Browsing by Author "Rischard, Franz"

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    Author Correction: Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood
    (Springer Nature, 2022-11-25) Kariotis, Sokratis; Jammeh, Emmanuel; Swietlik, Emilia M.; Pickworth, Josephine A.; Rhodes, Christopher J.; Otero, Pablo; Wharton, John; Iremonger, James; Dunning, Mark J.; Pandya, Divya; Mascarenhas, Thomas S.; Errington, Niamh; Thompson, A. A. Roger; Romanoski, Casey E.; Rischard, Franz; Garcia, Joe G. N.; Yuan, Jason X-J; Schwantes An, Tae-Hwi; Desai, Ankit A.; Coghlan, Gerry; Lordan, Jim; Corris, Paul A.; Howard, Luke S.; Condliffe, Robin; Kiely, David G.; Church, Colin; Pepke-Zaba, Joanna; Toshner, Mark; Wort, Stephen; Gräf, Stefan; Morrell, Nicholas W.; Wilkins, Martin R.; Lawrie, Allan; Wang, Dennis; UK National PAH Cohort Study Consortium; Medicine, School of Medicine
    Correction to: Nature Communications 10.1038/s41467-021-27326-0, published online 07 December 2021 The original version of this Article omitted Richard C Trembath from the UK National PAH Cohort Study consortium from Health and Life Sciences, King’s College London. This has been corrected in both the PDF and HTML versions of the Article.
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    Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood
    (Springer Nature, 2021-12-07) Kariotis, Sokratis; Jammeh, Emmanuel; Swietlik, Emilia M.; Pickworth, Josephine A.; Rhodes, Christopher J.; Otero, Pablo; Wharton, John; Iremonger, James; Dunning, Mark J.; Pandya, Divya; Mascarenhas, Thomas S.; Errington, Niamh; Thompson, A. A. Roger; Romanoski, Casey E.; Rischard, Franz; Garcia, Joe G. N.; Yuan, Jason X.-J.; Schwantes An, Tae-Hwi; Desai, Ankit A.; Coghlan, Gerry; Lordan, Jim; Corris, Paul A.; Howard, Luke S.; Condliffe, Robin; Kiely, David G.; Church, Colin; Pepke-Zaba, Joanna; Toshner, Mark; Wort, Stephen; Gräf, Stefan; Morrell, Nicholas W.; Wilkins, Martin R.; Lawrie, Allan; Wang, Dennis; UK National PAH Cohort Study Consortium; Medicine, School of Medicine
    Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH.
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    Cytokine profiling in pulmonary arterial hypertension: the role of redox homeostasis and sex
    (Elsevier, 2022) Rafikov, Ruslan; Rischard, Franz; Vasilyev, Mikhail; Varghese, Mathews V.; Yuan, Jason X-J; Desai, Ankit A.; Garcia, Joe G.; Rafikova, Olga; Medicine, School of Medicine
    Pulmonary arterial hypertension (PAH) is a fatal disease with a well-established sexual dimorphism. Activated inflammatory response and altered redox homeostasis, both known to manifest in a sex-specific manner, are implicated in the pathogenic mechanisms involved in PAH development. This study aimed to evaluate the impact of sex and plasma redox status on circulating cytokine profiles. Plasma oxidation-reduction potential (ORP), as a substitute measure of redox status, was analyzed in male and female Group 1 PAH and healthy subjects. The profiles of 27 circulating cytokines were compared in 2 PAH groups exhibiting the highest and lowest quartile for plasma ORP, correlated with clinical parameters, and used to predict patient survival. The analysis of the PAH groups with the highest and lowest ORP revealed a correlation between elevated cytokine levels and increased oxidative stress in females. In contrast, in males, cytokine expressions were increased in the lower oxidative environment (except for IL-1b). Correlations of the increased cytokine expressions with PAH severity were highly sex-dependent and corresponded to the increase in PAH severity in males and less severe PAH in females. Machine learning algorithms trained on the combined cytokine and redox profiles allowed the prediction of PAH mortality with 80% accuracy. We conclude that the profile of circulating cytokines in PAH patients is redox- and sex-dependent, suggesting the vital need to stratify the patient cohort subjected to anti-inflammatory therapies. Combined cytokine and/or redox profiling showed promising value for predicting the patients' survival.
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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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    Endothelial eNAMPT drives EndMT and preclinical PH: rescue by an eNAMPT-neutralizing mAb
    (Wiley, 2021-11-12) Ahmed, Mohamed; Zaghloul, Nahla; Zimmerman, Prisca; Casanova, Nancy G.; Sun, Xiaoguang; Song, Jin H.; Reyes Hernon, Vivian; Sammani, Saad; Rischard, Franz; Rafikova, Olga; Rafikov, Ruslan; Makino, Ayako; Kempf, Carrie L.; Camp, Sara M.; Wang, Jian; Desai, Ankit A.; Lussier, Yves; Yuan, Jason X.-J.; Garcia, Joe G. N.; Medicine, School of Medicine
    Pharmacologic interventions to halt/reverse the vascular remodeling and right ventricular dysfunction in pulmonary arterial hypertension (PAH) remains an unmet need. We previously demonstrated extracellular nicotinamide phosphoribosyltransferase (eNAMPT) as a DAMP (damage-associated molecular pattern protein) contributing to PAH pathobiology via TLR4 ligation. We examined the role of endothelial cell (EC)-specific eNAMPT in experimental PH and an eNAMPT-neutralizing mAb as a therapeutic strategy to reverse established PH. Hemodynamic/echocardiographic measurements and tissue analyses were performed in Sprague Dawley rats exposed to 10% hypoxia/Sugen (three weeks) followed by return to normoxia and weekly intraperitoneal delivery of the eNAMPT mAb (1 mg/kg). WT C57BL/6J mice and conditional EC-cNAMPTec-/- mice were exposed to 10% hypoxia (three weeks). Biochemical and RNA sequencing studies were performed on rat PH lung tissues and human PAH PBMCs. Hypoxia/Sugen-exposed rats exhibited multiple indices of severe PH (right ventricular systolic pressure, Fulton index), including severe vascular remodeling, compared to control rats. PH severity indices and plasma levels of eNAMPT, IL-6, and TNF-α were all significantly attenuated by eNAMPT mAb neutralization. Compared to hypoxia-exposed WT mice, cNAMPTec-/- KO mice exhibited significantly reduced PH severity and evidence of EC to mesenchymal transition (EndMT). Finally, biochemical and RNAseq analyses revealed eNAMPT mAb-mediated rectification of dysregulated inflammatory signaling pathways (TLR/NF-κB, MAP kinase, Akt/mTOR) and EndMT in rat PH lung tissues and human PAH PBMCs. These studies underscore EC-derived eNAMPT as a key contributor to PAH pathobiology and support the eNAMPT/TLR4 inflammatory pathway as a highly druggable therapeutic target to reduce PH severity and reverse PAH.
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    Genetic Admixture and Survival in Diverse Populations with Pulmonary Arterial Hypertension
    (American Thoracic Society, 2020-06-01) Karnes, Jason H.; Wiener, Howard W.; Schwantes-An, Tae-Hwi; Natarajan, Balaji; Sweatt, Andrew J.; Chaturvedi, Abhishek; Arora, Amit; Batai, Ken; Nair, Vineet; Steiner, Heidi E.; Giles, Jason B.; Yu, Jeffrey; Hosseini, Maryam; Pauciulo, Michael W.; Lutz, Katie A.; Coleman, Anna W.; Feldman, Jeremy; Vanderpool, Rebecca; Tang, Haiyang; Garcia, Joe G.N.; Yuan, Jason X.J; Kittles, Rick; de Jesus Perez, Vinicio; Zamanian, Roham T.; Rischard, Franz; Tiwari, Hemant K.; Nichols, William C.; Benza, Raymond L.; Desai, Ankit A.; Medicine, School of Medicine
    Rationale: Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).Objectives: Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Methods: Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis.Measurements and Main Results: After covariate adjustment, self-reported Hispanic patients (n = 290) exhibited significantly reduced mortality versus NHW patients (n = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87]; P = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01]; P = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients (n = 1,524) versus NHW patients (n = 8,829; OR, 0.65 [95% CI, 0.50-0.84]; P = 0.001). An inpatient mortality benefit was observed for Native American patients (n = 185; OR, 0.38 [95% CI, 0.15-0.93]; P = 0.034).Conclusions: This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.
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    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 Medicine
    Understanding 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.
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    Transcriptomic profiles in pulmonary arterial hypertension associate with disease severity and identify novel candidate genes
    (Sage, 2020-12-07) Romanoski, Casey E.; Qi, Xinshuai; Sangam, Shreya; Vanderpool, Rebecca R.; Stearman, Robert S.; Conklin, Austin; Gonzalez-Garay, Manuel; Rischard, Franz; Ayon, Ramon J.; Wang, Jian; Simonson, Tatum; Babicheva, Aleksandra; Shi, Yinan; Tang, Haiyang; Makino, Ayako; Kanthi, Yogendra; Geraci, Mark W.; Garcia, Joe G.N.; Yuan, Jason X.-J.; Desai, Ankit A.; Medicine, School of Medicine
    Using RNAseq, we identified a 61 gene-based circulating transcriptomic profile most correlated with four indices of pulmonary arterial hypertension severity. In an independent dataset, 13/61 (21%) genes were differentially expressed in lung tissues of pulmonary arterial hypertension cases versus controls, highlighting potentially novel candidate genes involved in pulmonary arterial hypertension development.