bluuebunny/crossref_metadata_2025 huggingface dataset:
Positioning Imatinib for Pulmonary Arterial Hypertension (PIPAH) study
Authors: Rothman A , Villar S , Middleton J , Law M , Varian F , Zafar H , Kiely D G , Roussakis A , Howard L , Toshner M , Wort J , Wilkins M
Published: October 2024

Introduction

Pulmonary arterial hypertension (PAH) is characterised by pre-capillary pulmonary vascular remodelling. Imatinib, a tyrosine kinase inhibitor, was the first treatment investigated in PAH patients with the primary aim of targeting vascular remodelling. A Phase 3 study showed that imatinib 400mg daily reduces pulmonary vascular resistance and increases exercise capacity but only 43% of patients continued the drug for 6 months. Concerns about safety prevented regulatory approval.

Purpose

To identify a safe and tolerated dose of oral Imatinib and evaluate efficacy in the dose range 100-400mg daily.

Methods

Oral Imatinib was added to the background therapy of 17 patients with PAH; prior intracranial haemorrhage was excluded by cross sectional imaging and none were receiving an anticoagulant. The first patient started on 100mg daily. The next 12 patients were recruited serially at a minimum of 4 week intervals and started on 200mg, 300mg or 400mg, according to a Bayesian adaptive design (Continuous Reassessment Method, CRM). Patients 14-17 were recruited as an extension cohort to better understand the safety and tolerability of the 100mg and 200mg doses. The primary endpoint was safety and tolerability at 4 weeks. Imatinib was continued for up to 24 weeks. Thirteen patients had implanted devices that provided remote daily measurements of cardiopulmonary haemodynamics and heart rate and rhythm and physical activity. Non-invasive measures of systemic blood pressure, weight and oxygen saturations were made remotely. We compared the time-haemodynamic response relationship with that produced by licensed treatments in a similar patient cohort.

Results

The recommended starting dose from the CRM was 200mg daily. The most common side effect was nausea. Imatinib reduced mean pulmonary artery pressure (P<0.01), increased cardiac output (P=0.08) and reduced total pulmonary resistance (TPR, P<0.001, Figure). There was a clear dose-TPR response relationship (r2=0.52, p<0.01). A reduction in TPR was evident within the first week and plateaued at 4-5 weeks. Withdrawal of Imatinib led to an increase to baseline in TPR over 4-5 weeks. This contrasts with a sharp fall in TPR with licensed therapy and rapid increase on treatment withdrawal. There was a small reduction in systemic vascular resistance (P<0.05) with Imatinib that reached plateau before TPR.

Conclusions

Oral Imatinib 200mg daily is well tolerated and effective as an add-on treatment in PAH. The time course of the initial haemodynamic response and the gradual return to baseline on withdrawal distinguishes Imatinib from licensed treatments and is supportive of a mechanism of action beyond reliance on vasodilation. Remote monitoring enables the safe evaluation of the withdrawal of an investigational drug in patients established on best medical therapy.Figure 1.
Mitigating health disparities by improving access to catheter-based therapies for vulnerable patients with acute pulmonary embolism
Authors: Bailey E , Zhang R , Keller N , Yuriditsky E , Elbaum L , Greco A , Postelnicu R , Hena K , Mukherjee V , Hall S , Alviar C , Bangalore S
Published: October 2024

Introduction

This study explores the implementation and outcomes of catheter-based thrombectomy (CBT) in acute pulmonary embolism (PE) within a safety-net hospital (SNH), addressing a critical gap in the literature concerning CBT in underserved and vulnerable populations.

Methods

This is a retrospective study of patients undergoing CBT between October 2020 and January 2024 at a SNH. The primary outcome was 30-day all-cause mortality.

Results

A total of 107 patients (47.6% female, mean age 58.4 years) underwent CBT for acute PE, with 23 (21.5%) high-risk and 84 (78.9%) intermediate-risk PE. Demographically, 64% identified as Black, 10% White, 19% Hispanic or Latino, and 5% Asian. In terms of insurance coverage, 50% had private insurance or Medicare, 36% had Medicaid, and 14% were uninsured. Notably, 67% of the patients resided in high poverty rate zip codes and 11% were non-citizen non-residents. Markers of risk severity, such as biomarkers (troponin, BNP), PE risk classification (high versus intermediate-risk), rates of low CI, lactate level, CPES/sPESI score, and rates of RV dysfunction did not vary significantly across race/ethnic groups, insurance status, level of poverty and citizenship status. Over a median follow up period of 30 days, 6 (5.6%) patients expired (all high-risk PE), 3 of which presented with cardiac arrest. No patients who presented with intermediate-risk PE died at 30 days. There was no difference in 30-day mortality based on race, insurance type, poverty level or citizenship status.

Conclusion

The findings emphasize the feasibility and success of implementing PERT and CBT at a SNH, offering a potential model to address healthcare disparities in acute PE on a broader scale.
Ultrasound assisted, catheter-directed thrombolysis for acute intermediate-high and high risk pulmonary embolism: focus on safety for oncological patients
Authors: Colombo C , Lorenzo Tua L T , Luca Villanova L V , Giovanna Viola G V , Marco Solcia M S , Antonio Rampoldi A R , Chiara Tognola C T , Francesco Musca F M , Nicolo Capsoni N C , Filippo Russo F R , Mario Iannaccone M I , Fabrizio Oliva F O , Andrea Garascia A G , Alice Sacco A S
Published: October 2024

Background

Catheter-based revascularization procedures have been developed as an alternative to systemic thrombolysis or surgical embolectomy for intermediate-high and high risk pulmonary embolism (PE) patients with. Little is known about the outcomes of oncological patients, who are notably at higher bleeding risk, undergoing such procedure.

Purpose

The USAT IH-PE registry is a retrospective and prospective multicenter registry of patients treated with ultrasound-facilitated, catheter-directed thrombolysis. We sought to determine whether patients with active cancer experience more bleeding complications and need for transfusions.

Methods: Between March 2018 and July 2023, 102 patients were included. The majority were at intermediate–high-risk PE (86%), mostly female (57%), with a mean age of 63.7 ± 14.5 years. Most patients (77.8%) had a bilateral involvement of the main pulmonary arteries on CT scan and 9 patients (8.8%) had at least one prior episode of PE. 28.4% had active cancer. We compared the oncological and non-oncological subpopulations. The primary endpoints were bleeding complications (defined as BARC > IIIa) and need for transfusion.

Results

Overall, 12% of patients experienced bleeding complications, of which 4.9% were BARC ≥ 3. When comparing bleeding complications, defined as BARC > IIIa or the need for transfusion, no significant difference was found between patients with active cancer and those without (OR 0.61, 95% CI 0.01-6.62, p=1, and OR 2.43, 95% CI 0.61-9.48, p=0.18, respectively).

Conclusions

In the USAT IH-PE registry, where a significant proportion of patients have active cancer, no significant difference in bleeding complications was observed in these subjects. This finding confirms the safety of the procedure, even in a subpopulation traditionally considered at higher risk for bleeding.
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

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<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

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

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 < 60 years, n=91; middle-aged: 60 ≤ age < 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

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

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

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 >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 < 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

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<0.001), with lower level of natriuretic peptide (p=0.013), higher 6MWD (p<0.001) and higher mPAP (p<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<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

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

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.
Mechanosensitive Ion Channel Piezo1 regulates tight junctions between endothelium and mediates the occurrence of aortic dissection
Authors: Teng P , Chen Z H , Ma L
Published: October 2024

Aims

Exploring whether changes in endothelial Piezo1 mechanically sensitive ion channels can lead to thoracic aortic dissection（TAD） and its specific mechanisms of action.

Methods and results

IF showed aberrant Piezo1 expressions in the CD31+ endothelial cells in thoracic aortas of patients with TAD. In a β-aminopropionitrile (BAPN)-induced TAD mouse model, knockout of Piezo1 in endothelial cells shows a protective effect on aortic dissection, while the crucial tight junction (TJ) components ZO-1 was significantly increased by En Face staining. For identified how the Piezo1 ion channel influences the ZO-1 between endothelium, we used mass spectrometry analysis and RNA sequencing to identify a key factor Trib1 mediating the ubiquitination degradation of ZO-1. Also, we found the low expression of Trib1 in endothelial cell of Piezo1 ECKO mouse with BAPN feeding. Finally, we rescued the expression of TRIB1 by targeting endothelial cells with AAV9-TIE2-TRIB1, demonstrating that Piezo1 indeed promotes the occurrence of aortic dissection through degrading the TRIB1-COP1-ZO-1 complex.

Conclusion

The activation of Piezo1 promotes the occurrence of （TAD） through Trib1 mediated degradation of endothelial tight junctions. Inhibiting endothelial Piezo has the potential to become a specific therapeutic and preventive target for（TAD）.
The aortic paradox: a nationwide analysis of 523,994 individual echocardiograms exploring aortic dissection
Authors: Paratz E , Nadel J , Humphries J , Rowe S , Fahy L , La Gerche A , Prior D , Celermajer D , Strange G , Playford D
Published: October 2024

Background

Increasing aortic dilation increases risk of aortic dissection. Nevertheless, dissection occurs below guideline-directed cut-offs for prophylactic surgery. There is no current large-scale population imaging data assessing aortic dimensions before dissection.

Purpose

To examine the proportion of aortic dissections occurring in people with aortic diameters below guidelines for prophylactic intervention.

Methods

Patients within the National Echo Database of Australia (NEDA) were stratified according to absolute, height-indexed and body surface area (BSA)-indexed aortic dimensions. Fatal thoracic aortic dissections (ICD-10-AM code I79) were identified via linkage with the National Death Index.

Results

524,994 individuals were assessed, comprising patients with normal aortic dimensions (n=460,992), mild dilation (n=53,402), moderate dilation (n=10,029) and severe dilation (n=572). 274,992 (52.4%) were male, with median age 64 years and median follow-up time 6.9 years. 899 fatal aortic dissections occurred (normal diameter=610, mildly-dilated aorta=215, moderately-dilated =53 and severely-dilated=21). Using normal aortas as the reference population, odds of fatal dissection increased with aortic diameter (mild=OR 3.05, 95% confidence interval (CI) 2.61-3.56; moderate=OR 4.0, 95% CI 3.02-5.30; severe=OR 28.72, 95% CI 18.44-44.72). Due to the much larger number of patients without severe aortic dilation, 97.7% of fatal aortic dissections occurred in non-severely dilated aortas. Following sensitivity analysis, severe aortic dilation was responsible for at most 24.4% of fatal aortic dissections. Results were robust for absolute, height-indexed or BSA-indexed aortic measurements.

Conclusion

Although severe aortic dilatation is associated with a thirty-fold increase in fatal dissection, severely dilated aortas are implicated in only 2.3-24.4% of fatal dissections. This highlights the ‘aortic paradox’ and limitations of current guidelines. Future studies should seek to refine risk predictors in patients without severe aortic dilation.
Twenty-year trends in peripheral artery disease, lower extremity revascularization, and lower extremity amputation in newly diagnosed type 2 diabetes
Authors: Gyldenkerne C , Olesen K K W , Kahlert J , Thrane P G , Hansen M K , Stoedkilde-Joergensen N , Soerensen H T , Thomsen R W , Maeng M
Published: October 2024

Background

Trends in risk of lower extremity complications in patients with newly diagnosed type 2 diabetes (T2DM) are largely unexplored.

Purpose

To examine the 5-year risk trends of peripheral artery disease (PAD), lower extremity revascularization (LER), and lower extremity amputation (LEA) in patients with newly diagnosed T2DM over a 25-year study period.

Methods

We conducted a cohort study that included all patients in Denmark diagnosed with T2DM from 1996 to 2015, who had no prior hospital diagnosis of atherosclerotic cardiovascular disease. These patients were age- and sex-matched with up to three comparisons from the general population. Individuals were assigned to 5-year calendar periods based on their year of inclusion and were followed for 5 years. The primary outcomes were the 5-year risks of PAD, LER, and LEA. Age- and sex-adjusted hazard ratios (aHR) were computed using Cox regression analysis.

Results

The study cohort consisted of 288,825 newly diagnosed T2DM patients (52% males; median age 61 years) and 782,232 comparisons from the general population. From 1996-2000 to 2015-2020, the 5-year risk of PAD decreased from 2.2% to 1.2% (aHR 0.56 [95% CI 0.52-0.61]), LER from 0.7% to 0.5% (aHR 0.73 [95% CI 0.63-0.84]), and LEA from 1.0% to 0.4% (aHR 0.44 [95% CI 0.38-0.50]) in T2DM patients (Figure). Compared with the general population, the 5-year risk differences decreased from 1.4% to 0.5% for PAD, from 0.4% to 0.2% for LER, and from 0.8% to 0.3% for LEA. The distribution of LEA types (hip/thigh, knee/lower leg, or ankle/foot/toe amputation) remained largely stable over time in T2DM patients. Use of prophylactic cardiovascular medications in T2DM patients increased notably during the study period, especially use of statins (5% to 50%) and multiple antihypertensive drugs (18% to 33%).

Conclusions

Over recent decades, the risks of PAD, LER, and LEA have decreased in patients with newly diagnosed T2DM, approaching the risk levels observed in the general population. This coincided with a great increase in use of prophylactic cardiovascular medications among T2DM patients.Trends in lower extremity complications.
Variation in care in individuals hospitalised with abdominal aortic aneurysm in nine high-income countries: a cross-sectional cohort study
Authors: Pasea L , Cram P , Bakx P , Huang N , Ko D T , Burrack N , Lix L , Kim S J , Al-Azazi S , Cordier J , Hatfield L , Hirani J C , Uyl-De Groot C , Landon B , Banerjee A
Published: October 2024

Background

Abdominal aortic aneurysms (AAA) can be safely repaired using either endovascular aneurysm repair (EVAR) or open repair when intact, but after rupture morbidity and mortality are extremely high. Treatment patterns and outcomes for intact AAA are likely to differ between countries due to differences in AAA screening policies, health system capacity and payment approaches, and other factors, such as demographics and lifestyle, but are poorly studied.

Methods

We conducted a retrospective serial cross-sectional cohort study of adults aged ≥66 years hospitalised for with an intact AAA and repair procedure in the same admission between 2011 and 2019 in nine countries (US, Canada, England, Denmark, Netherlands, Switzerland, Taiwan, South Korea and Israel) using population-representative administrative data. We investigated age-sex standardised (to the 2019 US population) repair rates (open repair or EVAR) and health system performance measures, including hospital length of stay (LOS), 30-day readmission, and all-cause mortality (30 days and 1 year).

Results

The number of intact AAA hospital admissions between 2011 and 2019 ranged from 1,290 in Israel to 199,764 in the US. The rates of intact AAA repair per 1000 population varied between countries and over time, from 0.11 per 1000 (South Korea) to 0.69 per 1000 (US) in 2011 and from 0.14 per 1000 (Taiwan) to 0.57 per 1000 (the Netherlands) in 2019. Most countries saw a decline in the rate of AAA repair over the study period. The proportion repaired using open repair vs EVAR also varied widely across the countries. In the US, Israel and Taiwan open repair was used in 11% or fewer cases whereas in the remaining countries we observed open repair in 25.1 % (South Korea) to 56.7% (Denmark) of cases. (Figure 1)

Mortality was generally higher following open repairs compared to EVAR in all countries. In 2019, following EVAR, 30-day mortality varied from 0.6% (8.1% at 1 year) in South Korea to 2.3% (11.7% at 1 year) in Israel and following open repair varied from 2.9 (4.4% at 1 year) in England to 7.6% (15.1% at 1 year) in the US. (Figure 2)

Mean hospital LOS in 2019 ranged from 2.5 days (US) to 12.2 days (South Korea), following EVAR and from 9.1 days (Taiwan) to 21.5 days (South Korea) following open repair. The 30-day readmission rate in 2019 ranged from 8.1% (US) to 31.8% in Israel following EVAR and from 11.4% (US) to 22.2% (South Korea) following open repair.

Conclusions

We observed substantial between-country variation in surgical approaches, mortality, and health system performance measures for AAA. Further research is needed to understand and plan optimal, evidence-based AAA screening and treatment strategies.Rates of EVAR and open repairAdjusted 30-day all-cause mortality
Study on screening and diagnosis of aortic dissection based on non-enhanced CT and deep learning
Authors: Cheng Z , Yan J , Yin L , Lin S M , Lin J Y
Published: October 2024

Objective

To develop a machine learning algorithm to detect aortic dissection on non-contrast-enhanced CT and evaluate the diagnostic ability of the algorithm compared with those of radiologists.

Methods

This study developed a machine learning algorithm using single-center data collected between May 1st, 2022, and April 30th, 2023. Included in the study were 220 patients (110 with AD and 110 without AD). An AD detection algorithm was developed using a 3D full-resolution U-net architecture. We have continuously trained and developed an algorithm based on machine learning to segment the true and false lumens of the aorta and then determine whether there is aortic dissection. The diagnostic capabilities of our algorithm and three radiologists were also compared.

Results

The developed algorithm achieved an accuracy of 95.8%, a sensitivity of 93.2%, and a specificity of 92.6%. For radiologists, accuracy, sensitivity, and specificity were 88.6%, 90.6%, and 94.2%, respectively. The algorithm's performance was not significantly different from the mean performance of radiologists in terms of accuracy, sensitivity, or specificity.

Conclusion

The proposed algorithm showed comparable diagnostic performance to radiologists for detecting AD on non-contrast-enhanced CT, which suggests that the proposed algorithm has the potential to reduce misdiagnosis of AD to improve clinical outcomes.Aortic SegmentationAlgorithm development
Marfan syndrome in children: large, single centre experience on management and outcome
Authors: Freixa-Benavente A , Tang L , Field E , Cervi E
Published: October 2024

Introduction

Beta-blockers (BBs) and angiotensin receptor blockers (ARBs) have been proved to decrease the growth rate of the aortic root in Marfan patients, we describe our single centre experience at a large tertiary paediatric institution.

Methods

This is a retrospective longitudinal study of a large, paediatric only, Marfan cohort through review of medical notes for clinical data and treatment and assessment of serial echocardiograms.

Results

167 patients were included, mean age at first assessment was 4.05 ± 3.12 years, 86 (51.50%) were males. 41 pts (24.55%) had a de novo FBN1 mutation. A 35.32% had a cysteine loss mutation. Median follow up was 9.54±4.37 years. 2 patients had a clinical and molecular diagnosis of early-onset Marfan, they both underwent mitral valve surgery in infancy and one of them died at 7 years old. No other deaths or acute aortic events in our cohort until transition to adult services at 18 years old. Of the entire study population 12 pts (7.2%) underwent aortic surgery at a median age of 13±7.02 years, 1 patient had a mitral valve repair. Chemoprophylaxis (currently only evaluated in a subgroup of our youngest 65 patients) was offered to all patients, 27.69% declined medicines. The remining 47 subjects are on treatment which was started at a mean age of 4.88 ±2.96 years, surveillance data available for a mean follow up of 2.75±2.41 years. 50 received BB (58.50% atenolol [average dose 0.79 mg/kg/day] and 19.15% bisoprolol [average dose 0.087 mg/kg/day]), 5 (8.51%) losartan [average dose 0.763 mg/kg/day], and 10 (15.38%) double therapy with BB and ARBs. The Sinus of Valsalva (SOV) z-scores, as assessed on echocardiograms and normalised according to Lopez dataset, showed a reduction over time in children treated with chemoprophylaxis (see figure 1). SOV mean z-score at starting treatment was 3.38 ± 2.06 which reduced to 2.79± 1.81, however, differences were not statistically significant (paired T-student p-value 0.078). In non-treated patients, initial SOV z-score was 1.89 ± 1.05. When comparing evolution there was a trend towards decreased average SOV z-score over the years in the treated group, not seen in the non-treated patients (see figure 2). No statistical differences in the SOV z-score reduction change were found when comparing different treatment groups (ANOVA p-value 0.851), but a tendency to more profound decrease in the losartan groups was observed. Reduction in blood pressure or heart rate did not differ amongst the treatment groups.

Conclusions

We present one of the largest single centre reviews on management of paediatric Marfan patients. Our data confirm a decrease in SOV z-score with chemoprophylaxis in a real-world cohort. This is in line with current evidence and corroborates clinical practice.SOV Z-SCORE EVOLUTION AFTER TREATMENTSOV Z-SCORE GROUP AVERAGE CHANGE
Comparative effectiveness of Castor single-branch stent and hybrid surgery for the left subclavian artery in managing acute Type B aortic dissection with an inadequate proximal landing zone
Authors: Cheng Z , Ma L Y
Published: October 2024

Background

Our study aims to compare the clinical outcomes and risk factors for adverse events between TEVAR with branch stent-graft and Hybrid surgery for the reconstruction of the left subclavian artery.

Methods

We retrospectively analyzed data from patients with insufficient proximal landing zones of acute Type B aortic dissection treated at our hospital from January 2017 to December 2022. According to the surgical method, patients were divided into TEVAR group (n=58) and Hybrid group (n=69). The primary endpoint was all-cause mortality.

Results

The diameter of the proximal landing zone in the TEVAR group was larger than that in the Hybrid group (31.5mm vs 30.3mm, P=0.037). Early Results: There was no significant difference in major adverse events and 30-day mortality between the TEVAR and Hybrid groups. The Hybrid group had significantly longer surgery time (110min vs 238min), hospital stay (8d vs 12d), and ICU stay (0d vs 1d) compared to the TEVAR group (P<0.001). Mid-Term Results: There was no statistical difference in mid-term mortality rates (3.4% vs 8.7%; P=0.398) between the TEVAR and Hybrid groups. The rate of mid-term adverse events was significantly higher in the Hybrid group compared to the TEVAR group (23.2% vs 6.9%; P=0.023). The rate of re-intervention was significantly higher in the Hybrid group compared to the TEVAR group (17.4% vs 3.4%; P=0.027). The 18-month freedom from mid-term adverse event rate was 93.1% (95% CI, 86.4% - 99.8%) for the TEVAR group and 76.8% (95% CI, 66.6% - 87.0%) for the Hybrid group. There was a significant difference in the rate of mid-term adverse events between the TEVAR and Hybrid groups, with the Hybrid group being higher (6.9% vs 23.2%, P=0.013). COX regression results showed: Diameter of the proximal landing zone (HR=0.6, 95%CI=0.4–0.9, P=0.009) was an independent risk factor for postoperative aortic-related adverse events.

Conclusions

TEVAR reconstruction of LSA and hybrid surgery are both safe and effective treatments for acute Type B aortic dissection with insufficient proximal landing zones. There is no difference in early adverse events and 30-day mortality rates between TEVAR reconstruction of LSA and hybrid surgery. Compared to hybrid surgery, TEVAR reconstruction of LSA has the advantages of shorter operation time, hospital stay, and ICU duration. There is no difference in aortic-related mortality and all-cause mortality between TEVAR reconstruction of LSA and hybrid surgery. However, TEVAR has significantly lower rates of mid-term adverse events and re-intervention compared to the hybrid group. The diameter of the proximal landing zone are risk factors for all-cause mortality.