STING Contributes to Pulmonary Hypertension by Targeting the Interferon and BMPR2 Signaling through Regulating F2RL3.

Pulmonary hypertension (PH) is an incurable disease characterized by pulmonary vascular remodeling. Endothelial injury and inflammation are the key triggers of the disease initiation. Recent findings suggest that STING (stimulator of interferon genes) activation plays a critical role in the endothelial dysfunction and interferon signaling. Here, we investigated the involvement of STING in the pathogenesis of PH. PH patients and rodent PH model samples, Sugen5416/hypoxia (SuHx) PH model, and pulmonary artery endothelial cells (PAECs) were used to evaluate the hypothesis. We found that the cyclic GMP-AMP (cGAS)-STING signaling pathway was activated in the lung tissues from rodent PH models and PH patients, and in the TNF-α induced PAECs in vitro. Specifically, STING expression was significantly elevated in the endothelial cell in PH disease settings. In SuHx mouse model, genetic knockout or pharmacological inhibition of STING prevented the progression of PH. Functionally, knockdown of STING reduced the proliferation and migration in PAECs. Mechanistically, STING transcriptional regulates its binding partner F2RL3 through STING-NF-κB axis, which activated the interferon signaling and repressed the BMPR2 signaling both in vitro and in vivo. Further analysis revealed that F2RL3 expression was increased in PH settings and identified negative feedback regulation of F2RL3/BMPR2 signaling. Accordingly, a positive correlation of expression levels between STING and F2RL3/interferon-stimulated genes (ISGs) was observed in vivo. Our findings suggest that STING activation in PAECs plays a critical role in the pathobiology of PH. Targeting STING may be a promising therapeutic strategy for preventing the development of PH.

Loss of lung microvascular endothelial Piezo2 expression impairs NO synthesis, induces EndMT, and is associated with pulmonary hypertension.

Mechanical forces are translated into biochemical stimuli by mechanotransduction channels, such as the mechanically activated cation channel Piezo2. Lung Piezo2 expression has recently been shown to be restricted to endothelial cells. Hence, we aimed to investigate the role of Piezo2 in regulation of pulmonary vascular function and structure, as well as its contribution to development of pulmonary arterial hypertension (PAH). The expression of Piezo2 was significantly reduced in pulmonary microvascular endothelial cells (MVECs) from patients with PAH, in lung tissue from mice with a Bmpr2+/R899X knock-in mutation commonly found in patients with pulmonary hypertension, and in lung tissue of monocrotaline (MCT) and sugen-hypoxia-induced PH (SuHx) PAH rat models, as well as from a swine model with pulmonary vein banding. In MVECs, Piezo2 expression was reduced in response to abnormal shear stress, hypoxia, and TGFß stimulation. Functional studies in MVECs exposed to shear stress illustrated that siRNA-mediated Piezo2 knockdown impaired endothelial alignment, calcium influx, phosphorylation of AKT, and nitric oxide production. In addition, siPiezo2 reduced the expression of the endothelial marker PECAM-1 and increased the expression of vascular smooth muscle markers ACTA2, SM22a, and calponin. Thus, Piezo2 acts as a mechanotransduction channel in pulmonary MVECs, stimulating shear-induced production of nitric oxide and is essentially involved in preventing endothelial to mesenchymal transition. Its blunted expression in pulmonary hypertension could impair the vasodilator capacity and stimulate vascular remodeling, indicating that Piezo2 might be an interesting therapeutic target to attenuate progression of the disease.NEW & NOTEWORTHY The mechanosensory ion channel Piezo2 is exclusively expressed in lung microvascular endothelial cells (MVECs). Patient MVECs as well as animal models of pulmonary (arterial) hypertension showed lower expression of Piezo2 in the lung. Mechanistically, Piezo2 is required for calcium influx and NO production in response to shear stress, whereas stimuli known to induce endothelial to mesenchymal transition (EndMT) reduce Piezo2 expression in MVECs, and Piezo2 knockdown induces a gene and protein expression pattern consistent with EndMT.

Kynurenine metabolites predict survival in pulmonary arterial hypertension: A role for IL-6/IL-6Rα.

Activation of the kynurenine pathway (KP) has been reported in patients with pulmonary arterial hypertension (PAH) undergoing PAH therapy. We aimed to determine KP-metabolism in treatment-naïve PAH patients, investigate its prognostic values, evaluate the effect of PAH therapy on KP-metabolites and identify cytokines responsible for altered KP-metabolism. KP-metabolite levels were determined in plasma from PAH patients (median follow-up 42 months) and in rats with monocrotaline- and Sugen/hypoxia-induced PH. Blood sampling of PAH patients was performed at the time of diagnosis, six months and one year after PAH therapy. KP activation with lower tryptophan, higher kynurenine (Kyn), 3-hydroxykynurenine (3-HK), quinolinic acid (QA), kynurenic acid (KA), and anthranilic acid was observed in treatment-naïve PAH patients compared with controls. A similar KP-metabolite profile was observed in monocrotaline, but not Sugen/hypoxia-induced PAH. Human lung primary cells (microvascular endothelial cells, pulmonary artery smooth muscle cells, and fibroblasts) were exposed to different cytokines in vitro. Following exposure to interleukin-6 (IL-6)/IL-6 receptor α (IL-6Rα) complex, all cell types exhibit a similar KP-metabolite profile as observed in PAH patients. PAH therapy partially normalized this profile in survivors after one year. Increased KP-metabolites correlated with higher pulmonary vascular resistance, shorter six-minute walking distance, and worse functional class. High levels of Kyn, 3-HK, QA, and KA measured at the latest time-point were associated with worse long-term survival. KP-metabolism was activated in treatment-naïve PAH patients, likely mediated through IL-6/IL-6Rα signaling. KP-metabolites predict response to PAH therapy and survival of PAH patients.

Purinergic Dysfunction in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by increased pulmonary arterial pressure and pulmonary vascular resistance, which result in an increase in afterload imposed onto the right ventricle, leading to right heart failure. Current therapies are incapable of reversing the disease progression. Thus, the identification of novel and potential therapeutic targets is urgently needed. An alteration of nucleotide- and nucleoside-activated purinergic signaling has been proposed as a potential contributor in the pathogenesis of PAH. Adenosine-mediated purinergic 1 receptor activation, particularly A2AR activation, reduces pulmonary vascular resistance and attenuates pulmonary vascular remodeling and right ventricle hypertrophy, thereby exerting a protective effect. Conversely, A2BR activation induces pulmonary vascular remodeling, and is therefore deleterious. ATP-mediated P2X7R activation and ADP-mediated activation of P2Y1R and P2Y12R play a role in pulmonary vascular tone, vascular remodeling, and inflammation in PAH. Recent studies have revealed a role of ectonucleotidase nucleoside triphosphate diphosphohydrolase, that degrades ATP/ADP, in regulation of pulmonary vascular remodeling. Interestingly, existing evidence that adenosine activates erythrocyte A2BR signaling, counteracting hypoxia-induced pulmonary injury, and that ATP release is impaired in erythrocyte in PAH implies erythrocyte dysfunction as an important trigger to affect purinergic signaling for pathogenesis of PAH. The present review focuses on current knowledge on alteration of nucleot(s)ide-mediated purinergic signaling as a potential disease mechanism underlying the development of PAH.

Lower Plasma Melatonin Levels Predict Worse Long-Term Survival in Pulmonary Arterial Hypertension.

: Exogenous melatonin has been reported to be beneficial in the treatment of pulmonary hypertension (PH) in animal models. Multiple mechanisms are involved, with melatonin exerting anti-oxidant and anti-inflammatory effects, as well as inducing vasodilation and cardio-protection. However, endogenous levels of melatonin in treatment-naïve patients with PH and their clinical significance are still unknown. Plasma levels of endogenous melatonin were measured by liquid chromatography-tandem mass spectrometry in PH patients (n = 64, 43 pulmonary arterial hypertension (PAH) and 21 chronic thromboembolic PH (CTEPH)) and healthy controls (n = 111). Melatonin levels were higher in PH, PAH, and CTEPH patients when compared with controls (Median 118.7 (IQR 108.2-139.9), 118.9 (109.3-147.7), 118.3 (106.8-130.1) versus 108.0 (102.3-115.2) pM, respectively, p all < 0.001). The mortality was 26% (11/43) in the PAH subgroup during a long-term follow-up of 42 (IQR: 32-58) months. Kaplan-Meier analysis showed that, in the PAH subgroup, patients with melatonin levels in the 1st quartile (<109.3 pM) had a worse survival than those in quartile 2-4 (Mean survival times were 46 (95% CI: 30-65) versus 68 (58-77) months, Log-rank, p = 0.026) with an increased hazard ratio of 3.5 (95% CI: 1.1-11.6, p = 0.038). Endogenous melatonin was increased in treatment-naïve patients with PH, and lower levels of melatonin were associated with worse long-term survival in patient with PAH.

Right ventricular oxygen delivery as a determinant of right ventricular functional reserve during exercise in juvenile swine with chronic pulmonary hypertension.

Assessing right ventricular (RV) functional reserve is important for determining clinical status and prognosis in patients with pulmonary hypertension (PH). In this study, we aimed to establish RV oxygen (O2) delivery as a determinant for RV functional reserve during exercise in swine with chronic PH. Chronic PH was induced by pulmonary vein banding (PVB), with sham operation serving as control. RV function and RV O2 delivery were measured over time in chronically instrumented swine, up to 12 wk after PVB at rest and during exercise. At rest, RV afterload (pulmonary artery pressure and arterial elastance) and contractility (Ees and dP/dtmax) were higher in PH compared with control with preserved cardiac index and RV O2 delivery. However, RV functional reserve, as measured by the exercise-induced relative change (Δ) in cardiac index, dP/dtmax, and end-systolic elastance (Ees), was decreased in PH, and RV pulmonary arterial coupling was lower both at rest and during exercise in PH. Furthermore, the increase in RV O2 delivery was attenuated in PH during exercise principally due to a lower systolic coronary blood flow in combination with an attenuated increase in aorta pressure while arterial O2 content was not significantly altered in PH. Moreover, RV O2 delivery reserve correlated with RV functional reserve, Δcardiac index (r2 = 0.85), ΔdP/dtmax (r2 = 0.49), and ΔEes (r2 = 0.70), all P < 0.05. The inability to sufficiently increase RV O2 supply to meet the increased O2 demand during exercise is principally due to the reduced RV perfusion relative to healthy control values and likely contributes to impaired RV contractile function and thereby to the limited exercise capacity that is commonly observed in patients with PH.NEW & NOTEWORTHY Impaired right ventricular (RV) O2 delivery reserve is associated with reduced RV functional reserve during exercise in a swine model of pulmonary hypertension (PH) induced by pulmonary vein banding. Our data suggest that RV function and exercise capacity might be improved by improving RV O2 delivery.

Cardiac remodelling in a swine model of chronic thromboembolic pulmonary hypertension: comparison of right vs. left ventricle.

KEY POINTS: Right ventricle (RV) function is the most important determinant of survival and quality of life in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The changes in right and left ventricle gene expression that contribute to ventricular remodelling are incompletely investigated. RV remodelling in our CTEPH swine model is associated with increased expression of the genes involved in inflammation (TGFß), oxidative stress (ROCK2, NOX1 and NOX4), and apoptosis (BCL2 and caspase-3). Alterations in ROCK2 expression correlated inversely with RV contractile reserve during exercise. Since ROCK2 has been shown to be involved in hypertrophy, oxidative stress, fibrosis and endothelial dysfunction, ROCK2 inhibition may present a viable therapeutic target in CTEPH. ABSTRACT: Right ventricle (RV) function is the most important determinant of survival and quality of life in patients with chronic thromboembolic pulmonary hypertension (CTEPH). The present study investigated whether the increased cardiac afterload is associated with (i) cardiac remodelling and hypertrophic signalling; (ii) changes in angiogenic factors and capillary density; and (iii) inflammatory changes associated with oxidative stress and interstitial fibrosis. CTEPH was induced in eight chronically instrumented swine by chronic nitric oxide synthase inhibition and up to five weekly pulmonary embolizations. Nine healthy swine served as a control. After 9 weeks, RV function was assessed by single beat analysis of RV-pulmonary artery (PA) coupling at rest and during exercise, as well as by cardiac magnetic resonance imaging. Subsequently, the heart was excised and RV and left ventricle (LV) tissues were processed for molecular and histological analyses. Swine with CTEPH exhibited significant RV hypertrophy in response to the elevated PA pressure. RV-PA coupling was significantly reduced, correlated inversely with pulmonary vascular resistance and did not increase during exercise in CTEPH swine. Expression of genes associated with hypertrophy (BNP), inflammation (TGFß), oxidative stress (ROCK2, NOX1 and NOX4), apoptosis (BCL2 and caspase-3) and angiogenesis (VEGFA) were increased in the RV of CTEPH swine and correlated inversely with RV-PA coupling during exercise. In the LV, only significant changes in ROCK2 gene-expression occurred. In conclusion, RV remodelling in our CTEPH swine model is associated with increased expression of genes involved in inflammation and oxidative stress, suggesting that these processes contribute to RV remodelling and dysfunction in CTEPH and hence represent potential therapeutic targets.

Transition from post-capillary pulmonary hypertension to combined pre- and post-capillary pulmonary hypertension in swine: a key role for endothelin.

KEY POINTS: Passive, isolated post-capillary pulmonary hypertension (PH) secondary to left heart disease may progress to combined pre- and post-capillary or 'active' PH This 'activation' of post-capillary PH significantly increases morbidity and mortality, and is still incompletely understood. In this study, pulmonary vein banding gradually produced post-capillary PH with structural and functional microvascular remodelling in swine. Ten weeks after banding, the pulmonary endothelin pathway was upregulated, likely contributing to pre-capillary aspects in the initially isolated post-capillary PH. Inhibition of the endothelin pathway could potentially stop the progression of early stage post-capillary PH. ABSTRACT: Passive, isolated post-capillary pulmonary hypertension (IpcPH) secondary to left heart disease may progress to combined pre- and post-capillary or 'active' PH (CpcPH) characterized by chronic pulmonary vascular constriction and remodelling. The mechanisms underlying this 'activation' of passive pulmonary hypertension (PH) remain incompletely understood. Here we investigated the role of the vasoconstrictor endothelin-1 (ET) in the progression from IpcPH to CpcPH in a swine model for post-capillary PH. Swine underwent pulmonary vein banding (PVB; n = 7) or sham-surgery (Sham; n = 6) and were chronically instrumented 4 weeks later. Haemodynamics were assessed for 8 weeks, at rest and during exercise, before and after administration of the ET receptor antagonist tezosentan. After sacrifice, the pulmonary vasculature was investigated by histology, RT-qPCR and myograph experiments. Pulmonary arterial pressure and resistance increased significantly over time. mRNA expression of prepro-endothelin-1 and endothelin converting enzyme-1 in the lung was increased, while ETA expression was unchanged and ETB expression was downregulated. This was associated with increased plasma ET levels from week 10 onward and a more pronounced vasodilatation to in vivo administration of tezosentan at rest and during exercise. Myograph experiments showed decreased endothelium-dependent vasodilatation to Substance P and increased vasoconstriction to KCl in PVB swine consistent with increased muscularization observed with histology. Moreover, maximal vasoconstriction to ET was increased whereas ET sensitivity was decreased. In conclusion, PVB swine gradually developed PH with structural and functional vascular remodelling. From week 10 onward, the pulmonary ET pathway was upregulated, likely contributing to pre-capillary activation of the initially isolated post-capillary PH. Inhibition of the ET pathway could thus potentially provide a pharmacotherapeutic target for early stage post-capillary PH.

MiR-125a-5p ameliorates monocrotaline-induced pulmonary arterial hypertension by targeting the TGF-ß1 and IL-6/STAT3 signaling pathways.

Pulmonary vascular remodeling due to excessive proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Recent evidence suggests that miR-125a-5p plays a role in a rat model of monocrotaline-induced PAH (MCT-PAH); however, the underlying mechanism is currently unknown. Here, we examined the expression profile of miR-125a-5p in MCT-PAH rats and investigated the putative therapeutic effect of miR-125a-5p using the miR-125a-5p agomir. In addition, the miR-125a-5p agomir or antagomir was transfected into rat PASMCs, and proliferation and apoptosis were measured. Activity of the miR-125a-5p target STAT3 was measured using a luciferase reporter assay, and the expression of downstream molecules was measured using RT-qPCR and/or western blot analysis. Importantly, inducing miR-125a-5p expression in vivo slowed the progression of MCT-PAH by reducing systolic pulmonary arterial pressure, the Fulton index, and pulmonary vascular remodeling. Moreover, overexpressing miR-125a-5p inhibited the proliferation and promoted the apoptosis of PASMCs. In addition, stimulating PASMCs with TGF-ß1 or IL-6 upregulated miR-125a-5p expression, whereas overexpressing miR-125a-5p reduced TGF-ß1 and IL-6 production, as well as the expression of their downstream targets STAT3 and Smad2/3; in contrast, downregulating miR-125a-5p increased TGF-ß1 and IL-6 production. Finally, a dual-luciferase reporter assay revealed that miR-125a-5p targets the 3'-UTR of STAT3, suppressing the downstream molecules PCNA, Bcl-2, and Survivin. Taken together, these findings suggest that miR-125a-5p ameliorates MCT-PAH in rats, has a negative feedback regulation with TGF-ß1 and IL-6, and regulates the proliferation and apoptosis of PASMCs by directly targeting STAT3.

Exercise facilitates early recognition of cardiac and vascular remodeling in chronic thromboembolic pulmonary hypertension in swine.

Chronic thromboembolic pulmonary hypertension (CTEPH) develops in 4% of patients after pulmonary embolism and is accompanied by an impaired exercise tolerance, which is ascribed to the increased right ventricular (RV) afterload in combination with a ventilation/perfusion (V/Q) mismatch in the lungs. The present study aimed to investigate changes in arterial Po2 and hemodynamics in response to graded treadmill exercise during development and progression of CTEPH in a novel swine model. Swine were chronically instrumented and received multiple pulmonary embolisms by 1) microsphere infusion (Spheres) over 5 wk, 2) endothelial dysfunction by administration of the endothelial nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (L-NAME) for 7 wk, 3) combined pulmonary embolisms and endothelial dysfunction (L-NAME + Spheres), or 4) served as sham-operated controls (sham). After a 9 wk followup, embolization combined with endothelial dysfunction resulted in CTEPH, as evidenced by mean pulmonary artery pressures of 39.5 ± 5.1 vs. 19.1 ± 1.5 mmHg (Spheres, P < 0.001), 22.7 ± 2.0 mmHg (L-NAME, P < 0.001), and 20.1 ± 1.5 mmHg (sham, P < 0.001), and a decrease in arterial Po2 that was exacerbated during exercise, indicating V/Q mismatch. RV dysfunction was present after 5 wk of embolization, both at rest (trend toward increased RV end-systolic lumen area, P = 0.085, and decreased stroke volume index, P = 0.042) and during exercise (decreased stroke volume index vs. control, P = 0.040). With sustained pulmonary hypertension, RV hypertrophy (Fulton index P = 0.022) improved RV function at rest and during exercise, but this improvement was insufficient in CTEPH swine to result in an exercise-induced increase in cardiac index. In conclusion, embolization in combination with endothelial dysfunction results in CTEPH in swine. Exercise increased RV afterload, exacerbated the V/Q mismatch, and unmasked RV dysfunction. NEW & NOTEWORTHY Here, we present the first double-hit chronic thromboembolic pulmonary hypertension swine model. We show that embolization as well as endothelial dysfunction is required to induce sustained pulmonary hypertension, which is accompanied by altered exercise hemodynamics and an exacerbated ventilation/perfusion mismatch during exercise.

5-Aminosalicylic Acid Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats by Increasing the Expression of Nur77.

The aim of this study is to investigate the effect of 5-aminosalicylic acid (5-ASA) on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats and its molecular mechanism. Sixty male Sprague-Dawley rats (250-300 g) were evenly randomized into six groups: control group; PAH group induced by MCT intraperitoneal injection (50 mg/kg) on day 1; and four PAH groups treated for 30 days from day 2 with 5-ASA at 50 (5-ASA-50 group), 100 (5-ASA-100 group), 150 (5-ASA-150 group), and 200 mg/kg/day (5-ASA-200 group), respectively. Body mass, weight increment, survival rates, pulmonary artery pressure (PAP), right ventricular hypertrophy index (RVHI), and the signal pathway regulated by 5-ASA were assessed. (1) Compared with the control group, the PAH group had lower body mass and weight increment, and relative to the latter, 5-ASA-treated groups had larger body mass and weight increment except for groups 5-ASA-150 and 5-ASA-200 and greater overall survival rates; (2) SPAP, DPAP, MPAP, and RVHI in 5-ASA-treated groups, except for MPAP and RVHI in 5-ASA-200 group, were lower than those in the PAH group; (3) compared with the PAH group, Nur77 expression in the pulmonary arteries of 5-ASA-treated groups was increased; and (4) expression of inflammatory mediators (NF-κB p65) was lower, while that of IκBα was higher in the pulmonary arteries of 5-ASA-treated groups and control group than that in the PAH group (all P < 0.05). 5-ASA attenuates PAH in MCT-injected rats, reducing pulmonary arterial pressures and right ventricular hypertrophy and improving survival rates, via the Nur77-NF-κB/IκBα pathway involved in modulating the pulmonary vascular remodeling.

The Application of Intravascular Ultrasound to Evaluate Pulmonary Vascular Properties and Mortality in Patients with Pulmonary Arterial Hypertension.

BACKGROUND: The aim of this study was to explore the application of intravascular ultrasound (IVUS) to evaluate pulmonary vascular properties and mortality in patients with pulmonary arterial hypertension (PAH). METHODS: Patients (n = 51) with systolic pulmonary artery pressures ≥ 40 mm Hg on echocardiography were prospectively enrolled. All patients underwent right-heart catheterization and IVUS and were divided into three groups: PAH associated with connective tissue diseases (group 1, n = 25), PAH due to other causes (group 2, n = 15), and patients with connective tissue diseases without pulmonary hypertension (group 3, n = 11). PAH groups (groups 1 and 2) were divided into distal (n = 22) and proximal (n = 18) remodeling subtypes on the basis of IVUS results. All patients were followed (19 ± 10 months) to compare the differences among clinical variables, pulmonary vascular properties, and survival rates. RESULTS: A total of 408 segments of pulmonary arteries were studied. The PAH groups demonstrated a greater mean wall thickness than group 3 (P < .01 for all). Pulmonary vascular mechanical properties, including compliance, distensibility, elastic modulus, and stiffness index ß, were found to be worse in the PAH groups than in group 3 (P < .01 for all), but they tended to be better in group 1 than in group 2. An inverse exponential association was found between pulmonary vascular mechanical properties and hemodynamics, with R(2) values ranging from 0.54 to 0.78 (P < .001). In the PAH groups, the mortality in group 1 was similar to that in group 2 (12% vs 13%, P > .05), while the distal remodeling subtype had higher mortality than the proximal remodeling subtype (23% vs 0%, P < .05). CONCLUSIONS: IVUS is useful in PAH assessment by evaluating pulmonary vascular properties and predicting mortality. The classification of the proximal and distal remodeling type of PAH may be proposed to predict mortality and evaluate the prognosis of patients with PAH in clinical practice.

[Value of intravascular ultrasound in the assessment of pulmonary vascular properties and mortality in patients with pulmonary artery hypertension associated with connective tissue diseases].

OBJECTIVE: To investigate the value of intravascular ultrasound (IVUS) on assessing pulmonary vascular properties (PVPs) and its relationship with hemodynamics, and mortality rate in patients with pulmonary arterial hypertension associated with connective tissue disease (PAH-CTD). METHODS: Patients (n=51) with highly suspected PAH-CTD were prospectively enrolled in our department between July 2011 and March 2014. All patients underwent right heart catheterization (RHC) and IVUS, and were divided into 3 groups: PAH-CTD (n=25), PAH due to other reasons (n=15), and non-PAH control group (n=11). Based on IVUS, PAH patients were divided into distal (n=22) and proximal (n=18) remodeling subtypes.A total of 408 pulmonary segments were detected by IVUS, and all patients were followed up to (19 ± 10) months. RESULTS: IVUS evidenced higher mean wall thickness (MWT) ((0.30 ± 0.02) mm and (0.33 ± 0.02) mm vs. (0.21 ± 0.02) mm) and percentage of MWT (WTP) ((13.62 ± 0.59)% and (14.39 ± 0.77)% vs. (9.57 ± 0.97)%) values in PAH patients compared to control patients (all P<0.01). Pulmonary vascular mechanical properties (PVMPs) including compliance ((8.85 ± 0.82) × 10(-2)mm(2)/mmHg(1 mmHg=0.133 kPa) and (6.28 ± 0.65) × 10(-2)mm(2)/mmHg vs. (41.59 ± 5.02) × 10(-2) mm(2)/mmHg, all P<0.01), distensibility ((0.83 ± 0.09)%/mmHg and (0.55 ± 0.06)%/mmHg vs. (3.16 ± 0.38) %/mmHg, all P<0.01), elastic modulus ((169.25 ± 15.10) mmHg and (253.00 ± 22.11) mmHg vs.(43.78 ± 4.27) mmHg, all P<0.01) and stiffness index ß (4.19 ± 0.41 and 5.18 ± 0.34 vs. 2.39 ± 0.27, P<0.05 or 0.01) in PAH groups were all significantly worse than in control group (all P<0.01). An inverse exponential association was found between PVMPs and hemodynamics with R(2) ranging from 0.544 to 0.777 (P<0.001). PVMPs tended to be better in group PAH-CTD than in PAH group due to other reasons.Mortality rate was similar between the two PAH groups, while PAH with distal remodeling subtype was linked with significantly higher mortality rate than PAH with the proximal remodeling subtype (23 % vs. 0, HR=10.14, P<0.05). CONCLUSIONS: IVUS plays an important role in the assessment of PAH-CTD patients in terms of evaluating PVPs and predicting mortality rate. PAH patients have deteriorated PVPs, but PVMPs tended to be better in PAH-CTD than in PAH patients due to other reasons. The mortality rate was similar between PAH groups, while PAH patients with the distal remodeling subtype is linked with a higher mortality rate than PAH patients with the proximal remodeling subtype.

Two-dimensional echocardiography in the assessment of long-term prognosis in patients with pulmonary arterial hypertension.

OBJECTIVE: To investigate the relationship between cardiac diastolic dysfunction and outcomes in patients with pulmonary arterial hypertension (PAH) and to clarify the potential effect of two-dimensional echocardiography (2D-echo) on prognostic value in patients with PAH. METHODS: Patients diagnosed with PAH (as WSPH (World Symposia on Pulmonary Hypertension) classification I) confirmed by right heart catheterization (RHC), received targeted monotherapy or combination therapy. 2D-echo parameters, World Health Organization (WHO) functional classification and 6-minute walking distance (6MWD) were recorded. The clinical prognosis of patients was assessed by the correlation between echo parameters and clinical 6MWD using receiver operating characteristic (ROC) curve analysis. RESULTS: Fifty-eight patients were included. Left and right ventricular diastolic dysfunction (LVDD and RVDD) scores measured by 2D-echo had good correlation with 6MWD at baseline (rLVDD  = -0.699; rRVDD  = -0.818, both P < 0.001) and at last follow-up (rLVDD  = -0.701; rRVDD  = -0.666, both P<0.001). Furthermore, bi-ventricular (LVDD + RVDD) scores measured by 2D-echo had a better correlation with 6MWD at baseline and last follow-up (r =  0.831; r = -0.771, both P < 0.001). ROC curve analysis showed that the area under curves (AUCs) for LVDD score, RVDD score and (LVDD + RVDD) scores were 0.823 (P < 0.0001), 0.737 (P = 0.0002), and 0.825 (P < 0.0001), respectively. Compared with ROC analysis of other single parameters, cardiac diastolic function score was more accurate in predicting survival in patients with PAH. CONCLUSION: LVDD score, RVDD score and (LVDD + RVDD) scores yielded a comprehensive quantitative assessment of LV and RV diastolic function that correlated moderately with clinical functional parameters and might be useful in the assessment of PAH.