Functional improvement in heart failure patients treated with beta-blockers is associated with a decline of cytokine levels

Background: In patients with severe heart failure (CHF), chronically elevated cytokine levels document a systemic inflammation. Experimental data suggest that activation of the beta-adrenergic system may participate in this inflammatory response. Herein, we studied as to whether beta-adrenergic blockade on top of standard CHF therapy affects plasma cytokine levels (interleukin-6 [IL-6] and tumor necrosis factor α [TNFα]). Moreover, we studied if beta-blocker related changes of these cytokines correspond to changes in left ventricular (LV) function and exercise capacity. Methods: In a prospective study, 21 patients with stable CHF (NYHA functional class II-III, ejection fraction <40%, mean age 57.6±12.4 years) were treated with captopril (100-150 mg/day), furosemide (40-120 mg/day), and/or digoxin (0.1-0.2 mg/day) for at least 1 month before they entered a 4 week run-in period in which dosages were kept unchanged. Metoprololsuccinate was administered in increasing dosages (up to 190 mg/day) for the following 3 months. Clinical, echocardiographic, spiroergometric, and biochemical changes were assessed at the start and the end of the run-in period as well as after 3 month of beta-blockade. Results: As compared to 210 healthy volunteers, CHF patients, prior to beta-blockade, presented with markedly elevated IL-6 (8.9±9.9 vs. 2.1±0.5 pg/ml; p<0.05) and TNFα levels (1.51±0.49 vs. 0.64±0.15 pg/ml; p<0.05) levels. In CHF patients, 3 month of beta-blockade lowered heart rate (84±14 vs. 68±12 bpm; p<0.01), systolic (131±7 vs. 118±6 mm Hg; p<0.01), and diastolic blood pressure (78±5 vs. 71±6 mm Hg; p<0.01). Spiroergometric determined VO₂ max (17.8±4.5 vs. 19.8±4.3 ml/min kg; p=0.013) increased significantly during 3 month of beta-blockade. Moreover, LV functional parameters tended to improve but the interindividual response varied and changes were non-significant. Interestingly, IL-6 levels decreased markedly during beta-blockade (8.9±9.9 vs. 4.5±3.1 pg/ml; p=0.036), whereas TNFα levels remained unchanged. Moreover, significant positive correlations were found between decrease of IL-6 levels and left ventricular end diastolic diameters (r²=0.59; p=0.012), whereas an inverse correlation was found between the decrease of IL-6 and the increase of VO ₂ max (r²=0.54; p=0.037), respectively. Conclusion: In heart failure patients, beta-blockade may lower IL-6 but not TNFα levels. Changes of IL-6 during beta-blockade may be related to changes of LV function and geometry.