Incidence Of Pulmonary Arterial Hypertension Research Articles

Abstract 4144559: Sex Differences in Vascular Remodeling in Pulmonary Hypertension are mediated by Endothelin-2

Pulmonary arterial hypertension (PAH) is characterized by pulmonary arterial vascular remodelingleading to increased pulmonary artery pressure causing right ventricular hypertrophy, failure anddeath. The incidence of PAH is much higher in female patients, indicating that males may have aprotective factor that could help elucidate the pathogenesis of PAH. We have recently demonstratedthat the Y chromosome gene UTY protects against PH development in mice, however the fulldownstream mechanisms remains unknown. By integrating RNA-Seq on whole lung tissues fromUty-KO and WT male mice with a publically available male and female PAH lung microarraydataset, we found increased expression of Endothelin 2 (ET-2) in the lungs of Uty-KO compared toWT mice with PH as well as in the lungs of female patients compared to males with PAH. The roleof ET-1 is known in PAH, and Endothelin receptor antagonists are a common PAH therapy to whichfemale patients are more responsive. However, ET-2 has yet to be investigated in this context. Wevalidated that ET-2 expression is significantly increased in lung tissue from PAH female patientscompared to males. Plasma ET-2 concentration is also significantly higher in PAH patients versuscontrols. Interestingly, plasma ET-2 negatively correlates with pulmonary vascular resistance (PVR)and mean pulmonary arterial pressure (mPAP) in male PAH patients, whereas plasma ET-2significantly positively correlates with PVR and mPAP in female PAH patients. Functionally, wefound that recombinant ET-2 significantly inhibits proliferation of male pulmonary artery endothelialcells (PAECs), but significantly promotes proliferation in female PAECs. Similarly, ET-2 significantlyincreased proliferation of female pulmonary artery smooth muscle cells (PASMC), but not malePASMC. Together, we show that increased ET-2 expression may contribute to worsening PH bypromoting vascular remodeling in the lung and that elevated ET2 in females may at least partiallyexplain the higher incidence of female PAH patients

Pay attention to the impact of cardiopulmonary comorbidities on the management strategies of pulmonary arterial hypertension

With the increasing age of patients with pulmonary arterial hypertension (PAH) at diagnosis, multiple comorbidities are more and more common in these patients, especially cardiopulmonary diseases. This article introduces the incidence of PAH combined with cardiovascular disease and/or chronic lung disease, elaborates on the impact of cardiopulmonary comorbidities on the diagnosis, prognosis, and targeted drug treatment strategies of PAH, and proposes management recommendations for PAH patients with comorbidities, aiming to further improve the diagnosis and treatment level of pulmonary hypertension.

A case report of postpartum idiopathic pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a pathophysiological condition characterized by pulmonary vascular remodeling and elevated vascular resistance, which may ultimately result in cardiovascular failure and sudden cardiac death. In recent years, the occurrence of pregnancy complicated by PAH has witnessed a notable increase, whereas the incidence of postpartum PAH is comparatively rare. This study presents a case involving a 39-year-old female who exhibited severe PAH, finally diagnosed as idiopathic pulmonary arterial hypertension, within two days postpartum. The diagnosis was made following a thorough clinical examination. The occurrence or exacerbation of PAH can be attributed to pregnancy. This case report emphasizes the significance of promptly initiating targeted therapy as an initial step in effectively managing patients and the criticality of conducting a thorough assessment of multidisciplinary collaboration in postpartum management. Prompt identification of PAH warrants early implementation of targeted therapy to enhance prognosis.

Abstract 2131: Bone Marrow-derived Macrophages May Contribute To Elevation Of Et-1 And Pulmonary Hypertension In Female Bmpr2 +/r899x Mutant Mice

Introduction: Mutation that causes loss of function of bone morphogenetic protein receptor 2 (BMPR2) has been implicated in the pathogenesis of Pulmonary Arterial Hypertension (PAH), a disease that currently has no cure and is characterized by elevated right ventricular systolic pressure and right ventricle hypertrophy. Females experience thrice more incidence of PAH. Elevation in the expression of ET-1, Endothelin-1, has been linked to the development of PAH. It is unclear what is contributing to the elevation of ET-1 observed in female mutants. Hypothesis: Macrophage activation in the microvasculature contributes to ET-1 elevation and PH pathogenesis in female BMPR2 +/R899X mice. Materials/Methods: Lung samples from 12-month-old male and female wild-type and BMPR2 +/R899X mutants were used for analysis of the ET-1 expression via Western Blot (WB). Accumulation of CD45+ET-1+ cells in the lungs was evaluated by immunohistochemistry (IHC). Finally, bone marrow-derived macrophages (BMDM) isolated from male and female mutant mice underwent a 24-hour treatment with 100 ng/mL Lipopolysaccharide (LPS) and vehicle (control) and ET-1 expression was measured in the cell lysate by WB. Results/Discussion: In exploring the source of ET-1, our initial findings indicated an accumulation in inflammatory perivascular cells. A double-blind analysis of the CD45 pan-leukocyte marker revealed a substantial increase in CD45+ cells in female mutants (4.09 +/- 0.68 and 10.46 +/- 1.15 CD45+ cells/microvessel, male and female, respectively; 8 micrographs/animal; 3 mice/group). Colocalization between CD45+ cells and ET-1 suggests these cells may be a source or contribute to ET-1 clearance in the lungs of female mutants. While the identity of CD45+ cells remain unclear, their morphology suggests they are likely macrophages. Indeed, preliminary results indicate a significant rise in ET-1 expression in BMDM from female mutants at baseline and upon LPS exposure. Conclusion: Accumulation of CD45+ cells in female mutant lungs, along with colocalization with ET-1, may contribute to PAH development. Additionally, increased ET-1 expression in macrophages from female mutant mice suggests macrophage activation as a potential factor in ET-1 elevation in female mutant lungs.

Role of KCNK3 Dysfunction in Dasatinib-associated PAH and Endothelial Cell Dysfunction.

Pulmonary arterial hypertension (PAH) is severe cardiopulmonary disease that may be triggered by exposure to drugs such as dasatinib or facilitated by genetic predispositions. The incidence of dasatinib-associated PAH is estimated at 0.45%, suggesting individual predispositions. The mechanisms of dasatinib-associated PAH are still incomplete. We discovered a KCNK3 gene (coding for outward K+ channel) variant in a patient with dasatinib-associated PAH, and we investigated the impact of this variant on KCNK3 function. Additionally, we assessed the effects of dasatinib exposure on KCNK3 expression. In control-human in pulmonary arterial smooth muscle cells (hPASMCs) and pulmonary endothelial cells (hPECs), we evaluated the consequence of KCNK3 knockdown on cell migration, mitochondrial membrane potential, ATP production, and in vitro tube formation. Using mass spectrometry, we determined the KCNK3 interactome. Patch-clamp revealed that the KCNK3 variant represents a loss-of-function variant. Dasatinib contributed to pulmonary artery constriction by decreasing KCNK3 function and expression. In control-hPASMCs, KCNK3 knockdown promotes mitochondrial membrane depolarization and glycolytic shift. Dasatinib exposure or KCNK3 knockdown reduced the number of caveolae in hPECs. Moreover, KCNK3 knockdown in control-hPECs reduced migration, proliferation, and in vitro tubulogenesis. Using proximity labeling and mass spectrometry, we identified the KCNK3 interactome, revealing that KCNK3 interacts with various proteins across different cellular compartments. We identified a novel pathogenic variant in the KCNK3 and showed that dasatinib downregulates KCNK3, emphasizing the relationship between dasatinib-associated PAH and KCNK3 dysfunction. We demonstrated that loss of KCNK3-dependent signaling contributes to endothelial dysfunction in PAH and glycolytic switch of hPASMCs.

Pulmonary Hypertension in Women.

Pulmonary arterial hypertension (PAH) is a rare devastating disease characterized by elevated pulmonary artery pressure and increased pulmonary vascular resistance. Females have a higher incidence of PAH, which is reflected globally across registries in the United States, Europe, and Asia. However, despite female predominance, women had better outcomes compared with male patients, a finding that has been labeled the "estrogen paradox." Special considerations should be given to women with PAH regarding sexual health, contraception, family planning, and treatment before, during, and after pregnancy. Pregnant women with PAH should be referred to a pulmonary hypertension care center; a multidisciplinary team approach is recommended, and Cesarean section is the preferred mode of delivery. While pregnancy outcomes have improved over the years with PAH-specific therapy, pregnancy portends a high-risk for those with PAH. Continued research is needed to tailor PAH treatment for women.

Заболеваемость и распространенность легочной артериальной гипертензии, ассоциированной с системной красной волчанкой. Систематический обзор

Relevance. Pulmonary arterial hypertension (PAH) is a rare complication of systemic lupus erythematosus (SLE). Due to the nonspecificity of symptoms and difficulties in diagnosis, the exact incidence and prevalence of PAH associated with SLE is unknown. Aim. A systematic review of studies assessing the incidence and prevalence of PAH associated with SLE. Material and methods. A systematic search was performed for studies investigating the incidence and prevalence of PAH associated with SLE published from January 1, 2000 to December 31, 2023. The search was carried out in the PubMed/MEDLINE database for English-language publications and in the RSCI database for studies in Russian according to pre-defined inclusion and exclusion criteria. Results. 53 potential publications were identified, all sources in English. 11 publications remained for further assessment after screening article titles and abstracts. After detailed analysis, 6 articles were excluded because they did not meet the inclusion and exclusion criteria. Totally, 5 studies were included in the systematic review. Three studies assessed prevalence only, one study assessed incidence only, and one study assessed both prevalence and incidence. The prevalence of PAH associated with SLE ranged from 0 to 4.2%, with 3-year and 5-year cumulative incidence rates of 0.53–1.2% and 0.77–1.8%, respectively.

Isogenic pairs of induced-pluripotent stem-derived endothelial cells identify DYRK1A/PPARG/EGR1 pathway is responsible for Down syndrome-associated pulmonary hypertension.

Down syndrome (DS) is the most prevalent chromosomal disorder associated with a higher incidence of pulmonary arterial hypertension (PAH). The dysfunction of vascular endothelial cells (ECs) is known to cause pulmonary arterial remodeling in PAH, although the physiological characteristics of ECs harboring trisomy 21 (T21) are still unknown. In this study, we analyzed the human vascular ECs by utilizing the isogenic pairs of T21-induced pluripotent stem cells (iPSCs) and corrected disomy 21 (cDi21)-iPSCs. In T21-iPSC-derived ECs, apoptosis and mitochondrial reactive oxygen species (mROS) were significantly increased, and angiogenesis and oxygen consumption rate (OCR) were significantly impaired as compared with cDi21-iPSC-derived ECs. The RNA-sequencing identified that EGR1 on chromosome 5 was significantly upregulated in T21-ECs. Both EGR1 suppression by siRNA and pharmacological inhibitor could recover the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Alternately, the study also revealed that DYRK1A was responsible to increase EGR1 expression via PPARG suppression, and that chemical inhibition of DYRK1A could restore the apoptosis, mROS, angiogenesis, and OCR in T21-ECs. Finally, we demonstrated that EGR1 was significantly upregulated in the pulmonary arterial ECs from lung specimens of a patient with DS and PAH. In conclusion, DYRK1A/PPARG/EGR1 pathway could play a central role for the pulmonary EC functions and thus be associated with the pathogenesis of PAH in DS.

Pulmonary Arterial Hypertension in Hyperthyroidism: Age, Ethnic, and Gender Disparities

Objective: Pulmonary arterial hypertension (PAH) affects 2.6% of adults and 36% of people with chronic obstructive pulmonary disease (COPD). Several case reports and small case series suggested a hyperthyroidism-PAH association.
 Design: Retrospective chart review.
 Methods: We undertook a retrospective chart review (1982–2018) to assess PAH prevalence in a multi-ethnic convenience sample of hyperthyroid adults with multiple etiologies. We calculated associations of pulmonary artery maximum systolic pressure (PSAPmax) with subject age, and maximum serum triiodothyronine (T3) and thyroxine (T4), free T3, and T4, minimum serum thyroid-stimulating hormone (TSH), and thyroid antibody titers, comparing PAH prevalence and the odds of being undiagnosed as to hyperthyroidism etiology by gender and ethnicity/race.
 Results: We found a high prevalence of PAH in hyperthyroid people, like that reported for people with COPD. We found no significant association between PSAPmax and any thyroid function test or thyroid antibody titer. As reported more recently in the general population, PSAPmax significantly correlated with age in hyperthyroid people. There was no significant disparity in the prevalence of PAH among White, non-Hispanic Black, and Latinx hyperthyroid people or between genders. The percentage of patients whose hyperthyroidism etiology was undiagnosed was high with significant disparity only between non-Hispanic Black and White people and between men and women. PAH was common in hyperthyroid subjects with any hyperthyroidism etiology.
 Conclusions: 2D-echocardiography should be performed in all hyperthyroid people because PAH is common, especially in older people because of their co-morbidities and poorer prognoses. Further research is needed regarding demographic disparities in being undiagnosed as to hyperthyroidism etiology.
 Principal Verdicts/Significance Statement: We reconfirmed the high PAH incidence in hyperthyroidism, previously reported, but profoundly under-recognized by physicians, to patients’ detriment. Further, we found that the shift in the general PAH population from younger to older individuals is mirrored in hyperthyroid people with PAH. This is concerning because older people have more co-morbidities and worse prognoses, necessitating early, effective intervention. PAH was present with diverse hyperthyroidism etiologies, suggesting that it is multicausal, resulting from autoimmunity, thyroid hormone excess, and goitrous upper airway obstruction and should be considered, regardless of etiology. Our observations that many subjects had no established hyperthyroidism etiology and that males and Blacks were likelier to be undiagnosed are concerning, warranting further study.

Clinical characteristics of patients with a risk of pulmonary artery hypertension secondary to ARDS in a high-altitude area

BackgroundHypoxaemia plays an important role in the development of pulmonary artery hypertension (PAH). Patients with acute respiratory distress syndrome (ARDS) in a high-altitude area have different pathophysiological characteristics from those...

Peroxisome proliferator-activated receptor gamma (PPARγ) activation: a potential treatment for ascites syndrome in broiler chickens

Ascites (serous fluid accumulation in the abdominal cavity) has been observed worldwide in fast growing broilers. Pulmonary vascular remodeling is an important pathological feature of broiler ascites syndrome. Peroxisome proliferators-activated receptor gamma (PPARγ) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) are expressed in pulmonary vascular endothelial cells and vascular smooth muscle cells (VSMC) where they participate in the regulation of normal pulmonary vascular function. The objective of the present study was to investigate the effects of omega-3 fatty acids (found in fish oil) and pioglitazone (PIO) as natural and synthetic PPARγ ligands supplementation on PPARγ and PGC-1α expression in the prevention of pulmonary arterial hypertension (PAH) syndrome in broiler chickens. The experiment was conducted with 4 treatment groups: 1) negative control, normal temperature conditions with basal diet; 2) positive control, low-temperature conditions with basal diet; 3) positive control+10 mg PIO/kg of weight/d and 4) positive control+1% FO. Each treatment had 5 replicates. Ascites heart index (RV/TV) was significantly (P < 0.05) reduced in chickens receiving FO (0.20) and PIO (0.21) compared to the positive control group (0.26). The addition of PIO in broilers under cold-induced ascites significantly increased the expression of PPARγ (9.44) and PGC-1α (5.81) genes in lung tissue compared to the negative control group (1.03, P < 0.05). Proliferative indexes of VSMC in pulmonary arteries such as PMT, PIT, and percentage wall thickness were significantly elevated in positive control group, indicating that pulmonary vascular remodeling occurred following VSMC proliferation in ascites. The vessel internal diameter was increased in FO and PIO groups. Based on these results, activation and expression of PPARγ and PGC-1α genes as a critical regulator of pulmonary artery smooth muscle cell using ligands, especially PIO, can be effective in reducing the incidence of PAH in broiler chickens.

Abstract 566: Perivascular Accumulation Of CD45+ Cells In The Lungs Of Female BMPR2 +/R899X Mutant Mice May Be A Factor To Sex-linked Pulmonary Arterial Hypertension

Introduction: Pulmonary arterial hypertension (PAH) is an uncurable disease characterized by pulmonary vasoconstriction and remodeling, elevated right ventricle systolic pressure (RVSP), and right ventricle hypertrophy (RVH). Recently, our group showed that BMPR2 +/R899X loss-of-function mutation per se significantly increased vasoconstrictive Endothelin-1 (ET-1) in the lungs of female animals, who also exhibited higher RVSP compared to males. Why females have higher PAH incidence remains unclear. Hypothesis: We hypothesize that higher PAH incidence in female mice carrying the BMPR2 +/R899X mutation is associated with the spontaneous development of pulmonary vascular inflammation and ET-1-mediated vasoconstriction. Methods: To test this hypothesis, we used 12-month-old male and female wild-type and BMPR2 +/R899X mutant mice for quantification of RVSP and RVH and for analysis of the ET-1 and CD45+ pulmonary expression by Western Blot and immunohistochemistry. Results: In opposition to BMPR2 +/R899X mutant animals, data indicated no significant difference between sexes regarding ET-1 expression and RVSP in wild-type animals. When investigating the source of ET-1 in the lungs of BMPR2 +/R899X female mice, our preliminary data suggested it accumulates in perivascular cells. Moreover, double-blind immunohistochemistry examination of the pan-leukocyte marker CD45 revealed a massive perivascular infiltration of CD45+ cells in the lungs of female mutant animals compared to males (4.09 +/- 0.68 and 10.46 +/- 1.15 CD45+ cells/microvessel, male and female, respectively; 8 micrographs/animal; 3 mice/group), supporting our hypothesis that BMPR2 +/R899X mutation is an important factor for sex-linked vascular inflammation in PAH. Conclusion: In conclusion, elevated perivascular CD45+ cells in the lungs of female BMPR2 +/R899X mutant mice may contribute to PAH sex bias.

Systemic sclerosis and primary biliary cholangitis: Longitudinal data to determine the outcomes.

Several studies described the cross-sectional characteristics of systemic sclerosis patients and coexisting primary biliary cholangitis, but longitudinal prognostic data are lacking. To describe the systemic sclerosis-primary biliary cholangitis phenotype, including baseline characteristics and outcomes. We performed a multicentre the European Scleroderma Trials and Research Group study of systemic sclerosis patients with primary biliary cholangitis or with primary biliary cholangitis-specific antibodies, matched with systemic sclerosis controls free from hepatobiliary involvement matched for disease duration and cutaneous subset. Data were recorded at baseline and at the last available visit. A total of 261 patients were enrolled (115 primary biliary cholangitis-systemic sclerosis, 161 systemic sclerosis). At baseline, systemic sclerosis-primary biliary cholangitis patients had a higher prevalence of anti-centromere antibodies (p = 0.0023) and a lower prevalence of complete absence of digital ulcers. The milder vascular involvement was confirmed at follow-up when crucial differences emerged in the percentage of patients experiencing digital ulcers; a significantly higher number of patients who never experienced digital ulcers were observed among primary biliary cholangitis-systemic sclerosis patients (p = 0.0015). Moreover, a greater incidence of pulmonary arterial hypertension (p < 0.001) and of conduction blocks (p = 0.0256) was observed in systemic sclerosis patients without primary biliary cholangitis. Patients with primary biliary cholangitis had higher levels of liver enzymes at baseline than systemic sclerosis patients; a significant decrease in liver enzymes was observed at follow-up. Out of 18 patients with cholangitis, one received a liver transplant at follow-up. Our data show that systemic sclerosis-primary biliary cholangitis exhibit a mild systemic sclerosis and primary biliary cholangitis phenotype with outcomes being in general favourable.

Development conceptual of pharmacoeconomic model of technology for early diagnosis and pharmacotherapy of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare, progressive disease with a poor prognosis in the absence of timely diagnosis and appropriate therapy. Despite significant advances in the treatment of PAH, many patients remain undiagnosed years after the onset of the disease. Evaluation of the implementation of early diagnostic technologies for PAH is increasingly being used to develop economic evidence for health care at the early stages of diagnosis. The development of models of early diagnosis technology for LAH is highly relevant and can be used in the development and management of new medical technologies, as well as to reduce the perceived risks during the implementation of screening programs for LAH diagnosis.&#x0D; The objective of the paper: Conceptual development of a pharmacoeconomic model of the technology of early diagnosis and pharmacotherapy of PAH.&#x0D; Our pharmacoeconomic analysis is based on the «cost–effectiveness» model, which reflects the effectiveness and associated costs of implementing diagnostic screening for early detection of patients with PAH. The analysis of input data of the existing health care system was conducted using systematic review, documentary, informational and graphical research methods.&#x0D; The presented pharmacoeconomic model describes not only the structure of the incidence of PAH in the studied risk group or at the level of the entire population, but also takes into account the pharmacoeconomic evaluation of the complex technology of timely medical care for patients with PAH based on diagnostic screening.&#x0D; A pharmacoeconomic model of the technology of early diagnosis and pharmacotherapy of pulmonary arterial hypertension was developed, which covered a horizon of 10 years and was conducted from the point of view of the existing health care system, showed that for patients with delayed diagnosis of PAH, the modeling determined the average life expectancy at the level of 4.13 years and 2.08 QALYs.&#x0D; It has been determined that a diagnostic screening strategy for PAH would be cost–effective compared to no screening at different thresholds of diagnostic cost. However, other factors such as public awareness and acceptance of the screening programme and availability of human resources should be considered.

Hypoxia-induced pulmonary hypertension upregulates eNOS and TGF-β contributing to sex-linked differences in BMPR2 +/R899X mutant mice.

Dysfunctional bone morphogenetic protein receptor 2 (BMPR2) and endothelial nitric oxide synthase (eNOS) have been largely implicated in the pathogenesis of pulmonary arterial hypertension (PAH); a life-threatening cardiopulmonary disease. Although the incident of PAH is about three times higher in females, males with PAH usually have a worse prognosis, which seems to be dependent on estrogen-associated cardiac and vascular protection. Here, we evaluated whether hypoxia-induced pulmonary hypertension (PH) in humanized BMPR2+/R899X loss-of-function mutant mice contributes to sex-associated differences observed in PAH by altering eNOS expression and inducing expansion of hyperactivated TGF-β-producing pulmonary myofibroblasts. To test this hypothesis, male and female wild-type (WT) and BMPR2+/R899X mutant mice were kept under hypoxic or normoxic conditions for 4 weeks, and then right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) were measured. Chronic hypoxia exposure elevated RVSP, inducing RVH in both groups, with a greater effect in BMPR2+/R899X female mice. Lung histology revealed no differences in vessel thickness/area between sexes, suggesting RVSP differences in this model are unlikely to be in response to sex-dependent vascular narrowing. On the other hand, hypoxia exposure increased vascular collagen deposition, the number of TGF-β-associated α-SMA-positive microvessels, and eNOS expression, whereas it also reduced caveolin-1 expression in the lungs of BMPR2+/R899X females compared to males. Taken together, this brief report reveals elevated myofibroblast-derived TGF-β and eNOS-derived oxidants contribute to pulmonary microvascular muscularization and sex-linked differences in incidence, severity, and outcome of PAH.

Pulmonary arterial hypertension incidence in Latvia in 2019.

Pulmonary arterial hypertension incidence in Latvia in 2019.

Incidence and outcomes of pulmonary hypertension in the Ireland

IntroductionPulmonary hypertension (PH) is a progressive disease of the pulmonary vasculature, which is characterised by premature morbidity and mortality. The aim of this study is to define the characteristics of...

Abstract 259: BMPR2 +/r899x Mutation Contributes To Sex-linked Disparity In Hypoxia-induced Pulmonary Hypertension

Introduction: Dysfunctional bone morphogenetic protein receptor 2 (BMPR2) and endothelial nitric oxide synthase (eNOS) have been implicated in the pathogenesis of pulmonary arterial hypertension (PAH), a life-threatening disease characterized by pulmonary vascular remodeling, elevated right ventricular systolic pressure (RVSP), and right ventricular hypertrophy (RVH). Although the incidence of this disease is three times higher in females, males with PAH usually have a worse prognosis. The mechanism behind this sex-associated difference remains undetermined. Objective: Determine whether BMPR2 +/R899X loss-of-function mutation contributes to sex-associated differences in PAH, including the degree of vascular remodeling, RVSP, and RVH. Methods: Wild-type (WT) and BMPR2 +/R899X mice (male/female) were exposed to hypoxia (Hx) or normoxia (Nx) for 4 weeks, when the RVSP and RVH were measured. Lung tissue was used for western blot and histological analysis. Results/Discussion: Hx exposure elevated RVSP, inducing RVH in both groups, with a greater effect in BMPR2 +/R899X mice compared to WT (RVSP: 45.0+/- 2.2 and 34.9 +/- 1.3 mmHg, respectively). A higher RVSP was observed in BMPR2 +/R899X female mice, with males exhibiting more pronounced RVH, suggesting females might have a protective mechanism against severe RVH. Lung histology revealed no differences in vessel thickness/area between sexes, which may indicate that the RVSP differences are unlikely a response to vascular remodeling. Hx exposure increased the amount of α-SMA+ microvessels and eNOS expression in BMPR2 +/R899X females compared to males, but further experiments are required to determine whether elevated eNOS reflects higher function or an oxidative stress-driven endothelial cell phenotype. Conclusion: This work is uncovering the translational relevance of BMPR2 +/R899X mutation in the sex-linked differences in PAH incidence, severity, and outcome.

Relationship between Dasatinib-induced Pulmonary Hypertension and Drug Dose

Objective Dasatinib, a second-generation tyrosine kinase inhibitor, is used for chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It reportedly causes pulmonary arterial hypertension (PAH) and the dose-dependent induction of apoptosis in pulmonary endothelial cells. However, no report has yet discussed the relationship between dasatinib-induced PAH and drug dose. We therefore investigated the incidence of dasatinib-induced PAH and the relationship between dasatinib-PAH and drug dose in consecutive patients with CML and Ph+ ALL who took dasatinib. Methods The clinical data of 128 patients with CML (94 patients) and Ph+ ALL (34 patients) were retrospectively analyzed. Patients All patients (>17 years old) who received dasatinib from January 2009 to March 2020 at Jichi Medical University (Tochigi, Japan) were included. Patients who transferred within one month of starting dasatinib administration were excluded. Results Four (4.3%) and three (8.8%) patients developed pulmonary hypertension (PH), which was considered present when the transtricuspid pressure gradient was ≥40 mmHg, in the CML and ALL groups, respectively. No significant difference was observed between the PH onset and the administration period, cumulative dose, or daily dose of dasatinib. PH occurred in seven patients (5.5%), and the period from the start of dasatinib administration to the PH onset ranged from 7 to 39 (median: 28) months. No patients died from PH in either group. Conclusion Dasatinib-induced PAH does not occur time- or dose-dependently. When administering dasatinib, cardiovascular diagnostic modalities should be routinely checked, and PAH occurrence should be promptly detected.

Prevalence, incidence, and survival of pulmonary arterial hypertension: A systematic review for the global burden of disease 2020 study.

Pulmonary arterial hypertension (PAH) is characterized by increased resistance in the pulmonary arterioles as a result of remodeled blood vessels. We sought all available epidemiologic data on population‐based prevalence, incidence, and 1‐year survival of PAH as part of the Global Burden of Disease Study. We performed a systematic review searching Global Index Medicus (GIM) for keywords related to PAH between 1980 and 2021 and identified population‐representative sources of prevalence, incidence, and mortality for clinically diagnosed PAH. Of 6772 articles identified we found 65 with population‐level data: 17 for prevalence, 17 for incidence, and 58 reporting case fatality. Reported prevalence ranged from 0.37 cases/100,000 persons in a referral center of French children to 15 cases/100,000 persons in an Australian study. Reported incidence ranged from 0.008 cases/100,000 person‐years in Finland, to 1.4 cases/100,000 person‐years in a retrospective chart review at a clinic in Utah, United States. Reported 1‐year survival ranged from 67% to 99%. All studies with sex‐specific estimates of prevalence or incidence reported higher levels in females than males. Studies varied in their size, study design, diagnostic criteria, and sampling procedures. Reported PAH prevalence, incidence, and mortality varied by location and study. Prevalence ranged from 0.4 to 1.4 per 100,000 persons. Harmonization of methods for PAH registries would improve efforts at disease surveillance. Results of this search contribute to ongoing efforts to quantify the global burden of PAH.