Browsing by Author "Newman, John H."

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    Clinical Characteristics and Transplant-Free Survival Across the Spectrum of Pulmonary Vascular Disease
    (Elsevier, 2022) Hemnes, Anna R.; Leopold, Jane A.; Radeva, Milena K.; Beck, Gerald J.; Abidov, Aiden; Aldred, Micheala A.; Barnard, John; Rosenzweig, Erika B.; Borlaug, Barry A.; Chung, Wendy K.; Comhair, Suzy A. A.; Desai, Ankit A.; Dubrock, Hilary M.; Erzurum, Serpil C.; Finet, J. Emanuel; Frantz, Robert P.; Garcia, Joe G. N.; Geraci, Mark W.; Gray, Michael P.; Grunig, Gabriele; Hassoun, Paul M.; Highland, Kristin B.; Hill, Nicholas S.; Hu, Bo; Kwon, Deborah H.; Jacob, Miriam S.; Jellis, Christine L.; Larive, A. Brett; Lempel, Jason K.; Maron, Bradley A.; Mathai, Stephen C.; McCarthy, Kevin; Mehra, Reena; Nawabit, Rawan; Newman, John H.; Olman, Mitchell A.; Park, Margaret M.; Ramos, Jose A.; Renapurkar, Rahul D.; Rischard, Franz P.; Sherer, Susan G.; Tang, W. H. Wilson; Thomas, James D.; Vanderpool, Rebecca R.; Waxman, Aaron B.; Wilcox, Jennifer D.; Yuan, Jason X-J; Horn, Evelyn M.; PVDOMICS Study Group; Medicine, School of Medicine
    Background: PVDOMICS (Pulmonary Vascular Disease Phenomics) is a precision medicine initiative to characterize pulmonary vascular disease (PVD) using deep phenotyping. PVDOMICS tests the hypothesis that integration of clinical metrics with omic measures will enhance understanding of PVD and facilitate an updated PVD classification. Objectives: The purpose of this study was to describe clinical characteristics and transplant-free survival in the PVDOMICS cohort. Methods: Subjects with World Symposium Pulmonary Hypertension (WSPH) group 1-5 PH, disease comparators with similar underlying diseases and mild or no PH and healthy control subjects enrolled in a cross-sectional study. PH groups, comparators were compared using standard statistical tests including log-rank tests for comparing time to transplant or death. Results: A total of 1,193 subjects were included. Multiple WSPH groups were identified in 38.9% of PH subjects. Nocturnal desaturation was more frequently observed in groups 1, 3, and 4 PH vs comparators. A total of 50.2% of group 1 PH subjects had ground glass opacities on chest computed tomography. Diffusing capacity for carbon monoxide was significantly lower in groups 1-3 PH than their respective comparators. Right atrial volume index was higher in WSPH groups 1-4 than comparators. A total of 110 participants had a mean pulmonary artery pressure of 21-24 mm Hg. Transplant-free survival was poorest in group 3 PH. Conclusions: PVDOMICS enrolled subjects across the spectrum of PVD, including mild and mixed etiology PH. Novel findings include low diffusing capacity for carbon monoxide and enlarged right atrial volume index as shared features of groups 1-3 and 1-4 PH, respectively; unexpected, frequent presence of ground glass opacities on computed tomography; and sleep alterations in group 1 PH, and poorest survival in group 3 PH. PVDOMICS will facilitate a new understanding of PVD and refine the current PVD classification.
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    Diagnosis and Treatment of Right Heart Failure in Pulmonary Vascular Diseases: A National Heart, Lung, and Blood Institute Workshop
    (American Heart Association, 2021) Leopold, Jane A.; Kawut, Steven M.; Aldred, Micheala A.; Archer, Stephen L.; Benza, Ray L.; Bristow, Michael R.; Brittain, Evan L.; Chesler, Naomi; DeMan, Frances S.; Erzurum, Serpil C.; Gladwin, Mark T.; Hassoun, Paul M.; Hemnes, Anna R.; Lahm, Tim; Lima, Joao A. C.; Loscalzo, Joseph; Maron, Bradley A.; Mercer Rosa, Laura; Newman, John H.; Redline, Susan; Rich, Stuart; Rischard, Franz; Sugeng, Lissa; Tang, W. H. Wilson; Tedford, Ryan J.; Tsai, Emily J.; Ventetuolo, Corey E.; Zhou, YouYang; Aggarwal, Neil R.; Xiao, Lei; Medicine, School of Medicine
    Right ventricular dysfunction is a hallmark of advanced pulmonary vascular, lung parenchymal, and left heart disease, yet the underlying mechanisms that govern (mal)adaptation remain incompletely characterized. Owing to the knowledge gaps in our understanding of the right ventricle (RV) in health and disease, the National Heart, Lung, and Blood Institute (NHLBI) commissioned a working group to identify current challenges in the field. These included a need to define and standardize normal RV structure and function in populations; access to RV tissue for research purposes and the development of complex experimental platforms that recapitulate the in vivo environment; and the advancement of imaging and invasive methodologies to study the RV within basic, translational, and clinical research programs. Specific recommendations were provided, including a call to incorporate precision medicine and innovations in prognosis, diagnosis, and novel RV therapeutics for patients with pulmonary vascular disease.
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    Familial Autonomic Ganglionopathy Caused by Rare CHRNA3 Genetic Variants
    (Wolters Kluwer, 2021) Shibao, Cyndya A.; Joos, Karen; Phillips, John A., III.; Cogan, Joy; Newman, John H.; Hamid, Rizwan; Meiler, Jens; Capra, John; Sheehan, Jonathan; Vetrini, Francesco; Yang, Yaping; Black, Bonnie; Diedrich, André; Roberston, David; Biaggioni, Italo; Medical and Molecular Genetics, School of Medicine
    Objective: To determine the molecular basis of a new monogenetic recessive disorder that results in familial autonomic ganglionopathy with diffuse autonomic failure. Methods: Two adult siblings from one family (I-4 and I-5) and another participant from a second family (II-3) presented with severe neurogenic orthostatic hypotension (nOH), small nonreactive pupils, and constipation. All 3 affected members had low norepinephrine levels and diffuse panautonomic failure. Results: Whole exome sequencing of DNA from I-4 and I-5 showed compound heterozygosity for c.907_908delCT (p.L303Dfs*115)/c.688 G>A (p.D230N) pathologic variants in the acetylcholine receptor, neuronal nicotinic, α3 subunit gene (CHRNA3). II-3 from the second family was homozygous for the same frameshift (fs) variant (p.L303Dfs*115//p.L303Dfs*115). CHRNA3 encodes a critical subunit of the nicotinic acetylcholine receptors (nAChRs) responsible for fast synaptic transmission in the autonomic ganglia. The fs variant is clearly pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). The p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits based on structural modeling and is predicted to destabilize the nAChR pentameric complex. Conclusions: We report a novel genetic disease that affected 3 individuals from 2 unrelated families who presented with severe nOH, miosis, and constipation. These patients had rare pathologic variants in the CHRNA3 gene that cosegregate with and are predicted to be the likely cause of their diffuse panautonomic failure.