Published Online
on November 21, 2005

A more recent version of this article appeared on November 29, 2005

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Submitted on January 21, 2005
Revised on August 25, 2005
Accepted on September 16, 2005

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, and 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.

^* To whom correspondence should be addressed. E-mail: lars.gullestad{at}medisin.uio.no.

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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