Publications by authors named "Stephen Y Wang"

13 Publications

  • Page 1 of 1

Challenges in interpreting cytokine data in COVID-19 affect patient care and management.

PLoS Biol 2021 08 6;19(8):e3001373. Epub 2021 Aug 6.

Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, United States of America.

Challenges in using cytokine data are limiting Coronavirus Disease 2019 (COVID-19) patient management and comparison among different disease contexts. We suggest mitigation strategies to improve the accuracy of cytokine data, as we learn from experience gained during the COVID-19 pandemic.
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http://dx.doi.org/10.1371/journal.pbio.3001373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8372945PMC
August 2021

Association of obesity with venous thromboembolism and myocardial injury in COVID-19.

Obes Res Clin Pract 2021 Jul 16. Epub 2021 Jul 16.

Section of Cardiovascular Medicine, Yale School of Medicine, New Haven, CT, 06510, USA. Electronic address:

Introduction: Although both obesity and coronavirus disease 2019 (COVID-19) independently induce inflammation and thrombosis, the association between obesity class and risk of thrombosis in patients with COVID-19 remains unclear.

Methods: This retrospective cohort study included consecutive patients hospitalized with COVID-19 at a single institution. Patients were categorized based on obesity class. The main outcomes were venous thromboembolism (VTE) and myocardial injury, a marker of microvascular thrombosis in COVID-19. Adjustments were made for sociodemographic variables, cardiovascular disease risk factors and comorbidities.

Results: 609 patients with COVID-19 were included. 351 (58%) patients were without obesity, 110 (18%) were patients with class I obesity, 76 (12%) were patients with class II obesity, and 72 (12%) were patients with class III obesity. Patients with class I and III obesity had significantly higher risk-adjusted odds of VTE compared to patients without obesity (OR = 2.54, 95% CI: 1.05-6.14 for class I obesity; and OR = 3.95, 95% CI: 1.40-11.14 for class III obesity). Patients with class III obesity had significantly higher risk-adjusted odds of myocardial injury compared to patients without obesity (OR = 2.15, 95% CI: 1.12-4.12). Both VTE and myocardial injury were significantly associated with greater risk-adjusted odds of mortality.

Conclusion: This study demonstrates that both macrovascular and microvascular thromboses may contribute to the elevated morbidity and mortality in patients with obesity and COVID-19.
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http://dx.doi.org/10.1016/j.orcp.2021.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283573PMC
July 2021

Out-of-Pocket Annual Health Expenditures and Financial Toxicity From Healthcare Costs in Patients With Heart Failure in the United States.

J Am Heart Assoc 2021 Jul 16;10(14):e022164. Epub 2021 May 16.

Section of Cardiovascular Medicine Department of Internal Medicine Yale School of Medicine New Haven CT.

Background Heart failure (HF) poses a major public health burden in the United States. We examined the burden of out-of-pocket healthcare costs on patients with HF and their families. Methods and Results In the Medical Expenditure Panel Survey, we identified all families with ≥1 adult member with HF during 2014 to 2018. Total out-of-pocket healthcare expenditures included yearly care-specific costs and insurance premiums. We evaluated 2 outcomes of financial toxicity: (1) high financial burden-total out-of-pocket healthcare expense to postsubsistence income ratio of >20%, and (2) catastrophic financial burden with the ratio of >40%-a bankrupting expense defined by the World Health Organization. There were 788 families in the Medical Expenditure Panel Survey with a member with HF representing 0.54% (95% CI, 0.48%-0.60%) of all families nationally. The overall mean annual out-of-pocket healthcare expenses were $4423 (95% CI, $3908-$4939), with medications and health insurance premiums representing the largest categories of cost. Overall, 14% (95% CI, 11%-18%) of families experienced a high burden and 5% (95% CI, 3%-6%) experienced a catastrophic burden. Among the two-fifths of families considered low income, 24% (95% CI, 18%-30%) experienced a high financial burden, whereas 10% (95% CI, 6%-14%) experienced a catastrophic burden. Low-income families had 4-fold greater risk-adjusted odds of high financial burden (odds ratio [OR] , 3.9; 95% CI, 2.3-6.6), and 14-fold greater risk-adjusted odds of catastrophic financial burden (OR, 14.2; 95% CI, 5.1-39.5) compared with middle/high-income families. Conclusions Patients with HF and their families experience large out-of-pocket healthcare expenses. A large proportion encounter financial toxicity, with a disproportionate effect on low-income families.
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http://dx.doi.org/10.1161/JAHA.121.022164DOI Listing
July 2021

Intermediate-dose anticoagulation, aspirin, and in-hospital mortality in COVID-19: A propensity score-matched analysis.

Am J Hematol 2021 04 22;96(4):471-479. Epub 2021 Feb 22.

Section of Hematology, Department of Medicine, Yale School of Medicine, New Haven, Connecticut, USA.

Thrombotic complications occur at high rates in hospitalized patients with COVID-19, yet the impact of intensive antithrombotic therapy on mortality is uncertain. We examined in-hospital mortality with intermediate- compared to prophylactic-dose anticoagulation, and separately with in-hospital aspirin compared to no antiplatelet therapy, in a large, retrospective study of 2785 hospitalized adult COVID-19 patients. In this analysis, we established two separate, nested cohorts of patients (a) who received intermediate- or prophylactic-dose anticoagulation ("anticoagulation cohort", N = 1624), or (b) who were not on home antiplatelet therapy and received either in-hospital aspirin or no antiplatelet therapy ("aspirin cohort", N = 1956). To minimize bias and adjust for confounding factors, we incorporated propensity score matching and multivariable regression utilizing various markers of illness severity and other patient-specific covariates, yielding treatment groups with well-balanced covariates in each cohort. The primary outcome was cumulative incidence of in-hospital death. Among propensity score-matched patients in the anticoagulation cohort (N = 382), in a multivariable regression model, intermediate- compared to prophylactic-dose anticoagulation was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.518 [0.308-0.872]). Among propensity-score matched patients in the aspirin cohort (N = 638), in a multivariable regression model, in-hospital aspirin compared to no antiplatelet therapy was associated with a significantly lower cumulative incidence of in-hospital death (hazard ratio 0.522 [0.336-0.812]). In this propensity score-matched, observational study of COVID-19, intermediate-dose anticoagulation and aspirin were each associated with a lower cumulative incidence of in-hospital death.
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http://dx.doi.org/10.1002/ajh.26102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013588PMC
April 2021

Changes in inflammatory and immune drivers in response to immunomodulatory therapies in COVID-19.

medRxiv 2020 Dec 25. Epub 2020 Dec 25.

As the global community strives to discover effective therapies for COVID-19, immunomodulatory strategies have emerged as a leading contender to combat the cytokine storm and improve clinical outcomes in patients with severe disease. Systemic corticosteroids and selective cytokine inhibitory agents have been utilized both as empiric therapies and in clinical trials. While multiple randomized, placebo controlled trials have now demonstrated that corticosteroids improve survival in patients with COVID-19, IL-6 inhibition, which gained significant early interest based on observational studies, has not demonstrated reliable efficacy in randomized, placebo controlled trials. To better understand the mechanistic basis of immunomodulatory therapies being implemented for treatment of COVID-19, we assessed longitudinal biochemical changes in response to such approaches in hospitalized patients with COVID-19. We demonstrate broad suppression of multiple immunomodulatory factors associated with adverse clinical outcomes in COVID-19 in patients who received corticosteroids, but no such response was seen in patients who either received tocilizumab or no immunomodulatory therapy. Our findings provide early insights into molecular signatures that correlate with immunomodulatory therapies in COVID-19 which may be useful in understanding clinical outcomes in future studies of larger patient cohorts.
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http://dx.doi.org/10.1101/2020.12.23.20248547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781335PMC
December 2020

Food Insecurity and Cardiovascular Mortality for Nonelderly Adults in the United States From 2011 to 2017: A County-Level Longitudinal Analysis.

Circ Cardiovasc Qual Outcomes 2021 01 9;14(1):e007473. Epub 2020 Nov 9.

Division of Cardiovascular Medicine (L.A.E., S.A.M.K.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.

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http://dx.doi.org/10.1161/CIRCOUTCOMES.120.007473DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855295PMC
January 2021

Non-Vitamin K Antagonist Oral Anticoagulant for Atrial Fibrillation in Obese Patients.

Am J Cardiol 2020 07 23;127:176-183. Epub 2020 Apr 23.

Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Electronic address:

Four non-vitamin K antagonist oral anticoagulants (NOACs) are approved for use to reduce the risk of stroke and systemic embolism in patients with atrial fibrillation (AF). However, data are limited regarding the use of NOACs in the obese population. This manuscript summarizes current concepts regarding obesity in patients with AF and reviews in depth the data on the efficacy and safety of NOACs in obese patients with AF. The Pubmed database was searched for relevant articles. When evaluating obese patients with AF, weight loss is important to reduce disease burden. Recent analyses of the four NOAC versus warfarin trials (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48) stratified by body mass index (BMI) demonstrate preserved efficacy with NOACs versus warfarin in obese patients, with similar risk of major bleeding. Although the data are limited in class III obese patients (body mass index ≥40kg/m), the efficacy and safety of apixaban or edoxaban appears to be similar to warfarin in patients with BMI 40-50kg/m. In conclusion, these new data should be considered in updated guidelines, which currently provide limited, and sometimes conflicting recommendations regarding the use of NOACs in obese patients, particularly in severely obese patients.
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http://dx.doi.org/10.1016/j.amjcard.2020.04.016DOI Listing
July 2020

Longitudinal Associations Between Income Changes and Incident Cardiovascular Disease: The Atherosclerosis Risk in Communities Study.

JAMA Cardiol 2019 12;4(12):1203-1212

Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Importance: Higher income is associated with lower incident cardiovascular disease (CVD). However, there is limited research on the association between changes in income and incident CVD.

Objective: To examine the association between change in household income and subsequent risk of CVD.

Design, Setting, And Participants: The Atherosclerosis Risk In Communities (ARIC) study is an ongoing, prospective cohort of 15 792 community-dwelling men and women, of mostly black or white race, from 4 centers in the United States (Jackson, Mississippi; Washington County, Maryland; suburbs of Minneapolis, Minnesota; and Forsyth County, North Carolina), beginning in 1987. For our analysis, participants were followed up until December 31, 2016.

Exposures: Participants were categorized based on whether their household income dropped by more than 50% (income drop), remained unchanged/changed less than 50% (income unchanged), or increased by more than 50% (income rise) over a mean (SD) period of approximately 6 (0.3) years between ARIC visit 1 (1987-1989) and visit 3 (1993-1995).

Main Outcomes And Measures: Our primary outcome was incidence of CVD after ARIC visit 3, including myocardial infarction (MI), fatal coronary heart disease, heart failure (HF), or stroke during a mean (SD) of 17 (7) years. Analyses were adjusted for sociodemographic variables, health behaviors, and CVD biomarkers.

Results: Of the 8989 included participants (mean [SD] age at enrollment was 53 [6] years, 1820 participants were black [20%], and 3835 participants were men [43%]), 900 participants (10%) experienced an income drop, 6284 participants (70%) had incomes that remained relatively unchanged, and 1805 participants (20%) experienced an income rise. After full adjustment, those with an income drop experienced significantly higher risk of incident CVD compared with those whose incomes remained relatively unchanged (hazard ratio, 1.17; 95% CI, 1.03-1.32). Those with an income rise experienced significantly lower risk of incident CVD compared with those whose incomes remained relatively unchanged (hazard ratio, 0.86; 95% CI, 0.77-0.96).

Conclusions And Relevance: Income drop over 6 years was associated with higher risk of subsequent incident CVD over 17 years, while income rise over 6 years was associated with lower risk of subsequent incident CVD over 17 years. Health professionals should have greater awareness of the influence of income change on the health of their patients.
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http://dx.doi.org/10.1001/jamacardio.2019.3788DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802267PMC
December 2019

Utility of the Cardiovascular Physical Examination and Impact of Spironolactone in Heart Failure With Preserved Ejection Fraction.

Circ Heart Fail 2019 07 21;12(7):e006125. Epub 2019 Jun 21.

Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA (B.C., A.S.D., E.F.L., M.V., S.Y.W., M.A.P., S.D.S.).

Background: The prognostic value of physical examination, its relation to quality of life, and influence of therapy in heart failure with preserved ejection fraction is not well known.

Methods And Results: We studied participants from the Americas with available physical examination (jugular venous distention, rales, and edema) at baseline in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist). The association of the number of signs of congestion with the primary outcome (cardiovascular death or heart failure hospitalization), its individual components, and all-cause mortality was assessed using time-updated, multivariable-adjusted Cox regression analyses. We evaluated whether spironolactone improved congestion at 4 months and whether improvement in congestion was related to quality of life as assessed by Kansas City Cardiomyopathy Questionnaire overall summary scores and to outcomes. Among 1644 participants, 22%, 54%, 20%, and 4% had 0, 1, 2, and 3 signs of congestion, respectively, at baseline. After multivariable adjustment, each additional increase in sign of congestion was associated with a 30% to 60% increased risk of each outcome ( P<0.001). Spironolactone reduced the total number of signs of congestion by -0.10 ( P=0.005) signs, jugular venous distention (odds ratio, 0.60; P=0.01), and edema (odds ratio, 0.74; P=0.006) at 4 months compared with placebo. Each reduction in sign of congestion was independently associated with a 4.0 (95% CI, 2.4-5.6) point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score. When assessed simultaneously, time-updated, but not baseline congestion, predicted outcomes.

Conclusions: In heart failure with preserved ejection fraction, the physical exam provides independent prognostic value for adverse outcomes. Spironolactone improved congestion compared with placebo. Reducing congestion was independently associated with improved quality of life and outcomes and is a modifiable risk factor.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00094302.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686863PMC
July 2019

The Beyond the Books Program: Improving Medical Student Attitudes Toward the Underserved.

Health Equity 2018 1;2(1):98-102. Epub 2018 Jun 1.

Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.

To determine the impact of the Beyond the Books (BTB) program, a short-term pre-clinical intervention, on medical student attitudes toward the underserved (MSATU). BTB was evaluated through a prospective cohort study using the validated MSATU questionnaire. There were no significant MSATU total score differences between BTB students (=13) and student controls (=29) at the beginning of the program. At the program's conclusion, BTB participant MSATU total scores were significantly higher than those of controls (<0.001). Although limited by selection methods, our MSATU data support the capability of short-term pre-clinical interventions to significantly improve medical student attitudes toward underserved communities.
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http://dx.doi.org/10.1089/heq.2018.0015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071908PMC
June 2018

Dofetilide-Associated QT Prolongation: Total Body Weight Versus Adjusted or Ideal Body Weight for Dosing.

J Cardiovasc Pharmacol 2018 09;72(3):161-165

Geisel School of Medicine at Dartmouth, Hanover, NH.

Dofetilide is an antiarrhythmic drug with dosing based on the Cockcroft-Gault formula using total body weight (TBW). We investigated the impact of calculating dofetilide dose using adjusted body weight (ABW) or ideal body weight (IBW) on subsequent dose reduction or discontinuation. We conducted a retrospective review of 265 patients admitted to an academic medical center for initiation of dofetilide using TBW. Dosing was recalculated using ABW or IBW. Patients who would have received a reduced dose using ABW or IBW (reduced dose group) were compared with patients whose dose would not have changed (same dose group). Manual measurement of QT intervals was performed. We found that Forty-one of 265 patients (15%) would have received a lower initial dose of dofetilide based on ABW. Patients in this reduced dose group had 2.95 times greater odds of drug discontinuations or dose reductions due to QTc prolongation (95% confidence interval, 1.47-5.90; P < 0.01) compared with the same dose group. Seventy-seven of 265 patients (29%) would have received a lower initial dose of dofetilide based on IBW. Patients in this reduced dose group had 1.78 times greater odds of drug discontinuations or dose reductions due to QTc prolongation (95% confidence interval, 0.98-3.21; P = 0.056) compared with the same dose group. These data suggest that caution should be used when dosing dofetilide using TBW, as it may lead to a greater frequency of dose reduction or discontinuation compared with dosing using ABW or IBW.
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http://dx.doi.org/10.1097/FJC.0000000000000610DOI Listing
September 2018

Spontaneous Closure of a Secundum Atrial Septal Defect.

Methodist Debakey Cardiovasc J 2018 Jan-Mar;14(1):60-62

aGEISEL SCHOOL OF MEDICINE AT DARTMOUTH, HANOVER, NEW HAMPSHIRE.

Spontaneous closure of an atrial septal defect (ASD) is well described in pediatric cardiology but may be less familiar to adult internists and cardiologists. We report a moderately sized 6-mm ASD that closed spontaneously without intervention. A literature review found that a smaller defect size and an early age of diagnosis are the most important predictors of closure. Possible mechanisms of a spontaneous ASD closure include adaptive endothelial migration, limited myocardial proliferation, and fibroblast migration with extracellular matrix deposition.
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http://dx.doi.org/10.14797/mdcj-14-1-60DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880562PMC
August 2018

Dysfunction of cholesterol sensor SCAP promotes inflammation activation in THP-1 macrophages.

Exp Cell Res 2018 06 27;367(2):162-169. Epub 2018 Mar 27.

Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, PR China; Centre for Lipid Research, Key Laboratory of Metabolism on Lipid and Glucose, Chongqing Medical University, Chongqing 400016, PR China. Electronic address:

Crosstalk occurs between dyslipidemia and chronic inflammation, which are both precipitants of atherosclerosis. Sterol regulatory element binding proteins cleavage-activating protein (SCAP) plays a key role in regulating cholesterol homeostasis. The present study investigated the effects of SCAP dysfunction on the expression of inflammatory cytokines and lipid metabolism in THP-1 macrophages. Intracellular cholesterol content was assessed by Oil Red O staining and quantitative assays. The expression of SCAP, HMGCR, pro-IL-1β and N-SREBP2, p65(N) in the nucleus were examined by real-time quantitative RT-PCR and Western blotting. The level of secretary proteins IL-1β, TNF-α and MCP-1 in the supernatants were determined by ELISA. The translocation of SCAP from the endoplasmic reticulum (ER) to the Golgi was detected by confocal microscopy. Our results demonstrated that over-expression of SCAP significantly increased the expression of HMGCR, pro-IL-1β in the cytoplasm, and mature IL-1β, TNF-α, MCP-1 in the supernatants, while knocking down SCAP dramatically decreased the expression of these molecules. Betulin effectively suppressed the accumulation of intracellular cholesterol in the SCAP over-expressed THP-1 macrophages, but did not affect the expression of inflammatory cytokines, indicating that the pro-inflammatory effect of SCAP was independent of its routine role in regulating cholesterol homeostasis. Furthermore, we investigated the molecular mechanisms mediating the crosstalk between dyslipidemia and inflammatory responses. Knocking down SCAP attenuated LPS-induced IκB phosphorylation and reduced the nuclear level of p65, while over-expression of SCAP increased the nuclear level of p65. Knocking down p65 abolished the proinflammatory effect represented by elevated expression of the inflammatory mediators in the SCAP over-expressed THP-1 macrophages, suggesting that SCAP dysfunction stimulated inflammatory responses via activating the NF-κB signaling pathway. In conclusion, the cholesterol sensor SCAP plays a role in regulating the expression of inflammatory factors such as IL-1β, TNF-α, and MCP-1 in THP-1 macrophages. SCAP mediates the inflammatory response via activating the NF-κB pathway. This new function of SCAP is independent of its role in lipid metabolism.
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http://dx.doi.org/10.1016/j.yexcr.2018.03.032DOI Listing
June 2018
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