Browsing by Subject "pulmonary hypertension"
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Item At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension(MDPI, 2020-11) Cirulis, Meghan M.; Dodson, Mark W.; Brown, Lynn M.; Brown, Samuel M.; Lahm, Tim; Elliott, Greg; Medicine, School of MedicineGroup 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH.Item Chronic Thromboembolic Pulmonary Hypertension Successfully Treated in a Six Year Old with Asthma(authorea, 2020) Serrano, Ryan; Montgomery, Gregory; Rao, Rohit; Kivett, Tisha; Johansen, Michael; Pediatrics, School of MedicineChronic thromboembolic pulmonary hypertension (CTEPH) is a rare but serious, sequala of acute pulmonary embolism. Symptoms can be subtle and non-specific and the prognosis is poor if severe pulmonary hypertension (PH) and right ventricular dysfunction are present. While PH-targeted therapies are often used, there is only one FDA approved therapy, and only for disease that is deemed inoperable. The greatest chance for potential cure and long-term survival is surgical pulmonary endarterectomy. We report a 6-year-old male with a history of asthma and two unprovoked deep venous thromboses who presented with syncope. Chest x-ray showed cardiomegaly and an echocardiogram showed severe PH with severely decreased right ventricular (RV) function. Ventilation-perfusion scan showed mismatched perfusion defects involving the right lower lobe, and CT of the chest showed right lower lobe subsegmental pulmonary thrombus, suspicious for chronic thromboembolism. Given his clinical presentation and the severity of his right ventricular dysfunction, he was started on ambrisentan, sildenafil and subcutaneous treprostinil. Bilateral pulmonary endarterectomy was performed with resection of level 2 to 3 disease and he was successfully weaned off all PH therapy. Four months post-op, he is clinically asymptomatic and his echo shows normal RV function without PH. In conclusion, CTEPH is a rare but likely underdiagnosed disease process in pediatrics. Clinicians should have a high index of suspicion for at risk patients with unexplained dyspnea. Even if right ventricular dysfunction and severe PH are present, surgical pulmonary endarterectomy can be performed successfully in young children.Item Current Understanding of Circulating Biomarkers in Pulmonary Hypertension Due to Left Heart Disease(Frontiers, 2020-10-07) Todd, Noah; Lai, Yen-Chun; Medicine, School of MedicinePulmonary hypertension due to left heart disease (PH-LHD; Group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most frequent cause of PH. Despite its prevalence, no effective therapies for PH-LHD are available at present. This is largely due to the lack of a concise definition for hemodynamic phenotyping, existence of significant gaps in the understanding of the underlying pathology and the impact of associated comorbidities, as well as the absence of specific biomarkers that can aid in the early diagnosis and management of this challenging syndrome. Currently, B-type natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are guideline-recommended biomarkers for the diagnosis and prognosis of heart failure (HF) and PH. Endothelin-1 (ET-1), vascular endothelial growth factor-D (VEGF-D), and microRNA-206 have also been recently identified as new potential circulating biomarkers for patients with PH-LHD. In this review, we aim to present the current state of knowledge of circulating biomarkers that can be used to guide future research toward diagnosis, refine specific patient phenotype, and develop therapeutic approaches for PH-LHD, with a particular focus on PH-HFpEF. Potential circulating biomarkers identified in pre-clinical models of PH-LHD are also summarized here.Item Development and comparison of a minimallyinvasive model of autologous clot pulmonary embolism in Sprague-Dawley and Copenhagen rats(2010-02) Runyon, Michael S; Gellar, Michael A; Sanapareddy, Nina; Kline, Jeffrey A.; Watts, John ABackground Experimental models of pulmonary embolism (PE) that produce pulmonary hypertension (PH) employ many different methods of inducing acute pulmonary occlusion. Many of these models induce PE with intravenous injection of exogenous impervious objects that may not completely reproduce the physiological properties of autologous thromboembolism. Current literature lacks a simple, well-described rat model of autlogous PE. Objective: Test if moderate-severity autologous PE in Sprague-Dawley (SD) and Copenhagen (Cop) rats can produce persistent PH. Methods blood was withdrawn from the jugular vein, treated with thrombin-Ca++ and re-injected following pretreatment with tranexamic acid. Hemodynamic values, clot weights and biochemical measurements were performed at 1 and 5 days. Results Infusion of clot significantly increased the right ventricular peak systolic pressure to 45-55 mm Hg, followed by normalization within 24 hours in SD rats, and within 5 days in COP rats. Clot lysis was 95% (24 hours) and 97% (5 days) in SD rats and was significantly lower in COP rats (70%, 24 hours; 87% 5 days). Plasma D-dimer was elevated in surgical sham animals and was further increased 8 hours after pulmonary embolism. Neither strain showed a significant increase in bronchoalveolar chemotactic activity, myeloperoxidase activity, leukocyte infiltration, or chemokine accumulation, indicating that there was no significant pulmonary inflammation. Conclusions Both SD and COP rats exhibited near complete fibrinolysis of autologous clot PE within 5 days. Neither strain developed persistent PH. Experimental models of PE designed to induce sustained PH and a robust inflammatory response appear to require significant, persistent pulmonary vascular occlusion.Item Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia(AJRCCM, 2015-01-01) Mourani, Peter M.; Sontag, Marci K.; Younoszai, Adel; Miller, Joshua I.; Kinsella, John P.; Baker, Christopher D.; Poindexter, Brenda B.; Ingram, David A.; Abman, Steven H.; Department of Pediatrics, IU School of MedicineRATIONALE: Pulmonary hypertension (PH) is associated with poor outcomes among preterm infants with bronchopulmonary dysplasia (BPD), but whether early signs of pulmonary vascular disease are associated with the subsequent development of BPD or PH at 36 weeks post-menstrual age (PMA) is unknown. OBJECTIVES: To prospectively evaluate the relationship of early echocardiogram signs of pulmonary vascular disease in preterm infants to the subsequent development of BPD and late PH (at 36 wk PMA). METHODS: Prospectively enrolled preterm infants with birthweights 500-1,250 g underwent echocardiogram evaluations at 7 days of age (early) and 36 weeks PMA (late). Clinical and echocardiographic data were analyzed to identify early risk factors for BPD and late PH. MEASUREMENTS AND MAIN RESULTS: A total of 277 preterm infants completed echocardiogram and BPD assessments at 36 weeks PMA. The median gestational age at birth and birthweight of the infants were 27 weeks and 909 g, respectively. Early PH was identified in 42% of infants, and 14% were diagnosed with late PH. Early PH was a risk factor for increased BPD severity (relative risk, 1.12; 95% confidence interval, 1.03-1.23) and late PH (relative risk, 2.85; 95% confidence interval, 1.28-6.33). Infants with late PH had greater duration of oxygen therapy and increased mortality in the first year of life (P < 0.05). CONCLUSIONS: Early pulmonary vascular disease is associated with the development of BPD and with late PH in preterm infants. Echocardiograms at 7 days of age may be a useful tool to identify infants at high risk for BPD and PH.Item High-intensity interval training, but not continuous training, reverses right ventricular hypertrophy and dysfunction in a rat model of pulmonary hypertension(APS, 2017) Brown, Mary Beth; Neves, Evandro; Long, Gary; Graber, Jeremy; Gladish, Brett; Wiseman, Andrew; Owens, Matthew; Fisher, Amanda J.; Presson, Robert G.; Petrache, Irina; Kline, Jeffrey A.; Lahm, Tim; Department of Physical Therapy, School of Health and Rehabilitation SciencesExercise is beneficial in pulmonary arterial hypertension (PAH), although studies to date indicate little effect on the elevated pulmonary pressures or maladaptive right ventricle (RV) hypertrophy associated with the disease. For chronic left ventricle failure, high-intensity interval training (HIIT) promotes greater endothelial stimulation and superior benefit than customary continuous exercise training (CExT); however, HIIT has not been tested for PAH. Therefore, here we investigated acute and chronic responses to HIIT vs. CExT in a rat model of monocrotaline (MCT)-induced mild PAH. Six weeks of treadmill training (5 times/wk) were performed, as either 30 min HIIT or 60 min low-intensity CExT. To characterize acute hemodynamic responses to the two approaches, novel recordings of simultaneous pulmonary and systemic pressures during running were obtained at pre- and 2, 4, 6, and 8 wk post-MCT using long-term implantable telemetry. MCT-induced decrement in maximal aerobic capacity was ameliorated by both HIIT and CExT, with less pronounced pulmonary vascular remodeling and no increase in RV inflammation or apoptosis observed. Most importantly, only HIIT lowered RV systolic pressure, RV hypertrophy, and total pulmonary resistance, and prompted higher cardiac index that was complemented by a RV increase in the positive inotrope apelin and reduced fibrosis. HIIT prompted a markedly pulsatile pulmonary pressure during running and was associated with greater lung endothelial nitric oxide synthase after 6 wk. We conclude that HIIT may be superior to CExT for improving hemodynamics and maladaptive RV hypertrophy in PAH. HIIT’s superior outcomes may be explained by more favorable pulmonary vascular endothelial adaptation to the pulsatile HIIT stimulus.Item Lung Transplantation for Bronchopulmonary Dysplasia in Adults: A Clinical and Pathological Study of Three Cases(Wolters Kluwer, 2020-04) Liu, Natalia; Cummings, Oscar W.; Lagstein, Amir; Hage, Chadi A.; Chan, Kevin M.; Zhang, Chen; Pathology and Laboratory Medicine, School of MedicineBronchopulmonary dysplasia (BPD) is usually seen in premature infants who require mechanical ventilation and oxygen therapy for acute respiratory distress. Although most patients wean from oxygen therapy by the ages of 2 to 3, rehospitalization for respiratory problems is common in these patients in adulthood. There have been few studies that document the long-term outcomes of BPD survivors and information about the pulmonary function and radiographic findings of adult BPD are limited. Data on pathologic features of adult BPD are scarce. Three adult patients who underwent recent lung transplantation for BPD from 2 institutions were identified. Clinical data including clinical presentation, chest radiographic images, pulmonary function tests, cardiac catheterization, and echocardiography were retrieved from the electronic medical records. Hematoxylin and eosin and selective elastic stained sections of the explant lungs were examined. CD31 immunohistochemical stain is performed on representative sections. All 3 cases had similar clinical and radiologic features including the history of prematurity and long-term mechanical ventilation after birth, hyperexpanded lungs with air trapping and mosaic attenuation on chest computed tomographic scan, severe obstructive changes on pulmonary function test, and pulmonary hypertension. Pathologic examination showed common features including enlarged and simplified alveoli, peribronchial, subpleural, and interlobular septal fibrosis, narrowing/obliteration of the small airways by elastosis and muscular hypertrophy, thickening of venous walls by fibromuscular hyperplasia, and bronchitis/bronchiolitis. Cholesterol granulomas were seen in 2 cases. The common pathologic findings in the lungs explain the clinical and radiologic findings. Future studies are warranted to further characterize the clinical and pathologic features of adult BPD to develop optimal management strategies for these patients.Item Multi-Institutional US Experience of the Occlutech© AFR Device in Congenital and Acquired Heart Disease(Tech Science Press, 2021) O’Callaghan, Barry; Zablah, Jenny; Vettukattil, Joseph; Levi, Daniel; Salem, Morris; Cabalka, Allison; Anderson, Jason; Ebeid, Makram; Alexy, Ryan; Morgan, Gareth; Pediatrics, School of MedicineObjectives: To detail the US multi-institutional experience with the Occlutech© (Occlutech International AB, Helsingborg, Sweden) atrial flow regulator (AFR) in children and adults with acquired or congenital heart disease. Background: The creation of a long-term atrial communication is desirable in several cardiovascular disease phenotypes, most notably pulmonary arterial hypertension, disorders of increased left ventricular filling and increased cavopulmonary pressures in patients with a Fontan type circulation. Methods: Patients were identified for inclusion from the AFR device manufacturer database. Data was collected using a RedCap database following IRB approval. 8 weeks of follow up data was sought for each patient based on available data. Data was analyzed and summarized using SPSS. Results: We report the experience of 6 US centers in the implantation of AFR devices in 15 patients, across a wide age range, with different disease phenotypes and a variety of indications. Implantation was technically successful in all patients and improvement was noted in both clinical and hemodynamic parameters. There were no immediate or intermediate term complications reported. 3 patients died remote from implantation. Their deaths were not felt to be related to the AFR device or related procedural complications. Conclusion: Compassionate use of the AFR device in children and adults with congenital & acquired heart disease is technically feasible and produces beneficial short term hemodynamic and symptomatic improvement. Widespread uptake of this technique and treatment at specialist centers has the potential to provide significant benefits to a variety of complex patients with currently limited treatment options and indeterminate prognosis.Item Preventative practices and effects of the COVID-19 pandemic on caregivers of children with pediatric pulmonary hypertension(BMC, 2022-12) Nelson, Erik J.; Cook, Ella; Pierce, Megan; Nelson, Samara; Bangerter Seelos, Ashley; Stickle, Heather; Brown, Rebecca; Johansen, Michael; Pediatrics, School of MedicineBackground Pulmonary hypertension (PH) is a serious and life-threatening disease characterized by elevated mean arterial pressure and pulmonary vascular resistance. COVID-19 may exacerbate PH, as evidenced by higher mortality rates among those with PH. The objective of this study was to understand the unique burdens that the COVID-19 pandemic has placed upon families of children living with PH. Methods Participants were recruited online through the “Families of children with pulmonary hypertension” Facebook group and asked to complete a survey about their experiences during the COVID-19 pandemic. Results A total of 139 parents/caregivers of children living with PH completed the online survey. Almost all (85.6%) of parents/caregivers had received the COVID-19 vaccine, though only 59.7% reported a willingness to vaccinate their child with PH against COVID-19. Over 75% of parents/caregivers felt that they practiced preventative measures (e.g., wearing a facemask, social distancing, and avoiding gatherings) more than those in the community where they live. They also reported several hardships related to caring for their child with PH during the pandemic such as financial duress, loss of work, and affording treatment costs. Conclusions These findings indicate that parents/caregivers of children at higher risk for COVID-19 complications may be more willing to act on clinical recommendations themselves as proxy for protecting those at high risk. The economic, emotional and social impacts of COVID-19 are significantly greater for high-risk individuals.Item Quantifying side effects and caregiver burdens of pediatric pulmonary hypertension therapies(BMC, 2023-01) Nelson, Erik J.; Cook, Ella; Nelson, Samara; Brown, Rebecca; Pierce, Megan; Bangerter Seelos, Ashley; Stickle, Heather; Johansen, Michael; Pediatrics, School of MedicineBackground and objectives Pulmonary hypertension (PH) is a rare, but serious disease among children. However, PH has been primarily evaluated among adults. Consequently, treatment therapies have not been fully evaluated among pediatric populations and are used in an ‘off label’ manner. The purpose of this study was to estimate the side effect profiles of the most commonly prescribed pediatric PH therapies and to understand the burdens placed upon families caring for children living with PH. Methods Participants were recruited online through the “Families of children with pulmonary hypertension” Facebook group and asked to complete a survey about PH treatments. Results A total of 139 parents of a child living with PH completed the survey. Almost all children used ≥ 1 medication to treat PH, with 52% using ≥ 3 medications. The highest average number of side effects was reported by users of Treprostinil, Selexipag and type-5 phosphodiesterase (PDE5) inhibitors. The most common side effects were skin flushing, headache, nasal congestion, joint/muscle pain, and nausea. In terms of accessing care, 81% travel ≥ 20 miles and 68% travel for ≥ 60 min to receive care. Conclusions We found an array of treatment combinations employed to mitigate symptoms of PH in children, with a wide range of side effects. We also found a large, unseen economic, emotional, and time burden of caring for a child living with PH. Further research is warranted to understand the clinical implications of these side effects to move towards labeled usage of these therapies rather than post-hoc off-label usage.