Ординатура / Офтальмология / Английские материалы / Retinal Degenerations biology, diagnostics, and therapeutics_Tombran-Tink, Barnstable_2007

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ARM in the later phases. In addition, although results from studies indicate that these treatments slow progression in the later stages of the disease, they have not been shown to reverse vision loss.

The public health impact of ARM is currently substantial and will grow rapidly with the aging of the population (5). Currently, there are no effective treatments for the earliest stages of ARM, although some treatments slow the loss of visual function in later stages of the disease (6). Although the search for effective treatments to reverse or slow the progression of ARM is of importance, identifying characteristics associated with the development of the disease is equally important. The identification of modifiable risk factors could lead to disease prevention initiatives. The impact on health care resources and quality of life is likely to be significantly greater by preventing ARM rather than by treating it. For nonmodifiable risk factors, disease prevention is precluded owing to their nature. However, should effective treatments become available, particularly treatments for early ARM, they allow for high-risk individuals to be identified and targeted for early intervention.

ARM is the leading cause of blindness among older adults in the United States and other industrialized nations (21). In the United States alone, more than 7 million people have drusen of sufficient size and number so that they are at substantial risk for severe visual loss (22). The prevalence of ARM is estimated to be approx 10% among those in their early 40s and 50s and nearly 40% among those 80 yr of age and older. In addition to age, the incidence and prevalence of ARM also differs according to gender and ethnicity. Males and whites appear to be at increased risk, although these findings are not consistent across all studies (22–24).

Epidemiological research points toward a variety of risk factors for ARM, including demographic, medical, nutritional, and genetic characteristics (24–27). Research on potentially modifiable risk factors has been extensive, focusing predominantly on lifestyle characteristics such as smoking, alcohol consumption, and diet as well as cardiovascular disease (CVD) characteristics including hypertension and atherosclerosis. To date, however, much of this research has been equivocal with the exception of smoking wherein most studies have reported an increased risk among smokers (28,29). One of the reasons for the varying results found in the current body of literature may relate to several study design issues. First, the definition of ARM varies from study to study with some relying on self report and others on fundus appearance as well as different studies using differing definitions of fundus appearance. Second, many studies have focused on late ARM or an unspecified combination of patients with early and late disease. If particular risk factors are differentially associated with certain disease subtypes and different levels of disease severity, then such studies may not provide a clear characterization of the etiology of ARM throughout the natural history of the disease, including its earliest phases. Obviously then, additional work is necessary to properly evaluate currently hypothesized etiologic risk factors.

HMG-CoA REDUCTASE INHIBITORS (STATINS)

Recent investigations have identified 3-hydroxy-3-methylgluatryl coenzyme A (HMG-CoA) reductase inhibitors or “statins” as being associated with a reduced risk of

ARM (30–32). Statins are prescribed to help reduce low-density lipoprotein (LDL)- cholesterol levels by inhibiting cholesterol production and increasing LDL-cholesterol removal from plasma. HMG-CoA reductase is a key enzyme not only for cholesterol biosynthesis but also for the biosynthesis of numerous nonsteroidal isoprenoid compounds (33). Numerous biological processes associated with atherosclerotic progression are modulated by HMG-CoA reductase inhibition (e.g., endothelial cell health, thrombosis, angiogenesis) (34,35). Statins were developed to lower plasma cholesterol levels in patients with atherosclerotic CVD. Recent recommendations for the aggressive use of antihyperlipidemic medications to lower LDL-cholesterol levels has contributed to a rising trend in the prescription of statins to reduce risk of CVD and CVD-related outcomes such as myocardial infarction and stroke (36). Statins have few side effects and those that occur tend to be mild (e.g., fatigue, nausea). Reports have also emerged linking statins with lowered risk of fracture, dementia, and depression, although findings have been inconsistent (37–43). However, the benefits of statin use may extend beyond that which can be explained by the direct effect of lowering plasma lipids concentrations (35).

HMG-CoAreductase is a key enzyme not only for cholesterol biosynthesis, but also for the biosynthesis of numerous nonsteroidal isoprenoid compounds (44). Mevalonate, the end product of the HMG-CoA reductase reaction, is a precursor to many other pathways requiring isoprenoids, including posttranslational modification of proteins involved in diverse cellular functions. Among the biological processes associated with atherosclerotic progression that are modulated by HMG-CoA reductase inhibition are endothelial cell health, inflammation, myocyte proliferation and migration, plaque stability, thrombosis, angiogenesis, and platelet activation (34,35). Statins were originally developed to lower plasma cholesterol levels in patients with atherosclerotic CVD, a condition for which elevated plasma cholesterol is a well-established risk factor. It is now recognized that the benefits of statin usage extend far beyond that which can be explained by direct effect of lowering plasma lipids concentrations to the so-called pleiotrophic effects (34,35). The association between statins and nonatherosclerotic conditions, such as Alzheimer’s disease (37–40), may be caused by an improvement of vascular health via plasma lipid lowering or by pleiotrophic effects, including a direct effect on neurons (45,46).

BIOLOGICAL PLAUSIBILITY FOR STATINS AS BENEFICIAL FOR ARM

The eye tissues affected by ARM are the photoreceptors, the RPE (a cellular layer dedicated to sustaining photoreceptor health), the choriocapillaris (the blood supply to the photoreceptors and the RPE), and Bruch’s membrane (a thin vascular intima between the RPE and the choriocapillaris) (47,48). ARM is a multifactorial process, involving a complex interplay of genetic and environmental factors. Early ARM is characterized by minor-to-moderate vision loss associated with characteristic extracellular lesions and changes in RPE pigmentation and morphology. Lesions between the RPE basal lamina and Bruch’s membrane can be either focal (drusen) or diffuse (basal linear deposits). Late ARM is characterized by severe vision loss associated with extensive RPE atrophy with or without the sequelae of choroidal neovascularization, that is,

in-growth of choroidal vessels through Bruch’s membrane and under the RPE in the plane of drusen and basal linear deposits.

There are potentially multiple biological bases for a potential association between statins and ARM, as statins could reduce the incidence of ARM through direct plasmalipid lowering or through pleiotrophic effects as described above. With regard to the potential for a lipid-lowering effect, it is notable that Bruch’s membrane accumulates lipids including cholesterol with normal aging, and cholesterol is a ubiquitous component of drusen in normal and ARM eyes (49–56).

The relative contributions of plasma lipoproteins and local cells to this cholesterol are still under investigation although recent evidence points to the fact these particles are intra-ocular in origin (51). Studies of normal human Bruch’s membrane cholesterol composition have implicated both local cells and plasma lipoproteins as sources (50,54), but cholesterol has not been detected in Bruch’s membrane following dietinduced hypercholesterolemia in mice (57–59). However, apolipoprotein B, the principal protein of the atherogenic plasma lipoproteins (60), is detectable in drusen, basal deposits, and in inner Bruch’s membrane in association with basal deposits (49), where it could undergo modifications with deleterious impact on surrounding cells (61).

With regard to the potential for pleiotrophic effects, it is notable that many of the same processes that occur in the atherosclerotic intima likely also occur in ARM. Neovascularization is a major complication in both conditions (62,63). Therefore, angiogenesis and associated processes such as metalloproteinase activity (64) are potential points of statin modulation. Choroidal neovascular membranes associated with ARM include macrophages (65,66) and smooth muscle actin-positive cells (67), which may respond to statin. Drusen contain many proteins associated with inflammation and complement activation (68), and multiple lines of evidence point to a role for inflammatory processes in ARM progression (69). Statins affect RPE cell survival and morphology in vitro (70). The challenge for future laboratory research will be to determine which processes are modulated by statins in vivo and therefore are may be primarily responsible for the purported beneficial effects observed in some epidemiological studies.

EXISTING STUDIES ON CHOLESTEROL-LOWERING MEDICATIONS AND ARM

Observational studies evaluating a potential association between plasma cholesterol and ARM risk have yielded conflicting results. Although the mechanism of putative action for lipid levels in the development of ARM is unknown, laboratory evidence suggests local rather than systemic sources of cholesterol may contribute to ARM pathogenesis. First, there is a ubiquitous presence of cholesterol in drusen and the accumulation of lipid deposits in Bruch’s membrane of older eyes, and second, there is evidence that the RPE is capable of producing cholesterol (49–55). In addition to the potential role of a statin in lowering plasma and potentially ocular lipid concentrations, statins have been shown to have a number of pleiotropic effects, such as helping to restore endothelial cell function, enhance atherosclerotic plaque stability, and decrease oxidative stress and vascular inflammation (35). These pleiotropic effects of statins, though well characterized for cardiovascular outcomes, have yet to be definitively linked to a reduction in ARM risk.

Table 1

Summary of Studies Investigating the Association Between Statins

and Cholesterol-Lowering Medications and ARM

aCholesterol-lowering medication rather than statin use. OR, odds ratio; HR, hazard ratio; CI, confidence interval.

To date, there have been 10 published studies on the relationship between cholesterollowering medications, including statins and ARM. Table 1 summarizes the results of each of these studies. Four of these studies (30–32,71) provide support for the potential protective role of statins, three of which reported statistically significant results studies (30,31,71),