Recent evidence points to common pathways in AMD, vascular disease
Research supports dietary modification or supplementation to reduce patients’ risk.
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Leo P. Semes |
Changes in human tissue are responses to metabolic processes governed by genetics and are expressed in a variety of ways. Reflections of diet and aging can be especially visible throughout the body. Those vascular changes occurring at the molecular level are manifested as clinically visible changes in the retina but may be more subtle.
As clinicians, we are confronted with sometimes conflicting presentations in patients whose risk factors are confusing or even unknown. To say that, “You are what you eat,” may best reflect the input of diet, nutrition and supplementation on vascular changes that occur at the cellular and molecular levels. What appears to be emerging is the confluence of the risk factors and the systemic and ocular markers that are parallel between cardiovascular disease and macular degeneration. This article will explore some of those connections.
Many of the processes that occur within retinal vessels are seen in the eye, as it represents a readily observable end organ. The consequences of some of these changes in the vasculature may show up specifically as the well characterized age-related changes of drusen, retinal pigment disruption, choroidal neovascularization and even inner retinal vascular changes. When they are documented in the eye they may reflect parallel deterioration of the entire circulatory system. Some of the specific connections will be explored here as we look at the relationship between vascular disease and macular degeneration.
Pathogenesis of AMD
The pathogenesis of age-related macular degeneration is clearly multifactorial. The spectrum of clinically observable changes may become evident only after the molecular-level processes have been in place for a considerable amount of time. The wide-ranging influences on AMD and vascular disease include aging, genetic and environmental factors as well as nutritional influences, according to Zarbin.
Image: LP Semes
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Delving further, with increasing age there is decreased ocular blood flow (both choroidal and retinal) that in the region of the outer retina leads to deterioration of the retinal pigment epithelium (RPE) and Bruch’s membrane. Other factors that may contribute to reduced local and systemic blood flow include inflammation and oxidative changes. It is well known that the RPE functions as the nutritional source for the overlying photoreceptors.
One result of RPE senescence is geographic atrophy, which can produce vision loss. Once the nutritional source to the photoreceptors is lost, they will deteriorate, and visual performance will suffer. The initial insult is likely at the level of the vascular endothelium, which may be a common pathway in such a spectrum of diseases as diabetes and glaucoma.
The consequence of breakdown at the level of Bruch’s membrane is, of course, the possibility of choroidal neovascularization and severe vision loss. In addition, oxidative stress/damage to structures of the outer retina may be potentiated by inflammatory responses, according to Hageman and Anderson. Looking just at the AMD side of the equation as clinicians we are familiar with the cascade that includes: extracellular matrix changes, drusen formation/appearance, geographic atrophy, upregulation of vascular endothelial growth factor (VEGF), perhaps other vasculogenic features and potentially the devastation of choroidal neovascular membrane formation.
Chemical markers for vascular disease
Among the earliest observable aging changes in the outer retina are the appearance of drusen and disruption of the RPE, as delineated from results of the Age-Related Eye Disease Studies (AREDS). These may occur in the absence of symptomatic vision changes, and patients may be unaware of early changes. If these early appearances are seen following initiation by inflammatory precursors, then assaying serum for their presence might prove valuable for detecting the earliest onset of AMD. Indirect evidence for such a cascade could be hypothesized.
Complement pathway components such as complement factor H (CFH) as well as a mitochondrial enzyme, nicotinamide adenine dinucleotide dehydrogenase subunit 2 (ND2), have been implicated in the enhancement of inflammatory signals, according to Zanke. Other proteins such as a matrix metalloproteinase (TIMP3), which is associated with neovascularization, and a cholesterol-metabolizing enzyme, LIPC, which is a xanthophyll transporter, have also been implicated as genetically directed risk markers for AMD, reported Chen and Reynolds.
Lifestyle risk factors for AMD
Several recognized alterable risks have become established and reinforced. Cigarette smoking in many studies over at least a decade, including those by DeBlack and Chakravarthy, has been associated with increased risk of developing macular degeneration. In fact, a study by Sun has shown an association among smoking, AMD and the risk of cardiovascular disease and stroke. The suggested mechanism involves but may not be limited to oxidative stress as an initiating event. It is no secret that this is at the top of the list of discussion items in patients with a history of other risks for AMD. Various independent risk factors such as certain inflammatory markers in serum may potentiate or follow the oxidative damage of cigarette smoking.
Lifetime exposure to blue light has also been named as a risk factor for developing AMD, according to a number of epidemiological and laboratory studies, including those by West and Szaflik. Blue light is specifically implicated, as it penetrates to the outer retina, and among the visible spectrum these wavelengths are the shortest and therefore most energetic.
The ultraviolet radiation (UVR) spectrum is largely absorbed by anterior segment structures so does not play a significant role in AMD formation or progression. Its chronic detrimental effect on the eye is likely limited to cataract formation. Acute damage from UVR absorption occurs in the corneal epithelium. The effect of the infrared (IR) spectrum and its role in AMD has not been fully characterized at this time. One suggestion of its contribution is the generation of heat and therefore elevated choroidal temperatures, but this remains speculative. The contribution of blue light damage to the outer retina appears to be an oxidative process which, like the effects of cigarette smoking, is cumulative over a lifetime.
One of the earliest dietary modifications to gain attention in regard to AMD amelioration was zinc. In a small short-term study by Newsome, zinc was demonstrated to be marginally protective. In addition, subsequent studies have shown the benefits of certain dietary components such as antioxidants. The support for this concept is exhaustive; selected milestones are cited, including Fletcher, AREDS Research Group and van Leeuwen, representing population studies in the U.S. and Europe.
Zinc seems to play an important role in the activation of complement and other inflammatory contributions to vascular disease to be discussed later. This is the reason it was initially chosen for clinical investigation.
The adverse influence of a high-lipid diet on AMD has also been demonstrated as part of AREDS. While a healthy diet is ideal for minimizing the contribution to AMD and promoting a healthy vascular system, making these recommendations often becomes impractical in the clinical setting, reported recently by Mares and colleagues. Some patients and practitioners may turn to supplements to balance the effects of a less-than-optimal diet.
The AREDS and other studies cited above have shown benefits of short-term (5 years) supplementation with selected antioxidants and zinc. Patients should understand that this intervention, which is typically of short duration later in life, will not reverse the effects of 50 to 60 years of suboptimal dietary habits. The regular consumption of fish, for example, has been shown by Flood and Tan to protect against AMD.
Turning away from certain preventive strategies, some risk factors for AMD are nonalterable. These include age older than 60 years, positive family history for AMD, fair complexion, hyperopia and cardiovascular disease. Let us now turn our attention to manifestations of cardiovascular disease within the retinal vascular tree.
Retinal vascular disease
The ocular fundus offers a unique opportunity to perform a visual biopsy of the circulatory system. Changes in the retinal arterioles and venules reflect changes consistent with a range of systemic conditions. Observing the ocular fundus and documenting changes is critical in such disorders as diabetes. As clinicians we are familiar with the devastating effects of diabetes as well as hypertension and atherosclerosis, for example. The retinal arterioles are histologically just that, arterioles. They are roughly 100 microns in diameter without internal elastic lamina or a continuous muscular coat. Atherosclerotic changes observed in the retina correlate closely with the extent of cardiovascular disease. Tedeschi-Reiner et al., in the MESA (Multi-Ethnic Study of Atherosclerosis) study, showed that cardiac artery calcification (CAC) was closely associated with the severity of retinopathy. Wong et al., however, were unable to connect retinal caliber variations with CAC.
Inflammatory markers
At the molecular level, lipoprotein A has been identified as playing a significant role in cardiovascular disease. Upregulation of this particularly aggressive inflammatory progenitor has been identified as such a significant risk factor that guidelines for healthy serum levels have been established, as reported by Nordestgaard. The evidence for lipoprotein A and its association with AMD is strengthened by its genetic connections, as well, according to Baird, Baird and Yu. Interestingly, some of this evidence includes the connection between cigarette smoking and AMD, making the speculation of the oxidative association that much more tempting, reported Vine.
Another component of the molecular-level mechanisms underlying endothelial dysfunction in cardiovascular risk damage, according to Lele, involves regulation of nitric oxide (NO) as a modulator of oxidative stress. (Reactive oxygen species and reactive nitrogen species are the basis of endothelial dysfunction, hence, increasing the bioavailability of NO and decreasing its inactivation is the aim of prevention and reversal of endothelial dysfunction). Antioxidant supplementation with vitamins E and C as well as lowering cholesterol seems to help regulate NO production and, therefore, protect vascular endothelium. Dietary supplements of EPA/DHA, regular physical exercise and control of mental stress have also been suggested as beneficial. Both vascular health and, as a consequence, retinal viability would, therefore, benefit.
Another powerful marker for inflammation that has been implicated directly in AMD is C-reactive protein (CRP). Seddon et al. have reported a strong connection between CRP and AMD among a subset of the AREDS population. Their results demonstrated a trend for an increased risk for intermediate and advanced AMD among smokers as well as those who never smoked with the highest level of CRP. This evidence identifies CRP as an independent risk factor for the development of AMD. These authors speculate that the connection with CRP as well as other chronic diseases may share a common pathogenetic pathway that is rooted in inflammation and reflected in vascular damage in the choroid and manifested as damage to the outer retina.
With the role of inflammation becoming better established, interest in anti-inflammatory mediators has grown. The evidence for a protective role of nonsteroidal anti-inflammatory drugs (NSAIDs) is conflicting, however. One possible pathway for modifying risk in AMD and vascular disease may be the use of anti-inflammatories. The evidence in this area continues to emerge.
In the Blue Mountains Eye Study (BMES), conducted near Sydney, Australia, among the nearly 2,500 participants with 5-year follow-up, 2.0% developed early AMD, and 4.9% developed late AMD, reported Wang. The authors of the study failed to find an association with either NSAID or steroid use.
However, a retrospective chart review comparing the records of 551 veterans with those of 5,500 controls was conducted from a searchable database at the Birmingham, Ala., Veterans Affairs Medical Center. The diagnoses and medications were based on ICD-9 coding and electronic medical records. Results showed that those who had prescriptions filled for anti-inflammatory medications were 81% less likely among AMD patients, implying a protective effect, according to Swanson and McGwin.
Combining the inflammatory component of initial drusen formation with an apparent protective effective from NSAIDs or steroids, it is tempting to speculate about alternative management strategies when the early signs of AMD appear. In fact, there is evidence to suggest a protective effect of the nonselective NSAID naproxen in reducing the risk of acute myocardial infarction, probably by blocking platelet aggregation, as reported in several studies, including those of Solomon, Watson and Rahme.
Blocking platelet aggregation may be helpful in reducing inflammatory vascular manifestations in the retinal circulation, as well.
Subsequent evidence of the connection between cardiovascular disease and AMD comes from epidemiological studies, one of which was the Women’s Health Initiative Sight Exam (WHISE) ancillary study. The results suggest that independent risk factors between cardiovascular disease and both early and late AMD among women included age, smoking, increased blood pressure and a history of diabetes, reported Klein and associates. Increased blood pressure may be the result of a host of factors including inflammatory signaling, oxidative stress and NO dysregulation as noted above.
Other recent evidence for the relationships between molecular-level inflammatory processes, oxidative and metabolic stress, and modulation of CRP was demonstrated in a small study of obese men. CRP was reduced when the intervention was an anti-inflammatory diet mix that included vitamin C, reported Bakker. While these connections are complex and still emerging, this study represents additional evidence for the role of inflammation and its effect on the vascular system as a whole as well as its influence on the outer retina.
It may also be useful to consider the role of genetics in AMD and overcoming some of the effects with dietary modification or supplements. Ho et al connect the dots in the following manner:
- Pro-inflammatory fatty acids present from food intake activate the complement cascade that results in oxidative damage to cell membranes. (This may be counteracted by reducing reactive oxidative species in the outer retina with dietary modification or selected supplement intake, for example.)
- Zinc may play a protective role by interrupting the complement cascade.
- Omega-3 fatty acids (anti-inflammatory) may reduce up-regulation of CRP.
- Beta-carotene, although controversial, has been suggested to be beneficial in the AREDS as it is inversely related to CRP and other pro-inflammatory levels.
Additional connections between AMD and vascular disease involve the role of omgea-3 free fatty acids. While the evidence is still emerging, there appears to be beneficial effects to the circulatory system.
A recent review by Mozaffarian and Wu forms the basis for the American College of Cardiology recommendation for the general population of at least 250 mg/day of long-chain n-3 PUFA or at least two servings per week of oily fish. Interestingly, the protective role of omgea-3 free fatty acids in AMD is being investigated in the AREDS 2 trial by SanGiovanni et al. This redesign of the original nutritional intervention for AMD (AREDS) includes 1,000 mg daily of EPA/DHA in one of the randomization arms of the study. The study design also includes the carotenoids lutein and zeaxanthin, which may have a role in cardiovascular benefits. AREDS 2 also eliminates beta-carotene. Final results are expected in 2014.
Together, the recent evidence points to common pathways in vascular disease and AMD. Further, the nutritional evidence supports dietary modification or supplementation to reduce the risk for AMD and vascular disease because they share so many common molecular pathways and clinical manifestations.
A summary of the cascade of damage may go something like this: Inflammation initiates many adverse vascular consequences that are the direct result of pro-inflammatory products that are ingested or generated within the body. The endothelial damage is manifested by clinical examination of tissues in the eye as well as serum markers in the systemic circulation.
References:
- Age-Related Eye Disease Study Research Group. AREDS Classification. Risk factors associated with the incidence of age-related macular degeneration in the Age-Related Eye Disease Study (AREDS). AREDS Report No. 19. Ophthalmology. 2005;112:533-539.
- The Age-Related Eye Disease Research Group: A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss. AREDS Report No. 8. Arch Ophthalmol. 2001;119:1417-1436.
- The Age-Related Eye Disease Research Group. The Relationship of Dietary Lipid Intake and Age-Related Macular Degeneration in a Case-Control Study: AREDS Report No. 20. Arch Ophthalmol. 2007;125:671-679.
- Age-Related Eye Disease Study Research Group. A Simplified Severity Scale for Age-Related Macular Degeneration. AREDS Report No. 18. Arch Ophthalmol.2005;123:1570-1574.
- The Age-Related Eye Disease Study severity scale for age-related macular degeneration. AREDS Report No. 17. Arch Ophthalmol. 2005;123:1484-1498.
- Anderson DH, Mullins RF, Hageman GS, Johnson LV. A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol. 2002;134:411–431.
- Baird PN, Richardson AJ, Robman LD, et al. Apolipoprotein (APOE) gene is associated with progression of age-related macular degeneration (AMD). Hum Mutat.2006;27(4):337-342.
- Baird PN, Robman LD, Richardson AJ, et al. Gene-environment interaction in progression of AMD: the CFH gene, smoking and exposure to chronic infection. Hum Mol Genet. 2008;17(9):1299-1305.
- Bakker GC, van Erk MJ, Pellis L, et al. An anti-inflammatory dietary mix modulates inflammation and oxidative and metabolic stress in overweight men: a nutrigenomics approach. Am J Clin Nutr.2010;91(4):1044-1059.
- Chakravarthy U, et al. Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. [BMES.] BMC Ophthalmol. 2010;10:31.
- Chen W, Stambolian D, Edwards AO, et al. Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci USA. 2010;107:7401-7406.
- Chu J, Zhou CC, Lu N, Zhang X, Dong FT. Genetic variants in three genes and smoking show strong associations with susceptibility to exudative age-related macular degeneration in a Chinese population. Chin Med J (Engl). 2008;121(24):2525-2533.
- Cruickshanks KJ, Klein R, Klein BE. Sunlight and age-related macular degeneration. The Beaver Dam Eye Study. Arch Ophthalmol. 1993;111:514–518.
- Cruickshanks KJ, Klein R, Klein BE, Nondahl DM. Sunlight and the 5-year incidence of early age-related maculopathy: the Beaver Dam Eye Study. Arch Ophthalmol.2001;119:246–250.
- Darzins P, Mitchell P, Heller RF. Sun exposure and age-related macular degeneration. An Australian case-control study. Ophthalmology. 1997;104:770–776.
- DeBlack SS. Cigarette smoking as a risk factor for cataract and age-related macular degeneration: a review of the literature. Optometry. 2003;74:99-110.
- Fletcher AE, Bentham GC, Agnew M, et al. Sunlight exposure, antioxidants and age-related macular degeneration. Arch Ophthalmol. 2008;126:1396–1403.
- Flood VM, Webb KL, Rochtchina E, Kelly B, Mitchell P. Fatty acid intakes and food sources in a population of older Australians. Asia Pac J Clin Nutr. 2007;16(2):322-330.
- Francis PJ, George S, Schultz DW, et al. The LOC387715 gene, smoking, body mass index, environmental associations with advanced age-related macular degeneration. Hum. Hered.2007;63:212–218.
- Hageman GS, Luthert, PJ, Chong N H, et al. Prog Ret Eye Res. 2001;20:705-732.
- Ho L, van Leeuwen R, Witteman JC, et al. Reducing the genetic risk of age-related macular degeneration with dietary antioxidants, zinc and omega-3 fatty acids: the Rotterdam study. Arch Ophthalmol. 2011;129(6):758-766.
- Hughes AE, Orr N, Patterson C, et al. Neovascular age-related macular degeneration risk based on CFH, LOC387715/ HTRA1, and smoking. PLoS Med. 2007;4(12):e355.
- Klein R, Deng Y, Klein BE, et al. Cardiovascular disease, its risk factors and treatment, and age-related macular degeneration: Women’s Health Initiative Sight Exam ancillary study. Am J Ophthalmol. 2007;143(3):473-483.
- Klein R, Klein BE, Klein A, et al. The Wisconsin Age-Related Maculopathy Grading System. Am J Epidemiol. 2002;156(7):589-598.
- Lele RD. Causation, prevention and reversal of vascular endothelial dysfunction. J Assoc Physicians India. 2007;55:643-651.
- Mares JA, Voland RP, Sondel SA, et al. Healthy lifestyles related to subsequent prevalence of age-related macular degeneration. Arch Ophthalmol. 2011;129(4):470-480.
- Mitchell P, The Blue Mountains Eye Study. Smoking and the 5-year incidence of age-related maculopathy. Arch Ophthalmol. 2002; 120: 1357-1363.
- Mitchell P, Smith W, Wang JJ. Iris color, skin sun sensitivity, and age-related maculopathy. The Blue Mountains Eye Study. Ophthalmology. 1998;105(8):1359–1363.
- Mori K, Gehlbach PL, Kabasawa S, et al. Coding and noncoding variants in the CFH gene and cigarette smoking influence the risk of age-related macular degeneration in a Japanese population. Invest Ophthalmol Vis Sci. 2007;48:5315–5319.
- Mozaffarian D, Wu JH. Omega-3 Fatty acids and cardiovascular disease: effects on risk factors, molecular pathways and clinical events. J Am Coll Cardiol. 2011;58(20):2047-2067.
- Neuner B, Wellmann J, Dasch B, et al. LOC387715, smoking and their prognostic impact on visual functional status in age-related macular degeneration – The Muenster Aging and Retina Study (MARS) cohort. Ophthalmic Epidemiol. 2008;15:148-154.
- Newsome DA, Swartz M, Leone NC, Elston RC, Miller E. Oral zinc in macular degeneration. Arch Ophthalmol. 1988;106:192-198.
- Nordestgaard BG, Chapman MJ, Ray K, et al. European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J.2010;31(23):2844-2853.
- O’Connell ED, et al. Diet and risk factors for age-related maculopathy. Am J Clin Nutr.2008;87:712-722.
- Rahme E, Pilote L, LeLorier J. Association between naproxen use and protection against acute myocardial infarction. Arch Int Med. 2002;162:1111–1115. doi: 10.1001/archinte.162.10.1111.
- Reynolds R, Rosner B, Seddon JM. Serum lipid biomarkers and hepatic lipase gene associations with age-related macular degeneration. Ophthalmology. 2010;117:1989-1995.
- SanGiovanni JP, Chew EY, Clemons TE, et al; Age-Related Eye Disease Study Research Group. The relationship of dietary lipid intake and age-related macular degeneration in a case-control study: AREDS Report No. 20. Arch Ophthalmol. 2007;125(5):671-679.
- Schaumberg DA, Hankinson SE, Guo Q, Rimm E, Hunter DJ. A prospective study of two major age-related macular degeneration susceptibility alleles and interactions with modifiable risk factors. Arch Ophthalmol. 2007;125(1):55–62.
- Schmidt S, Hauser MA, Scott WK, et al. Cigarette smoking strongly modifies the association of LOC387715 and age-related macular degeneration. Am J Hum Genet. 2006;78:852–864.
- Seddon JM, Gensler G, Milton RC, Klein ML, Rifai N. Association between C-reactive protein and age-related macular degeneration. JAMA. 2004;291(6):704-710.
- Solomon DH, Glynn RJ, Levin R, Avorn J. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med. 2002;162:1099–1104.
- Sun C, Klein R, Wong TY. Age-related macular degeneration and risk of coronary heart disease and stroke: the Cardiovascular Health Study. Ophthalmology. 2009;116:1913-1919.
- Swanson MW, McGwin G Jr. Anti-inflammatory drug use and age-related macular degeneration. Optom Vis Sci. 200885(10):947-950.
- Szaflik JP, Janik-Papis K, Synowiec E, et al. DNA damage and repair in age-related macular degeneration. Mutat Res. 2009; 669(1-2):169-176. Epub 2009 Jun 25.
- Tan JSL, et al. Dietary fatty acids and the 10-year incidence of age-related macular degeneration. Arch Ophthalmol. 2009;127(5):656-665.
- Tedeschi-Reiner E, Strozzi M, Skoric B, Reiner Z. Relation of atherosclerotic changes in retinal arteries to the extent of coronary artery disease. Am J Cardiol. 2005;96(8):1107-1109.
- van Leeuwen R, Boekhoorn S, Vingerling JR, et al. Dietary intake of antioxidants and risk of age-related macular degeneration. JAMA. 2005;294(24):3101-3107.
- Vine AK, Stader J, Branham K, Musch DC, Swaroo PA. Biomarkers of cardiovascular disease as risk factors for age-related macular degeneration. Ophthalmology. 2005;112:2076-2080.
- Wang JJ, Mitchell P, Cumming RG, et al. Visual impairment and nursing home placement in older Australians: the Blue Mountains Eye Study. Ophthalmic Epidemiol. 2003;10:3–13.
- Watson DJ, Rhodes T, Cai B, Guess HA. Lower risk of thromboembolis cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med.2002;162:1105-1110.
- West SK, Rosenthal FS, Bressler NM, et al. Exposure to sunlight and other risk factors for age-related macular degeneration. Arch Ophthalmol. 1989;107:875–859.
- Wong TY, Islam FM, Klein R, et al. Retinal vascular caliber, cardiovascular risk factors and inflammation: the multi-ethnic study of atherosclerosis (MESA). Invest Ophthalmol Vis Sci. 2006;47(6):2341-2350.
- Young RW. Solar radiation and age-related macular degeneration. Surv Ophthalmol. 1988;32:252.
- Yu Y, Bhangale TR, Fagerness J, et al. Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration. Hum Mol Genet.2011;20(18):3699-3709.
- Zanke B, Hawken S, Chow D. A genetic approach to stratification of the risk for age-related macular degeneration. Can J Ophthalmol. 2010;45:22-27.
- Zarbin MA. Current concepts in the pathogenesis of age-related macular degeneration. Arch Ophthalmol. 2004;122:598-614.
For more information:
- Leo P. Semes, OD, FAAO, FACMO, is a professor of optometry, University of Alabama at Birmingham and a member of the Primary Care Optometry News Editorial Board. He may be contacted at 1716 University Blvd., Birmingham, AL 35294-0010; (205) 934-6773; fax: (205) 934-6758; lsemes@uab.edu.
- Disclosure: Dr. Semes is on the speaker’s bureau for Alcon, Allergan, Optovue and Carl Zeiss Meditec.