摘要：Objectives. We postulated the existence of a statin–iron nexus by which statins improve cardiovascular disease outcomes at least partially by countering proinflammatory effects of excess iron stores. Methods. Using data from a clinical trial of iron (ferritin) reduction in advanced peripheral arterial disease, the Iron and Atherosclerosis Study, we compared effects of ferritin levels versus high-density lipoprotein to low-density lipoprotein ratios (both were randomization variables) on clinical outcomes in participants receiving and not receiving statins. Results. Statins increased high-density lipoprotein to low-density lipoprotein ratios and reduced ferritin levels by noninteracting mechanisms. Improved clinical outcomes were associated with lower ferritin levels but not with improved lipid status. Conclusions. There are commonalities between the clinical benefits of statins and the maintenance of physiologic iron levels. Iron reduction may be a safe and low-cost alternative to statins. Statins, prescribed widely for primary and secondary prevention of cardiovascular disease (CVD), 1,2 have been recommended for expanded use in apparently healthy individuals at risk for CVD. 3 On February 8, 2010 the US Food and Drug Administration approved rosuvastatin (Crestor) for reducing the likelihood of a heart attack or stroke or the need for a procedure to treat blocked or narrowed arteries in patients who have never been told they have heart disease but are nevertheless at increased risk of a cardiac event. 3 The target population included men older than 50 years and women older than 60 years with elevated levels of high-sensitivity C-reactive protein and an additional CVD risk factor such as smoking, hypertension, a family history of premature CVD, or low levels of high-density lipoprotein (HDL) cholesterol. 4 Computational studies concluded that a “treat-all” approach to CVD prevention is cost-effective. 5–7 However, misgivings over widespread statin use have been expressed on the basis of overall societal impact, including cost and toxicity, especially with the extension of treatment to children. 8–10 The wholesale cost of a 40-milligram rosuvastatin tablet at a local pharmacy recently was $4.22. Side effects of statins involve primarily liver 11 and muscle 12 damage. Statins also have been associated with risk of diabetes, 13 nonmelanotic skin cancer, 14 and adverse drug interactions. 15–17 Although statins are of proven efficacy, 1,2 CVD remains a major public health problem beckoning further innovative approaches to prevention and treatment. 18 The clinical benefits of statins relate to their ability to reduce cholesterol levels by inhibiting the rate-limiting cholesterol biosynthetic enzyme 3-hydroxy-3-methylglutaryl-CoA reductase. 1,2 However, drugs other than statins that effectively lower lipids have not improved clinical outcomes. 19 Statins are effective in individuals with normal lipid levels 1,2 exhibiting pleiotropic properties unrelated to lipid reduction. 20,21 These properties include stimulation of new blood vessel 22 and bone formation 23 and the reduction of inflammation and oxidative stress. 24–35 Mascitelli and Goldstein provided evidence that the beneficial effects of statins may result from their ability to favorably alter iron homeostasis. 36 Pathologic cellular iron retention has been implicated in systemic oxidative stress, vascular inflammation, and atherogenesis. Statins reduce ferritin levels in patients with advanced CVD, 37–39 renal disease, 40 and diabetes. 41 Data from a randomized trial of iron (ferritin) reduction (the Iron and Atherosclerosis Study [FeAST]) in participants with advanced peripheral arterial disease (PAD) showed significant improvement in all-cause mortality and combined death plus nonfatal myocardial infarction and stroke with iron reduction. 42 There is evidence suggesting that iron reduction may provide an alternative to statins for reducing inflammation associated with atherosclerosis.
