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

Levels of tumor necrosis factor-a (TNF-a) not only increase in heart failure, but do so in parallel with New York Heart Association (NYHA) functional class. More recently, TNF-a has been revealed as an independent prognostic indicator. However, many investigators are uncertain whether TNF-a is a marker of disease progression or a disease determinant in its own right. Although we are rapidly accumulating information on its adverse cardiovascular effects, it is too early to give a definite answer to the question posed in the title.

In normal hearts, hyperexpression of TNF-a induces progressively worsening left ventricular dysfunction, acute pulmonary edema, and biventricular cardiomyopathy with a generalized increase in myocardial apoptosis. In hamster myocyte cultures, it has a dose-propor-tional negative inotropic effect, which is immediate and completely reversible after cytokine removal. TNF-a and other proinflammatory cytokines induce cellular modifications typical of a failing heart, such as downregulation of the sarcoplasmic-reticulum/endoplasmic-reticulum Ca2+ (SERCA) ATPase calcium pump and uncoupling of P-adrenergic cellular receptors from intracellular cyclic adenosine monophosphate (cAMP) production.

In experimental settings, the negative effects of TNF-a are completely reversible, with full recovery from TNF-a mediated cardiomyopathy. Despite the clear causal role of TNF-a in vitro or in in vivo animal studies, definite demonstration is still lacking that its inhibition in humans produces clinical improvement and lowers mortality.

Etanercept is the only anti-TNF-a therapy to have been validated by clinical trials in man. The rationale behind its use is that of the two soluble TNFR receptors, p55 and p75, TNFR p75 has the closest affinity to TNF-a. DNA encoding the soluble portion of human TNFR p75 was linked to DNA encoding the Fc portion of a human IgGj molecule, and the combined DNA was then expressed in a mammalian cell line. The resulting immunoglobulin-like dimer, etanercept, composed exclusively of human amino acid sequences, acts as a competitive inhibitor of TNF and prevents binding of TNF to the cell-surface TNFR, thereby reducing the biologic activity of TNF. Fusion with the Fc portion increases the drug’s half-life. Safety and efficacy in humans were first validated in 1999. A dou-ble-blind dose-escalation study in NYHA class III heart failure assessed the effects of a single intravenous infusion of etanercept (1,4, or 10 mg/m2) vs placebo in 12 and 6 patients, respectively, after 1,2, 7, and 14 days. In the patients receiving 4 mg/m2 and 10 mg/m2, improvement was reported in the ejection fraction, 6-minute walk distance, and quality of life. No side effects were reported. The same group, from the Veterans Administration Medical Center in Houston, subsequently studied 47 patients with NYHA class III-IV heart failure, administering etanercept 5 or 12 mg/m2, or placebo, by biweekly subcutaneous injection for 3 months. These doses were suggested by the earlier dose-escalation study and by experience accumulated in rheumatoid arthritis. No adverse hemodynamic effect or other adverse events were reported, apart from a spontaneously reversible local reaction in 10% of the patients. At 3 months, treated patients showed a dose-dependent increase in the ejection fraction and a reduction in left ventricular volume vs no change on placebo. Although the slight improvement in treated patientsfunctional status was not statistically significant at 3 months, these preliminary results prompted larger studies of immunomodu-lating therapy with etanercept: the Randomized Etanercept North American Strategy to Study ANtagonism of CytokinEs (RENAISSANCE) in the USA, and the Research into Etanercept; Cytokine antagonism in Ventricular Dysfunction Research in Europe. The aim was to pool the data received from these two trials into the Randomized EtaNErcept Worldwide evALuation (RENEWAL), but the manufacturer, Wyeth, terminated the trials on April 1 2001 after interim analysis showed no significant effects with the enrolled sample size. The data have not been reported.

It is too early to tell whether the nil-effect of anti-TNF-a therapy in these trials reflects pharmacologic failure to control TNF-a activation or side effects or simply the fact that TNF-a is a marker of disease progression.

Keywords

pathophysiology; immune activation; TNF-a; cytokine; etanercept

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