Pulmonary Arterial Resistance Research Articles

A novel modified Steen solution limits inflammatory processes during ex vivo lung perfusion and improves graft function post-transplantation

BackgroundEx vivo lung perfusion allows donor lung preservation, assessment and reconditioning prior to transplantation, but is associated with increased inflammatory injury over time. Addition of anti-oxidative and anti-inflammatory agents to perfusate formulations could limit iatrogenic injury during perfusion. The effectiveness of a modified Steen solution containing acetyl salicylic acid, retinoic acid and methylprednisolone, was examined using a porcine extended criteria donor ex vivo lung perfusion and transplantation model. MethodsPorcine donor lungs underwent 24 hours cold storage and were then randomised to 4 hours normothermic ex vivo lung perfusion with modified Steen or original Steen, followed by single lung transplantation into a recipient pig. RNA-sequencing was used to assess tissue inflammatory changes during perfusion. Organ function was examined during perfusion and following transplantation and compared between groups. ResultsLungs perfused with modified Steen showed reduced pulmonary vascular resistance (p=0.0391) and stable pulmonary artery pressure despite achieving higher flows (p=0.0001) compared to Steen. Lung tissue showed negative enrichment of the TNF-α signalling via NF-κB pathway (p=0.0040) in modified Steen compared to Steen. Recipients of lungs perfused with modified Steen also showed improved post-transplantation oxygenation (p=0.0462). ConclusionsThis study highlights the superiority of modified Steen compared with original Steen. The modifications to Steen solution appear to limit inflammatory injury via the NF-κB signalling pathway during perfusion, leading to improved post-transplant function. Modified Steen provides the potential to improve post-transplant outcomes following EVLP of extended criteria lungs and could also facilitate extended assessment and preservation, as well as administration of advanced therapies.

Sleep-disordered breathing and nocturnal hypoxemia in chronic thromboembolic pulmonary disease.

Sleep-disordered breathing (SDB) and nocturnal hypoxemia were known to be present in patients with chronic thromboembolic pulmonary hypertension (CTEPH), but the difference betweenSDB and nocturnal hypoxemia in patients who have chronic thromboembolic pulmonary disease (CTEPD) with or without pulmonary hypertension (PH) at rest remains unknown. Patients who had CTEPH (n = 80) or CTEPD without PH (n= 40) and who had undergone sleep studies from July 2020 to October 2022 at Shanghai Pulmonary Hospital were enrolled. Nocturnal mean SpO2 (Mean SpO2) <90% was defined as nocturnal hypoxemia, and the percentage of time with a saturation below 90% (T90%) exceeding 10% was used to evaluate the severity of nocturnal hypoxemia. Logistic and linear regression analyses were performed to investigate the difference and potential predictor of SDB or nocturnal hypoxemia between CTEPH and CTEPD without PH. SDB was similarly prevalent in CTEPH and CTEPD without PH (P = 0.104), both characterised by obstructive sleep apnoea (OSA). Twenty-two patients with CTEPH were diagnosed with nocturnal hypoxemia, whereas only three were diagnosed with CTEPD without PH (P = 0.021). T90% was positively associated with mean pulmonary arterial pressure (mPAP) and pulmonary vascular resistance in patients with CTEPH and CTEPD without PH (P < 0.001); T90% was also negatively related to cardiac output in these patients. Single-breath carbon monoxide diffusing capacity, sex and mPAP were all correlated with nocturnal hypoxemia in CTEPH and CTEPD without PH (all P < 0.05). Nocturnal hypoxemia was worse in CTEPD with PH; T90%, but not SDB, was independently correlated with the hemodynamics in CTEPD with or without PH.

Preferential vasodilator effects of levosimendan in resistance pulmonary arteries in a rodent pulmonary embolism model

Background: We compared the vasoactive effects of levosimendan on isolated conduit pulmonary arteries (CPA) and resistance pulmonary arteries (RPA) versus mesenteric arteries, and we assessed the pulmonary artery (PA) vascular function and the PA vasoactive effects of levosimendan in a rodent pulmonary embolism (PE) model.Methods: One group of male Wistar rats (200-300 g) was killed by decapitation to obtain pulmonary and mesenteric rings. Another group was assigned to a massive PE or saline solution infusion. After euthanasia, mesenteric arteries and CPA (1-2 mm) and RPA (≤0.5 mm) were dissected and cut into 2-3 mm wide rings, recording contractile tension. We obtained the concentration-response curves of cumulative doses of levosimendan on pre-contracted arterial rings from decapitated and sham/embolized animals. A set of RPA rings was exposed to acute hypoxia. The effect of PE on the pulmonary vasoactive function was assessed by dose-response curves of acetylcholine (ACh) and endothelin-1 (ET-1) of PA rings from sham/embolized animals.Results: Levosimendan relaxant potency of RPA was similar to that of mesenteric arteries and higher than CPA, while mesenteric rings showed the maximal relaxant effect, followed by RPA and CPA, respectively. PE did not affect the vasoactive response of PA rings either to ACh or to ET-1, and the relaxant effects of CPA and RPA to levosimendan were also preserved. Acute hypoxia reduced (p&lt;0.05) but did not avoid the RPA relaxant effect of levosimendan.Conclusions: Levosimendan is a more specific vasodilator of RPA with a similar relaxant potency as mesenteric arteries, which is preserved after PE but significantly reduced during hypoxia.

Basic aspects of pathophysiology, diagnosis and treatment of patients with pulmonary arterial hypertension associated with human immunodeficiency virus infection: what has been achieved and what remains to be achieved?

Human immunodeficiency virus (HIV) infection is characterized by high morbidity and is a significant threat to human health, increasing global mortality. The number of people living with HIV infection is estimated by the United Nations Joint Program on Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (UNAIDS) to be 39 million (33.1-45.7 million) in 2022. With the introduction of highly effective antiretroviral therapy (cART) into clinical practice and the resulting increase in life expectancy in this cohort of patients, HIV-associated complications have come to the forefront, among which the most severe is pulmonary arterial hypertension (PAH), characterized by a progressive increase in pulmonary vascular resistance and pulmonary artery pressure, leading to the development of right ventricular failure. Subsequently, it became evident that this pathology can occur at all stages of HIV infection and, apparently, has no clear relationship with the degree of immunodeficiency, and is an independent predictor of mortality in patients with LAH-HIV, and therefore requires separate, close attention. This article provides an overview covering the basic pathophysiology, clinical manifestations, diagnosis and treatment of HIV-associated LAH (LAHHIV), emphasizing the challenges encountered at each stage. The review also considers current aspects aimed at studying LAH in patients with HIV, including new experimental drug therapies that take into account the interaction of different regimens with LAH-specific drugs.

Diagnosis, management and long term cardiovascular outcomes of phenotypic profiles in pulmonary hypertension associated with congenital diaphragmatic hernia.

Congenital diaphragmatic hernia (CDH) is a developmental defect of the diaphragm resulting in herniation of viscera into the chest. This condition is characterized by pulmonary hypoplasia, pulmonary hypertension (PH) and cardiac ventricular dysfunction. PH is a key component of the pathophysiology of CDH in neonates and contributes to morbidity and mortality. Traditionally, PH associated with CDH (CDH-PH) is thought to be secondary to increased pulmonary arterial resistance and vasoreactivity resulting from pulmonary hypoplasia. Additionally, there is increasing recognition of associated left ventricular hypoplasia, dysfunction and elevated end diastolic pressure resulting in pulmonary venous hypertension in infants with CDH. Thus, hemodynamic management of these infants is complex and cautious use of pulmonary vasodilators such as inhaled nitric oxide (iNO) is warranted. We aim to provide an overview of different phenotypic profiles of CDH associated PH and potential management options based on current evidence and pathophysiology.

Effect of Nasal High Flow (NHF) on Right Heart Function in Stable Patients with Pulmonary Hypertension of Different WHO Classes.

Background: Nasal high flow (NHF) has various effects on the respiratory system in acute and chronic conditions. There are initial reports that NHF is also able to influence cardiac function in acute decompensation. This study was designed to clarify whether NHF has an influence on the right heart in stable patients with chronic pulmonary hypertension. Methods: Forty-one stable patients from different pulmonary hypertension (PH) WHO classes were recruited. Most patients were assigned to WHO classes 1 and 3. All received a right heart catheterization and blood gas analysis. Oxygenation was kept constant. The mean pulmonary arterial pressure (mPAP), wedge pressure (PC), cardiac output (CO), diastolic pulmonary gradient (DPG), pulmonary arterial resistance (PVR) and other parameters were determined. The patients then used NHF at 35 L/min for 20 min, after which the right heart catheter measurements were repeated with ongoing NHF therapy. Results: In the entire cohort and in the subgroups, there were no changes in right heart function or cardiac ejection fraction. The blood gases did not change either. Conclusions: Thus, there is no effect of NHF on right heart function in stable patients with PH.

The place of tadalafil in the treatment of PAH in the light of new clinical guidelines of the Eurasian Association of Cardiologists

Pulmonaryarterialhypertension(PAH)isalife-threateningcardiovascular disease that is characterized by a marked increase in pulmonary vascular resistance and pulmonary artery pressure due to obstructive remodeling of the pulmonary vascular bed with the development of right ventricular heart failure as a cause of premature mortality. Impaired synthesis and reduced bioavailability of nitric oxide is one of the key pathophysiological mechanisms of the development and progression of the disease. The review paper presents key data from the evidence base on the clinical use of tadalafil, a phosphodiesterase type 5 inhibitor (PDE5), which in August 2023 approved by the Pharmaceutical Committee of the Russian Ministry of Health for the indication – treatment of patients with PAH. Tadacardil from Canonpharma Production is the first and only drug in Russian practice today with the active substance tadalafil with the registered indication “PAH”, approved in the Eurasian Guidelines for the diagnosis and treatment of pulmonary hypertension 2023 and available on the territory of the Russian Federation and the EAEU. Tadacardil is indicated for use in adult patients with PAH functional class II and III according to the WHO classification to increase exercise tolerance. The efficacy of tadalafil has been shown in idiopathic PAH and PAH associated with connective tissue diseases. The recommended dose is 40 mg (2 tablets of 20 mg) once a day. The paper describes the mechanism of action and pharmacological effects of PDE5 inhibitors, features of the pharmacokinetics of tadalafil in comparison with other drugs of the class. The advantages of Tadacardil from Canonpharma Production are the proven effecacy of use in patients with PAH, ease of use due to a single dose of 2 tablets of 20 mg once a day in a standard dose; good tolerability and favorable safety profile; proven bioequivalence to the reference drug. In light of the new Eurasian recommendations for the diagnosis and treatment of PH, tadalafil has a wide field for clinical use, which will improve the treatment options for patients with PAH both in mono- and combination therapy.

Detrimental Impact of Comorbid Mental Disorders in Chronic Thromboembolic Pulmonary Hypertension - A Retrospective Observational Study.

Background: The relationship between the prognosis of patients with both chronic thromboembolic pulmonary hypertension (CTEPH) and a mental disorder (MD) remains unclear. Methods and Results: The study group comprised 157 patients with CTEPH who underwent right heart catheterization and were subdivided into 2 groups according to the presence of MDs: MD and non-MD. The patients with MDs were defined as those who had visited a psychiatrist and were under psychotropic drug treatment. The primary outcome was a composite of all-cause death and worsening of PH. The median follow-up period was 1,164 days. The incidence of the primary composite outcome was higher in the MD group than in the non-MD group (24.0% vs. 6.8%), whereas the all-cause mortality rate was comparable between groups (12.0% vs. 6.1%). The mean pulmonary arterial pressure, cardiac index, and pulmonary vascular resistance at baseline were all similar between groups. The Cox proportional hazards model indicated that MD was an independent risk factor for the primary composite outcome (hazard ratio, 2.990; 95% confidence interval, 1.034-8.642). Conclusions: In the present study, concomitant CTEPH and MD was significantly associated with a poor prognosis and such patients should be carefully followed.

Polymerized Human Hemoglobin-Based Oxygen Carrier Preserves Lung Allograft Function During Normothermic Ex Vivo Lung Perfusion.

Normothermic ex vivo lung perfusion (EVLP) can resuscitate marginal lung allografts to increase organs available for transplantation. During normothermic perfusion, cellular metabolism is more active compared with subnormothermic perfusion, creating a need for an oxygen (O 2 ) carrier in the perfusate. As an O 2 carrier, red blood cells (RBCs) are a scarce resource and are susceptible to hemolysis in perfusion circuits, thus releasing cell-free hemoglobin (Hb), which can extravasate into the tissue space, thus promoting scavenging of nitric oxide (NO) and oxidative tissue damage. Fortunately, polymerized human Hb (PolyhHb) represents a synthetic O 2 carrier with a larger molecular diameter compared with Hb, preventing extravasation, and limiting adverse reactions. In this study, a next-generation PolyhHb-based perfusate was compared to both RBC and asanguinous perfusates in a rat EVLP model. During EVLP, the pulmonary arterial pressure and pulmonary vascular resistance were both significantly higher in lungs perfused with RBCs, which is consistent with RBC hemolysis. Lungs perfused with PolyhHb demonstrated greater oxygenation than those perfused with RBCs. Post-EVLP analysis revealed that the PolyhHb perfusate elicited less cellular damage, extravasation, iron tissue deposition, and edema than either RBCs or colloid control. These results show promise for a next-generation PolyhHb to maintain lung function throughout EVLP.

Chronic Thromboembolic Pulmonary Hypertension: A Review of the Multifaceted Pathobiology.

Chronic thromboembolic pulmonary disease results from the incomplete resolution of thrombi, leading to fibrotic obstructions. These vascular obstructions and additional microvasculopathy may lead to chronic thromboembolic pulmonary hypertension (CTEPH) with increased pulmonary arterial pressure and pulmonary vascular resistance, which, if left untreated, can lead to right heart failure and death. The pathobiology of CTEPH has been challenging to unravel due to its rarity, possible interference of results with anticoagulation, difficulty in selecting the most relevant study time point in relation to presentation with acute pulmonary embolism (PE), and lack of animal models. In this article, we review the most relevant multifaceted cross-talking pathogenic mechanisms and advances in understanding the pathobiology in CTEPH, as well as its challenges and future direction. There appears to be a genetic background affecting the relevant pathological pathways. This includes genetic associations with dysfibrinogenemia resulting in fibrinolysis resistance, defective angiogenesis affecting thrombus resolution, and inflammatory mediators driving chronic inflammation in CTEPH. However, these are not necessarily specific to CTEPH and some of the pathways are also described in acute PE or deep vein thrombosis. In addition, there is a complex interplay between angiogenic and inflammatory mediators driving thrombus non-resolution, endothelial dysfunction, and vascular remodeling. Furthermore, there are data to suggest that infection, the microbiome, circulating microparticles, and the plasma metabolome are contributing to the pathobiology of CTEPH.

Autonomic nervous modulation: early treatment for pulmonary artery hypertension.

Pulmonary artery hypertension (PAH) is a chronic vascular disease defined by the elevation of pulmonary vascular resistance and mean pulmonary artery pressure, which arises due to pulmonary vascular remodelling. Prior research has already established a link between the autonomic nervous system (ANS) and PAH. Therefore, the rebalancing of the ANS offers a promising approach for the treatment of PAH. The process of rebalancing involves two key aspects: inhibiting an overactive sympathetic nervous system and fortifying the impaired parasympathetic nervous system through pharmacological or interventional procedures. However, the understanding of the precise mechanisms involved in neuromodulation, whether achieved through medication or intervention, remains insufficient. This limited understanding hinders our ability to determine the appropriate timing and scope of such treatment. This review aims to integrate the findings from clinical and mechanistic studies on ANS rebalancing as a treatment approach for PAH, with the ultimate goal of identifying a path to enhance the safety and efficacy of neuromodulation therapy and improve the prognosis of PAH.

Adult-onset idiopathic peripheral pulmonary artery stenosis.

Peripheral pulmonary artery stenosis (PPS) refers to stenosis of the pulmonary artery from the trunk to the peripheral arteries. Although paediatric PPS is well described, the clinical characteristics of adult-onset idiopathic PPS have not been established. Our objectives in this study were to characterise the disease profile of adult-onset PPS. We collected data in Japanese centres. This cohort included patients who underwent pulmonary angiography (PAG) and excluded patients with chronic thromboembolic pulmonary hypertension or Takayasu arteritis. Patient backgrounds, right heart catheterisation (RHC) findings, imaging findings and treatment profiles were collected. 44 patients (median (interquartile range) age 39 (29-57) years; 29 females (65.9%)) with PPS were enrolled from 20 centres. In PAG, stenosis of segmental and peripheral pulmonary arteries was observed in 41 (93.2%) and 36 patients (81.8%), respectively. 35 patients (79.5%) received medications approved for pulmonary arterial hypertension (PAH) and 22 patients (50.0%) received combination therapy. 25 patients (56.8%) underwent transcatheter pulmonary angioplasty. RHC data showed improvements in both mean pulmonary arterial pressure (44 versus 40 mmHg; p<0.001) and pulmonary vascular resistance (760 versus 514 dyn·s·cm-5; p<0.001) from baseline to final follow-up. The 3-, 5- and 10-year survival rates of patients with PPS were 97.5% (95% CI 83.5-99.6%), 89.0% (95% CI 68.9-96.4%) and 67.0% (95% CI 41.4-83.3%), respectively. In this study, patients with adult-onset idiopathic PPS presented with segmental and peripheral pulmonary artery stenosis. Although patients had severe pulmonary hypertension at baseline, they showed a favourable treatment response to PAH drugs combined with transcatheter pulmonary angioplasty.

Reverse remodelling of right ventricle induced by pregnancy

Abstract Introduction During pregnancy, the cardiovascular (CV) system is exposed to haemodynamic overload and is required to meet the increased demands of the growing foetus. Many studies have focused on left ventricular remodelling, overlooking right cardiac chamber changes. Aim To characterize the right cardiac reverse remodelling (RR) through echocardiography during pregnancy and postpartum. Methods This prospective cohort study included volunteer pregnant women (healthy and women with CV risk factors - obese and/or hypertensive and/or with gestational diabetes) recruited at two tertiary centres from 2019 to 2021. Women were evaluated by transthoracic echocardiography at the 3rd trimester [PT3, 30-35 weeks, peak of cardiac remodelling] of pregnancy and 6 months after delivery [PP2] (RR). Wilcoxon test was used to compare values between PT3 and PP2. Results We included 130 pregnant women with a median age of 33 years, 42% had CV risk factors. RV volume reduced significantly from PT3 to PP2 (33.9 mL to 30.5 mL, p=0.015). Similar significant regression of RA area was observed (13.6 cm2 to 13.1 cm2, p=0.045). Regarding systolic function of the RV, a significant increase in fractional area change (FAC) was reported from PT3 to PP2 (47.4% to 49.4%, p=0.019), while the opposite progression was found for tricuspid annular plane systolic excursion (TAPSE, 24.6 mm to 23.4 mm, p&amp;lt;0.001) and S' tricuspid wave (14.2 cm/s to 12.7 cm/s, p&amp;lt;0.001). In terms of myocardial deformation, a significant increase of RV global longitudinal strain (GLS) (-23% to -25%, p=0.016) and RA (34% to 37%, p=0.026) from the pre- to the postpartum period. Regarding the changes in diastolic function, E/A tricuspid ratio increased significantly after delivery (1.3 to 1.7, p&amp;lt;0.001), mostly due to a decrease of A wave velocity (38 cm/s to 29 cm/s, p&amp;lt;0.001), while no significant difference was found in E/e’ from PT3 to PP2 (3.8 to 3.7, p=0.140). No differences were observed in pulmonary vascular resistance and pulmonary artery systolic pressure (1.3 woods in both and 18 mmHg in both, respectively). Conclusion We report a significative regression of right chambers size up to 6 months after delivery. Pregnancy significantly impacts right systolic function as assessed by decreased FAC and strain analysis with a compensatory increase of TAPSE. Right diastolic function reflects pregnancy adaptation to volume overload as observed by the augmented velocity of atrial contraction.

Classification and Predictors of Right Ventricular Functional Recovery in Pulmonary Arterial Hypertension.

Normative changes in right ventricular (RV) structure and function have not been characterized in the context of treatment-associated functional recovery (RV functional recovery [RVFnRec]). The aim of this study is to assess the clinical relevance of a proposed RVFnRec definition. We evaluated 63 incident patients with pulmonary arterial hypertension by right heart catheterization and cardiac magnetic resonance imaging at diagnosis and cardiac magnetic resonance imaging and invasive cardiopulmonary exercise testing following treatment (≈11 months). Sex, age, ethnicity matched healthy control subjects (n=62) with 1-time cardiac magnetic resonance imaging and noninvasive cardiopulmonary exercise testing were recruited from the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) project. We examined therapeutic cardiac magnetic resonance imaging changes relative to the evidence-based peak oxygen consumption (VO2peak)>15 mL/(kg·min) to define RVFnRec by receiver operating curve analysis. Afterload was measured as mean pulmonary artery pressure, resistance, compliance, and elastance. A drop in RV end-diastolic volume of -15 mL best defined RVFnRec (area under the curve, 0.87; P=0.0001) and neared upper 95% CI RV end-diastolic volume of controls. This cutoff was met by 22 out of 63 (35%) patients which was reinforced by freedom from clinical worsening, RVFnRec 1 out of 21 (5%) versus no RVFnRec 17 out of 42, 40% (log-rank P=0.006). A therapy-associated increase of 0.8 mL/mm Hg in compliance had the best predictive value of RVFnRec (area under the curve, 0.76; [95% CI, 0.64-0.88]; P=0.001). RVFnRec patients had greater increases in stroke volume, and cardiac output at exercise. RVFnRec defined by RV end-diastolic volume therapeutic decrease of -15 mL predicts exercise capacity, freedom from clinical worsening, and nears normalization. A therapeutic improvement of compliance is superior to other measures of afterload in predicting RVFnRec. RVFnRec is also associated with increased RV output reserve at exercise.

Resistance exercise training benefits pulmonary, cardiac, and muscular structure and function in rats with stable pulmonary artery hypertension

AimWe tested the effects of low- to moderate-intensity resistance exercise training (RT) on the structure and function of pulmonary, right ventricle (RV), and skeletal muscle tissues in rats with stable pulmonary artery hypertension (PAH). Main methodsAfter the first monocrotaline (MCT; 20 mg/kg) injection, male rats were submitted to a RT program (Ladder climbing; 55–65 % intensity), 5 times/week. Seven days later rats received the second MCT dose. Physical effort tolerance test and echocardiographic examination were performed. After euthanasia, lung, heart, and biceps brachii were processed for histological, single myocyte, and biochemical analysis. Key findingsRT improved survival and physical effort tolerance (i.e., maximum carrying load), mitigated the pulmonary artery resistance increase (i.e., TA/TE), and preserved cardiac function (i.e., fractional shortening, ejection fraction, stroke volume and TAPSE). RT counteracted oxidative stress (i.e., CAT, SOD, GST, MDA and NO) and adverse remodeling in lung (i.e., collapsed alveoli) and in biceps brachii (i.e., atrophy and total collagen) tissues. RT delayed RV adverse remodeling (i.e., hypertrophy, extracellular matrix, collagen types I and III, and fibrosis) and impairments in single RV myocyte contractility (i.e., amplitude and velocity to peak and relaxation). RT improved the expression of gene (i.e., miRNA 214) and intracellular Ca2+ cycling regulatory proteins (i.e., PLBser16); and of pathological (i.e., α/β-MHC and Foxo3) and physiological (i.e., Akt, p-Akt, mTOR, p-mTOR, and Bcl-xL) hypertrophy pathways markers in RV tissue. SignificanceLow- to moderate-intensity RT benefits the structure and function of pulmonary, RV, and skeletal muscle tissues in rats with stable pulmonary artery hypertension.

Mid-Systolic Notching of the Pulmonary Valve Doppler Signal is Highly Associated with Pulmonary Hypertension.

Mid-systolic notching (MSN) of the pulmonary valve Doppler signal represents a reflected systolic pressure wave from the pulmonary vasculature and is often seen in pulmonary hypertension (PH). We hypothesize that MSN is associated with a higher pulmonary vascular resistance (PVR) and mean pulmonary artery pressure (mPAP), and a diagnosis of PH in pediatric patients. This was a retrospective study of patients ≤ 18years who had an echocardiogram obtained ≤ 30days before catheterization for suspected PH. MSN was defined as an indentation in the initial two thirds of the systolic Doppler signal. PH was defined as mPAP > 20mmHg and PVR ≥ 3.0 Wu m2. Subgroups (MSN vs. normal) were compared. Receiver operator characteristic determined a continuous variable's discriminatory ability for a diagnosis of PH. Reproducibility of MSN was assessed. In total, 90 patients (73 with congenital heart disease) were included, of which 36 had MSN and 54 were normal. MSN patients were more likely to have PH, and had significantly higher mPAP, PVR, and lower pulmonary stroke volume. The presence of MSN had good discriminatory ability for PH diagnosis. The presence of MSN had high specificity (96%) for PH, whereas sensitivity was lower (54%). Reproducibility was 100% for MSN. MSN is a simple, highly reproducible echocardiographic metric associated with higher mPAP and PVR. When present, there is a high likelihood a diagnosis of PH confirmed by catheterization. Incorporation of MSN into imaging protocols may be useful. MSN appears worthy of further investigation in pediatric patients with suspected PH.

High-Soluble-Fiber Diet Attenuates Hypoxia-Induced Vascular Remodeling and the Development of Hypoxic Pulmonary Hypertension.

Hypoxic pulmonary hypertension is a difficult disease to manage that is characterized by sustained elevation of pulmonary vascular resistance and pulmonary artery pressure due to vasoconstriction, perivascular inflammation, and vascular remodeling. Consumption of soluble-fiber is associated with lower systemic blood pressure, but little is known about its ability to affect the pulmonary circulation. Mice were fed either a low- or high-soluble-fiber diet (0% or 16.9% inulin) and then exposed to hypoxia (FiO2, 0.10) for 21 days to induce pulmonary hypertension. The impact of diet on right ventricular systolic pressure and pulmonary vascular resistance was determined in vivo or in ex vivo isolated lungs, respectively, and correlated with alterations in the composition of the gut microbiome, plasma metabolome, pulmonary inflammatory cell phenotype, and lung proteome. High-soluble-fiber diet increased the abundance of short-chain fatty acid-producing bacteria, with parallel increases in plasma propionate levels, and reduced the abundance of disease-related bacterial genera such as Staphylococcus, Clostridioides, and Streptococcus in hypoxic mice with parallel decreases in plasma levels of p-cresol sulfate. High-soluble-fiber diet decreased hypoxia-induced elevations of right ventricular systolic pressure and pulmonary vascular resistance. These changes were associated with reduced proportions of interstitial macrophages, dendritic cells, and nonclassical monocytes. Whole-lung proteomics revealed proteins and molecular pathways that may explain the effect of soluble-fiber supplementation. This study demonstrates for the first time that a high-soluble-fiber diet attenuates hypoxia-induced pulmonary vascular remodeling and the development of pulmonary hypertension in a mouse model of hypoxic pulmonary hypertension and highlights diet-derived metabolites that may have an immuno-modulatory role in the lung.

Comprehensive analyses of m6A RNA methylation patterns and related immune microenvironment in idiopathic pulmonary arterial hypertension.

Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disease with a poor prognosis and high heritability, characterized by elevated pulmonary vascular resistance (PVR) and pulmonary artery pressure. N6-methyladenosine (m6A) RNA modification influences many RNA metabolism pathways. However, the position of m6A methylation regulators in IPAH remains unknown. Therefore, the study aims to disclose the function m6A regulators exert in the pathological mechanisms of IPAH and the immune microenvironment involved. The GSE117261 dataset was downloaded from the Gene Expression Omnibus (GEO) to screen the differentially expressed genes (DEGs) between normal and IPAH samples. Functional and pathway enrichment analyses of DEGs were then conducted by Gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG). We also identified the differentially-expressed m6A (DEm6A) regulators between normal and IPAH samples. Key m6A regulators related to the prediction of IPAH were selected using the random forest model. The results showed that FMR1, RBM15, HNRNPA2B1 and IGFBP3 were upregulated in IPAH. In contrast, LRPPRC was downregulated. The single sample gene set enrichment analysis (ssGSEA) method was then adopted to estimate the immune microenvironment in distinct m6A clusters and m6A phenotype-related genes (PRGs) clusters, respectively. Furthermore, we calculated the m6A score via principal component analysis (PCA), and the Sankey diagram was selected to present the correlation among the m6A clusters, m6A PRGs clusters and m6A score. Finally, quantitative RT-PCR and Western blotting were used to validate the key genes in human pulmonary artery smooth muscle cells (HPASMCs) treated by human platelet-derived growth factor-BB (PDGF-BB). The relative mRNA and protein expression levels of FMR1 were significantly elevated, however, the relative mRNA and protein expression levels of LRPPRC were downregulated. Besides, the relative mRNA level of HNRNPA2B1 was increased. Generally, this bioinformatics analysis might provoke more insights into diagnosing and treating IPAH.

Prediction of Operability by Pulmonary Artery Acceleration Time and Right Ventricular Ejection Time in Large Ventricular Septal Defects with Severe Pulmonary Arterial Hypertension

Background: Diagnosing and treating cardiopulmonary illnesses in children depend heavily on evaluating pulmonary hemodynamics. Severe pulmonary artery hypertension (PAH) and Eisenmenger’s syndrome are most frequently seen in post-tricuspid shunts. Right heart catheterization is the gold standard test for calculating pulmonary vascular resistance and pulmonary artery pressures, but it has many flaws, especially regarding shunt abnormalities. Right ventricular ejection and pulmonary artery acceleration times can be useful alternatives for determining pulmonary vascular resistance. Aims and Objectives: This study aimed to correlate pulmonary artery acceleration time (PAAT) and right ventricular ejection time (RVET) with PAH. Materials and Methods: We included 52 patients with large ventricular septal defects (VSD) and severe pulmonary artery hypertension. All children with large VSD and severe PAH admitted for diagnostic catheterization after satisfying the inclusion criteria were included in the study following approval from the institutional ethics committee. All pre-catheterization echocardiographic data were collected with a Philips iE33 ultrasound machine. All of them underwent diagnostic catheterizations. Results: We observed that the chance of operability was high earlier in the age of presentation. PAAT: RVET had a positive correlation with Qp:Qs (pulmonary flow: systemic flow) and were negatively correlated with pulmonary vascular resistance index (PVRI), pulmonary vascular resistance: systemic vascular resistance (PVR:SVR), and mean pulmonary artery pressure (mPAP). In our study, we found that both PAAT and PAAT: RVET were moderately negatively correlated with PVRI and PVR: SVR (r: -0.72, P &lt; 0.001, r: -0.71, P &lt; 0.001 and r: -0.67, P &lt; 0.001, r: -0.71, P &lt; 0.001 respectively). PAAT and PAAT: RVET were moderately negatively correlated with mPAP (r: -0.7. P &lt; 0.001; r: -0.71, P &lt; 0.001 respectively) and positively with Qp:Qs (r: +0.63, P &lt; 0.001; r: 0.67, P &lt; 0.001 respectively). Conclusion: PAAT and PAAT: RVET index are important parameters in assessing pulmonary arterial pressure in large VSD with severe PAH.

Evaluating the role of serum uric acid in the risk stratification and therapeutic response of patients with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD).

Background: Pulmonary arterial hypertension (PAH) is a malignant pulmonary vascular disease that negatively impacts quality of life, exercise capacity, and mortality. This study sought to investigate the relationship between serum uric acid (UA) level and the disease severity and treatment response of patients with PAH and congenital heart disease (PAH-CHD). Methods: This study included 225 CHD patients and 40 healthy subjects. Serum UA was measured in all patients, and UA levels and haemodynamic parameters were re-evaluated in 20 patients who had received PAH-specific drug treatment for at least 7 ± 1month. Results: Serum UA levels were significantly higher in PAH-CHD patients than in CHD patients with a normal pulmonary artery pressure and normal subjects (347.7 ± 105.7μmol/L vs. 278.3 ± 84.6μmol/L; 347.7 ± 105.7μmol/L vs. 255.7 ± 44.5μmol/L, p < 0.05). UA levels in the intermediate and high risk groups were significantly higher than those in the low-risk group (365.6 ± 107.8μmol/L vs. 311.2 ± 82.8μmol/L; 451.6 ± 117.6μmol/L vs. 311.2 ± 82.8μmol/L, p < 0.05). Serum UA levels positively correlated with mean pulmonary arterial pressure, WHO functional class, pulmonary vascular resistance, and NT-proBNP (r = 0.343, 0.357, 0.406, 0.398; p < 0.001), and negatively with mixed venous oxygen saturation (SvO2) and arterial oxygen saturation (SaO2) (r = -0.293, -0.329; p < 0.001). UA significantly decreased from 352.7 ± 97.5 to 294.4 ± 56.8μmol/L (p = 0.001) after PAH-specific drug treatment for at least 6months, along with significant decreases in mean pulmonary arterial pressure and pulmonary vascular resistance and increases in cardiac index and mixed SvO2. Conclusion: Serum UA can be used as a practical and economic biomarker for risk stratification and the evaluation of PAH-specific drug treatment effects for patients with PAH-CHD.