Pulmonary Vasculature Research Articles

A generalized health index: automated thoracic CT-derived biomarkers predict life expectancy.

To identify image biomarkers associated with overall life expectancy from low-dose computed tomography and integrate them as an index for assessing an individual's health. Two categories of CT image features, body composition tissues and cardiopulmonary vasculature characteristics, were quantified from LDCT scans in the Pittsburgh Lung Screening Study cohort(n = 3,635). Cox proportional-hazards models identified significant image features which were integrated with subject demographics to predict the subject's overall hazard. Subjects were stratified using composite model predictions and feature-specific risk stratification thresholds. The model's performance was validated extensively, including 5-fold cross-validation on PLuSS baseline, PLuSS follow-up examinations, and the National Lung Screening Trial (NLST). The composite model had significantly improved prognostic ability compared to the baseline model (p < 0.01) with AUCs of 0.774 (95% CI: 0.757-0.792) on PLuSS, 0.723 (95% CI: 0.703-0.744) on PLuSS follow-up, and 0.681 (95% CI: 0.651-0.710) on the NLST cohort. The identified high-risk stratum were several times more likely to die, with mortality rates of 79.34% on PLuSS, 76.47% on PLuSS follow-up, and 46.74% on NLST. Two cardiopulmonary structures (intrapulmonary artery vein ratio, intrapulmonary vein density) and two body composition tissues (SM density, bone density) identified high-risk patients. Body composition and pulmonary vasculatures are predictive of an individual's health risk; their integrations with subject demographics facilitate the assessment of an individual's overall health status or susceptibility to disease. CT-computed body composition and vasculature biomarkers provide improved prognostic value. The integration of CT biomarkers and patient demographic information improves subject risk stratification.

Vitamin D receptor and its antiproliferative effect in human pulmonary arterial hypertension

Vitamin D (vitD) deficiency is frequently observed in patients with pulmonary arterial hypertension (PAH) and, in these patients, low levels of vitD correlate with worse prognosis. The aim of this study was to examine the expression and the antiproliferative role of vitD receptor (VDR) and its signalling pathway in the human pulmonary vasculature. VDR presence and expression was analyzed in lungs, pulmonary artery smooth muscle cells (PASMC) and endothelial cells (PAEC) from controls and PAH-patients. VDR expression and VDR-target genes were examined in PASMC treated with calcitriol. The antiproliferative effect of 48 h-calcitriol was studied in PASMC by MTT and BrdU assays. VDR is expressed in PASMC. It is downregulated in lungs and in PASMC, but not in PAEC, from PAH-patients compared to non-hypertensive controls. Calcitriol strongly upregulated VDR expression in PASMC and the VDR target genes KCNK3 (encoding TASK1), BIRC5 (encoding survivin) and BMP4. Calcitriol produced an antiproliferative effect which was diminished by silencing or by pharmacological inhibition of survivin or BMPR2, but not of TASK1. In conclusion, the expression of VDR is low in PAH-patients and can be rescued by calcitriol. VDR exerts an antiproliferative effect in PASMC by modulating survivin and the BMP signalling pathway.

Elevated Perspectives: Unraveling Cardiovascular Dynamics in High-Altitude Realms.

High-altitude regions pose distinctive challenges for cardiovascular health because of decreased oxygen levels, reduced barometric pressure, and colder temperatures. Approximately 82 million people live above 2400 meters, while over 100 million people visit these heights annually. Individuals ascending rapidly or those with pre-existing cardiovascular conditions are particularly vulnerable to altitude-related illnesses, including Acute Mountain Sickness (AMS) and Chronic Mountain Sickness (CMS). The cardiovascular system struggles to adapt to hypoxic stress, which can lead to arrhythmias, systemic hypertension, and right ventricular failure. Pathophysiologically, high-altitude exposure triggers immediate increases in cardiac output and heart rate, often due to enhanced sympathetic activity. Over time, acclimatisation involves complex changes, such as reduced stroke volume and increased blood volume. The pulmonary vasculature also undergoes significant alterations, including hypoxic pulmonary vasoconstriction and vascular remodelling, contributing to conditions, like pulmonary hypertension and high-altitude pulmonary edema. Genetic adaptations in populations living at high altitudes, such as gene variations linked to hypoxia response, further influence these physiological processes. Regarding cardiovascular disease risk, stable coronary artery disease patients generally do not face significant adverse outcomes at altitudes up to 3500 meters. However, those with unstable angina or recent cardiac interventions should avoid high-altitude exposure to prevent exacerbation. Remarkably, high-altitude living correlates with reduced cardiovascular mortality rates, possibly due to improved air quality and hypoxia-induced adaptations. Additionally, there is a higher incidence of congenital heart disease among children born at high altitudes, highlighting the profound impact of hypoxia on heart development. Understanding these dynamics is crucial for managing risks and improving health outcomes in high-altitude environments.

Preacinar Arterial Dilation Mediates Outcomes of Quantitative Interstitial Abnormalities in the COPDGene Study.

Rationale: Quantitative interstitial abnormalities (QIAs) are a computed tomography (CT) measure of early parenchymal lung disease associated with worse clinical outcomes, including exercise capacity and symptoms. The presence of pulmonary vasculopathy in QIAs and its role in the QIA-outcome relationship is unknown. Objectives: To quantify radiographic pulmonary vasculopathy in QIAs and determine whether this vasculopathy mediates the QIA-outcome relationship. Methods: Ever-smokers with QIAs, outcomes, and pulmonary vascular mediator data were identified from the Genetic Epidemiology of COPD (COPDGene) study cohort. CT-based vascular mediators were right ventricle-to-left ventricle ratio, pulmonary artery-to-aorta ratio, and preacinar intraparenchymal arterial dilation (pulmonary artery volume, 5-20 mm2 in cross-sectional area, normalized to total arterial volume). Outcomes were 6-minute walk distance and a modified Medical Council Research Council Dyspnea Scale score of 2 or higher. Adjusted causal mediation analyses were used to determine whether the pulmonary vasculature mediated the QIA effect on outcomes. Associations of preacinar arterial dilation with select plasma biomarkers of pulmonary vascular dysfunction were examined. Measurements and Main Results: Among 8,200 participants, QIA burden correlated positively with vascular damage measures, including preacinar arterial dilation. Preacinar arterial dilation mediated 79.6% of the detrimental impact of QIA on 6-minute walk distance (56.2-100%; P < 0.001). Pulmonary artery-to-aorta ratio was a weak mediator, and right ventricle-to-left ventricle ratio was a suppressor. Similar results were observed in the relationship between QIA and modified Medical Council Research Council dyspnea score. Preacinar arterial dilation correlated with increased pulmonary vascular dysfunction biomarker levels, including angiopoietin-2 and N-terminal brain natriuretic peptide. Conclusions: Parenchymal QIAs deleteriously impact outcomes primarily through pulmonary vasculopathy. Preacinar arterial dilation may be a novel marker of pulmonary vasculopathy in QIAs.

Specific Biobank for Chronic Thromboembolic Pulmonary Hypertension (Perspectives and Implementation)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease characterized by incomplete resolution of the thrombus after an acute pulmonary embolism (PE), accompanied by changes in the pulmonary vasculature with thickening of the intima, changes in pulmonary endothelial cells and subsequent fibrosis

Impact of right ventricular - pulmonary arterial coupling on mortality after transcatheter aortic valve implantation in patients with aortic stenosis

Abstract Background Aortic stenosis (AS) leads to left ventricle (LV) pressure overload. In more advanced stages of the disease, this pressure, which is transmitted through the pulmonary vasculature, may result in right ventricle (RV) remodeling and eventual dilatation and disfunction. RV failure is associated with impair prognosis, even after relief of the obstruction. The interplay of pulmonary arterial (PA) pressure and RV function can be assess using RV-PA coupling index; in a compensate state RV function is coupled with pulmonary pressure, and this function has a proper response to an increase in pulmonary afterload; in contrast, when RV function uncouples with pulmonary pressure it means that RV function can no longer sustain PA afterload, leading to a decompensate state. RV-PA uncoupling has already been associated with poor prognosis in other heart conditions, such as heart failure or pulmonary hypertension; however, there is still not much evidence on how RV-PA uncoupling prior transcatheter aortic valve implantation (TAVI) impacts on mortality. Purpose Assess the impact of RV-PA uncoupling on all-cause mortality after TAVI in patients with aortic stenosis. Methods In a prospective TAVI registry, patients were included if they had an adequate echocardiographic evaluation prior TAVI. All-cause mortality after the procedure was analyzed in two subgroups, according to their RV-PA coupling status. RV-PA was assess using tricuspid annular plane systolic excursion (TAPSE) and pulmonary arterial systolic pressure (PASP). The cut-off value was 0.39, consistent with other studies. Hazard ratios (HR) are calculated by univariate and multivariate Cox proportional hazard model. Multivariate adjustment included baseline characteristics – including age, gender, hypertension, diabetes, dyslipidemia, atrial fibrillation, and serum albumin –, and Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) and European System for Cardiac Operative Risk Evaluation (EUROSCORE) II. Results A total of 1190 patients underwent TAVI from January 2011 to December 2023; 315 patients were eligible, with mean age 82,24 years (± 8,0), 52% being women, and a mean EUROSCORE II score of 4.0 (± 9,3). The RV-PA cut-off value of 0.39 stratified patients into groups of RV-PA coupling (n = 194/63,6 %) or uncoupling (n = 121/38,4 %). During follow-up time (35,94 months ±25,6), patients with unpaired coupling had a 64% more risk of all-cause mortality in univariate analysis and, after adjusting for the parameters above, a 58% increased risk in multivariate analysis. Table. Conclusions Patients with significant aortic stenosis who had an impair RV-PA coupling prior TAVI had a significant increased risk of all-cause mortality. This suggests the need to incorporate this parameter to our right-side hemodynamics evaluation prior the procedure. Broader experience to determine its application and cut-off value are still needed.

Myocardial work and aortic valve stenosis cardiac damage stages are predictors of all-cause mortality in patients undergoing transcatheter aortic valve replacement

Abstract In aortic stenosis (AS) patients, assessment of left ventricular (LV) systolic function is complicated due to the significant impact of increased afterload on conventional parameters. Myocardial work (MW) analysis, a novel echocardiographic method adjusts myocardial deformation to instantaneous LV pressure which may better reflect the LV contractile state. Importantly, long-term LV pressure overload has marked backward effects beyond the LV: classification of this extravalvular cardiac damage effectively represents the involvement of the cardiopulmonary system in AS. Both MW and cardiac damage staging could hold remarkable prognostic power in the clinically complex population of transcatheter aortic valve replacement (TAVR) candidates. Accordingly, our aim was to assess the prognostic value of MW analysis and cardiac damage staging in patients undergoing TAVR. We enrolled 289 patients (79±6 years, 41% female) prior to TAVR. Echocardiographic measurements were performed one day before the procedure. We calculated LV ejection fraction (EF) and by speckle-tracking echocardiography global longitudinal strain (GLS), as well. Global constructive work (GCW) was quantified with dedicated software and LV pressure was estimated using transaortic mean gradient and systolic blood pressure. Based on the echocardiographic data, we also determined the extent of cardiac damage associated with AS: patients were classified as Stage 0 (no cardiac damage), Stage 1 (LV damage), Stage 2 (mitral valve or left atrial damage), Stage 3 (pulmonary artery vasculature or tricuspid valve damage), or Stage 4 (right ventricular damage). Our primary outcome was all-cause mortality, reached by 68 patients (median follow-up: 26 months). In our cohort, preprocedural EF was 47±13 %, GLS was -12.3±4 %, while GCW was 2043±791 mmHg%. 14 (5%) patients were classified as Stage 0, 61 (21%) as Stage 1, 128 (44%) as Stage 2, 15 (5%) as Stage 3, and 71 (25%) as Stage 4. GCW showed a continuous decline through the AS Stages (from Stage 0-4: 2963±652 vs. 2154±652 vs. 2168±718 vs. 1988±969 vs. 1552±772 mmHg%; p&amp;lt;0.001). Using univariate Cox analysis GCW (HR 0.968 [95% CI 0.938-0.998] per 100 unit change; p=0.034) and AS Staging (HR 1.236 [95% CI 1.015-1.505]; p=0.035) were both associated with all-cause mortality, while EF (HR 0.984 [95% CI 0.966-1.002]; p=0.085) and GLS (HR 1.042 [95% CI 0.984-1.103]; p=0.160) were not. In multivariate Cox regression models, both GCW (HR 0.957 [95% CI 0.922-0.992] per 100 unit change; p=0.018) and AS cardiac damage staging (HR 1.263 [95% CI 1.029-1.549]; p=0.025) were proven to be significant independent predictors of all-cause mortality. In TAVR patients, preoperative GCW values exhibited a persistent decrease across AS Stages. As opposed to EF and GLS, GCW and AS Staging both showed strong association with all-cause mortality in our cohort. Moreover, GCW had higher prognostic value than any other conventional or advanced measure of LV function.

Gender-related differences in the timing of intervention for aortic stenosis: focus on cardiac damage

Abstract Background and aim: There is an increasing awareness of gender-related differences in the management of cardiovascular diseases. Our aim was to assess whether cardiac damage prior to intervention for severe aortic stenosis (AS) differs according to gender. Methods Retrospective analysis of a prospective cohort of patients with AS who underwent surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) in a tertiary care center from 2017 to 2022. Echocardiographic parameters prior to surgery were collected, and patients were classified into categories of a cardiac damage staging system. (1) Several echocardiographic variables according to gender were evaluated. Results 869 patients were included, of which 350 underwent TAVR and 519 were treated with SAVR. Females represented 52.4% (n=272) of TAVR patients and 37.7% (n=132) of SAVR patients. In the echocardiogram performed before the intervention, both in the TAVR and the SAVR cohort, female patients had worse diastolic function (significantly higher values of E/e’), and greater involvement of pulmonary vasculature damage (significantly higher pulmonary artery systolic pressure and worse right ventricular-arterial coupling (Table-Figure 1). When applying an available cardiac damage staging system (1), we documented that women were treated at a statistically significant more advanced stage compared to men (Figure 2). Conclusions There are gender-related differences in the timing of aortic stenosis intervention, both with TAVR and SAVR. Women are operated on at a more advanced stage of cardiac damage, particularly regarding the parameters of diastolic function and right-side damage. These findings should be taken into account to improve intervention timing and outcomes, especially for women.Table-Figure 1Figure 2

Colchicine as a therapeutic option for the treatment of pulmonary arterial hypertension (PAH) in a rat model

Abstract Introduction Pulmonary arterial hypertension (PAH) is a cardiovascular disease that is characterized by severe structural and functional damages, resulting from the obstructive remodeling of the pulmonary vasculature and consequent right ventricular pressure overload. The current therapy mainly focuses on the pulmonary vascular system, with uncertain efficacy. Therefore, it is crucial to explore new therapeutic approaches. The mechanism of colchicine is complex and not-fully understood, but it has been proven to exert cardiopulmonary protective effects. Methods PAH induction was carried out in 8-week-old male WKY rats with a single subcutaneous injection of 60 mg/kg monocrotaline. Monocrotaline, a pyrrolizidine alkaloid, is metabolized in liver and induces inflammatory processes, which can cause PAH in rats. Starting from day 14 after MCT injection, the animals received three times a week intraperitoneal colchicine treatment at a dose of 0.5 mg/kg for two weeks. Echocardiographic examinations were performed during the study. At the end of the study, besides histological examination of the right ventricles and lungs [arterial wall thickness (WT%) and area (WA%)], the expression and phosphorylation levels of the proteins involved in cardiac remodeling were evaluated using Western blot. We assessed the pyruvate dehydrogenase (PDH) enzyme activity in the heart, which plays an important role in energy metabolism. We also examined the production of cytokines and chemokines in the right ventricle. Results The VW/BW ratio in the colchicine-treated group was significantly reduced compared to the MCT group (p&amp;lt;0.01). Echocardiographic parameters, EF% and E/e' ratio – characterizing the left ventricular function – did not differ considerably between the groups during the treatment. The TAPSE and PAT values characterizing right ventricular function improved in the MCT+C group (p&amp;lt;0.05). Collagen deposition and TGFβ level were significantly reduced by colchicine (p&amp;lt;0.05) in PAH animals. In the MCT+C group, the vascular remodeling (WT% and WA%) significantly decreased compared to the MCT group (p&amp;lt;0.01). The expression of α-SMA in vessel walls was most pronounced in the MCT group (p&amp;lt;0.01), which was significantly reduced by colchicine treatment. The phosphorylation of prosurvival signaling factors (ERK1/2, Akt1, GSK3β) was significantly increased in the MCT+C group (p&amp;lt;0.01) compared to the MCT group. In the right ventricle, PDH enzyme activity increased in the MCT+C group compared to the MCT group (p&amp;lt;0.01). According to cytokine array, cytokines involved in mediating fibrosis and inflammatory processes (TIMP-1, VEGF, L-selectin, CXCL7) showed increased secretion in the MCT group, which was moderately attenuated by colchicine treatment. Conclusion Colchicine treatment reduced the extent of fibrosis and inflammation, improved the structure of the pulmonary vasculature, and enhanced right ventricular function and energy supply.

Single-cell transcriptomics reveal diverging pathobiology and opportunities for precision targeting in scleroderma-associated versus idiopathic pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) involves progressive cellular and molecular change within the pulmonary vasculature, leading to increased vascular resistance. Current therapies targeting nitric oxide (NO), endothelin, and prostacyclin pathways yield variable treatment responses. Patients with systemic sclerosis-associated PAH (SSc-PAH) often experience worse outcomes than those with idiopathic PAH (IPAH). Lung tissue samples from four SSc-PAH, four IPAH, and four failed donor specimens were obtained from the Pulmonary Hypertension Breakthrough Initiative (PHBI) lung tissue bank. Single-cell RNA sequencing (scRNAseq) was performed using the 10X Genomics Chromium Flex platform. Data normalization, clustering, and differential expression analysis were conducted using Seurat. Additional analyses included gene set enrichment analysis (GSEA), transcription factor activity analysis, and ligand-receptor signaling. Pharmacotranscriptomic screening was performed using the Connectivity Map. SSc-PAH samples showed a higher proportion of fibroblasts and dendritic cells/macrophages compared to IPAH and donor samples. GSEA revealed enriched pathways related to epithelial-to-mesenchymal transition (EMT), apoptosis, and vascular remodeling in SSc-PAH samples. There was pronounced differential gene expression across diverse pulmonary vascular cell types and in various epithelial cell types in both IPAH and SSc-PAH, with epithelial to endothelial cell signaling observed. Macrophage to endothelial cell signaling was particularly pronounced in SSc-PAH. Pharmacotranscriptomic screening identified TIE2, GSK-3, and PKC inhibitors, among other compounds, as potential drug candidates for reversing SSc-PAH gene expression signatures. Overlapping and distinct gene expression patterns exist in SSc-PAH versus IPAH, with significant molecular differences suggesting unique pathogenic mechanisms in SSc-PAH. These findings highlight the potential for precision-targeted therapies to improve SSc-PAH patient outcomes. Future studies should validate these targets clinically and explore their therapeutic efficacy.

Autonomic control of the pulmonary circulation: Implications for pulmonary hypertension.

The autonomic regulation of the pulmonary vasculature has been under-appreciated despite the presence of sympathetic and parasympathetic neural innervation and adrenergic and cholinergic receptors on pulmonary vessels. Recent clinical trials targeting this innervation have demonstrated promising effects in pulmonary hypertension, and in this context of reignited interest, we review autonomic pulmonary vascular regulation, its integration with other pulmonary vascular regulatory mechanisms, systemic homeostatic reflexes and their clinical relevance in pulmonary hypertension. The sympathetic and parasympathetic nervous systems can affect pulmonary vascular tone and pulmonary vascular stiffness. Local afferents in the pulmonary vasculature are activated by elevations in pressure and distension and lead to distinct pulmonary baroreflex responses, including pulmonary vasoconstriction, increased sympathetic outflow, systemic vasoconstriction and increased respiratory drive. Autonomic pulmonary vascular control interacts with, and potentially makes a functional contribution to, systemic homeostatic reflexes, such as the arterial baroreflex. New experimental therapeutic applications, including pulmonary artery denervation, pharmacological cholinergic potentiation, vagal nerve stimulation and carotid baroreflex stimulation, have shown some promise in the treatment of pulmonary hypertension.

Epidemiological Aspects, Clinicopathology, Hemato-biochemistry and Therapeutic Management of Viperine Snake Envenomation in Buffaloes (Bubalus bubalis)

Background: Poisonous snakebite is a neglected tropical disease, frequently reported in animals including buffaloes. Snakebites are responsible for considerable morbidity and mortality in animals causing economic losses to dairy farmers. Methods: To establish the baseline data of epidemiology, clinical syndrome, hemato-biochemistry and diagnosis of viper snakebites and to standardize the treatment of viper snakebite in buffaloes. Result: The highest incidence of viper envenomation was observed during the monsoon and post-monsoon season in female buffaloes above 4 years of age. The clinical signs such as tachycardia, increased respiration rate, ascending swelling of affected limbs, asymmetrical swelling with dyspnea in case of bite over face and bleeding at the site of bite were observed in envenomed buffaloes. Hemato-biochemical analysis revealed neutrophilic leukocytosis, thrombocytopenia, prolonged capillary blood clotting time, elevated values of blood urea nitrogen (BUN) and creatinine. Post-mortem examination showed hemorrhages and blood-stained serous fluid in subcutaneous tissue and skeletal muscles of the affected limbs. The histopathological changes such as extensive myonecrosis and hemorrhages with marked edema in skeletal muscles, widespread interstitial and intra-alveolar hemorrhages and fibrinous microthrombi in pulmonary vasculature, multifocal to coalescing areas of massive hemorrhages and coagulative necrosis within hepatic parenchyma and marked degeneration of renal tubular epithelium were evident. Therapeutic regimen consisting of polyvalent anti-snake venom, with antibiotics, diuretics, vitamin B complex, styptics, fluids and corticosteroids in non-pregnant while non-steroidal anti-inflammatory drugs in pregnant buffaloes was used. The present treatment strategy showed subsidence of clinical signs, restoration of platelet count, blood clotting time, urea nitrogen and creatinine values depicting clinical recovery with 88.15% survival rate in treated buffaloes.

Physiological Challenges and Adaptations in Competitive Freediving

Competitive freediving is associated with extreme physiologic challenges due to the effects of apnea, submersion in water, and increased ambient pressure. There has nevertheless been a continued progression of world records across freediving disciplines in recent years, with breath-hold times exceeding 10 minutes, and reaching diving depths beyond 200 meters of seawater. The main physiological determinants of breath-hold endurance are the available oxygen stores, i.e., intrapulmonary gas volume, inspired gas concentration, and rate of oxygen consumption. Other factors such as psychological and inherent factors contribute to the individual tolerance to an increasing respiratory stimulus with prolonged breath-hold duration. A freediving athlete must be able to tolerate apnea to stay underwater long enough to reach great distance or depth and resurface safely. Elite freedivers exhibit somewhat remarkable physiological adaptations such as a more pronounced diving-response and hypercapnia tolerance compared to non-divers, as well as metabolic and cerebrovascular adaptations. To reach great depths, elite freedivers employ a breathing technique called glossophyryngeal insufflation (GI) that is enlarging the ratio of total lung capacity to residual volume, thus, mitigating risk of lung squeeze and increasing intrapulmonary gas volume, and thereby enhancing available oxygen stores. Pulmonary anatomy and physiology could not be accounted to restrict the breath-hold diving depths achieved by competitive athletes. However, the acutely increased intrapulmonary pressure during GI is transmitted to the pulmonary vasculature, thereby eliciting a right ventricular pressure overload, and left ventricular dysfunction that may augment hypotension and syncope during glossopharyngeal insufflation. Due to extreme diffusion gradients between alveolar pN2 and N2 pressures in the body tissues at great depth, N2 will be forced into blood and body tissues during descent, elevating risk of N2 narcosis and decompression illness during deep dives. Breath-hold training and preparation have been shown to enhance breath-hold performance. This review highlights recent data on the profound cardiovascular, respiratory, and gas exchange effects that are observed in competitive freedivers, and discusses possible adaptations and risks for humans.

Ferroptosis-Mediated Inflammation Promotes Pulmonary Hypertension.

Mitochondrial dysfunction, characterized by impaired lipid metabolism and heightened reactive oxygen species generation, results in lipid peroxidation and ferroptosis. Ferroptosis is an inflammatory mode of cell death that promotes complement activation and macrophage recruitment. In pulmonary arterial hypertension (PAH), pulmonary arterial endothelial cells exhibit cellular phenotypes that promote ferroptosis. Moreover, there is ectopic complement deposition and inflammatory macrophage accumulation in the pulmonary vasculature. However, the effects of ferroptosis inhibition on these pathogenic mechanisms and the cellular landscape of the pulmonary vasculature are incompletely defined. Multiomics and physiological analyses evaluated how ferroptosis inhibition-modulated preclinical PAH. The impact of adeno-associated virus 1-mediated expression of the proferroptotic protein ACSL (acyl-CoA synthetase long-chain family member) 4 on PAH was determined, and a genetic association study in humans further probed the relationship between ferroptosis and pulmonary hypertension. Ferrostatin-1, a small-molecule ferroptosis inhibitor, mitigated PAH severity in monocrotaline rats. RNA-sequencing and proteomics analyses demonstrated ferroptosis was associated with PAH severity. RNA-sequencing, proteomics, and confocal microscopy revealed complement activation and proinflammatory cytokines/chemokines were suppressed by ferrostatin-1. In addition, ferrostatin-1 combatted changes in endothelial, smooth muscle, and interstitial macrophage abundance and gene activation patterns as revealed by deconvolution RNA-sequencing. Ferroptotic pulmonary arterial endothelial cell damage-associated molecular patterns restructured the transcriptomic signature and mitochondrial morphology, promoted the proliferation of pulmonary artery smooth muscle cells, and created a proinflammatory phenotype in monocytes in vitro. Adeno-associated virus 1-Acsl4 induced an inflammatory PAH phenotype in rats. Finally, single-nucleotide polymorphisms in 6 ferroptosis genes identified a potential link between ferroptosis and pulmonary hypertension severity in the Vanderbilt BioVU repository. Ferroptosis promotes PAH through metabolic and inflammatory mechanisms in the pulmonary vasculature.

Evaluation of an engineered vascular graft exhibiting somatic growth in lambs to model repair of absent pulmonary artery branch

BackgroundGrowth is the holy grail of tissue implants in pediatrics. No vascular graft currently in use for surgical repairs of congenital heart defects has somatic growth capacity.MethodsBiologically-engineered grafts (6 mm) grown from donor ovine fibroblasts in a sacrificial fibrin gel were implanted into the left pulmonary branch of 3-month old lambs for 3, 6, and 18 months. A control group of Propaten® PTFE grafts was implanted for 6 months.ResultsThe engineered grafts exhibit extensive site-appropriate recellularization after only 3 months and near-normal increase of diameter from the preimplant value of 6 mm to 12.9 mm and also a doubling of length from 6.0 mm to 13.0 mm at 6 months (n = 3) associated with apparent somatic graft growth (collagen content increase of 265% over 18-month, n = 2), along with excellent hemodynamics and no calcification, in contrast to the Propaten® grafts. The left-right flow distribution is nearly 50–50 for the engineered grafts at 6 months (n = 3) compared to about 20–80 for the Propaten® grafts (n = 3), which have less than one-half the diameter, a 6-fold higher pressure gradient, and stunted vascular development downstream of the graft. The engineered grafts exhibit a stable diameter over months 12–18 when the lambs become adult sheep (n = 2).ConclusionsThis study supports the use of these regenerative grafts with somatic growth capacity for clinical trial in patients born with a unilateral absent pulmonary artery branch, and it shows their potential for improving development of the downstream pulmonary vasculature.

Key Imaging Factors for Transcatheter Management of Tricuspid Regurgitation: Device and Patient Selection

The growing awareness of tricuspid regurgitation (TR) and the fast-expanding array of devices aiming to percutaneously repair or replace the tricuspid valve have underscored the central role of multi-modality imaging in comprehensively assessing the anatomical and functional characteristics of TR. Accurate phenotyping of TR, the right heart, and pulmonary vasculature via echocardiography, computed tomography, and, occasionally, cardiovascular magnetic resonance and right heart catheterization is deemed crucial in choosing the most suitable treatment strategy for each patient and achieving procedural success. In the first part of the present review, key imaging factors for patient selection will be discussed. In the ensuing sections, an overview of the most commonly used, commercially available systems for transcatheter repair/replacement will be presented, along with their respective selection criteria and information on intraprocedural imaging guidance; these are edge-to-edge repair, orthotopic and heterotopic replacement, and valve-in-valve procedures.

Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins diagnosed at autopsy in association with novel FOXF1 variant

Abstract Introduction/Objective Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACD/MPV) is a rare disorder characterized by abnormal development of the pulmonary vasculature resulting in intractable pulmonary hypertension in neonates. Affected newborns present with progressive hypoxemia that is nearly always fatal. ACD/MPV is typically seen in the setting of other congenital anomalies, including gastrointestinal, genitourinary, and cardiac systems. Although the pathogenesis of ACD/MPV is poorly understood, inactivating mutations in the FOXF1 gene have been implicated. We present a case of ACD/MPV with associated gastrointestinal/cardiac anomalies and a novel heterozygous mutation of FOXF1. Methods/Case Report A complete autopsy was perfomed. Rapid whole exome sequencing of whole blood was done via reference laboratory. Results (if a Case Study enter NA) A 36-week gestational age male was born via cesarean delivery following a pregnancy course complicated by polyhydramnios. The neonate developed respiratory failure requiring intubation and Extracorporeal Membranous Oxygenation (ECMO). Further clinical evaluation revealed a patent foremen ovale and ductus arteriosus with right to left shunting. After 18 days on ECMO, he was transferred to comfort care where he later died. The body was that of a small for gestational age, phenotypic male neonate without gross dysmorphia noted on external examination. Internal examination revealed duodenal atresia, a patent ductus arteriosus and foramen ovale, and heavy, edematous lungs. Histologic examination of the lungs demonstrated prominent congested veins abutting small arteries with medial hypertrophy within shared adventitial sheaths. The interlobar septa contained dilated lymphatic spaces. Airspaces showed a dense neutrophilic exudate. Rapid whole exome sequencing revealed heterozygous mutations in FOXF1 (c.182T&amp;gt;C, p.Ile61Thr), NOTCH1 (c.7495A&amp;gt;C, p.Ser2499Arg) and a hemizygous mutation in SSR4 (c.20G&amp;gt;T, p.Gly7Val). The FOXF1 mutation was predicted to be damaging and has not yet been reported in the literature; however, its clinical significance was interpreted as uncertain. The significance of the NOTCH1 and SSR4 mutations were considered unknown. Given these findings, a diagnosis of ACD/MPV was given as the cause of death. Conclusion This case illustrates the classic clinical, gross and histologic findings described in ACD/MPV. Additionally, a novel heterozygous mutation of FOXF1 was identified and predicted to be damaging, supporting the role of FOXF1 mutations in the pathogenesis of ACD/MPV.

Correlation between staging classification of aortic stenosis based on the extent of cardiac damage and platelet indices

BackgroundPlatelets play a key role in the natural history of aortic stenosis (AS) and after transcatheter aortic valve implantation (TAVI). An echo-based staging system stratifies patients with severe AS into 5 groups according to the associated cardiac damage phenotype. We aimed to correlate these AS stages with platelet indices in post-TAVI patients.MethodsPatients with severe AS who underwent TAVI and were admitted to intensive cardiac care unit (ICCU) were prospectively identified and divided into 5 groups according to extra-valvular cardiac damage [no extravalvular cardiac damage (Stage 0), left ventricular damage (Stage 1), left atrial or mitral valve damage (Stage 2), pulmonary vasculature or tricuspid valve damage (Stage 3), or right ventricular damage (Stage 4)]. Baseline characteristics and complete blood count including mean platelet volume (MPV) and immature platelet fraction (IPF) were collected within 2 h after the procedure and analyzed in relation to aortic stenosis staging.ResultsA total of 220 patients were included. The mean age was 81 years old and 112 (50.9%) were female. Two (1%) patients were classified in stage 0; 34 (15%) in stage 1; 48 (22%) in stage 2; 49 (22%) in stage 3 and 87 (40%) in stage 4. Higher mean MPV values were correlated with higher AS staging (10.8 fL, 11 fL, 11.3 fL and 10.8 fL in stages 1, 2, 3 and 4, respectively, P = 0.02) as well as lower hemoglobin values (12 mg/dl, 11.6 mg/dl, 11 mg/dl and 11.3 mg/dl in stages 1, 2, 3 and 4, respectively P = 0.04). Mean IPF values were 5.3%, 5.58%, 5.57% and 4.83% in stage 1, 2, 3 and 4, respectively (P = 0.4). In a multivariate logistic regression model only MPV (OR = 2.6, P = 0.03) and body mass index (BMI) (OR = 1.17, P = 0.004) were correlated with higher staging (0–3) of AS.ConclusionsAlthough IPF and MPV levels increased in stages 0–3, there was a decrease in indices in stage 4, (probably due to bone marrow dysfunction) in this end-stage population. Higher levels of MPV and lower levels of hemoglobin were independently correlated with higher stages (0–3) of AS.

Incidence and predictors of in-stent restenosis following intervention for pulmonary vein stenosis due to fibrosing mediastinitis

BackgroundFibrosing mediastinitis (FM) is a rare yet fatal condition, caused by different triggers and frequently culminating in the obstruction of the pulmonary vasculature and airways, often leading to pulmonary hypertension and right heart failure. Percutaneous transluminal pulmonary venoplasty (PTPV) is an emerging treatment for pulmonary vein stenosis (PVS) caused by FM. Our previous study showed as high as 24% of in-stent restenosis (ISR) in FM. However, the predictors of ISR are elusive.ObjectivesWe sought to identify the predictors of ISR in patients with PVS caused by extraluminal compression due to FM.MethodsWe retrospectively enrolled patients with PVS-FM who underwent PTPV between July 1, 2018, and December 31, 2022. According to ISR status, patients were divided into two groups: the ISR group and the non-ISR group. Baseline characteristics (demographics and lesions) and procedure-related information were abstracted from patient records and analyzed. Univariate and multivariate analyses were performed to determine the predictors of ISR.ResultsA total of 142 stents were implanted in 134 PVs of 65 patients with PVS-FM. Over a median follow-up of 6.6 (3.4–15.7) months, 61 of 134 PVs suffered from ISR. Multivariate analysis demonstrated a significantly lower risk of ISR in PVs with a larger reference vessel diameter (RVD) (odds ratio (OR): 0.79; 95% confidence interval [CI]: 0.64 to 0.98; P = 0.032), and stenosis of the corresponding pulmonary artery (Cor-PA) independently increased the risk of restenosis (OR: 3.41; 95% CI: 1.31 to 8.86; P = 0.012). The cumulative ISR was 6.3%, 21.4%, and 39.2% at the 3-, 6-, and 12-month follow-up, respectively.ConclusionISR is very high in PVS-FM, which is independently associated with RVD and Cor-PA stenosis.Trail RegistrationChinese Clinical Trials Register; No.: ChiCTR2000033153. URL: http://www.chictr.org.cn.Graphical

Assessment of pulmonary hypertension in patients diagnosed with chronic kidney disease

BackgroundPulmonary hypertension (PH) represents a condition affecting small arteries of the pulmonary vasculature, inducing progressive blockage that results in increased pulmonary vascular resistance (PVR) as well as pulmonary arterial pressure (PAP), which are defining features of such a disorder. This work was aimed at investigating the PH prevalence among chronic kidney disease (CKD) cases and its linkage to disease severity and the relations between CKD management and PH.MethodsOur prospective observational descriptive cross-sectional study was conducted on 120 CKD patients at the Chest Department, Tanta University Hospitals and Air Forces Specialized Hospitals from December 2020 to December 2022.ResultsThe most frequent diagnosis of PH was Group 1 pulmonary arterial hypertension (36.7%) followed by Group 2 cardiac causes (30%) followed by Group 4 chronic thromboembolic PH (26.7%) and (6.7%) experienced normal pulmonary hemodynamics by RHC. Also, a statistically significant correlation was documented among CKD staging as well as risk assessment of PH (p 0.024). A significant association was documented among treatment as well as risks for developing PH (p 0.034). Patients on medical treatment (60%) showed low risk while (33.3%) of patients depending on dialysis showed high risk.ConclusionsPH was diagnosed in 28 CKD patients confirmed by right (RT) side cardiac catheterization among 120 CKD patients studied for PH assessment representing 23.5%. Right-side cardiac catheterization is more accurate than echocardiography in confirming the diagnosis of PH. The severity of PH showed significant association with the CKD stage.