Search

Background: To investigate changes in pulmonary artery pressure (PAP), blood indices, and myocardial microcirculation in rats returning from high altitude (HA) to moderate altitude (MA)., Methods: Forty 4-week-old male Sprague-Dawley rats were randomly divided into four groups with ten rats in each group. One group was transported to the MA area (MA-group), and the other three groups were transported to HA (HA-group-A, HA-group-B, and HA-group-C). After 28 weeks of age, the rats from the HA area were transported to the MA area for 0 days, 10 days, and 20 days, respectively. PAP, routine blood tests, and computed tomography myocardial perfusion indices were measured., Results: Compared with the MA-group, the body weight of HA-groups decreased (p < 0.05), and PAP in HA-group-A and HA-group-B increased (p < 0.05). In the HA groups, PAP initially increased and then decreased. Compared with the MA-group, red blood cells (RBC), hemoglobin (HGB), and hematocrit (HCT) of rats in HA-group-A increased (p < 0.05). Compared with the HA-group-A, RBC, HGB, and HCT of HA-group-B gradually decreased (p < 0.05) while MCV decreased (p < 0.05), and PLT of HA-group-C increased (p < 0.05). Compared with the MA group, blood flow (BF) and blood volume (BV) of the HA-group-A decreased (p < 0.05). Compared with the HA-group-A, TTP increased first and then decreased (p < 0.05), and BF and BV increased gradually (p < 0.05). Pathological results showed that myocardial fiber arrangement was disordered, and cell space widened in the HA group., Conclusion: PAP, blood parameters, and myocardial microcirculation in rats returning from high to MA exhibited significant changes., Relevance Statement: This study provides an experimental basis for understanding the physiological and pathological mechanisms during the process of deacclimatization to HA and offers new insights for the prevention and treatment of deacclimatization to HA syndrome., Key Points: Forty rats were raised in a real plateau environment. Myocardial microcirculation was detected by CT myocardial perfusion imaging. The PAP of the unacclimated rats increased first and then decreased. The myocardial microcirculation of the deacclimated rats showed hyperperfusion changes., Competing Interests: Declarations. Ethics approval and consent to participate: The Medical Ethics Committee of Qinghai Provincial People’s Hospital approved the study (2020-115). Consent for publication: Not applicable. Competing interests: The authors have no competing interests to declare., (© 2024. The Author(s).)

Backgrounds: A soluble guanylyl cyclase stimulator vericiguat has been shown to reduce cardiovascular mortality or hospitalization for heart failure in patients with worsening heart failure in the VICTORIA study. However, little is known about the effects of vericiguat on biventricular structure and function., Methods and Results: A retrospective analysis of 63 consecutive patients with heart failure with reduced ejection fraction (HFrEF) who were treated with vericiguat was performed. Clinical data and echocardiographic parameters were compared between baseline and follow-up after the initiation of vericiguat. The median follow-up duration was 266 days. Treatment with vericiguat significantly reduced the plasma BNP levels (log-transformed) compared to baseline (2.46 ± 0.51 vs. 2.14 ± 0.58, p < 0.0001). Left ventricular end-diastolic volume index and left ventricular end-systolic volume index were significantly reduced (LVEDVI, 113.5 ± 46.3 vs. 103.6 ± 51.0, p = 0.0056; LVESVI, 82.0 ± 41.9 vs. 72.8 ± 44.7, p = 0.0077; respectively). The tricuspid annular plane systolic excursion to pulmonary artery systolic pressure (TAPSE/PASP) ratio, an indicator of right ventricle-pulmonary artery (RV-PA) coupling, increased significantly after the treatment (0.56 ± 0.29 vs. 0.92 ± 1.09, p < 0.0001). Univariate and multivariate analyses showed that the treatment effects of vericiguat on BNP levels, LV reverse remodeling, and RV-PA coupling were not correlated with the achievement of the quadruple therapy with beta-blockers, renin-angiotensin system inhibitors, mineralocorticoid inhibitors, and sodium-glucose cotransporter-2 inhibitors, nor with worsening heart failure (WHF)., Conclusion: Treatment with vericiguat improved adverse LV remodeling and RV-PA uncoupling in HFrEF patients. These effects were independent of WHF and achieving the quadruple therapy. Patients with HFrEF may benefit from early initiation of vericiguat to prevent biventricular adverse remodeling., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Calcification is common in chronic vascular disease, yet its role in pulmonary hypertension due to left heart disease is unknown. Here, we probed for the role of runt-related transcription factor-2 (RUNX2), a master transcription factor in osteogenesis, and its regulation by the HIPPO pathway transcriptional coactivator with PDZ-binding motif (TAZ) in the osteogenic reprogramming of pulmonary artery smooth muscle cells and vascular calcification in patients with pulmonary hypertension due to left heart disease. We similarly examined its role using an established rat model of pulmonary hypertension due to left heart disease induced by supracoronary aortic banding., Methods: Pulmonary artery samples were collected from patients and rats with pulmonary hypertension due to left heart disease. Genome-wide RNA sequencing was performed, and pulmonary artery calcification assessed. Osteogenic signalling via TAZ and RUNX2 was delineated by protein biochemistry. In vivo , the therapeutic potential of RUNX2 or TAZ inhibition by CADD522 or verteporfin was tested in the rat model., Results: Gene ontology term analysis identified significant enrichment in ossification and osteoblast differentiation genes, including RUNX2 , in pulmonary arteries of patients and lungs of rats with pulmonary hypertension due to left heart disease. Pulmonary artery calcification was evident in both patients and rats. Both TAZ and RUNX2 were upregulated and activated in pulmonary artery smooth muscle cells of patients and rats. Co-immunoprecipitation revealed a direct interaction of RUNX2 with TAZ in pulmonary artery smooth muscle cells. TAZ inhibition or knockdown decreased RUNX2 abundance due to accelerated RUNX2 protein degradation rather than reduced de novo synthesis. Inhibition of either TAZ or RUNX2 attenuated pulmonary artery calcification, distal lung vascular remodelling and pulmonary hypertension development in the rat model., Conclusion: Pulmonary hypertension due to left heart disease is associated with pulmonary artery calcification that is driven by TAZ-dependent stabilisation of RUNX2, causing osteogenic reprogramming of pulmonary artery smooth muscle cells. The TAZ-RUNX2 axis may present a therapeutic target in pulmonary hypertension due to left heart disease., Competing Interests: Conflict of interest: N. Nambiar Veetil reports support for the present manuscript from the German Centre for Cardiovascular Research (DZHK) Young Scientist Doctoral Scholarship and German Society for Cardiology (DGK) (Otto-Hess Doctoral Scholarship). J. Voelkl reports support for the present manuscript from Austrian Science Fund (FWF) (grant number P34724-BBL). J. Grune reports support for the present manuscript from the DZHK, the German Research Foundation (DFG) (CRC-1470 A04, CRC-1425), Corona-Stiftung, DynAge Freie Universität Berlin, the DGK, Corona-Stiftung, dt. Stiftung für Herzforschung and Charité 3R. W.M. Kuebler reports support for the present manuscript from the DFG, DZHK and German Ministry of Education and Research (BMBF); outside the submitted work; W.M. Kuebler reports consulting fees from Bayer AG, Germany, and a leadership role as Chair of Publications Committee for American Physiological Society. The remaining authors have nothing to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Objective: Vascular endothelial growth factor is a signaling protein created by cells performing important bodily functions. Vascular endothelial growth factor is abundant in the lung, and plasma levels are elevated in patients with severe pulmonary arterial hypertension. An association between soluble urokinase plasminogen activator receptor, an inflammatory biomarker, and soluble urokinase plasminogen activator receptor levels and interstitial pulmonary and vascular involvement (e.g., development of pulmonary hypertension) has been shown in SSc patients. The tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio, which has been recommended as a useful diagnostic tool in the last guideline, is one of the additional echocardiographic signs suggestive of pulmonary hypertension. We aimed to examine whether these biomarkers contribute to the diagnosis and management of pulmonary hypertension., Methods: Patients with group E chronic obstructive lung disease were included in this prospective study. Demographic data, echocardiographic signs about the right ventricle (right atrium area, tricuspid annular plane systolic excursion/systolic pulmonary artery pressure, fractional area change, and right ventricular outflow tract), and peripheral blood analysis were examined and recorded., Results: A total of 70 patients, 12 of whom were female, were analyzed in the study. The mean age was 66.6±8.7 years. The mean vascular endothelial growth factor-A and soluble urokinase plasminogen activator receptor were 91.05±70.7 and 955.8±571.1, and their Pearson correlation coefficients between vascular endothelial growth factor-A and tricuspid annular plane systolic excursion/systolic pulmonary artery pressure, and soluble urokinase plasminogen activator receptor and tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio were 0.341 (p=0.004) and -0.045 (p=0.70), respectively. The linear regression model included four variables with significant correlation (vascular endothelial growth factor-A, right atrium area, fractional area change, and right ventricular outflow tract). Three steps were performed, and adjusted r2 was 0.22, 0.22, 0.20, and p<0.001 for each step. Vascular endothelial growth factor-A and right ventricular outflow tract remained in the last step. It was detected a standardized coefficient beta of 0.322 (p=0.004) and a 95%CI 0.000-0.001 for vascular endothelial growth factor-A., Conclusion: Vascular endothelial growth factor-A is correlated with the tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio and not with soluble urokinase plasminogen activator receptor.

Background: Unveiling pro-proliferation genes involved in crosstalk between pulmonary artery endothelial cells and pulmonary artery smooth muscle cells (PASMCs) are important to improving the therapeutic outcome of pulmonary hypertension (PH). Although growing studies have shown that super-enhancers (SEs) play a pivotal role in pathological and physiological processes, the SE-associated genes in PH and their impact on PASMC proliferation remain largely unexplored., Methods and Results: We used serotype 5 adenovirus-associated virus to interfere with syndecan-4 and constructed an SU5416 combined with hypoxia-PH model. Chromatin immunoprecipitation sequencing analysis, chromatin immunoprecipitation quantitative polymerase chain reaction, and bioinformatics were used to confirm early growth response 1 was involved in regulating syndecan-4-associated SE in PASMCs. The effects of syndecan-4 and its underlying mechanisms were subsequently elucidated using Western blot, coimmunoprecipitation, and cell coculture assays. Herein, we identified a novel SE-associated gene, syndecan-4, in hypoxia-exposed PASMCs. Syndecan-4 was transcriptionally driven by early growth response 1 via an SE and was significantly overexpressed in hypoxic PASMCs and plasma from patients with PH. Mechanism studies revealed that syndecan-4 induces PASMC proliferation by interacting and regulating protein kinase C α ubiquitination. In addition, syndecan-4 was enriched in exosomes secreted from hypoxic PASMCs, which subsequently transported and led to pulmonary artery endothelial cell dysfunction. Syndecan-4 inhibition in hypoxia by serotype 5 adenovirus-associated virus treatment attenuated the pulmonary artery remodeling and development of PH in vivo., Conclusions: Taken together, our results demonstrate that an SE-driven syndecan-4 modulates crosstalk of PASMCs and pulmonary artery endothelial cells and promotes vascular remodeling via the protein kinase C α and exosome pathway, thus providing potential targets for the early diagnosis and treatment of hypoxic PH.

Aims: Chronic hypoxia causes detrimental structural alterations in the lung, which may cause pulmonary hypertension and are partially mediated by the endothelium. While its relevance for the development of hypoxia-associated lung diseases is well known, determinants controlling the initial adaptation of the lung endothelium to hypoxia remain largely unexplored., Methods and Results: We revealed that hypoxia activates the transcription factor nuclear factor of activated T-cells 5 (NFAT5) and studied its regulatory function in murine lung endothelial cells (MLECs). EC-specific knockout of Nfat5 (Nfat5(EC)-/-) in mice exposed to normobaric hypoxia (10% O2) for 21 days promoted vascular fibrosis and aggravated the increase in pulmonary right ventricular systolic pressure as well as right ventricular dysfunction as compared with control mice. Microarray- and single-cell RNA-sequencing-based analyses revealed an impaired growth factor-, energy-, and protein-metabolism-associated gene expression in Nfat5-deficient MLEC after exposure to hypoxia for 7 days. Specifically, loss of NFAT5 boosted the expression and release of platelet-derived growth factor B (Pdgfb)-a hypoxia-inducible factor 1 alpha (HIF1α)-regulated driver of vascular smooth muscle cell (VSMC) growth-in capillary MLEC of hypoxia-exposed Nfat5(EC)-/- mice, which was accompanied by intensified VSMC coverage of distal pulmonary arteries., Conclusion: Collectively, our study shows that early and transient subpopulation-specific responses of MLEC to hypoxia may determine the degree of organ dysfunction in later stages. In this context, NFAT5 acts as a protective transcription factor required to rapidly adjust the endothelial transcriptome to cope with hypoxia. Specifically, NFAT5 restricts HIF1α-mediated Pdgfb expression and consequently limits muscularization and resistance of the pulmonary vasculature., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Pulmonary hypertension, characterized by vascular remodeling, currently lacks curative therapeutic options. The dysfunction of pulmonary artery endothelial cells plays a pivotal role in the initiation and progression of pulmonary hypertension (PH). ErbB3 (human epidermal growth factor receptor 3), also recognized as HER3, is a member of the ErbB family of receptor tyrosine kinases., Methods: Microarray, immunofluorescence, and Western blotting analyses were conducted to investigate the pathological role of ErbB3. Blood samples were collected for biomarker examination from healthy donors or patients with hypoxic PH. The pathological functions of ErbB3 were further validated in rodents subjected to chronic hypoxia- and Sugen-induced PH, with or without adeno-associated virus-mediated ErbB3 overexpression, systemic deletion, or endothelial cell-specific ErbB3 knockdown. Primary human pulmonary artery endothelial cells and pulmonary artery smooth muscle cells were used to elucidate the underlying mechanisms., Results: ErbB3 exhibited significant upregulation in the serum, lungs, distal pulmonary arteries, and pulmonary artery endothelial cells isolated from patients with PH compared with those from healthy donors. ErbB3 overexpression stimulated hypoxia-induced endothelial cell proliferation, exacerbated pulmonary artery remodeling, elevated systolic pressure in the right ventricle, and promoted right ventricular hypertrophy in murine models of PH. Conversely, systemic deletion or endothelial cell-specific knockout of ErbB3 yielded opposite effects. Coimmunoprecipitation and proteomic analysis identified YB-1 (Y-box binding protein 1) as a downstream target of ErbB3. ErbB3 induced nuclear translocation of YB-1 and subsequently promoted hypoxia-inducible factor 1/2α transcription. A positive loop involving ErbB3-periostin-hypoxia-inducible factor 1/2α was identified to mediate the progressive development of this disease. MM-121, a human anti-ErbB3 monoclonal antibody, exhibited both preventive and therapeutic effects against hypoxia-induced PH., Conclusions: Our study reveals, for the first time, that ErbB3 serves as a novel biomarker and a promising target for the treatment of PH., Competing Interests: None.

Recent discoveries have identified intrapulmonary bronchopulmonary anastomoses (IBAs) as a relatively common phenomenon forming intrapulmonary right-to-left shunts. This study hypothesizes that IBAs play a significant role in the pathophysiology of heart failure. We aim to investigate the impact of these intrapulmonary right-to-left shunts on pulmonary arterial and venous pressures in heart failure patients, utilizing mixed venous oxygen saturation (SvO₂) as a key measurement. This study included 237 patients with heart failure who underwent cardiac catheterization. The relationships between SvO₂ and pulmonary artery systolic pressure (sPAP), pulmonary artery wedge pressure (PAWP), and left ventricular end-diastolic pressure (LVEDP) were examined using various statistical methods (single regression analysis, partial correlation analysis, structural equation modeling, and Bayesian estimation). All statistical methods that we performed showed that SvO₂ was significantly and negatively correlated with both sPAP and PAWP (p < 0.01, respectively). However, SvO₂ did not significantly correlate with LVEDP. These results suggest that a decrease in SvO₂ leads to an increase in PAWP and sPAP, while LVEDP is only passively influenced by PAWP. This phenomenon likely reflects the impact of an intrapulmonary right-to-left shunt caused by IBAs. The decrease in SvO₂ causes an increase in sPAP and may also cause an increase in PAWP via IBAs., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Background: Unilateral chronic thromboembolism pulmonary disease (CTEPD) is very rare. There is limited information on the safety and efficacy of pulmonary endarterectomy (PEA) in this population. This study investigated the effectiveness of PEA in this unique disease., Methods: This multicentre study included patients with unilateral CTEPD from three referral centres in the United States, Turkey, and Iran. The patients' demographic information, 6-minute walk test distance (6MWD), New York Heart Association (NYHA) functional class, and haemodynamics were evaluated., Result: Of the 1,031 patients who had undergone PEA, 39 patients (3.7%) had pure unilateral involvement, of whom 28 were female (71.8%). There was a significant improvement in the mean pulmonary artery pressure (mPAP, 26 mmHg vs 21 mmHg; p=0.011) and pulmonary vascular resistance (PVR, 202 vs 136 dynes∗sec 1 ∗cm -5 ; p=0.014). There was also a significant improvement in NYHA functional class (p<0.001) and 6MWD (360 vs 409 m; p<0.001). In the nine patients with normal haemodynamic parameters at rest, there was no significant change in median 6MWD (448.5 vs 449 m; p=0.208), mPAP (19 mmHg vs 16.5 mmHg; p=0.397), and PVR (129 vs 84.5 dynes∗sec 1 ∗cm -5 ; p=0.128). The most common postoperative complication was ipsilateral pleural effusion. One patient needed extracorporeal membrane oxygenation support. No patient died within the 1-year follow up., Conclusion: Pulmonary endarterectomy is a safe and effective procedure for improving the symptoms and haemodynamic parameters of patients with unilateral CTEPH. Symptomatic patients with unilateral chronic thromboembolic disease are suitable for PEA., Competing Interests: Conflicts of Interest The authors declare no conflict of interest regarding this study., (Copyright © 2024 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Introduction: The ratio between tricuspid annular plane systolic excursion (TAPSE) and estimated pulmonary artery systolic pressure (PASP) has been shown to be a reliable, non-invasive surrogate of the right ventricular-pulmonary artery (RV-PA) coupling. The present study analysed the association between TAPSE/PASP and response to cardiac resynchronization therapy (CRT) and the prognostic role of RV-PA in patients undergoing CRT implantation. The primary endpoints were: the association between baseline TAPSE/PASP and CRT response/cardiovascular and all-cause death., Methods and Results: All patients having undergone CRT implantation in our Center from 2016 to 2020 were included in our retrospective analysis. The RV-PA coupling was assessed by echocardiography at baseline and 1 year follow up in CRT recipients. The cut-off value of TAPSE/PASP resulted from ROC curve analysis (i.e.<0.33 mm/mmHg). A total of 229 patients (age 69.9 ± 10.1 years; 77.7% men) were included. During a mean follow-up of 44.2 ± 17.9 months, 40 (17.5%) patients died. The baseline value of TAPSE/PASP was not significantly associated with CRT response. Patients with a more impaired TAPSE/PASP ratio had significantly worse survival rates. On multivariate Cox regression, only TAPSE/PASP ratio and estimated glomerular filtration rate were independently associated with all-cause death. Finally, the TAPSE/PASP ratio significantly increased after CRT implantation in the group of "responders" whereas it did not change in 'non-responders'., Conclusions: The baseline value of TAPSE/PASP ratio was not associated with CRT response. However, the TAPSE/PASP ratio was a strong predictor of both all-cause and cardiovascular death in CRT recipients., Competing Interests: Declarations Competing interests The authors report no relationships that could be construed as a conflict of interest., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: Monitoring supine pulmonary artery pressures to guide heart failure (HF) management has reduced HF hospitalizations in select patients., Objectives: The purpose of this study was to evaluate the effect of managing seated mean pulmonary artery pressure (mPAP) with the Cordella Pulmonary Artery sensor on outcomes in patients with HF., Methods: Following GUIDE-HF (Hemodynamic-GUIDEd Management of Heart Failure Trial), with U.S. Food and Drug Administration input, PROACTIVE-HF (A Prospective, Multi-Center, Open Label, Single Arm Clinical Trial Evaluating the Safety and Efficacy of the Cordella Pulmonary Artery Sensor System in NYHA Class III Heart Failure Patients trial) was changed from a randomized to a single-arm, open label trial, conducted at 75 centers in the USA and Europe. Eligible patients had chronic HF with NYHA functional class III symptoms, irrespective of the ejection fraction, and recent HF hospitalization and/or elevated natriuretic peptides. The primary effectiveness endpoint at 6 months required the HF hospitalization or all-cause mortality rate to be lower than a performance goal of 0.43 events/patient, established from previous hemodynamic monitoring trials. Primary safety endpoints at 6 months were freedom from device- or system-related complications or pressure sensor failure., Results: Between February 7, 2020, and March 31, 2023, 456 patients were successfully implanted in modified intent-to-treat cohort. The 6-month event rate was 0.15 (95% CI: 0.12-0.20) which was significantly lower than performance goal (0.15 vs 0.43; P < 0.0001). Freedom from device- or system-related complications was 99.2% and freedom from sensor failure was 99.8% through 6 months., Conclusions: Remote management of seated mPAP is safe and results in a low rate of HF hospitalizations and mortality. These results support the use of seated mPAP monitoring and extend the growing body of evidence that pulmonary artery pressure-guided management improves outcomes in heart failure. (Multi-Center, Open Label, Single Arm Clinical Trial Evaluating the Safety and Efficacy of the Cordella Pulmonary Artery Sensor System in NYHA Class III Heart Failure Patients trial [PROACTIVE-HF]; NCT04089059)., Competing Interests: Funding Support and Author Disclosures This work was supported by Endotronix Inc. Drs Miranda, Shah, Macaluso, and Hickey were on the Eligibility Committee of PROACTIVE-HF. Prof Sharif is funded by the Science Foundation Ireland SFI 17/RI/5353. Drs Hiivala, Owens, Sauerland, and Forouzan are employees of Endotronix. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Assessment of the pattern of the RV outflow tract Doppler provides insights into the hemodynamics of chronic thromboembolic pulmonary hypertension (CTEPH). We studied whether pre-operative assessment of timing of the pulmonary flow systolic notch by Doppler echocardiography is associated with long-term survival after pulmonary endarterectomy (PEA) for CTEPH., Methods: Fifty-nine out of 61 consecutive CETPH patients (mean age 53 ± 14 years, 34% male) whom underwent PEA between June 2002 and June 2005 were studied. Clinical, echocardiographic and hemodynamic variables were assessed pre-operatively and repeat echocardiography was performed 3 months after PEA. Notch ratio (NR) was assessed with pulsed Doppler and calculated as the time from onset of pulmonary flow until notch divided by the time from notch until end of pulmonary flow. Long-term follow-up was obtained between May 2021 and February 2022., Results: Pre-operative mean pulmonary artery pressure (mPAP) was 45 ± 15 mmHg and pulmonary vascular resistance (PVR) was 646 ± 454 dynes.s.cm-5. Echocardiography before PEA showed that 7 patients had no notch, 33 had a NR < 1.0 and 19 had a NR > 1.0. Three months after PEA, echocardiography revealed a significant decrease in sPAP in long-term survivors with a NR < 1.0 and a NR > 1.0, while a significant increase in TAPSE/sPAP was only observed in the NR < 1.0 group. Mean long-term clinical follow-up was 14 ± 6 years. NR was significantly different between survivors and non-survivors (0.73 ± 0.25 vs. 1.1 ± 0.44, p < 0.001) but no significant differences were observed in mPAP or PVR. Long-term survival at 14 years was significantly better in patients with a NR < 1.0 compared to patients with a NR > 1.0 (83% vs. 37%, p =  < 0.001)., Conclusion: Pre-operative assessment of NR is a predictor of long-term survival in CTEPH patients undergoing PEA, with low mortality risk in patients with NR < 1.0. Long-term survivors with a NR < 1.0 and NR > 1.0 had a significant decrease in sPAP after PEA. However, the TAPSE/sPAP only significantly increased in the NR < 1.0 group. In the NR < 1.0 group, the 6-min walk test increased significantly between pre-operative and at 1-year post-operative follow-up. NR is a simple echocardiographic parameter that can be used in clinical decision-making for PEA., (© 2024. The Author(s).)

Rationale: Quantitative interstitial abnormalities (QIAs) are a computed tomography (CT) measure of early parenchymal lung disease associated with worse clinical outcomes, including exercise capacity and symptoms. The presence of pulmonary vasculopathy in QIAs and its role in the QIA-outcome relationship is unknown. Objectives: To quantify radiographic pulmonary vasculopathy in QIAs and determine whether this vasculopathy mediates the QIA-outcome relationship. Methods: Ever-smokers with QIAs, outcomes, and pulmonary vascular mediator data were identified from the Genetic Epidemiology of COPD (COPDGene) study cohort. CT-based vascular mediators were right ventricle-to-left ventricle ratio, pulmonary artery-to-aorta ratio, and preacinar intraparenchymal arterial dilation (pulmonary artery volume, 5-20 mm 2 in cross-sectional area, normalized to total arterial volume). Outcomes were 6-minute walk distance and a modified Medical Council Research Council Dyspnea Scale score of 2 or higher. Adjusted causal mediation analyses were used to determine whether the pulmonary vasculature mediated the QIA effect on outcomes. Associations of preacinar arterial dilation with select plasma biomarkers of pulmonary vascular dysfunction were examined. Measurements and Main Results: Among 8,200 participants, QIA burden correlated positively with vascular damage measures, including preacinar arterial dilation. Preacinar arterial dilation mediated 79.6% of the detrimental impact of QIA on 6-minute walk distance (56.2-100%; P  < 0.001). Pulmonary artery-to-aorta ratio was a weak mediator, and right ventricle-to-left ventricle ratio was a suppressor. Similar results were observed in the relationship between QIA and modified Medical Council Research Council dyspnea score. Preacinar arterial dilation correlated with increased pulmonary vascular dysfunction biomarker levels, including angiopoietin-2 and N-terminal brain natriuretic peptide. Conclusions: Parenchymal QIAs deleteriously impact outcomes primarily through pulmonary vasculopathy. Preacinar arterial dilation may be a novel marker of pulmonary vasculopathy in QIAs.

This brief report reviews the clinical, procedural, and imaging data of 7 patients with p.Arg4810Lys variant of the ring finger protein 213 (RNF213) gene-related peripheral pulmonary arterial stenosis who underwent percutaneous transluminal pulmonary angioplasties (PTPAs) for demographics, clinical presentation, indications for angioplasty, and procedural and clinical outcomes. During median follow-up of 64.4 months since the first confirmed diagnosis, PTPA was performed for 62 segmental pulmonary arteries with 38 sessions of the procedure in 7 patients. Vascular stent placement because of resistance to balloon dilation and immediate elastic recoil was performed in 48 of 62 procedures (77%). Except for 1 death, 6 patients showed an improvement in dyspnea and 5 patients showed a decrease in mean pulmonary arterial pressure (mean, 55.5-42.7 mm Hg) and increase in 6-minute walk distance (mean, 415.5-484.3 m). Reperfusion edema occurred in 4 of 7 patients (57%), which was 6 of 38 sessions (16%)., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: The aim of this study was to analyze the risk factors for acute events after systemic-to-pulmonary shunt (SPS) and to investigate the effectiveness of pulmonary blood flow regulation with a metal clip., Methods: The case histories of 116 patients (78 biventricular [BV] and 38 single ventricle [SV] physiology) who underwent SPS between 2010 and 2021 were retrospectively reviewed. Our strategy was to delay SPS until 1 month of age; pulmonary blood flow (PBF) regulation by partial clipping of the graft, if needed. Cases of aortic cross-clamping were excluded from this study., Results: CPB was used in 49 (42%) patients: the median age at SPS was 1 month (2 days to 16 years), and the sternotomy approach in 65. Discharge survival was 98.3% (114/116); hospital death occurred in 1.7% due to coronary ischemia. Inter-stage mortality occurred in 1.7% (shunt thrombosis, 1; pneumonia, 1). Pre-discharge acute events occurred in 7 patients (6.0%): thrombosis 3, pulmonary over-circulation 2, and coronary ischemia 2. Multiple logistic regression analysis revealed that pulmonary atresia with intact ventricular septum (PA/IVS) (p = 0.0253) was an independent risk factor for acute events. Partial clipping of the graft was performed in 24 patients (pulmonary atresia 15) and clip removal was performed by catheter intervention in 9 patients; no coronary ischemic events and graft injury occurred in these patients., Conclusion: Surgical outcomes after SPS were acceptable and metal clip regulation of pulmonary blood flow appears to be safe and effective. PA/IVS was still a significant risk factor for acute events., (© 2024. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Background: Pulse wave velocity (PWV) in the pulmonary arteries (PA) is a marker of vascular stiffening. Currently, only phase-contrast (PC) MRI-based options exist to measure PA-PWV., Purpose: To test feasibility, repeatability, and correlation to clinical data of Phase-Resolved Functional Lung (PREFUL) MRI-based calculation of PA-PWV., Study Type: Retrospective., Subjects: 79 (26 female) healthy subjects (age range 19-78), 58 (24 female) patients with chronic obstructive pulmonary disease (COPD, age range 40-77), 60 (33 female) patients with suspected pulmonary hypertension (PH, age range 28-85)., Sequence: 2D spoiled gradient echo, 1.5T., Assessment: PA-PWV was measured from PREFUL-derived cardiac cycles based on the determination of temporal and spatial distance between lung vasculature voxels using a simplified (sPWV) method and a more comprehensive (cPWV) method including more elaborate distance calculation. For 135 individuals, PC MRI-based PWV (PWV-QA) was measured., Statistical Tests: Intraclass-correlation-coefficient (ICC) and coefficient of variation (CoV) were used to test repeatability. Nonparametric tests were used to compare cohorts. Correlation of sPWV/cPWV, PWV-QA, forced expiratory volume in 1 sec (FEV 1 ) %predicted, residual volume (RV) %predicted, age, and right heart catheterization (RHC) data were tested. Significance level α = 0.05 was used., Results: sPWV and cPWV showed no significant differences between repeated measurements (P-range 0.10-0.92). CoV was generally lower than 15%. COPD and PH patients had significantly higher sPWV and cPWV than healthy subjects. Significant correlation was found between sPWV or cPWV and FEV 1 %pred. (R = -0.36 and R = -0.44), but not with RHC (P-range -0.11 - 0.91) or age (P-range 0.23-0.89). Correlation to RV%pred. was significant for cPWV (R = 0.42) but not for sPWV (R = 0.34, P = 0.055). For all cohorts, sPWV and cPWV were significantly correlated with PWV-QA (R = -0.41 and R = 0.48)., Data Conclusion: PREFUL-derived PWV is feasible and repeatable. PWV is increased in COPD and PH patients and correlates to airway obstruction and hyperinflation., Level of Evidence: 3 TECHNICAL EFFICACY: Stage 2., (© 2024 The Authors. Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: According to the most recent pulmonary hypertension (PH) guidelines, a main pulmonary artery (MPA) diameter > 25 mm on transthoracic echocardiography supports the diagnosis of PH. However, the size of the pulmonary artery (PA) may vary according to body size, age, and cardiac phases., Research Question: (1) What are the reference limits for PA size on transthoracic echocardiography, considering differences in body size, sex, and age? (2) What is the diagnostic value of the PA size for classifying PH? (3) How does the selection of different reference groups (healthy volunteers vs patients referred for right heart catheterization [RHC]) influence the diagnostic OR (DOR)?, Study Design and Methods: The study included a reference cohort of 248 healthy individuals as control patients, 693 patients with PH proven by RHC, and 156 patients without PH proven by RHC. In the PH cohort, 300 had group 1 PH, 207 had group 2 PH, and 186 had group 3 PH. MPA and right PA diameters and areas were measured in the upper sternal short-axis and suprasternal notch views. Reference limits (5th-95th percentile) were based on absolute values and height-indexed measures. Quantile regression analysis was used to derive median and 95th quantile reference equations for the PA measures. DORs and probability diagnostic plots for PH were then determined using healthy control and non-PH cohorts., Results: The 95th percentile for indexed MPA diameter was 15 mm/m in diastole and 19 mm/m in systole in both sexes. Quantile regression analysis revealed a weak age effect (pseudo-R 2 of 0.08-0.10 for MPA diameters). Among measures, the MPA size in diastole had the highest DOR (156.2; 95% CI, 68.3-357.5) for detection of group 1 PH. Similarly, the DORs were also high for groups 2 and 3 PH when compared with the control cohort but significantly lower compared with the non-PH cohort., Interpretation: This study presents novel reference limits for MPA based on height indexing and quantile regression., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: F. H. received funding from Janssen Inc to conduct the research. None declared (S. P. B., B. E. C., E. J. S., M. S., K. C. N., A. J. S., R. T. Z.)., (Published by Elsevier Inc.)

Background: Balloon pulmonary angioplasty (BPA) has exhibited substantial progress in the management of chronic thromboembolic pulmonary hypertension (CTEPH). However, nearly one-half of the patients with CTEPH experience persistent pulmonary hypertension after undergoing BPA, emphasizing the need for enhanced therapies., Objectives: The authors sought to investigate the clinical significance of functional assessment-guided dilation of the pulmonary artery (PA) in patients with CTEPH undergoing BPA treatment., Methods: The prospective single-center cohort study enrolled 95 patients who underwent 278 consecutive BPA sessions. Lung parenchymal perfusion was assessed via 2-dimensional perfusion angiography, and pressure catheter measurements were taken to determine the PA pressure ratios. The correlation between lung perfusion and the pressure ratio was analyzed to establish an optimal target pressure ratio. Patients were stratified into 2 groups, a pressure-guided group (n = 28) and an angiographic group (n = 63), to evaluate whether optimizing the pressure ratio led to improvements in residual PH and complications., Results: The pressure ratio and lung perfusion measurements of 141 PA lesions were analyzed. A piecewise linear regression model identified a target pressure ratio of 0.7, associated with significant enhancement in lung perfusion. The pressure-guided strategy achieved a higher rate of mean pulmonary artery pressure <25 mm Hg (92.8% [26/28 patients] vs 60.3% [38/63 patients]; P = 0.001) and a concurrent reduction in BPA relevant complications (3.9% [4/101 sessions] vs 12.9% [23/177 sessions]; P = 0.019)., Conclusions: Functional assessment-guided PA dilation with a target pressure ratio of 0.7 proved beneficial in BPA treatment for patients with CTEPH. This approach improved the residual PH and reduced complications, highlighting its potential to enhance CTEPH management outcomes., Competing Interests: Funding Support and Author Disclosures The present study was supported by Japan Agency for Medical Research and Development under grant number 22ek0210149h0003. Dr S.Y. has received grants support from Takeda Pharmaceutical, Abbott, and Boston Scientific and lecture fees from Daiichi-Sankyo and Bristol Myers Squibb. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hyperglycemia upon admission is associated with poor prognosis of many cardiovascular diseases. However, the relationship of stress hyperglycemia ratio (SHR), admission blood glucose (ABG), and hemoglobin A1c (HbA1c) with pulmonary hypertension has not been reported. This study aimed to explore the association of hyperglycemia indices with disease severity and long-term adverse outcomes in patients with idiopathic pulmonary arterial hypertension (IPAH)., Methods: This multi-center cohort study included 625 consecutive patients diagnosed with or treated for IPAH between January 2015 and June 2023. SHR was calculated using the followings: ABG (mmol/L)/(1.59 × HbA1c [%] - 2.59). The primary endpoint was defined as clinical worsening events. Multivariable Cox regression and restricted cubic spline analyses were employed to evaluate the association of SHR, ABG, and HbA1c with endpoint events. The mediating effect of pulmonary hemodynamics was evaluated to investigate the potential mechanism between hyperglycemia and clinical outcomes., Results: During a mean follow-up period of 3.8 years, 219 (35.0%) patients experienced all-cause death or clinical worsening events. Hyperglycemia indices correlated with well-validated variables that reflected the severity of IPAH, such as the World Health Organization functional class, 6-min walk distance, and N-terminal pro-brain natriuretic peptide levels. Multivariable Cox regression analyses indicated that SHR (hazard ratio [HR] 1.328, 95% confidence intervals [CI]: 1.185, 1.489 per 0.1-unit increment, P < 0.001) and ABG (HR 1.317, 95% CI: 1.134, 1.529 per 1.0-unit increment, P < 0.001) were independent predictors of primary endpoint events. Mediation analysis indicated that pulmonary vascular resistance mediated 5.65% and 14.62% of the associations between SHR and ABG and clinical worsening events, respectively. The addition of SHR significantly improved reclassification, discrimination ability, and model fit beyond the clinical risk prediction model., Conclusions: SHR is positively associated with clinical worsening in patients with IPAH. The association appeared to be partially mediated through the pathway of pulmonary vascular remodeling, indicating that SHR may serve as a valuable indicator for providing additional risk information., (© 2024. The Author(s).)

Introduction: The indications for concominant tricuspid valve surgery in patients undergoing mitral valve surgery for rheumatic reasons are limited. The aim of our study was to investigate the effects of severe pulmonary hypertension and low TAPSE values on early-term mortality and morbidity in patients undergoing mitral valve replacement., Methods: The data of all patients who underwent mitral valve replacement between January 2013 and August 2020 were examined retrospectively. Patients were divided into 2 groups according to pulmonary artery pressure (PAP ≥ 50 and PAP < 50). The group with PAP > 50 was then divided into 2 subgroups according to TAPSE (1.5 ≥ or < 1.5) values. The early-term mortality and morbidity rates of these groups were compared., Results: Seventy-nine patients who underwent mitral valve replacement were included in the study. Fifty-four (68%) of them were female, and 25 (32%) were male. During the preoperative period, the TAPSE was 16.8 ± 3.0 mm, and the PAP was 52.1 ± 14.1 mmHg. There were 53 patients with PAP > 50 and 26 patients with PAP < 50. In the PAP > 50 group, the rates of tricuspid regurgitation (p < 0.001), blood transfusion (p < 0.001), intensive care unit stay (p < 0.001), need for CPAP (p = 0.043), reintubation (p = 0.048), acute renal failure (p = 0.028), and mortality (p = 0.026) were found to be significantly different., Conclusion: In conclusion, we believe that in patients with mitral valve pathology, early referral for surgical intervention, before the pulmonary pressures significantly increase and right ventricular function deteriorates, can enhance survival outcomes., (© 2024. The Author(s).)

Aims: Pulmonary vascular and right ventricular (RV) remodelling processes are important for development and progression of pulmonary hypertension (PH). The current study analysed the functional role of the extra domain A-containing fibronectin (ED-A+ Fn) for the development of PH by comparing ED-A+ Fn knockout (KO) and wild-type (WT) mice as well as the effects of an antibody-based therapeutic approach in a model of monocrotaline (MCT)-induced PH, which will be validated in a model of Sugen 5416/hypoxia-induced PH., Methods and Results: PH was induced using MCT (PH mice). Sixty-nine mice were divided into the following groups: sham-treated controls (WT: n = 7; KO: n = 7), PH mice without specific treatment (WT: n = 12; KO: n = 10), PH mice treated with a dual endothelin receptor antagonist (macitentan; WT: n = 6; KO: n = 11), WT PH mice treated with the F8 antibody, specifically recognizing ED-A+ Fn, (n = 8), and WT PH mice treated with an antibody of irrelevant antigen specificity (KSF, n = 8). Compared to controls, WT&#95;PH mice showed a significant elevation of the RV systolic pressure (P = 0.04) and RV functional impairment including increased basal RV (P = 0.016) diameter or tricuspid annular plane systolic excursion (P = 0.008). In contrast, KO PH did not show such effects compared to controls (P = n.s.). In WT&#95;PH mice treated with F8, haemodynamic and echocardiographic parameters were significantly improved compared to untreated WT&#95;PH mice or those treated with the KSF antibody (P < 0.05). On the microscopic level, KO&#95;PH mice showed significantly less tissue damage compared to the WT&#95;PH mice (P = 0.008). Furthermore, lung tissue damage could significantly be reduced after F8 treatment (P = 0.04). Additionally, these findings could be verified in the Sugen 5416/hypoxia mouse model, in which F8 significantly improved echocardiographic, haemodynamic, and histologic parameters., Conclusion: ED-A+ Fn is of crucial importance for PH pathogenesis representing a promising therapeutic target in PH. We here show a novel therapeutic approach using antibody-mediated functional blockade of ED-A+ Fn capable of attenuating and partially reversing PH-associated tissue remodelling., Competing Interests: Conflict of interest: M.M. is an employee of Philochem AG (www.philochem.ch), daughter company of Philogen. M.F. obtained financial support from Philogen (www.philogen.com). A.B., P.C.S., and M.F. have transferred IP rights to Philogen (www.philogen.com) concerning antibody–cytokine fusions. D.N. is CEO and shareholder of Philogen (www.philogen.com), a company working on the discovery and development of targeted therapeutics, including antibody–cytokine fusions. The remaining co-authors did not declare any conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Pulmonary hypertension (PH) is highly prevalent in patients with interstitial lung disease (ILD) and is associated with increased morbidity and mortality. Widely available noninvasive screening tools are warranted to identify patients at risk for PH, especially severe PH, that could be managed at expert centres. This review summarises current evidence on noninvasive diagnostic modalities and prediction models for the timely detection of PH in patients with ILD. It critically evaluates these approaches and discusses future perspectives in the field. A comprehensive literature search was carried out in PubMed and Scopus, identifying 39 articles that fulfilled inclusion criteria. There is currently no single noninvasive test capable of accurately detecting and diagnosing PH in ILD patients. Estimated right ventricular pressure (RVSP) on Doppler echocardiography remains the single most predictive factor of PH, with other indirect echocardiographic markers increasing its diagnostic accuracy. However, RVSP can be difficult to estimate in patients due to suboptimal views from extensive lung disease. The majority of existing composite scores, including variables obtained from chest computed tomography, pulmonary function tests and cardiopulmonary exercise tests, were derived from retrospective studies, whilst lacking validation in external cohorts. Only two available scores, one based on a stepwise echocardiographic approach and the other on functional parameters, predicted the presence of PH with sufficient accuracy and used a validation cohort. Although several methodological limitations prohibit their generalisability, their use may help physicians to detect PH earlier. Further research on the potential of artificial intelligence may guide a more tailored approach, for timely PH diagnosis., Competing Interests: Conflict of interest: A. Arvanitaki, M.A. Gatzoulis and C. McCabe declare no conflicts of interest relevant to this work. ​G.P. Diller has received honoraria and travel grants from Janssen Global. L.C. Price has received consultancy fees from Janssen and educational support and conference support from Janssen and Ferrer. S.J. Wort has received consultancy fees from Janssen, Acceleron, MSD, Ferrer and Bayer, honoraria from Janssen, Acceleron, MSD, Ferrer and Bayer, as well as travel and research grants from Janssen and Ferrer., (Copyright ©The authors 2024.)

Background: Pulmonary arterial hypertension (PAH) is a worldwide challenging disease characterized by progressive elevation of pulmonary artery pressure. The proliferation, migration and phenotypic transformation of pulmonary smooth muscle cells are the key steps of pulmonary vascular remodeling. Quercetin (3,3', 4', 5, 6-pentahydroxyflavone, Que) is a natural flavonol compound that has antioxidant, anti-inflammatory, anti-tumor and other biological activities. Studies have shown that Que has therapeutic effects on PAH. However, the effect of quercetin on pulmonary vascular remodeling in PAH and its mechanism remain unclear., Methods and Results: In vivo, PAH rats were constructed by intraperitoneal injection of monocrotaline (MCT) at 60 mg/kg. Human pulmonary artery smooth muscle cells (HPASMCs) were treated with platelet-derived growth factor BB (PDGF-BB) 20 ng/mL to construct PAH cell model in vitro. The results showed that in vivo studies, MCT could induce right ventricular wall hyperplasia, narrow the small and medium pulmonary artery cavity, up-regulate the expression of proliferating and migration-related proteins proliferating cell nuclear antigen (PCNA) and osteopontin (OPN), and down-regulate the expression of alpha-smooth muscle actin (α-SMA). Que reversed the MCT-induced results. This process works by down-regulating the transforming growth factor-β1 (TGF-β1)/ Smad2/3 signaling pathway. In vitro studies, Que had the same effect on PDGF-BB-induced proliferation and migration cell models., Conclusions: Que inhibits the proliferation, migration and phenotypic transformation of HPASMCs by down-regulating TGF-β1/Smad2/Smad3 pathway, thereby reducing right ventricular hyperplasia (RVH) and pulmonary vascular remodeling, providing potential pharmacological and molecular explanations for the treatment of PAH., (© 2024. The Author(s).)

Pulmonary hypertension (PH) is a vascular disease characterized by pulmonary artery remodeling and right heart failure. PH related to COPD is a precapillary form of the disease, with hemodynamic measurements including a mean pulmonary artery pressure of greater than 20 mm Hg, a wedge pressure of less than 15 mm Hg, and a pulmonary vascular resistance of greater than 3 WU (Woods units), categorized under the World Health Organization classification as group 3. The presence of PH in COPD has been known to increase morbidity and mortality. Limited studies have evaluated treatment options for PH related to COPD., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Current guidelines recommend intervention for asymptomatic rheumatic mitral stenosis (MS) with mitral valve area ≤1.5 cm 2 based on indicators including pulmonary arterial systolic pressure (PASP) >50 mm Hg and new-onset atrial fibrillation; however, evidence supporting this is lacking., Methods: This single-center retrospective study included patients with rheumatic MS between 2006 and 2022. Pulmonary hypertension was evaluated by using echocardiography to estimate PASP. Primary outcomes were major adverse cardiovascular events (MACE), including all-cause mortality, hospitalization for heart failure, and arterial thromboembolic events for up to 5 years., Results: Overall, 287 patients with severe rheumatic MS were enrolled (mean age, 62.5±11.3 years; 74.6% women). During a median follow-up of 2.52 years, MACE occurred in 99 patients. There were no differences in echocardiographic parameters, such as the mean mitral valve pressure gradient, mitral valve area, and proportion of mitral valve area <1.0 cm 2 , between patients who developed primary outcomes and those who did not. Survival analysis showed a worse prognosis in patients with estimated PASP (ePASP) >50 mm Hg than in those with ePASP ≤50 mm Hg (log-rank P <0.001); however, atrial fibrillation was not a significant prognostic indicator. As a continuous variable, ePASP (mm Hg) was a significant predictor of MACE (adjusted hazard ratio, 1.027 [95% CI, 1.011-1.042]; P <0.001). Receiver operating characteristic analysis revealed an optimal ePASP threshold of >45 mm Hg, which was an independent predictor of MACE in patients with severe rheumatic MS (adjusted hazard ratio, 2.127 [95% CI, 1.424-3.177]; P <0.001). Competing risk analysis considering mitral valve intervention as a competing risk showed similar results., Conclusions: Our study demonstrated the prognostic significance of ePASP, rather than atrial fibrillation, in relation to MACE among patients with severe rheumatic MS. Additionally, we proposed a lower ePASP threshold (>45 mm Hg) as a predictor of an unfavorable prognosis., Competing Interests: None.

The Sugen 5416/hypoxia (Su/Hx) rat model of pulmonary arterial hypertension (PAH) demonstrates most of the distinguishing features of PAH in humans, including increased wall thickness and obstruction of the small pulmonary arteries along with plexiform lesion formation. Recently, significant advancement has been made describing the epidemiology, genomics, biochemistry, physiology, and pharmacology in Su/Hx challenge in rats. For example, there are differences in the overall reactivity to Su/Hx challenge in different rat strains and only female rats respond to estrogen treatments. These conditions are also encountered in human subjects with PAH. Also, there is a good translation in both the biochemical and metabolic pathways in the pulmonary vasculature and right heart between Su/Hx rats and humans, particularly during the transition from the adaptive to the nonadaptive phase of right heart failure. Noninvasive techniques such as echocardiography and magnetic resonance imaging have recently been used to evaluate the progression of the pulmonary vascular and cardiac hemodynamics, which are important parameters to monitor the efficacy of drug treatment over time. From a pharmacological perspective, most of the compounds approved clinically for the treatment of PAH are efficacious in Su/Hx rats. Several compounds that show efficacy in Su/Hx rats have advanced into phase II/phase III studies in humans with positive results. Results from these drug trials, if successful, will provide additional treatment options for patients with PAH and will also further validate the excellent translation that currently exists between Su/Hx rats and the human PAH condition.

Background: Sympathetic hyperactivity plays an important role in the initiation and maintenance of pulmonary hypertension. Carotid baroreceptor stimulation (CBS) is an effective autonomic neuromodulation therapy. We aim to investigate the effects of CBS on hypoxia-induced pulmonary hypertension and its underlying mechanisms., Methods and Results: Rats were randomly assigned into 4 groups, including a Control-sham group (n=7), a Control-CBS group (n=7), a Hypoxia-sham group (n=10) and a Hypoxia-CBS group (n=10). Echocardiography, ECG, and hemodynamics examination were performed. Samples of blood, lung tissue, pulmonary arteries, and right ventricle were collected for the further analysis. In the in vivo study, CBS reduced wall thickness and muscularization degree in pulmonary arterioles, thereby improving pulmonary hemodynamics. Right ventricle hypertrophy, fibrosis and dysfunction were all improved. CBS rebalanced autonomic tone and reduced the density of sympathetic nerves around pulmonary artery trunks and bifurcations. RNA-seq analysis identified BDNF and periostin ( POSTN ) as key genes involved in hypoxia-induced pulmonary hypertension, and CBS downregulated the mRNA expression of BDNF and POSTN in rat pulmonary arteries. In the in vitro study, norepinephrine was found to promote pulmonary artery smooth muscle cell proliferation while upregulating BDNF and POSTN expression. The proliferative effect was alleviated by silence BDNF or POSTN ., Conclusions: Our results showed that CBS could rebalance autonomic tone, inhibit pulmonary arterial remodeling, and improve pulmonary hemodynamics and right ventricle function, thus delaying hypoxia-induced pulmonary hypertension progression. There may be a reciprocal interaction between POSTN and BDNF that is responsible for the underlying mechanism.

Neonates with congenital heart disease (CHD) and ductal-dependent pulmonary blood flow (DD-PBF) require early intervention. Historically, this intervention was most often a surgical systemic-to-pulmonary shunt (SPS; e.g., Blalock-Thomas-Taussig shunt). However, over the past two decades an alternative to SPS has emerged in the form of transcatheter ductal artery stenting (DAS). While many reports have indicated safety and durability of the DAS approach, few studies compare outcomes between DAS and SPS. The reports that do exist are comprised primarily of small-cohort single-center reviews. Two multicenter retrospective studies suggest that DAS is associated with similar or superior survival compared to SPS. These studies offer the best evidence to-date, and yet both have important limitations. The authors describe herein the rationale and design of the COMPASS (COmparison of Methods for Pulmonary blood flow Augmentation: Shunt vs. Stent) Trial (NCT05268094, IDE G210212). The COMPASS Trial aims to randomize 236 neonates with DD-PBF to either DAS or SPS across approximately 27 pediatric centers in North America. The goal of this trial is to compare important clinical outcomes between DAS and SPS over the first year of life in a cohort of neonates balanced by randomization to assess whether one method of palliation demonstrates therapeutic superiority., (© 2024 The Author(s). Catheterization and Cardiovascular Interventions published by Wiley Periodicals LLC.)

Background: G6PD (glucose-6-phosphate-dehydrogenase) is a key enzyme in the glycolytic pathway and has been implicated in the pathogenesis of cancer and pulmonary hypertension-associated vascular remodeling. Here, we investigated the role of an X-linked G6pd mutation (N126D polymorphism), which is known to increase the risk of cardiovascular disease in individuals from sub-Saharan Africa and many others with African ancestry, in the pathogenesis of pulmonary hypertension induced by a vascular endothelial cell growth factor receptor blocker used for treating cancer., Methods and Results: CRISPR-Cas9 genome editing was used to generate the G6pd variant (N126D; G6pd N126D ) in rats. A single dose of the vascular endothelial cell growth factor receptor blocker sugen-5416 (SU; 20 mg/kg in DMSO), which is currently in a Phase 2/3 clinical trial for cancer treatment, was subcutaneously injected into G6pd N126D rats and their wild-type littermates. After 8 weeks of normoxic conditions, right ventricular pressure and hypertrophy, pulmonary artery remodeling, the metabolic profile, and cytokine expression were assessed. Right ventricular pressure and pulmonary arterial wall thickness were increased in G6PD N126D +SU/normoxic rats. Simultaneously, levels of oxidized glutathione, inositol triphosphate, and intracellular Ca 2+ were increased in the lungs of G6PD N126D +SU/normoxic rats, whereas nitric oxide was decreased. Also increased in G6PD N126D +SU/normoxic rats were pulmonary levels of plasminogen activator inhibitor-1, thrombin-antithrombin complex, and expression of proinflammatory cytokines CCL3 (chemokine [C-C motif] ligand), CCL5, and CCL7., Conclusions: Our results suggest G6PD N126D increases inositol triphosphate-Ca 2+ signaling, inflammation, thrombosis, and hypertrophic pulmonary artery remodeling in SU-treated rats. This suggests an increased risk of vascular endothelial cell growth factor receptor blocker-induced pulmonary hypertension in those carrying this G6PD variant.

Despite exercise intolerance being predictive of outcomes in pulmonary arterial hypertension (PAH), its underlying cardiac mechanisms are not well described. The aim of the study was to explore the biventricular response to exercise and its associations with cardiorespiratory fitness in children with PAH. Participants underwent incremental cardiopulmonary exercise testing and simultaneous exercise echocardiography on a recumbent cycle ergometer. Linear mixed models were used to assess cardiac function variance and associations between cardiac and metabolic parameters during exercise. Eleven participants were included with a mean age of 13.4 ± 2.9 yr old. Right ventricle (RV) systolic pressure (RVsp) increased from a mean of 59 ± 25 mmHg at rest to 130 ± 40 mmHg at peak exercise ( P < 0.001), whereas RV fractional area change (RV-FAC) and RV-free wall longitudinal strain (RVFW-S l ) worsened (35.2 vs. 27%, P = 0.09 and -16.6 vs. -14.6%, P = 0.1, respectively). At low- and moderate-intensity exercise, RVsp was positively associated with stroke volume and O 2 pulse ( P < 0.1). At high-intensity exercise, RV-FAC, RVFW-S l , and left ventricular longitudinal strain were positively associated with oxygen uptake and O 2 pulse ( P < 0.1), whereas stroke volume decreased toward peak ( P = 0.04). In children with PAH, the increase of pulmonary pressure alone does not limit peak exercise, but rather the concomitant reduced RV functional reserve, resulting in RV to pulmonary artery (RV-PA) uncoupling, worsening of interventricular interaction and LV dysfunction. A better mechanistic understanding of PAH exercise physiopathology can inform stress testing and cardiac rehabilitation in this population. NEW & NOTEWORTHY In children with pulmonary arterial hypertension, there is a marked increase in pulmonary artery pressure during physical activity, but this is not the underlying mechanism that limits exercise. Instead, right ventricle-to-pulmonary artery uncoupling occurs at the transition from moderate to high-intensity exercise and correlates with lower peak oxygen uptake. This highlights the more complex underlying pathological responses and the need for multiparametric assessment of cardiac function reserve in these patients when feasible.

Aims: Novel echocardiographic parameters of right ventricular (RV) function, including speckle-tracking-derived, three-dimensional, and RV-pulmonary artery coupling parameters, have emerged for the evaluation of pulmonary arterial hypertension (PAH). The relative role of these parameters in the risk stratification of PAH patients is unclear. We compared the performance of multiple RV parameters and sought to establish an optimal model for identifying the risk profile of patients with PAH., Methods and Results: Comprehensive risk assessments were performed for 70 patients with PAH. The risk profile of every patient was determined based on the guideline recommendations. Conventional parameters, including fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE), novel speckle-tracking-derived RV longitudinal strain (RVLS), and three-dimensional RV ejection fraction (3D-RVEF), were used to evaluate RV function. Pressure-strain loops were measured for the assessment of RV myocardial work, including RV global wasted work (RVGWW). RV-pulmonary artery coupling was assessed by indexing RV parameters to the estimated pulmonary artery systolic pressure (PASP). The median age was 34 (30-43) years, and 62 (88.6%) patients were female. Forty-five patients were classified into the low-risk group, while 25 patients were classified into the intermediate-high-risk group. Most RV parameters could be used to determine the risk profile and exhibited significantly improved diagnostic performance after indexing to PASP (including FAC/PASP, TAPSE/PASP, and 3D-RVEF/PASP). RVLS/PASP showed the best performance, with an area under the curve of 0.895. In multivariate analysis (Model 1), only RVGWW (>90.5 mmHg%), RVLS (> -16.7%), and TAPSE (<17.5 mm) remained significant (all P < 0.05). Model 1 outperformed every single RV parameter, with a significantly larger area under the curve (all P < 0.05). With PASP indexing in Model 2, RVLS/PASP > -0.275 [odds ratio (OR) 20.63, 95% confidence interval (CI) 4.62-92.11, P < 0.001] and RVGWW > 90.5 mmHg% (OR 6.17, 95% CI 1.37-27.76, P = 0.018) independently identified a higher risk profile. The addition of RVGWW to two models determined incremental value in identification (continuous net reclassification improvement 1.058, 95% CI 0.639-1.477, P < 0.001)., Conclusions: The combination models for RV function outperformed any single parameter in identifying the risk profile of patients with PAH. Comprehensive assessment of RV-pulmonary artery coupling using multiparametric methods is clinically meaningful in patients with PAH., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Sex differences are recognized in pulmonary hypertension. However, the progression of disease with regard to vascular lesion formation and circulating cytokines/chemokines is unknown. To determine whether vascular lesion formation, changes in hemodynamics, and alterations in circulating chemokines/cytokines differ between males and females, we used a progressive model of pulmonary arterial hypertension (PAH), Sugen/hypoxia, and analyzed cohorts of male and female rats at time points suggested to indicate worsening disease. Our analysis included echocardiography for hemodynamics, morphometry, immunofluoresecence, and chemokine/cytokine analysis of plasma at each time point in both sexes. We found that male rats had significantly increased Fulton index, compared with those for females at each time point, as well as increased medial artery thickening at 8 weeks of PAH. Furthermore, females exhibited fewer obliterative vascular lesions than males at our latest time point. Our data also show increased IL-4, granulocyte-macrophage colony-stimulating factor, IL-10, and macrophage interacting protein-1α that were not observed in females, whereas females were observed to have increased RANTES (whose name derives from Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted) and CXCL-10 that were not found in males. Males also have increased infiltrating macrophages in vascular lesions, compared with females. We found that development of progressive PAH in hemodynamics, morphology, and chemokine/cytokine circulation differs significantly between males and females. These data suggest a macrophage-driven pathology in males, whereas there may be T cell protection from vascular damage in females with PAH.

Pulmonary hypertension is a rare, incurable, and progressive disease. Although there is increasing evidence that immune disorders, particularly those associated with connective tissue diseases, are a strong predisposing factor in the development of pulmonary arterial hypertension (PAH), there is currently a lack of knowledge about the detailed molecular mechanisms responsible for this phenomenon. Exploring this topic is crucial because patients with an immune disorder combined with PAH have a worse prognosis and higher mortality compared with patients with other PAH subtypes. Moreover, data recorded worldwide show that the prevalence of PAH in women is 2× to even 4× higher than in men, and the ratio of PAH associated with autoimmune diseases is even higher (9:1). Sexual dimorphism in the pathogenesis of cardiovascular disease was explained for many years by the action of female sex hormones. However, there are increasing reports of interactions between sex hormones and sex chromosomes, and differences in the pathogenesis of cardiovascular disease may be controlled not only by sex hormones but also by sex chromosome pathways that are not dependent on the gonads. This review discusses the role of estrogen and genetic factors including the role of genes located on the X chromosome, as well as the potential protective role of the Y chromosome in sexual dimorphism, which is prominent in the occurrence of PAH associated with autoimmune diseases. Moreover, an overview of animal models that could potentially play a role in further investigating the aforementioned link was also reviewed., Competing Interests: None.

Aims: The initial bundle of cares strongly affects haemodynamics and outcomes in acute decompensated heart failure cardiogenic shock (ADHF-CS). We sought to characterize whether 24 h haemodynamic profiling provides superior prognostic information as compared with admission assessment and which haemodynamic parameters best predict in-hospital death., Methods and Results: All patients with ADHF-CS and with available admission and 24 h invasive haemodynamic assessment from two academic institutions were considered for this study. The primary endpoint was in-hospital death. Regression analyses were run to identify relevant predictors of study outcome. We included 127 ADHF-CS patients [65 (inter-quartile range 52-72) years, 25.2% female]. Overall, in-hospital mortality occurred in 26.8%. Non-survivors were older, with greater CS severity. Among admission variables, age [odds ratio (OR) = 1.06; 95% confidence interval (CI): 1.02-1.11; P adj  = 0.005] and CPI RAP (OR = 0.62 for 0.1 increment; 95% CI: 0.39-0.95; P adj  = 0.034) were found significantly associated with in-hospital death. Among 24 h haemodynamic univariate predictors of in-hospital death, pulmonary elastance (PaE) was the strongest (area under the curve of 0.77; 95% CI: 0.68-0.86). PaE (OR = 5.98; 95% CI: 2.29-17.48; P adj  < 0.001), pulmonary artery pulsatility index (PAPi, OR = 0.77; 95% CI: 0.62-0.92; P adj  = 0.013) and age (OR = 1.06; 95% CI: 1.02-1.11; P adj  = 0.010) were independently associated with in-hospital death. Best cut-off for PaE was 0.85 mmHg/mL and for PAPi was 2.95; cohort phenotyping based on these PaE and PAPi thresholds further increased in-hospital death risk stratification; patients with 24 h high PaE and low PAPi exhibited the highest in-hospital mortality (56.2%)., Conclusions: Pulmonary artery elastance has been found to be the most powerful 24 h haemodynamic predictor of in-hospital death in patients with ADHF-CS. Age, 24 h PaE, and PAPi are independently associated with hospital mortality. PaE captures ventricular (RV) afterload mismatch and PAPi provides a metric of RV adaptation, thus their combination generates four distinct haemodynamic phenotypes, enhancing in-hospital death risk stratification., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: A recent guideline presented by the ESC Congress in 2022 had indicated a novel therapy targeted at pulmonary artery hypertension, known as pulmonary artery denervation (PADN), which get inspired from a laboratorial trial that could lowering the pulmonary artery pressure through the intervention on the animals. Our aim is to conduct a network meta-analysis to compare the efficacy and safety of PADN from six aspects with the current conventional therapies., Methods and Results: According to the PRISMA guidance, databases including Ovid, ClinicalTrials.gov, Medline, Embase, and PubMed were searched from inception to 22 August 2023, along with a full assessment of the previous five meta-analyses. Data were extracted and curated for Bayesian network meta-analysis. The primary outcome was the change in the 6-min walking distance (6MWD) from baseline with a secondary outcome called change in mean pulmonary artery pressure (mPAP) from baseline. The four safety outcomes included risk of clinical worsening, hospitalization, mortality and severe adverse events (SAEs). The comparison is structured on a contrast model based on 65 randomized controlled trials (RCTs) on PADN and the other conventional mainstream drugs. PADN had a better effect in improving 6MWD than Placebo (-77.76 m, 95% CI: -102.04 to -54.34 m), Macitentan (-65.32 m, 95% CI: -95.34 to -36.1 m), Bosentan (-64.5 m, 95% CI: -94.7 to -35.07 m), Iloprost (-62.66 m, 95% CI: -99.48 to -27.13 m), Oxygen (-62.42 m, 95% CI: -100.01 to -25.78 m), Treprostinil (-62.01 m, 95% CI: -89.04 to -35.61 m), Riociguat (-60.59 m, 95% CI: -86.11 to -35.98 m), Selexipag (-47.2 m, 95% CI: -85.61 to -10.19 m), Sildenafil (-44.92 m, 95% CI: -74.43 to -16.15 m), or Sitaxsentan (-39.53 m, 95% CI: -78.99 to -0.76 m). PADN had a better antihypertensive effect than placebo and showed statistical significant lower risks to induce clinical worsening and re-hospitalization than treprostinil, riociguat, and placebo groups. No statistically significant difference in risk of mortality and severe adverse events was observed between PADN versus the other interventions., Conclusions: Compared with 16 types of conventional therapies and Placebo, PADN has advantage over nine single therapies and Placebo in improving 6MWD and appears to be better than two types of dual-drug combined therapies while with no statistical significance. PADN shows a favourable antihypertensive effect on mPAP and has a lower risk to trigger clinical worsening or hospitalization, while its risk on mortality and severe adverse events is still inconclusive., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Pulmonary artery stenosis (PAS) often presents in children with congenital heart disease, altering blood flow and pressure during critical periods of growth and development. Variability in stenosis onset, duration, and severity result in variable growth and remodeling of the pulmonary vasculature. Computational fluid dynamics (CFD) models enable investigation into the hemodynamic impact and altered mechanics associated with PAS. In this study, a one-dimensional (1D) fluid dynamics model was used to simulate hemodynamics throughout the pulmonary arteries of individual animals. The geometry of the large pulmonary arteries was prescribed by animal-specific imaging, whereas the distal vasculature was simulated by a three-element Windkessel model at each terminal vessel outlet. Remodeling of the pulmonary vasculature, which cannot be measured in vivo, was estimated via model-fitted parameters. The large artery stiffness was significantly higher on the left side of the vasculature in the left pulmonary artery (LPA) stenosis group, but neither side differed from the sham group. The sham group exhibited a balanced distribution of total distal vascular resistance, whereas the left side was generally larger in the LPA stenosis group, with no significant differences between groups. In contrast, the peripheral compliance on the right side of the LPA stenosis group was significantly greater than the corresponding side of the sham group. Further analysis indicated the underperfused distal vasculature likely moderately decreased in radius with little change in stiffness given the increase in thickness observed with histology. Ultimately, our model enables greater understanding of pulmonary arterial adaptation due to LPA stenosis and has potential for use as a tool to noninvasively estimate remodeling of the pulmonary vasculature., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: To evaluate the correlation between clot burden and pulmonary artery pressures in patients undergoing suction thromboembolectomy for high-risk and intermediate-high-risk pulmonary embolism with secondary outcomes of 30-day mortality and intensive care unit (ICU) length of stay., Materials and Methods: Institutional review board (IRB) exemption was granted for this retrospective study. The charts of 120 consecutive patients who underwent mechanical thromboembolectomy using the Flowtriever system (Inari Medical, Irvine, California) between February 2020 and August 2022 were retrospectively reviewed, and the following data were collected: (a) preprocedural B-type natriuretic peptide and creatinine levels, (b) echocardiographic findings, (c) preprocedural and postprocedural pulmonary artery pressures, (d) ICU length of stay, and (e) 30-day mortality. Clot burden was scored using Qanadli and Miller indices and correlated with the clinical outcomes., Results: Of the 120 patients who underwent thromboembolectomy, pulmonary artery pressures and diagnostic-quality angiograms were available in 109 patients. In the 109 patients with adequate data, Qanadli, preprocedural Miller, and postprocedural Miller scores correlated with pulmonary artery pressures. Neither was independently associated with ICU length of stay. Freedom from 30-day mortality was 91%, and embolism-specific mortality was 92%. All-risk and high-risk patients who survived demonstrated a significantly lower preprocedural and postprocedural Miller score, respectively., Conclusions: Thrombus burden as measured by the Qanadli and Miller scores appeared to be correlated with pulmonary artery pressures. Furthermore, catheter-directed thromboembolectomy led to a reduction in Miller scores, which appeared to be correlated with a reduction in pulmonary pressures. In high-risk patients, a reduced postprocedural Miller score and pulmonary pressure demonstrated improved 30-day survival. Further investigation into the association between Miller scores and patient mortality is warranted to stratify patients who would benefit from emergency intervention., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Objectives: Hughes-Stovin syndrome (HSS) is a rare inflammatory condition defined as pulmonary artery aneurysms (PAA) associated with deep vein thrombosis. It is similar to vascular involvement of Behçet's syndrome (BS), but differs in the absence of typical skin-mucosal findings. Whether HSS is a distinct entity or a form fruste of BS is debated. We formally compared HSS cases retrieved from the literature to BS patients with PAI followed by a tertiary centre., Methods: A systemic literature search using 'Hughes Stovin syndrome' as the key word covering the period between 2000 and 2023 revealed 58 (43 M/15 F) case reports (PROSPERO: CRD42023413537). We identified 74 (62M/12 F) BS patients with PAI followed up in a tertiary centre in Turkey from 2000 until 2020. We evaluated two cohorts head-to-head in terms of demographic and clinical features., Results: BS and HSS patients were found to be comparable with regard to several demographic, clinical and histopathological features. However, PAA were significantly more frequent and isolated pulmonary artery thrombosis (PAT) less common in HSS than that found in BS. Moreover, patients with HSS were more likely to be treated with anti-coagulants and vascular or surgical interventions, whereas less likely to receive immunosuppressive treatment., Conclusions: Our study indicates that HSS is indeed an 'incomplete form of BS'. It can be considered as evidence supporting the notion that the vascular phenotype develops independently from skin-mucosa lesions and uveitis in BS. However, HSS has been described mainly focusing on aneurysms, overlooking the aspect of in-situ thrombosis.

Purpose: Chronic, high-altitude hypoxic exposure increases the risk of high-altitude pulmonary hypertension (PH). Emerging evidence shows maternal exercise may improve offspring resistance to disease throughout life. The purpose of this study is to determine if maternal exercise mitigates chronic hypoxic-induced changes in the offspring indicative of high-altitude PH development., Methods: Female adult C57BL/6J mice were randomly allocated to nonexercise or exercise conditions. Exercise consisted of voluntary running wheel exercise for 4 wk during the perinatal period. Three days after birth, the pups remained at low altitude (normoxia) or were exposed to hypobaric hypoxia of 450 mm Hg to simulate ~4500 m of altitude exposure until 8 wk of age. The study consisted of four groups: hypoxia + nonexercise pregnancy, hypoxia + exercise, or the respective normoxia conditions (normoxia + nonexercise or normoxia + exercise). Offspring body size, motor function, right ventricular systolic pressure (RVSP), and cardiopulmonary morphology were assessed after 8 wk in normoxia or hypoxia., Results: Both hypoxic groups had smaller body sizes, reduced motor function, increased hematocrit, RVSP, muscularization in medium-sized pulmonary arteries, as well as right ventricular hypertrophy and contractility compared with the normoxic groups ( P < 0.05)., Conclusions: Chronic hypoxia simulating 4500 m attenuated growth, lowered motor function, and elicited PH development. Voluntary maternal exercise did not significantly decrease RVSP in the offspring, which aligned with a lack of effect to attenuate abnormal body size and cardiopulmonary development due to chronic hypoxia. These findings are preliminary in nature, and more powered studies through larger group sizes are required to generalize the results to the population., (Copyright © 2024 by the American College of Sports Medicine.)

Background: European and U.S. clinical guidelines diverge regarding pulmonary hypertension (PHTN) in degenerative mitral regurgitation (DMR). Gaps in knowledge underpinning these divergences affect risk assessment and management recommendations attached to systolic pulmonary pressure (SPAP) in DMR., Objectives: This study sought to define PHTN links to DMR severity, prognostic thresholds, and independent outcome impact in a large quantitative DMR registry., Methods: This study gathered a large multicentric registry of consecutive patients with isolated moderate-to-severe DMR, with DMR and SPAP quantified prospectively at diagnosis., Results: In 3,712 patients (age 67 ± 15 years, 36% women) with ≥ moderate-to-severe DMR, effective regurgitant orifice (ERO) was 0.42 ± 0.19 cm 2 , regurgitant volume 66 ± 327 mL/beat and SPAP 41 ± 16 mm Hg. Spline-curve analysis showed excess mortality under medical management emerging around SPAP 35 mm Hg and doubling around SPAP 50 mm Hg. Accordingly, severe pulmonary hypertension (sPHTN) (SPAP ≥50 mm Hg) was detected in 916 patients, moderate pulmonary hypertension (mPHTN) (SPAP 35-49 mm Hg) in 1,128, and no-PHTN (SPAP <35 mm Hg) in 1,668. Whereas SPAP was strongly associated with DMR-ERO, nevertheless excess mortality with sPHTN (adjusted HR: 1.65; 95% CI: 1.24-2.20) and mPHTN (adjusted HR: 1.44; 95% CI: 1.11-1.85; both P ≤ 0.005) was observed independently of ERO and all baseline characteristics and in all patient subsets. Nested models demonstrated incremental prognostic value of mPHTN and sPHTN (all P < 0.0001). Despite higher operative risk with mPHTN and sPHTN, DMR surgical correction was followed by higher survival in all PHTN ranges with strong survival benefit of early surgery (<3 months). Postoperatively, excess mortality was abolished (P ≥ 0.30) in mPHTN, but only abated in sPHTN., Conclusions: This large international registry, with prospectively quantified DMR and SPAP, demonstrates a Doppler-defined PHTN impact on mortality, independent of DMR severity. Crucially, it defines objectively the new and frequent mPHTN range, independently linked to excess mortality under medical management, which is abolished by DMR correction. Thus, at DMR diagnosis, Doppler-SPAP measurement defining these new PHTN ranges, is crucial to guiding DMR management., Competing Interests: Funding Support and Author Disclosures This study was supported by the Mayo Foundation, French Ministry of Health “PHRC-I 2012” (Dr Le Tourneau, API12/N/019), Fédération Française de Cardiologie (Dr Le Tourneau, 2015), and Fondation Cœur et Recherche (Dr Le Tourneau, 2015). The Department of Cardiology of the Leiden University Medical Center received research grants from Abbott Vascular, Bioventrix, Medtronic, Biotronik, Boston Scientific, GE Healthcare, and Edwards Lifesciences. Drs Bax and Ajmone Marsan have received speaker fees from Abbott Vascular. Dr Enriquez-Sarano has received consulting fees from Edwards LLC, Cryolife Inc, ChemImage, and HighLife Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: As one of the most common traffic-related pollutants, diesel exhaust (DE) confers high risk for cardiovascular and respiratory diseases. However, its impact on pulmonary vessels is still unclear., Methods: To explore the effects of DE exposure on pulmonary vascular remodeling, our study analyzed the number and volume of small pulmonary vessels in the diesel engine testers (the DET group) from Luoyang Diesel Engine Factory and the controls (the non-DET group) from the local water company, using spirometry and carbon content in airway macrophage (CCAM) in sputum. And then we constructed a rat model of chronic DE exposure, in which 12 rats were divided into the DE group (6 rats with 16-week DE exposure) and the control group (6 rats with 16-week clean air exposure). During right heart catheterization, right ventricular systolic pressure (RVSP) was assessed by manometry. Macrophage migration inhibitory factor (MIF) in lung tissues and bronchoalveolar lavage fluid (BALF) were measured by qRT-PCR and ELISA, respectively. Histopathological analysis for cardiovascular remodeling was also performed., Results: In DET cohort, the number and volume of small pulmonary vessels in CT were positively correlated with CCAM in sputum (P<0.05). Rat model revealed that chronic DE-exposed rats had elevated RVSP, along with increased wall thickness of pulmonary small vessels and right the ventricle. What's more, the MIF levels in BALF and lung tissues were higher in DE-exposed rats than the controls., Conclusion: Apart from airway remodeling, DE also induces pulmonary vascular remodeling, which will lead to cardiopulmonary dysfunction., (© 2024. The Author(s).)

Background: Pulmonary hypertension (PH) is a major complication linked to adverse outcomes in heart failure with preserved ejection fraction (HFpEF), yet no specific therapies exist for PH associated with HFpEF (PH-HFpEF). We have recently reported on the role of skeletal muscle SIRT3 (sirtuin-3) in modulation of PH-HFpEF, suggesting a novel endocrine signaling pathway for skeletal muscle modulation of pulmonary vascular remodeling., Methods: Using skeletal muscle-specific Sirt3 knockout mice ( Sirt3 skm-/- ) and mass spectrometry-based comparative secretome analysis, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF., Results: Sirt3 skm-/- mice exhibited reduced pulmonary vascular density accompanied by pulmonary vascular proliferative remodeling and elevated pulmonary pressures. Comparative analysis of secretome by mass spectrometry revealed elevated secretion levels of LOXL2 (lysyl oxidase homolog 2) in SIRT3-deficient skeletal muscle cells. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3 skm-/- mice, a rat model of PH-HFpEF, and humans with PH-HFpEF. In addition, expression levels of CNPY2 (canopy fibroblast growth factor signaling regulator 2), a known proliferative and angiogenic factor, were increased in pulmonary artery endothelial cells and pulmonary artery smooth muscle cells of Sirt3 skm-/- mice and animal models of PH-HFpEF. CNPY2 levels were also higher in pulmonary artery smooth muscle cells of subjects with obesity compared with nonobese subjects. Moreover, treatment with recombinant LOXL2 protein promoted pulmonary artery endothelial cell migration/proliferation and pulmonary artery smooth muscle cell proliferation through regulation of CNPY2-p53 signaling. Last, skeletal muscle-specific Loxl2 deletion decreased pulmonary artery endothelial cell and pulmonary artery smooth muscle cell expression of CNPY2 and improved pulmonary pressures in mice with high-fat diet-induced PH-HFpEF., Conclusions: This study demonstrates a systemic pathogenic impact of skeletal muscle SIRT3 deficiency in remote pulmonary vascular remodeling and PH-HFpEF. This study suggests a new endocrine signaling axis that links skeletal muscle health and SIRT3 deficiency to remote CNPY2 regulation in the pulmonary vasculature through myokine LOXL2. Our data also identify skeletal muscle SIRT3, myokine LOXL2, and CNPY2 as potential targets for the treatment of PH-HFpEF., Competing Interests: M.T.G. is a coinventor of patents and patent applications directed to the use of recombinant neuroglobin and heme-based molecules as antidotes for carbon monoxide poisoning, which have been licensed by Globin Solutions, Inc. M.T.G. is a shareholder, advisor, and director in Globin Solutions, Inc. M.T.G. is also coinventor on patents directed to the use of nitrite salts in cardiovascular diseases, which were previously licensed to United Therapeutics, and are now licensed to Globin Solutions and Hope Pharmaceuticals. M.T.G. is a principal investigator in an investigator-initiated research study with Bayer Pharmaceuticals to evaluate riociguat as a treatment for patients with sickle cell disease.

We previously reported pulmonary arterial remodelling and active endothelial-to-mesenchymal transition (EndMT) in smokers and patients with early chronic obstructive pulmonary disease (COPD). In the present study, we aimed to evaluate the role of different drivers of EndMT. Immunohistochemical staining for EndMT drivers, TGF-β1, pSMAD-2/3, SMAD-7, and β-catenin, was performed on lung resections from 46 subjects. Twelve were non-smoker-controls (NC), six normal lung function smokers (NLFS), nine patients with small-airway diseases (SAD), nine mild-moderate COPD-current smokers (COPD-CS) and ten COPD-ex-smokers (COPD-ES). Histopathological measurements were done using Image ProPlus softwarev7.0. We observed lower levels of total TGF-β1 (P<0.05) in all smoking groups than in the non-smoking control (NC). Across arterial sizes, smoking groups exhibited significantly higher (P<0.05) total and individual layer pSMAD-2/3 and SMAD-7 than in the NC group. The ratio of SAMD-7 to pSMAD-2/3 was higher in COPD patients compared with NC. Total β-catenin expression was significantly higher in smoking groups across arterial sizes (P<0.05), except for COPD-ES and NLFS groups in small and medium arteries, respectively. Increased total β-catenin was positively correlated with total S100A4 in small and medium arteries (r = 0.35, 0.50; P=0.02, 0.01, respectively), with Vimentin in medium arteries (r = 0.42, P=0.07), and with arterial thickness of medium and large arteries (r = 0.34, 0.41, P=0.02, 0.01, respectively). This is the first study uncovering active endothelial SMAD pathway independent of TGF-β1 in smokers, SAD, and COPD patients. Increased expression of β-catenin indicates its potential interaction with SMAD pathway, warranting further research to identify the deviation of this classical pathway., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Background: Branch pulmonary artery (PA) stenosis is one of the most common indications for percutaneous interventions in patients with transposition of the great arteries (TGA), tetralogy of Fallot (ToF), and truncus arteriosus (TA). However, the effects of percutaneous branch PA interventions on exercise capacity remains largely unknown. In addition, there is no consensus about the optimal timing of the intervention for asymptomatic patients according to international guidelines. This trial aims to identify the effects of percutaneous interventions for branch PA stenosis on exercise capacity in patients with TGA, ToF, and TA. In addition, it aims to assess the effects on RV function and to define early markers for RV adaptation and RV dysfunction to improve timing of these interventions., Methods: This is a randomized multicenter interventional trial. TGA, ToF, and TA patients ≥ 8 years with a class IIa indication for percutaneous branch PA intervention according to international guidelines are eligible to participate. Patients will be randomized into the intervention group or the control group (conservative management for 6 months). All patients will undergo transthoracic echocardiography, cardiac magnetic resonance (CMR) imaging, and cardiopulmonary exercise testing at baseline, 6 months, and 2-4 years follow-up. Quality of life (QoL) questionnaires will be obtained at baseline, 2 weeks post intervention or a similar range for the control group, and 6 months follow-up. The primary outcome is exercise capacity expressed as maximum oxygen uptake (peak VO 2 as percentage of predicted). A total of 56 patients (intervention group n = 28, control group n = 28) is required to demonstrate a 14% increase in maximum oxygen uptake (peak VO 2 as percentage of predicted) in the interventional group compared to the control group (power 80%, overall type 1 error controlled at 5%). Secondary outcomes include various parameters for RV systolic function, RV functionality, RV remodeling, procedural success, complications, lung perfusion, and QoL., Discussion: This trial will investigate the effects of percutaneous branch PA interventions on exercise capacity in patients with TGA, ToF, and TA and will identify early markers for RV adaptation and RV dysfunction to improve timing of the interventions., Trial Registration: ClinicalTrials.gov NCT05809310. Registered on March 15, 2023., (© 2024. The Author(s).)

Background: The interplay between intrauterine and early postnatal environments has been associated with an increased risk of cardiovascular diseases in adulthood, including pulmonary arterial hypertension (PAH). While emerging evidence highlights the crucial role of mitochondrial pathology in PAH, the specific mechanisms driving fetal-originated PAH remain elusive., Methods and Results: To elucidate the role of mitochondrial dynamics in the pathogenesis of fetal-originated PAH, we established a rat model of postnatal catch-up growth following intrauterine growth restriction (IUGR) to induce pulmonary arterial hypertension (PAH). RNA-seq analysis of pulmonary artery samples from the rats revealed dysregulated mitochondrial metabolic genes and pathways associated with increased pulmonary arterial pressure and pulmonary arterial remodeling in the RC group (postnatal catch-up growth following IUGR). In vitro experiments using pulmonary arterial smooth muscle cells (PASMCs) from the RC group demonstrated elevated proliferation, migration, and impaired mitochondrial functions. Notably, reduced expression of Mitofusion 2 (Mfn2), a mitochondrial outer membrane protein involved in mitochondrial fusion, was observed in the RC group. Reconstitution of Mfn2 resulted in enhanced mitochondrial fusion and improved mitochondrial functions in PASMCs of RC group, effectively reversing the Warburg effect. Importantly, Mfn2 reconstitution alleviated the PAH phenotype in the RC group rats., Conclusions: Imbalanced mitochondrial dynamics, characterized by reduced Mfn2 expression, plays a critical role in the development of fetal-originated PAH following postnatal catch-up growth after IUGR. Mfn2 emerges as a promising therapeutic strategy for managing IUGR-catch-up growth induced PAH., (© 2024. The Author(s).)

The main challenges of Biventricular Assist Devices (BiVAD) as a treatment modality for patients with Bicardiac heart failure heart failure are the balance of systemic blood flow during changes in physiological activity and the prevention of ventricular suction. In this study, a model of the Biventricular Circulatory System (BCS) was constructed and a physiological combination controller based on Starling-Like controller and Sliding Mode Controller (SMC) was proposed. The effects of the physiological controller on the hemodynamics of the BCS were investigated by simulating two sets of physiological state change experiments: elevated pulmonary artery resistance and resting-exercise, with constant speed (CS) control and combined Starling-like and PI control (SL-PI) as controllers. Simulation and experimental results showed that the Starling-like and Sliding Mode Control (SL-SMC) physiological combination controller was effective in preventing the occurrence of ventricular suction, providing higher cardiac output, maintain balance of systemic blood flow, and have higher response speed and robustness in the face of physiological state changes., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Studies have shown exercise rehabilitation training improves exercise tolerance in pulmonary arterial hypertension (PAH) patients. However, implementing such programs in developing countries can be challenging. We investigated the benefits of short-term exercise rehabilitation training for PAH patients in a developing country., Methods: This study was a prospective study of adult PAH patients attending the cardiology outpatient unit of a tertiary referral hospital. The patients were equally divided into an intervention group and a control group. We measured hemodynamic characteristics and six-minute walking distance (6MWD) before and after four weeks of exercise rehabilitation training. The Shapiro-Wilk normality test was performed, followed by an independent t -test or Mann-Whitney test to statistically compare the data., Results: We included 28 patients aged 29.1 ± 11 years. We found no significant differences in all hemodynamic characteristics between the groups before and after the rehabilitation (all p -values >0.05). The intervention group showed a significant increase in 6MWD (300.6 ± 90.8 (95% CI: 248.2, 352.9) vs 436.3 ± 58.8 (95% CI: 402.3, 470.2), p -value <0.001) and consequently, the Δ6MWD in the intervention group was remarkably higher (17.1 ± 48.3 (95% CI: -10.8, 44.9) vs 115.36 ± 54.69 m (95% CI: 83.8, 146.9), p -value <0.001)., Conclusion: A short-term exercise rehabilitation training safely improved the exercise tolerance of patients with PAH. Our findings may lead to the improvement of rehabilitation strategies for this detrimental disease in countries with limited resources.