Immune activation is associated with reduced skeletal muscle mass and physical function in chronic heart failure

Abstract

Background

Chronic heart failure is characterized by immune activation and increased circulating levels of cytokines. Whether humoral factors contribute to the peripheral manifestations of the heart failure syndrome, such as muscle atrophy and reduced physical work capacity, however, is not clear.

Methods

We measured circulating cytokines (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6)), their soluble receptors (sTNF-α RII, IL-6sR), markers of immune activation (C-reactive protein (CRP)), muscle mass, aerobic capacity and muscle strength in 10 patients with heart failure (mean ± S.E.; 63 ± 3 years) and 11 controls (70 ± 3 years).

Results

Heart failure patients exhibited decreased aerobic capacity (P < 0.01) and leg muscle strength (P < 0.05). Reduced muscle strength persisted in heart failure patients after statistical adjustment for differences in skeletal muscle size. All inflammatory markers were increased in heart failure patients (P ≤ 0.05 to P < 0.01) compared to controls, with the exception of TNF-α. Despite no group differences in TNF-α, higher concentrations of this cytokine were correlated to lower skeletal muscle mass in the combined study population (range of r-values: − 0.436 to − 0.545; P < 0.05 to P < 0.02), as were IL-6 levels (range of r-values: − 0.438 to − 0.443; P < 0.05). TNF-α, sTNF-α RII, IL-6 and CRP showed strong negative relationships to aerobic capacity (range of r-values: − 0.579 to − 0.751; P < 0.01 to P < 0.001). In addition, elevated levels of IL-6 and TNF-α were associated with reduced leg and forearm skeletal muscle strength (range of r-values: − 0.440 to − 0.674; P < 0.05 to P < 0.01). Finally, correlations between cytokines and functional measures were present when heart failure patients were analyzed separately (range of r-values: − 0.646 to − 0.673; P < 0.05).

Conclusions

Our results suggest that circulating cytokines are related to both skeletal muscle mass and physical function. These findings provide further evidence to support the hypothesis that immune activation contributes to skeletal muscle atrophy and reduced functional capacity in heart failure patients.

Introduction

Chronic heart failure is characterized by immune activation and increased circulating concentrations of several proinflammatory cytokines [1], [2], [3]. These inflammatory mediators may contribute to the pathophysiology and progression of the disease by altering cardiac structure and function [4], [5]. In addition to their detrimental effects on cardiac muscle, elevated cytokine levels may contribute to the peripheral manifestations of the heart failure syndrome; most notably, skeletal muscle wasting and reduced muscle function. The catabolic effects of cytokines on skeletal muscle have been well-characterized [6], [7]. In addition, recent evidence has shown that, similar to cardiac muscle, cytokines promote contractile dysfunction in skeletal muscle [8], [9]. Despite these detrimental effects, few studies have explored the relationship of inflammatory mediators to muscle mass and function. Thus, our goals in the present study were threefold: (1) to measure and compare aerobic capacity, muscle strength and cytokine levels between heart failure patients and controls; (2) to examine the relationship of circulating cytokines to skeletal muscle mass; and (3) to determine the relationship of cytokine levels to aerobic capacity and skeletal muscle strength measures. To accomplish these objectives, we measured circulating tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), their soluble receptors (sTNF-α RII, IL-6sR) and markers of immune activation (C-reactive protein (CRP)) and related these measures to total and regional skeletal muscle mass, peak aerobic capacity and knee and forearm muscle strength in a cohort of heart failure patients and controls. We hypothesized that heart failure patients would be characterized by decreased aerobic capacity and muscle strength and increased circulating concentrations of inflammatory markers. Moreover, immune activation would be related to reduced muscle mass and physical function.