Person: Waxman, Aaron
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Waxman
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Aaron
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Waxman, Aaron
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Publication Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron–sulfur deficiency and pulmonary hypertension(BlackWell Publishing Ltd, 2015) White, Kevin; Lu, Yu; Annis, Sofia; Hale, Andrew E; Chau, B Nelson; Dahlman, James E; Hemann, Craig; Opotowsky, Alexander; Vargas, Sara; Rosas, Ivan; Perrella, Mark; Osorio, Juan C; Haley, Kathleen; Graham, Brian B; Kumar, Rahul; Saggar, Rajan; Saggar, Rajeev; Wallace, W Dean; Ross, David J; Khan, Omar F; Bader, Andrew; Gochuico, Bernadette R; Matar, Majed; Polach, Kevin; Johannessen, Nicolai M; Prosser, Haydn M; Anderson, Daniel; Langer, Robert; Zweier, Jay L; Bindoff, Laurence A; Systrom, David; Waxman, Aaron; Jin, Richard C; Chan, Stephen YIron–sulfur (Fe-S) clusters are essential for mitochondrial metabolism, but their regulation in pulmonary hypertension (PH) remains enigmatic. We demonstrate that alterations of the miR-210-ISCU1/2 axis cause Fe-S deficiencies in vivo and promote PH. In pulmonary vascular cells and particularly endothelium, hypoxic induction of miR-210 and repression of the miR-210 targets ISCU1/2 down-regulated Fe-S levels. In mouse and human vascular and endothelial tissue affected by PH, miR-210 was elevated accompanied by decreased ISCU1/2 and Fe-S integrity. In mice, miR-210 repressed ISCU1/2 and promoted PH. Mice deficient in miR-210, via genetic/pharmacologic means or via an endothelial-specific manner, displayed increased ISCU1/2 and were resistant to Fe-S-dependent pathophenotypes and PH. Similar to hypoxia or miR-210 overexpression, ISCU1/2 knockdown also promoted PH. Finally, cardiopulmonary exercise testing of a woman with homozygous ISCU mutations revealed exercise-induced pulmonary vascular dysfunction. Thus, driven by acquired (hypoxia) or genetic causes, the miR-210-ISCU1/2 regulatory axis is a pathogenic lynchpin causing Fe-S deficiency and PH. These findings carry broad translational implications for defining the metabolic origins of PH and potentially other metabolic diseases sharing similar underpinnings.Publication Impaired systemic oxygen extraction in treated exercise pulmonary hypertension: a new engine in an old car?(SAGE Publications, 2018) Faria-Urbina, Mariana; Oliveira, Rudolf K.F.; Segrera, Sergio A.; Lawler, Laurie; Waxman, Aaron; Systrom, DavidAmbrisentan in 22 patients with pulmonary hypertension diagnosed during exercise (ePH) improved pulmonary hemodynamics; however, there was only a trend toward increased maximum oxygen uptake (VO2max) secondary to decreased maximum exercise systemic oxygen extraction (Ca-vO2). We speculate that improved pulmonary hemodynamics at maximum exercise “unmasked” a pre-existing skeletal muscle abnormality.Publication Functional impact of exercise pulmonary hypertension in patients with borderline resting pulmonary arterial pressure(SAGE Publications, 2017) Oliveira, Rudolf K. F.; Faria-Urbina, Mariana; Maron, Bradley; Santos, Mario; Waxman, Aaron; Systrom, DavidBorderline resting mean pulmonary arterial pressure (mPAP) is associated with adverse outcomes and affects the exercise pulmonary vascular response. However, the pathophysiological mechanisms underlying exertional intolerance in borderline mPAP remain incompletely characterized. In the current study, we sought to evaluate the prevalence and functional impact of exercise pulmonary hypertension (ePH) across a spectrum of resting mPAP’s in consecutive patients with contemporary resting right heart catheterization (RHC) and invasive cardiopulmonary exercise testing. Patients with resting mPAP <25 mmHg and pulmonary arterial wedge pressure ≤15 mmHg (n = 312) were stratified by mPAP < 13, 13–16, 17–20, and 21–24 mmHg. Those with ePH (n = 35) were compared with resting precapillary pulmonary hypertension (rPH; n = 16) and to those with normal hemodynamics (non-PH; n = 224). ePH prevalence was 6%, 8%, and 27% for resting mPAP 13–16, 17–20, and 21–24 mmHg, respectively. Within each of these resting mPAP epochs, ePH negatively impacted exercise capacity compared with non-PH (peak oxygen uptake 70 ± 16% versus 92 ± 19% predicted, P < 0.01; 72 ± 13% versus 86 ± 17% predicted, P < 0.05; and 64 ± 15% versus 82 ± 19% predicted, P < 0.001, respectively). Overall, ePH and rPH had similar functional limitation (peak oxygen uptake 67 ± 15% versus 68 ± 17% predicted, P > 0.05) and similar underlying mechanisms of exercise intolerance compared with non-PH (peak oxygen delivery 1868 ± 599 mL/min versus 1756 ± 720 mL/min versus 2482 ± 875 mL/min, respectively; P < 0.05), associated with chronotropic incompetence, increased right ventricular afterload and signs of right ventricular/pulmonary vascular uncoupling. In conclusion, ePH is most frequently found in borderline mPAP, reducing exercise capacity in a manner similar to rPH. When borderline mPAP is identified at RHC, evaluation of the pulmonary circulation under the stress of exercise is warranted.Publication Right heart failure: toward a common language(University of Chicago Press, 2013) Mehra, Mandeep; Park, Myung H.; Landzberg, Michael; Lala, Anuradha; Waxman, AaronAbstract In this guideline, the International Right Heart Foundation Working Group moves a step forward to develop a common language to describe the development and defects that exemplify the common syndrome of right heart failure. We first propose fundamental definitions of the distinctive components of the right heart circulation and provide consensus on a universal definition of right heart failure. These definitions will form the foundation for describing a uniform nomenclature for right heart circulatory failure with a view to foster collaborative research initiatives and conjoint education in an effort to provide insight into mechanisms of disease unique to the right heart.Publication Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation(Public Library of Science, 2013) Nakahira, Kiichi; Kyung, Sun-Young; Rogers, Angela J.; Gazourian, Lee; Youn, Sojung; Massaro, Anthony; Quintana, Carolina; Osorio, Juan C.; Wang, Zhaoxi; Zhao, Yang; Lawler, Laurie A.; Christie, Jason D.; Meyer, Nuala J.; Causland, Finnian R. Mc.; Waikar, Sushrut S.; Waxman, Aaron; Chung, Raymond; Bueno, Raphael; Rosas, Ivan; Fredenburgh, Laura; Baron, Rebecca; Christiani, David; Hunninghake, Gary; Choi, Augustine M. K.Background: Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients. Methods and Findings: Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6–15.8, p = 1×10−7) and ME ARDS (OR 8.4, 95% CI 2.9–24.2, p = 9×10−5) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10−4) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers. Conclusions: Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients. Please see later in the article for the Editors' SummaryPublication Improving Decision Making for Massive Transfusions in a Resource Poor Setting: A Preliminary Study in Kenya(Public Library of Science, 2015) Riviello, Beth; Letchford, Stephen; Cook, Earl; Waxman, Aaron; Gaziano, ThomasBackground: The reality of finite resources has a real-world impact on a patient’s ability to receive life-saving care in resource-poor settings. Blood for transfusion is an example of a scarce resource. Very few studies have looked at predictors of survival in patients requiring massive transfusion. We used data from a rural hospital in Kenya to develop a prediction model of survival among patients receiving massive transfusion. Methods: Patients who received five or more units of whole blood within 48 hours between 2004 and 2010 were identified from a blood registry in a rural hospital in Kenya. Presenting characteristics and in-hospital survival were collected from charts. Using stepwise selection, a logistic model was developed to predict who would survive with massive transfusion versus those who would die despite transfusion. An ROC curve was created from this model to quantify its predictive power. Results: Ninety-five patients with data available met inclusion criteria, and 74% survived to discharge. The number of units transfused was not a predictor of mortality, and no threshold for futility could be identified. Preliminary results suggest that initial blood pressure, lack of comorbidities, and indication for transfusion are the most important predictors of survival. The ROC curve derived from our model demonstrates an area under the curve (AUC) equal to 0.757, with optimism of 0.023 based on a bootstrap validation. Conclusions: This study provides a framework for making prioritization decisions for the use of whole blood in the setting of massive bleeding. Our analysis demonstrated an overall survival rate for patients receiving massive transfusion that was higher than clinical perception. Our analysis also produced a preliminary model to predict survival in patients with massive bleeding. Prediction analyses can contribute to more efficient prioritization decisions; these decisions must also include other considerations such as equity, acceptability, affordability and sustainability.Publication A Review of Sitaxsentan Sodium in Patients with Pulmonary Arterial Hypertension(Dove Medical Press, 2007) Waxman, AaronPulmonary arterial hypertension (PAH) is a life threatening, progressive condition which eventually leads to fatal right heart failure. Endothelin-1 (ET-1), a potent vasoconstrictor peptide, is increased in the pulmonary arteries of patients with pulmonary hypertension. Endothelin-1 acts through the stimulation of 2 subtypes of receptors (endothelin receptor subtypes A [ET\(_A\)] and B [ET\(_B\)]). In PAH patients, ETRAs block the deleterious vasoconstrictor effects of ET-1, and ETRA treatment in PAH patients has been shown to be safe and efficacious. Sitaxsentan is an orally active, highly ET\(_A\) selective ETRA that, in clinical trials, has demonstrated improvements in exercise capacity, functional class and hemodynamics in PAH patients. Sitaxsentan has been shown to be safe, well tolerated, and associated with a lower incidence of liver toxicity than other approved ETRAs.Publication Plasma Gelsolin Depletion and Circulating Actin in Sepsis—A Pilot Study(Public Library of Science, 2008) Lee, Po-Shun; Patel, Sanjay R.; Christiani, David; Bajwa, Ednan; Stossel, Thomas; Waxman, AaronBackground: Depletion of the circulating actin-binding protein, plasma gelsolin (pGSN) has been described in septic patients and animals. We hypothesized that the extent of pGSN reduction correlates with outcomes of septic patients and that circulating actin is a manifestation of sepsis. Methodology/Principal Findings: We assayed pGSN in plasma samples from non-surgical septic patients identified from a pre-existing database which prospectively enrolled patients admitted to adult intensive care units at an academic hospital. We identified 21 non-surgical septic patients for the study. Actinemia was detected in 17 of the 21 patients, suggesting actin released into circulation from injured tissues is a manifestation of sepsis. Furthermore, we documented the depletion of pGSN in human clinical sepsis, and that the survivors had significantly higher pGSN levels than the non-survivors (163±47 mg/L vs. 89±48 mg/L, p = 0.01). pGSN levels were more strongly predictive of 28-day mortality than APACHE III scores. For every quartile reduction in pGSN, the odds of death increased 3.4-fold. Conclusion: We conclude that circulating actin and pGSN deficiency are associated with early sepsis. The degree of pGSN deficiency correlates with sepsis mortality. Reversing pGSN deficiency may be an effective treatment for sepsis.Publication Roundtable Debate: Controversies in the Management of the Septic Patient – Desperately Seeking Consensus(BioMed Central, 2005) Waxman, Aaron; Ward, Nicholas; Thompson, Taylor; Lilly, Craig M.; Lisbon, Alan; Hill, Nicholas Edward; Nasraway, Stanley A.; Heard, Stephen; Corwin, Howard; Levy, MitchellDespite continuous advances in technologic and pharmacologic management, the mortality rate from septic shock remains high. Care of patients with sepsis includes measures to support the circulatory system and treat the underlying infection. There is a substantial body of knowledge indicating that fluid resuscitation, vasopressors, and antibiotics accomplish these goals. Recent clinical trials have provided new information on the addition of individual adjuvant therapies. Consensus on how current therapies should be prescribed is lacking. We present the reasoning and preferences of a group of intensivists who met to discuss the management of an actual case. The focus is on management, with emphasis on the criteria by which treatment decisions are made. It is clear from the discussion that there are areas where there is agreement and areas where opinions diverge. This presentation is intended to show how experienced intensivists apply clinical science to their practice of critical care medicine.Publication The Invasive Cardiopulmonary Exercise Test(Ovid Technologies (Wolters Kluwer Health), 2013-03-12) Maron, Bradley A.; Cockrill, Barbara A.; Systrom, David M.; Waxman, Aaron