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(Circulation. 2005;112:3408-3414.)
© 2005 American Heart Association, Inc.

Heart Failure

Effect of Thalidomide on Cardiac Remodeling in Chronic Heart Failure

Results of a Double-Blind, Placebo-Controlled Study

Lars Gullestad, MD, PhD; Thor Ueland, PhD; Jan G. Fjeld, MD, PhD; Even Holt, MD, PhD; Torstein Gundersen, MD; Kjell Breivik, MD, PhD; Magne Følling, MD, PhD; Anders Hodt, MD; Rita Skårdal, RN; John Kjekshus, MD, PhD; Arne Andreassen, MD, PhD; Elin Kjekshus, BSc; Ragnhild Wergeland, MSc; Arne Yndestad, PhD; Stig S. Frøland, MD, PhD; Anne Grete Semb, MD, PhD; Pål Aukrust, MD, PhD

From the Department of Cardiology (L.G., J.K., A.A., E.K.), Section of Endocrinology (T.U.), Research Institute for Internal Medicine (A.Y., T.U., S.S.F., P.A.), and Section of Clinical Immunology and Infectious Diseases (S.S.F., P.A.), Rikshospitalet, Oslo; Department of Internal Medicine (L.G., E.H., R.S.), Bærum Hospital, Bærum; Department of Internal Medicine (A.H.), Aker Hospital; Department of Internal Medicine (A.G.S.), Diakonhjemmet Hospital; Department of Internal Medicine (T.G.), Aust Agder Hospital, Arendal; and Department of Internal Medicine (K.B., M.F.), Haukeland University Hospital, Bergen, Norway.

Correspondence to Lars Gullestad, Department of Cardiology, Rikshospitalet, 0027 Oslo, Norway. E-mail lars.gullestad{at}medisin.uio.no

Received January 21, 2005; de novo received May 27, 2005; revision received August 25, 2005; accepted September 16, 2005.

Background— Inflammation and matrix degradation may play a pathogenic role in chronic heart failure (CHF), and therefore, we examined whether thalidomide, a drug with potential immunomodulating and matrix-stabilizing properties, could improve left ventricular (LV) function in patients with CHF secondary to idiopathic dilated cardiomyopathy (IDCM) or coronary artery disease (CAD).

Methods and Results— Fifty-six patients with CHF and an LV ejection fraction (LVEF) <40% who were already on optimal conventional cardiovascular treatment were randomized to thalidomide (25 mg QD increasing to 200 mg QD) or placebo and followed up for 12 weeks. Our main findings were as follows: (1) During thalidomide treatment but not during placebo, there was a marked increase in LVEF (&7 EF units) along with a significant decrease in LV end-diastolic volume and heart rate. (2) This improvement in LVEF was accompanied by a decrease in matrix metalloproteinase-2 without any changes in its endogenous tissue inhibitor, suggesting a matrix-stabilizing net effect. (3) Thalidomide also induced a decrease in total neutrophil count and an increase in plasma levels of tumor necrosis factor-, suggesting both proinflammatory and antiinflammatory effects. (4) The effect of thalidomide on LVEF was more marked in IDCM than in CAD, possibly partly reflecting that the former group was able to tolerate a higher thalidomide dosage.

Conclusions— Although our results must be confirmed in larger studies that also examine the effects on morbidity and mortality, our findings suggest a role for thalidomide in the management of CHF in addition to traditional cardiovascular medications.

Key Words: heart failure • inflammation • leukocytes • matrix metalloproteinases • remodeling

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