CLINICAL STUDIES
Natural variability of circulating levels of cytokines and cytokine receptors in patients with heart failure: implications for clinical trials
Ziad Dibbs, MD*  ,
John Thornby, PhD* ,
B. G. White, PhD and
Douglas L. Mann, MD, FACC*
* Winters Center for Heart Failure Research, Cardiology Section, Department of Medicine, Veterans Administration Medical Center, USA
Baylor College of Medicine, Houston, Texas, USA
Clinical Cardiovascular Research, LLC, Gaithersburg, Maryland, USA
Manuscript received October 5, 1998;
revised manuscript received January 25, 1999,
accepted February 24, 1999.
Reprint requests and correspondence: Dr. Douglas L. Mann, Cardiology Research (151C), VA Medical Center, 2002 Holcombe Blvd, Houston, Texas 77030
dmann{at}bcm.tmc.edu
OBJECTIVES
The purpose of this study was to examine the variability in cytokines and cytokine receptors in patients with heart failure in comparison with a group of healthy control subjects who were free of cardiovascular disease.
BACKGROUND
Despite increasing interest in cytokines as mediators of disease progression in heart failure and the recent interest in suppressing cytokines in clinical studies, the extent of variability in cytokines and cytokine receptors is largely unknown. This information is important for interpreting the results of studies in which changes in cytokine levels are measured in response to a specific form of therapy.
METHODS
Circulating levels of tumor necrosis factor-alpha (TNF- ), and soluble TNF receptors (types 1 and 2), as well as interleukin (IL)-6 and IL-6 receptor were measured on a daily, weekly and monthly basis in heart failure patients (New York Heart Association class IIIa and IIIb; n = 10) and healthy volunteer subjects (n = 10). Measurements of cytokines and cytokine receptors were performed on plasma samples by enzyme-linked immunoassay. The daily, weekly and monthly degree of variability in cytokine and cytokine receptor levels was assessed by determining the coefficient of variation each point in time.
RESULTS
The coefficient of variation for TNF- and IL-6 levels increased over time in patients with heart failure; moreover, the coefficient of variation in heart failure subjects was significantly greater for IL-6 than for TNF-. The coefficient of variation in cytokine receptor levels was minimal, and did not differ significantly between heart failure and control subjects.
CONCLUSIONS
In patients with heart failure the degree of natural variability in circulating cytokine levels increases with time, and is greater for IL-6 than for TNF-. Accordingly, the results of the present study suggest that the sample size needed to show a statistically significant change in the circulating level of a given cytokine will vary depending on the specific cytokine that is being measured, as well as the time period over which that cytokine is being assayed.
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Abbreviations and Acronyms
| | ANOVA | = analysis of variance | | IL-6 | = interleukin-6 | | NYHA | = New York Heart Association | | sIL-6R | = soluble interleukin-6 receptor | | sTNFR1 | = soluble type 1 TNF receptor | | sTNFR2 | = soluble type 1 TNF receptor | | TNF- | = tumor necrosis factor-alpha |
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