Pulmonary Vascular Disease Research Articles

Exploring the Role of Trial Occlusion Test in Patent Ductus Arteriosus (PDA) Closure: A Serial Case

Background: Patent ductus arteriosus occurs in around 1 in 2000 full-term live newborns, making up 10-15% of cases of congenital heart disease. Percutaneous device closure is largely regarded as the preferred therapy for people diagnosed with PDA. Nevertheless, the closure of the PDA with a device is still a difficult task in patients with severe PAH. The trial occlusion strategy is used to evaluate the response of patients with severe pulmonary hypertension after closing the defect by briefly blocking it. This test has the potential to serve as a reliable predictor of the future progression of pulmonary hypertension. Case Presentation: We provide a report on three instances that underwent percutaneous closure of patent ductus arteriosus (PDA) in the presence of pulmonary hypertension. A 24-year-old adult patient arrived at our hospital with symptoms of intermittent dyspnea, easy fatigability, and occasional non-productive cough. The examination detected a persistent murmur located at the upper left sternal boundary. The patient received a diagnosis of patent ductus aorta and pulmonary hypertension. Discussion: The condition was successfully treated with transcatheter closure, which included a trial occlusion test. In the second instance, a toddler aged 2 was diagnosed with patent ductus aorta and pulmonary hypertension. The procedure of percutaneous PDA closure was scheduled. Following the trial occlusion test using the device occluder, we observed an elevation in pulmonary pressure which persisted and led to a pulmonary crisis. Conclusion: The trial occlusion test aids in identifying individuals who are prone to experiencing long-term regression of pulmonary hypertension and those who may deteriorate due to progressive pulmonary vascular disease (PVD) and right heart failure, therefore determining their suitability for PDA closure.

Nonspecific therapy for Eisenmenger syndrome

Eisenmenger syndrome (ES) is systemic pulmonary hypertension with venoarterial or bidirectional shunting of blood between the ventricles, atria or great arteries due to the progression of pulmonary vascular disease in the natural course of “simple” and “complex” congenital heart defects.Patients with ES require constant attention from a multidisciplinary team of specialists. One of the main tasks is not to destabilize the fragile pathological physiology, which relies on the balance of pulmonary and peripheral vascular resistance. Surgical interventions with anesthesia, if they cannot be avoided, should be performed in specialized centers. Pregnancy is contraindicated in patients with ES. Clinical symptoms of blood hyperviscosity in ES are rare.The anachronistic practice of venesections, which leads to a decrease in the oxygen transport function of the blood, iron deficiency and an increased risk of cerebrovascular complications, should be avoided. Oral and intravenous replenishment of iron deficiency improves exercise tolerance and quality of life. Routine administration of anticoagulants for ES is not indicated. In most cases, endovascular embolization of pathological collateral arteries can eliminate hemoptysis. The use of venous access requires careful prevention of embolism. Therapeutic tactics for ES are discussed in detail in this review

Symposium review: high altitude travel with pulmonary vascular disease.

Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension are the main precapillary forms of pulmonary hypertension (PH) summarized as pulmonary vascular diseases (PVD). PVDs are characterized by exertional dyspnoea and oxygen desaturation, and reduced quality of life and survival. Medical therapies improve life expectancy and physical performance of PVD patients, of whom many wish to participate in professional work and recreational activities including traveling to high altitude. The exposure to the hypobaric hypoxic environment of mountain regions incurs the risk of high altitude adverse events (AEHA) due to severe hypoxaemia exacerbating symptoms and further increase in pulmonary artery pressure, which may lead to right heart decompensation. Recent prospective and randomized trials show that altitude-induced hypoxaemia, pulmonary haemodynamic changes and impairment of exercise performance in PVD patients are in the range found in healthy people. The vast majority of optimally treated stable PVD patients who do not require long-term oxygen therapy at low altitude can tolerate short-term exposure to moderate altitudes up to 2500m. PVD patients that reveal persistent severe resting hypoxaemia ( <80% for >30min) at 2500m respond well to supplemental oxygen therapy. Although there are no accurate predictors for AEHA, PVD patients with unfavourable risk profiles at low altitude, such as higher WHO functional class, lower exercise capacity with more pronounced exercise-induced desaturation and more severely impaired haemodynamics, are at increased risk of AEHA. Therefore, doctors with experience in PVD and high-altitude medicine should counsel PVD patients before any high-altitude sojourn. This review aims to summarize recent literature and clinical recommendations about PVD patients travelling to high altitude.

Contemporary Management of the Failing Fontan.

Adult patients with congenital heart disease have now surpassed the pediatric population due to advances in surgery and improved survival. One such complex congenital heart disease seen in adult patients is the Fontan circulation. These patients have complex physiology and are at risk for several complications, including thrombosis of the Fontan pathway, pulmonary vascular disease, heart failure, atrial arrhythmias, atrioventricular valve regurgitation, and protein-losing enteropathy. This review discusses the commonly encountered phenotypes of Fontan circulatory failure and their contemporary management.

Pediatric three-dimensional quantitative cardiovascular computed tomography.

High-resolution, isotropic, 3-dimensional (D) data from pediatric cardiovascular computed tomography (CT) offer great potential for the accurate quantitative evaluation of pediatric cardiovascular and pulmonary vascular diseases. Recent pilot studies using pediatric 3-D cardiovascular CT have shown promising results in assessing cardiac function in conditions such as tetralogy of Fallot, cardiac defects with a hypoplastic ventricle, Ebstein anomaly, and in quantifying myocardial mass. In addition, the quantitative assessment of pulmonary vascularity is useful for evaluating differential right-to-left pulmonary vascular volume ratio, the effectiveness of pulmonary angioplasty, and predicting pulmonary hypertension. These initial experiences could broaden the role of pediatric cardiovascular CT in clinical practice. Furthermore, the current barriers to its widespread use, pertinent solutions to these problems, and new applications are discussed. In this review, the 3-D quantitative evaluations of cardiac function and pulmonary vascularity using high-resolution pediatric cardiovascular CT data are illustrated.

Postnatal cytomegalovirus infection and pulmonary vascular disease in extremely premature infants: A case series.

Pulmonary vascular disease (PVD) is a major determinant of both morbidity and mortality in extremely low birth weight infants. It is biologically plausible that postnatal cytomegalovirus (pCMV) infection may lead to PVD in premature infants secondary to pneumonitis or via derangement of pulmonary vascular development directly through endothelial dysfunction. Uncertainty remains, however, regarding thresholds for intervention in premature infants with cardiorespiratory instability and presumed CMV infection likely secondary to the limited understanding of the natural history of the disease. We describe four cases of premature infants with clinical and echocardiography features of PVD, in the setting of postnatally acquired CMV. All patients had atypical PVD trajectories, refractory to vasodilator treatment, which improved after initiation of CMV treatment. We highlight the need to consider postnatally acquired CMV infection in patients with PVD non-responsive to standard pulmonary vasodilator therapies or disease severity which is out of proportion of the usual clinical trajectory. Treatment of extremely premature infants with CMV-associated PVD may have positive impact on cardiorespiratory health, although duration of therapy remains uncertain.

A NEGLECTED RARE DISORDER: IGG4 RELATED DISEASE

Abstract IgG4–related disease (IgG4–RD) is an autoimmune disorder characterized by infiltration of plasma cells with IgG4. Almost any organ could be affected. Common presentations include lung manifestation, autoimmune pancreatitis, retroperitoneal fibrosis and tubulointerstitial nephritis. Cardiovascular involvement is less frequent. Corticosteroids are first line therapy, with or without anti–rheumatic drugs. Long–term prognosis of IgG4–RLD remains unknown. We present the case of a 65–years old woman, with a previuos diagnosis of IgG4–RD with mediastinal involvement. In the meantime she was recovered for pyelonephritis with high fever and positive blood coltures (S. hominis). We were called to perform a transthoracic echocardiogram to rule out infective endocarditis. The exam showed normal size of cardiac chambers, normal biventricular systolic function, absence of relevant valvular disease. In apical view we noticed a hyperechogenic ovalar imagine in the right atrium, not visible in all the projections. A first differential diagnosis included a mass with site of implantation at the top of the right atrium or something external but contiguous to heart structures. To clear this doubt the patient performed a thoracic CT with stunning results. The CT highlighted parietal encasement of chardiac structures and, particularly, of the superior vena cava at the confluence in right atrium, explaining the image we saw with transthoracic echo. The exam also showed encasement of ascending aorta, aortic arch and descending aorta with maximum thickness of 18 mm. CT also reported encasement of right pulmonary arthery. The CT highlighted a progression of the disease with indication to more aggressive therapy. In fact IgG4–RD of the cardiovascular system results in serious complications that need to be recognized and treated. Aortic involvement in IgG4–RD is extremely rare and tipically affects the infrarenal abdominal aorta. Cardiovascular IgG4–RD could also lead to aortitis, medium–vessel arteritis, pulmonary vascular disease, phlebitis, valvulopathy, pericarditis and myocardial disease. These forms of Igg4–RD are often underdiagnosed as clinical presentations is similar to cardiovascular disease due to more common aetiologies. Regarding our case the patient began methotrexate based on the results of the CT. This was a really interesting case for our working group to deepen this little–known disease. “The eyes see only what the mind is prepared to comprehend”.

Pulmonary arterial hypertension related to congenital heart disease with a left-to-right shunt: phenotypic spectrum and approach to management.

Patients with pulmonary hypertension associated with a left-right shunt include a wide spectrum of pathophysiological substrates, ranging from those characterized by pulmonary over-circulation to those with advanced pulmonary vascular disease. The former group may benefit from shunt repair in carefully selected cases but, when advanced pulmonary vascular disease has developed, defect closure should be avoided, and pulmonary vasodilators may be used to improve effort tolerance and hemodynamics. There is a paucity of evidence, however, to support decision-making in the care of these patients. We discuss the principles of management in patients with pulmonary hypertension and a predominant left-right shunt. The recommendations and statements made in this paper are based on pathophysiological considerations and expert opinion.

Purinergic regulation of pulmonary vascular tone.

Purinergic signaling is a crucial determinant in the regulation of pulmonary vascular physiology and presents a promising avenue for addressing lung diseases. This intricate signaling system encompasses two primary receptor classes: P1 and P2 receptors. P1 receptors selectively bind adenosine, while P2 receptors exhibit an affinity for ATP, ADP, UTP, and UDP. Functionally, P1 receptors are associated with vasodilation, while P2 receptors mediate vasoconstriction, particularly in basally relaxed vessels, through modulation of intracellular Ca2+ levels. The P2X subtype receptors facilitate extracellular Ca2+ influx, while the P2Y subtype receptors are linked to endoplasmic reticulum Ca2+ release. Notably, the primary receptor responsible for ATP-induced vasoconstriction is P2X1, with α,β-meATP and UDP being identified as potent vasoconstrictor agonists. Interestingly, ATP has been shown to induce endothelium-dependent vasodilation in pre-constricted vessels, associated with nitric oxide (NO) release. In the context of P1 receptors, adenosine stimulation of pulmonary vessels has been unequivocally demonstrated to induce vasodilation, with a clear dependency on the A2B receptor, as evidenced in studies involving guinea pigs and rats. Importantly, evidence strongly suggests that this vasodilation occurs independently of endothelium-mediated mechanisms. Furthermore, studies have revealed variations in the expression of purinergic receptors across different vessel sizes, with reports indicating notably higher expression of P2Y1, P2Y2, and P2Y4 receptors in small pulmonary arteries. While the existing evidence in this area is still emerging, it underscores the urgent need for a comprehensive examination of the specific characteristics of purinergic signaling in the regulation of pulmonary vascular tone, particularly focusing on the disparities observed across different intrapulmonary vessel sizes. Consequently, this review aims to meticulously explore the current evidence regarding the role of purinergic signaling in pulmonary vascular tone regulation, with a specific emphasis on the variations observed in intrapulmonary vessel sizes. This endeavor is critical, as purinergic signaling holds substantial promise in the modulation of vascular tone and in the proactive prevention and treatment of pulmonary vascular diseases.

The Intersection of HIV and Pulmonary Vascular Health: From HIV Evolution to Vascular Cell Types to Disease Mechanisms.

People living with HIV (PLWH) face a growing burden of chronic diseases, owing to the combinations of aging, environmental triggers, lifestyle choices, and virus-induced chronic inflammation. The rising incidence of pulmonary vascular diseases represents a major concern for PLWH. The study of HIV-associated pulmonary vascular complications ideally requires a strong understanding of pulmonary vascular cell biology and HIV pathogenesis at the molecular level for effective applications in infectious diseases and vascular medicine. Active HIV infection and/or HIV proteins disturb the delicate balance between vascular tone and constriction, which is pivotal for maintaining pulmonary vascular health. One of the defining features of HIV is its high genetic diversity owing to several factors including its high mutation rate, recombination between viral strains, immune selective pressures, or even geographical factors. The intrinsic HIV genetic diversity has several important implications for pathogenic outcomes of infection and the overall battle to combat HIV. Challenges in the field present themselves from two sides of the same coin: those imposed by the virus itself and those stemming from the host. The field may be advanced by further developing in vivo and in vitro models that are well described for both pulmonary vascular diseases and HIV for mechanistic studies. In essence, the study of HIV-associated pulmonary vascular complications requires a multidisciplinary approach, drawing upon insights from both infectious diseases and vascular medicine. In this review article, we discuss the fundamentals of HIV virology and their impact on pulmonary disease, aiming to enhance the understanding of either area or both simultaneously. Bridging the gap between preclinical research findings and clinical practice is essential for improving patient care. Addressing these knowledge gaps requires interdisciplinary collaborations, innovative research approaches, and dedicated efforts to prioritize HIV-related pulmonary complications on the global research agenda.

Right ventricular outflow tract diameter change with exercise: a prospective exercise echocardiography and invasive CPET study.

While cardiac output reserve with exercise predicts outcomes in cardiac and pulmonary vascular disease, precise quantification of exercise cardiac output requires invasive cardiopulmonary testing (iCPET). To improve the accuracy of cardiac output reserve estimation with transthoracic echocardiography (TTE), this prospective study aims to define changes in right ventricular outflow tract diameter (RVOTd) with exercise and its relationship with invasively measured haemodynamics. Twenty subjects underwent simultaneous TTE and iCPET, with data collected at rest, leg-raise, 25 W, 50 W (n = 16), 75 W (n = 14), and 100 W (n = 6). This was followed by a second exercise study with real-time RV pressure-volume loops at similar stages (except leg-raise). The overall cohort included heart failure with preserved ejection fraction (n = 12), pulmonary arterial hypertension (n = 5), and non-cardiac dyspnoea (n = 3). RVOTd was reverse engineered from the TTE-derived RVOT velocity time integral (VTI) and iCPET-derived stroke volume, using the formula: Fick stroke volume = RVOT VTI × RVOT area (wherein RVOT area = π × [RVOTd/2]2). RVOTd increased by nearly 3-4% at every 25 W increment. Using linear regression models, where each subject is treated as a categorical variable and adjusting for subject intercept, RVOTd was correlated with haemodynamic variables (cardiac output, heart rate, pulmonary artery and RV pressures). Of all the predictor haemodynamic variables, cardiac output had the highest r2 model fit (adjusted r2 = 0.68), with a unit increase in cardiac output associated with a 0.0678 increase in RVOTd (P < 0.001). Our findings indicate that RVOTd increases by 3-4% with every 25 W increment, predominantly correlated with cardiac output augmentation. These results can improve the accuracy of cardiac output reserve estimation by adjusting for RVOTd with graded exercise during non-invasive CPET and echocardiogram. However, future studies are needed to define these relationships for left ventricular outflow tract diameter.

Analysis of clinical features and prognostic factors in Takayasu arteritis involving pulmonary hypertension: A retrospective study.

Multiple takayasu arteritis (TA) is a chronic nonspecific large to medium vasculitis disease that mainly accumulates the aorta and its branches. Pulmonary vascular disease is often seen as stenosis and occlusion, and patients may show no moderate to severe pulmonary hypertension (PH). This study aims to summarize the clinical characteristics and analysis of prognostic factors in patients with PH caused by TA. Patients diagnosed with aortitis involving the pulmonary artery by pulmonary arteriography or pulmonary artery and total aortic computed tomography arteriography (CTA). All patients underwent detailed clinical assessment, laboratory data collection, and analysis of imaging data. Patients were followed up and factors affecting the prognosis of the pulmonary arteries were analyzed. Most of the patients' complaints were chest tightness, shortness of breath, decreased activity tolerance, hemoptysis and chest pain. 56.90% of the patients were in at the time of admission. Echocardiographic estimation of pulmonary artery systolic pressure was 90.39 ± 22.87 mm Hg. In terms of laboratory tests, 39.66%% of the patients had elevated C-reactive protein and erythrocyte sedimentation rate, and amino-terminal natriuretic peptide precursor on admission. In terms of imaging, all patients had pulmonary artery involvement, which was combined with aortic involvement in 31.03%. Nuclide lung perfusion/ventilation imaging of the patients revealed multiple perfusion defects/absences in the segmental and subsegmental distribution of the lungs. Univariate Cox regression model analysis suggested that patients' WHO functional class at admission, age ≧ 51 years at the time of consultation, and amino-terminal natriuretic peptide precursor ≧ 3500 pg/mL were factors affecting the prognosis. Further multifactorial Cox regression model analysis suggested amino-terminal natriuretic peptide precursor ≧ 3500 pg/mL was an independent predictor of poor prognosis with a hazard ratio (HR) value of 5.248. Electrocardiogram and echocardiogram may suggest an increased right heart load; some patients have elevated serum inflammatory indexes. Characteristic imaging manifestations include widening of the main pulmonary artery, multiple pulmonary segmental and subsegmental stenoses.

Patent ductus arteriosus presenting as dilated cardiomyopathy with heart failure in an adult managed with percutaneous intervention

ABSTRACT Patent ductus arteriosus (PDA) is a common congenital heart disease, presenting with symptoms of increased pulmonary blood flow in infancy and childhood. In adults PDA if it is small detected accidentally because of the continuous murmur or if PDA is large they develop severe pulmonary vascular disease and develop Eisenmenger syndrome. Very few patients with large PDA present with dilated cardiomyopathy without pulmonary hypertension. Herewith, we report a case of large PDA who presented with symptoms of heart failure without pulmonary vascular disease and manage successfully with percutaneous device closure.

Low circulating lysophosphatidylcholine and phosphatidylcholine are linked to pulmonary hypertension severity

Background: Pulmonary hypertension (PH) is a progressive pulmonary vascular disease. Given the mechanistic role of lipids in peripheral vascular diseases, we hypothesized that PH is also associated with pathologic circulating lipid metabolites. To test this, lipid metabolites of patients with PH were evaluated in association with clinical severity, including right ventricle systolic pressure (RVSP), pulmonary vascular resistance (PVR), right ventricular size and function, and plasma endothelin-1. Methods and Results: Participants were recruited as a part of a small site clinical trial (Clinicaltrials.gov, # NCT01586156). Comprehensive lipidomes were determined using unbiased nontargeted lipidomics (Metabolon Inc., Durham, NC) in 30 PH patients and 12 healthy controls. RVSP, right ventricular end diastolic (RVED) and end systolic (RVES) area were measured by echocardiogram and PVR was calculated. Plasma endothelin-1 was measured by Elisa. Nontargeted analysis detected 1099 lipid-related metabolites of which 83 and 60 metabolites were upregulated and downregulated in PH ( p&lt;0.05), respectively. Pathway enrichment analysis identified abnormalities of lipid metabolic pathways including choline-related, acylcarnitine, and sphingolipid metabolism. Targeted measures of lysophosphatidylcholine (lysoPC) and phosphatidylcholine (PC) confirmed these findings. Total circulating lysoPC and PC were downregulated [Healthy vs. PH, mean ± SD, mM; LysoPC, 786±102 vs. 586±139, p&lt;0.01; PC, 1855±389 vs. 1495±282, p&lt;0.01]. Sixteen out of the 25 lysoPC detected, and 25 out of 39 PC detected, were lower in PH, including the most abundant lysoPC-16:0 [226±31 vs. 186±39, p&lt;0.01] and PC-34:2 [436±91 vs. 360±75, p&lt;0.01]. RVSP, PVR, RVED area, RVES area and endothelin-1 were all higher in PH (all, p&lt;0.01). Lipid metabolites were inversely related to clinical measures of PH severity. For example, lysoPC-20:3 was related to RVSP [ r=−0.63, p&lt;0.01], PVR [ r=−0.50, p&lt;0.01], and endothelin-1 [ r=−0.51, p&lt;0.01], and PC-36:5 was inversely related to RVSP [ r=−0.36, p=0.02], PVR [ r=−0.43, p&lt;0.01], and endothelin-1 [ r=−0.50, p&lt;0.01]. Additionally, both lysoPC-20:3 and PC36:5 metabolites were inversely associated with right ventricular size, measured as RVED area [lysoPC-20:3, r=−0.62, p&lt;0.01; PC-36:5, r=−0.69, p&lt;0.01], RVES area [lysoPC-20:3, r=−0.66, p&lt;0.01; PC-36:5, r=−0.71, p&lt;0.01] and related with RV systolic function, measured as RV fractional area change [lysoPC-20:3, r=0.57, p&lt;0.01; PC-36:5, r=0.50, p&lt;0.01). Conclusion: Plasma phosphatidylcholine is low in PH and is associated with disease severity, suggesting disturbances in PC metabolism are important in pulmonary vascular disease. NIH NHLBI R37HL60917, R01HL115008 CTSA UL1TR000439; UL1TR002548. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pulmonary Hypertension Associated with Chronic Lung Disease

Abstract: Patients with Chronic Lung Disease (CLD) are frequently burdened by pulmonary hypertension (PH), which is associated with reduced functional capacity, poor quality of life, increased oxygen requirements, and increased morbidity and mortality. The development of PH associated with chronic lung disease (PH-CLD) is complex and multifactorial and varies between different types of CLD. In this review, we provide an update on PH-CLD, with a particular focus on Interstitial Lung Disease (ILD), chronic obstructive pulmonary disease (COPD), obstructive sleep apnea (OSA), and obesity hypoventilation syndrome (OHS). We discussed epidemiology, histopathology, pathophysiology, diagnostic evaluation, and treatment approaches. There are limited data on the use of pulmonary arterial hypertension-specific treatments in PH-CLD, so it has been proposed to phenotype patients based on their degree of pulmonary vascular disease to guide individualized care. The heterogeneity within PH-CLD highlights the importance of identifying novel molecular pathways unique to each subgroup to ultimately achieve precision medicine.

Management of pulmonary vascular disease associated with congenital left-to-right shunts: A single-center experience

ObjectiveThe study objective was to describe the course and outcomes of children under 18 years of age, with left-to-right shunts and pulmonary arterial hypertension undergoing 1 of 2 management approaches: pulmonary arterial hypertension treatment before left-to-right shunt repair (Treat First) and left-to-right shunt repair first with or without subsequent pulmonary arterial hypertension treatment (Repair First). MethodsWe performed a retrospective single-center study, conducted from September 2015 to September 2021, of children with left-to-right shunts and pulmonary arterial hypertension (defined as indexed pulmonary vascular resistance ≥ 4 Wood units [WU]∗m2) but without Eisenmenger physiology. Patient characteristics, longitudinal hemodynamics data, pulmonary arterial hypertension management, left-to-right shunt repair, and outcomes were reviewed. ResultsOf 768 patients evaluated for left-to-right shunt closure, 51 (6.8%) had left-to-right shunts associated with pulmonary arterial hypertension (median age 1.1 [0.37-5] years, median indexed pulmonary vascular resistance 6 [5.2-8.7] WU∗m2). In the "Treat First" group (n = 33, 65%), 27 patients (82%) underwent left-to-right shunt closure and 6 patients (18%) did not respond to pulmonary arterial hypertension therapy and did not undergo left-to-right shunt closure. In the "Repair First" group (n = 18, 35%), 12 patients (67%) received pulmonary arterial hypertension therapy and 6 patients (33%) did not. Mortality rates were 6% in the "Treat First" group and 11% in "Repair First" group with follow-ups of 3.4 and 2.5 years, respectively. After left-to-right shunt closure, there was no significant change in indexed pulmonary vascular resistance over a median follow-up of 2 years after surgery (P = .77). ConclusionsIn children with left-to-right shunts and associated pulmonary arterial hypertension, treatment with pulmonary arterial hypertension–targeted therapy before defect repair does not appear to endanger the subjects and may have some benefit. The response to pulmonary arterial hypertension–targeted therapy before shunt closure persists 2 to 3 years postclosure, providing valuable insights into the long-term management of these patients.

Sildenafil Versus Placebo for Early Pulmonary Vascular Disease in Scleroderma (SEPVADIS): protocol for a randomized controlled trial

BackgroundPulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21–24 mmHg).MethodsThe SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks.DiscussionThe SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP.Trial registrationClinicalTrials.gov Identifier NCT04797286.

Native lung surgery after single lung transplantation: clinical characteristics and outcomes.

Single lung transplantation (SLT) is a viable option for patients with end-stage pulmonary parenchymal and vascular diseases. However, various diseases can occur in native lungs after SLT. Between January 2000 and December 2021, 35 patients underwent cadaveric SLT and survived for more than 30days in our hospital. Among these 35 patients, 10 required surgery for diseases that developed in their native lungs. The clinical characteristics of these 10 patients and the outcomes of native lung surgery (NLS) were investigated. Among these ten patients, the indications for lung transplantation were chronic obstructive pulmonary disease and idiopathic interstitial pneumonia in three patients each, and lymphangioleiomyomatosis and collagen vascular disease-related interstitial pneumoniain two patients each. The causes of NLS included pneumothorax (n = 4), primary lung cancer (n = 2), native lung hyperinflation (n = 2), and pulmonary aspergilloma (n = 2). The surgical procedures were pneumonectomy (n = 7), lobectomy (n = 2), and alveolar-pleural fistula repair (n = 1). Only one postoperative complication, empyema, was treated with antibiotics. The 5-year overall survival rates after transplantation with and without NLS were 70.0% and 80.0%, respectively, and did not differ to a statistically extent (p = 0.56). NLS is an effective treatment option for diseases that develop in the native lungs after SLT.

Atrial Shunt Device Effects on Cardiac Structure and Function in Heart Failure With Preserved Ejection Fraction

Although the results of A Study to Evaluate the Corvia Medical Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients with Heart Failure (REDUCE LAP-HF II) trial were neutral overall, atrial shunt therapy demonstrated potential efficacy in responders (no latent pulmonary vascular disease and no cardiac rhythm management device). Post hoc analyses were conducted to evaluate the effect of shunt vs sham stratified by responder status. To evaluate the effect of atrial shunt vs sham control on cardiac structure/function in the overall study and stratified by responder status. This was a sham-controlled randomized clinical trial of an atrial shunt device in heart failure with preserved ejection fraction (HFpEF)/HF with mildly reduced EF (HFmrEF). Trial participants with evaluable echocardiography scans were recruited from 89 international medical centers. Data were analyzed from April 2023 to January 2024. Atrial shunt device or sham control. Changes in echocardiographic measures from baseline to 1, 6, 12, and 24 months after index procedure. The modified intention-to-treat analysis of the REDUCE LAP-HF II trial included 621 randomized patients (median [IQR] age, 72.0 [66.0-77.0] years; 382 female [61.5%]; shunt arm, 309 [49.8%]; sham control arm, 312 [50.2%]). Through 24 months, 212 of 217 patients (98%) in the shunt arm with evaluable echocardiograms had patent shunts. In the overall trial population, the shunt reduced left ventricular (LV) end-diastolic volume (mean difference, -5.65 mL; P <.001), left atrial (LA) minimal volume (mean difference, -2.8 mL; P =.01), and improved LV systolic tissue Doppler velocity (mean difference, 0.69 cm/s; P <.001) and LA emptying fraction (mean difference, 1.88 percentage units; P =.02) compared with sham. Shunt treatment also increased right ventricular (RV; mean difference, 9.58 mL; P <.001) and right atrial (RA; mean difference, 9.71 mL; P <.001) volumes but had no effect on RV systolic function, pulmonary artery pressure, or RA pressure compared with sham. In the shunt arm, responders had smaller increases in RV end-diastolic volume (mean difference, 5.71 mL vs 15.18 mL; interaction P =.01), RV end-systolic volume (mean difference, 1.58 mL vs 7.89 mL; interaction P =.002), and RV/LV ratio (mean difference, 0.07 vs 0.20; interaction P <.001) and larger increases in transmitral A wave velocity (mean difference, 5.08 cm/s vs -1.97 cm/s; interaction P =.02) compared with nonresponders randomized to the shunt, suggesting greater ability to accommodate shunted blood through the pulmonary circulation enabling LA unloading. In this post hoc analysis of the REDUCE LAP-HF II trial, over 2 years of follow-up, atrial shunting led to reverse remodeling of left-sided chambers and increases in volume of right-sided chambers consistent with the shunt flow but no change in RV systolic function compared with sham. Changes in cardiac structure/function were more favorable in responders compared with nonresponders treated with the shunt, supporting the previously identified responder group hypothesis and mechanism, although further evaluation with longer follow-up is needed. ClinicalTrials.gov Identifier: NCT03088033.

Single cell transcriptomic analyses reveal diverse and dynamic changes of distinct populations of lung interstitial macrophages in hypoxia-induced pulmonary hypertension.

Hypoxia is a common pathological driver contributing to various forms of pulmonary vascular diseases leading to pulmonary hypertension (PH). Pulmonary interstitial macrophages (IMs) play pivotal roles in immune and vascular dysfunction, leading to inflammation, abnormal remodeling, and fibrosis in PH. However, IMs' response to hypoxia and their role in PH progression remain largely unknown. We utilized a murine model of hypoxia-induced PH to investigate the repertoire and functional profiles of IMs in response to acute and prolonged hypoxia, aiming to elucidate their contributions to PH development. We conducted single-cell transcriptomic analyses to characterize the repertoire and functional profiles of murine pulmonary IMs following exposure to hypobaric hypoxia for varying durations (0, 1, 3, 7, and 21 days). Hallmark pathways from the mouse Molecular Signatures Database were utilized to characterize the molecular function of the IM subpopulation in response to hypoxia. Our analysis revealed an early acute inflammatory phase during acute hypoxia exposure (Days 1-3), which was resolved by Day 7, followed by a pro-remodeling phase during prolonged hypoxia (Days 7-21). These phases were marked by distinct subpopulations of IMs: MHCIIhiCCR2+EAR2+ cells characterized the acute inflammatory phase, while TLF+VCAM1hi cells dominated the pro-remodeling phase. The acute inflammatory phase exhibited enrichment in interferon-gamma, IL-2, and IL-6 pathways, while the pro-remodeling phase showed dysregulated chemokine production, hemoglobin clearance, and tissue repair profiles, along with activation of distinct complement pathways. Our findings demonstrate the existence of distinct populations of pulmonary interstitial macrophages corresponding to acute and prolonged hypoxia exposure, pivotal in regulating the inflammatory and remodeling phases of PH pathogenesis. This understanding offers potential avenues for targeted interventions, tailored to specific populations and distinct phases of the disease. Moreover, further identification of triggers for pro-remodeling IMs holds promise in unveiling novel therapeutic strategies for pulmonary hypertension.