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. The findings have been published in Haematologica and the summary below is adapted from the abstract: Although red cell rigidity is clearly the principal pathophysiological component of sickle cell disease (SCD), substantial evidence also indicates disordered blood vessel wall function. Many of these abnormalities, such as vascular dysfunction are also seen in atherosclerosis and other vasculopathies, in which they can be reversed by stating within two weeks. We recruited 25 adults with SCD with high levels of soluble vascular cell adhesion molecule (sVCAM-1) or other markers of vascular dysfunction, and 10 healthy control subjects. Baseline blood flow measurements and other markers were studied at baseline and after 4 weeks of oral atorvastatin therapy (10 mg daily for two weeks and 20 mg daily for two more weeks). Atorvastatin reduced serum cholesterol by 21% (p<0.0001), low density lipoprotein cholesterol by 31% (p<0.0001), and triglycerides by 24% (p<0.05). Peak vasodilatory responses to brachial artery infusion of acetylcholine rose by 26% (p<0.05), indicating improvement in endothelial function, although the pre-specified primary outcome variable, resting nitric oxide synthase-dependent blood flow, was not affected. Other markers that did not change with atorvastatin included estimated pulmonary arterial pressure, sVCAM-1, C-reactive protein, monocyte chemokines, amino-terminal brain natriuretic peptide, urinary microalbumin and circulating endothelial progenitor cells. These results are consistent with a limited effect of statins on endothelial function in SCD. This study remains closed to accrual and is open for planned secondary outcome assays of blood specimens and data analysis only. 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|