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Circulation Jun 2024Endothelial cell (EC) apoptosis and proliferation of apoptosis-resistant cells is a hallmark of pulmonary hypertension (PH). Yet, why some ECs die and others proliferate...
BACKGROUND
Endothelial cell (EC) apoptosis and proliferation of apoptosis-resistant cells is a hallmark of pulmonary hypertension (PH). Yet, why some ECs die and others proliferate and how this contributes to vascular remodeling is unclear. We hypothesized that this differential response may: (1) relate to different EC subsets, namely pulmonary artery (PAECs) versus microvascular ECs (MVECs); (2) be attributable to autophagic activation in both EC subtypes; and (3) cause replacement of MVECs by PAECs with subsequent distal vessel muscularization.
METHODS
EC subset responses to chronic hypoxia were assessed by single-cell RNA sequencing of murine lungs. Proliferative versus apoptotic responses, activation, and role of autophagy were assessed in human and rat PAECs and MVECs, and in precision-cut lung slices of wild-type mice or mice with endothelial deficiency in the autophagy gene (). Abundance of PAECs versus MVECs in precapillary microvessels was assessed in lung tissue from patients with PH and animal models on the basis of structural or surface markers.
RESULTS
In vitro and in vivo, PAECs proliferated in response to hypoxia, whereas MVECs underwent apoptosis. Single-cell RNA sequencing analyses support these findings in that hypoxia induced an antiapoptotic, proliferative phenotype in arterial ECs, whereas capillary ECs showed a propensity for cell death. These distinct responses were prevented in hypoxic mice or after silencing, yet replicated by autophagy stimulation. In lung tissue from mice, rats, or patients with PH, the abundance of PAECs in precapillary arterioles was increased, and that of MVECs reduced relative to controls, indicating replacement of microvascular by macrovascular ECs. EC replacement was prevented by genetic or pharmacological inhibition of autophagy in vivo. Conditioned medium from hypoxic PAECs yet not MVECs promoted pulmonary artery smooth muscle cell proliferation and migration in a platelet-derived growth factor-dependent manner. Autophagy inhibition attenuated PH development and distal vessel muscularization in preclinical models.
CONCLUSIONS
Autophagic activation by hypoxia induces in parallel PAEC proliferation and MVEC apoptosis. These differential responses cause a progressive replacement of MVECs by PAECs in precapillary pulmonary arterioles, thus providing a macrovascular context that in turn promotes pulmonary artery smooth muscle cell proliferation and migration, ultimately driving distal vessel muscularization and the development of PH.
PubMed: 38873770
DOI: 10.1161/CIRCULATIONAHA.124.068726 -
International Journal of Cardiology.... Sep 2024Limited data exists on upfront combination therapy for portopulmonary hypertension. We evaluated the clinical efficacy, long-term outcomes, and safety of upfront...
BACKGROUND
Limited data exists on upfront combination therapy for portopulmonary hypertension. We evaluated the clinical efficacy, long-term outcomes, and safety of upfront combination therapy in patients with portopulmonary hypertension.
METHODS
We performed a retrospective, single-center cohort study involving a final analysis of 33 consecutive patients diagnosed with portopulmonary hypertension who were taking pulmonary arterial hypertension-specific medication. We compared hemodynamic parameters, risk profiles, composite clinical worsening events, and safety between monotherapy (n = 23) and upfront combination therapy (n = 10).
RESULTS
Twenty-seven patients (82 %) were classified into the Child-Pugh A stage. The change ratios of pulmonary vascular resistance (-32 % vs. -57 %, P = 0.006) were significantly better with upfront combination therapy. Upfront combination therapy also showed significant improvement in risk profiles. Kaplan-Meier analysis showed that the composite event-free rate was significantly lower in patients who received upfront combination therapy than in those who received monotherapy (P = 0.016), although no statistical differences were observed in all-cause death. In the univariate Cox proportional hazards analysis, upfront combination therapy was a factor for decreasing composite clinical worsening outcomes (hazard ratio 0.190, 95 % confidence interval 0.042-0.854; P = 0.030). No significant hepatic impairments were observed over 2 years of follow-up in the upfront combination group.
CONCLUSIONS
In patients with portopulmonary hypertension, upfront combination therapy significantly improved symptoms and short-term hemodynamics, and reduced long-term clinical worsening events without serious adverse effects. This study's findings suggest that patients with portopulmonary hypertension presenting with mild hepatic impairment benefit from upfront combination therapy.
PubMed: 38872733
DOI: 10.1016/j.ijcrp.2024.200294 -
Pulmonary Circulation Apr 2024A blood test identifying patients at increased risk of pulmonary hypertension (PH) could streamline the investigative pathway. The prospective, multicenter CIPHER study...
A blood test identifying patients at increased risk of pulmonary hypertension (PH) could streamline the investigative pathway. The prospective, multicenter CIPHER study aimed to develop a microRNA-based signature for detecting PH in breathless patients and enrolled adults with a high suspicion of PH who had undergone right heart catheterization (RHC). The CIPHER-MRI study was added to assess the performance of this CIPHER signature in a population with low probability of having PH who underwent cardiac magnetic resonance imaging (cMRI) instead of RHC. The microRNA signature was developed using a penalized linear regression (LASSO) model. Data were modeled both with and without N-terminal pro-brain natriuretic peptide (NT-proBNP). Signature performance was assessed against predefined thresholds (lower 98.7% CI bound of ≥0.73 for sensitivity and ≥0.53 for specificity, based on a meta-analysis of echocardiographic data), using RHC as the true diagnosis. Overall, 926 CIPHER participants were screened and 888 were included in the analysis. Of 688 RHC-confirmed PH cases, approximately 40% were already receiving PH treatment. Fifty microRNA (from 311 investigated) were algorithmically selected to be included in the signature. Sensitivity [97.5% CI] of the signature was 0.85 [0.80-0.89] for microRNA-alone and 0.90 [0.86-0.93] for microRNA+NT-proBNP, and the corresponding specificities were 0.33 [0.24-0.44] and 0.28 [0.20-0.39]. Of 80 CIPHER-MRI participants with evaluable data, 7 were considered PH-positive by cMRI whereas 52 were considered PH-positive by the microRNA signature. Due to low specificity, the CIPHER miRNA-based signature for PH (either with or without NT-proBNP in model) did not meet the prespecified diagnostic threshold for the primary analysis.
PubMed: 38868397
DOI: 10.1002/pul2.12386 -
European Heart Journal Supplements :... Apr 2024Patients with advanced heart failure, due to the instability of their clinical conditions, need close surveillance to avoid dangerous exacerbations or sudden events....
Patients with advanced heart failure, due to the instability of their clinical conditions, need close surveillance to avoid dangerous exacerbations or sudden events. Digital technology can be of great help in this contest, thanks to remote monitoring, made possible with the use of wearable or implantable instruments. The latter are currently generally inserted inside defibrillators or resynchronization systems, or inserted inside the pulmonary circulation for monitoring pulmonary pressure. Parameters such as thoracic impedance, physical activity, heart rate variability, atrial and ventricular arrhythmias, blood pressure, and O saturation can be controlled remotely. The data relating to the actual benefit in terms of avoidable events (death and hospitalizations) are not definitive, but certainly from an organizational point of view, the benefit is evident, both on the part of the patient and of the organization of care. The latter, provided in the form of televisits, requires a re-modulation of the system, making use of trained personnel, a well-structured network, and digital technologies (platforms, electronic health records) that are not yet perfectly developed. The evolution of the solutions offered by artificial intelligence guarantees a rapid and progressive refinement of telemedicine in this sector.
PubMed: 38867862
DOI: 10.1093/eurheartjsupp/suae026 -
JMIR Research Protocols Jun 2024Postinduction hypotension (PIHO) is a hemodynamic abnormality commonly observed during the induction of general anesthesia. Etomidate is considered a safer drug for the...
BACKGROUND
Postinduction hypotension (PIHO) is a hemodynamic abnormality commonly observed during the induction of general anesthesia. Etomidate is considered a safer drug for the induction of anesthesia because it has only minor adverse effects on the cardiovascular and pulmonary systems. Recent evidence indicates that the novel benzodiazepine remimazolam has minimal inhibitory effects on the circulation and respiration. However, the efficacy and safety of remimazolam versus etomidate in the induction of anesthesia are unclear.
OBJECTIVE
To further understand the potential of remimazolam in anesthesia induction, it is necessary to design a meta-analysis to compare its effects versus the classic safe anesthetic etomidate. The aim of this study is to determine which drug has more stable hemodynamics and a lower incidence of PIHO. Our study will also yield data on sedation efficiency, time to loss of consciousness, time to awakening, incidence of injection pain, and postoperative nausea and vomiting with the two drugs.
METHODS
We plan to search the Web of Science, Cochrane Library, Embase, PubMed, China National Knowledge Infrastructure, and Wanfang databases from the date of their creation until March 31, 2025. The language is limited to English and Chinese. The search terms are "randomized controlled trials," "etomidate," and "remimazolam." The incidence of PIHO is the primary outcome measure. Secondary outcomes include depth of anesthesia after induction, sedation success rate, time to loss of consciousness, hemodynamic profiles, recovery time, incidence of injection pain, and postoperative nausea and vomiting. Reviews, meta-analyses, case studies, abstracts from conferences, and commentaries will not be included. The heterogeneity of the results will be evaluated by sensitivity and subgroup analyses. RevMan software and Stata software will be used for data analysis. We will evaluate the quality of included studies using version 2 of the Cochrane risk-of-bias tool. The confidence of the evidence will be assessed through the Grading of Recommendations, Assessments, Developments, and Evaluations system.
RESULTS
The protocol was registered in the international PROSPERO (Prospective Register of Systematic Reviews) registry in November 2023. As of June 2024, we have performed a preliminary article search and retrieval for further review. The review and analyses are expected to be completed in March 2025. We expect to submit manuscripts for peer review by the end of June 2025.
CONCLUSIONS
By synthesizing the available evidence and comparing remimazolam and etomidate, we hope to provide valuable insights into the selection of anesthesia-inducing drugs to reduce the incidence of PIHO and improve patient prognosis.
TRIAL REGISTRATION
PROSPERO CRD42023463120; https://tinyurl.com/333jb8bm.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID)
PRR1-10.2196/55948.
Topics: Etomidate; Humans; Systematic Reviews as Topic; Anesthesia, General; Meta-Analysis as Topic; Benzodiazepines; Anesthetics, Intravenous
PubMed: 38865185
DOI: 10.2196/55948 -
Clinical and Translational Medicine Jun 2024Patients with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) have an increased risk of disease exacerbation and decreased survival. We...
BACKGROUND
Patients with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) have an increased risk of disease exacerbation and decreased survival. We aimed to develop and validate a non-invasive nomogram for predicting COPD associated with severe PH and a prognostic nomogram for patients with COPD and concurrent PH (COPD-PH).
METHODS
This study included 535 patients with COPD-PH from six hospitals. A multivariate logistic regression analysis was used to analyse the risk factors for severe PH in patients with COPD and a multivariate Cox regression was used for the prognostic factors of COPD-PH. Performance was assessed using calibration, the area under the receiver operating characteristic curve and decision analysis curves. Kaplan-Meier curves were used for a survival analysis. The nomograms were developed as online network software.
RESULTS
Tricuspid regurgitation velocity, right ventricular diameter, N-terminal pro-brain natriuretic peptide (NT-proBNP), the red blood cell count, New York Heart Association functional class and sex were non-invasive independent variables of severe PH in patients with COPD. These variables were used to construct a risk assessment nomogram with good discrimination. NT-proBNP, mean pulmonary arterial pressure, partial pressure of arterial oxygen, the platelet count and albumin were independent prognostic factors for COPD-PH and were used to create a predictive nomogram of overall survival rates.
CONCLUSIONS
The proposed nomograms based on a large sample size of patients with COPD-PH could be used as non-invasive clinical tools to enhance the risk assessment of severe PH in patients with COPD and for the prognosis of COPD-PH. Additionally, the online network has the potential to provide artificial intelligence-assisted diagnosis and treatment.
HIGHLIGHTS
A multicentre study with a large sample of chronic obstructive pulmonary disease (COPD) patients diagnosed with PH through right heart catheterisation. A non-invasive online clinical tool for assessing severe pulmonary hypertension (PH) in COPD. The first risk assessment tool was established for Chinese patients with COPD-PH.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Male; Female; Hypertension, Pulmonary; Risk Assessment; Aged; Middle Aged; Nomograms; Prognosis; Risk Factors
PubMed: 38861300
DOI: 10.1002/ctm2.1702 -
Circulation Jun 2024
Correction to: Status and Future Directions for Balloon Pulmonary Angioplasty in Chronic Thromboembolic Pulmonary Disease With and Without Pulmonary Hypertension: A Scientific Statement From the American Heart Association.
PubMed: 38857331
DOI: 10.1161/CIR.0000000000001261 -
Frontiers in Immunology 2024This study aimed to employ plasma proteomics to investigate the molecular changes, pathway alterations, and potential novel biochemical markers associated with balloon...
BACKGROUND
This study aimed to employ plasma proteomics to investigate the molecular changes, pathway alterations, and potential novel biochemical markers associated with balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH).
METHODS
Pre- and post-BPA plasma samples from five CTEPH patients in the PRACTICE study were analyzed to identify differentially expressed proteins. Proteomic and bioinformatics analyses were conducted, and the identified proteins were further validated using ELISA assays in a separate cohort of the same study. Correlation and multivariate regression analyses were performed to investigate the associations between these differentially expressed proteins and clinical parameters.
RESULTS
Significantly higher serum levels of asialoglycoprotein receptor 2 (ASGR2) were detected in 5 CTEPH patients compared to those in healthy individuals but decreased significantly after successful BPA procedures. The decrease in serum levels of ASGR2 after the completion of BPA procedures was further validated in a separate cohort of 48 patients with CTEPH [0.70 (0.51, 1.11) ng/mL vs. 0.38 (0.27, 0.59) ng/mL, < 0.001]. Significant associations were found between the pre-BPA ASGR2 level and clinical parameters, including neutrophil percentage (R = 0.285, < 0.05), platelet (PLT) count (R = 0.386, < 0.05), and high-density lipoprotein cholesterol (HDL-C) before BPA (R = -0.285, < 0.05). Significant associations were detected between post-BPA serum ASGR2 levels and lymphocyte percentage (LYM%) (R = 0.306, < 0.05), neutrophil-to-lymphocyte ratio (R = -0.294, < 0.05), and pulmonary vascular resistance after BPA (R = -0.35, < 0.05). Multivariate stepwise regression analysis revealed that pre-BPA ASGR2 levels were associated with HDL-C and PLT count (both < 0.001), while post-BPA ASGR2 levels were associated with LYM% ( < 0.05).
CONCLUSION
Serum levels of ASGR2 may be a biomarker for the effectiveness of BPA treatment in CTEPH patients. The pre-BPA serum level of ASGR2 in CTEPH patients was associated with HDL-C and the PLT count. The post-BPA serum level of ASGR2 was correlated with the LYM%, which may reflect aspects of immune and inflammatory status.
Topics: Humans; Male; Hypertension, Pulmonary; Female; Biomarkers; Angioplasty, Balloon; Middle Aged; Pulmonary Embolism; Aged; Proteomics; Chronic Disease
PubMed: 38855107
DOI: 10.3389/fimmu.2024.1402250 -
Pulmonary Circulation Apr 2024Prostacyclin therapy is a mainstay of the management of pulmonary arterial hypertension (PAH). Inhaled prostacyclins present safe and effective options for the...
Prostacyclin therapy is a mainstay of the management of pulmonary arterial hypertension (PAH). Inhaled prostacyclins present safe and effective options for the management of PAH that limit systemic side effects. We describe the first reported case of life-threatening bronchospasm and acute respiratory failure associated with inhaled prostacyclin administration.
PubMed: 38854955
DOI: 10.1002/pul2.12396 -
Kardiologia Polska Jun 2024
PubMed: 38845432
DOI: 10.33963/v.phj.100678