DOI: 10.1161/CIRCULATIONAHA.114.011036 The Complex Association Between Alcohol Consumption and Myocardial Infarction: Always Good for a New Paradox Running title: Kiechl et al.; Alcohol consumption and myocardial infarction Stefan Kiechl, MD; Johann Willeit, MD ustria Department of Neurology, Innsbruck Medical University, Innsbruck, A Austria Address Add dr forr Correspondence: Corr Co rresspo rr pond nden nd ence ncee: Address S effan St a Kiechl Kiech hl MD MD Stefan Depa De part pa rtme rt ment me nt ooff Neur N eur urol olog ol ogyy og Department Neurology nnsbbruckk Medical Medi Me dica call University Univ Un iversi sity ty y Innsbruck A i h 35 Anichstrasse A-6020 Innsbruck, Austria Tel: 0043-512-504-24244 Fax: 0043-512-504-23987 E-mail: [email protected]. Journal Subject Code: Etiology:[4] Acute myocardial infarction Key words: Editorial, myocardial infarction, cardiovascular disease, alcohol, epidemiology 1 Copyright by American Heart Association, Inc. All rights reserved. DOI: 10.1161/CIRCULATIONAHA.114.011036 First mention of alcohol as a component of diet and communal events dates back to the 7th millennium B.C. Famous ancient savants like Hippocrates used alcohol as a solvent for herb extracts, an antiseptic, and to counteract lethargy and diarrhoea, while in medieval times alcohol was well within the armamentarium of anaesthetics, sedatives, disinfectants, and diuretics. Nowadays, alcohol is no longer administered for medicinal purposes, but is a frequent constituent of regular diet favoured for its broad availability and lack of effective sale restrictions. In 2010, the worldwide average amount of pure alcohol consumed per person aged 15 or over was 6.2 litres per year or 13.5 grams per day. 1 There is now solid evidence that alcohol, when consumed on a regular basis and at low volumes (up to one drink for women and wo drinks for men daily), confers protection against cardiovascular disease, wh her ereaas re regu gula gu larr la two whereas regular amounts of more than four to five drinks daily and heavy episodic drinking have opposite effects effects. 2,3 ,3 The The J-shaped J-ssha happedd as asso association sociation applies to low- and hhigh-risk ighh-risk individ ig individuals, dua u ls,, th thee primary prevention ettting, in and too survivors suurv viv vorss of myocardial myoca yocaardia dial iinfarction. nfarrcttion.. S ex ddifferences iffe if feereenc ncees are re aattributed tttri ribu bu ute tedd to distinct dis isti t ncct gastric ti gasstric setting, Sex allco coho holl dehydrogenase ho dehy de hyddrog hy drog ogeenas asee (ADH) (ADH (A DH H) activity acti ac tivvit ti ityy an andd bo body d ddistribution dy istrrib i ut utio ionn vo io vvolumes. l me lu mes. s.. 4 C Consumption on nsuump mpti tionn off al ti alc alcohol cohhol ho alcohol during mealss on on a daily dail da illy basis basi ba siss is deemed si dee e me m d an ideal idea eall drinking drin dr in nki k ng pattern, pat atte teern rn, characterized char ch arac ar acte ac teri te r zeed by prolonged ri pro r longed absorption and persistency, because its most favourable effects are transient and it blunts postprandial glucose spikes. Strictly speaking, however, the bulk of studies supporting this knowledge operate in high-income countries with little evidence available from South America, Africa or Asia, except China and Japan. 2 In this regard, the study by Leong et al. in the current issue of Circulation delivers unique and, to some extent, surprising results. 5 Alcohol consumers living in South Asia and the Middle East, in contrast to the rest of the world, do not enjoy protection against myocardial infarction. Inhabitants of the South Asian countries Sri Lanka, Pakistan, India and Bangladesh (1.644 Mio, 23.04% of the world population as of 2013) even 2 Copyright by American Heart Association, Inc. All rights reserved. DOI: 10.1161/CIRCULATIONAHA.114.011036 faced a significantly elevated risk after adjusting for body composition, physical activity, smoking, quality of diet, classic vascular risk factors, as well as socioeconomic and sociocultural factors. 5 INTERHEART is among the pioneer initiatives aimed at scrutinizing effects of lifestyle on human diseases on a large scale and around the globe. 6 It involves more than 27.000 individuals from 52 countries and employs rigorous methodological standards. Early releases from this database already point to differential effects of alcohol in South Asia 6,7, but full data have not been made available until now. 5 INTERHEART’s findings are relevant and timely given that alcohol consumption is on the rise in South Asia, especially India, according to the most recent WHO report released in ongoing ing ddiscussion isscu cuss ssio ss ionn on io 2014 (Figure 1A). 1 The elegant study by Leong et al. inevitably fuels the ongoi he mechanisms linking alcohol intake and cardiovascular disease. Beyond doubt, alcohol exerts the mu mult ltip lt iple ip le effects eff ffec eccts all all aalong long the atherosclerosis process pro oce c ss from early lesion leesi s on n formation formation or to plaque multiple fi isssur u ing and thrombus th hromb mbuus formation forrma m ti tion on and and n directly directtlyy affects aff ffec fects he hear artt rh hyt ythm hm aand nd myoc m yoc ocar ardi diial a ccontractile onntrracti acti tilee fissuring heart rhythm myocardial 3,8,9 9 pe perf rfor rf orrma m ncce. e 3,8 Most M osst pro pproperties ropeerti ertiies pproposed rop ro pose pose sedd ar are re do dose-dependent ose-d dep pen ende deent n aand nd m mediated edia ed iate teed by eethanol than th noll pe perr se, se , performance. with moderate moderat atee amounts amou am ount ou ntts offering offe of feri fe ring ri ng g protection pro ote t ct ctio io on and and larger laarg rger e qquantities er uant ua ntit nt i ie it iess ma aki king ng tthe he ppoison. oiso oi son. so n n. making Alcohol and vascular disease – the bright side Figure 2 illustrates current knowledge on potential athero- and cardio-protective consequences of alcohol consumption. In brief, alcohol in moderation favourably affects reverse cholesterol transport, insulin sensitivity, abdominal obesity, systemic inflammation and oxidative stress, endothelial function, endogenous fibrinolysis, postprandial hypercoagulability, and platelet aggregation. 3,8-13 These effects are in part of reasonable size and may well contribute to the health benefits of habitual moderate alcohol consumption regarding coronary heart disease (decrease of 29%), 2 diabetes (decrease of 30%-40%), 3 and life span (decrease of 17%-18% in 3 Copyright by American Heart Association, Inc. All rights reserved. DOI: 10.1161/CIRCULATIONAHA.114.011036 total mortality). 3 The “South Asian paradox” The beneficial effects of alcohol, however, are difficult to reconcile with INTERHEART’s observation of an elevated vascular risk among mainly moderate drinkers in South Asia. As discussed by Leong et al., genetic differences in alcohol metabolism, reflected by functional polymorphisms in the genes encoding alcohol degradation enzymes like ADH and aldehyde dehydrogenase (ALDH)-2, are unlikely to explain the paradox, because health hazards diminish in emigrants leaving South Asia. 5 Other potential explanations for the paradox are chance, unmeasured confounding, disease-modifying life-style and dietary peculiarities, unique drinking patterns and the quality of alcoholic beverages consumed. Chance is abrogated byy cconsistent onsi on sist si sten st entt en evidence from another large-scale study from India. 14 Importantly, this study demonstrates that de eleete teri riou ri ou us effects effect ef ctts of o alcohol are not confined too frequent freequent binge dr rinki king ng in India, but extend to deleterious drinking m odderate de drink nker errs consuming co onsum umin um ingg minor in minnor mi nor amounts amounnts of aalcohol. lccoho ho ol. l. C on nfo fouundi unding ng gm ay y aarise rise ffrom rise ro om th he use use of moderate drinkers Confounding may the elf lf-r -rep -r epor ep ortt in inst stru ru ument mentss on on a fundamentally fun unda dame da m nttallly different me diff ffer ff e ent er ent sociocultural soociioc ocul ultu tura tu raal background, back ba ck kgrrou ound nd,, bu nd ut it it iss not n ot self-report instruments but mmediately y ap appa pare pa rent re n w nt hy y tthis his sh hi shou ou uld l ppretend reete tend nd hharm arm m iin n So Sout uthh As ut Asia i bbut ut nnot ot iin n ot oother herr co he comp m arable immediately apparent why should South comparable Asian regions or countries tabooing alcohol. Nutritional modifiers of alcohol effects remain to be unravelled and hold some promise to resolve the paradox. Unique characteristics of alcohol consumption in South Asia are the globally highest proportion of unrecorded (homemade) alcohol (one-half in India) 1 and the almost exclusive consumption of spirits (93.1% spirits, 6.8% beer, and 0.1% wine in India). 1,14 In small intervention trials and based on pathophysiological considerations, wine surpassed other types of alcoholic beverages in terms of favourable shortterm metabolic changes. 3,9,11,12 To date, epidemiological research has not confirmed the superiority of wine over spirits. 2 However, it must be remembered that in epidemiological work 4 Copyright by American Heart Association, Inc. All rights reserved. DOI: 10.1161/CIRCULATIONAHA.114.011036 it is challenging, if possible at all, to disentangle effects of different types of beverages in “mixed” drinkers, and drinking behaviours allocated to one type of beverage only are usually driven by cultural and regional peculiarities. The stimulating INTERHEART publication should motivate further scientific elaboration of alcohol’s preferential harm in South Asia and revive research targeting alcohol quality. Promising research foci may address unexplored areas like alcohol’s influence on the gut microbiota and metabolome, and the effects of distinct alcoholic beverages on lipid composition 15 and de novo lipogenesis. Alcohol and health – the dark side Harmful use of alcohol is a component cause of more than 200 disease and injury conditions 1,3 ncluding myocardial infarction, stroke, diabetes, atrial fibrillation, non-ischemic ic including cardiomyopathy, sleep apnea, cancer (most notably of the breast and gastrointestinal tract), foeta foetal allco oho holl syndrome, syynd ndrrome me,, and me and liver cirrhosis. It is the th hird ird-leading causee of premature pre rem mature death in the US, alcohol third-leading urp pas a sed onlyy by by smoking sm mok okin ingg and in and overweight, ov ver erw weight,, and and eve eeven ven cconstitutes onsttittut onst utees tthe he nnumber umbe um beer on onee ki kill ller ll err aamong mong mo ng surpassed killer meen aged aged 15 15 to 50 50 ye yyears. arss. s. 3 O On n a po pop population pulaatiion llevel, pula ev vel e , hhazardous azaard dou ouss ef eff effects fects ts ooff al alcohol lco cohhol hol in aaggregate ggreegaate m ggre may ay ay men 18 nef efic i ia ic iall on nes e , 1,8 aand ndd cardiovascular car ardi d ov ovas ascu as cula cu larr disease la dise di seas se a e is a key key contributor co ont n ri ribu buto bu torr too alcohol-related to alc lcoh ohol oh o -related offset the ben beneficial ones, mortality (33.4% globally). 1 Despite the intriguing novel findings for South Asia, it must be emphasized that the dimension of the problem is still greatest in the Western world and in emerging economies with rates of alcohol-related deaths peaking in the Russian Federation and successor states of the former USSR (2014 WHO Report, Figure 1B). 1 Figure 2 summarizes mechanistic pathways linking heavy drinking and vascular disease (3, 8). The second main finding of INTERHEART, namely that more than four alcoholic drinks in men and three in women (or 6 drinks unisex in an alternative analysis), consumed on a single occasion, translates into short-term harm 5, fits very well with these pathophysiological considerations. Alcohol in 5 Copyright by American Heart Association, Inc. All rights reserved. DOI: 10.1161/CIRCULATIONAHA.114.011036 excess produces an immediate rise in blood pressure, a short-lived oxidative and proinflammatory burst, impaired fibrinolysis, and temporary heart rhythm changes with enhanced oxygen demands. 3,8-13 Briefly delayed, the platelet-rebound phenomenon creates a reversible pro-coagulant state and vulnerable period. Moreover, heavy drinking interferes with the absorption, metabolism, and action of several drugs used in cardiovascular prevention and may prompt irregular or delayed pill intake, which further amplifies risk. The enhanced burden of atherosclerosis and more common alcohol-drug interferences provide a plausible explanation why individuals older than 65 years are more susceptible to injurious effects of heavy episodic drinking in INTERHEART. 5 Some notes on limitations Limitations of the INTERHEART Study are the case-control design with control recruitment from fr rom m hospitals, hospi ospi pita talls, the ta th he general general community, and visitors visit ittor o s or relatives off thee iindex ndex patient. Subsidiary nd analyses, an nallys y es, however, howe wevver, argue arg guee against aga gain in nst a meaningful meaninggfuul influence infflu uen ncee of of this th his heterogeneous heter ete ogeneo ous us enrolment enr nrol olme ol ment nt procedure obtained. pr proc oced oc edur ed uree on tthe hee kkey ey ffindings in ndi ding nggs ob obta tain ta ined in ed d. 5 A Analyses naly na lyse ly sees off sho short-term hort ho rt-tter rt erm m ef effe effects ffe f cts of aalcohol lccoh o ol ol iingestion ng gessti tion onn entail the problem pro obl b em that tha h t alcohol a co al oho hol consumption cons co nsum ns umpt um p io pt ionn inn the the 24 24 hours hoour urss prior prio pr iorr too myocardial io myo yoca card ca r ia rd iall infarction infa in farc fa r tion is rc compared with alcohol consumption in the 24-to-48-hour period prior to infarction as a picture of customary drinking pattern. Acute effects of alcohol do not strictly follow a 24-hour cut-off. Still, this comparison is more robust than the approach commonly used in case-crossover studies, namely using self-reported long-term consumption as a reference. Finally, INTERHEART did not record alcohol quantities, types of alcoholic beverages, or previous drinking behaviours, and thus missed the opportunity to further deepen its findings in these respects. 5 Finally, problems inherently linked to epidemiological alcohol research also apply to INTERHEART, such as recall bias and deliberate denial of alcohol intake. Realistically speaking, however, all these 6 Copyright by American Heart Association, Inc. All rights reserved. DOI: 10.1161/CIRCULATIONAHA.114.011036 limitations are unlikely to invalidate the key findings of INTERHEART. Some thoughts about thresholds and moderation The dispute surrounding the optimal quantity of alcohol that should be consumed has a history almost as long as the history of alcohol itself. The Greek poet Eubulus (375 B.C.) voted for three “Kylix” cups (à 250 mL) and in one of his plays had Dionysos, the god of wine, say: “Three bowls do I mix for the temperate: one to health, which they empty first, the second to love and pleasure, the third to sleep. When this bowl is drunk up, wise guests go home.” Since it was customary at that time to dilute wine in a ratio of 1:2 or 1:3, Eubulus’s view comes close to current guidelines. However, all recommendations suffer from the fact that the thresholds of individual healthy moderation are population averages and do not necessarily reflect correct correcct in ndi divi vidu vi dual du al thresholds. hresholds. 8 Actually, intestinal degradation, absorption, metabolism, and blood clearance of etthaano noll ar re al all su ubj bjec e t to high interindividual va ari riab ab bility. Accordin in ngly, y, oone ne is well advised to ethanol are subject variability. Accordingly, co onsider ns thressho hold lds ann uppermost upp pper ermo er m st limit. mo lim imiit. On On the the other ottheer hand, hand, han nd, alcohol allco cohhol hol consumption connsuump co umpti ption ion is i underreported und nderrre repporrted consider thresholds sel elff es festi tiima m te te,, ass evident eviddent den from fro r m comparisons comp co mp parris isoons ons of o prospective prosp rosppeccti tivve ve diet dieet records rec ecor orrdss and and nd tax tax iincomes ncom om mes es by self-estimate, alcohol sales), sales es), ), and and the the non-differential non n-d dif iffe fere fe r nt re ntiaal response reespo pons nsee error ns erro er rorr is 330%-65%, ro 0%-6 0% -6 65% 5%,, or eeven venn hi ve igh gher er.. 16 This bias er (alcohol higher. is not relevant in terms of clinical recommendations, because it strikes epidemiological studies and the routine setting equally. Summary and implications Overall, men and women consuming alcohol in moderation face a lower risk of myocardial infarction, stroke, congestive heart failure, diabetes, and death in many high-income, emerging, and developing communities. The current publication from the INTERHEART Study, however, casts doubts on whether this is a universal finding that is valid around the globe. Most guidelines explicitly do not advise starting alcohol consumption for the purpose of cardiovascular 7 Copyright by American Heart Association, Inc. All rights reserved. DOI: 10.1161/CIRCULATIONAHA.114.011036 prevention, but instead recommend limiting alcohol intake to quantities below or equal to the thresholds of one or two drinks in women and men daily, respectively. They advise abstention in heavy drinkers only, but the current INTERHEART findings suggest extending this recommendation to South Asians en bloc. Heavy habitual or episodic drinking, on top of its long-term hazards, may be a short-term trigger of myocardial infarction already at amounts well below the conception of binge drinking. “In vino veritas” said the Greek lyric poet Alkaios of Mytilene (630 B.C.). The full truth regarding the complex interplay between alcohol consumption and vascular disease, however, remains a well-guarded secret. The INTERHEART Study in this issue of Circulation is another tep in deciphering the truth and the “South Asian a paradox” is a valuable startingg point pooin nt for for new n w ne step esearch. research. Ack Ac kn knowledg dggme m nt nts: s: We We thank than th ankk P. P. Werner Wer erne nerr MD for forr assistance assisstaance with witth the the preparation prep pr e arrat ep atio ionn of Figure io Fig igur u e 2. ur 2 Acknowledgments: Co onf nfli lict li ct of of Interest Inte In tere rest re st Disclosures: Disscl clos osur u es ur es:: N onne. Conflict None. References s: References: 1. Global status report on alcohol and health 2014. Geneva, World Health Organization, 2014 (http://apps.who.int/iris/bitstream/10665/112736/1/9789240692763_eng.pdf?ua=1, accessed 22 May 2014). 2. Ronksley PE, Brien SE, Turner BJ, Mukamal KJ, Ghali WA. Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and metaanalysis. BMJ. 2011;342:d671. 3. O'Keefe JH, Bhatti SK, Bajwa A, DiNicolantonio JJ, Lavie CJ. Alcohol and cardiovascular health: the dose makes the poison…or the remedy. Mayo Clin Proc. 2014;89:382-393. 4. Baraona E, Abittan CS, Dohmen K, Moretti M, Pozzato G, Chayes ZW, Schaefer C, Lieber CS. Gender differences in pharmacokinetics of alcohol. Alcohol Clin Exp Res. 2001;25:502-507. 5. Leong DP, Smyth A, Teo KK, McKee M, Rangarajan S, Pais P, Liu L, Anand SS, Yusuf S; INTERHEART Study investigators. Patterns of alcohol consumption and myocardial infarction 8 Copyright by American Heart Association, Inc. All rights reserved. DOI: 10.1161/CIRCULATIONAHA.114.011036 risk: observations from 52 countries in the INTERHEART case-control study. Circulation. 2014;120:XX-XXX. 6. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): casecontrol study. Lancet. 2004;364:937-952. 7. Joshi P, Islam S, Pais P, Reddy S, Dorairaj P, Kazmi K, Pandey MR, Haque S, Mendis S, Rangarajan S, Yusuf S. Risk factors for early myocardial infarction in South Asians compared with individuals in other countries. JAMA. 2007;297:286-294. 8. Kiechl S, Willeit J, Rungger G, Egger G, Oberhollenzer F, Bonora E. Alcohol consumption and atherosclerosis: what is the relation? Prospective results from the Bruneck Study. Stroke. 1998;29:900-907. 9. O'Keefe JH, Bybee KA, Lavie CJ. 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Roy A, Prabhakaran D, Jeemon P, Thankappan KR, Mohan V, Ramakrishnan L, Joshi P, Ahmed F, Mohan BV, Saran RK, Sinha N, Reddy KS; Sentinel Surveillance in Industrial Populations Study Group. Impact of alcohol on coronary heart disease in Indian men. Atherosclerosis. 2010;210:531-535. 15. di Giuseppe R, de Lorgeril M, Salen P, Laporte F, Di Castelnuovo A, Krogh V, Siani A, Arnout J, Cappuccio FP, van Dongen M, Donati MB, de Gaetano G, Iacoviello L; European Collaborative Group of the IMMIDIET Project. Alcohol consumption and n-3 polyunsaturated fatty acids in healthy men and women from 3 European populations. Am J Clin Nutr. 2009;89:354-362. 16. Nelson DE, Naimi TS, Brewer RD, Roeber J. US state alcohol sales compared to survey data, 1993-2006. Addiction. 2010;105:1589-1596. 9 Copyright by American Heart Association, Inc. All rights reserved. DOI: 10.1161/CIRCULATIONAHA.114.011036 Figure Legends: Figure 1. A) Five-year changes in recorded per capita alcohol (15+ years) consumption, 20062010. B) Alcohol-attributable fractions for all-cause deaths, 2012 (in percent). Reproduced, with the permission of the publisher, from the Global status report on alcohol and health 2014. Geneva, WHO 2014. Figure 2. Proposed mechanistic insights into athero- and cardio-protective (in green) as well as injurious (in red) effects of alcohol consumption regarding inflammation (CRP, C-reactive protein; IL-6, interleukin-6; IL-10, interleukin-10; TNFĮ, tumor necrosis factor alpha; alph al phha;; IICAM-1, CAMCA M-1,, ntra-cellular adhesion molecule-1; VCAM, vascular adhesion molecule), oxidation (LDL, lowintra-cellular deens nsit ityy lipoprotein; it lipo li popr po prrotei einn; ei n; ROS, reactive oxygen species), speciies e ), endothelial function fun u ctio io on (NO, ( O, nitric oxide: (N density eN NOS, endothelial endoth hellia i l NO synthase; syn ynth nth thas asse; ET-1, ET-1 T-1, endothelin-1), endoothhelinn-1 n-1), co oag gullat atio io on, lliver iveer ffunction iv unncttio ionn an andd in iinsulin suli su linn eNOS, coagulation, ens nsit itiv it ivit iv ityy (H (HDL DL L, high hhigh-density igh h-d den ensiity llipoprotein; ipop ip opro op ro ote tein in;; ap in apoo A -I, I,, aapolipoprotein poli po lipo li popr po prot pr o ei ot e n AA-I I),, th thee he hear arrt (PK ((PKC-İ, PKCKC-İ, sensitivity (HDL, A-I, A-I), heart see C-epsilon; C-eeps psil ilon on;; HSP-70, on HSPHS P 70 P70,, heat-shock h att-s he - ho hock ck k protein pro ote tein in 70; 70; 0 HO-1, HOO 1, heme hem emee oxygenase-1; oxyg ox ygen yg en nas asee 1; MnSOD, eMnSOD, protein kinase manganese superoxide dismutase), and fat tissue. Most effects refer to ethanol. Effects demonstrated for non-alcohol components of red wine (polyphenols) only are labeled with the following symbol “ ”. 10 Copyright by American Heart Association, Inc. All rights reserved. A B Figure 1 Copyright by American Heart Association, Inc. All rights reserved. InsulinsensitivityĹ HDLĹ Apo AͲIĹ LiverToxicity eNOS eN eNOS,NOĹ O , NO OS N Ĺ ETͲ1Ļ ETͲ1 1Ļ BloodPressureĻ Blood Pr Pressure eĻ FlowͲmediateddilationĹ FlowͲmediat ated at e dila lati at on nĹ BloodpressureĹ Blood pressure ur Ĺ InsulinsensitivityĹ AbdominalobesityĻ TriglyceridesĹ AbdominalobesityĹ Diabetes Preconditioning,PKCͲİ Ĺ HeartHSPͲ70,HOͲ1,MnSODĹ CoronaryflowĹ ProtectionagainstI/R Myocyte aldehyde toxicity PKCͲİ Ļ ArrhythmiaĹ Arrhythmia Ĺ Platelet reactivity Ļ PlateletreactivityĻ CoagulationĻĻ Coagulation Fibrinolysis Ĺ Plateletrebound Platelet rebound d Fibrinolysis FFi ibr b inol in nolys y is Ļ ys Fibr FibrinogenĻ b in nogen e Ļ CRP,ILͲ6Ļ CR RP,, ILͲ6 6Ļ TNFĮ TN NFĮ Ļ IL IILͲ10Ĺ Ͳ10 10 Ĺ ICAMͲ1,VCAMĹ ICAM MͲ1, 1 VC CAM Ĺ xida Ļ LDLoxidationĻ ROSĻĻ OxidativestressĹ LDLoxidationĹ Figure 2