Yangzhou, China - From cancer to rheumatoid arthritis to—heart failure? Twelve weeks of low-dose methotrexate appeared to improve six-minute-walk distance and other health measures among patients with chronic HF in a tiny but randomized, placebo-controlled study [1]. Patients receiving the drug showed comprehensive improvements in circulating inflammatory mediators, evidence for the proposed mechanism behind the drug's observed benefits.

Also in the study, from Dr Kaizheng Gong (First People's Hospital of Yanghzou, China) and associates, patients in both the placebo and methotrexate groups showed significantly improved NYHA class, but the change seemed more pronounced among those taking the active drug.

We assume that a more generalized approach targeting this network may produce certain beneficial effects in patients with chronic HF.

"This is the first study to show that the addition of methotrexate to conventional therapy in patients with chronic heart failure exerts a significant anti-inflammatory effect and improves several indices of functional status," the group writes in the January 2006 issue of the American Heart Journal. Their research follows published evidence that methotrexate therapy in patients with rheumatoid arthritis may also cut HF risk [2,3].

The group randomized 71 consecutive patients with chronic HF of NYHA class 2-4 and various etiologies who had an LVEF <45% and echocardiographic evidence of ventricular enlargement to receive methotrexate at 7.5 mg once weekly or placebo for 12 weeks. Patients with rheumatoid arthritis, infectious diseases, or any connective-tissue disease were excluded. Four and five patients in the two groups, respectively, failed to complete the study (only two because of side effects), leaving 62 for analysis.

The group observed that:

• Patients in the methotrexate group showed significant downregulation of tumor necrosis factor- (TNF-) (p<0.05), interleukin (IL)-6 (p<0.01), soluble intercellular adhesion molecule-1 (sICAM-1), and C-reactive protein (CRP), all markers of inflammation.
• They also showed significant upregulation of the anti-inflammatory cytokines IL-10 and soluble IL-1 receptor antagonist (sIL-1Ra).
• Six-minute-walk distance, quality-of-life scores (SF-36 Health Survey, Chinese edition), and physical-health scores (patient global self-assessment) were significantly improved among actively treated patients compared with the control group.
• There were no changes in LVEF or LV end-diastolic volumes. But the study was likely too brief for such findings, according to the authors.

Noting the disappointing findings of the ENBREL and ATTACH studies, in which treatment tightly focused against TNF- failed to show benefit in patients with HF [4, 5] Gong and associates question the use of agents aimed at a single member of what is likely a complex, interacting network of inflammatory molecules. "We assume that a more generalized approach targeting this network may produce certain beneficial effects in patients with chronic HF." In such patients, they write, "methotrexate could be a beneficial adjunct to conventional therapy."