bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex differences in in-hospital management and outcomes of patients with acute pulmonary embolism
Authors: Becattini C , Savonitto S , De Laura D , Ameri P , Fiorini R , Cinelli F , Ubaldi S , Forgione C , Numoli N , Predieri S , Romaniello A , Fabbri A , Enea I , Agnelli G , Gulizia M M 
Published: October 2024

Abstract

Background
Acute pulmonary embolism (PE) is a life-threatening disease with specific risk factors among women. Systematic evaluation of contemporary quality of care and outcomes in women hospitalized with acute PE is needed.

Methods
The COPE Registry (COntemporary management of acute Pulmonary Embolism) is a nationwide registry that was run in Internal Medicine, Cardiology and Emergency Departments in Italy. Using data from the COPE Registry, we evaluated sex differences in acute management, medical therapies, in-hospital and 30-day mortality and major bleeding in 5,213 patients admitted for acute PE at 182 hospitals in Italy from 2018 to 2020.

Results
Women (n=2,728) were older than men (71.2 versus 66.6 years, P&lt;0.001) and had different distribution of comorbidities, with dementia and severe renal failure being more prevalent (13.6 vs 6.4% and 6.1 vs 3.0%, respectively) and cancer, COPD and recent bed-rest less prevalent (15.2 vs 18.5% and 11.1 vs 14.5% and 23.5 vs 20.2%) in women than men. At presentation, PE was more severe in women than men in terms of hemodynamic instability (4.1 vs 2.7%), prevalence of right ventricle overload at echocardiography (64.5 vs 57%) and prevalence of sPESI=0 (29.4 vs 38.5%). Concerning the likelihood to receive evidence-based acute treatments for PE, women were more likely than men to receive reperfusion in the case of hemodynamic compromise at presentation after adjusting for age and dementia (63.1 vs 50.0%; OR 1.934, 95% CI 1.01-3.71), and to receive direct oral anticoagulants during hospitalization after adjusting for age, dementia and severe renal failure (50.9 vs 48.6%; OR 1.14, 95% CI 1.01-1.28); similar proportions of low-risk women and men were managed as outpatients or by short hospital stay (1.4% vs 1.4% and 8.6 vs 6.0%, respectively). In-hospital and 30-day mortality rates were not different in women and in men (3.7% versus 3.1% and 5.5 vs 4.8%), but PE-related mortality was higher in women than in men (2.1 vs 1.3%). The sex difference in PE-related mortality was no longer observed in after adjusting for age, hemodynamic instability and dementia (adjusted HR 1.20; 95% CI 0.77-1.88; P=0.415). Similar rates of early and delayed major bleedings occurred in women and in men, both at univariate analysis and after adjusting for age, creatinine clearance and use of thrombolysis. None of 22 pregnant women and 1 out of 204 women with estro-progestin associated PE died or experienced major bleeding.

Conclusions
Women hospitalized for acute PE in Italy received evidence-based acute treatments more commonly than men. The observed sex differences in PE-related mortality were mainly attributable to worse clinical profiles and older age. Women with sex-related risk factor for PE had favorable prognosis.
Continuous heart monitoring to evaluate treatment effects in pulmonary hypertension
Authors: Andersen M 
Published: October 2024

Abstract

Background
The treatment of pulmonary hypertension (PH) has improved rapidly in recent years, and there is increasing evidence to support the role of early intervention. However, studies demonstrate that timely intervention is often still lagging which affects clinical outcomes in patients with PH.

Purpose
To assess treatment effects after escalation of specific PH treatments using continuous heart monitoring via a Reveal LINQ loop recorder.

Methods
The patients change in heart rate variability (HRV), heart rate (HR), and physical activity were assessed before and after treatment escalation. Treatment escalation was defined as an additional PAH drug, pulmonary endarterectomy (PEA), percutaneous balloon angioplasty (PBA), or bilateral lung transplantation (BLTX).

Results
In this prospective study, 41 patients (27 with PAH and 14 with chronic thromboembolic pulmonary hypertension) were enrolled. Among them, 15 patients (36.6%) underwent PH treatment escalation. Prior to escalation, patients were monitored for a median of 100 (range: 68–100) days and after therapy escalation for a median duration of 165 (range: 89–308) days. In the escalation group, a significant increase in HRV (Figure), physical activity indexed by daytime HR was observed, while a significant decrease was seen in nighttime HR assessed at baseline and after treatment escalation. These changes were found both in the PAH and CTEPH group. In parallel a significant improvement in WHO functional class, 6-minute walking distance, and N-terminal pro-b-type natriuretic peptide (NT-proBNP) was observed.

Conclusions
This is the first study to demonstrate a direct association between specific PH therapies and changes in HRV, HR nighttime and physical activity in patients with PAH and CTEPH. Continuous monitoring allows for an early intervention with supplementary treatment for PH. This is especially relevant considering the increasing availability of wearables that allow for a convenient measurement of relevant prognostic parameters in PH.
Age-dependent changes in cardiac output following balloon pulmonary angioplasty: Implications for combination therapy in chronic thromboembolic pulmonary hypertension
Authors: Shimokawahara H , Kanezawa M , Matsubara H 
Published: October 2024

Abstract

Background
Balloon pulmonary angioplasty (BPA) is an accepted treatment for patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, some patients still have exercise intolerance even after normalizing mean pulmonary arterial pressure with BPA. Although medical therapy may be a potential option for such patients, it cannot be necessary for all patients. Low cardiac output (CO) after BPA is associated with exercise intolerance. However, the change in CO with BPA could be affected by the patient’s age and pulmonary hypertension (PH) medication status. The specific patients’ characteristics that require medical therapy following BPA remain unknown.

Methods
This single-centre, retrospective observational study included 286 patients with CTEPH who underwent BPA and right heart catheterization one year BPA at our hospital. The patients were classified into three age groups (younger: age &lt; 60 years, n=91; middle-aged: 60 ≤ age &lt; 70 years, n=91; elderly: 70 years ≤ age, n=104), and also stratified by two groups based on PH medication status (Group 1: patients without PH medications before and after BPA, Group 2: patients who received PH medications before BPA and discontinued them after BPA). CO and its percent change were compared between Groups 1 and 2 in each age group.

Results
CO increased significantly in the younger group (4.3±0.2 to 4.5±0.1 L/min, p=0.040) and decreased in the elderly group (4.0±0.1 to 3.8±0.1 L/min, p=0.035), resulting in no significant change overall. CO in the younger and middle-aged groups significantly increased after BPA in Group 1, whereas in Group 2, those in the middle-aged and elderly groups significantly decreased after BPA. The percent CO changes declined in an age-dependent manner in both groups.

Conclusions
Increasing CO with BPA alone may be challenging in elderly patients. Adjuvant medical therapy might be necessary, even after successful BPA, especially in elderly patients.Percent change in CO stratified by age
Quantitative perfusion by cardiac magnetic resonance analysis reveals compromised myocardial perfusion in patients with angina with non-obstructive coronary artery disease
Authors: Vink C E M , Borodzicz-Jazdzyk S , De Jong E A M , Woudstra J , Van De Hoef T P , Chamuleau S A J , Eringa E C , Gotte M J W , Appelman Y 
Published: October 2024

Abstract

Introduction
Stress perfusion cardiac magnetic resonance (CMR) visually detects myocardial ischemia through first-pass contrast-enhanced imaging by identifying perfusion defects. However, in generalized myocardial diseases like angina with non-obstructed coronary arteries (ANOCA), visual assessment becomes challenging due to diffuse sub-endocardial perfusion defects, or the findings may even falsely appear normal. Fully automated quantitative perfusion (QP), allowing absolute quantification of myocardial blood flow (MBF) and deriving myocardial perfusion reserve (MPR), might increase diagnostic accuracy in ANOCA patients. Therefore, the purpose of this study is to test the use of QP in detecting ANOCA diagnosed by the invasive golden standard.

Methods
This study is a cross-sectional cohort study assessing the use of fully automated QP CMR in patients with ANOCA compared with age- and sex-matched healthy controls. All participants underwent adenosine stress perfusion CMR, including visual assessment and quantification of MBF and MPR. Furthermore, all ANOCA patients underwent intracoronary function testing (ICFT) to idenity vasospasm and/or coronary microvascular dysfunction.

Results
This study included 24 ANOCA patients (83% women, 56.8±8.9 years) and 25 healthy controls (80% women, 56.2±7.2 years). Visual perfusion assessment showed no group differences in terms of perfusion defects (p=0.536). However, in QP, ANOCA patients had higher relative MBF than healthy controls (0.83±0.15 vs 0.74±0.17, p=0.046), while global perfusion was significantly lower during stress (2.43±0.72 vs 2.99±0.65 ml/g/min, p=0.006). Moreover, ANOCA patients had significantly lower MPR than healthy controls (2.24 ±0.79 vs 2.68 ±0.64, respectively p=0.036), with a higher prevalence of an impared MPR (50% vs. 20%, p=0.027). MPR was not significantly different between the various ANOCA entities as stratified during ICFT (p=0.766).

Conclusions
ANOCA patients displayed significantly reduced MPR, indicating impaired perfusion. The prevalence of diminished MPR was higher in the ANOCA group compared to the healthy controls, constrasting with no differences in visual assessment. These results are promising and underscores the possibilities of the use of QP in detecting vasomotor dysfunction non-invasively in ANOCA patients.Quantitative Perfusion by CMR results
Comprehensive bioinformatic analysis identified m6A methylation as an important regulator in mediating immune response during idiopathic pulmonary arterial hypertension
Authors: Liu N , Zeng Y H , Huang T , Zuo W Y , Xiao Y B , Li B , Xiao Z H , Peng B , Liu Y Z , Liu Q M 
Published: October 2024

Abstract

Background
Despite its functional importance in various fundamental bioprocesses, studies of N6-methyladenosine (m6A) in the pulmonary arterial hypertension (PAH) are lacking. Here we studied the potential relevance of m6A RNA methylation and immune response in PAH development.

Methods
We constructed a monocrotaline (MCT) induced PAH rat model and performed Methylated RNA immunoprecipitation sequencing (MeRIP-Seq). The 18 idiopathic PAH (IPAH) microarray data obtained from the GEO database was used to construct co-expression networks by weighted gene co-expression network analysis (WGCNA). CIBERSORT was used to investigate the effect of m6A methylation on immune cell infiltration during PAH.

Results
A differential pattern of m6A abundance, mainly up-methylation, was observed in the lung tissues of rats with MCT induced PAH. By WGCNA, multi-list pathway enrichment analysis and protein-protein interaction (PPI) analysis, we found that m6A methylation modification may play important roles in mediating immune response during PAH. CYBERSORT algorithm indicated that the m6A methylation can drive monocyte to form M1 macrophage, which may be mediated by CCR5 and CXCL9.

Conclusion
Collectively, m6A landscape is altered in PAH. We summarize newly discovered m6A in controlling immune response, which caused activation of M1 macrophage during PAH. It’s provided a novel insight into the therapeutic mechanisms of PAH.
Long-standing response to calcium channel blocker therapy on patients with various types of pulmonary hypertension: a systematic review and meta analysis
Authors: Santos B , Ramos F O , Salton Y D , Coutinho M 
Published: October 2024

Abstract

Background
It is widely acknowledged that the extended use of calcium channel blocker (CCBs) therapy in patients diagnosed with Idiopathic Pulmonary Arterial Hypertension (IPAH), Heritable Pulmonary Arterial Hypertension (HPAH), or Drug- or Toxin-Associated Pulmonary Arterial Hypertension (DPAH) who exhibit a positive acute vasoreactivity test (VdT+) provides benefits to patients. However, this practice is supported by a limited body of evidence in the scientific literature, mainly derived from expert consensus and/or small-scale studies, retrospective analyses, and registries, as per the European Society of Cardiology (ESC) guidelines.

Objectives
We performed a meta-analysis to evaluate the long-standing response to CCBs in patients diagnosed with various forms of pulmonary hypertension.

Design
We conducted searches in PubMed, Embase, and Cochrane to select both randomised and non-randomised studies. The primary outcomes of interest identified were Mean Pulmonary Artery Pressure (mPAP), 6-minute walk distance (6MWD), Cardiac Index (CI), Mean Right Atrial Pressure (mRAP), and Mixed venous oxygen saturation (SvO₂) measured at the beginning and end of the studies. Additionally, we performed subgroup analyses for all outcomes based on age groups: ≤18 years and &gt;18 years. Statistical analysis was carried out using OpenMeta[Analyst] 12.11.14, and heterogeneity was assessed using I² statistics.

Results
We identified 7 non-randomised studies comprising a total of 131 patients with an average follow-up duration of 2.74 (1.3) years. The following are the mean values observed for individual outcomes: mPAP (33.1 mmHg; 95% CI [31.6, 34.6]; p &lt; 0.001; I²=0%), 6MWD (470.1 m; 95% CI [452.6, 487.7]; I²=0%), Cardiac index (3.8 L/min/m²; 95% CI [3.6, 4.0]; I²=0%), mRAP (4.2 mmHg; 95% CI [3.6, 4.8]; I²=0%) and SvO₂ (73.9%; 95% CI [72.5, 75.3]; I²=0%) in patients with positive acute vasoreactivity test (VdT+) treated long-term with CCBs. Additionally, at study initiation, we found the following means: mPAP (51.2 mmHg; 95% CI [49.3, 53.0]; I²=0%), 6MWD (428.4 m; 95% CI [410.3, 446.6]; I²=0%), Cardiac index (2.8 L/min/m²; 95% CI [2.7, 2.9]; I²=0%), mRAP (6.4 mmHg; 95% CI [5.6, 7.2]; I²=0%), and SvO₂ (68.5%; 95% CI [66.5, 70.5]; I²=0%).

Conclusion
The findings from this meta-analysis suggest that in VdT+ patients, the means of certain haemodynamic parameters with long-standing use of CCBs are similar or nearly similar to those of patients without any subtype of PAH. These results align with current guidelines and reinforce their level of evidence.
Comparison of pulmonary arterial risk assessment tools to predict mortality or morbidity in treatment naive and previously diagnosed patients
Authors: Fauvel C , Liu Y , Correa-Jaque P , Everett A , Perer A , Kanwar M , Vanderpool R , Kraisangka J , Lin S , Benza R L 
Published: October 2024

Abstract

Background
Pulmonary arterial hypertension (PAH) risk stratification (1-year prediction of risk) is crucial and should be the most accurate to ensure appropriate aggressiveness of the treatment choices. According to the European guidelines, several risk tools can be used both at baseline and/or follow-up assessment. Yet, a comparison of risk tools performances only in treatment-naïve or only previously diagnosed patients is still missing.

Aims
To compare the available risk assessment tools performances to predict 1-year mortality but also 1-year clinical worsening in treatment-naïve and previously diagnosed PAH patients.

Methods
Eight PAH trials (AMBITION, ARIES1, ARIES2, FREEDOM, GRIPHON, PATTENT, PHIRST and SERAPHIN) provided by the FDA were harmonized and treatment-naïve patients were separated from previously diagnosed patients. Outcomes were 1-year mortality and 1-year clinical worsening (i.e., morbidity) either from baseline assessment or at follow-up. Kaplan-Meier and log-rank tests were performed for each of the following risk tools: European 4-strata, REVEAL2.0, REVEAL Lite, noninvasive FRENCH. In each subgroup, their C-indices were calculated and compared using a total of 100 bootstrap samples from the original data, providing a robust method for comparing across the different tools.

Results
Among the 4,122 patients included, 1,701 (41%) were treatment-naïve and 2,411 (59%) were previously diagnosed patients. Compared to treatment naïve patients, previously diagnosed patients were younger (p&lt;0.001), with lower level of natriuretic peptide (p=0.013), higher 6MWD (p&lt;0.001) and higher mPAP (p&lt;0.001). At 1-year, the mortality rate was the same in the 2 subgroups (5.6% 5.1%, p=0.05) but clinical worsening occurred more often among previously diagnosed patients (19% vs 8.4%, p&lt;0.001). Each of the risk tools were able to predict both 1-year mortality or morbidity in each subgroup, especially among previously diagnosed or at follow-up, with fair to good C-index (Figure 1). Forrest plots of 95%CI for the C-index differences among the 100 bootstrap samples showed that REVEAL 2.0 was the best performer, followed by REVEAL Lite (Figure 2).

Conclusions
In this large dataset, we showed that all PAH risk tools were able to predict not only 1-year mortality but also 1-year morbidity, both in treatment naïve and previously diagnosed patients. REVEAL 2.0 depicted the higher C-index.Figure 1.C-index for PAH risk toolsFigure 2.Forrest plots of 95%CI
The safety and efficacy of treprostinil for the treatment of pulmonary arterial hypertension: a systematic review and meta-analysis of randomized controlled trials
Authors: Khasawneh H , Alqudah M , Zaitoun K , Al-Malkawi F , Aldalal'ah M , Alzghoul B 
Published: October 2024

Abstract

Introduction
Pulmonary arterial hypertension (PAH) is a severe and life-threatening condition characterized by increased pulmonary vascular resistance and elevated mean pulmonary artery pressure. Treprostinil, a prostacyclin analog, has vasodilatory and anti-remodeling effects on pulmonary arterial smooth muscle cells, indicating promising benefits in enhancing exercise capacity, improving hemodynamics, and reducing morbidity in patients with PAH.

Aim
The primary objective of this systematic review and Meta-analysis is to assess the efficacy and safety of Treprostinil in patients with PAH.

Methods
We systematically searched PubMed, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov from inception until July 2023. Randomized controlled trials comparing Treprostinil with Placebo were selected. We used the mean values to compare continuous data and odds ratio (OR) for dichotomous outcomes with their 95% confidence interval (CI).

Results
We included 7 studies with a total of 2,447 patients. The Treprostinil group was favored over the control group in terms of 6-minute walk distance (6MWD) (Mean difference (MD), meters (m)) (MD = 15.16 m, 95% confidence interval (CI) (10.42 – 19.90 )). Subgroup analysis based on the route of administration revealed a 6MWD of (MD = 13.55 m (95% CI (7.82 – 19.28)) for oral administration and (MD = 17.49 m, 95% CI (6.01 – 28.89)) for intravenous (IV)/subcutaneous (SC) administration, indicating enhanced exercise capacity. When evaluating the efficacy of Treprostinil for oral administration, there was a slight but non-significant trend toward functional improvement (Odds Ratio (OR): 1.36; 95% CI: 0.95 to 1.93) and no significant change in maintaining functional status (OR: 0.94; 95% CI: 0.59 to 1.51). In terms of functional deterioration, the risk was also not significantly reduced (OR: 0.84; 95% CI: 0.36 to 1.98). Safety assessment of the drug was based on clinical, mortality, and adverse events outcomes. Clinically, Treprostinil demonstrated a protective effect against disease progression, evidenced by a reduced risk of clinical worsening (OR: 0.69; 95% CI: 0.52 to 0.91). Mortality rates were not significantly impacted by Treprostinil addition (OR: 0.95; 95% CI: 0.57 to 1.58 for oral, 0.80; 95% CI: 0.32 to 1.98 for IV/SC). However, the incidence of adverse events was notably higher among Treprostinil-treated patients, particularly with oral administration.

Conclusion
The addition of Treprostinil therapy for patients with PAH significantly improved exercise capacity, as evidenced by an increase in the 6MWD compared to control groups and demonstrated a reduced risk of clinical worsening. The incidence of adverse events was higher among Treprostinil-treated patients, especially with oral administration, potentially impacting quality of life.Forest plot of the 6MWD
Oral low-dose rapamycin treatment prevents aortic aneurysms in marfan mice
Authors: Zaradzki M , Zwaans V , Soethoff J , Piluso A , Burhenne J , Karck M , Hecker M , Wagner A H 
Published: October 2024

Abstract

Background/Introduction
Marfan syndrome (MFS) is a hereditary connective tissue disorder caused by fibrillin-1 (FBN1) gene mutations. Life-threatening complications are cardiovascular, e.g. thoracic aortic aneurysms and dissections. The pathophysiological cause is the increased release of transforming growth factor β-1 (TGF-β1) from the FBN1-deficient extracellular matrix (ECM) and structural disintegrity. Overactivation of the mechanistic target of rapamycin (mTOR) pathway has been demonstrated in the murine mgR/mgR model of MFS. Short-term administration of rapamycin significantly reduced aortic aneurysm formation and increased the life span in these mice.

Purpose
To assess the effect of an early continuous oral low-dose rapamycin treatment on the aortic aneurysm formation in the FBN1 hypomorphic mgR/mgR mouse model.

Methods
Male and female 3-4 week-old mgR/mgR mice were orally administered vehicle or rapamycin through diet (8mg/kg/KG) and sacrificed after 11 weeks. Rapamycin concentration was measured by liquid chromatography-mass spectrometry in whole blood. Aortic diameter was studied using echocardiography. Histopathological and immunofluorescence analyses were performed using aortic tissue sections and techniques.

Results
Blood rapamycin concentration following oral administration remained below detection level. Rapamycin normalized the aortic wall thickness and the diameter in female mgR/mgR mice to levels of the littermate control mice but not in male mgR/mgR mice. The circumferentially distributed elastin fibres remained significantly intact in sections of the ascending aorta of female mice. Echocardiography revealed that rapamycin-treated female mice stayed below a cut-off value for aortic aneurysms of 2 mm inner aortic diameter eight weeks after starting therapy. In contrast, vehicle-treated female animals already exceeded this value after five weeks.
In female but not in male mice, the abundance of the mTOR downstream target phosphorylated ribosomal protein S6 was effectively suppressed by low-dose rapamycin up to levels detected in control animals. At the same time, extracellular matrix proteins like the proteoglycan aggrecan (ACAN) and the related chondroitin sulfate were significantly decreased in female mice. The abundance of ADAMTS5 transglutaminase-2 and xylosyltransferase-1, key enzymes involved in the turnover of proteoglycans and biosynthesis of glycosaminoglycan chains, was improved by the rapamycin treatment in female mice. No decrease in mTOR activity could be detected in male mgR/mgR animals. Here, the ACAN and chondroitin sulphate levels also remained at the level of the vehicle-treated animals.

Conclusions
Chronic low-dose rapamycin treatment reduced aneurysm formation only in female mgR/mgR mice, since the dose was too low for male mgR/mgR mice, by affecting the composition and organization of key ECM components essential for maintaining aortic homeostasis and mechanical properties.