Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure.
OBJECTIVE
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 m g 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.
Gullestad
L
L
Section of Clinical Immunology and Infectious Diseases and Research Institute for Internal Medicine, Medical Department A, Rikshospitalet University Hosptial, Oslo, Norway. lagulles@online.no
Aukrust
P
P
Ueland
T
T
Espevik
T
T
Yee
G
G
Vagelos
R
R
Frøland
S S
SS
Fowler
M
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D018932:Chemokine CCL2 / Q000097:blood; D002908:Chronic Disease; D016207:Cytokines / Q000097:blood*; D004311:Double-Blind Method; D004452:Echocardiography; D004656:Enalapril / Q000627:therapeutic use*; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D006346:Heart Septum / Q000000981:diagnostic imaging; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000188:drug therapy; D007124:Immunoenzyme Techniques; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008727:Methotrexate / Q000097:blood; D008875:Middle Aged; D019798:Neopterin / Q000097:blood; D019007:P-Selectin / Q000097:blood; D019947:Receptors, Interleukin-6 / Q000097:blood; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D015415:Biomarkers; D018932:Chemokine CCL2; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D019007:P-Selectin; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D019798:Neopterin; D004656:Enalapril; D008727:Methotrexate