Immune activation: what causes the massive cytokine generation in heart failure?

He stimulus and site of origin of the increased cytokine generation in heart failure remain unknown. There are three main hypotheses:

The most fascinating, but least probable, site of origin is the heart itself. Myocytes in normal human heart do not produce umor necrosis factor-a (TNF-a). On the other hand, in ischemia or acute/chronic wall stretch, TNF-a mRNA is synthesized and the TNF-a protein is detectable in the heart. However, this does not mean that the heart itself is responsible for TNF-a release into circulation. Munger et al found no significant cardiac spillover of cytokines in stable ambulatory patients.

The decreased cardiac output in heart failure may stimulate cytokine production by underperfused metabolic tissue. Part of this theory holds that increased endotoxin translocation from gut to general circulation results in immune system activation via CD 14-monocyte interaction. Circulating soluble CD 14 levels have been reported to correlate with TNF-a levels. However, this finding is insufficient to corroborate the gut-origin hypothesis, which requires further study.

The immune system may appear the most probable source of cytokine production, but this remains unproven. In vitro studies of cytokine production by immune cells from heart failure patients have yielded inconsistent results. Also, the stimulus to immune activation is unknown.

Recently, it was observed that circulating TNF-a is significantly increased in peripheral venous blood vs coronary sinus blood in advanced heart failure. This finding is consistent with the theory that more than one mechanism is responsible for cytokine production in heart failure.

Anker SD, Egerer KR, Volk HD, Kox WJ, Poole-Wilson PA, Coots

AJ. Elevated soluble CD14 receptors and altered cytokines in chronic heart failure. Am J Cardiol. 1997;79:1426-1430.

Grossman GB, Rohde LE, Claused N. Evidence for increased peripheral production of tumor necrosis factor-alpha in advanced congestive heart failure. Am J Cardiol. 2001 ;88:578-581.

Munger MA, Johnson B, Amber U, Callahan KS, Gilbert EM. Circulating concentrations of proinflammatory cytokines in mild or moderate heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. ] 996.77.723-727.


pathophysiology; immune activation; cytokine; TNF-a

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