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Background: Mitochondrial DNA (mtDNA)-induced myocardial inflammation is intimately involved in cardiac remodeling. ZBP1 (Z-DNA binding protein 1) is a pattern recognition receptor positively regulating inflammation in response to mtDNA in inflammatory cells, fibroblasts, and endothelial cells. However, the role of ZBP1 in myocardial inflammation and cardiac remodeling remains unclear. The aim of this study was to elucidate the role of ZBP1 in mtDNA-induced inflammation in cardiomyocytes and failing hearts. Methods: mtDNA was administrated into isolated cardiomyocytes. Myocardial infarctionwas conducted in wild type and ZBP1 knockout mice. Results: We here found that, unlike in macrophages, ZBP1 knockdown unexpectedly exacerbated mtDNA-induced inflammation such as increases in IL (interleukin)-1β and IL-6, accompanied by increases in RIPK3 (receptor interacting protein kinase 3), phosphorylated NF-κB (nuclear factor-κB), and NLRP3 (nucleotide-binding domain and leucine-rich-repeat family pyrin domain containing 3) in cardiomyocytes. RIPK3 knockdown canceled further increases in phosphorylated NF-κB, NLRP3, IL-1β, and IL-6 by ZBP1 knockdown in cardiomyocytes in response to mtDNA. Furthermore, NF-κB knockdown suppressed such increases in NLRP3, IL-1β, and IL-6 by ZBP1 knockdown in response to mtDNA. CpG-oligodeoxynucleotide, a Toll-like receptor 9 stimulator, increased RIPK3, IL-1β, and IL-6 and ZBP1 knockdown exacerbated them. Dloop, a component of mtDNA, but not Tert and B2m , components of nuclear DNA, was increased in cytosolic fraction from noninfarcted region of mouse hearts after myocardial infarction compared with control hearts. Consistent with this change, ZBP1, RIPK3, phosphorylated NF-κB, NLRP3, IL-1β, and IL-6 were increased in failing hearts. ZBP1 knockout mice exacerbated left ventricular dilatation and dysfunction after myocardial infarction, accompanied by further increases in RIPK3, phosphorylated NF-κB, NLRP3, IL-1β, and IL-6. In histological analysis, ZBP1 knockout increased interstitial fibrosis and myocardial apoptosis in failing hearts. Conclusions: Our study reveals unexpected protective roles of ZBP1 against cardiac remodeling as an endogenous suppressor of mtDNA-induced myocardial inflammation.

Background While current guidelines require lung ventilation-perfusion (V/Q) scanning as the first step to diagnose chronic pulmonary embolism in pulmonary hypertension (PH), its use may be limited by low availability and/or exposure to ionizing radiation. Purpose To compare the performance of dynamic chest radiography (DCR) and lung V/Q scanning for detection of chronic thromboembolic PH (CTEPH). Materials and Methods Patients with PH who underwent DCR and V/Q scanning in the supine position from December 2019 to July 2021 were retrospectively screened. The diagnosis of CTEPH was confirmed with right heart catheterization and invasive pulmonary angiography. Observer tests were conducted to evaluate the diagnostic accuracy of DCR and V/Q scanning. The lungs were divided into six areas (upper, middle, and lower for both) in the anteroposterior image, and the number of lung areas with thromboembolic perfusion defects was scored. Diagnostic performance was compared between DCR and V/Q scanning using the area under the receiver operating characteristic curve. Agreement between the interpretation of DCR and that of V/Q scanning was assessed using the Cohen kappa coefficient and percent agreement. Results A total of 50 patients with PH were analyzed: 29 with CTEPH (mean age, 64 years ± 15 [SD]; 19 women) and 21 without CTEPH (mean age, 61 years ± 22; 14 women). The sensitivity, specificity, and accuracy of DCR were 97%, 86%, and 92%, respectively, and those of V/Q scanning were 100%, 86%, and 94%, respectively. Areas under the receiver operating characteristic curve for DCR and V/Q scanning were 0.92 (95% CI: 0.79, 0.97) and 0.93 (95% CI: 0.78, 0.98). Agreement between the consensus interpretation of DCR and that of V/Q scanning was substantial (κ = 0.79 [95% CI: 0.61, 0.96], percent agreement = 0.9 [95% CI: 0.79, 0.95]). Conclusion Dynamic chest radiography had similar efficacy to ventilation-perfusion scanning in the detection of chronic thromboembolic pulmonary hypertension. © RSNA, 2022

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Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by pulmonary arterial vasoconstriction and remodeling. Src family tyrosine kinases, including Fyn, play critical roles in vascular remodeling via the inhibition of STAT3 signaling. EPA is known to inhibit Fyn kinase activity. This study investigated the therapeutic potential and underlying mechanisms of EPA and its metabolite, resolvin E1 (RvE1), to treat PAH using monocrotaline-induced PAH model rats (MCT-PAH), human pulmonary artery endothelial cells (HPAECs), and human pulmonary artery smooth muscle cells (HPASMCs). Administration of EPA 1 and 2 weeks after MCT injection both ameliorated right ventricular hypertrophy, remodeling and dysfunction, and medial wall thickening of the pulmonary arteries and prolonged survival in MCT-PAH rats. EPA attenuated the enhanced contractile response to 5-hydroxytryptamine in isolated pulmonary arteries of MCT-PAH rats. Mechanistically, the treatment with EPA and RvE1 or the introduction of dominant-negative Fyn prevented TGF-β2-induced endothelial-to-mesenchymal transition and IL-6-induced phosphorylation of STAT3 in cultured HPAECs. EPA and RvE1 suppressed Src family kinases' activity as evaluated by their phosphorylation status in cultured HPAECs and HPASMCs. EPA and RvE1 suppressed vasocontraction of rat and human PA. Furthermore, EPA and RvE1 inhibited the enhanced proliferation and activity of Src family kinases in HPASMCs derived from patients with idiopathic PAH. EPA ameliorated PAH's pathophysiology by mitigating vascular remodeling and vasoconstriction, probably inhibiting Src family kinases, especially Fyn. Thus, EPA is considered a potent therapeutic agent for the treatment of PAH.

The Na+/Ca2+ exchanger type-1 (NCX1) is a bidirectional transporter that is controlled by membrane potential and transmembrane gradients of Na+ and Ca2+. Vascular smooth muscle NCX1 plays an important role in intracellular Ca2+ homeostasis and Ca2+ signaling. We found that NCX1 was upregulated in the pulmonary arteries of mice exposed to chronic hypoxia (10% O2 for 4 weeks). Hence, we investigated the pathophysiological role of NCX1 in hypoxia-induced pulmonary arterial hypertension (PAH), using NCX1-heterozygous (NCX1+/−) mice, in which NCX1 expression is reduced by half, and SEA0400, a specific NCX1 inhibitor. NCX1+/− mice exhibited attenuation of hypoxia-induced PAH and right ventricular (RV) hypertrophy compared with wild-type mice. Furthermore, continuous administration of SEA0400 (0.5 mg/kg/day for 4 weeks) to wild-type mice by osmotic pumps significantly suppressed hypoxia-induced PAH and pulmonary vessel muscularization, with a slight reduction in RV hypertrophy. These findings indicate that the upregulation of NCX1 contributes to the development of hypoxia-induced PAH, suggesting that NCX1 inhibition might be a novel approach for the treatment of PAH.

Background The latest guidelines recommend early intervention in adult atrial septal defect (ASD) patients with signs of right ventricular (RV) enlargement. However, the criteria of RV enlargement for optimal intervention remain unclear. We investigated the preoperative determinants for normalizing the RV volume after transcatheter closure of ASD in adults.Methods and Results:We retrospectively analyzed 52 ASD patients who underwent transcatheter closure. Cardiac magnetic resonance imaging (CMR) measured RV volume before and 1 year after the closure. The patients were divided into normalized (postoperative RV end-systolic volume index [RVESVI] Conclusions Preoperative RVESVI is an independent predictor for normalization of RV volume at 1 year after transcatheter closure of ASD in adults. Early intervention before RVESVI reaches 75 mL/m2may confer optimal timing for normalizing RV volume.

Background: The emPHasis-10 questionnaire is a disease-specific patient-reported outcome assessment of quality of life (QOL) in pulmonary hypertension (PH). The aim of this study was to psychometrically validate a linguistically validated Japanese version of the emPHasis-10. Methods and Results: Japanese patients with PH (age ≥18 years) and no change in functional status, or initiation or change in PH-specific treatment during the past 3 months were recruited from 5 institutions from August 2018 to July 2019. A set of questionnaires was administered twice. The validity and reliability of the emPHasis-10 were assessed using the data of 76 patients. On concurrent validity analysis, a moderate-to-strong correlation was seen with the total score of all 5 external criteria (the Minnesota Living with Heart Failure modified for PH [MLHFQ-PH], Hospital Anxiety and Depression Scale, Dyspnea-12 questionnaire, European Quality of Life-5 Dimensions questionnaire [EQ-5D], and 6-min walk test), with a notably strong correlation with the MLHFQ-PH (0.77) and EQ-5D (–0.64). On known-group validity, a linear increasing trend of the emPHasis-10 score was observed across 4 World Health Organization functional status groups (Jonckheere-Terpstra test, 1-sided, P

Objective: / We propose a deep learning-based fully automatic right ventricle (RV) segmentation technique that targets radially reconstructed long-axis (RLA) images of the center of the RV region in routine short axis (SA) cardiovascular magnetic resonance (CMR) images. Accordingly, the purpose of this study is to compare the accuracy of deep learning-based fully automatic segmentation of RLA images with the accuracy of conventional deep learning-based segmentation in SA orientation in terms of the measurements of RV strain parameters. / Materials and Methods: / We compared the accuracies of the above-mentioned methods in RV segmentations and in measuring RV strain parameters by Dice similarity coefficients (DSCs) and correlation coefficients. Results: DSC of RV segmentation of the RLA method exhibited a higher value than those of the conventional SA methods (0.84 vs. 0.61). Correlation coefficient with respect to manual RV strain measurements in the fully automatic RLA were superior to those in SA measurements (0.5-0.7 vs. 0.1-0.2). / Results: / DSC of RV segmentation of the RLA method exhibited a higher value than those of the conventional SA methods (0.84 vs. 0.61). Correlation coefficient with respect to manual RV strain measurements in the fully automatic RLA were superior to those in SA measurements (0.5-0.7 vs. 0.1-0.2). / Discussion: / Our proposed RLA realizes accurate fully automatic extraction of the entire RV region from an available CMR cine image without any additional imaging. Our findings overcome the complexity of image analysis in CMR without the limitations of the RV visualization in echocardiography.

The AMBITION study (NCT01178073) provided the first long-term clinical evidence for initial combination therapy with ambrisentan and tadalafil in patients with pulmonary arterial hypertension (PAH). Nevertheless, predictors of treatment response were not assessed.To identify predictors for response to initial combination therapy, we examined data from 302 patients with PAH (World Health Organization Functional Class II or III) who received initial combination therapy from the modified intention-to-treat population of the AMBITION study (n = 605). A responder was defined as not having undergone a clinical failure event. Univariate and multivariate analyses were performed. Multivariate logistic regression with interactive backward selection was used to assess the independent association of potential predictors with response.Treatment responders were younger, more often female, and less likely to have comorbidities or a requirement for oxygen therapy, compared with nonresponders. At multivariate analysis, female sex (odds ratio [OR] 2.67; 95% confidence interval [CI] 1.29, 5.52; P = 0.0081), longer 6-minute walk distance (OR 1.01; 95% CI 1.00, 1.01; P = 0.0039), lower baseline log N-terminal-prohormone of brain natriuretic peptide (OR 0.70; 95% CI 0.52, 0.94; P = 0.0190), and aldosterone antagonist use (OR 2.54; 95% CI 1.03, 6.26; P = 0.0436) independently predicted response to initial combination therapy.Besides demographic factors, the absence of comorbidities and less severe disease state, and the use of aldosterone antagonist therapy identified patients with PAH most likely to respond to initial combination therapy with ambrisentan and tadalafil. Further study to evaluate the role of aldosterone antagonist therapy in PAH is warranted.

Histological observations in human pulmonary arterial hypertension (PAH) suggest a link between plexiform lesions and pulmonary supernumerary arteries. Pulmonary microvascular endothelial cells are characterized as hyperproliferative and progenitor-like. This study investigates the hypothesis that aneurysm-type plexiform lesions form in pulmonary supernumerary arteries because of their anatomical properties and endothelial characteristics similar to pulmonary microvascular endothelial cells. To induce PAH, rats were injected with Sugen5416, and exposed to hypoxia (10% O2) for 3 days (early stage) or 3 wk (mid-stage), or 3 wk of hypoxia with an additional 10 wk of normoxia (late-stage PAH). We examined morphology of pulmonary vasculature and vascular remodeling in lung serial sections from PAH and normal rats. Aneurysm-type plexiform lesions formed in small side branches of pulmonary arteries with morphological characteristics similar to supernumerary arteries. Over the course of PAH development, the number of Ki67-positive cells increased in small pulmonary arteries, including supernumerary arteries, whereas the number stayed consistently low in large pulmonary arteries. The increase in Ki67-positive cells was delayed in supernumerary arteries compared with small pulmonary arteries. In late-stage PAH, ~90% of small unconventional side branches that were likely to be supernumerary arteries were nearly closed. These results support our hypothesis that supernumerary arteries are the predominant site for aneurysm-type plexiform lesions in Sugen5416/hypoxia/normoxia-exposed PAH rats partly because of the combination of their unique anatomical properties and the hyperproliferative potential of endothelial cells. We propose that the delayed and extensive occlusive lesion formation in supernumerary arteries could be a preventive therapeutic target in patients with PAH.

Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice. Conclusions Increased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.

BackgroundTreatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) remain limited. Selexipag, an oral selective IP prostacyclin receptor agonist approved for pulmonary arterial hypertension, is a potential treatment option for CTEPH.MethodsIn this multicentre, randomised, double-blind, placebo-controlled study, 78 Japanese patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy and/or balloon pulmonary angioplasty were randomly assigned to receive placebo or selexipag. The primary end-point was the change in pulmonary vascular resistance (PVR) from baseline to week 20. Secondary end-points were changes in other haemodynamic parameters: 6-min walk distance (6MWD), Borg dyspnoea scale score, World Health Organization (WHO) functional class, EuroQol five-dimension five-level tool and N-terminal pro-brain natriuretic peptide.ResultsThe change in PVR was −98.2±111.3 dyn·s·cm−5 and −4.6±163.6 dyn·s·cm−5 in the selexipag and placebo groups, respectively (mean difference −93.5 dyn·s·cm−5; 95% CI −156.8 to −30.3; p=0.006). The changes in cardiac index (pConclusionSelexipag significantly improved PVR and other haemodynamic variables in patients with CTEPH, although exercise capacity remained unchanged. Further large-scale investigation is necessary to prove the role of selexipag in CTEPH.

[Objectives] / To evaluate the usefulness of right ventricular (RV) area strain analysis via cardiac MRI (CMRI) as a tool for assessing the treatment effects of balloon pulmonary angioplasty (BPA) in inoperable chronic thromboembolic pulmonary hypertension (CTEPH), RV area strain was compared to two-dimensional (2D) strain with feature-tracking MRI (FTMRI) before and after BPA. / [Methods] / We retrospectively analyzed 21 CTEPH patients who underwent BPA. End-systolic global area strain (GAS), longitudinal strain (LS), circumferential strain (CS), and radial strain (RS) were measured before and after BPA. Changes in GAS and RV ejection fraction (RVEF) values after BPA were defined as ΔGAS and ΔRVEF. Receiver operating characteristic (ROC) analyses were performed to determine the optimal cutoff of the strain at after BPA for detection of improved patients with decreased mean pulmonary artery pressure (mPAP) less than 30 mmHg and increased RVEF more than 50 %. / [Results] / ROC analysis revealed the optimal cutoffs of strains (GAS, LS, CS, and RS) for identifying improved patients with mPAP50 % (cutoff (%) = -37.2, -29.5, -2.9, and 14.4: area under the curve, 0.81, 0.60, 0.56, and 0.56). / [Conclusions] / Area strain analysis via CMRI may be a more useful tool for assessing the treatment effects of BPA in patients with CTEPH than 2D strains with FTMRI., [Key points] / ・Area strain values can detect improvement of right ventricular (RV) pressure and function after balloon pulmonary angioplasty (BPA) equally or more accurately than two-dimensional strains. / ・Area strain analysis is a useful analytical method that reflects improvements in complex RV myocardial deformation by BPA. / ・Area strain analysis is a robust method with reproducibility equivalent to that of 2D strain analysis.

NEW FINDINGS What is the central question of this study? The impact of pulmonary arterial hypertension on open-loop baroreflex function, which determines how powerfully and rapidly the baroreflex operates to regulate arterial pressure, remains poorly understood. What is the main finding and its importance? The gain of the baroreflex total arc, indicating the baroreflex pressure-stabilizing function, is markedly attenuated in rats with monocrotaline-induced pulmonary arterial hypertension. This is caused by a rightward shift of the baroreflex neural arc and a downward shift of the peripheral arc. These findings contribute greatly to our understanding of arterial pressure regulation by the sympathetic nervous system in pulmonary arterial hypertension. ABSTRACT Sympathoexcitation has been documented in patients with established pulmonary arterial hypertension (PAH). Although the arterial baroreflex is the main negative feedback regulator of sympathetic nerve activity (SNA), the way in which PAH impacts baroreflex function remains poorly understood. In this study, we conducted baroreflex open-loop analysis in a rat model of PAH. Sprague-Dawley rats were injected with monocrotaline (MCT) s.c. to induce PAH (60 mg kg-1 ; n = 11) or saline as a control group (CTL; n = 8). At 3.5 weeks after MCT injection, bilateral carotid sinuses were isolated, and intrasinus pressure (CSP) was controlled while SNA at the coeliac ganglia and arterial pressure (AP) were recorded. To examine the static baroreflex function, CSP was increased stepwise while steady-state AP (total arc) and SNA (neural arc) responses to CSP and the AP response to SNA (peripheral arc) were measured. Monocrotaline significantly decreased the static gain of the baroreflex total arc at the operating AP compared with CTL (-0.80 ± 0.31 versus -0.22 ± 0.22, P

IntroductionChronic thromboembolic pulmonary hypertension (CTEPH) is a complication of prior pulmonary thromboembolism (PE), caused by incomplete clot dissolution after PE. In patients with CTEPH, lifelong anticoagulation is mandatory to prevent recurrence of PE and secondary in situ thrombus formation. Warfarin, a vitamin K antagonist, is commonly used for anticoagulation in CTEPH based on historical experience and evidence. The anticoagulant activity of warfarin is affected by food and drug interactions, requiring regular monitoring of prothrombin time. The lability of anticoagulant effect often results in haemorrhagic and thromboembolic complications. Thus, lifelong warfarin is a handicap in terms of safety and convenience. Currently, the use of direct oral anticoagulants (DOACs) in CTEPH has increased with the advent of four DOACs. The safety of DOACs is superior to warfarin, with less intracranial bleeding in patients with non-valvular atrial fibrillation and venous thromboembolism. Edoxaban, the latest DOAC, also has proven efficacy and safety for those diseases in two large clinical trials; the ENGAGE-AF trial and HOKUSAI-VTE trial. The present trial seeks to evaluate whether edoxaban is non-inferior to warfarin in preventing worsening of CTEPH.Methods and analysisThe KABUKI trial (is an investigator-initiated, multicentre, phase 3, randomised, single-blind, parallel-group, warfarin-controlled, non-inferiority trial to evaluate the efficacy and safety of edoxaban versus warfarin (vitamin K Antagonist) in subjects with chronic thromBoembolic pUlmonary hypertension taking warfarin (vitamin K antagonIst) at baseline) is designed to prove the non-inferiority of edoxaban to warfarin in terms of efficacy and safety in patients with CTEPH.Ethics and disseminationThis study is approved by the Institutional Review Board of each participating institution. The findings will be published in a peer-reviewed journal, including positive, negative and inconclusive results.Trial registration numberNCT04730037.Protocol versionThis paper was written per the study protocol V.4.0, dated 29 January 2021.

Background Recent accumulating evidence suggests that toll‐like receptor 9 (TLR9) is involved in the pathogenesis of cardiovascular diseases. However, its role in pulmonary hypertension remains uncertain. We hypothesized that TLR9 is involved in the development of pulmonary hypertension. Methods and Results A rat model of monocrotaline‐induced pulmonary hypertension was used to investigate the effects of TLR9 on hemodynamic parameters, vascular remodeling, and survival. Monocrotaline‐exposed rats significantly showed increases in plasma levels of mitochondrial DNA markers, which are recognized by TLR9, TLR9 activation in the lung, and interleukin‐6 mRNA level in the lung on day 14 after monocrotaline injection. Meanwhile, monocrotaline‐exposed rats showed elevated right ventricular systolic pressure, total pulmonary vascular resistance index and vascular remodeling, together with macrophage accumulation on day 21. In the preventive protocol, administration (days −3 to 21 after monocrotaline injection) of selective (E6446) or nonselective TLR9 inhibitor (chloroquine) significantly ameliorated the elevations of right ventricular systolic pressure and total pulmonary vascular resistance index as well as vascular remodeling and macrophage accumulation on day 21. These inhibitors also significantly reduced NF‐κB activation and interleukin‐6 mRNA levels to a similar extent. In the short‐term reversal protocol, E646 treatment (days 14–17 after monocrotaline injection) almost normalized NF‐κB activation and interleukin‐6 mRNA level, and reduced macrophage accumulation. In the prolonged reversal protocol, E6446 treatment (days 14–24 after monocrotaline injection) reversed total pulmonary vascular resistance index and vascular remodeling, and improved survival in monocrotaline‐exposed rats. Conclusions TLR9 is involved in the development of pulmonary hypertension concomitant via activation of the NF‐κB‒IL‐6 pathway. Inhibition of TLR9 may be a novel therapeutic strategy for pulmonary hypertension.

Background Balloon pulmonary angioplasty (BPA) improved pulmonary arterial compliance (CPA) and exercise tolerance in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Objectives To investigate whether CPA is a useful index to indicate exercise tolerance improvement by BPA in CTEPH patients. Methods The correlation between changes in CPA and improvements in 6-minute walk distance (6MWD) by BPA was retrospectively analyzed in 70 patients (Analysis 1), and it was sequentially analyzed in 46 symptomatic patients who achieved mean pulmonary arterial pressure (mPAP) Results We enrolled 70 patients (female/male:57/13, mean age:59 years) who underwent a total of 352 BPA sessions which significantly increased CPA (1.5±0.8 vs. 3.0±1.0 mL/mmHg) and decreased pulmonary vascular resistance (PVR) (8.0 ± 3.9 vs. 3.6 ± 1.7 wood units). The correlation coefficient between improvement in 6MWD and changes in PVR and CPA were r=0.21 (p=0.09) and r=0.14 (p=0.26) (Analysis 1). In Analysis 2, those were r=0.32 (p=0.06) and r=0.38 (p=0.02), respectively. Conclusions CPA can be a useful index to indicate the improvement in exercise tolerance by BPA in symptomatic patients with lower mPAP.

Background Right ventricular (RV) extracellular volumes (ECVs), as a surrogate for histologic fibrosis, have not been sufficiently investigated. Purpose To evaluate and compare RV and left ventricular (LV) ECVs obtained with dual-layer spectral detector CT (DLCT) in chronic thromboembolic pulmonary hypertension (CTEPH) and investigate the clinical importance of RV ECV. Materials and Methods Retrospective analysis was performed on data from 31 patients with CTEPH (17 were not treated with pulmonary endarterectomy [PEA] or balloon pulmonary angioplasty [BPA] and 14 were) and eight control subjects who underwent myocardial delayed enhancement (MDE) DLCT from January 2019 to June 2020. The ECVs in the RV and LV walls were calculated by using iodine density as derived from spectral data pertaining to MDE. Statistical analyses were performed with one-way repeated analysis of variance with the Tukey post hoc test or the Kruskal-Wallis test with the Steel-Dwass test and linear regression analysis. Results The PEA- and BPA-naive group showed significantly higher ECVs than the PEA- or BPA-treated group and control group in the septum (28.2% ± 2.9 vs 24.3% ± 3.6, P = .005), anterior right ventricular insertion point (RVIP) (32.9% ± 4.6 vs 25.3% ± 3.6, P < .001), posterior RVIP (35.2% ± 5.2 vs 27.3% ± 4.2, P < .001), mean RVIP (34.0% ± 4.2 vs 26.3% ± 3.4, P < .001), RV free wall (29.5% ± 3.3 vs 25.9% ± 4.1, P = .036), and mean RV wall (29.1% ± 3.0 vs 26.1% ± 3.1, P = .029). There were no significant differences between the PEA- or BPA-treated group and control subjects in these segments (septum, P = .93; anterior RVIP, P = .38; posterior RVIP, P = .52; mean RVIP, P = .36; RV free wall, P = .97; and mean RV, P = .33). There were significant correlations between ECV and mean pulmonary artery pressure (PAP) or brain natriuretic peptide (BNP) in the mean RVIP (mean PAP: R = 0.66, P < .001; BNP: R = 0.44, P = .014) and the mean RV (mean PAP: R = 0.49, P = .005; BNP: R = 0.44, P = .013). Conclusion Right ventricular and right ventricular insertion point extracellular volumes could be noninvasive surrogate markers of disease severity and reverse tissue remodeling in chronic thromboembolic pulmonary hypertension. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Sandfort and Bluemke in this issue.

Back ground: Ventilator-associated pneumonia (VAP) is a common nocosomial infection in intensive care unit (ICU). Local microbiological surveillance of pathogens and resistance patterns for early-onset VAP (EOVAP) and late-onset VAP (LOVAP) will help to choose appropriate empiric antibiotics. Objective: To compare the multi-drug resistant (MDR) pathogens, treatment outcomes, and factors associated with hospital mortality of VAP. Method: A cross-sectional study between 1 January 2015 and 31 December 2017 at Srinagarind hospital, Khon Kaen University was conducted. The demographic data, causative pathogens, hospital length of stay (LOS), ICU LOS, mechanical ventilator (MV) days, and hospital mortality were retrospectively reviewed. Results: One hundred and ninety patients were enrolled; 42 (22%) were EOVAP and 148 (78%) were LOVAP. Acinetobacter baummanii was the most common pathogen in both groups (50 % EOVAP vs 52.7% LOVAP). MDR pathogens were significant greater in LOVAP (81.8 %) than EOVAP (61.9%) (p = 0.007). The EOVAP had a significantly better ICU LOS (median 20.0 (11.0, 30.0) vs. 26.5 (17.0, 43.0) days), hospital LOS (median 26.5 (15.0, 44.0) vs. 35.5 (24.0, 56.0) days) shorter MV days (14.0 (10.0, 29.0) vs. 23.0 (14.0, 35.5) days) and lower hospital mortality (11.9 % VS 27.7%) than LOVAP ( p < 0.05). The factor associated with hospital mortality was having simplified acute physiology score (SAP) ≥ 40 with an adjusted odds ratio (aOR) of 2.22 (95%CI, 1.08-4.54, p = 0.02). Conclusion: LOVAP had significantly higher MDR pathogens, MV days, ICU LOS, hospital LOS and hospital mortality than EOVAP. A broad-spectrum antibiotic to cover MDR pathogens should be considered in LOVAP. The factor associated with hospital mortality of VAP was a SAPII score ≥ 40.

Aims Pulmonary hypertension (PH) is characterized by progressive increases in pulmonary vascular resistance (PVR). Thrombotic lesions are common pathological findings. The pulmonary artery has a unique property regarding the vasoconstrictive response to thrombin, which is mediated by proteinase-activated receptor 1 (PAR1). We aim to elucidate the role of PAR1 in the development and progression of PH. Methods and results A rat model of monocrotaline-induced PH and a mouse model of hypoxia (Hx)-induced PH were used to investigate the effects of atopaxar (a PAR1 antagonist) and PAR1 knockout on haemodynamic parameters, right ventricular hypertrophy (RVH), vascular remodelling and survival. In perfused lung preparations, the pressor response to PAR1 agonist was significantly augmented in monocrotaline-induced PH. Both the preventive and therapeutic administration of atopaxar significantly inhibited the increase in PVR and the development of RVH and prolonged survival. A real-time PCR revealed that the level of PAR1 mRNA in the pulmonary artery was significantly higher than that in any of the systemic arteries examined in control rats, and the level was significantly up-regulated in monocrotaline-induced PH. PAR1 gene knockout significantly attenuated the haemodynamic and histological findings in the mouse model of Hx-induced PH. Conclusion The specific expression of PAR1 in the pulmonary artery and its up-regulation were suggested to play a critical role in the development and progression of experimental PH in murine models. PAR1 is a potential therapeutic target for the treatment of PH.

Aims Although pulmonary arterial remolding in pulmonary hypertension (PH) changes the mechanical properties of the pulmonary artery, most clinical studies have focused on static mechanical properties (resistance), and dynamic mechanical properties (compliance) have not attracted much attention. As arterial compliance plays a significant role in determining afterload of the right ventricle, we evaluated how PH changes the dynamic mechanical properties of the pulmonary artery using high-resolution, wideband input impedance (ZPA). We then examined how changes in ZPA account for arterial remodeling. Clarification of the relationship between arterial remodeling and ZPA could help evaluate arterial remodeling according to hemodynamics. Main methods PH was induced in Sprague–Dawley rats with an injection of Sugen5416 (20 mg/kg) and 3-week exposure to hypoxia (10% oxygen) (SuHx). ZPA was evaluated from pulmonary artery pressure and flow under irregular pacing. Pulmonary histology was examined at baseline and 1, 3, and 8 weeks (n = 7, each) after Sugen5416 injection. Key findings SuHx progressively increased pulmonary arterial pressure. ZPA findings indicated that SuHx progressively increased resistance (baseline: 9.3 ± 3.6, SuHx1W: 20.7 ± 7.9, SuHx3W: 48.8 ± 6.9, SuHx8W: 62.9 ± 17.8 mm Hg/mL/s, p Significance The finding that changes in resistance were reciprocally associated with those in compliance indicates that resistant and compliant vessels are anatomically inseparable. The analysis of ZPA might help evaluate arterial remodeling in PH according to hemodynamics.

Visual Abstract, Highlights • Autonomic imbalance has been documented in patients with PAH. • Electrical VNS is known to restore autonomic balance and improve heart failure. • This study aimed to elucidate the therapeutic effects of VNS on severe PAH in a rat model. • VNS significantly restored autonomic balance, decreased mean pulmonary arterial pressure, attenuated pulmonary vascular remodeling, and preserved right ventricular function. In addition, VNS markedly improved the survival of rats with PAH. • Our findings may contribute greatly to the development of device therapy for PAH and widen the clinical applicability of VNS., Summary This study aimed to elucidate the therapeutic effects of electrical vagal nerve stimulation (VNS) on severe pulmonary arterial hypertension in a rat model. In a pathophysiological study, VNS significantly restored autonomic balance, decreased mean pulmonary arterial pressure, attenuated pulmonary vascular remodeling, and preserved right ventricular function. In a survival study, VNS significantly improved the survival rate in both the prevention (VNS from 0 to 5 weeks after a SU5416 injection) and treatment (VNS from 5 to 10 weeks) protocols. Thus, VNS may serve as a novel therapeutic strategy for pulmonary arterial hypertension.

AIMS Chronic thromboembolic pulmonary hypertension (CTEPH) is characterised by organised thrombotic obliteration of major vessels and small-vessel arteriopathy in the non-thrombosed vessels. The aim of this study was to investigate the impact of balloon pulmonary angioplasty (BPA) on the non-BPA-side pulmonary vasculature in patients with CTEPH. METHODS AND RESULTS This study explored the outcomes of 20 unilateral BPA sessions in 13 CTEPH patients. We measured the pulmonary vascular resistance (PVR), pulmonary artery (PA) flow in the BPA-side and non-BPA-side lungs, respectively, using phase contrast MRI and cardiac catheterisation. The interval from BPA to the follow-up evaluation was 92.8±52.0 days. A single session of BPA decreased mean PA pressure from 37.4±6.2 to 30.9±6.5 mmHg (p