ZBP1 Protects Against mtDNA-Induced Myocardial Inflammation in Failing Hearts.

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)-1ß 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-1ß, and IL-6 by ZBP1 knockdown in cardiomyocytes in response to mtDNA. Furthermore, NF-κB knockdown suppressed such increases in NLRP3, IL-1ß, and IL-6 by ZBP1 knockdown in response to mtDNA. CpG-oligodeoxynucleotide, a Toll-like receptor 9 stimulator, increased RIPK3, IL-1ß, 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-1ß, 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-1ß, 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.

Overview of the 87th Annual Scientific Meeting of the Japanese Circulation Society (JCS2023)　- New Challenge With Next Generation.

The 87thAnnual Meeting of the Japanese Circulation Society (JCS2023) was held in March 2023 in Fukuoka, Japan, marking the first in-person gathering after the COVID-19 pandemic. With the theme of "New Challenge With Next Generation" the conference emphasized the development of future cardiovascular leaders and technologies such as artificial intelligence (AI). Notable sessions included the Mikamo Lecture on heart failure and the Mashimo Lecture on AI in medicine. Various hands-on sessions and participatory events were well received, promoting learning and networking. Post-event surveys showed high satisfaction among participants, with positive feedback on face-to-face interactions and the overall experience. JCS2023, attended by 17,852 participants, concluded successfully, marking a significant milestone in post-pandemic meetings, and advancing cardiovascular medicine.

Efficacy of Dynamic Chest Radiography for Chronic Thromboembolic Pulmonary Hypertension.

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 Online supplemental material is available for this article. See also the editorial by Wandtke and Koproth-Joslin in this issue.

Selexipag for the treatment of chronic thromboembolic pulmonary hypertension.

BACKGROUND: Treatment 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. METHODS: In 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. RESULTS: The 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 (p<0.001) and Borg dyspnoea scale score (p=0.036) were also significantly improved over placebo. 6MWD and WHO functional class were not significantly improved. The common adverse events in the selexipag group corresponded to those generally observed following administration of a prostacyclin analogue. CONCLUSION: Selexipag 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.

Right ventricular strain and volume analyses through deep learning-based fully automatic segmentation based on radial long-axis reconstruction of short-axis cine magnetic resonance images.

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). 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.

Positive Predictors for Response to Ambrisentan Combination Therapy in Pulmonary Arterial Hypertension.

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.

Right Ventricular Extracellular Volume with Dual-Layer Spectral Detector CT: Value in Chronic Thromboembolic Pulmonary Hypertension.

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.

Improvements in French risk stratification score were correlated with reductions in mean pulmonary artery pressure in pulmonary arterial hypertension: a subanalysis of the Japan Pulmonary Hypertension Registry (JAPHR).

BACKGROUND: Since there was no previous report, we analyzed the relationship between French Risk Stratification parameters in pulmonary arterial hypertension (PAH) and mean pulmonary arterial pressures (mPAP) using Japan PH Registry (JAPHR) national-wide cohort. METHODS: We enrolled 108 patients with PAH from JAPHR from previous reported cohort and analyzed the relations between French Risk Stratification scores and hemodynamic improvements. RESULTS: The ratio meeting 0 to 4 French Risk Stratification score was 21.3%, 31.5%, 32.4%, 13.0%, and 1.9% at baseline, and 6.5%, 23.2%, 33.3%, 23.2%, 13.9% at follow-up, respectively. The improvements in the number of criteria met were associated both with mPAP at follow-up (p = 0.03) and with the improvements in mPAP (p < 0.001). CONCLUSION: The improvements in French Risk Stratification may become a marker of improved hemodynamics including mPAP.

Eicosapentaenoic acid ameliorates pulmonary hypertension via inhibition of tyrosine kinase Fyn.

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-ß2-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.

Genetic knockout and pharmacologic inhibition of NCX1 attenuate hypoxia-induced pulmonary arterial hypertension.

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.

Preoperative Threshold for Normalizing Right Ventricular Volume After Transcatheter Closure of Adult Atrial Septal Defect.

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] <47 mL/m2and end-diastolic volume index [RVEDVI] <108 mL/m2) and non-normalized (postoperative RVESVI ≥47 mL/m2or RVEDVI ≥108 mL/m2) groups. Preoperative RVESVI was significantly smaller (72 mL/m2vs. 80 mL/m2) and RVEF was higher (56% vs. 51%) in the normalized group compared with the non-normalized group. Receiver-operating characteristic analysis for the normalization of postoperative RV volume showed that the preoperative threshold value of RVESVI was 75 mL/m2. In addition, multivariate analysis showed that preoperative RVESVI was an independent predictor for normalization of RV volume. 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.

Aneurysm-type plexiform lesions form in supernumerary arteries in pulmonary arterial hypertension: potential therapeutic implications.

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.

Suppressed baroreflex peripheral arc overwhelms augmented neural arc and incapacitates baroreflex function in rats with pulmonary arterial hypertension.

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 < 0.05). Given that MCT markedly increased plasma noradrenaline, an index of SNA, by approximately 3.6-fold compared with CTL, calibrating SNA by plasma noradrenaline revealed that MCT shifted the neural arc to a higher SNA level and shifted the peripheral arc downwards. Monocrotaline also decreased the dynamic gain of the baroreflex total arc (-0.79 ± 0.16 versus -0.35 ± 0.17, P < 0.05), while the corner frequencies that reflect the speed of the baroreflex remained unchanged (0.06 ± 0.02 versus 0.08 ± 0.02 Hz, n.s.). In rats with MCT-induced PAH, the suppressed baroreflex peripheral arc overwhelms the augmented neural arc and, in turn, attenuates the gain of the total arc, which determines the pressure-stabilizing capacity of the baroreflex.

Clinical usefulness of right ventricular 3D area strain in the assessment of treatment effects of balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension: comparison with 2D feature-tracking MRI.

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 mPAP < 30 mmHg (cutoff (%) = - 41.2, - 13.8, - 16.7, and 14.4: area under the curve, 0.75, 0.56, 0.65, and 0.75) and patients with RVEF > 50% (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.

A pro-con debate: current controversies in PAH pathogenesis at the American Thoracic Society International Conference in 2017.

The following review summarizes the pro-con debate about current controversies regarding the pathogenesis of pulmonary arterial hypertension (PAH) that took place at the American Thoracic Society Conference in May 2017. Leaders in the field of PAH research discussed the importance of the immune system, the role of hemodynamic stress and endothelial apoptosis, as well as bone morphogenetic protein receptor-2 signaling in PAH pathogenesis. Whereas this summary does not intend to resolve obvious conflicts in opinion, we hope that the presented arguments entice further discussions and draw a new generation of enthusiastic researchers into this vibrant field of science to bridge existing gaps for a better understanding and therapy of this fatal disease.

Effectiveness and Outcome of Pulmonary Arterial Hypertension-Specific Therapy in Japanese Patients With Pulmonary Arterial Hypertension.

BACKGROUND: The trend of the initial treatment strategy for pulmonary arterial hypertension (PAH) has changed from monotherapies to upfront combination therapies. This study analyzed treatments and outcomes in Japanese patients with PAH, using data from the Japan PH Registry (JAPHR), which is the first organized multicenter registry for PAH in Japan.Methods and Results:We studied 189 consecutive patients (108 treatment-naïve and 81 background therapy patients) with PAH in 8 pulmonary hypertension (PH) centers enrolled from April 2008 to March 2013. We performed retrospective survival analyses and analyzed the association between upfront combination and hemodynamic improvement, adjusting for baseline NYHA classification status. Among the 189 patients, 1-, 2-, and 3-year survival rates were 97.0% (95% CI: 92.1-98.4), 92.6% (95% CI: 87.0-95.9), and 88.2% (95% CI: 81.3-92.7), respectively. In the treatment-naïve cohort, 33% of the patients received upfront combination therapy. In this cohort, 1-, 2-, and 3-year survival rates were 97.6% (95% CI: 90.6-99.4), 97.6% (95% CI: 90.6-99.4), and 95.7% (95% CI: 86.9-98.6), respectively. Patients on upfront combination therapy were 5.27-fold more likely to show hemodynamic improvement at the first follow-up compared with monotherapy (95% CI: 2.68-10.36). CONCLUSIONS: According to JAPHR data, initial upfront combination therapy is associated with improvement in hemodynamic status.