Differential Long-term Effects of Carvedilol on Proinflammatory and Antiinflammatory Cytokines, Asymmetric Dimethylarginine, and Left Ventricular Function in Patients With Heart Failure

Abstract

Neuroendocrine/inflammatory and endothelial functions have been indicated as crucial for heart failure (HF) patients. We evaluated relation in HF patients among cytokines and asymmetric dimethylarginine (ADMA) and left ventricular ejection fraction (LVEF) at baseline and after long-term administration of carvedilol. Interleukin 10 (IL-10), interleukin 18 (IL-18), and ADMA were measured in 22 NYHA class II to IV HF patients at baseline and after 40 +/- 14 months of carvedilol treatment. Patients were divided into 2 groups according to whether, after treatment with carvedilol, LVEF had increased at least 5% (responders) or less than 5% (non-responders). In responders (11 of 22 patients), LVEF increased from 38 +/- 6% to 50 +/- 7%, (P < 0.001); in non-responders, it decreased from 36 +/- 9% to 31 +/- 6%, (P = 0.02); NYHA class significantly decreased in both groups. IL-18 decreased in responders (from 586.4 +/- 128 to 183.13 +/- 64.4 pg/mL; P < 0.001) and in non-responders (from 529.3 +/- 116.25 to 142.4 +/- 58.9 pg/mL; P < 0.001). IL-10 increased in responders (from 0.49 +/- 0.25 to 2.01 +/- 1.01 pg/mL; P < 0.001) and in non-responders (from 0.64 +/- 0.31 to 1.33 +/- 0.59 pg/mL; P < 0.001). Conversely, ADMA levels decreased only in responders (from 0.67 +/- 0.16 to 0.44 +/- 0.15 micromol/L; P < 0.001), and an inverse correlation was observed between basal ADMA levels and changes in LVEF after treatment. In HF patients, carvedilol appears to reduce symptoms and the expression of inflammation, regardless of the LV functional response. In those patients showing improvement of LVEF, the reduction of inflammation is paralleled by a reduction of ADMA. We surmise that carvedilol could be effective at various independent levels as a result of possible pleiotropic effects of this agent.

Asymmetric dimethylarginine (ADMA) as a possible risk marker for ischemic stroke

“…Similarly, some but not all antihypertensive drugs have been shown to be associated with a reduction in ADMA concentration and the effects seemed not to be a class effect [12][13][14]. Therefore, further studies are needed to assess which drugs may have an effect on ADMA concentration and whether a reduction will have long-term consequences on risk of cardiovascular events.…”

Sympathetic Nerve Traffic and Asymmetric Dimethylarginine in Chronic Kidney Disease

“…Indeed ␤-adrenergic blockade by celiprolol prevents LVH induced by aortic banding, but such a beneficial effect of ␤-blockade is almost completely abolished by NO inhibition (36). Carvedilol, a ␤-adrenergic blocker with anti-oxidant properties, increases survival and decreases plasma ADMA in patients with heart failure (37) and reduces mortality in stage 5D-CKD patients with cardiomyopathy (38).…”

The Role of Carvedilol in the Treatment of Dilated and Anthracyclines-Induced Cardiomyopathy

“…The cytokines hypothesis for HF holds that HF progresses, at least in part, as a result of the toxic effects exerted by endogenous cytokine cascades on the heart and the peripheral circulation [51,52]. Interleukin (IL)-18 is among the pro-inflammatory cytokines involved in cardiovascular changes [53] and serum IL-18/IL-10 ratio is an independent predictor of adverse cardiovascular events in acute coronary syndrome patients [54,55].…”

“…Interleukin (IL)-18 is among the pro-inflammatory cytokines involved in cardiovascular changes [53] and serum IL-18/IL-10 ratio is an independent predictor of adverse cardiovascular events in acute coronary syndrome patients [54,55]. Alfieri et al have reported that long-term treatment with carvedilol induced an improvement in symptoms of HF paralleled by an increase of IL-10 levels and a reduction of IL-18 levels, resulting in a 9-times reduction of IL-18/IL-10 ratio and reaching values similar to healthy subjects [52]. However, in this subpopulation of HF patients, inflammation, endothelial function and LV response to carvedilol do not appear to be strictly related [52].…”

“…Alfieri et al have reported that long-term treatment with carvedilol induced an improvement in symptoms of HF paralleled by an increase of IL-10 levels and a reduction of IL-18 levels, resulting in a 9-times reduction of IL-18/IL-10 ratio and reaching values similar to healthy subjects [52]. However, in this subpopulation of HF patients, inflammation, endothelial function and LV response to carvedilol do not appear to be strictly related [52]. Additionally, in the endothelial cell apoptosis induced by serum of CHF patients, apoptosis of endothelial cells were found to be correlated with elevated tumor necrosis factor (TNF)-α and soluble TNF receptor serum levels [56].…”