Rochester, MN - Increased serum levels of tumor necrosis factor alpha (TNF-), a proinflammatory cytokine known to play a role in progressive cardiomyopathy, were common and emerged as a significant mortality predictor, independent of LVEF and other heart-failure risk measures, in a prospectively studied community-based heart-failure population [1].

Serum TNF- "improves risk prediction above other established indicators and can be useful for risk stratification in patients with heart failure," conclude the authors, led by Dr Shannon M Dunlay (Mayo Clinic, Rochester, MN), in their report published online July 21, 2008 in Circulation and slated for the journal's August 5 issue.

Levels of the cytokine were obtained from 486 consecutive persons with chronic heart failure, who averaged 77 years in age and of whom 266, or about 55%, had echocardiography-defined LVEF >50%; 73% were in NYHA class 3 or 4. Comorbidities were prevalent; 29% had chronic obstructive pulmonary disease (COPD), 53% were anemic, and 32% had atrial fibrillation or flutter.

TNF- levels exceeding the reference value of 2.8 pg/mL were observed in 29% of the cohort and were inversely related to creatinine clearance and hemoglobin levels but weren't related to NYHA class or LVEF.

Dunlay et al put special emphasis on the latter finding, noting a particular dearth of information about the relationship between TNF- and heart failure in patients with preserved LV systolic function.

Mortality was 30.2% over a mean of 17 months, the rate increasing with baseline TNF- concentrations. Levels of the cytokine in the highest quartile, compared with the lowest, corresponded to a significant 88% increase in mortality risk in an analysis that was adjusted for age, sex, LVEF, hypertension, hyperlipidemia, smoking, body-mass index, diabetes, coronary disease, COPD, NYHA class, atrial fibrillation or flutter, creatinine clearance, and anemia. "Adding C-reactive protein to the model did not appreciably change the association between TNF- and mortality," the group writes.

Hazard ratios^a for death by quartile of baseline TNF- concentrations

a. Relative to quartile 1, TNF- <1.5 pg/mL

TNF- could potentially find more success as a risk stratifier than as a treatment target in patients with heart failure, at least those with poor systolic function. As previously reported by heartwire, specific blockade of the TNF- receptor in randomized trials, including the randomized ATTACH study (using infliximab) and the RENEWAL trial (of etanercept), has worsened rather than improved HF outcomes. There is some evidence that a more generalized approach of suppressing multiple proinflammatory molecules may be more successful.