Onset Of Pulmonary Arterial Hypertension Research Articles

The prognostic value of prognostic nutritional index in postoperative onset of PAH in children with isolated VSD: a prospective cohort study based on propensity score matching analysis.

The mechanism of pulmonary arterial hypertension (PAH) after surgery/intervention for isolated venticlular septal defect (VSD) in children is unknown. Reliable prognostic indicators for predicting postoperative PAH are urgently needed. Prognostic nutration index (PNI) is widely used to predict postoperative complications and survival in adults, but it is unclear whether it can be used as an indicator of prognosis in children. A total of 251 children underwent VSD repair surgery or interventional closure in Hunan Children's Hospital from 2020 to 2023 were collected. A 1:1 propensity score matching (PSM) analysis was performed using the nearest neighbor method with a caliper size of 0.2 Logistics regression analysis is used to examine factors associated with the development of PAH. The cut-off value for PNI was determined as 58.0. After 1:1 PSM analysis, 49 patients in the low PNI group were matched with high PNI group. Children in the low PNI group had higher risk of postoperative PAH (P = 0.002) than those in the high PNI group. Multivariate logistics regression analysis showed that PNI (RR: 0.903, 95% CI: 0.816-0.999, P = 0.049) and tricuspid regurgitation velocity (RR: 4.743, 95% CI: 1.131-19.897, P = 0.033) were independent prognostic factors for the development of PAH. PNI can be used as a prognostic indicator for PAH development after surgery/intervention in children with isolated VSD.

Abstract 14112: Reproductive Risk Factors and Pulmonary Arterial Hypertension in Women

Introduction: Pulmonary arterial hypertension (PAH) is a devastating disease that affects women more often than men. The female predominance has increased over time; recent U.S. cohorts demonstrate a female:male ratio of nearly 4:1. The role of women-specific risk, such as reproductive exposures, is poorly understood in the pathophysiology of PAH. Hypothesis/Goals: We hypothesize that reproductive exposures influence the development and/or severity of PAH in women. We sought to investigate the role of reproductive factors and contribution of exogenous estrogen exposures to PAH onset and severity. Methods: Using reproductive history/exposure questionnaires from 390 women with PAH, enrolled in both the PAH Biobank and United States Pulmonary Hypertension Scientific Registry, we conducted linear regression analyses to assess the association between individual disease severity variables, as well as REVEAL Lite 2.0 scores, and patient reported reproductive variables as the predictors (Table 1). We adjusted for potential confounders including age, race, BMI, and PAH sub-group (idiopathic, heritable, or associated). Results: We found that younger menopause age, less than or equal to 40 years old, associates with a lower cardiac index (CI) at diagnosis [β -0.57, p 0.02]. The association persisted when controlling for use of hormone replacement therapy (HRT). There was a trend toward lower CI in those with menopause age of 41 to 50 years old, but not statistically significant [p 0.10]. Ever use of HRT was associated with a higher pulmonary vascular resistance [β 1.6, p 0.05] and lower CI [β -0.28, p 0.01] at diagnosis. Conclusion: Premature menopause (age less than 40 years) and ever use of HRT associate with worse hemodynamics at diagnosis in women with PAH, including lower cardiac index. Further investigations into reproductive exposures may offer an opportunity for more comprehensive risk factor screening and modification by physicians treating PAH patients.

The soluble receptor for advanced glycation end products is potentially predictive of pulmonary arterial hypertension in systemic sclerosis.

Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are the leading causes of death in systemic sclerosis (SSc). Until now, no prospective biomarker to predict new onset of SSc-ILD or SSc-PAH in patients with SSc has reached clinical application. In homeostasis, the receptor for advanced glycation end products (RAGE) is expressed in lung tissue and involved in cell-matrix adhesion, proliferation and migration of alveolar epithelial cells, and remodeling of the pulmonary vasculature. Several studies have shown that sRAGE levels in serum and pulmonary tissue vary according to the type of lung-related complication. Therefore, we investigated levels of soluble RAGE (sRAGE) and its ligand high mobility group box 1 (HMGB1) in SSc and their abilities to predict SSc-related pulmonary complications. One hundred eighty-eight SSc patients were followed retrospectively for the development of ILD, PAH, and mortality for 8 years. Levels of sRAGE and HMGB1 were measured in serum by ELISA. Kaplan-Meier survival curves were performed to predict lung events and mortality and event rates were compared with a log-rank test. Multiple linear regression analysis was performed to examine the association between sRAGE and important clinical determinants. At baseline, levels of sRAGE were significantly higher in SSc-PAH-patients (median 4099.0 pg/ml [936.3-6365.3], p = 0.011) and lower in SSc-ILD-patients (735.0 pg/ml [IQR 525.5-1988.5], p = 0.001) compared to SSc patients without pulmonary involvement (1444.5 pg/ml [966.8-2276.0]). Levels of HMGB1 were not different between groups. After adjusting for age, gender, ILD, chronic obstructive pulmonary disease, anti-centromere antibodies, the presence of puffy fingers or sclerodactyly, use of immunosuppression, antifibrotic therapy, or glucocorticoids, and use of vasodilators, higher sRAGE levels remained independently associated with PAH. After a median follow-up of 50 months (25-81) of patients without pulmonary involvement, baseline sRAGE levels in the highest quartile were predictive of development of PAH (log-rank p = 0.01) and of PAH-related mortality (p = 0.001). High systemic sRAGE at baseline might be used as a prospective biomarker for patients with SSc at high risk to develop new onset of PAH. Moreover, high sRAGE levels could predict lower survival rates due to PAH in patients with SSc.

Temporal Changes in Key Signal Transduction Pathways Mediating Muscle Protein Synthesis with Adaptive and Maladaptive Right Ventricular Hypertrophy in Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension (PAH) is a progressive disease characterized by occlusive remodeling of pulmonary arteries < 500 micron and increased pulmonary vascular resistance. With the onset of PAH, the right ventricle (RV) of the heart adapts to the increased afterload pressure by undergoing adaptive hypertrophic remodeling to maintain adequate blood flow. However, for unknown reasons, maladaptive influences ensue, resulting in impaired RV function with progressive decompensation and right heart failure. Using a rodent model of PAH, key signaling pathways mediating cardiac muscle protein synthesis in the RV were evaluated during both the adaptive hypertrophy phase, with preserved right heart function, and the decompensated maladaptive phase, in which right heart failure (RHF) was present. Analysis of protein and gene expression changes in PAH animals identified three key signaling pathways involved in the shift toward maladaptive right heart failure: i) PI3K/Akt/mTOR; ii) GSK-3; iii) MAPK/ERK, as well as IGF-1 regulation. During adaptive hypertrophy, significant increments of phosphorylated proteins in the three signaling pathways were observed with increases in RV fibrosis and decreased capillarity found. In the maladaptive phase, mTORC1 and its downstream effector p-70S6K were significantly activated, contributing to the decreased LC3-I/II ratio, a marker of autophagy inhibition together with further significant RV muscle fibrosis and greater capillary rarefaction. We propose that autophagy inhibition in conjunction with other maladaptive processes reported in the decompensated RV muscle contributes to the genesis of overt RHF in PAH, and that a continuum of changes characterizes the adaptive and maladaptive phases in the RV muscle Keywords: Pulmonary Arterial Hypertension (P

BMPR1A promotes ID2-ZEB1 interaction to suppress excessive endothelial to mesenchymal transition.

Components of bone morphogenetic protein (BMP) signalling have been implicated in both pathogenesis of pulmonary arterial hypertension (PAH) and endothelial-mesenchymal transition (EndoMT). In particular, the importance of BMP type 2 receptor in these processes has been extensively analysed. However, the contribution of BMP type 1 receptors (BMPR1s) to the onset of PAH and EndoMT remains poorly understood. BMPR1A, one of BMPR1s, was recently implicated in the pathogenesis of PAH, and was found to be down-regulated in the lungs of PAH patients, neither the downstream mechanism nor its contribution to EndoMT has been described. Therefore, we aim to delineate the role of endothelial BMPR1A in modulating EndoMT and pathogenesis of PAH. We find that BMPR1A knockdown in endothelial cells (ECs) induces hallmarks of EndoMT, and deletion of endothelial Bmpr1a in adult mice (Bmpr1aiECKO) leads to development of PAH-like symptoms due to excessive EndoMT. By lineage tracing, we show that endothelial-derived smooth muscle cells are increased in endothelial Bmpr1a-deleted mice. Mechanistically, we identify ZEB1 as a primary target for BMPR1A in this setting; upon BMPR1A activation, ID2 physically interacts and sequesters ZEB1 to attenuate transcription of Tgfbr2, which in turn lowers the responses of ECs towards transforming growth factor beta (TGFβ) stimulation and prevents excessive EndoMT. In Bmpr1aiECKO mice, administering endothelial targeting lipid nanoparticles containing siRNA against Tgfbr2 effectively ameliorate PAH, reiterating the importance of BMPR1A-ID2/ZEB1-TGFBR2 axis in modulating progression of EndoMT and pathogenesis of PAH. We demonstrate that BMPR1A is key to maintain endothelial identity and to prevent excessive EndoMT. We identify BMPR1A-induced interaction between ID2 and ZEB1 is the key regulatory step for onset of EndoMT and pathogenesis of PAH. Our findings indicate that BMPR1A-ID2/ZEB1-TGFBR2 signalling axis could serve as a potential novel therapeutic target for PAH and other EndoMT-related vascular disorders.

Identifying new drugs associated with pulmonary arterial hypertension: A WHO pharmacovigilance database disproportionality analysis.

We used VigiBase, the largest pharmacovigilance database worldwide to generate disproportionality signals through the Bayesian neural network method. All disproportionality signals were further independently reviewed by experts in pulmonary arterial hypertension, pharmacovigilance and vascular pharmacology and their plausibility ranked according to World Health Organization causality categories. We included 2184 idiopathic PAH cases, yielding a total of 93 disproportionality signals. Among them, 25 signals were considered very likely, 15 probable, 28 possible and 25 unlikely. Notably, we identified 4 new protein kinases inhibitors (lapatinib, lorlatinib, ponatinib and ruxolitinib), 1 angiogenesis inhibitor (bevacizumab), and several chemotherapeutics (etoposide, trastuzumab), antimetabolites (cytarabine, fludarabine, fluorouracil, gemcitabine) and immunosuppressants (leflunomide, thalidomide, ciclosporin). Such signals represent plausible adverse drug reactions considering the knowledge of iatrogenic PAH, the drugs' biological and pharmacological activity and the characteristics of the reported case. Although confirmatory studies need to be performed, the signals identified may help clinicians envisage an iatrogenic aetiology when faced with a patient who develops PAH.

English

BACKGROUND Multiple mechanisms have been identified contributing to pulmonary arterial hypertension (PAH) in chronic kidney disease (CKD) patients and it is one of the important sequelae of CKD and needs early detection. We wanted to study PAH in various stages of CKD and its association with renal and cardiovascular parameters. METHODS This was an observational study. PAH was diagnosed if mean pulmonary artery pressure (MPAP) was ≥ 25 mmHg using 2D - Doppler echocardiography in 96 CKD patients. Staging of CKD was done as per Kidney Disease Improving Global Outcomes (KDIGO) stages 1 - 5. Age, gender, diabetes, hypertension, stages of CKD, corticomedullary differentiation (CMD), estimated glomerular filtration rate (EGFR), urinary albumin creatinine ratio (UACR), left ventricular ejection fraction (LVEF) and left ventricular hypertrophy (LVH) were included as risk factors. Data was analysed by calculating percentage, mean, standard deviation, chi square and t test. P value < 0.05 was taken as statistically significant. RESULTS PAH was detected in 37 (38.5 %) of CKD patients. Prevalence of PAH increased with stages of CKD being highest (59 %) in stage 5 and this was found to be statistically significant (P = 0.04). PAH was detected earliest in stage 2 (23.5 %). Lower mean eGFR ml / min / 1.733m2 (24.43 ± 17.8 vs 40.98 ± 25.7, P = 0.001) altered corticomedullary differentiation (50.9 % vs 20.5 % p = 0.003), reduced LVEF (81 % vs 26.7 % P = 0.000) and LVH (65 % vs 19.6 %, P = 0.000) were significantly associated with PAH in CKD patients. CONCLUSIONS PAH in CKD patients increases with CKD stages. Onset of PAH in CKD patients may be earlier and significantly associated with left ventricular dysfunction. KEYWORDS Pulmonary Arterial Hypertension, Chronic Kidney Disease, Left Ventricular Ejection Fraction, Left Ventricular Hypertrophy

Endothelial Autocrine Signaling through CXCL12/CXCR4/FoxM1 Axis Contributes to Severe Pulmonary Arterial Hypertension.

Endothelial autocrine signaling is essential to maintain vascular homeostasis. There is limited information about the role of endothelial autocrine signaling in regulating severe pulmonary vascular remodeling during the onset of pulmonary arterial hypertension (PAH). In this study, we employed the first severe pulmonary hypertension (PH) mouse model, Egln1Tie2Cre (Tie2Cre-mediated disruption of Egln1) mice, to identify the novel autocrine signaling mediating the pulmonary vascular endothelial cell (PVEC) proliferation and the pathogenesis of PAH. PVECs isolated from Egln1Tie2Cre lung expressed upregulation of many growth factors or angiocrine factors such as CXCL12, and exhibited pro-proliferative phenotype coincident with the upregulation of proliferation-specific transcriptional factor FoxM1. Treatment of CXCL12 on PVECs increased FoxM1 expression, which was blocked by CXCL12 receptor CXCR4 antagonist AMD3100 in cultured human PVECs. The endothelial specific deletion of Cxcl12 (Egln1/Cxcl12Tie2Cre) or AMD3100 treatment in Egln1Tie2Cre mice downregulated FoxM1 expression in vivo. We then generated and characterized a novel mouse model with endothelial specific FoxM1 deletion in Egln1Tie2Cre mice (Egln1/Foxm1Tie2Cre), and found that endothelial FoxM1 deletion reduced pulmonary vascular remodeling and right ventricular systolic pressure. Together, our study identified a novel mechanism of endothelial autocrine signaling in regulating PVEC proliferation and pulmonary vascular remodeling in PAH.

Pulmonary arterial hypertension: Cellular and molecular changes in the lung.

The range of cell types identified in the pathogenesis of pulmonary arterial hypertension (PAH) has expanded substantially since the first pathological descriptions of this disease. This, in turn, has provided needed clarity on the gamut of molecular mechanisms that regulate vascular remodeling and promote characteristic cardiopulmonary hemodynamic changes that define PAH clinically. Insight derived from these scientific advances suggest that the PAH arteriopathy is due to the convergence of numerous molecular mechanisms driving cornerstone endophenotypes, such as plexigenic, hypertrophic, and fibrotic histopathological changes. Interestingly, while some endophenotypes are observed commonly in multiple cell types, such as dysregulated metabolism, other events such as endothelial-mesenchymal transition are cell type-specific. Integrating data from classical PAH vascular cell types with fresh information in pericytes, adventitial fibroblasts, and other PAH contributors recognized more recently has enriched the field with deeper understanding on the molecular basis of this disease. This added complexity, however, also serves as the basis for utilizing novel analytical strategies that emphasize functional signaling pathways when extracting information from big datasets. With these concepts as the backdrop, the current work offers a concise summary of cellular and molecular changes in the lung that drive PAH and may, thus, be important for discovering novel therapeutic targets or applications to clarify PAH onset and disease trajectory.

The Renal Resistive Index: A New Biomarker for the Follow-up of Vascular Modifications in Systemic Sclerosis.

The aim of the present retrospective observational study was to evaluate the change of Renal Resistive Index (RRI) over time (ΔRRI) and under treatment in patients with systemic sclerosis (SSc) as well as to correlate these changes with disease complications. Two hundred thirty patients [29 male, median age 57 (IQR 48-67) yrs] were enrolled. At baseline and follow-up (3.43, IQR 2.81-4.45 yrs), we collected the following data: disease variables, nailfold videocapillaroscopy (NVC) pattern, forced vital capacity (FVC), diffusing lung capacity for carbon monoxide (DLCO), systolic pulmonary arterial pressure (sPAP), presence of interstitial lung disease, RRI, evaluation of glomerular filtration rate, and new onset of pulmonary arterial hypertension (PAH). RRI value is high in SSc patients with digital ulcers and anticentromere antibodies, active and late NVC patterns, and limited cutaneous SSc. A significant correlation was observed between ΔRRI and ΔsPAP (R = 0.17, P = 0.02), with statistically higher ΔRRI (0.08 ± 0.02 vs 0.03 ± 0.05, P = 0.04) in patients complicated by PAH onset. No other new-onset complication was associated with ΔRRI. The receiver-operating characteristic curve analysis confirmed the predictive role of ΔRRI in development of new PAH (area under the curve 0.84, 95% CI 0.75-0.93, P = 0.02). In patients with SSc never exposed to sildenafil, ΔRRI was higher (0.04 ± 0.05) compared to both patients exposed to sildenafil during the study period (0.01 ± 0.05, P = 0.03) or in those exposed at the time of baseline evaluation (0.00 ± 0.05, P = 0.01). RRI and its variation in time are a reliable marker of SSc-related vasculopathy, both in renal and extrarenal compartments.

Neonatal Autopsies with Heart Disease: A Challenge for Pathologist

Congenital Heart Diseases (CHD) carry significant morbidity and mortality in paediatric patients. Transposition of Great Arteries (TGA) is a common cyanotic CHD. However, onset of Pulmonary Arterial Hypertension (PAH) is potentially severe and rare complication reported in 1-3% of newborns. Hypertrophic Cardiomyopathy (HOCM) is a primary disease of cardiac muscle usually recognised in adulthood. Neonatal HOCM without other congenital anomalies, no family history of HOCM, no history of exposure to corticosteroids or any inborn errors of metabolism is rarely recognised. Authors hereby report two cases of neonatal autopsy showing TGA with PAH (Grade 2) and another with HOCM without any primary cause received in our hospital. With this case report authors wish to stress on the importance of cardiac examination (heart and the associated vessels) in autopsy specimen which in turn requires training of pathologists in cardiac pathology along with routine fetal anomaly scanning in arriving successively at the final diagnosis and detecting the cause of death which helps in management of future pregnancies by the clinicians.

Fli1 deficiency induces endothelial adipsin expression, contributing to the onset of pulmonary arterial hypertension in systemic sclerosis.

Adipsin, or complement factor D, is a serine proteinase catalysing complement factor C3 breakdown, leading to the production of opsonin (C3b), membrane attack complex (C5b-C9) and anaphylatoxins (C3a and C5a). Since adipsin is potentially associated with pulmonary arterial hypertension in SSc, we investigated adipsin expression in dermal small vessels of SSc-involved skin, the mechanism regulating adipsin expression in endothelial cells, and the correlation of serum adipsin levels with SSc clinical symptoms. Adipsin expression was assessed by immunohistochemistry with skin sections of SSc and healthy subjects. mRNA levels of target genes and transcription factor binding to the ADIPSIN promoter were evaluated by quantitative reverse transcription PCR and chromatin immunoprecipitation, respectively. Serum adipsin levels were determined by enzyme-linked immunosorbent assay. Adipsin expression was remarkably increased in dermal small vessels of SSc-involved skin as compared with those of healthy control skin. Consistent with the notion that Fli1 deficiency induces SSc-like phenotypes in various types of cells, FLI1 siRNA enhanced adipsin expression at protein and mRNA levels and Fli1 bound to the ADIPSIN promoter in human dermal microvascular endothelial cells. Serum adipsin levels were significantly lower in diffuse cutaneous SSc patients than in limited cutaneous SSc patients and healthy controls, and were associated positively with elevated right ventricular systolic pressure and inversely with interstitial lung disease by multivariate regression analysis. Adipsin is up-regulated at least partially by Fli1 deficiency in endothelial cells, potentially contributing to the development of pulmonary vascular involvement in SSc.

Atrial natriuretic peptide predicts disease progression and digital ulcers development in systemic sclerosis patients.

Systemic sclerosis (SSc) is an autoimmune disease characterized by micro/macrovascular damage due to the underlying fibrosis. Markers able to predict the progression of cardiovascular damage, including digital ulcers, in SSc are warranted. We aimed at characterizing the relevance of N-terminal proatrial natriuretic peptide (NT-proANP) and N-terminal probrain natriuretic peptide plasma levels in relation to cardiovascular damage and digital ulcers in a cohort of Italian SSc patients. Seventy patients were enrolled (64 women and six men; mean age 56.7 ± 14 years) with a disease duration of 11.1 ± 8.3 years. Clinical, instrumental (nailfold videocapillaroscopy, ECG, transthoracic echocardiography, pulmonary function test with diffusion lung CO), NT-proANP and N-terminal probrain natriuretic peptide plasma levels measurement were performed at baseline. The clinical follow-up lasted 24 months. The statistical approach used to achieve the study objectives included multivariate analysis, receiver operating characteristic curve, Kaplan-Meier and Cox regression analyses. Both NT-proNPs levels correlated with systolic pulmonary arterial pressure, but only the NT-proANP level correlated with right heart dimension. Both NT-proNPs levels were higher in patients experiencing events at follow-up but only the NT-proANP level significantly predicted the progression of cardiovascular damage, including development of pulmonary arterial hypertension (PAH). NT-proANP levels were higher in patients with digital ulcers and strongly predicted their development. Our results show that the NT-proANP plasma level significantly correlates with disease progression such as new onset of PAH, worsening of pulmonary hypertension and development of digital ulcers in a cohort of SSc Italian patients. If future studies will confirm our findings, the plasma NT-proANP level could be used in clinical practice as a novel sensitive marker for PAH and digital ulcers development in SSc.

The prognosis of pulmonary arterial hypertension associated with primary Sjögren's syndrome: a cohort study.

Pulmonary arterial hypertension (PAH) is a rare and severe complication of primary Sjögren's syndrome (pSS). Cohort studies indicate that the underlying diseases of PAH associated with connective tissue disease (CTD-PAH) in Asian countries are different from that in the United States and in Europe. This study investigated the clinical characteristics, survival, and prognostic factors of pSS-PAH in Chinese patients. We enrolled 29 patients with pSS-PAH who visited our referral center during August 2007 and May 2015. PAH was confirmed by right heart catheterization (RHC). Baseline demographic data, clinical manifestations, laboratory tests, autoantibody results, hemodynamics data, and treatment regimens were analyzed. All patients were followed up at the Department of Rheumatology, Peking Union Medical College Hospital (PUMCH) every three to six months. All patients were female. Mean age of pSS onset was 34.4 ± 11.1 years. Mean age of PAH diagnosed by RHC was 40.6 ± 9.0 years. There was no significant difference in age, disease duration, and hemodynamic findings between the survivors and the non-survivors in this cohort. The overall one-, three-, and five-year survival rates were 80.2%, 74.8%, and 67.4%, respectively. Prognostic factors of mortality were time between pSS onset and PAH onset (HR 1.102, 95% CI 1.017-1.185, p = 0.018) and cardiac index < 2 l/min/m2 (HR 5.497, 95% CI 1.063-28.434, p = 0.042). In contrast, the use of immunosuppressants (HR 0.110, 95% CI 0.024-0.495, p = 0.004) was related to better survival. This study demonstrates that the predictors of mortality in patients with pSS-PAH include delayed onset of PAH in pSS and worse cardiac function. Immunosuppressants can improve the prognosis of pSS-PAH.

Role for Functional SOD2 Polymorphism in Pulmonary Arterial Hypertension in a Chinese Population

The superoxide dismutase 2 (SOD2) gene is a pivotal part of oxidative stress system, which could induce the onset of pulmonary arterial hypertension (PAH). In this study, we quantified the influence of a SOD2 exonic polymorphism (rs4880) on PAH susceptibility. We genotyped this single nucleotide polymorphism (SNP) by TaqMan, and evaluated its association with PAH susceptibility in a case-control study of 460 patients and 530 controls in China. There were significant differences between PAH cases and controls in both CC and TC+CC genotypes (p = 0.013 and p = 0.010, respectively). Furthermore, the number of variant alleles followed a dose-response manner (p trend was 0.023). Besides, the mRNA level and protein expression also indicated that the C allele of this variant decreased the expression of SOD2 gene (p = 0.004 in mRNA level and p = 0.012 in protein level) after the transfection of plasmids containing the different genotype of rs4480. There is significant association between SOD rs4880 polymorphism and the PAH susceptibility, and this polymorphism influenced PAH susceptibility by altering the expression of SOD2.

Pulmonary arterial hypertension in children after neonatal arterial switch operation

ObjectivesPaediatric pulmonary arterial hypertension (PAH) after neonatal arterial switch operation (ASO) for transposition of the great arteries (TGA) is a clinically recognised entity with an estimated incidence of 0.6%–1.0%. Nevertheless,...

Effects of Longterm Treatment with Bosentan and Iloprost on Nailfold Absolute Capillary Number, Fingertip Blood Perfusion, and Clinical Status in Systemic Sclerosis.

To quantify in patients with systemic sclerosis (SSc) the absolute nailfold capillary number/mm (the absolute number of capillaries, observable in the first row, in 1 mm per field) and fingertip blood perfusion (FBP) during longterm therapy with the endothelin receptor antagonist bosentan (BOSE) and the synthetic analog of prostacyclin PGI2 iloprost (ILO) by multiple diagnostic tools. Observed values were correlated with clinical outcomes. Thirty patients with SSc already receiving intravenous ILO (80 μg/day) for 5 continuous days (every 3 mos) were recruited in the clinic. Fifteen patients continued such treatment (ILO group), while in 15 patients BOSE (125 mg twice/day) was added (ILO + BOSE group) because of the onset of pulmonary arterial hypertension or digital ulcers (DU). The followup period was 4 years (T0-T4). Every year the following were evaluated: absolute nailfold capillary number/mm by nailfold videocapillaroscopy, FBP by laser Doppler flowmetry, DU incidence, DLCO, systolic pulmonary arterial pressure (sPAP), renal arterial resistive index, and other biomarkers. From T2 to T4, laser speckled contrast analysis was added. Nonparametric tests were used for statistical analysis. Limited to the ILO + BOSE group, absolute capillary number/mm and FBP showed a progressive increase independently from other variables. In addition, during followup there was a significant reduction (80%) in the incidence of new DU, whereas DLCO and sPAP did not worsen. The study shows in patients with SSc with up to 4 years of combined therapy a progressive significant recovery in structure and function of microvasculature linked to improved clinical outcomes, independent of disease severity.

ECMO cannulation strategy for pulmonary hypertension: an alternative approach to traditional Veno-Arterial ECMO

Pulmonary arterial hypertension (PAH) is a severe disease characterized by a progressive increase of pulmonary pressure and resistance, leading to right heart failure. PAH is commonly diagnosed at a late stage of the disease and is associated with progressive clinical deterioration and premature death. The treatment of PAH continues to be complicated, especially when considering treatment with extracorporeal membrane oxygenation (ECMO). A case is described that involves a heart failure patient placed on a ventricular assist device as a bridge to heart transplantation with recent onset of PAH. The goal was to rest the entire pulmonary circulation during ECMO while allowing the ventricular assist device to continue to function using a modified veno-arterial (VA) cannulation strategy. This configuration allowed the patient's right heart to rest and ultimately recover while the left ventricular assist device (LVAD) maintained systemic perfusion, successfully allowing the patient to maintain a United Network for Organ Sharing (UNOS) status 1a listing.

Clinical features of pulmonary arterial hypertension in patients receiving dasatinib.

The prognosis of most leukemia patients treated with BCR-ABL tyrosine kinase inhibitors (TKIs) is favorable, and a more precise understanding of serious and potentially irreversible treatment-related toxicities is essential to properly inform treatment choice. Few cases of pulmonary arterial hypertension (PAH) have been reported in patients with leukemia treated with dasatinib, a second-generation BCR-ABL TKI. To better understand characteristics and outcomes of dasatinib-treated patients with PAH, all clinical cases of PAH confirmed by right-heart catheterization in the Bristol-Myers Squibb pharmacovigilance database (N = 41), including 22 previously unpublished cases, were examined for previous treatments for leukemia, patient characteristics, time to PAH onset, and outcomes. Our analysis shows that compared with PAH due to other etiologies, dasatinib-related PAH is atypical, in that it is associated with partial to complete reversibility upon treatment discontinuation. The incidence of dasatinib-related PAH appears to be low. Most PAH cases were observed in patients who had received prior treatments for leukemia. No specific patient attributes appear to be associated with an increased risk of developing PAH while receiving dasatinib. Symptoms of PAH in dasatinib-treated leukemia patients should prompt a thorough workup, including consideration of confirmatory right-heart catheterization. In cases of confirmed PAH, dasatinib should be discontinued.

Determinants of arterial stiffness and central blood pressure in the very elderly

Pulmonary arterial hypertension (PAH) is a severe and increasingly prevalent disease, manifested by the maladaptation of pulmonary vasculature, which consequently leads to right heart failure and possibly even death. The development of PAH is characterized by specific functional as well as structural changes, primarily associated with the aberrant function of the pulmonary artery endothelial cells, smooth muscle cells, and vascular fibroblasts. MicroRNAs constitute a class of small ≈22–nucleotides–long non–coding RNAs that post–transcriptionally regulate gene expression and that may lead to significant cell proteome changes. While the involvement of miRNAs in the development of various diseases—especially cancer—has been reported, numerous miRNAs have also been associated with PAH onset, progression, or treatment responsiveness. This review focuses on the role of microRNAs in the development of PAH as well as on their potential use as biomarkers and therapeutic tools in both experimental PAH models and in humans. Special attention is given to the roles of miR–21, miR–27a, the miR–17–92 cluster, miR–124, miR–138, the miR–143/145 cluster, miR–150, miR–190, miR–204, miR–206, miR–210, miR–328, and the miR–424/503 cluster, specifically with the objective of providing greater insight into the pervasive roles of miRNAs in the pathogenesis of this deadly condition.