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Browsing by Author "Tang, W. H. Wilson"
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Item Circulating trimethylamine N-oxide levels following fish or seafood consumption(Springer, 2022) Wang, Zeneng; Tang, W. H. Wilson; O’Connell, Thomas; Garcia, Erwin; Jeyarajah, Elias J.; Li, Xinmin S.; Jia, Xun; Weeks, Taylor L.; Hazen, Stanley L.; Otolaryngology -- Head and Neck Surgery, School of MedicinePurpose: Some species of fish and seafood are high in trimethylamine N-oxide (TMAO), which accumulates in muscle where it protects against pressure and cold. Trimethylamine (TMA), the metabolic precursor to TMAO, is formed in fish during bacterial spoilage. Fish intake is promoted for its potential cardioprotective effects. However, numerous studies show TMAO has pro-atherothrombotic properties. Here, we determined the effects of fish or seafood consumption on circulating TMAO levels in participants with normal renal function. Methods: TMAO and omega-3 fatty acid content were quantified across multiple different fish or seafood species by mass spectrometry. Healthy volunteers (n = 50) were recruited for three studies. Participants in the first study consented to 5 consecutive weekly blood draws and provided dietary recall for the 24 h preceding each draw. In the second study, TMAO levels were determined following defined low and high TMAO diets. Finally, participants consumed test meals containing shrimp, tuna, fish sticks, salmon or cod. TMAO levels were quantified by mass spectrometry in blood collected before and after dietary challenge. Results: TMAO + TMA content varied widely across fish and seafood species. Consumption of fish sticks, cod, and to a lesser extent salmon led to significant increases in circulating TMAO levels. Within 1 day, circulating TMAO concentrations in all participants returned to baseline levels. Conclusions: We conclude that some fish and seafood contain high levels of TMAO, and may induce a transient elevation in TMAO levels in some individuals. Selection of low TMAO content fish is prudent for subjects with elevated TMAO, cardiovascular disease or impaired renal function.Item 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 MedicineBackground: 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.Item 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 MedicineRight 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.Item Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry(American Medical Association, 2023) Jordan, Elizabeth; Kinnamon, Daniel D.; Haas, Garrie J.; Hofmeyer, Mark; Kransdorf, Evan; Ewald, Gregory A.; Morris, Alanna A.; Owens, Anjali; Lowes, Brian; Stoller, Douglas; Tang, W. H. Wilson; Garg, Sonia; Trachtenberg, Barry H.; Shah, Palak; Pamboukian, Salpy V.; Sweitzer, Nancy K.; Wheeler, Matthew T.; Wilcox, Jane E.; Katz, Stuart; Pan, Stephen; Jimenez, Javier; Fishbein, Daniel P.; Smart, Frank; Wang, Jessica; Gottlieb, Stephen S.; Judge, Daniel P.; Moore, Charles K.; Mead, Jonathan O.; Hurst, Natalie; Cao, Jinwen; Huggins, Gordon S.; Cowan, Jason; Ni, Hanyu; Rehm, Heidi L.; Jarvik, Gail P.; Vatta, Matteo; Burke, Wylie; Hershberger, Ray E.; DCM Precision Medicine Study of the DCM Consortium; Medical and Molecular Genetics, School of MedicineImportance: Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients. Objective: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM. Design: Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance. Exposure: Presence of DCM. Main outcomes and measures: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic). Results: A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001). Conclusion and relevance: Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.Item Kynurenine pathway metabolism evolves with development of preclinical and scleroderma-associated pulmonary arterial hypertension(American Physiological Society, 2023) Simpson, Catherine E.; Ambade, Anjira S.; Harlan, Robert; Roux, Aurelie; Aja, Susan; Graham, David; Shah, Ami A.; Hummers, Laura K.; Hemnes, Anna R.; Leopold, Jane A.; Horn, Evelyn M.; Berman-Rosenzweig, Erika S.; Grunig, Gabriele; Aldred, Micheala A.; Barnard, John; Comhair, Suzy A. A.; Tang, W. H. Wilson; Griffiths, Megan; Rischard, Franz; Frantz, Robert P.; Erzurum, Serpil C.; Beck, Gerald J.; Hill, Nicholas S.; Mathai, Stephen C.; Hassoun, Paul M.; Damico, Rachel L.; PVDOMICS Study Group; Medicine, School of MedicineUnderstanding metabolic evolution underlying pulmonary arterial hypertension (PAH) development may clarify pathobiology and reveal disease-specific biomarkers. Patients with systemic sclerosis (SSc) are regularly surveilled for PAH, presenting an opportunity to examine metabolic change as disease develops in an at-risk cohort. We performed mass spectrometry-based metabolomics on longitudinal serum samples collected before and near SSc-PAH diagnosis, compared with time-matched SSc subjects without PAH, in a SSc surveillance cohort. We validated metabolic differences in a second cohort and determined metabolite-phenotype relationships. In parallel, we performed serial metabolomic and hemodynamic assessments as the disease developed in a preclinical model. For differentially expressed metabolites, we investigated corresponding gene expression in human and rodent PAH lungs. Kynurenine and its ratio to tryptophan (kyn/trp) increased over the surveillance period in patients with SSc who developed PAH. Higher kyn/trp measured two years before diagnostic right heart catheterization increased the odds of SSc-PAH diagnosis (OR 1.57, 95% CI 1.05-2.36, P = 0.028). The slope of kyn/trp rise during SSc surveillance predicted PAH development and mortality. In both clinical and experimental PAH, higher kynurenine pathway metabolites correlated with adverse pulmonary vascular and RV measurements. In human and rodent PAH lungs, expression of TDO2, which encodes tryptophan 2,3 dioxygenase (TDO), a protein that catalyzes tryptophan conversion to kynurenine, was significantly upregulated and tightly correlated with pulmonary hypertensive features. Upregulated kynurenine pathway metabolism occurs early in PAH, localizes to the lung, and may be modulated by TDO2. Kynurenine pathway metabolites may be candidate PAH biomarkers and TDO warrants exploration as a potential novel therapeutic target. NEW & NOTEWORTHY: Our study shows an early increase in kynurenine pathway metabolism in at-risk subjects with systemic sclerosis who develop pulmonary arterial hypertension (PAH). We show that kynurenine pathway upregulation precedes clinical diagnosis and that this metabolic shift is associated with increased disease severity and shorter survival times. We also show that gene expression of TDO2, an enzyme that generates kynurenine from tryptophan, rises with PAH development.Item Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure(Springer Nature, 2019-06-24) Cordero, Pablo; Parikh, Victoria N.; Chin, Elizabeth T.; Erbilgin, Ayca; Gloudemans, Michael J.; Shang, Ching; Huang, Yong; Chang, Alex C.; Smith, Kevin S.; Dewey, Frederick; Zaleta, Kathia; Morley, Michael; Brandimarto, Jeff; Glazer, Nicole; Waggott, Daryl; Pavlovic, Aleksandra; Zhao, Mingming; Moravec, Christine S.; Tang, W. H. Wilson; Skreen, Jamie; Malloy, Christine; Hannenhalli, Sridhar; Li, Hongzhe; Ritter, Scott; Li, Mingyao; Bernstein, Daniel; Connolly, Andrew; Hakonarson, Hakon; Lusis, Aldons J.; Margulies, Kenneth B.; Depaoli-Roach, Anna A.; Montgomery, Stephen B.; Wheeler, Matthew T.; Cappola, Thomas; Ashley, Euan A.; Biochemistry and Molecular Biology, School of MedicineHeart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and perturbed respiratory metabolism. Mice lacking PPP1R3A are protected against pressure-overload heart failure. We present a global gene interaction map of the human heart failure transition, identify previously unreported cardiac eQTLs, and demonstrate the discovery potential of disease-specific networks through the description of PPP1R3A as a central regulator in heart failure.