Simvastatin treatment is associated with improvement in coronary endothelial function and decreased cytokine activation in patients after heart transplantation.
OBJECTIVE
This study was designed to assess the association between 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibition, coronary endothelial function and cytokine activation in heart transplant recipients without angiographically detectable disease.


BACKGROUND
Coronary endothelial dysfunction contributes to cardiac allograft vasculopathy. The vasoprotective effects of statins in heart transplant recipients may include restoration of endothelial function and suppression of allograft inflammatory activity.


METHODS
Heart transplant recipients (one to three years after heart transplant) were divided into three groups based on the total cholesterol levels: group 1 (n = 21), patients with a history of hypercholesterolemia adequately controlled with simvastatin; group 2 (n = 19), patients with hypercholesterolemia not adequately treated with simvastatin; and group 3 (n = 40), patients without hypercholesterolemia. Coronary vasomotor function and intimal thickness as well as coronary sinus and aortic cytokine concentrations (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6 and soluble IL-2 receptor) were investigated. In a prospective one-year follow-up study, changes in coronary endothelial function and cytokine levels were compared between 11 hypercholesterolemic patients treated with simvastatin and 9 controls.


RESULTS
Epicardial and microvascular endothelial functions were better in groups 1 and 3 than they were in group 2 (p < 0.01 and p < 0.05). Transcardiac IL-6 and TNF-alpha gradients were significantly increased in groups 2 and 3 compared with group 1 (IL-6: p < 0.05; TNF-alpha: p < 0.01). Plaque areas were significantly increased in groups 1 and 2 (p < 0.05 vs. group 3), whereas lumen area was increased in group 2 compared with group 1 (p < 0.05), demonstrating adaptive vascular remodeling. In patients treated with simvastatin, coronary endothelial function and cardiac cytokine activity significantly improved during the one-year follow-up.


CONCLUSIONS
Inhibition of allograft inflammatory activity and attenuation of the coronary endothelial dysfunction observed in cardiac transplant recipients during treatment with simvastatin may represent an important mechanism by which HMG-CoA reductase inhibitors protect against the development of cardiac allograft vasculopathy.
Weis
M
M
Stanford University Medical School, Falk Cardiovascular Research Center, Stanford, California 94305, USA. michaweis@yahoo.com
Pehlivanli
S
S
Meiser
B M
BM
von Scheidt
W
W
D017023:Coronary Angiography; D016207:Cytokines / Q000097:blood*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006321:Heart / Q000187:drug effects*; D016027:Heart Transplantation / Q000502:physiology*; D006439:Hemodynamics; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000150:complications; D007376:Interleukin-2 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008875:Middle Aged; D019821:Simvastatin / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007376:Interleukin-2; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D019821:Simvastatin