Progressive Pulmonary Hypertension Research Articles

Pulmonary tumor thrombotic microangiopathy: Two case reports and literature review

Rationale: Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare but serious complication in patients with malignancy; its main manifestation includes acute pulmonary hypertension with severe respiratory distress. More than 200 cases have been reported since it was first identified in 1990. PTTM accounts for approximately 0.9% to 3.3% of deaths due to malignancy, but only a minority of patients are diagnosed ante-mortem, with most patients having a definitive diagnosis after autopsy. Patient concerns: Two middle-aged women both died within a short period of time due to progressive dyspnea and severe pulmonary hypertension. Diagnoses: One patient was definitively confirmed as a gastrointestinal malignant tumor by liver puncture biopsy pathology. Ultimately, the clinical diagnosis was pulmonary tumor thrombotic microangiopathy. Interventions: The patient was treated symptomatically with oxygen, diuresis, and anticoagulation, while a liver puncture was perfected to clarify the cause. Outcomes: Two cases of middle-aged female patients with rapidly progressive pulmonary hypertension and respiratory failure resulted in death with malignant neoplasm. Lessons: PTTM has a rapid onset and a high morbidity and mortality rate. Our clinicians need to be more aware of the need for timely diagnosis through a targeted clinical approach, leading to more targeted treatment and a better prognosis.

Multimodal Assessment and Intramodal Comparison of Imaging Techniques for Pediatric Pulmonary Vein Stenosis with Pulmonary Hypertension.

Pulmonary vein stenosis (PVS) is a rare, serious, and progressive disease in the pediatric population. Evaluation is complex and involves multimodality imaging. Diagnosis is important as early treatment to prevent progressive pulmonary hypertension and right ventricular dysfunction is essential. Adult studies have shown good correlation between various imaging modalities; however, there are limited data in children. This is a single-center retrospective pilot study to determine the reliability of measurement of pulmonary vein stenosis and pulmonary hypertension across different imaging modalities-computed tomography angiography (CTA), echocardiography (echo), lung perfusion scan (LPS), and cardiac catheterization (cath). PVS was defined as > 2mmHg by echo and cath and/or 50% reduction in diameter by CTA. Patients had to have an echo, CTA and cath performed within a 1-month timeframe of one another to be included in the study, with LPS data included if testing was completed at initial evaluation. Fifteen total patients were enrolled; 87% were categorized as primary PVS; a condition not directly related to direct injury or prior surgical intervention. Twenty-seven total stenotic pulmonary veins were identified (mean 1.8, range 1-4). CTA had a slightly better agreement with cath than echo in identifying PVS in different vein locations except in the LLPV. Additionally, echo and CTA had excellent sensitivity (91%) and specificity (100%) compared to cath for diagnosis of PH. We conclude that non-invasive imaging of echo and CTA has an acceptable correlation to cardiac catheterization for screening and initial evaluation of PVS and PH, as directly related to PVS, in pediatrics.

Flemish network on rare connective tissue diseases (CTD): patient pathways in systemic sclerosis. First steps taken

ABSTRACT Despite the low prevalence of each rare disease, the total burden is high. Patients with rare diseases encounter numerous barriers, including delayed diagnosis and limited access to high-quality treatments. In order to tackle these challenges, the European Commission launched the European Reference Networks (ERNs), cross-border networks of healthcare providers and patients representatives. In parallel, the aims and structure of these ERNs were translated at the federal and regional levels, resulting in the creation of the Flemish Network of Rare Diseases. In line with the mission of the ERNs and to ensure equal access to care, we describe as first patient pathways for systemic sclerosis (SSc), as a pilot model for other rare connective and musculoskeletal diseases. Consensus was reached on following key messages: 1. Patients with SSc should have multidisciplinary clinical and investigational evaluations in a tertiary reference expert centre at baseline, and subsequently every three to 5 years. Intermediately, a yearly clinical evaluation should be provided in the reference centre, whilst SSc technical evaluations are permissionably executed in a centre that follows SSc-specific clinical practice guidelines. In between, monitoring can take place in secondary care units, under the condition that qualitative examinations and care including interactive multidisciplinary consultations can be provided. 2. Patients with early diffuse cutaneous SSc, (progressive) interstitial lung disease and/or pulmonary arterial hypertension should undergo regular evaluations in specialised tertiary care reference institutions. 3. Monitoring of patients with progressive interstitial lung disease and/or pulmonary (arterial) hypertension will be done in agreement with experts of ERN LUNG.

Rapidly Progressive Idiopathic Pulmonary Arterial Hypertension in a Paediatric Patient Treated with Lung Transplantation.

Pulmonary arterial hypertension (PAH) is a rare heterogeneous disorder in the paediatric population which is mostly associated with congenital heart disease. The management of paediatric idiopathic PAH (IPAH) is difficult due to insufficient comparative data and depends on the results of evidence-based adult studies with several pulmonary vasodilators, as well as the clinical experiences of paediatric experts. Our aim was to present the case of a 9-year-old girl who underwent several methods of treatment, including pharmacotherapy with a significant reaction to treprostinil, as well as bilateral lung transplantation. The patient's treatment was distinguished by the fact that the dose escalation was as rapid as that observed in the adult population. Due to the limited current evidence and knowledge, the initiation of treatment for these patients remains an individual choice. On the grounds of the number of non-specific symptoms, the diagnosis of this patient was a long process and based mainly on the differential diagnosis. The purpose of this paper is to study this example in order to highlight the importance of early symptoms and the quick implementation of intensive treatment. The applied methods may be useful in doubtful diagnosis processes and treatment procedures in the paediatric population.

Right ventricular strain by speckle tracking echocardiography in patients with systemic scleroderma and absence of pulmonary hypertension

Abstract Funding Acknowledgements Type of funding sources: None. Introduction In patients with scleroderma the morphological remodeling and alteration of right ventricular (RV) function begins even before the setting of pulmonary artery hypertension (PAH). These alterations are associated with worse outcomes and high mortality rate as 30% of deaths are attributed to cardiovascular causes followed by respiratory causes (17%). Purpose Early detection of RV dysfunction is possible using advanced imaging techniques and can lead to specific therapeutic management before installation of PAH and clinical signs and symptoms of heart failure . Purpose of this study is to evaluate new indices, based on speckle tracking echocardiography, for identification of subclinical RV systolic failure. Methods Thirty (30) scleroderma patients without any signs or symptoms of PAH and forty (40) healthy subjects were included in the present study. Two-dimensional echocardiography (2DE) and two-dimensional speckle-tracking echocardiography (2DSTE) were performed. All the usual 2DE, Doppler and tissue Doppler imaging measurements were obtained for the evaluation of RV function. Moreover, TAPSE, maximum systolic myocardial velocity from TDI of lateral tricuspid valve annulus (SRV), auto RV global longitudinal strain (aRVGLS) and auto RV free wall longitudinal strain (aRVFWLS) by 2DSTE were measured. aRVGLS and aRVFWLS are new indices, with appropriate RV function echo logistics in new technology echo systems, independent from known manual measurements. Results In scleroderma patients significantly higher systolic pulmonary artery pressure was recorded, although it remained within normal limits in both groups (24.6+-5.4mmHg vs 19.2+-5.9 mmHg) . Scleroderma patients had significant decreased RV systolic function with significantly lower TAPSE and SRV. Both aRVGLS and aRVFWLS were also lower in scleroderma patients compared to the control group (−18.6+-2.7 vs −23.1+-2.3 % and −25.4+-3.1 vs −26.4+-2.2 % respectively). aRVGLS was the best significant predictor of early RV systolic impairment in patients with scleroderma.The difference in aRVFWLS was not significant. Conclusions Scleroderma is a severe systematic disease associated with high mortality rates. RV remodeling, dysfunction, and progressive pulmonary artery hypertension are among the most important internal organ manifestations of this disease. Early detection of RV dysfunction before installation of pulmonary hypertension is possible by 2DSTE, and may be helpful to guide further therapy in these patients.

P87: Fracture Of A Dual Lumen Protekduo Cannula With Ventricular Perforation And Tamponade In A Recovery COVID-19 Patient

Background: In the absence of formal registry data anecdotal reports of cannula complications provide the only mechanism of risk assessment in the extended use of short term mechanical circulatory support devices. We report an unrecognized cannula fracture with perforation of the right ventricular apex and subsequent tamponade at the time of de-cannulation. Methods and Results: Patient is a 38 yo AAF with a history of asthma diagnosed with COVID 19 (nasal PCR) and admitted to an OSH with hypoxia (O2 sat 70%) and progressive dyspnea on exertion requiring HFNC and subsequent deployment of a right internal jugular 29 Fr Protek-DUO double lumen cannula with in-line oxygenator for venovenous ECMO respiratory support. After 36 days of VV ECMO support and mechanical ventilation, the patient was transferred with a diagnosis of COVID ARDS for transplant evaluation. Fourteen days post-transfer the patient was ambulatory and no longer required mechanical ventilation. No flow related issues were noted during the entire period of ECMO support (flow 2.8 to 3.4 L/min, delta P 20 mmHg or less, single oxygenator exchange on ECMO day 38). On ECMO day 67 the patients CxR was clear (Figure 1) and the RIJ cannula was removed without complication. Approximately two minutes after cannula removal the patient became unresponsive with tachycardia and hypotension (SBP 60 mmHg) which initially responded to volume resuscitation. With progressive loss of systolic blood pressure chest compressions were started with complete hemodynamic collapse. A transthoracic ECHO suggested tamponade and the chest was opened at the bedside demonstrating a chronic appearing hematoma with blood extravasation at the apex of the right ventricle (Figure 2). Bleeding was controlled with a single prolene stitch. Subsequent examination of the cannula demonstrated a fracture in the wire reinforced cannula at the point where the catheter transitioned from the apical RV into the RVOT (Figure 3). Conclusion: Given the progressive pulmonary hypertension frequently seen with prolonged COVID ECMO support, the RA to PA dual-lumen cannula has proven an effective MCS strategy (1) with survival advantage when compared to standard VV ECMO support (2). The Protek-DUO cannula was not designed for prolonged ambulatory MCS (> 60 days). Given the recent report of a seemingly identical cannula fracture event (3), clinicians should be aware of the potential for cannula fracture over time. Literature Cited (1) Mustafa AK, et al. (2020) ECMO for patients with COVID-19 in severe respiratory failure. JAMA Surg 155(10):990-992. (2) Saeed O, et al (2022) Outcomes by cannulation method for venovenous ECMO during COVID-19: a multicenter retrospective study. 46(8):1659-1668. doi: 10.1111/aor.14213. (3) Odish MF, et al (2022) Fracture right atrial-pulmonary artery cannula (Protek-DUO) in a 164-day extracorporeal membrane oxygenation bridge to lung transplant. doi: 10.1097/MAT.0000000000001879. Online ahead of print.

An intronic variant in TBX4 in a single family with variable and severe pulmonary manifestations

A male infant presented at term with neonatal respiratory failure and pulmonary hypertension. His respiratory symptoms improved initially, but he exhibited a biphasic clinical course, re-presenting at 15 months of age with tachypnea, interstitial lung disease, and progressive pulmonary hypertension. We identified an intronic TBX4 gene variant in close proximity to the canonical donor splice site of exon 3 (hg 19; chr17:59543302; c.401 + 3 A > T), also carried by his father who had a typical TBX4-associated skeletal phenotype and mild pulmonary hypertension, and by his deceased sister who died shortly after birth of acinar dysplasia. Analysis of patient-derived cells demonstrated a significant reduction in TBX4 expression resulting from this intronic variant. Our study illustrates the variable expressivity in cardiopulmonary phenotype conferred by TBX4 mutation and the utility of genetic diagnostics in enabling accurate identification and classification of more subtly affected family members.

Abstract 14134: Associations of Social Determinants of Health With Pulmonary Hypertension Severity and Reported Quality of Life

Introduction: Though the chronic, progressive disease Pulmonary Hypertension (PH) has no known cure, timely and appropriate treatment can improve outcomes. Social determinants of health (SDH) may influence treatment accessibility and outcomes. We hypothesized that Social Vulnerability Index (SVI) and Hardship Index (HDX, i.e., living in a zip code of higher hardship) are associated with measures of PH severity and quality of life (QoL). Methods: Patients at UI Health aged ≥18 years, diagnosed with PH from 2017-2021, and with EmPHasis-10 QoL scores and residence zip code data were included. SDH included Social Vulnerability Index (SVI) and Hardship Index (HDX). Income was retrieved from 2019 US Census data and most recent socio-behavioral data from the Chicago Health Atlas. Multivariate and logistic regression analysis were performed using SAS. Results: In 58 patients, mean age was 58 (SD 13.5), 47 (81.0%) were women, and 42 (72.4%) were non-Hispanic black. In this cohort, the uninsured rate showed a significant positive correlation with tricuspid regurgitant velocity on echocardiogram (p = 0.048) and, as SVI increased, there was a trend toward higher right atrial pressure (p = 0.07). Unexpectedly, there was a trend toward lower EmPHasis 10 scores (indicating better reported QoL) in subjects with worse SVI or HDX. When examining this further, a modified EmPHasis 10 QoL score focused on rest, exhaustion, and energy showed a significant inverse correlation of QoL with either SVI or HDX (p = .025 and p = .045, respectively). Conclusions: SDH appear to be associated with measures of PH severity. These findings suggest that SDH may negatively impact disease, which will need to be tested in a longitudinal study. The inverse correlation of SVI and HDX with QoL, particularly when focusing on personal experience, was unexpected. In theory, perceived norms and cultural context in high hardship, socially vulnerable communities may alter patient perception of disease impact on QoL. Future analysis should focus on further characterization of patient experiences in diverse populations with PH to ensure that we have accurate tools and are addressing the needs of our diverse community.

Adenotonsillar Hypertrophy and Cardiopulmonary Status: A Correlative Study.

Introduction Adenotonsillar hyperplasia in childhood is a common phenomenon. It has been reported in the literature that increased upper-airway resistance resulting from hypertrophied tonsils and adenoids can cause intermittent airway obstruction, chronic alveolar hypoventilation, and even lead to severe cardiopulmonary complications such as right ventricular (RV) failure and cor-pulmonale, a near-lethal culmination of pulmonary artery hypertension (PAH). This study was undertaken to explore and examine the association of adenotonsillar hypertrophy and cardiopulmonary status in patients with complaints of upper airway obstruction below the age of 20 yearsandto analyze the effect of adenotonsillar enlargement on pulmonary function tests and cardiac aberration reflectedin the electrocardiography (ECG) changes. Methods This study included patients visiting or admitted to the Otolaryngology/Ear, Nose, and Throat (ENT) and Paediatrics department of Acharya Vinoba Bhave Hospital, Sawangi (Meghe), Wardha, Maharashtra, India. It is anObservational Prospective Study conducted on 75 Patients (50 cases and 25 controls) below the age of 20 years. Inclusion criteria for cases included all patients of adenoid hypertrophy (AH) and adenotonsillar hypertrophy (ATH). Inclusion criteria for controls comprised all patients with a history and clinical examination not suggestive of any upper airway and pulmonary disease. All the patients were subjected to pulmonary function tests (PFT) and electrocardiography (ECG), and thevalues were compared. Results It was found that there was a decrease in the value of the parameters of the pulmonary function tests (PFT), which includesforced expiratory volume in the first second (FEV1), forced vital capacity (FVC), the ratio of the forced expiratory volume in the first one second to the forced vital capacity of the lungs (FEV1/FVC) and peak expiratory flow rate (PEFR) with increasing severity of theendoscopic grades of adenoid hypertrophy. This was found to be statistically significant. All the PFT parameters were significantly lower in the subset of patients with ATH compared to those with AH only, emphasizing the compounding effect of tonsillar volume. Between case and control subjects also, these differences were statistically significant. Seventeen (34%) out of the 50 patients studied in the present work were found to have abnormalities in their ECG, while no subject in the control group had any departure from normal. Nine of these 17 patients had AH, and eight had the adenotonsillar disease. In the 9 patients (18%) with AH, sinus arrhythmia was seen in 5 (10%), sinus tachycardia in 3 (6%), and Mobitz type 1 block in 1 (2%) patients. In 8 patients (16%) with AH, sinus arrhythmia was seen in 4 (8%), sinus tachycardia in 3 (6%), and Mobitz type 1 block in 1 (2%) patients. Overall, sinus arrhythmia was the commonest finding seen in 9 patients (18%). Conclusion Chronic obstructive adenotonsillar hypertrophy causes significant cardiovascular and pulmonary changes, which is often overlooked in the clinical setting. Symptoms of progressive pulmonary hypertension are minimal until the rapid onset of severe cardiac decompensation occurs. These entire cascades of events are reversible in the early stages and thus mandate early detection and treatment. Performing PFT and ECGin children with adenotonsillar disease is not mandatory but profitable even in the absence of obvious symptoms of upper airway obstruction.

Automated right ventricular strain by speckle tracking echocardiography in patients with systemic scleroderma

Abstract Introduction In patients with scleroderma the morphological remodeling and alteration of right ventricular (RV) function begins even before the setting of pulmonary artery hypertension (PAH). These alterations are associated with worse outcomes and high mortality. Purpose Early detection of RV dysfunction is possible using advanced imaging techniques and can lead to specific therapeutic measures before installation of PAH. Purpose of this study is to evaluate new indices, based on speckle tracking technology, for identification of subclinical RV systolic failure. Methods Twenty-five (25) scleroderma patients without any signs or symptoms of PAH and twenty-five (25) healthy subjects were included in the present study. Two-dimensional echocardiography (2DE) and two-dimensional speckle-tracking echocardiography (2DSTE) were performed. All the usual 2DE, Doppler and tissue Doppler imaging measurements were obtained for the evaluation of RV function. Moreover, TAPSE, maximum systolic myocardial velocity from TDI of lateral tricuspid valve annulus (SRV), auto RV global longitudinal strain (aRVGLS) and auto RV free wall longitudinal strain (aRVFWLS) by 2DSTE were measured. aRVGLS is a new index, with appropriate RV function echo logistics in new technology echo systems, independent from known manual measurements. Results In scleroderma patients significantly higher systolic pulmonary artery pressure was recorded, although it remained within normal limits in both groups. Scleroderma patients had significant decreased RV systolic function with significantly lower TAPSE and SRV. Both aRVGLS and aRVFWLS were also significantly lower in scleroderma patients compared to the control group. aRVGLS was the best predictor of early RV systolic impairment in patients with scleroderma. Conclusions Scleroderma is a severe systematic disease associated with high mortality rates. RV remodeling, dysfunction, and progressive pulmonary artery hypertension are among the most important internal organ manifestations of this disease. Early detection of RV dysfunction is possible by 2DSTE, and may be helpful to guide further therapy in these patients. Funding Acknowledgement Type of funding sources: None.

Update on balloon pulmonary angioplasty for treatment of chronic thromboembolic pulmonary hypertension

To provide an update on balloon pulmonary angioplasty (BPA) for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH), a pulmonary vascular disease that is characterized by fibro-thrombotic material mechanically obliterating major pulmonary arteries, resulting in increased pulmonary vascular resistance (PVR), progressive pulmonary hypertension (PH) combined with a microscopic pulmonary vasculopathy [1▪▪], right ventricular (RV) failure [2] and premature death. Data from a most recent CTEPH European registry (2015 and 2016) suggest significantly improved survival [3▪] of CTEPH patients compared with survival in the eighties [4], or with data from 2007 and 2009 [5]. Pulmonary endarterectomy (PEA) is still the gold-standard therapy for CTEPH [6,7]. However, only around two thirds of all CTEPH patients are amenable to surgery [3▪,5]. Patients not suitable for PEA and treated conservatively have a poor prognosis [8]. BPA may have a role for this particular group of patients. [9-11]. Currently, BPA programs are available in many countries, with excellent results at expert centers [12-15,16▪,17,18▪▪]. Based on recent data, BPA seems to have a greater impact on symptomatic and hemodynamic improvement than medical therapy with riociguat alone [15]. The evidence favoring BPA is growing, but there is still a lack of published controlled trials. In addition, treatment concepts including indication, technical performance, use of PH-targeted medication, and the concept of follow-up vary between centers. In addition, there is a significant learning curve impacting outcomes [13]. The data from the International BPA registry will provide answers for some of the open questions.

Two Case Reports of Progressive Pulmonary Hypertension with Type-1 Gaucher Disease: Efficient PAH-Specific Therapy and 1-Year Follow-Up

Two Case Reports of Progressive Pulmonary Hypertension with Type-1 Gaucher Disease: Efficient PAH-Specific Therapy and 1-Year Follow-Up

Pulmonary Hypertension and Diastolic Heart Failure in an Adolescent African-American Cantú Syndrome Patient

<h3>Introduction</h3> Cantú syndrome is a rare congenital condition characterized by hypertrichosis, coarse facial features, cardiomegaly, skeletal abnormalities, and tortuous vasculature. While progress has been made in the understanding of the molecular basis of this disease, there is still much to be uncovered regarding its natural history. Here, we present the clinical course of an African-American male with Cantú syndrome. <h3>Case Report</h3> A 4-month-old African-American male presented to the hospital with respiratory distress. A large pericardial effusion was identified, which required a pericardial window. Cardiac catheterization revealed pulmonary hypertension. At age 4, a diagnosis of Cantú syndrome was made on the basis of developmental delay, cardiomegaly, history of pericardial effusion, pulmonary hypertension, coarse facial features, hypertrichosis, wide/thickened ribs, and osteopenia. He developed chronic diastolic heart failure secondary to cardiomegaly and chronic hypercarbic respiratory failure requiring home oxygen and nocturnal bi-level positive airway pressure (BiPAP) therapy. Pulmonary hypertension treatment was initiated with sildenafil at age 13, resulting in significant improvement in exercise tolerance. Cardiac catheterization at 17 years of age demonstrated worsening pulmonary hypertension with baseline RV pressures of 85/18 mmHg and pulmonary artery (PA) pressures of 85/40 mmHg. Baseline pulmonary vascular resistance (PVR) was 15.7 Woods Units/m2. Vasoreactivity to O2 and inhaled nitric oxide was demonstrated with PVR decreasing to 6.6 and 5.5 Woods Units/m2 respectively. Carvedilol and cardiac rehabilitation therapy were initiated at age 19. On a recent admission, he required milrinone support due to worsening right ventricular (RV) dysfunction which was weaned prior to discharge. <h3>Summary</h3> Cantú syndrome is a rare genetic condition and its prevalence and prognosis are still unknown. Interestingly, nearly all patients in the International Cantú Syndrome Registry are Caucasian while our patient is African-American. Additionally, with no family history of the disease, it is possible that his case represents a sporadic mutation. Unfortunately, our patient exhibited progressive heart failure, pulmonary hypertension, and hypercarbic respiratory failure during his adolescent years.

КОМБИНАЦИЯ АТРЕЗИИ ПИЩЕВОДА С ТРАХЕОПИЩЕВОДНЫМ СВИЩОМ И ДУОДЕНАЛЬНОЙ АТРЕЗИЕЙ: АНАЛИЗ ЛЕЧЕНИЯ ПЯТНАДЦАТИ ПАЦИЕНТОВ

КОМБИНАЦИЯ АТРЕЗИИ ПИЩЕВОДА С ТРАХЕОПИЩЕВОДНЫМ СВИЩОМ И ДУОДЕНАЛЬНОЙ АТРЕЗИЕЙ: АНАЛИЗ ЛЕЧЕНИЯ ПЯТНАДЦАТИ ПАЦИЕНТОВ

Macroscopic Characteristics of the Native Liver in Children With MPV17-Related Mitochondrial DNA Depletion Syndrome: An Indication for Performing Liver Transplantation?

Mitochondrial respiratory chain disorders (MRCDs) are rare conditions with various clinical manifestations that depend on the genetic type, with subsequent severity of the liver disease. Clinical presentations include acute liver failure or chronic liver failure with liver cirrhosis, which are cruelly progressive and fatal. We report six cases of LT for acute liver failure diagnosed pathogenic MPV17 variants. Three out of six cases were siblings with the MPV17-mutation (c.148C>T, p.R50W / c.149G>A; p.R50Q), also known as the childhood form of Navajo neurohepatopathy. Those three patients underwent LT for liver cirrhosis at the ages of 5, 7, and 7 years, respectively. All three recipients are currently doing well without any neurological sequelae. In contrast, the three additional patients that presented with an acute liver failure and subsequent diagnosis of mutation in MPV17 (homozygous c.451dupC: p.L151PfsX39; homozygous c.451dupC : p.L151PfsX39; c.451dupC : p.L151PfsX39 / c.71-2_79del11ins4), underwent LT at the ages of 4 months, 11 months, and 1 year, respectively. All three recipients died from pulmonary hypertension following successful LT. Interestingly, the intraoperative macroscopic findings of the native liver at the time of LT revealed distinctive, microgranular nodules and liver fibrosis with severe steatosis ("avocado-like" liver). LT might be contraindicated in MPV17 patients with c.451dupC mutation due to the extremely poor prognosis caused by fatal progressive pulmonary hypertension. The identification of the typical macroscopic finding ("avocado-like"), seen in such pediatric transplant candidates with acute liver failure, might be helpful to provide an early diagnosis of MPV17-related c.451dupC mutation.

Coronavirus disease 2019-associated pulmonary fibrosis: clinical findings, pathogenesis, and potential treatment.

Coronavirus disease 2019-associated pulmonary fibrosis: clinical findings, pathogenesis, and potential treatment.

Hospitalisations related to systemic sclerosis and the impact of interstitial lung disease. Analysis of patients hospitalised at the University of Michigan, USA.

To determine the primary reason for hospitalisations in systemic sclerosis (SSc) and impact of underlying interstitial lung disease (ILD) in a tertiary scleroderma centre. A retrospective analysis on a subset of a scleroderma cohort from 2011-2019 was performed to assess causes for hospitalisations and mortality. A chart review was performed to extract demographics, primary reason for hospitalisation and inpatient mortality. Admissions were classified as SSc (if hospitalisation reason was related to primary organ dysfunction) and non-SSc related causes. The mean age of the cohort was 53.1 years, 78% were women, and the mean disease duration was 5.2 years. Among 484 patients, 182 (37.6%) were admitted for a total of 634 admissions. In 382 SSc-related admissions, pulmonary hypertension (12.0%) and gastrointestinal dysmotility (11.0%), were major causes of urgent admissions; management of digital vasculopathy (26.1%) was the major reason for elective admissions. In 252 non-SSc related admissions, infection (respiratory:11.5%, skin and soft tissue: 6.3%) was the major reason for urgent admissions, and elective surgery (21.4%) was the major reason for elective admissions. We found 65% of all patients had underlying ILD and a greater proportion of patients with ILD were hospitalised (122 patients). Overall inpatient mortality was 9.3% and the leading cause for mortality was progressive pulmonary hypertension. Among a large cohort of SSc patients who are followed at a tertiary scleroderma centre, 37.6 % had hospital admissions, while worsening pulmonary hypertension, ILD, cardiac involvement and infectious complications were the major cause of mortality and morbidity.

Perturbation of semaphorin and VEGF signaling in ACDMPV lungs due to FOXF1 deficiency

BackgroundAlveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare lethal congenital lung disorder in neonates characterized by severe progressive respiratory failure and refractory pulmonary hypertension, resulting from underdevelopment of the peripheral pulmonary tree. Causative heterozygous single nucleotide variants (SNVs) or copy-number variant (CNV) deletions involving FOXF1 or its distant lung-specific enhancer on chromosome 16q24.1 have been identified in 80–90% of ACDMPV patients. FOXF1 maps closely to and regulates the oppositely oriented FENDRR, with which it also shares regulatory elements.MethodsTo better understand the transcriptional networks downstream of FOXF1 that are relevant for lung organogenesis, using RNA-seq, we have examined lung transcriptomes in 12 histopathologically verified ACDMPV patients with or without pathogenic variants in the FOXF1 locus and analyzed gene expression profile in FENDRR-depleted fetal lung fibroblasts, IMR-90.ResultsRNA-seq analyses in ACDMPV neonates revealed changes in the expression of several genes, including semaphorins (SEMAs), neuropilin 1 (NRP1), and plexins (PLXNs), essential for both epithelial branching and vascular patterning. In addition, we have found deregulation of the vascular endothelial growth factor (VEGF) signaling that also controls pulmonary vasculogenesis and a lung-specific endothelial gene TMEM100 known to be essential in vascular morphogenesis. Interestingly, we have observed a substantial difference in gene expression profiles between the ACDMPV samples with different types of FOXF1 defect. Moreover, partial overlap between transcriptome profiles of ACDMPV lungs with FOXF1 SNVs and FENDRR-depleted IMR-90 cells suggests contribution of FENDRR to ACDMPV etiology.ConclusionsOur transcriptomic data imply potential crosstalk between several lung developmental pathways, including interactions between FOXF1-SHH and SEMA-NRP or VEGF/VEGFR2 signaling, and provide further insight into complexity of lung organogenesis in humans.

Echocardiographic, Biochemical, and Electrocardiographic Correlates Associated With Progressive Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH) is a progressive proliferative vasculopathy associated with mechanical and electrical changes, culminating in increased vascular resistance, right ventricular (RV) failure, and death. With a main focus on invasive tools, there has been an underutilization of echocardiography, electrocardiography, and biomarkers to non-invasively assess the changes in myocardial and pulmonary vascular structure and function during the course of PAH.Methods: A SU5416-hypoxia rat model was used for inducing PAH. Biventricular functions were measured using transthoracic two-dimensional (2D) echocardiography/Doppler (echo/Doppler) at disease onset (0 week), during progression (3 weeks), and establishment (5 weeks). Similarly, electrocardiography was performed at 0, 3, and 5 weeks. Invasive hemodynamic measurements and markers of cardiac injury in plasma were assessed at 0, 3, and 5 weeks.Results: Increased RV systolic pressure (RVSP) and rate of isovolumic pressure rise and decline were observed at 0, 3, and 5 weeks in PAH animals. EKG showed a steady increase in QT-interval with progression of PAH, whereas P-wave height and RS width were increased only during the initial stages of PAH progression. Echocardiographic markers of PAH progression and severity were also identified. Three echocardiographic patterns were observed: a steady pattern (0–5 weeks) in which echo parameter changed progressively with severity [inferior vena cava (IVC) expiratory diameter and pulmonary artery acceleration time (PAAT)], an early pattern (0–3 weeks) where there is an early change in parameters [RV fractional area change (RV-FAC), transmitral flow, left ventricle (LV) output, estimated mean PA pressure, RV performance index, and LV systolic eccentricity index], and a late pattern (3–5 weeks) in which there is only a late rise at advanced stages of PAH (LV diastolic eccentricity index). RVSP correlated with PAAT, PAAT/PA ejection times, IVC diameters, RV-FAC, tricuspid systolic excursion, LV systolic eccentricity and output, and transmitral flow. Plasma myosin light chain (Myl-3) and cardiac troponin I (cTnI) increased progressively across the three time points. Cardiac troponin T (cTnT) and fatty acid-binding protein-3 (FABP-3) were significantly elevated only at the 5-week time point.Conclusion: Distinct electrocardiographic and echocardiographic patterns along with plasma biomarkers were identified as useful non-invasive tools for monitoring PAH progression.

Necrosis-Released HMGB1 (High Mobility Group Box 1) in the Progressive Pulmonary Arterial Hypertension Associated With Male Sex.

Damage-associated molecular patterns, such as HMGB1 (high mobility group box 1), play a well-recognized role in the development of pulmonary arterial hypertension (PAH), a progressive fatal disease of the pulmonary vasculature. However, the contribution of the particular type of vascular cells, type of cell death, or the form of released HMGB1 in PAH remains unclear. Moreover, although male patients with PAH show a higher level of circulating HMGB1, its involvement in the severe PAH phenotype reported in males is unknown. In this study, we aimed to investigate the sources and active forms of HMGB1 released from damaged vascular cells and their contribution to the progressive type of PAH in males. Our results showed that HMGB1 is released by either pulmonary artery human endothelial cells or human pulmonary artery smooth muscle cells that underwent necrotic cell death, although only human pulmonary artery smooth muscle cells produce HMGB1 during apoptosis. Moreover, only human pulmonary artery smooth muscle cell death induced a release of dimeric HMGB1, found to be mitochondrial reactive oxygen species dependent, and TLR4 (toll-like receptor 4) activation. The modified Sugen/Hypoxia rat model replicates the human sexual dimorphism in PAH severity (right ventricle systolic pressure in males versus females 54.7±2.3 versus 44.6±2 mm Hg). By using this model, we confirmed that necroptosis and necrosis are the primary sources of circulating HMGB1 in the male rats, although only necrosis increased circulation of HMGB1 dimers. Attenuation of necrosis but not apoptosis or necroptosis prevented TLR4 activation in males and blunted the sex differences in PAH severity. We conclude that necrosis, through the release of HMGB1 dimers, predisposes males to a progressive form of PAH.