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    • Several clinical and epidemiological studies have establishe

    2018-11-07

    Several clinical and epidemiological studies have established cardiovascular risk factors (including smoking, hypertension, and serum lipid status) to be associated with AMD development and progression, and both diseases share susceptibility genes (Miller, 2013; Yip et al., 2015; Tomany et al., 2004; Sene and Apte, 2014; Sene et al., 2015). This suggests that both diseases share similarities in their pathogenesis, and that interventions that reduce cardiovascular disease risk factors may be useful in AMD. Bruch\'s membrane (BM) lies under the RPE and forms the inner margin of the choriocapillaris, and thus is considered the structural analog of the vascular intima (Curcio et al., 2001). Analogous aging changes in the vascular intima and BM are thought to relate to the pathogenesis of atherosclerosis and AMD, respectively (Sivaprasad et al., 2005). Similarities in the protein molecular composition of drusen and arteriosclerotic deposits corroborate this perception (Mullins et al., 2000). In both conditions, apolipoprotein B (apo B) and cholesterol accumulate, with subsequent modification, oxidation, and aggregation. Drusen components are derived from local tissues (retina/RPE secreting apo B,E-containing lipoproteins (Wang et al., 2009; Johnson et al., 2011)) and from the circulation (Curcio et al., 2011; Wu et al., 2010), and both AMD and atherosclerotic coronary artery disease involve lipoprotein retention. In AMD, an inflammatory response to the accumulated material may ensue with activation of complement and other components of the immune system, which can lead to atrophy of RPE rotenone and/or induction of a pro-angiogenic state and neovascular AMD. Given these observations and similarities between atherosclerosis and AMD, it has been hypothesized that statin treatment may affect AMD status and/or progression (Hall et al., 2001). Statins suppress cholesterol synthesis by inhibiting HMG-CoA reductase (the enzyme catalyzing the rate limiting step in cholesterol biosynthesis). In addition, they increase liver LDL receptors levels (Bilheimer et al., 1983), reduce apo B synthesis (Arad et al., 1990) and suppress prenylation (the addition of hydrophobic molecules to a protein that is a physiologic process that control localization and function) (Kino et al., 2005). Multiple epidemiological studies have examined this relationship with conflicting data (Gehlbach et al., 2009). A 2015 Cochrane report (Gehlbach et al., 2015) concluded that “[evidence is] insufficient to conclude if statins have a role in preventing or delaying the onset or progression of AMD.” A small, proof-of-concept, randomized, placebo-controlled study of the effect of simvastatin on the course of AMD was recently published, and suggested that simvastatin at 40mg (equivalent to 20mg atorvastatin) daily may slow progression of early/intermediate AMD, especially for those with the at-risk complement factor H (CFH) genotype CC (Y402H) (Guymer et al., 2013). Another recent study in patients with elevated plasma lipid levels found that statin use for more than a year was associated with an increased hazard for neovascular AMD (VanderBeek et al., 2013), and the authors postulated that these patients were resistant to statin treatment, rather than statins leading to increased risk for neovascular AMD. The Alienor study suggested that elderly patients with high HDL concentration may be at increased risk for AMD; furthermore, it found that HDL dysfunction might be implicated in AMD pathogenesis (Cougnard-Gregoire et al., 2014). In contrast, data from a recent meta-analysis of three population-based cohorts over a 20-year follow-up period did not show a significant association between lipid levels or lipid pathway genes with the incidence or progression of AMD (Klein et al., 2014a). A major limitation in almost all studies thus far is the large heterogeneity of AMD disease (more than 100 at-risk genes and several phenotypes) (Miller, 2013; Fritsche et al., 2015) and lack of standardization in statin dosage (Gehlbach et al., 2009, 2015) or lipophilicity (Wu et al., 2010; Chitose et al., 2014; Fong, 2014). There is clear evidence from the cardiovascular literature that statin dose does matter (Cannon et al., 2004; Pitt et al., 1999). The PROVE-IT study (Khush and Waters, 2004) suggested that statin dose may be more important than LDL-c levels, whereas the REVERSAL and ASTEROID trials showed benefit of aggressive over moderate intensity/dosage therapy (Nissen, 2005; Nissen et al., 2006, 2004). The ASTEROID trial even showed regression of coronary atherosclerosis with very high-intensity statin therapy (Nissen et al., 2006). Similarly, Yu et al. showed that intensive but not regular-dose atorvastatin therapy resulted in regression of carotid atherosclerotic disease (Yu et al., 2007) and two magnetic resonance (MR) imaging studies have shown regression of the lipid core of atheromatous plaque after high-dose statin (Kramer et al., 2011; Zhao et al., 2011).