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.
|
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 |
|
This article has been cited by other articles:
|
|
|
|
 
R. C Parish and J. D Evans
Inflammation in Chronic Heart Failure
Ann. Pharmacother.,
July 1, 2008;
42(7):
1002 - 1016.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. M. Mortensen, M. J. Pugh, L. A. Copeland, M. I. Restrepo, J. E. Cornell, A. Anzueto, and J. A. Pugh
Impact of statins and angiotensin-converting enzyme inhibitors on mortality of subjects hospitalised with pneumonia
Eur. Respir. J.,
March 1, 2008;
31(3):
611 - 617.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Barani, I. Mattiasson, B. Lindblad, and A. Gottsater
Cardiac Function, Inflammatory Mediators and Mortality in Critical Limb Ischemia
Angiology,
August 1, 2006;
57(4):
437 - 444.
[Abstract]
[PDF]
|
|
|
|
|
|
|
J. E Morley, D. R Thomas, and M.-M. G Wilson
Cachexia: pathophysiology and clinical relevance.
Am. J. Clinical Nutrition,
April 1, 2006;
83(4):
735 - 743.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. B. Kritchevsky, M. Cesari, and M. Pahor
Inflammatory markers and cardiovascular health in older adults
Cardiovasc Res,
May 1, 2005;
66(2):
265 - 275.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Sekiguchi, X. Li, M. Coker, M. Flesch, P. M Barger, N. Sivasubramanian, and D. L Mann
Cross-regulation between the renin-angiotensin system and inflammatory mediators in cardiac hypertrophy and failure
Cardiovasc Res,
August 15, 2004;
63(3):
433 - 442.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S Roffman
High-Versus Low-Dose ACE Inhibitor Therapy in Chronic Heart Failure
Ann. Pharmacother.,
May 1, 2004;
38(5):
831 - 838.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Bahrmann, U. M. Hengst, B. M. Richartz, and H. R. Figulla
Pentoxifylline in ischemic, hypertensive and idiopathic-dilated cardiomyopathy: effects on left-ventricular function, inflammatory cytokines and symptoms
Eur J Heart Fail,
March 1, 2004;
6(2):
195 - 201.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Sattar, A. McConnachie, D. O'Reilly, M. N. Upton, I. A. Greer, G. D. Smith, and G. Watt
Inverse Association Between Birth Weight and C-Reactive Protein Concentrations in the MIDSPAN Family Study
Arterioscler. Thromb. Vasc. Biol.,
March 1, 2004;
24(3):
583 - 587.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
S. Adamopoulos, J. T. Parissis, I. Paraskevaidis, D. Karatzas, E. Livanis, M. Georgiadis, G. Karavolias, D. Mitropoulos, D. Degiannis, and D. Th. Kremastinos
Effects of growth hormone on circulating cytokine network, and left ventricular contractile performance and geometry in patients with idiopathic dilated cardiomyopathy
Eur. Heart J.,
December 2, 2003;
24(24):
2186 - 2196.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Jessup and S. Brozena
Heart Failure
N. Engl. J. Med.,
May 15, 2003;
348(20):
2007 - 2018.
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Sattar, C. G Perry, and J. R Petrie
Type 2 diabetes as an inflammatory disorder
The British Journal of Diabetes & Vascular Disease,
January 1, 2003;
3(1):
36 - 41.
[Abstract]
[PDF]
|
|
|
|
|
|
|
R. Sirera, A. Salvador, I. Roldan, R. Talens, A. Gonzalez-Molina, and M. Rivera
Quantification of proinflammatory cytokines in the urine of congestive heart failure patients. Its relationship with plasma levels
Eur J Heart Fail,
January 1, 2003;
5(1):
27 - 31.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. E. Lipshultz, S. R. Lipsitz, S. E. Sallan, V. C. Simbre II, S. L. Shaikh, S. M. Mone, R. D. Gelber, and S. D. Colan
Long-Term Enalapril Therapy for Left Ventricular Dysfunction in Doxorubicin-Treated Survivors of Childhood Cancer
J. Clin. Oncol.,
December 1, 2002;
20(23):
4517 - 4522.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. Pugh, R. D. Jones, T.H. Jones, and K. S. Channer
Heart failure as an inflammatory condition: potential role for androgens as immune modulators
Eur J Heart Fail,
December 1, 2002;
4(6):
673 - 680.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. L. Mann
Inflammatory Mediators and the Failing Heart: Past, Present, and the Foreseeable Future
Circ. Res.,
November 29, 2002;
91(11):
988 - 998.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. J. Holycross and M. J. Radin
Cytokines in Heart Failure: Potential Interactions with Angiotensin II and Leptin
Mol. Interv.,
November 1, 2002;
2(7):
424 - 427.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
T. S. Han, N. Sattar, K. Williams, C. Gonzalez-Villalpando, M. E.J. Lean, and S. M. Haffner
Prospective Study of C-Reactive Protein in Relation to the Development of Diabetes and Metabolic Syndrome in the Mexico City Diabetes Study
Diabetes Care,
November 1, 2002;
25(11):
2016 - 2021.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Kluft, R. Kleemann, and M.P.M. de Maat
How best to counteract the enemies? By controlling inflammation in the coronary circulation
Eur. Heart J. Suppl.,
November 1, 2002;
4(suppl_G):
G53 - G65.
[Abstract]
[PDF]
|
|
|
|
|
|
|
D. J. Freeman, J. Norrie, M. J. Caslake, A. Gaw, I. Ford, G. D.O. Lowe, D. St. J. O'Reilly, C. J. Packard, and N. Sattar
C-Reactive Protein Is an Independent Predictor of Risk for the Development of Diabetes in the West of Scotland Coronary Prevention Study
Diabetes,
May 1, 2002;
51(5):
1596 - 1600.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Adamopoulos, J. Parissis, D. Karatzas, C. Kroupis, M. Georgiadis, G. Karavolias, J. Paraskevaidis, K. Koniavitou, A. J. S. Coats, and D. T. Kremastinos
Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fasligand system in patients with chronic heart failure
J. Am. Coll. Cardiol.,
February 20, 2002;
39(4):
653 - 663.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Kell, A. Haunstetter, T.J. Dengler, C. Zugck, W. Kubler, and M. Haass
Do cytokines enable risk stratification to be improved in NYHA functional class III patients?. Comparison with other potential predictors of prognosis
Eur. Heart J.,
January 1, 2002;
23(1):
70 - 78.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A.Q. Adigun and A.A. L. Ajayi
The effects of enalapril-digoxin-diuretic combination therapy on nutritional and anthropometric indices in chronic congestive heart failure: preliminary findings in cardiac cachexia
Eur J Heart Fail,
June 1, 2001;
3(3):
359 - 363.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Ohtsuka, M. Hamada, G. Hiasa, O. Sasaki, M. Suzuki, Y. Hara, Y. Shigematsu, and K. Hiwada
Effect of beta-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy
J. Am. Coll. Cardiol.,
February 1, 2001;
37(2):
412 - 417.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P.P. Davey and H. Ashrafian
New therapies for heart failure: is thalidomide the answer?
QJM,
May 1, 2000;
93(5):
305 - 311.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. B. Young
Angiotensin-converting enzyme inhibitors and cytokines in heart failure: dose and effect?
J. Am. Coll. Cardiol.,
December 1, 1999;
34(7):
2068 - 2071.
[Full Text]
[PDF]
|
|
|
|
