Chronic Pulmonary Arterial Hypertension Research Articles

Effect of dapagliflozin on pulmonary vascular remodeling in rats with chronic hypoxic pulmonary arterial hypertension

Objective To investigate the effects of sodium-glucose co-transporter 2 inhibitor dapagliflozin on pulmonary vascular remodeling in a rat model of chronic hypoxic pulmonary arterial hypertension. Methods Eighteen female Sprague–Dawley rats were divided into three groups: control (CON), chronic hypoxia (HYP), and chronic hypoxia + dapagliflozin. The HYP and dapagliflozin groups were subjected to hypoxia and received saline or dapagliflozin. The CON group was normoxic and received saline. Body weight and fasting blood glucose were measured, and after 21 days, lung and heart tissues were analyzed for pulmonary artery reconstruction and right ventricular hypertrophy. Western blotting assessed Bax and Bcl-2 protein levels. Results Chronic hypoxia increased pulmonary artery wall thickness and lung fibrosis and caused right ventricular hypertrophy. Dapagliflozin reduced these changes, decreasing artery wall thickness, fibrosis, and hypertrophy while increasing the Bax/Bcl-2 ratio. Conclusion Dapagliflozin alleviates chronic hypoxia-induced pulmonary artery wall thickening and lung tissue fibrosis in rats, potentially through proapoptotic effects.

Rat Model of Right-Sided Cardiac Remodeling and Arrhythmia using Pulmonary Artery Banding.

Clinical conditions, including chronic obstructive pulmonary disease or pulmonary arterial hypertension (PAH), can lead to chronic right ventricle pressure overload and progressive right heart failure (RHF). RHF can be identified by right-sided cardiac hypertrophy and dilation associated with abnormal myocardial function affecting the RV and the right atrium (RA). We recently demonstrated that severe RHF is accompanied by an increased risk of atrial inflammation, atrial fibrosis, and atrial fibrillation (AF), the most common type of cardiac arrhythmia (CA). Recent studies have shown that RV and RA inflammation plays an important role in the arrhythmogenesis of CA, including AF. However, the impact of inflammation in the development of CA and AF in RHF is poorly described. Experimental models of RHF are required to better understand the association between right-sided myocardial inflammation and CA. The rat model of monocrotaline (MCT)-induced pulmonary hypertension (PH) is well-established to provoke RHF. However, MCT triggers severe pneumo-toxicity and pulmonary inflammation. Hence, MCT-induced RHF does not help to distinguish whether the subsequent myocardial inflammation originates from the RHF per se or circulating inflammatory signals secreted by the injured lung. In this article, a mechanical method involving pulmonary artery trunk banding (PAB) was used to provoke right-sided cardiac arrhythmogenesis. The PAB consists of performing a permanent suture of the pulmonary artery trunk for 3 weeks. Such an approach generates increased right-sided pressure overload. At D21 post-PAB, the suture results in hypertrophied, dilated, and inflamed RV and RA. The PAB-induced RHF is also accompanied by vulnerability to ventricular and atrial arrhythmias, including AF.

Inhaled Nanoparticulate Systems: Composition, Manufacture and Aerosol Delivery.

An increasing growth in nanotechnology is evident from the growing number of products approved in the past decade. Nanotechnology can be used in the effective treatment of several pulmonary diseases by developing therapies that are delivered in a targeted manner to select lung regions based on the disease state. Acute or chronic pulmonary disorders can benefit from this type of therapy, including respiratory distress syndrome (RDS), chronic obstructive pulmonary disease (COPD), asthma, pulmonary infections (e.g. tuberculosis, Yersinia pestis infection, fungal infections, bacterial infections, and viral infections), lung cancer, cystic fibrosis (CF), pulmonary fibrosis, and pulmonary arterial hypertension. Modification of size and surface property renders nanoparticles to be targeted to specific sites, which can serve a vital role in innovative pulmonary drug delivery. The nanocarrier type chosen depends on the intended purpose of the formulation and intended physiological target. Liquid nanocarriers and solid-state nanocarriers can carry hydrophilic and hydrophobic drugs (e.g. small molecular weight drug molecules, large molecular weight drugs, peptide drugs, and macromolecular biological drugs), while surface modification with polymer can provide cellular targeting, controlled drug release, and/or evasion of phagocytosis by immune cells, depending on the polymer type. Polymeric nanocarriers have versatile architectures, such as linear, branched, and dendritic forms. In addition to the colloidal dispersion liquid state, the various types of nanoparticles can be formulated into the solid state, offering important unique advantages in formulation versatility and enhanced stability of the final product. This chapter describes the different types of nanocarriers, types of inhalation aerosol device platforms, liquid aerosols, respirable powders, and particle engineering design technologies for inhalation aerosols.

Cardiovascular Events in Patients with Severe Asthma-A Retrospective Study of Two Cohorts: Asthma Type T2 Treated with Biologics and Non-Type T2.

Background: The prevalence of cardiovascular events (CVEs) in patients with asthma varies amongst studies, with little evidence as to their prevalence in patients treated with monoclonal antibodies (mAbs). In this retrospective, observational study, we aimed to evaluate the prevalence of CVEs in patients with T2 and non-T2 asthma and to identify risk factors associated with CVEs. Methods: A total of 206 patients with severe asthma were included. Demographic variables, respiratory comorbidities and cardiovascular risk factors were collected, along with respiratory function, laboratory parameters and respiratory pharmacotherapy, including treatment with mAbs. Results: A total of 10.7% of the patients had any CVE from the date of asthma diagnosis, with a higher risk in those patients with chronic obstructive pulmonary disease (odds ratio [OR] = 5.36, 95% CI 1.76-16.31; p = 0.003), arterial hypertension (OR = 2.71, 95% CI 1.13-6.55; p = 0.026) and dyslipidaemia (OR = 9.34, 95% CI 3.57-24.44; p < 0.001). No association between mAb treatment and a CVE or between time of mAb treatment and the event was found. No significant differences were observed between the T2 and non-T2 cohort. After a multivariate analysis, dyslipidaemia was identified as an independent risk factor (OR = 13.33, 95% CI 4.49-39.58; p < 0.001), whereas regular use of inhaled corticosteroids was associated with a reduced risk of a CVE (OR = 0.103, 95% CI 0.021-0.499; p = 0.005). Further research is needed to fully understand the relationship between severe asthma and CVEs. Conclusions: This study suggests that patients with severe asthma experience a higher percentage of CVEs compared with the general population.

Initial Respiratory System Involvement in Juvenile Idiopathic Arthritis with Systemic Onset Is a Marker of Interstitial Lung Disease: The Results of Retrospective Cohort Study Analysis.

Background: Pulmonary involvement in systemic juvenile idiopathic arthritis (SJIA) is a rare but dangerous complication. The main risk factors are already known, such as macrophage activation syndrome, a refractory course of systemic juvenile arthritis, infusion reaction to interleukin 1 and/or interleukin 6 blockers, trisomy 21, and eosinophilia. However, information about respiratory system involvement (RSI) at the onset of SJIA is scarce. Our study aimed to evaluate the specific features of children with SJIA with RSI and their outcomes. Methods: In a single-center retrospective cohort study, we compared the information from the medical records of 200 children with SJIA according to ILAR criteria or SJIA-like disease (probable/possible SJIA) with and without signs of RSI (dyspnea, shortness of breath, pleurisy, acute respiratory distress syndrome, and interstitial lung disease (ILD)) at the disease onset and evaluated their outcomes (remission, development of chronic ILD, clubbing, and pulmonary arterial hypertension). Results: A quarter (25%) of the SJIA patients had signs of the RSI at onset and they more often had rash; hepato- and splenomegaly; heart (pericarditis, myocarditis), central nervous system, and kidney involvement; hemorrhagic syndrome; macrophage activation syndrome (MAS, 44.4% vs. 9.0%, p = 0.0000001); and, rarely, arthritis with fewer active joints, compared to patients without RSI. Five patients (10% from the group having RSI at the onset of SJIA and 2.5% from the whole SJIA cohort) developed fibrosing ILD. All of them had a severe relapsed/chronic course of MAS; 80% of them had a tocilizumab infusion reaction and further switched to canakinumab. Unfortunately, one patient with Down's syndrome had gone. Conclusion: Patients with any signs of RSI at the onset of the SJIA are required to be closely monitored due to the high risk of the following fibrosing ILD development. They required prompt control of MAS, monitoring eosinophilia, and routine checks of night oxygen saturation for the prevention/early detection of chronic ILD.

Functional autoantibodies against G protein-coupled receptors in hepatic and pulmonary hypertensions in human schistosomiasis.

Schistosomiasis (SM) is a parasitic disease caused by Schistosoma mansoni. SM causes chronic inflammation induced by parasitic eggs, with collagen/fibrosis deposition in the granuloma process in the liver, spleen, central nervous system, kidneys, and lungs. Pulmonary arterial hypertension (PAH) is a clinical manifestation characterized by high pressure in the pulmonary circulation and right ventricular overload. This study investigated the production of functional autoantibodies (fAABs) against the second loop of the G-protein-coupled receptor (GPCR) in the presence of hepatic and PAH forms of human SM. Uninfected and infected individuals presenting acute and chronic manifestations (e.g., hepatointestinal, hepato-splenic without PAH, and hepato-splenic with PAH) of SM were clinically evaluated and their blood was collected to identify fAABs/GPCRs capable of recognizing endothelin 1, angiotensin II, and a-1 adrenergic receptor. Human serum was analyzed in rat cardiomyocytes cultured in the presence of the receptor antagonists urapidil, losartan, and BQ123. The fAABs/GPCRs from chronic hepatic and PAH SM individuals, but not from acute SM individuals, recognized the three receptors. In the presence of the antagonists, there was a reduction in beating rate changes in cultured cardiomyocytes. In addition, binding sites on the extracellular domain functionality of fAABs were identified, and IgG1 and/or IgG3 antibodies were found to be related to fAABs. Our data suggest that fAABs against GPCR play an essential role in vascular activity in chronic SM (hepatic and PAH) and might be involved in the development of hypertensive forms of SM.

CDDO, an Anti-Inflammatory and Antioxidant Compound, Attenuates Vasospasm and Neuronal Cell Apoptosis in Rats Subjected to Experimental Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) is a type of stroke caused by bleeding into the subarachnoid space. SAH is a medical emergency and requires prompt treatment to prevent complications such as seizures, stroke, or other brain damage. Treatment options may include surgery, medication, or a combination of both. 2-Cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), a compound with anti-inflammatory and antioxidant properties, is currently being investigated as a potential treatment for various diseases, including chronic kidney disease and pulmonary arterial hypertension. In this study, the effects of CDDO on rats subjected to SAH were evaluated. Male Sprague-Dawley rats were divided into four groups (n = 6/group): (1) control group, (2) SAH group, (3) SAH + low-dose CDDO (10 mg/kg injected into the subarachnoid space at 24 h after SAH) group, and (4) SAH + high-dose CDDO (20 mg/kg) group. CDDO improved SAH-induced poor neurological outcomes and reduced vasospasm in the basal artery following SAH. It also decreased the SAH-induced expression of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 in both the cerebrospinal fluid and serum samples as determined by ELISA. A Western blot analysis confirmed an increase in the p-NF-κB protein level after SAH, but it was significantly decreased with CDDO intervention. Immunofluorescence staining highlighted the proliferation of microglia and astrocytes as well as apoptosis of the neuronal cells after SAH, and treatment with CDDO markedly reduced the proliferation of these glial cells and apoptosis of the neuronal cells. The early administration of CDDO after SAH may effectively mitigate neuronal apoptosis and vasospasm by suppressing inflammation.

СОВРЕМЕННЫЕ АСПЕКТЫ СОЧЕТАННОГО ТЕЧЕНИЯ ХРОНИЧЕСКОЙ ОБСТРУКТИВНОЙ БОЛЕЗНИ ЛЕГКИХ И АРТЕРИАЛЬНОЙ ГИПЕРТЕНЗИИ: В ФОКУСЕ НАРУШЕНИЕ ФУНКЦИИ ПОЧЕК

Abstract. This literature review examines the relationship between the combined course of chronic obstructive pulmonary disease (COPD) and arterial hypertension (AH) in the context of functional renal impairment that develops against the background of the disease. Features of the combined course of COPD and hypertension can also lead to an increased risk of developing renal dysfunction. For example, both diseases can cause tissue hypoxia. Studying the features of the combined course of these conditions may be useful for developing more effective programs for the prevention and treatment of complications in the cardiovascular, respiratory and urinary systems. This will reduce the risk of disability, improve the quality of life of patients and extend their lives. Thus, studying the effect of the combined course of COPD and hypertension on renal functional disorders is an important area of research that can benefit patients and help in more effective prevention and treatment of these diseases.

Abstract 17842: 3D Visualization and Quantitative Assessment of the Pulmonary Arteries on CT Using Deep Learning Segmentation

Introduction: Assessment of the pulmonary arteries (PA) on CT scan is typically qualitative and requires review of hundreds of images. PA segmentation would enable creation of 3D reconstructions that visualize the entire pulmonary arterial tree in a single image, similar to catheter angiography, and also enable quantification of pathophysiologic changes. Manual segmentation is very time-consuming, but deep-learning (DL) can automate the process. Hypothesis: A DL segmentation algorithm can be used to automatically generate 3D reconstructions of the PAs and quantify morphologic changes seen in Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH). Methods: A DL algorithm based on a 3D U-Net architecture which segments PAs larger than 2 mm was trained and validated on a total of 250 contrast-enhanced CT chest. The study group included 15 CTEPH and 15 PAH patients seen consecutively in pulmonary hypertension (PH) clinic in 2022 with prior CT chest and right heart catheterization, and 10 additional patients with prior CT chest and no evidence of PH on same day echo (normal). After running the DL algorithm on CTs, 3D renderings were created from segmentations and the relative volume of the central, interlobar, and segmental/subsegmental PAs was derived. Results: 3D renderings of PAH and CTEPH patients showed larger central and interlobar PAs compared with those of normal patients, whereas segmental and subsegmental PAs were smaller and pruned in CTEPH patients (Figure). Quantitatively, the volume of the central and interlobar PAs was higher in CTEPH and PAH compared to normal (p &lt; 0.05). The combined volume of segmental/subsegmental PAs was smaller in CTEPH patients relative to normal and PAH patients (p &lt; 0.005). Conclusions: DL segmentation enables intuitive visualization and quantification of the morphologic changes to the PAs seen in conditions causing PH. This method may improve diagnosis and assessment of PH on CT.

Effect of Nicorandil on Endothelial Markers and Tissue Remodeling in Pulmonary Arterial Hypertension Model of Male Rats

Background: Chronic pulmonary arterial hypertension (PAH) is a rare, long-lasting illness that makes pulmonary artery endothelial cells (PAEC) not work properly and leads to heart failure and death. Objective: To evaluate the effect of nicorandil in the treatment of PAH compared to tadalafil in a rat model of monocrotaline-induced PAH. Methods: Monocrotaline injection (60 mg/kg) was used for the induction of PAH in male rats; healthy control and induction groups were not treated. The other 4 groups were treated with either nicorandil or tadalafil with or without treatment blockers (glimepiride and N-Nitroarginine methyl ester (L-NAME)) for 21 days orally. Serum was obtained for assessment of endothelin-1 (ET-1) and tissue harvested for nuclear factor kappa B (NFκB) by ELISA, western blot analysis of endothelial nitric oxide synthase (eNOS), and an apoptosis assay to examine the endothelial function. Results: Nicorandil showed a significant reduction in ET-1 and significant elevation in eNOS compared to the induction group, with comparable efficacy to tadalafil; blocker groups showed significantly elevated levels of ET-1 and reduced levels of eNOS compared to healthy control; NFκB was significantly inhibited in nicorandil and tadalafil groups and significantly elevated in blocker and induction groups; while in the TUNEL apoptosis assay, nicorandil showed the highest level of inhibition to apoptosis with apparently normal endothelium lining. Conclusions: Nicorandil shows anti-inflammatory, antiapoptotic, and enhanced endothelial morphology and function compared to the induction model.

A Bioinformatic Algorithm based on Pulmonary Endoarterial Biopsy for Targeted Pulmonary Arterial Hypertension Therapy.

Optimal pharmacological therapy for pulmonary arterial hypertension (PAH) remains unclear, as pathophysiological heterogeneity may affect therapeutic outcomes. A ranking methodology based on pulmonary vascular genetic expression analysis could assist in medication selection and potentially lead to improved prognosis. To describe a bioinformatics approach for ranking currently approved pulmonary arterial antihypertensive agents based on gene expression data derived from percutaneous endoarterial biopsies in an animal model of pulmonary hypertension. We created a chronic PAH model in Micro Yucatan female swine by surgical anastomosis of the left pulmonary artery to the descending aorta. A baseline catheterization, angiography and pulmonary endoarterial biopsy were performed. We obtained pulmonary vascular biopsy samples by passing a biopsy catheter through a long 8 French sheath, introduced via the carotid artery, into 2- to 3-mm peripheral pulmonary arteries. Serial procedures were performed on days 7, 21, 60, and 180 after surgical anastomosis. RNA microarray studies were performed on the biopsy samples. Utilizing the medical literature, we developed a list of PAH therapeutic agents, along with a tabulation of genes affected by these agents. The effect on gene expression from pharmacogenomic interactions was used to rank PAH medications at each time point. The ranking process allowed the identification of a theoretical optimum three-medication regimen. We describe a new potential paradigm in the therapy for PAH, which would include endoarterial biopsy, molecular analysis and tailored pharmacological therapy for patients with PAH.

Long-Term Safety, Outcome, and Clinical Effects of Subcutaneous and Intravenous Treprostinil Treatment in Patients with Severe Chronic Pulmonary Arterial Hypertension

Background: Current guidelines recommend treatment with parenteral prostacyclin analogs in patients with severe pulmonary arterial hypertension (PAH), who have insufficient response to treatment. Real-life data are sought to help physicians in treatment decisions and clinical care of patients. Objective: This study analyzed safety, clinical effects, and long-term outcomes of subcutaneous (sc) and/or intravenous (iv) treprostinil via different pump systems in consecutive patients with PAH. Methods: Thirty-seven patients with severe progressive PAH despite dual combination therapy (20 female, mean age: 52.3 ± 15 years, mean pulmonary vascular resistance: 12.1 ± 5.1 WU) were initiated with add-on treprostinil sc and were routinely clinically assessed. Changes in clinical parameters, adverse events, and outcome were analyzed retrospectively. Results: In 24 of 37 patients, treprostinil administration was continued iv via implantation of LENUS Pro® pump after 3 ± 1.3 months, 6 patients continued with sc therapy, and 7 discontinued treatment. After 3, 6, 9, and 12 months of treprostinil treatment, patients showed a significant improvement in mean 6-min walk distance and tricuspid annular plane systolic excursion compared to baseline. In 8 of the 24 patients, iv pumps required surgical revision. During a mean follow-up of 2.82 ± 1.95 years, 12 patients died, four received lung transplantation. Transplant-free survival after 1, 2, and 3 years was 85.7%, 69.2%, and 65.3%, respectively. Conclusion: sc treprostinil as add-on to double combination treatment significantly improved exercise capacity and right heart function. In most patients, treprostinil could be continued via more tolerable iv administration approach (LENUS Pro® pump), showing reasonable overall survival with respect to the severity of PAH.

Physiological and Psychological Response to Acute Mental Stress in Female Patients Affected by Chronic Pulmonary Arterial Hypertension: An Explorative Controlled Pilot Trial.

Little is known about physiological and psychological responses to mental stress in stable patients affected by pulmonary arterial hypertension (PAH). The current explorative controlled pilot study was conducted to investigate whether heart rate (HR) and perceived stress would differ during standardized mental stress testing in PAH patients compared to healthy subjects. Correlation analysis between HR, perceived stress, participants' psychological status and performance on the mental stress task was also performed. The study included 13 female PAH patients (average age: 44.38 ± 10.88 years; average education: 14 ± 3.07 years; mean duration of illness: 9.15 ± 5.37 years) and 13 female controls similar in age (mean age: 47.85 ± 6.36 years) and education (15.92 ± 1.55 years). Participants performed a standardized 9 min mental stress test (computer based, adaptive math task). HR and perceived stress during the task were compared to resting baseline and correlated with psychological state and task performance. Both HR and perceived stress significantly increased during mental stress in a similar way in both groups. A significant correlation was found between HR and perceived stress. Our data show that moderate mental stress has a comparable effect on HR and perceived stress increase in stable PAH patients and control subjects.

Evaluation of left ventricular function in patients with chronic obstructive disease and pulmonary arterial hypertension

Evaluation of left ventricular function in patients with chronic obstructive disease and pulmonary arterial hypertension

CTLA-4 Expression Is a Promising Biomarker of Idiopathic Pulmonary Arterial Hypertension and Allows Differentiation of the Type of Pulmonary Hypertension.

Pulmonary arterial hypertension (PAH) is an increasingly frequently diagnosed disease, the molecular mechanisms of which have not been thoroughly investigated. The aim of our study was to investigate subpopulations of lymphocytes to better understand their role in the molecular pathomechanisms of various types of PAH and to find a suitable biomarker that could be useful in the differential diagnosis of PAH. Using flow cytometry, we measured the frequencies of lymphocyte subpopulations CD4+CTLA-4+, CD8+ CTLA-4+ and CD19+ CTLA-4+ in patients with different types of PAH, namely pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH), pulmonary arterial hypertension associated with connective tissue disorders (CTD-PAH), chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH), and in an age- and sex-matched control group in relation to selected clinical parameters. Patients in the iPAH group had the significantly highest percentage of CD4+CTLA-4+ T lymphocytes among all PAH groups, as compared to those in the control group (p < 0.001), patients with CTEPH (p < 0.001), CTD-PAH (p < 0.001) and CHD-PAH (p < 0.01). In iPAH patients, the percentages of CD4+CTLA-4+ T cells correlated strongly positively with the severity of heart failure New York Heart Association (NYHA) Functional Classification (r = 0.7077, p < 0.001). Moreover, the percentage of B CD19+CTLA-4+ cells strongly positively correlated with the concentration of NT-proBNP (r = 0.8498, p < 0.001). We have shown that statistically significantly higher percentages of CD4+CTLA-4+ (p ≤ 0.01) and CD8+ CTLA-4+ (p ≤ 0.001) T cells, measured at the time of iPAH diagnosis, were found in patients who died within 5 years of the diagnosis, which allows us to consider both of the above lymphocyte subpopulations as a negative prognostic/predictive factor in iPAH. CTLA-4 may be a promising biomarker of noninvasive detection of iPAH, but its role in planning the treatment strategy of PAH remains unclear. Further studies on T and B lymphocyte subsets are needed in different types of PAH to ascertain the relationships that exist between them and the disease.

AD-9308 ameliorates the impacts of 4-HNE on the progress of pulmonary arterial hypertension in aldehyde dehydrogenase 2*1*2 knock-in mice

Abstract Endothelial dysfunctions play a critical role on the development of pulmonary arterial hypertension (PAH). It has been reported that the one-year mortality rate is still up to 15% even with PAH-targeted therapy, implying that there may be untargeted pathways. 4-hydroxynenonal (4-HNE), an unsaturated aldehyde, is highly induced in the lungs of PAH animals and its serum levels were also reported to be higher in PAH patients. 4-HNE is metabolized by mitochondrial aldehyde dehydrogenase (ALDH2), which is dysfunctional in near 40% of East Asian people. Currently, the impacts of 4-HNE on endothelial dysfunctions in the development of PAH are unclear. In terms of translational medicine, we proposed that modulation of 4-HNE level may alleviate the progress of PAH patients with ALDH2 deficiency. We found that 4-HNE alone was not sufficient to induce pulmonary artery endothelial cell (PAEC) functional changes, including proliferation, migration and tube formation, whereas their effects emerge from the depletion of ALDH2. We further mimicked human ALDH2 functional deficiency by using daidzin (DZN), an inhibitor which is able to block the substrate binding site of ALDH2. ALDH2 functional inhibition alone did not induce any PAEC functional change, while an add-on of 4-HNE impaired PAEC functions. In addition, 4-HNE significantly reduced eNOS activity with combined DZN treatment. Consistent with the mechanism of ALDH2 activity-mediated angiogensis, ALDH2 enhancers Alda-1 and AD-5591 completely reverse the anti-angiogenic effects of 4-HNE in the presence of DZN. To further confirm whether ALDH2 functional deficiency impact on PAH development in mammals, heterozygous ALDH2*1/*2 transgenic and wild-type mice were subjected to chronic hypoxia to induce PAH. ALDH2*1/*2 transgenic mice had similar right ventricular systolic pressure (RVSP) as wild-type mice. However, after exposure to chronic hypoxia, ALDH2*1/*2 transgenic mice indeed developed a significantly higher RVSP than that in wild-type mice. Furthermore, we demonstrated that 4-HNE expression was profoundly enhanced in ALDH2*1/*2 transgenic mice by chronic hypoxia-induced PAH with pulmonary artery smooth muscle cell hyperplasia. More importantly, we found that AD-9308, an enhancer of ALDH2 significantly decreased hypoxia-induced RVSP elevation in heterozygous ALDH2*1/*2 transgenic mice. Taken together, our data demonstrate that 4-HNE and ALDH2 functional deficiency potentially contribute to PAH development and worsening, and that ALDH2 enhancers may be promising as a PAH adjunct therapy, particularly for patients with ALDH2 nonfunctional alleles. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Ministry of Science and Technology, Taiwan

Microvasculopathy Evaluated by Dual-Energy Computed Tomography in Patients with Chronic Thromboembolic Pulmonary Hypertension and Pulmonary Arterial Hypertension.

Background: Poor subpleural perfusion (PSP) on dual-energy computed tomography (DE-CT) suggests microvasculopathy in chronic thromboembolic pulmonary hypertension (CTEPH). However, whether the microvasculopathy findings are equivalent to those in pulmonary arterial hypertension (PAH) remains unclear. The aim of this study was to elucidate the characteristics of microvasculopathy in CTEPH compared to those of that in PAH. Methods: We retrospectively reviewed subpleural perfusion on DE-CT and the hemodynamics of 23 patients with PAH and 113 with inoperable CTEPH. Subpleural perfusion on DE-CT was classified as poor (subpleural spaces in all segments with little or no perfusion) or normal. Results: PSP was observed in 51% of patients with CTEPH and in 4% of those with PAH (p < 0.01). CTEPH patients with PSP had poorer baseline hemodynamics and lower diffusing capacity for carbon monoxide divided by the alveolar volume (DLCO/VA) than those with CTEPH with normal perfusion (pulmonary vascular resistance [PVR]: 768 ± 445 dynes-sec/cm5 vs. 463 ± 284 dynes-sec/cm5, p < 0.01; DLCO/VA, 60.4 ± 16.8% vs. 75.9 ± 15.7%, p < 0.001). Despite the existence of PSP, hemodynamics improved to nearly normal in both groups after balloon pulmonary angioplasty. Conclusions: PSP on DE-CT, which is one of the specific imaging findings in CTEPH, might suggest a different mechanism of microvasculopathy from that in PAH.

Maternal and perinatal obesity induce bronchial obstruction and pulmonary hypertension via IL-6-FoxO1-axis in later life

Obesity is a pre-disposing condition for chronic obstructive pulmonary disease, asthma, and pulmonary arterial hypertension. Accumulating evidence suggests that metabolic influences during development can determine chronic lung diseases (CLD). We demonstrate that maternal obesity causes early metabolic disorder in the offspring. Here, interleukin-6 induced bronchial and microvascular smooth muscle cell (SMC) hyperproliferation and increased airway and pulmonary vascular resistance. The key anti-proliferative transcription factor FoxO1 was inactivated via nuclear exclusion. These findings were confirmed using primary SMC treated with interleukin-6 and pharmacological FoxO1 inhibition as well as genetic FoxO1 ablation and constitutive activation. In vivo, we reproduced the structural and functional alterations in offspring of obese dams via the SMC-specific ablation of FoxO1. The reconstitution of FoxO1 using IL-6-deficient mice and pharmacological treatment did not protect against metabolic disorder but prevented SMC hyperproliferation. In human observational studies, childhood obesity was associated with reduced forced expiratory volume in 1 s/forced vital capacity ratio Z-score (used as proxy for lung function) and asthma. We conclude that the interleukin-6-FoxO1 pathway in SMC is a molecular mechanism by which perinatal obesity programs the bronchial and vascular structure and function, thereby driving CLD development. Thus, FoxO1 reconstitution provides a potential therapeutic option for preventing this metabolic programming of CLD.

LOW LEVELS OF COAGULATION FACTOR XI AND XII IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION COMPARED WITH PUMONARY EMBOLISM

TYPE: Late Breaking Abstract TOPIC: Pulmonary Vascular Disease PURPOSE: We aimed to explore the difference of coagulation factor XI and XII in chronic thromboembolic pulmonary hypertension (CTEPH), pulmonary embolism (PE) and idiopathic pulmonary arterial hypertension (IPAH). METHODS: The retrospectively cross-sectional study included 316 patients from June 2013 to June 2017. Plasma activity of factor XI and XII were measured and compared in 111 CTEPH patients, 82 APE survivors, who have not developed chronic pulmonary hypertension after at least 2 years from the acute episode, and123 IPAH patients. All the clinical and laboratory profiles were documented after a full anti-coagulation therapy at least for 3 months in PE and CTEPH patients. RESULTS: In CTEPH patients, factor XI activity was significant lower than in PE patients (P<0.001) and IPAH group (P<0.001), while PE was higher than IPAH patients. Factor XII activity of CTEPH was lower than PE patients’ (P<0.001) while comparable to IPAH. Receiver-operating characteristic curves showed the great performance of factor XI and XII activity in distinguishing PE from CTEPH. Besides, Adjustment for age, gender, BMI, antiphospholipid antibody syndrome, autoimmune diseases, thyroid replacement therapy, splenectomy, and blood group didn’t change the effect size of every 10% increase of factor XI and XII activity for risk of CTEPH (OR = 0.78, 95%Cl 0.70-0.87 and 0.90, 95%Cl 0.83-0.98). CONCLUSIONS: Plasma XI and XII activity seems to represent important factors in CTEPH pathophysiology and may have been continuously consumed during the whole process of its pathophysiology, which may contribute to the clinical diagnosis and therapy. CLINICAL IMPLICATIONS: This results may contribute to the clinical diagnosis and therapy. DISCLOSURE: Nothing to declare. KEYWORD: FACTOR XI; FACTOR XII; CTEPH; PULMONARY EMBOLISM

THERAPEUTIC EFFECTS OF NEBULIZATION- BASED DELIVERY OF ANTI-MIR-146A IN EXPERIMENTAL PULMONARY ARTERIAL HYPERTENSION

Objective: Pulmonary arterial hypertension (PAH), is a chronic disorder characterized by excessive pulmonary vascular remodelling, resulting in elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. PAH remains incurable, and new therapeutic approaches are required. The microRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both important hallmarks of PAH. This study aimed to investigate the role of miR-146a in the pathophysiology of PAH and in the progression to RV hypertrophy and failure. Design and method: Sprague Dawley rats received a subcutaneous injection of monocrotaline (MCT group) or vehicle (CTRL group) and, after fourteen days they were treated, by intratracheal nebulization, with an anti-miR-146a, forming four distinct groups: CTRL-treated; CTRL-untreated, MCT-treated, and MCT-untreated. Twenty-seven days after MCT injection, echocardiographic and invasive hemodynamic evaluations were performed in all animal groups. Also, wild-type (WT) and miR-146a knock-out (KO) (miR-146a-/-) mice were submitted to either 3 weeks of chronic hypoxia-induced PAH with weekly Sugen 5416 administration (SuHx). Results: Compared to MCT-untreated rats, the MCT-treated rats showed decreased RV hypertrophy, (as measured by the Fulton index), decreased RV end-diastolic diameter/left ventricle end-diastolic diameter (RVEDD/LVEDD) ratio, and decreased in RV diastolic pressures. KO-SuHx group, when compared to WT-SuHx group, showed decreased RV hypertrophy (as measured by the Fulton index), and decreased RV systolic pressures and dilation, as well as lower RV end end-diastolic diameter (RVEDDi) and right atria area (RAAi). Conclusions: Our findings show that miR-146a pharmacological or genetic inhibition reduces RV remodelling and improves cardiac function. Thus, miR-146a represents a promising therapeutic target in PAH.