Simvastatin Reduces Graft Vessel Disease and Mortality After Heart Transplantation

Wenke, K; Meiser, Bruno; Thiery, Joachim; Nagel, Dorothea; Scheidt, Wolfgang von; Steinbeck, Gerhard; Seidel, D.; Reichart, Bruno

doi:10.1161/01.cir.96.5.1398

Cited by 426 publications

(237 citation statements)

References 17 publications

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“…The use of calcium antagonists, ACE inhibitors, hydroxymethylglutaryl Co-A reductase inhibitors, antioxidants, and intensified immunosuppression have been suggested to limit disease progression and improve outcome. [21][22][23][24][25] Chronic allograft rejection is associated with the development of transplantation vasculopathy. Direct allorecognition is the primary immunologic pathway responsible for acute cellular rejection early after organ transplantation.…”

Section: Discussionmentioning

confidence: 99%

Use of Rapamycin Slows Progression of Cardiac Transplantation Vasculopathy

et al. 2003

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Background-Cardiac transplantation vasculopathy is the leading cause of late death in heart transplantation recipients.Rapamycin is an immunosuppressant drug with potent antiproliferative and antimigratory effects. We investigated whether rapamycin could prevent progression of graft vasculopathy in 46 patients (age, 54Ϯ10 years; 4.3Ϯ2.3 years after transplantation) with severe disease. Methods and Results-At annual cardiac catheterization, patients were randomly assigned to treatment with rapamycin (nϭ22) versus continued current immunosuppression (nϭ24). Clinical characteristics including recipient age and sex, underlying cause of congestive heart failure, donor age and sex, and ischemic time were recorded. Cardiac catheterization was graded with the use of a semiquantitative scale and repeated annually. Clinically significant adverse events were defined as death, need for angioplasty or bypass surgery, myocardial infarction, and a Ͼ25% worsening of the catheterization score. These events were monitored as primary study end points. Anti-HLA class I and II antibody production and lymphocyte growth assays were measured with each biopsy. Patients selected for rapamycin had azathioprine or mycophenolate mofetil discontinued and were given rapamycin. Outcomes were compared by means of log-rank analysis. There were no significant differences in baseline characteristics. Duration of follow-up was comparable (rapamycin, 689Ϯ261; control, 630Ϯ207 days; NS). In the rapamycin group, 3 patients reached primary end points versus 14 patients in the control group (PϽ0.001). There was no difference in baseline or subsequent anti-HLA class I or II antibody production. Conclusions-In

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Section: Discussionmentioning

confidence: 99%

Use of Rapamycin Slows Progression of Cardiac Transplantation Vasculopathy

et al. 2003

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“…For example, treatment with HMG-CoA reductase inhibitors reduces post-angioplasty re-stenosis, coronary bypass occlusions (6,7), and transplant arteriosclerosis (8). Although HMG-CoA reductase inhibitors have been shown to inhibit SMC proliferation in vitro (9), the mechanism(s) by which they inhibit cell growth is not known.…”

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confidence: 99%

3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitors Attenuate Vascular Smooth Muscle Proliferation by Preventing Rho GTPase-induced Down-regulation of p27

Laufs¹,

Marra²,

Node

et al. 1999

Journal of Biological Chemistry

372

270

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The mechanism by which platelet-derived growth factor (PDGF) regulates vascular smooth muscle cell (SMC) DNA synthesis is unknown, but may involve isoprenoid intermediates of the cholesterol biosynthetic pathway. Inhibition of isoprenoid synthesis with the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, simvastatin (Sim, 1-10 M), inhibited PDGF-induced SMC DNA synthesis by >95%, retinoblastoma gene product hyperphosphorylation by 90%, and cyclin-dependent kinases (cdk)-2, -4, and -6 activity by 80 ؎ 5, 50 ؎ 3, and 48 ؎ 3%, respectively. This correlated with a 20-fold increase in p27Kip1 without changes in p16, p21 Waf1 , or p53 levels compared with PDGF alone. Since Ras and Rho require isoprenoid modification for membrane localization and are implicated in cell cycle regulation, we investigated the effects of Sim on Ras and Rho. Up-regulation of p27Kip1 and inhibition of Rho but not Ras membrane translocation by Sim were reversed by geranylgeranylpyrophosphate, but not farnesylpyrophosphate. Indeed, inhibition of Rho by Clostridium botulinum C3 transferase or overexpression of dominant-negative N19RhoA mutant increased p27Kip1 and inhibited retinoblastoma hyperphosphorylation. In contrast, activation of Rho by Escherichia coli cytotoxic necrotizing factor-1 decreased p27Kip1 and increased SMC DNA synthesis. These findings indicate that the down-regulation of p27Kip1 by Rho GTPase mediates PDGF-induced SMC DNA synthesis and suggest a novel direct effect of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors on the vascular wall.

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“…33,35 The HMG-CoA reductase inhibitors (statins) are as effective in reducing LDL cholesterol in heart transplant recipients as in the nontransplant population. 8,9 Two randomized trials comparing pravastatin (20 to 40 mg) or simvastatin (5 to 20 mg) with placebo in heart transplant recipients have demonstrated benefits of statins on mortality, rejection associated with hemodynamic compromise, and CAV. 8 -10 The benefits of statins in heart transplant recipients have been suggested to be even greater than in the general population and may be due to both cholesterol lowering and immune modulating effects.…”

Section: Hyperlipidemiamentioning

confidence: 99%