Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure

J Am Coll Cardiol. 1999 Dec;34(7):2061-7. doi: 10.1016/s0735-1097(99)00495-7.


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 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.

Publication types

  • Clinical Trial
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Biomarkers / blood
  • Chemokine CCL2 / blood
  • Chronic Disease
  • Cytokines / blood*
  • Double-Blind Method
  • Echocardiography
  • Enalapril / therapeutic use*
  • Female
  • Heart Failure / blood*
  • Heart Failure / drug therapy*
  • Heart Failure / immunology
  • Heart Septum / diagnostic imaging
  • Humans
  • Hypertrophy, Left Ventricular / diagnostic imaging
  • Hypertrophy, Left Ventricular / drug therapy
  • Immunoenzyme Techniques
  • Interleukin-1 / blood
  • Interleukin-6 / blood
  • Male
  • Methotrexate / blood
  • Middle Aged
  • Neopterin / blood
  • P-Selectin / blood
  • Receptors, Interleukin-6 / blood
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Cell Adhesion Molecule-1 / blood


  • Angiotensin-Converting Enzyme Inhibitors
  • Biomarkers
  • Chemokine CCL2
  • Cytokines
  • Interleukin-1
  • Interleukin-6
  • P-Selectin
  • Receptors, Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Vascular Cell Adhesion Molecule-1
  • Neopterin
  • Enalapril
  • Methotrexate