CLINICAL STUDIES
Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure
Lars Gullestad, MD, PhD*,
P.ål Aukrust, MD, PhD*,
Thor Ueland, SIBa,
Terje Espevik, PhD ,
Gail Yee, SIB ,
Randall Vagelos, MD,
Stig S. Frøland, MD, PhD* and
Michael Fowler, MD, FACC
a Department of Cardiology, Medical Department B, Rikshospitalet University Hospital, Oslo, Norway
* Section of Clinical Immunology and Infectious Diseases and Research Institute for Internal Medicine, Medical Department A, Rikshospitalet University Hospital, Oslo, Norway
Institute of Cancer Research and Molecular Biology, the Norwegian University of Science and Technology, Trondheim, Norway
Falk Cardiovascular Research Center, Stanford University School of Medicine, Stanford, California, USA
Manuscript received November 6, 1998;
revised manuscript received March 2, 1999,
accepted September 7, 1999.
Reprint requests and correspondence: Dr. Lars Gullestad, Medical Department B, Rikshospitalet, 0027 Oslo, Norway
lagulles{at}online.no
OBJECTIVES
We examined the effect of long-term treatment with two doses of the angiotensin converting enzyme (ACE) inhibitor enalapril on various immunological variables in patients with chronic congestive heart failure (CHF).
BACKGROUND
Immunological mediators are increasingly recognized to play a pathogenic role in the pathophysiology of CHF. Whether ACE inhibitor therapy modifies immunological variables has not previously been investigated.
METHODS
Seventy-five patients (mean age 52 ± 11 years) with CHF were randomized between low- (5 mg daily) and high-dose (40 mg daily) enalapril in a double-blind trial. Circulating levels of immunological parameters (i.e., proinflammatory cytokines, chemokines and adhesion molecules) were measured at baseline, at 10 weeks and at the end of the study (34 weeks).
RESULTS
All immunological parameters, except soluble interleukin (IL)-6 receptor, were increased in CHF compared with 21 healthy controls. During the study immunoreactive IL-6 levels decreased (p < 0.05) and soluble IL-6 receptor increased (p < 0.05) during high-dose but not during low-dose enalapril therapy. Furthermore, IL-6 bioactivity decreased only during the high-dose (p < 0.001), resulting in a significant difference in change during treatment between the two dosage groups (p < 0.001). This decrease in IL-6 bioactivity was significantly associated with decreased interventricular septum thickness as assessed by echocardiography (r = 0.56, p = 0.013). No other variables changed during treatment.
CONCLUSIONS
In patients with severe CHF, high-dose enalapril therapy is associated with a significant decrease in IL-6 activity. However, despite treatment with a high-dose ACE inhibitor, a persistent immune activation exists in these patients which may be of importance for the progression of CHF.
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Abbreviations and Acronyms
| | ACE | = angiotensin converting enzyme | | CHF | = congestive heart failure | | CONSENSUS | = Cooperative North Scandinavian Enalapril Survival Study | | EIA | = enzyme immunoassays | | IL | = interleukin | | IVS | = interventricular septum thickness | | MCP-1 | = monocyte chemoattractant peptide-1 | | s | = soluble | | sIL-6R | = soluble interleukin-6 receptor | | TNF alpha | = Tumor necrosis factor alpha |
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