Inflammatory biomarkers as predictors of heart failure in women without obstructive coronary artery disease: A report from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE)

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Abstract

Background

Women with signs and symptoms of ischemia, no obstructive coronary artery disease (CAD) and preserved left ventricular ejection fraction (EF) often have diastolic dysfunction and experience elevated rates of major adverse cardiac events (MACE), including heart failure (HF) hospitalization with preserved ejection fraction (HFpEF). We evaluated the predictive value of inflammatory biomarkers for long-term HF hospitalization and all-cause mortality in these women.

Methods

We performed a cross-sectional analysis to investigate the relationships between inflammatory biomarkers [serum interleukin-6 (IL-6), C-reactive protein (hs-CRP) and serum amyloid A (SAA)] and median of 6 years follow-up for all-cause mortality and HF hospitalization among women with signs and symptoms of ischemia, non-obstructive CAD and preserved EF. Multivariable Cox regression analysis tested associations between biomarker levels and adverse outcomes.

Results

Among 390 women, mean age 56 ± 11 years, median follow up of 6 years, we observed that there is continuous association between IL-6 level and HF hospitalization (adjusted hazard ratio [AHR] 2.5 [1.2–5.0], p = 0.02). In addition, we found significant association between IL-6, SAA levels and all-cause mortality AHR (1.8 [1.1–3.0], p = 0.01) (1.5 [1.0–2.1], p = 0.04), respectively.

Conclusion

In women with signs and symptoms of ischemia, non-obstructive CAD and preserved EF, elevated IL-6 predicted HF hospitalization and all-cause mortality, while SAA level was only associated with all-cause mortality. These results suggest that inflammation plays a role in the pathogenesis of development of HFpEF, as well all-cause mortality.

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Most cited references 23

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C-Reactive Protein, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events: An 8-Year Follow-Up of 14 719 Initially Healthy American Women

Paul Ridker, Julie Buring, Nancy Cook … (2003)

The metabolic syndrome describes a high-risk population having 3 or more of the following clinical characteristics: upper-body obesity, hypertriglyceridemia, low HDL, hypertension, and abnormal glucose. All of these attributes, however, are associated with increased levels of C-reactive protein (CRP). We evaluated interrelationships between CRP, the metabolic syndrome, and incident cardiovascular events among 14 719 apparently healthy women who were followed up for an 8-year period for myocardial infarction, stroke, coronary revascularization, or cardiovascular death; 24% of the cohort had the metabolic syndrome at study entry. At baseline, median CRP levels for those with 0, 1, 2, 3, 4, or 5 characteristics of the metabolic syndrome were 0.68, 1.09, 1.93, 3.01, 3.88, and 5.75 mg/L, respectively (P(trend) <0.0001). Over the 8-year follow-up, cardiovascular event-free survival rates based on CRP levels above or below 3.0 mg/L were similar to survival rates based on having 3 or more characteristics of the metabolic syndrome. At all levels of severity of the metabolic syndrome, however, CRP added prognostic information on subsequent risk. For example, among those with the metabolic syndrome at study entry, age-adjusted incidence rates of future cardiovascular events were 3.4 and 5.9 per 1000 person-years of exposure for those with baseline CRP levels less than or greater than 3.0 mg/L, respectively. Additive effects for CRP were also observed for those with 4 or 5 characteristics of the metabolic syndrome. The use of different definitions of the metabolic syndrome had minimal impact on these findings. These prospective data suggest that measurement of CRP adds clinically important prognostic information to the metabolic syndrome.

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Loss to follow-up in cohort studies: how much is too much?

Vicki Kristman, Michael Manno, Pierre Côté (2003)

Loss to follow-up is problematic in most cohort studies and often leads to bias. Although guidelines suggest acceptable follow-up rates, the authors are unaware of studies that test the validity of these recommendations. The objective of this study was to determine whether the recommended follow-up thresholds of 60-80% are associated with biased effects in cohort studies. A simulation study was conducted using 1000 computer replications of a cohort of 500 observations. The logistic regression model included a binary exposure and three confounders. Varied correlation structures of the data represented various levels of confounding. Differing levels of loss to follow-up were generated through three mechanisms: missing completely at random (MCAR), missing at random (MAR) and missing not at random (MNAR). The authors found no important bias with levels of loss that varied from 5 to 60% when loss to follow-up was related to MCAR or MAR mechanisms. However, when observations were lost to follow-up based on a MNAR mechanism, the authors found seriously biased estimates of the odds ratios with low levels of loss to follow-up. Loss to follow-up in cohort studies rarely occurs randomly. Therefore, when planning a cohort study, one should assume that loss to follow-up is MNAR and attempt to achieve the maximum follow-up rate possible.

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Inflammatory markers and the risk of coronary heart disease in men and women.

Jennifer K Pai, Tobias Pischon, Jing Ma … (2004)

Few studies have simultaneously investigated the role of soluble tumor necrosis factor alpha (TNF-alpha) receptors types 1 and 2 (sTNF-R1 and sTNF-R2), C-reactive protein, and interleukin-6 as predictors of cardiovascular events. The value of these inflammatory markers as independent predictors remains controversial. We examined plasma levels of sTNF-R1, sTNF-R2, interleukin-6, and C-reactive protein as markers of risk for coronary heart disease among women participating in the Nurses' Health Study and men participating in the Health Professionals Follow-up Study in nested case-control analyses. Among participants who provided a blood sample and who were free of cardiovascular disease at baseline, 239 women and 265 men had a nonfatal myocardial infarction or fatal coronary heart disease during eight years and six years of follow-up, respectively. Using risk-set sampling, we selected controls in a 2:1 ratio with matching for age, smoking status, and date of blood sampling. After adjustment for matching factors, high levels of interleukin-6 and C-reactive protein were significantly related to an increased risk of coronary heart disease in both sexes, whereas high levels of soluble TNF-alpha receptors were significant only among women. Further adjustment for lipid and nonlipid factors attenuated all associations; only C-reactive protein levels remained significant. The relative risk among all participants was 1.79 for those with C-reactive protein levels of at least 3.0 mg per liter, as compared with those with levels of less than 1.0 mg per liter (95 percent confidence interval, 1.27 to 2.51; P for trend <0.001). Additional adjustment for the presence or absence of diabetes and hypertension moderately attenuated the relative risk to 1.68 (95 percent confidence interval, 1.18 to 2.38; P for trend = 0.008). Elevated levels of inflammatory markers, particularly C-reactive protein, indicate an increased risk of coronary heart disease. Although plasma lipid levels were more strongly associated with an increased risk than were inflammatory markers, the level of C-reactive protein remained a significant contributor to the prediction of coronary heart disease. Copyright 2004 Massachusetts Medical Society.

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Author and article information

Contributors

Raffaele Bugiardini: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 19 May 2017

Publication date Collection: 2017

Volume: 12

Issue: 5

Electronic Location Identifier: e0177684

Affiliations

[1 ]Barbra Streisand Women’s Heart Center, Cedars-Sinai Heart Institute, Los Angeles, California, United States of America

[2 ]Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, California, United States of America

[3 ]Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America

[4 ]Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America

[5 ]Division of Cardiovascular Disease, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America

[6 ]Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America

[7 ]Division of Cardiovascular Medicine, University of Florida College of Medicine, Gainesville, Florida, United States of America

University of Bologna, ITALY

Author notes

Competing Interests: Dr. AlBadri, Dr. Lai, Dr Wei, Dr. Landes, Dr. Mehta, Mr. Quanlin, Dr. Johnson, Dr. Reis, Dr. Kelsey, Dr. Bittner, Dr. Sopko, Dr. Shaw, and Dr. Pepine have nothing to disclose. Dr. Bairey Merz reports consulting revenue paid to CSMC from Gilead, Medscape, Research Triangle Institute, research money from Gilead, Erika Glazer, payments for lectures from Beaumont Hospital, European Horizon, Florida Hospital, INOVA, Korean Cardiology Society, Practice Point Communications, Pri-Med, University of Chicago, VBWG, University of Colorado, University of Utah, WomenHeart, Harold Buchwald Heart-Health, Tufts. Dr. Mehta received a significant research support from Gilead and General Electric. Dr. Anderson is a consultant for BioSense Webster and subsidiary of Johnson and Johnson. Dr. Samuels is a consultant for Abbot Vascular and Volcano Corporation. Dr. Handberg reports unrestricted educational grants from Amarin, Amgen, AstraZeneca, Baxter, Boehringer Ingleheim, Catadasis, Cytori, Daiichi Sankyo, Esperion, Genentech, Gilead, ISIS Pharmaceuticals, Mesoblast, Neostem, Sanofi/Aventis, and Unified Therapeutics, outside the submitted work. Mrs. Minissian reports receiving grants from NIH/NHLBI, AHA, National Lipid Foundation, Gilead, Cover Letter honorarium from Preventative Cardiovascular Nurses Association and WebMD and consultant for Sanofi Aventis-Regeneron. Dr. Pepine reports grants from NIH/NHLBI, during the conduct of the study; grants from Amarin, Amgen, AstraZeneca, Baxter, Boehringer Ingleheim, Catadasis, Cytori, Daiichi Sankyo, Esperion, Genentech, ISIS Pharmaceuticals, Neostem, Sanofi/Aventis, and Unified Therapeutics, outside the submitted work. QMED, Inc. donated digital ambulatory ECG monitors used in a subgroup of WISE cohort. There were no other relevant declaration relating to employment, consultancy, patents, products in development, marketed products. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Conceptualization: AAB KL JW CNBM.
Data curation: AAB JW PKM DJ.
Formal analysis: QL DJ.
Funding acquisition: SER SFK VB GS LJS CJP CNBM.
Investigation: AAB KL JW CJP CNBM.
Methodology: AAB SL JW CJP CNBM A.
Project administration: AAB CNBM.
Resources: SER SFK VB GS LJS CJP CNBM.
Software: QL DJ.
Supervision: CJP CNBM.
Validation: DJ PKM CJP CNBM.
Visualization: AAB KL JW SL.
Writing – original draft: AAB KL JW.
Writing – review & editing: AAB JW CNBM.

* E-mail: Noel.BaireyMerz@ 123456cshs.org

Article

Publisher ID: PONE-D-17-09605

DOI: 10.1371/journal.pone.0177684

PMC ID: 5438124

PubMed ID: 28542263

SO-VID: f989b4fb-432b-4169-afa7-423a29c582f2

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 10 March 2017

Date accepted : 1 May 2017

Page count

Figures: 2, Tables: 3, Pages: 10

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100000050, National Heart, Lung, and Blood Institute;

This work was supported by contracts from the National Heart, Lung and Blood Institutes nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164, grants U0164829, U01 HL649141, U01 HL649241, K23HL105787, T32HL69751, R01 HL090957, 1R03AG032631 from the National Institute on Aging, GCRC grant MO1-RR00425 from the National Center for Research Resources, the National Center for Advancing Translational Sciences Grant UL1TR000124 and UL1TR001427, and grants from the Gustavus and Louis Pfeiffer Research Foundation, Danville, NJ, The Women’s Guild of Cedars-Sinai Medical Center, Los Angeles, CA, The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, and QMED, Inc., Laurence Harbor, NJ, the Edythe L. Broad and the Constance Austin Women’s Heart Research Fellowships, Cedars-Sinai Medical Center, Los Angeles, California, the Barbra Streisand Women’s Cardiovascular Research and Education Program, Cedars-Sinai Medical Center, Los Angeles, The Society for Women’s Health Research (SWHR), Washington, D.C., The Linda Joy Pollin Women’s Heart Health Program, and the Erika Glazer Women’s Heart Health Project, Cedars-Sinai Medical Center, Los Angeles, California. This work is solely the responsibility of the authors and does not necessarily represent the official views of the National Heart, Lung, and Blood Institute or National Institutes of Health.

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Inflammatory biomarkers as predictors of heart failure in women without obstructive coronary artery disease: A report from the NHLBI-sponsored Women’s Ischemia Syndrome Evaluation (WISE)

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Most cited references 23

C-Reactive Protein, the Metabolic Syndrome, and Risk of Incident Cardiovascular Events: An 8-Year Follow-Up of 14 719 Initially Healthy American Women

Loss to follow-up in cohort studies: how much is too much?

Inflammatory markers and the risk of coronary heart disease in men and women.

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