Browsing by Author "Redfield, Margaret M."

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    Advancing Research on the Complex Interrelations between Atrial fibrillation and Heart Failure: A Report from a National Heart, Lung, and Blood Institute Virtual Workshop
    (American Heart Association, 2020-06-09) Al-Khatib, Sana M.; Benjamin, Emelia J.; Albert, Christine M.; Alonso, Alvaro; Chauhan, Cynthia; Chen, Peng-Sheng; Curtis, Anne B.; Desvigne-Nickens, Patrice; Ho, Jennifer E.; Lam, Carolyn S.P.; Link, Mark S.; Patton, Kristen K.; Redfield, Margaret M.; Rienstra, Michiel; Rosenberg, Yves; Schnabel, Renate; Spertus, John A.; Warner Stevenson, Lynne; Hills, Mellanie True; Voors, Adriaan A.; Cooper, Lawton S.; Go, Alan S.; Medicine, School of Medicine
    The interrelationships between atrial fibrillation (AF) and heart failure (HF) are complex and poorly understood, yet the number of patients with AF and HF continues to increase worldwide. Thus, there is a need for initiatives that prioritize research on the intersection between AF and HF. This report summarizes the proceedings of a virtual workshop convened by the National Heart, Lung, and Blood Institute to identify important research opportunities in AF and HF. Key knowledge gaps were reviewed and research priorities were proposed for characterizing the pathophysiological overlap and deleterious interactions between AF and HF; preventing HF in persons with AF; preventing AF in individuals with HF; and addressing symptom burden and health status outcomes in AF and HF. These research priorities will hopefully help inform, encourage, and stimulate innovative, cost-efficient, and transformative studies to enhance the outcomes of patients with AF and HF.
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    Frataxin deficiency promotes endothelial senescence in pulmonary hypertension
    (The American Society for Clinical Investigation, 2021-06-01) Culley, Miranda K.; Zhao, Jingsi; Tai, Yi Yin; Tang, Ying; Perk, Dror; Negi, Vinny; Yu, Qiujun; Woodcock, Chen-Shan C.; Handen, Adam; Speyer, Gil; Kim, Seungchan; Lai, Yen-Chun; Satoh, Taijyu; Watson, Annie M.M.; Al Aaraj, Yassmin; Sembrat, John; Rojas, Mauricio; Goncharov, Dmitry; Goncharova, Elena A.; Khan, Omar F.; Anderson, Daniel G.; Dahlman, James E.; Gurkar, Aditi U.; Lafyatis, Robert; Fayyaz, Ahmed U.; Redfield, Margaret M.; Gladwin, Mark T.; Rabinovitch, Marlene; Gu, Mingxia; Bertero, Thomas; Chan, Stephen Y.; Medicine, School of Medicine
    The dynamic regulation of endothelial pathophenotypes in pulmonary hypertension (PH) remains undefined. Cellular senescence is linked to PH with intracardiac shunts; however, its regulation across PH subtypes is unknown. Since endothelial deficiency of iron-sulfur (Fe-S) clusters is pathogenic in PH, we hypothesized that a Fe-S biogenesis protein, frataxin (FXN), controls endothelial senescence. An endothelial subpopulation in rodent and patient lungs across PH subtypes exhibited reduced FXN and elevated senescence. In vitro, hypoxic and inflammatory FXN deficiency abrogated activity of endothelial Fe-S–containing polymerases, promoting replication stress, DNA damage response, and senescence. This was also observed in stem cell–derived endothelial cells from Friedreich’s ataxia (FRDA), a genetic disease of FXN deficiency, ataxia, and cardiomyopathy, often with PH. In vivo, FXN deficiency–dependent senescence drove vessel inflammation, remodeling, and PH, whereas pharmacologic removal of senescent cells in Fxn-deficient rodents ameliorated PH. These data offer a model of endothelial biology in PH, where FXN deficiency generates a senescent endothelial subpopulation, promoting vascular inflammatory and proliferative signals in other cells to drive disease. These findings also establish an endothelial etiology for PH in FRDA and left heart disease and support therapeutic development of senolytic drugs, reversing effects of Fe-S deficiency across PH subtypes.