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Circulation Jun 2024We assessed the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in patients with heart failure with preserved ejection fraction and combined...
Tadalafil for Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension in Patients With Heart Failure and Preserved Ejection Fraction: A Randomized Controlled Phase 3 Study.
BACKGROUND
We assessed the efficacy and safety of tadalafil, a phosphodiesterase type 5 inhibitor, in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension.
METHODS
In the double-blind PASSION study (Phosphodiesterase-5 Inhibition in Patients With Heart Failure With Preserved Ejection Fraction and Combined Post- and Pre-Capillary Pulmonary Hypertension), patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension were randomized 1:1 to receive tadalafil at a target dose of 40 mg or placebo. The primary end point was the time to the first composite event of adjudicated heart failure hospitalization or all-cause death. Secondary end points included all-cause mortality and improvements in New York Heart Association functional class or ≥10% improvement in 6-minute walking distance from baseline.
RESULTS
Initially targeting 372 patients, the study was terminated early because of disruption in study medication supply. At that point, 125 patients had been randomized (placebo: 63; tadalafil: 62,). Combined primary end-point events occurred in 20 patients (32%) assigned to placebo and 17 patients (27%) assigned to tadalafil (hazard ratio, 1.02 [95% CI, 0.52-2.01]; =0.95). There was a possible signal of higher all-cause mortality in the tadalafil group (hazard ratio, 5.10 [95% CI, 1.10-23.69]; =0.04). No significant between-group differences were observed in other secondary end points. Serious adverse events occurred in 29 participants (48%) in the tadalafil group and 35 (56%) in the placebo group.
CONCLUSIONS
The PASSION trial, terminated prematurely due to study medication supply disruption, does not support tadalafil use in patients with heart failure with preserved ejection fraction and combined postcapillary and precapillary pulmonary hypertension, with potential safety concerns and no observed benefits in primary and secondary end points.
REGISTRATION
URL: https://www.clinicaltrialsregister.eu/; Unique identifier: 2017-003688-37. URL: https://drks.de; Unique identifier: DRKS -DRKS00014595.
PubMed: 38939948
DOI: 10.1161/CIRCULATIONAHA.124.069340 -
Pulmonary Circulation Apr 2024
PubMed: 38939305
DOI: 10.1002/pul2.12408 -
Journal of Extracellular Biology Jun 2023Extracellular vesicles (EVs) secreted by stem and progenitor cells have significant potential as cell-free 'cellular' therapeutics. Yet, small EVs (<200 nm) are rapidly...
Extracellular vesicles (EVs) secreted by stem and progenitor cells have significant potential as cell-free 'cellular' therapeutics. Yet, small EVs (<200 nm) are rapidly cleared after systemic administration, mainly by the liver, presenting challenges targeting EVs to a specific organ or tissue. Microencapsulation using natural nano-porous hydrogels (microgels) has been shown to enhance engraftment and increase the survival of transplanted cells. We sought to encapsulate EVs within microgels to target their delivery to the lung by virtue of their size-based retention within the pulmonary microcirculation. Mesenchymal stromal cell (MSC) derived EVs were labelled with the lipophilic dye (DiR) and encapsulated within agarose-gelatin microgels. Endothelial cells and bone marrow derived macrophages were able to take up EVs encapsulated in microgels in vitro, but less efficiently than the uptake of free EVs. Following intrajugular administration, microgel encapsulated EVs were selectively retained within the lungs for 72h, while free EVs were rapidly cleared by the liver. Furthermore, microgel-loaded EVs demonstrated greater uptake by lung cells, in particular CD45 immune cells, as assessed by flow cytometry compared to free EVs. Microencapsulation of EVs may be a novel tool for enhancing the targeted delivery of EVs for future therapeutic applications.
PubMed: 38938918
DOI: 10.1002/jex2.94 -
Cardiology in Review Jun 2024Severe tricuspid regurgitation (TR) is an underrated, common pathology that affects over 70 million individuals worldwide. Traditionally, TR has been managed with...
Severe tricuspid regurgitation (TR) is an underrated, common pathology that affects over 70 million individuals worldwide. Traditionally, TR has been managed with diuretic therapies without any significant mortality benefit. The underlying cause of TR can be primary, coming from structural issues with tricuspid valve and more commonly secondary, arising from conditions affecting the right ventricle or the pulmonary circulation. Management of TR has seen few improvements until recently. Traditionally, valve replacement and surgical repair were the therapeutic options available. Tricuspid valve is a complex cardiac structure with many technical challenges for surgical intervention. Transcatheter valve interventions have proven to be safe and effective novel therapeutic options for severe TR, which reduce the severity of TR with associated improvement in quality of life. In this review, we will provide an overview of the management of severe TR utilizing transcatheter edge-to-edge repair with the TriClip device (Abbott, Santa Clara, CA).
PubMed: 38934619
DOI: 10.1097/CRD.0000000000000740 -
ACS Applied Materials & Interfaces Jun 2024Polyplexes are required to be equipped with multiple functionalities to accomplish adequate structure stability and gene transfection efficacy for gene therapy. Herein,...
Polyplexes are required to be equipped with multiple functionalities to accomplish adequate structure stability and gene transfection efficacy for gene therapy. Herein, a 4-carboxy-3-fluorophenylboronic acid (FPBA)-functionalized block copolymer of PEG--PAsp(DET/FBA) and PAsp(DET/FBA) (abbreviated as PB and HB) was synthesized and applied for engineering functional polyplex micelles (PMs) through ionic complexation with pDNA followed by strategic cross-linking with nordihydroguaiaretic acid (NDGA) in respect to the potential linkage of polyphenol and FPBA moieties. In relation to polyplex micelles void of cross-linking, the engineered multifunctional polyplex micelles (PBHBN-PMs) were determined to possess improved structural tolerability against the exchange reaction with charged species. Besides, the FPBA/NDGA cross-linking appeared to be selectively cleaved in the acidic endosomal compartments but not the neutral milieu. Furthermore, the PBHB-PMs with the optimal FPBA/NDGA cross-linking degree were identified to possess appreciable cellular uptake and endosomal escape activities, eliciting a significantly high level of gene expression relative to P-PMs and PB-PMs. Eventually, antitumor therapy by our proposed multifunctional PMs appeared to be capable of facilitating expression of the antiangiogenic genomic payloads (sFlt-1 pDNA) via systemic administration. The enriched antiangiogenic sFlt-1 in the tumors could silence the activities of angiogenic cytokines for the inhibited neo-vasculature and the suppressed growth of orthotopic 4T1 tumors. Of note, the persistent expression of the antiangiogenic sFlt-1 is also presumed to migrate into the blood circulation, thereby accounting for an overall antiangiogenic environment in preventing the potential pulmonary metastasis. Hence, our elaborated multifaceted PMs inspired fascinating potential as an intriguing gene delivery system for the treatment of clinical solid tumors and metastasis.
PubMed: 38934519
DOI: 10.1021/acsami.4c05311 -
Pulmonary Circulation Apr 2024Pulmonary hypertension (PH) is a severe medical condition with a number of treatment options, the majority of which are introduced without consideration of the... (Review)
Review
Pulmonary hypertension (PH) is a severe medical condition with a number of treatment options, the majority of which are introduced without consideration of the underlying mechanisms driving it within an individual and thus a lack of tailored approach to treatment. The one exception is a patient presenting with apparent pulmonary arterial hypertension and shown to have vaso-responsive disease, whose clinical course and prognosis is significantly improved by high dose calcium channel blockers. PH is however characterized by a relative abundance of available data from patient cohorts, ranging from molecular data characterizing gene and protein expression in different tissues to physiological data at the organ level and clinical information. Integrating available data with mechanistic information at the different scales into computational models suggests an approach to a more personalized treatment of the disease using model-based optimization of interventions for individual patients. That is, constructing digital twins of the disease, customized to a patient, promises to be a key technology for personalized medicine, with the aim of optimizing use of existing treatments and developing novel interventions, such as new drugs. This article presents a perspective on this approach in the context of a review of existing computational models for different aspects of the disease, and it lays out a roadmap for a path to realizing it.
PubMed: 38933181
DOI: 10.1002/pul2.12392 -
Pulmonary Circulation Apr 2024Pollution and climate change constitute a combined, grave and pervasive threat to humans and to the life-support systems on which they depend. Evidence shows a strong... (Review)
Review
Pollution and climate change constitute a combined, grave and pervasive threat to humans and to the life-support systems on which they depend. Evidence shows a strong association between pollution and climate change on cardiovascular and respiratory diseases, and pulmonary vascular disease (PVD) is no exception. An increasing number of studies has documented the impact of environmental pollution and extreme temperatures on pulmonary circulation and the right heart, on the severity and outcomes of patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (PH), on the incidence of pulmonary embolism, and the prevalence and severity of diseases associated with PH. Furthermore, the downstream consequences of climate change impair health care systems' accessibility, which could pose unique obstacles in the case of PVD patients, who require a complex and sophisticated network of health interventions. Patients, caretakers and health care professionals should thus be included in the design of policies aimed at adaptation to and mitigation of current challenges, and prevention of further climate change. The purpose of this review is to summarize the available evidence concerning the impact of environmental pollution and climate change on the pulmonary circulation, and to propose measures at the individual, healthcare and community levels directed at protecting patients with PVD.
PubMed: 38933180
DOI: 10.1002/pul2.12394 -
Frontiers in Medicine 2024The fetal haemodynamic response to acute episodes of hypoxaemia are well characterised. However, how these responses change when the hypoxaemia becomes more chronic in...
INTRODUCTION
The fetal haemodynamic response to acute episodes of hypoxaemia are well characterised. However, how these responses change when the hypoxaemia becomes more chronic in nature such as that associated with fetal growth restriction (FGR), is less well understood. Herein, we utilised a combination of clinically relevant MRI techniques to comprehensively characterize and differentiate the haemodynamic responses occurring during acute and chronic periods of fetal hypoxaemia.
METHODS
Prior to conception, carunclectomy surgery was performed on non-pregnant ewes to induce FGR. At 108-110 days (d) gestational age (GA), pregnant ewes bearing control ( = 12) and FGR ( = 9) fetuses underwent fetal catheterisation surgery. At 117-119 days GA, ewes underwent MRI sessions where phase-contrast (PC) and T oximetry were used to measure blood flow and oxygenation, respectively, throughout the fetal circulation during a normoxia and then an acute hypoxia state.
RESULTS
Fetal oxygen delivery (DO) was lower in FGR fetuses than controls during the normoxia state but cerebral DO remained similar between fetal groups. Acute hypoxia reduced both overall fetal and cerebral DO. FGR increased ductus venosus (DV) and foramen ovale (FO) blood flow during both the normoxia and acute hypoxia states. Pulmonary blood flow (PBF) was lower in FGR fetuses during the normoxia state but similar to controls during the acute hypoxia state when PBF in controls was decreased.
CONCLUSION
Despite a prevailing level of chronic hypoxaemia, the FGR fetus upregulates the preferential streaming of oxygen-rich blood via the DV-FO pathway to maintain cerebral DO. However, this upregulation is unable to maintain cerebral DO during further exposure to an acute episode of hypoxaemia. The haemodynamic alterations required at the level of the liver and lung to allow the DV-FO pathway to maintain cerebral DO, may have lasting consequences on hepatic function and pulmonary vascular regulation after birth.
PubMed: 38933113
DOI: 10.3389/fmed.2024.1340012 -
Annals of Pediatric Cardiology 2024Retrieval of embolized ductal stents from the pulmonary or systemic circulation can be challenging. Most children benefit from surgical shunts in such scenarios....
Retrieval of embolized ductal stents from the pulmonary or systemic circulation can be challenging. Most children benefit from surgical shunts in such scenarios. Although early retrieval is advised, stents lodged in the peripheral pulmonary tree can be inaccessible, making the removal complicated. In such patients, stents can be "parked" in the segmental pulmonary arterial branches for retrieval later. In the low-pressure single ventricle pulmonary circulation, partially expanded embolized stents, if left , can precipitate pulmonary arterial thrombosis. This subset of patients may benefit from meticulous anticoagulation and antiplatelet agents. In our case report, we describe the successful extraction of an embolized ductal stent without damage to the right lower lobe pulmonary artery (PA). In the follow-up evaluation, the growth of the right PA is good.
PubMed: 38933049
DOI: 10.4103/apc.apc_177_23 -
Journal of Clinical Medicine Jun 2024There was increased risk of mental disturbances during the COVID-19 pandemic. Patients with chronic diseases, including pulmonary arterial hypertension (PAH) and...
Anxiety and Depression in Patients with Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension after the Removal of COVID-19 Pandemic Restrictions.
There was increased risk of mental disturbances during the COVID-19 pandemic. Patients with chronic diseases, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), were particularly vulnerable. Our previous study showed high levels of fear of COVID-19 (FCV-19S), anxiety (HADS-A), and depression (HADS-D) in the second year of the pandemic among PAH/CTEPH patients. The aim of the present study was to assess changes in the levels of FCV-19S, HADS-A, and HADS-D after removing restrictions related to the COVID-19 pandemic. In this prospective, single-center study, 141 patients (62% females, 64% PAH) with a median age of 60 (range 42-72) years were included. Patients completed appropriate surveys in the second year of the pandemic, and then, after the restrictions were lifted in Poland (after 28 March 2022). FVC-19S decreased significantly from 18 (12-23) to 14 (9-21), < 0.001. The levels of anxiety (HADS-A ≥ 8 points) and depression (HADS-D ≥ 8 points) were abnormal in 26% and 16% of patients, respectively; these did not change at follow-up ( = 0.34 for HADS-A and = 0.39 for HADS-D). : Among PAH/CTEPH patients, fear of COVID-19 decreased significantly after the COVID-19 pandemic restrictions were removed, but anxiety and depression remained high, indicating that the COVID-19 pandemic was not a major factor in causing these disorders.
PubMed: 38930062
DOI: 10.3390/jcm13123532