Cell Tracking Suggests Pathophysiological and Therapeutic Role of Bone Marrow Cells in Sugen5416/Hypoxia Rat Model of Pulmonary Arterial Hypertension

BackgroundThe mechanism of vascular remodelling in pulmonary arterial hypertension (PAH) remains unclear. Hence, defining the origin of cells constituting intractable vascular lesions in PAH is expected to facilitate therapeutic progress. Herein, we aimed to evaluate the origin of intractable vascular lesions in PAH rodent models via bone marrow (BM) and orthotopic lung transplantation (LT).MethodsTo trace BM-derived cells, we prepared chimeric rats transplanted with BM cells from green fluorescent protein (GFP) transgenic rats. Male rats were transplanted with lungs obtained from female rats and vice versa. Pulmonary hypertension was induced in the transplanted rats via Sugen5416 treatment and subsequent chronic hypoxia (Su/Hx).ResultsIn the chimeric Su/Hx models, GFP-positive cells were observed in the pulmonary vascular area. Moreover, the right ventricular systolic pressure was significantly lower compared with wild-type Su/Hx rats without BM transplantation (P = 0.009). PAH suppression was also observed in rats that received allograft transplanted BM transplantation. In male rats that received LT and Su/Hx, BM-derived cells carrying the Y chromosome were also detected in neointimal occlusive lesions of the transplanted lungs received from female rats.ConclusionsBM-derived cells participate in pulmonary vascular remodelling in the Su/Hx rat model, whereas BM transplantation may contribute to suppression of development of PAH.     

Long-Term Outcomes With Ambrisentan Monotherapy in Pulmonary Arterial Hypertension

BackgroundThis study evaluated long-term outcomes in patients with pulmonary arterial hypertension (PAH) undergoing treatment with ambrisentan monotherapy, a selective oral endothelin-1 receptor antagonist.Methods and ResultsPatients who participated in the Ambrisentan in Pulmonary Arterial Hypertension: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Multicenter Efficacy Study (ARIES-1) clinical trial and extension phase at our institution were included. Cardiac catheterization, 6-minute walk distance (6MWD), and cardiac magnetic resonance (MRI) data were retrospectively reviewed. Twelve patients with PAH (11 idiopathic, 1 fenfluramine) had follow-up from 3 to 5.5 years from the initiation of ARIES-1. Patients received ambrisentan therapy throughout the study period and were on ambrisentan monotherapy for the first 2 years. At year 1, improvements in median mean pulmonary arterial pressure (PA), cardiac output, and pulmonary vascular resistance (PVR) were seen (P = .02, P = .03, P < .01), and the improvement in PVR persisted at 2 years. 6MWD also improved significantly between baseline (350 m) and 1 and 2 years (397 m, P < .01 and 393 m, P = .01). Cardiac MRI results were more varied, with an increase in RV ejection fraction from 29% at baseline to 46% at 2 years (P = .02), but other MRI variables did not improve.ConclusionsAmbrisentan monotherapy led to improvements in catheterization, 6MWD, and RV ejection fraction, and shows promise as a long-term treatment for pulmonary arterial hypertension.     

YC-1 attenuates hypoxia-induced pulmonary arterial hypertension in mice

BackgroundPulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance and elevation of pulmonary arterial pressure, leading to right ventricular failure and eventual death. Currently, no curative therapy for PAH is available, and the overall prognosis is very poor. Recently, direct activators of soluble guanylyl cyclase (sGC) have been tested as a novel therapeutic modality in experimental models of pulmonary arterial hypertension (PAH).ObjectiveIn this study, we used in vitro and in vivo models to evaluate the therapeutic potential of 3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole (YC-1), a dual functioning chemical, as a direct activator of guanylyl cyclase and an inhibitor of hypoxia-inducible factor-1.MethodsWe analyzed the effects of YC-1 on cell proliferation and the levels of p21 and p53 in human pulmonary artery smooth muscle cells (HPASMCs) under hypoxia. We also determined the effects of YC-1 on expression of endothelin-1 (ET-1) and phosphorylation status of endothelial nitric oxide synthase (eNOS) at Ser¹¹⁷⁹ in human pulmonary artery endothelial cells (HPAECs) under hypoxia. In mice, hypoxic PAH was induced by exposure to normobaric hypoxic conditions for 28 days. To assess preventive or therapeutic effects, randomized mice were subjected to once daily i.p. injections of YC-1 for the entire hypoxic period (5 mg/kg) or for the last seven days of a 28-day hypoxic period (5 and 10 mg/kg). On day 28, we measured the right ventricular systolic pressure (RVSP) and determined the degrees of right ventricular hypertrophy (RVH) and vascular remodeling.ResultsIn HPASMCs, YC-1 inhibited hypoxia-induced proliferation and induction of p53 and p21 in a concentration-dependent manner. Also, YC-1 suppressed the hypoxia-induced expression of ET-1 mRNA and dephosphorylation of eNOS at Ser¹¹⁷⁹ in HPAECs. In the preventive in vivo model, a daily dose of 5 mg/kg YC-1 significantly prevented the elevation of RVSP, development of RVH, and pulmonary vascular remodeling, which were caused by hypoxic exposure. In the therapeutic model, YC-1 at daily doses of 5 and 10 mg/kg alleviated RVH and pulmonary vascular remodeling but did not prevent the elevation of RVSP.ConclusionsOur results indicate that YC-1 prevents the development of hypoxia-induced PAH in a preventive model and alleviates RVH and pulmonary vascular remodeling in a therapeutic model. Therefore, these data imply that YC-1 has therapeutic potential for use in a single or combination therapy for PAH.     

Pulmonary Artery Denervation for Pulmonary Arterial Hypertension: A Sham-Controlled Randomized PADN-CFDA Trial

BackgroundWorld Health Organization (WHO) group 1 pulmonary arterial hypertension (PAH) is a progressive, debilitating disease. Previous observational studies have demonstrated that pulmonary artery denervation (PADN) reduces pulmonary artery pressures in PAH. However, the safety and effectiveness of PADN have not been established in a randomized trial.ObjectivesThe aim of this study was to determine the treatment effects of PADN in patients with group 1 PAH.MethodsPatients with WHO group 1 PAH not taking PAH-specific drugs for at least 30 days were enrolled in a multicenter, sham-controlled, single-blind, randomized trial. Patients were assigned to receive PADN plus a phosphodiesterase-5 inhibitor or a sham procedure plus a phosphodiesterase-5 inhibitor. The primary endpoint was the between-group difference in the change in 6-minute walk distance from baseline to 6 months.ResultsAmong 128 randomized patients, those treated with PADN compared with sham had a greater improvement in 6-minute walk distance from baseline to 6 months (mean adjusted between-group difference 33.8 m; 95% CI: 16.7-50.9 m; P < 0.001). From baseline to 6 months, pulmonary vascular resistance was reduced by ?3.0 ± 0.3 WU after PADN and ?1.9 ± 0.3 WU after sham (adjusted difference ?1.4; 95% CI: ?2.6 to ?0.2). PADN also improved right ventricular function, reduced tricuspid regurgitation, and decreased N-terminal pro–brain natriuretic peptide. Clinical worsening was less (1.6% vs 13.8%; OR: 0.11; 95% CI: 0.01-0.87), and a satisfactory clinical response was greater (57.1% vs 32.3%; OR: 2.79; 95% CI: 1.37-5.82) with PADN treatment during 6-month follow-up.ConclusionsIn patients with WHO group 1 PAH, PADN improved exercise capacity, hemodynamic status, and clinical outcomes during 6-month follow-up. (Safety and Efficacy of Pulmonary Artery Denervation in Patients With Pulmonary Arterial Hypertension [PADN-CFDA]; NCT03282266)     

Current Therapy of Pulmonary Hypertension

Abstract Pulmonary arterial hypertension (PAH) affects vascular proliferation and remodeling in small pulmonary arteries and results in right ventricular failure and death due to a progressive increase in pulmonary vascular resistance. Recent advances in understanding of the molecular mechanisms involved in PAH suggest that endothelial dysfunction plays a major role. Impaired production of vasoactive mediators, such as prostacyclin and nitric oxide, accompanied with prolonged overexpression of vasoconstrictors such as endothelin-1, affects vascular tone and reinforces vascular remodeling. As the latter substances represent logical pharmacological targets, new drugs affecting these mechanisms have evolved during the past 2 decades and led to umpteen placebo-controlled trials in bygone years. Prognosis and quality of life of patients suffering from PAH seem to improve due to these new treatment strategies resulting in a reduction of mortality and morbidity, but there is still a substantial need for further long-term and head-to-head trials.     

Inhibition of the prolyl isomerase Pin1 improves endothelial function and attenuates vascular remodelling in pulmonary hypertension by inhibiting TGF-β signalling

Pulmonary arterial hypertension (PAH) is a devastating disease, characterized by obstructive pulmonary vascular remodelling ultimately leading to right ventricular (RV) failure and death. Disturbed transforming growth factor-β (TGF-β)/bone morphogenetic protein (BMP) signalling, endothelial cell dysfunction, increased proliferation of smooth muscle cells and fibroblasts, and inflammation contribute to this abnormal remodelling. Peptidyl-prolyl isomerase Pin1 has been identified as a critical driver of proliferation and inflammation in vascular cells, but its role in the disturbed TGF-β/BMP signalling, endothelial cell dysfunction, and vascular remodelling in PAH is unknown. Here, we report that Pin1 expression is increased in cultured pulmonary microvascular endothelial cells (MVECs) and lung tissue of PAH patients. Pin1 inhibitor, juglone significantly decreased TGF-β signalling, increased BMP signalling, normalized their hyper-proliferative, and inflammatory phenotype. Juglone treatment reversed vascular remodelling through reducing TGF-β signalling in monocrotaline?+?shunt-PAH rat model. Juglone treatment decreased Fulton index, but did not affect or harm cardiac function and remodelling in rats with RV pressure load induced by pulmonary artery banding. Our study demonstrates that inhibition of Pin1 reversed the PAH phenotype in PAH MVECs in vitro and in PAH rats in vivo, potentially through modulation of TGF-β/BMP signalling pathways. Selective inhibition of Pin1 could be a novel therapeutic option for the treatment of PAH.

     

Pulmonary Artery Denervation Attenuates Pulmonary Arterial Remodeling in Dogs With Pulmonary Arterial Hypertension Induced by Dehydrogenized Monocrotaline

ObjectivesThis study aimed to investigate sympathetic nerve (SN) ultrastructural changes and hemodynamic and pulmonary artery (PA) pathological improvements by pulmonary arterial denervation (PADN) in animals with pulmonary arterial hypertension (PAH), as well as the underlying mechanisms.BackgroundSN overactivity plays a role in PAH. Previous studies have reported short-term improvements in pulmonary arterial pressure (PAP) and cardiac function by PADN, but PA remodeling and the associated mechanisms remain unclear.MethodsForty dogs were randomly (ratio of 1:3) assigned to the control (intra-atrial injection of N-dimethylacetamide, 3 mg/kg) and test (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg) groups. After 8 weeks, the animals in the test group with a mean PAP >25 mm Hg (n = 20) were randomized (ratio of 1:1) into the sham and PADN groups. At 14 weeks, the hemodynamics, medial wall thickness and PA muscularization, and messenger ribonucleic acid expression of genes in lung tissues were measured. Another 35 PAH dogs were used to measure the SN conduction velocity, electron microscopic assessment, and nerve distribution.ResultsPADN induced significant SN demyelination and axon loss and slowed SN conduction velocity over time, with resulting profound reductions in the mean PAP (23.5 ± 2.3 mm Hg vs. 33.7 ± 5.8 mm Hg), pulmonary vessel resistance (3.5 ± 2.3 Wood units vs. 7.7 ± 1.7 Wood units), medial wall thickness (22.3 ± 3.3% vs. 30.4 ± 4.1%), and full muscularization (40.3 ± 9.3% vs. 57.1 ± 5.7%) and increased nonmuscularization (29.8 ± 6.1% vs. 12.9 ± 4.9%) compared with the Sham group (all p < 0.001). PADN inhibited the messenger ribonucleic acid expression of genes correlated with inflammation, proliferation, and vasoconstriction.ConclusionsPADN induces permanent SN injury and subsequent improvements in hemodynamics and PA remodeling in animals with PAH through mechanisms that may be experimentally and clinically beneficial.     

The REPAIR Study: Effects of Macitentan on RV Structure and Function in Pulmonary Arterial Hypertension

ObjectivesThe REPAIR (Right vEntricular remodeling in Pulmonary ArterIal hypeRtension) study evaluated the effect of macitentan on right ventricular (RV) and hemodynamic outcomes in patients with pulmonary arterial hypertension (PAH), using cardiac magnetic resonance (CMR) and right heart catheterization (RHC).BackgroundRV failure is the primary cause of death in PAH. CMR is regarded as the most accurate noninvasive method for assessing RV function and remodeling and CMR measures of RV function and structure are strongly prognostic for survival in patients with PAH. Despite this, CMR is not routinely used in PAH clinical trials.MethodsREPAIR was a 52-week, open-label, single-arm, multicenter, phase 4 study evaluating the effect of macitentan 10 mg, with or without phosphodiesterase type-5 inhibition, on RV remodeling and function and cardiopulmonary hemodynamics. Primary endpoints were change from baseline to week 26 in RV stroke volume, determined by CMR; and pulmonary vascular resistance, determined by RHC. Efficacy measures were assessed for all patients with baseline and week 26 data for both primary endpoints.ResultsAt a prespecified interim analysis in 42 patients, both primary endpoints were met, enrollment was stopped, and the study was declared positive. At final analysis (n = 71), RV stroke volume increased by 12 mL (96% confidence level: 8.4-15.6 mL; P < 0.0001) and pulmonary vascular resistance decreased by 38% (99% confidence level: 31%-44%; P < 0.0001) at week 26. Significant positive changes were also observed in secondary and exploratory CMR (RV and left ventricular), hemodynamic, and functional endpoints at week 26. Improvements in CMR RV and left ventricular variables and functional parameters were maintained at week 52. Safety (n = 87) was consistent with previous clinical trials.ConclusionsIn the context of this study, macitentan treatment in patients with PAH resulted in significant and clinically-relevant improvements in RV function and structure and cardiopulmonary hemodynamics. At 52 weeks, improvements in RV function and structure were sustained. (REPAIR: Right vEntricular remodeling in Pulmonary ArterIal hypeRtension [REPAIR]; NCT02310672)     

Swietenine Alleviates Vascular Remodelling by Enhancing Mitophagy of Pulmonary Arterial Smooth Muscle Cells in Experimental Pulmonary Hypertension

BackgroundVascular remodelling during pulmonary hypertension (PH) is characterized by the phenotypic transformation of pulmonary arterial smooth muscle cells (PASMCs). Swietenine (Swi), extracted from the seeds of traditional medicine Swietenia mahagoni, has been used to treat cardiac remodelling, but the effect of Swi on PH is unknown. This study aims to evaluate the effect of Swi on hypoxia-induced phenotypic transformation of PASMCs in experimental PH.MethodsIn our research, C57BL/6 mice were treated with SU5416 and exposed to hypoxia for 4 weeks to establish HySu-PH model. Mice in the Swi treatment group were subjected to HySu with daily administration of Swi. Hemodynamic parameters, echocardiography, and degree of vascular muscularization were measured to evaluate the PH model. Proliferation of PASMC was assessed by Ki67 and EdU assay. Cell migration was detected by wound-healing assay. Mitophagy levels were evaluated by mito-tracker and lyso-tracker, autophagic flux, and protein expression of Pink1 and Lc3 II. The molecular docking was used to validate the interaction of Swi with Nrf2. Immunofluorescence and immunohistochemical staining were applied to determine the subcellular localization of Nrf2.ResultsThe results showed that Swi attenuated hypoxia-induced increase of right ventricle systolic pressure, Fulton index, and vascular remodelling and decreased PASMC proliferation, migration, and enhanced mitophagy. Furthermore, the interaction of Swi with Nrf2 promoted the translocation of Nrf2 into the nucleus, resulting in the induction of Pink1.ConclusionsThis study demonstrates that Swi prevents vascular remodelling in experimental PH through inhibition of phenotypic transformation and hyperproliferation of PASMCs caused by reversing hypoxia-induced inhibition of mitophagy.     

Novel Treatment Pathways in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a severe and progressive vascular disease characterized by pulmonary vascular remodeling, proliferation, and inflammation. Despite the availability of effective treatments, PAH may culminate in right ventricular failure and death. Currently approved medications act through three well-characterized pathways: the nitric oxide, endothelin, and prostacyclin pathways. Ongoing research efforts continue to expand our understanding of the molecular pathogenesis of this complex and multifactorial disease. Based on recent discoveries in the pathobiology of PAH, several new treatments are being developed and tested with the goal of modifying the disease process and ultimately improving the long-term prognosis.     

Angiotensin-converting enzyme 2 activation suppresses pulmonary vascular remodeling by inducing apoptosis through the Hippo signaling pathway in rats with pulmonary arterial hypertension

Objective: To investigate the effects of angiotensin-converting enzyme 2 (ACE2) activation on pulmonary arterial cell apoptosis during pulmonary vascular remodeling associated with pulmonary arterial hypertension (PAH) and to elucidate potential mechanisms related to Hippo signaling. Methods: PAH model was developed by injecting monocrotaline combined with left pneumonectomy using Sprague-Dawley rat. Then, resorcinolnaphthalein (Res; ACE2 activator), MLN-4760 (ACE2 inhibitor), A-779 (Mas inhibitor), and 4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino) benzenesulfonamide (XMU-MP-1; MST1/2 inhibitor) were administered via continuous subcutaneous or intraperitoneal injection for 3 weeks. Animals were randomly divided into six groups: control, PAH, PAH+Res, PAH+Res+MLN-4760, PAH+Res+A-779, and PAH+Res+XMU-MP-1. On 21 day, hemodynamics and pathologic lesions were evaluated. Apoptosis and apoptosis-associated proteins were detected by TUNEL and western blotting. ACE2 activity and Hippo pathway components including large tumor suppressor 1 (LATS1), Yes-associated protein (Yap), and phosphorylated Yap (p-Yap) were investigated by fluorogenic peptide assays and western blotting. Results: In the PAH models, the mean pulmonary arterial pressure, right ventricular hypertrophy index, pulmonary vascular remodeling, anti-apoptotic protein Bcl-2 and Yap were all increased but the pulmonary arterial cell apoptosis, pro-apoptotic proteins caspase-3 and Bax were lower. ACE2 activation significantly ameliorated pulmonary arterial remodeling, this action was related to increased apoptosis and up-regulation of LATS1 and p-Yap. These protective effects were mitigated by the co-administration of A779 or MLN-4760. Moreover, inhibiting the Hippo/LATS1/Yap pathway with XMU-MP-1 blocked apoptosis in pulmonary vascular cells induced by ACE2 activation during the prevention of PAH. Conclusions: Our findings suggest that ACE2 activation attenuates pulmonary vascular remodeling by inducing pulmonary arterial cell apoptosis via Hippo/Yap signaling during the development of PAH.     

Pulmonary hypertension

Pulmonary arterial hypertension (PAH) must be classified into primary pulmonary hypertension and PAH related to other diseases such as collagen vascular diseases, HIV infection or portal hypertension. PAH must also be differentiated from other entities, in particular pulmonary hypertension secondary to thromboembolic diseases, requiring specific approaches. All PAH results in similar histological remodelling of pulmonary arteries, with thickening of the intima, proliferation of the media and plexogenic lesions. Today the physiopathology of these lesions is much better understood and has resulted in new therapies involving substances such as prostacyclins, endothelin receptor antagonists or phosphodiesterase inhibitors, aimed not only at dilating arteries but also at preventing their remodelling. Thromboendarterectomy, septostomy and transplantation remain the only option where medical treatment has failed.     

Notch3 signaling activation in smooth muscle cells promotes extrauterine growth restriction-induced pulmonary hypertension

Background and aimsEarly postnatal life is a critical developmental period that affects health of the whole life. Extrauterine growth restriction (EUGR) causes cardiovascular development problems and diseases, including pulmonary arterial hypertension (PAH). PAH is characterized by proliferation, migration, and anti-apoptosis of pulmonary artery smooth muscle cells (PASMCs). However, the role of PASMCs in EUGR has not been studied. Thus, we hypothesized that PASMCs dysfunction played a role in EUGR-induced pulmonary hypertension.Methods and resultsHere we identified that postnatal nutritional restriction-induced EUGR rats exhibited an elevated mean pulmonary arterial pressure and vascular remodeling at 12 weeks old. PASMCs of EUGR rats showed increased cell proliferation and migration features. In EUGR-induced PAH rats, Notch3 signaling was activated. Relative mRNA and protein expression levels of Notch3 intracellular domain (Notch3 ICD), and Notch target gene Hey1 in PASMCs were upregulated. We further demonstrated that pharmacological inhibition of Notch3 activity by using a γ-secretase inhibitor DAPT, which blocked the cleavage of Notch proteins to ICD peptides, could effectively inhibit PASMC proliferation. Specifically knocked down of Notch3 in rat PASMCs by shRNA restored the abnormal PASMC phenotype in vitro. We found that administration of Notch signaling inhibitor DAPT could successfully reduce mean pulmonary arterial pressure in EUGR rats.ConclusionsThe present study demonstrated that upregulation of Notch3 signaling in PASMCs was crucial for the development of EUGR-induced PAH. Blocking Notch3-Hey1 signaling pathway in PASMCs provides a potential therapeutic target for PAH.     

Anticoagulation in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is characterized by molecular and pathologic alteration to the pulmonary circulation, resulting in increased pulmonary vascular resistance, right ventricular failure, and eventual death. Pharmacologic treatment of PAH consists of use of a multitude of pulmonary vasodilators, sometimes in combination. PAH has been associated with increased thrombosis and disrupted coagulation and fibrinolysis, making anticoagulation an attractive and frequently employed therapeutic modality. Observational studies have provided some insight into the therapeutic potential of anticoagulation in idiopathic PAH, but there is a distinct lack of well-controlled prospective trials. Due to the conflicting evidence, there is a large amount of heterogeneity in the application of therapeutic anticoagulation in PAH and further well-controlled prospective trials are needed to clarify its role in treating PAH.     

Pulmonary Arterial Hypertension in the Elderly-Clinical Characteristics and Long-Term Survival

Background

Recent registries describe a significant prevalence of pulmonary arterial hypertension (PAH) in the elderly, but little is known of their characteristics. We aimed to examine the features and prognostic factors of long-term survival in elderly (??65?years) PAH patients.

Methods

Clinical, echocardiographic, angiographic, hemodynamic, treatments, and survival data were reviewed in consecutive patients over the course of 20?years. Elderly PAH patients (n?=?47) were compared to younger PAH patients (n?=?107).

Results

At presentation, elderly patients were more likely to have hypertension, diabetes, dyslipidemia, coronary disease, and PAH associated with scleroderma (42.6 vs. 24.3?%; p?=?0.02) than younger patients. Prior to PAH therapy, elderly patients had better right ventricular myocardial performance index (RV-MPI; 0.48?±?0.20 vs. 0.62?±?0.23, p?=?0.006) and lower mean pulmonary arterial pressure (PAP; 45.0?±?11.1 vs. 49.2?±?11.8?mmHg, p?=?0.04). Elderly patients were treated less often with epoprostenol (8.5 vs. 29?%, p?=?0.006) or trepostinil (8.5 vs. 23.4?%, p?=?0.04). The 1, 3, and 5?year survival rates of elderly patients were estimated to be 76.4, 50.5, and 37.6?%, respectively. In comparison, younger patients had survival estimates of 92.2, 74.2 and 64.0?% (p?=?0.002). Baseline right atrial pressure, mean PAP, cardiac index, and RV-MPI were associated with survival in elderly patients; however in these patients, survival was not affected by any PAH subgroup or age (per year) by itself.

Conclusions

The diagnosis of PAH in elderly patients is associated with poorer survival which is in part explained by a greater vulnerability to the hemodynamic disturbances of PAH.     

Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension

Background

Diabetes mellitus is associated with left ventricular hypertrophy and dysfunction. Parallel studies have also reported associations between diabetes mellitus and right ventricular dysfunction and reduced survival in patients with pulmonary arterial hypertension. However, the impact of diabetes mellitus on the pulmonary vasculature has not been well characterized. We hypothesized that diabetes mellitus and hyperglycemia could specifically influence right ventricular afterload and remodeling in patients with Group I pulmonary arterial hypertension, providing a link to their known susceptibility to right ventricular dysfunction.

Pulmonary arterial hypertension (PAH) in connective tissue diseases

Pulmonary arterial hypertension (PAH) is characterized by progressive obliteration of the small pulmonary vascular bed as a result of vascular proliferation and remodelling of the vessel wall leading to permanently increased pulmonary vascular resistance and elevated pulmonary artery pressures, which result in right heart failure and premature death. Pathologic processes behind the complex vascular changes associated with PAH include vasoconstrictor/vasodilator imbalance, thrombosis, misguided angiogenesis and inflammation. Besides idiopathic PAH, it can also occur in association with portal hypertension, HIV infection, congenital cardiac left-to-right shunts and connective tissue diseases (CTD). Unfortunately, despite recent major improvements in PAH treatment, no current therapy can yet cure this devastating condition. This review will briefly highlight epidemiology, pathogenesis, and diagnostic and treatment options known so far for PAH occurring in connection with CTD.     

Genotypes and Phenotypes of Chinese Pediatric Patients With Idiopathic and Heritable Pulmonary Arterial Hypertension—A Single-Center Study

BackgroundThe relationship between clinical outcomes and gene mutations in Chinese pediatric patients with idiopathic and heritable pulmonary arterial hypertension (PAH) is unclear.MethodsWe retrospectively studied the clinical characteristics and outcomes of pediatric patients who visited Beijing Anzhen Hospital from September 2008 to December 2018.ResultsEighty-two pediatric patients were included. Forty-two gene mutations were identified in 41 patients (50%), including 25 mutations in BMPR2, 5 mutations in ACVRL1, 3 mutations each in ABCA3 and NOTCH3, 2 mutations each in KCNK3 and HTR2B, 1 mutation in ENG, and 1 mutation in EIF2AK4. The mean age at diagnosis of PAH was 86.4 ± 55.1 months. Forty-eight patients (twenty-eight mutation carriers) underwent cardiac catheterization examinations, with acute vasodilator testing performed simultaneously. Results showed that mutation carriers demonstrated a higher pulmonary vascular resistance index (P = 0.037). Patients with gene mutations responded poorly to vasodilators (P = 0.001). The 1-, 2-, and 3-year survival rates of mutation noncarriers were 95.1%, 87.8%, and 82.5% respectively; while for mutation carriers, the proportions were 86.6% (P = 0.216), 63.8% (P = 0.021), and 52.2% (P = 0.010), respectively. Cardiac index was an independent predictor of death (P = 0.005; odds ratio [OR] 2.16, 95% confidence interval [CI] 1.258-3.704), as well as RAP (P = 0.01; OR 1.26, 95% CI 1.056-1.503).ConclusionsIn our cohort of Chinese pediatric patients, those with an identified gene mutation demonstrated worse clinical outcomes. Therefore, early gene screening for pediatric patients with idiopathic and heritable PAH is recommended, and more aggressive treatment for mutation carriers may be advisable.     

Cardiac-MRI Predicts Clinical Worsening and Mortality in Pulmonary Arterial Hypertension: A Systematic Review and Meta-Analysis

ObjectivesThis meta-analysis evaluates assessment of pulmonary arterial hypertension (PAH), with a focus on clinical worsening and mortality.BackgroundCardiac magnetic resonance (CMR) has prognostic value in the assessment of patients with PAH. However, there are limited data on the prediction of clinical worsening, an important composite endpoint used in PAH therapy trials.MethodsThe Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and Web of Science databases were searched in May 2020. All CMR studies assessing clinical worsening and the prognosis of patients with PAH were included. Pooled hazard ratios of univariate regression analyses for CMR measurements, for prediction of clinical worsening and mortality, were calculated.ResultsTwenty-two studies with 1,938 participants were included in the meta-analysis. There were 18 clinical worsening events and 8 deaths per 100 patient-years. The pooled hazard ratios show that every 1% decrease in right ventricular (RV) ejection fraction is associated with a 4.9% increase in the risk of clinical worsening over 22 months of follow-up and a 2.1% increase in the risk of death over 54 months. For every 1 ml/m² increase in RV end-systolic volume index or RV end-diastolic volume index, the risk of clinical worsening increases by 1.3% and 1%, respectively, and the risk of mortality increases by 0.9% and 0.6%. Every 1 ml/m² decrease in left ventricular stroke volume index or left ventricular end-diastolic volume index increased the risk of death by 2.5% and 1.8%. Left ventricular parameters were not associated with clinical worsening.ConclusionsThis review confirms CMR as a powerful prognostic marker in PAH in a large cohort of patients. In addition to confirming previous observations that RV function and RV and left ventricular volumes predict mortality, RV function and volumes also predict clinical worsening. This study provides a strong rationale for considering CMR as a clinically relevant endpoint for trials of PAH therapies.