The statin class of drugs has been shown to reduce stroke and myocardial infarction in patients with hypercholesterolemia. Intriguingly, the statins have been shown to accomplish this not only by reducing cholesterol levels, but also by improving nitric oxide bioactivity and thereby reversing endothelial dysfunction in human subjects. Atorvastatin is one of the most widely prescribed drugs in the United States, with a well-characterized and very acceptable side effect profile. Our group and others have published evidence that approximately half of patients with sickle cell disease have physiological and biochemical evidence of impaired nitric oxide bioavailability. This appears to contribute to impaired regional blood flow in patients with sickle cell disease, particularly during vaso-occlusive episodes. Therefore, it is attractive to test atorvastatin for its hypothetical ability to restore nitric oxide dependent blood flow in patients with sickle cell disease. We measured forearm blood flow by plethysmography to determine the response to infusion of L-NMMA, a nitric oxide synthase inhibitor, to which sickle cell patients have a blunted response. After four weeks of oral outpatient atorvastatin therapy, this study was repeated, with increased responsiveness to L-NMMA as the primary outcome variable. Atorvastatin-induced alterations in blood flow to acetylcholine and to nitroprusside were also evaluated. Additional secondary studies evaluated the degree to which the elevated level of xanthine oxidase in sickle cell patients inhibits nitric oxide-mediated blood flow;markers of inflammation and oxidation;and gene expression by microarray and pilot studies of proteomics in sickle cell patients. In addition, endothelial progenitor cells (EPC) in circulating blood were researched, which are indicative of vascular health in the general population. As of 28 October 2003, we obtained IRB approval to begin these studies. We began enrollment in March 2004. Subjects with SCD with features of vasculopathy were selectively recruited if they had higher than median plasma levels of soluble VCAM-1, tricuspid regurgitant jet velocity (TRV) greater than or equal to 2.5 meters per second (m/s), or previous demonstration of impaired vasodilatory response to a nitric oxide donor. Twenty-four adult subjects with HbSS and 10 control subjects underwent measurement of baseline EPC levels in peripheral blood. The SCD subjects were then treated with a 4-week course of atorvastatin, with a repeat measurement of circulating EPC levels. TRV was measured by Doppler echocardiography before and after atorvastatin treatment. As seen in previous studies, SCD patients at baseline had poor augmentation of NO-dependent forearm blood flow by SNP, but hyperactive responses to ACh, and very high levels of sVCAM-1 compared to controls. Confirming compliance and biological effect, atorvastatin significantly reduced serum cholesterol (p<0.001), LDL cholesterol (p<0.001), and triglycerides (p<0.05). No hepatic, muscle, or other significant toxicity was observed. Post-atorvastatin measures revealed no significant changes in any of the following parameters: forearm blood flow responses to SNP, TRV, plasma levels of sVCAM-1, RANTES, macrophage inhibitory protein-1_, C-reactive protein, homocysteine, NT-proBNP, leukocyte count or circulating endothelial progenitor cell count. ACh-induced forearm blood flow improved slightly, but significantly (23.0 2.6 vs. 28.9 3.1 mL/min/100 mL, p<0.05). This increase was sensitive to L-NMMA (28.9 3.1 vs. 23.0 2.6 mL/min/100 mL, p<0.001), indicating improvement in NOS-dependent blood flow, likely through re-coupling uncoupled NOS. Four weeks of atorvastatin was well tolerated. A beneficial effect of atorvastatin on SCD vascular health is detectable, but limited in scope to a small increase in endothelial-dependent blood flow. Higher doses (80 mg oral daily) might be considered, but the limited response reduces enthusiasm for this drug in high-risk SCD. This study remains closed to accrual and is open for planned secondary outcome assays of blood specimens and data analysis only. A manuscript is being submitted on the primary endpoint. Frozen blood specimens collected from sickle cell subjects will be tested in the CPB research laboratory for plasma hemoglobin and other markers of hemolysis. Coded aliquots will be provided to Dr. James Casella at The Johns Hopkins University School of Medicine for measurement of plasma hemopexin and other markers of hemolysis. Dr. Casella will be provided with the coded corresponding plasma hemoglobin results from the CPB laboratory.
|van Beers, Eduard J; Yang, Yanqin; Raghavachari, Nalini et al. (2015) Iron, inflammation, and early death in adults with sickle cell disease. Circ Res 116:298-306|
|Bereal-Williams, Candice; Machado, Roberto F; McGowan 2nd, Vicki et al. (2012) Atorvastatin reduces serum cholesterol and triglycerides with limited improvement in vascular function in adults with sickle cell anemia. Haematologica 97:1768-70|