine has the characteristics of simple operation, low damage to animals and high success rate. Inhibition of MMP 9 synthesis or reduction of MMP 9 activity may be one of the mechanisms by which MMP 9 inhibits wilylin-induced pulmonary hypertension and pulmonary vascular structural reconstruction in rats.

Mechanisms of Pulmonary Hypertension in Acute Respiratory Distress Syndrome (ARDS).

Background: Acute respiratory distress syndrome (ARDS) is a severe and often fatal disease. The causes that lead to ARDS are multiple and include inhalation of salt water, smoke particles, or as a result of damage caused by respiratory viruses. ARDS can also arise due to systemic complications such as blood transfusions, sepsis, or pancreatitis. Unfortunately, despite a high mortality rate of 40%, there are limited treatment options available for ARDS outside of last resort options such as mechanical ventilation and extracorporeal support strategies.Aim of review: A complication of ARDS is the development of pulmonary hypertension (PH); however, the mechanisms that lead to PH in ARDS are not fully understood. In this review, we summarize the known mechanisms that promote PH in ARDS.Key scientific concepts of review: (1) Provide an overview of acute respiratory distress syndrome; (2) delineate the mechanisms that contribute to the development of PH in ARDS; (3) address the implications of PH in the setting of coronavirus disease 2019 (COVID-19).

Systemic thrombolysis and anticoagulation improved biomarker measurements in massive-like pulmonary embolism and severe COVID-19 pneumonia: a case report.

BackgroundFrom asymptomatic patients to severe acute respiratory distress syndrome, COVID-19 has a wide range of clinical presentations, and venous thromboembolism has emerged as a critical and frequent complication.Case summaryWe present a case of a 69-year-old man with a clinical presentation of massive-like pulmonary embolism (PE) overlapping with severe COVID-19 pneumonia. The diagnosis was made based on hypotension, severe oxygen desaturation (33%), and right ventricular dysfunction (RVD). We used alteplase and low-molecular-weight heparin, obtaining immediate clinical improvement. Also, we identified an extremely elevated D-dimer (31.2 mcg/mL), and computed tomography pulmonary angiography (CTPA) revealed an unexpected low thrombus burden and a crazy-paving pattern. Considering this, we decided to discontinue the alteplase. Therefore, the mechanisms of pulmonary hypertension and RVD could be multifactorial. Despite the patient’s respiratory status worsening and ongoing mechanical ventilation, biomarkers kept lowering to normal ranges. It appears a favourable outcome was related to early PE diagnosis and a multimodal therapeutic approach.DiscussionPhysicians in the ER should be warned about extremely high D-dimer measurements and severe oxygen desaturation as possible markers of severe COVID-19 pneumonia in patients with high-clinical suspicion of PE. Although ESC guidelines recommend immediate reperfusion in cardiogenic shock secondary to PE, we suggest initial CTPA in patients with high-clinical suspicion of severe COVID-19.

Identification of novel mechanisms in pulmonary hypertension using omics data

Identification of novel mechanisms in pulmonary hypertension using omics data

Aberrant Caveolin-1-Mediated Smad Signaling and Proliferation Identified by Analysis of Adenine 474 Deletion Mutation (c.474delA) in Patient Fibroblasts: A New Perspective in the Mechanism of Pulmonary Hypertension.

A heterozygous Caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to caveolin-1 protein that contains all known functional domains but has a change only in the final 20 amino acids of the C terminus. Here we studied how this mutation alters caveolin-1 function using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation formed typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, co-expression of wild type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed 2-fold increase in proliferation rate associated with hyper-phosphorylation of Smad1/5/8. This mutation impaired the anti-proliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyper-proliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation through dampening Smad signaling, and suggest that augmented Smad signaling and fibroblast hyper-proliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation.

Important role of endothelium-dependent hyperpolarization in the pulmonary microcirculation in male mice: implications for hypoxia-induced pulmonary hypertension.

Endothelium-dependent hyperpolarization (EDH) plays important roles in the systemic circulation, whereas its role in the pulmonary circulation remains largely unknown. Furthermore, the underlying mechanisms of pulmonary hypertension (PH) also remain to be elucidated. We thus aimed to elucidate the role of EDH in pulmonary circulation in general and in PH in particular. In isolated perfused lung and using male wild-type mice, endothelium-dependent relaxation to bradykinin (BK) was significantly reduced in the presence of Nω-nitro-l-arginine by ~50% compared with those in the presence of indomethacin, and the combination of apamin plus charybdotoxin abolished the residual relaxation, showing the comparable contributions of nitric oxide (NO) and EDH in the pulmonary microcirculation under physiological conditions. Catalase markedly inhibited EDH-mediated relaxation, indicating the predominant contribution of endothelium-derived H2O2. BK-mediated relaxation was significantly reduced at day 1 of hypoxia, whereas it thereafter remained unchanged until day 28. EDH-mediated relaxation was diminished at day 2 of hypoxia, indicating a transition from EDH to NO in BK-mediated relaxation before the development of hypoxia-induced PH. Mechanistically, chronic hypoxia enhanced endothelial NO synthase expression and activity associated with downregulation of caveolin-1. Nitrotyrosine levels were significantly higher in vascular smooth muscle of pulmonary microvessels under chronic hypoxia than under normoxia. A similar transition of the mediators in BK-mediated relaxation was also noted in the Sugen hypoxia mouse model. These results indicate that EDH plays important roles in the pulmonary microcirculation in addition to NO under normoxic conditions and that impaired EDH-mediated relaxation and subsequent nitrosative stress may be potential triggers of the onset of PH. NEW & NOTEWORTHY This study provides novel evidence that both endothelium-dependent hyperpolarization and nitric oxide play important roles in endothelium-dependent relaxation in the pulmonary microcirculation under physiological conditions in mice and that hypoxia first impairs endothelium-dependent hyperpolarization-mediated relaxation, with compensatory upregulation of nitric oxide, before the development of hypoxia-induced pulmonary hypertension.

PULMONARY VASCULAR RESISTANCE BY ECHOCARDIOGRAPHY-DOPPLER IN ISCHEMIC HEART DISEASE WITH LEFT VENTRCULAR SYSTOLIC DYSFUNCTION

Objective: To determine pulmonary vascular resistance (PVR) by echocardiography - Doppler and to find correlation between pulmonary vascular resistance with left ventricular EF, PAPs, TAPSE, tissue S-wave of the tricuspid valve in patients with ischemic heart disease. Subjects and Methods: We studied on 82 patients with ischemic heart disease and EF&lt;40% including 36 females, 46 males. Patients were estimated for pulmonary vascular resistance, EF, PAPs, TAPSE, tissue S-wave of the tricuspid valve by echocardiographyDoppler. Results: 64.6% of patients are increased PVR, average of PVR is 3.91 ± 1.85 Wood units and it is increasing with NYHA severity. There are negative correlations between pulmonary vascular resistance with left ventricular ejection fraction (r = - 0.545; p &lt;0.001), TAPSE index (r= -0.590; p &lt;0.001) and tissue S-wave of the tricuspid valve (r = -0.420; p &lt;0.001); positive correlation with systolic pulmonary artery pressure (r = 0.361, p = 0.001), Conclusions: Increased PVR is the primary mechanism for pulmonary hypertension and right heart failure in patients with left heart disease. Determination of PVR in patients with left ventricular dysfunction by echocardiography is important in clinical practice. Key words: Echocardiography-Doppler; Pulmonary vascular resistance; ischemic heart disease

Aberrant caveolin-1-mediated Smad signaling and proliferation identified by analysis of adenine 474 deletion mutation (c.474delA) in patient fibroblasts: a new perspective on the mechanism of pulmonary hypertension.

A heterozygous caveolin-1 c.474delA mutation has been identified in a family with heritable pulmonary arterial hypertension (PAH). This frameshift mutation leads to a caveolin-1 protein that contains all known functional domains but has a change in only the final 20 amino acids of the C-terminus. Here we studied how this mutation alters caveolin-1 function, using patient-derived fibroblasts. Transmission electron microscopy showed that fibroblasts carrying the c.474delA mutation form typical caveolae. Expression of mutated caveolin-1 in caveolin-1-null mouse fibroblasts failed to induce formation of caveolae due to retention of the mutated protein in the endoplasmic reticulum. However, coexpression of wild-type caveolin-1 with mutated caveolin-1 restored the ability to form caveolae. Importantly, fibroblasts carrying the mutation showed twofold increase in proliferation rate associated with hyperphosphorylation of Smad1/5/8. This mutation impaired the antiproliferative function of caveolin-1. Inhibition of type I TGFβ receptors ALK1/2/3/6 responsible for phosphorylation of Smad1/5/8 reduced the hyperproliferation seen in c.474delA fibroblasts. These results demonstrate the critical role of the final 20 amino acids of caveolin-1 in modulating fibroblast proliferation by dampening Smad signaling and suggest that augmented Smad signaling and fibroblast hyperproliferation are contributing factors in the pathogenesis of PAH in patients with caveolin-1 c.474delA mutation.

Pulmonary hypertension associated with left-sided heart disease.

Pulmonary hypertension associated with left-sided heart disease (PH-LHD) is the most common type of pulmonary hypertension. In patients with left-sided heart disease, the presence of pulmonary hypertension is typically a marker of more advanced disease, more severe symptoms, and worse prognosis. In contrast to pulmonary arterial hypertension, PH-LHD is characterised by an elevated pulmonary artery wedge pressure (postcapillary pulmonary hypertension) without or with an additional precapillary component (isolated postcapillary versus combined postcapillary and precapillary pulmonary hypertension). Transthoracic echocardiography is the primary nonin-vasive imaging tool to estimate the probability of pulmonary hypertension and to establish a working diagnosis on the mechanism of pulmonary hyperten-sion. However, right heart catheterisation is always required if significant pulmonary hypertension is sus-pected and exact knowledge of the haemodynamic constellation is necessary. The haemodynamic con-stellation (mean pulmonary artery pressure, mean pulmonary artery wedge pressure, left ventricular end-diastolic pressure) in combination with clinical infor-mation and imaging findings (mainly echocardiog-raphy, coronary angiography and cardiac magnetic resonance imaging) will usually allow the exact mech-anism underlying PH-LHD to be defined, which is a prerequisite for appropriate treatment. The general principle for the management of PH-LHD is to treat the underlying left-sided heart disease in an optimal man-ner using drugs and/or interventional or surgical ther-apy. There is currently no established indication for pulmonary arterial hypertension-specific therapies in PH-LHD, and specific therapies may even cause harm in patients with PH-LHD.

Pulmonary hypertension associated with left-sided heart disease.

Pulmonary hypertension associated with left-sided heart disease (PH-LHD) is the most common type of pulmonary hypertension. In patients with left-sided heart disease, the presence of pulmonary hypertension is typically a marker of more advanced disease, more severe symptoms, and worse prognosis. In contrast to pulmonary arterial hypertension, PH-LHD is characterised by an elevated pulmonary artery wedge pressure (postcapillary pulmonary hypertension) without or with an additional precapillary component (isolated postcapillary versus combined postcapillary and precapillary pulmonary hypertension). Transthoracic echocardiography is the primary nonin-vasive imaging tool to estimate the probability of pulmonary hypertension and to establish a working diagnosis on the mechanism of pulmonary hyperten-sion. However, right heart catheterisation is always required if significant pulmonary hypertension is sus-pected and exact knowledge of the haemodynamic constellation is necessary. The haemodynamic con-stellation (mean pulmonary artery pressure, mean pulmonary artery wedge pressure, left ventricular end-diastolic pressure) in combination with clinical infor-mation and imaging findings (mainly echocardiog-raphy, coronary angiography and cardiac magnetic resonance imaging) will usually allow the exact mech-anism underlying PH-LHD to be defined, which is a prerequisite for appropriate treatment. The general principle for the management of PH-LHD is to treat the underlying left-sided heart disease in an optimal man-ner using drugs and/or interventional or surgical ther-apy. There is currently no established indication for pulmonary arterial hypertension-specific therapies in PH-LHD, and specific therapies may even cause harm in patients with PH-LHD.

Circulation Research “In This Issue” Anthology

Circulation Research “In This Issue” Anthology

Biomarker screening of rat pulmonary hypertension model by transcriptome sequencing

To screen relative gene and pathway of rat severe pulmonary hypertension by transcriptome sequencing. Pulmonary hypertension animal model of SD rats was established by left lung resection and hypodermic injection of monocrotaline.Monocrotaline was injected subcutaneously one week after left lung resection.Eight rats at 1, 3, 5 weeks after the injection of monocrotaline respectively were named group M1, group M2 and group M3.Eight normal rats were assigned into control group (group C). The right lung tissue was used for transcriptome sequencing to screen the differentially expressed genes.KEGG pathway analysis was performed to screen the pathways with enriched differentially expressed genes. The animal model was established successfully.The pulmonary artery pressure was as follows: group C (28.6±3.0) mmHg(1 mmHg=0.133 kPa), group M1 (38.9±3.3) mmHg, group M2 (50.8±3.9) mmHg, group M3 (51.5±3.5) mmHg.The pressure elevated in group M1 compared with group C (P=0.007). The pressure in M2 and M3 elevated compared with M1(P=0.002 and P<0.001 respectively). The pressure showed no significant difference between group M3 and group M2(P=1.000). The genes possibly associated with the formation of severe pulmonary hypertension were epithelial specific receptor tyrosine kinase(Tie2) and thrombospondin-1(TSP-1). Tie2 was down-regulated (q<0.005) in the early stage of pulmonary hypertension and up-regulated (q<0.005) in the late stage of pulmonary hypertension.TSP-1 was up-regulated (q<0.005) in the early stage of pulmonary hypertension and down-regulated (q<0.005) in the late stage of pulmonary hypertension.In the stage of severe pulmonary hypertension, the differentially expressed genes were enriched mainly in the pathways of phosphatidylinostitol 3-kinase, focal adhesion kinase and extracellular matrix receptor interaction. The study provides transcriptome information of rat pulmonary hypertension model and normal rat.Possible mechanisms of pulmonary hypertension are found.These genes and pathways might be new precursor for the diagnosis and treatment of pulmonary hypertension.

RADIOFREQUENCY DENERVATION OF PULMONARY ARTERY IN SURGERY OF DYSPLASTIC MITRAL VALVE DEFECTS WITH SEVERE PULMONARY HYPERTENSION

Pulmonary hypertension is an increase of pulmonary artery mean pressure for more than 25 mmHg at rest, measured by direct tensometry, and it includes a broad spectrum of diseases. Mechanisms of pulmonary hypertension are a connection of diverse vicious circles determining chronic progression of the disease, progradient worsening of patient’s condition and serious decline in life quality, and premature death. Severe pulmonary hypertension significantly raises risk of perioperation mortality and closely correlates with long-term survival. We propose an original technics of pulmonary artery denervation during one-stage cardiosurgical interventions, that confirmed its safety. Radiofrequency ablation of pulmonary artery in patients with dysplasia of connective tissue and high combined (precapillary and postcapillary) pulmonary hypertension, undergoing surgery for severe sympthomatic mitral insufficiency, is an effective procedure. An assessment is needed for short- and long-term results. Further studies will make it to know, whether the achieved hemodynamical benefits do turn to better clinical outcomes.