The Effect of Short-Term Simvastatin On Markers of Vascular Dysfunction in Patients with Sickle Cell Disease (SCD).

Abstract 260

Sickle cell disease (SCD) is characterized by frequent painful vaso-occlusive episodes, acute life-threatening complications, and progressive vascular injury resulting in multi-organ failure. Emerging data indicate that nitric oxide (NO) plays a central role in mediating the pathogenesis of sickle-induced vascular injury. Because antisickling agents only partially ameliorate the vasculopathy of SCD, therapeutic agents that modulate NO homeostasis are rational candidates for further exploration. Simvastatin and other HMG-CoA reductase inhibitors have been shown to exert NO-mediated vasculoprotective and anti-inflammatory effects in cardiovascular disease populations. Recent experimental and clinical studies have implicated the Rho/Rho-kinase (ROCK) signaling pathway as a principal mechanism by which statins increase NO availability. We enrolled twelve SCD patients in an ongoing FDA-approved dose-escalation study of the effect of simvastatin treatment on markers of vascular dysfunction and inflammation. Patients were treated at steady-state with low-dose oral simvastatin (20 mg/day) with serial blood samples obtained prior to treatment day 0, during treatment on days 7, 14, 21, 25 and after discontinuation of treatment on day 39. Plasma samples were assayed for nitrite/nitrate (NOx) concentration using NO chemiluminescence, and high-sensitivity C-reactive protein (hs-CRP), interleukin 6 (IL-6), tissue factor (TF), vascular endothelial growth factor (VEGF) and vascular cell adhesion molecule (VCAM1) by ELISA. The effect of simvastatin on leukocyte ROCK activity was assessed by Western blot analyses in a subset of patients. Changes in biomarker levels from baseline in response to simvastatin at 21 days were assessed using matched paired t-tests.

The mean age of subjects was 31.4 years (range, 13–55); 7 males and 5 females. Four subjects experienced an uneventful vaso-occlusive pain episode during the study with an acute decrease in NO levels and these data points were removed from the analysis. Short-term simvastatin treatment resulted in a 24% increase in mean plasma NOx level (p=.02). Both hs-CRP (p=.01) and IL-6 levels (p=.05) decreased dramatically by 62% and 63%, respectively. There was no difference between baseline and day 21 levels of TF, VEGF and VCAM1. Although limited to qualitative assessment in a subset of patients, our pilot data also demonstrated a decrease in leukocyte ROCK activity after treatment with simvastatin. These preliminary data showing increased NO availability and anti-inflammatory effects of simvastatin treatment in SCD are consistent with studies in cardiovascular disease populations documenting the cholesterol-independent benefits of statins and provide a compelling rationale to further investigate the potential therapeutic efficacy of statins in SCD. Correlation of the effect of simvastatin on ROCK inhibition may provide further evidence for a possible mechanism by which statins modulate NO bioavailability in SCD.