Effect of thalidomide on cardiac remodeling in chronic heart failure: results of a double-blind, placebo-controlled study.
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).


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-alpha, 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.
Gullestad
Lars
L
Department of Cardiology, Rikshospitalet, 0027 Oslo, Norway. lars.gullestad@medisin.uio.no
Ueland
Thor
T
Fjeld
Jan G
JG
Holt
Even
E
Gundersen
Torstein
T
Breivik
Kjell
K
Følling
Magne
M
Hodt
Anders
A
Skårdal
Rita
R
Kjekshus
John
J
Andreassen
Arne
A
Kjekshus
Elin
E
Wergeland
Ragnhild
R
Yndestad
Arne
A
Frøland
Stig S
SS
Semb
Anne Grete
AG
Aukrust
Pål
P
D000368:Aged; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology; D006801:Humans; D007107:Immune System / Q000187:drug effects; D066298:In Vitro Techniques; D016209:Interleukin-8 / Q000097:blood; D020778:Matrix Metalloproteinase 2 / Q000097:blood; D008875:Middle Aged; D010919:Placebos; D013792:Thalidomide / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy
D016209:Interleukin-8; D010919:Placebos; D019715:Tissue Inhibitor of Metalloproteinase-1; D014409:Tumor Necrosis Factor-alpha; D013792:Thalidomide; D020778:Matrix Metalloproteinase 2