Alcohol and Heart Disease
Alcohol and Heart Disease
currents in the guinea-pig heart. European Journal of Pharmacologv January 13, 1995; 292(2): 143
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19 Patel R, McArdle JJ, Regan TJ. Increased ventricular vulnerability in chronic ethanol model despite
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21 Segel LD, Rendig SV, Mason DT. Alcohol-induced cardiac hemodynamic and calcium Ilux dysIunction
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22 Lieber. CS. Microsomal ethanol-oxidizing system. En:vme 1987; 37: 4556.
23 Sandor P, Sellers EM, Dumbrell M, Klouw V. EIIects oI short- and long-term alcohol use on phenytoin
kinetics in chronic alcoholics. Clin. Pharmacol. Ther. 1981; 30: 390397.
24 Caballeria J, Freaaz M, Hernandez-Munoz R, Dipadova C, Korsten MA, Baraona E, Lieber CS. Gastric
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25 Kupari M, Heikkila J, Ylikahri R. Does alcohol intensiIy the hemodynamic eIIects oI nitroglycerin?
Clin. Cardio. 1984; 7: 382386.
26 Shook TL, Kirshenbaum JM, Hundley RF, Shorey JM, Lanas GA. Ethanol intoxication complicating
intravenous nitroglycerin therapy. Ann. Intern. Med. 1984; 101(4): 498499.
27 Allison RD et al. EIIects oI alcohol and nitroglycerin on vascular response in man. Angiologv 1971; 22:
211.
28 Goldberg MR, Robertson D. Yohimbine: a pharmacological probe oI the alpha 2 adrenoreceptor.
Pharmacol. Rev. 1983; 35: 143180.
29 Abdel-Rahman AA, Wooles WR. Ethanol-induced hypertension involves impairment oI baroreceptors.
Hvpertension 1987; 10: 6773.
30 Mao L, Abdel-Rahman ARA. Ethanol counteraction oI clonidine-evoked inhibition oI norepinephrine
release in rostral ventrolateral medulla oI rats. The Alcohol Clin. Exp. Res. 1988; 22(6): 12851291.
31 Szmigielski A, Szmigielski H, Weiman I. The eIIects oI prolonged ethanol administration on central
alpha-2 adrenoreceptors sensitivity. Pol. J. Pharmacol. Pharm. 1989; 41: 263272.
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32 Russ RD, Abdel-Rahman A-RA, Wooles WR. Role oI sympathetic nervous system in ethanol-induced
hypertension in rats. Alcohol 1991; 8: 301307.
33 Green MA, Egle JL. The eIIects oI acetaldehyde and acrolein on blood pressure in guanethidine-
pretreated hypertensive rats. Toxicol. Appl. Pharmacol. 1983; 69(1): 2936.
34 American Society oI Hospital Pharmacists. American Hospital Formulary Service Drug InIormation.
Bethesda, MD: American Society oI Hospital Pharmacists, 1984.
35 Grabowski BS et al. EIIects oI acute alcohol administration on propranolol absorption. Int. J. Clin.
Pharmacol. Ther. Toxicol. 1980; 18: 317.
36 Sontaniemi EA et al. Propranolol and sotalol metabolism aIter a drinking party. Clin. Pharmacol. Ther.
1981; 29: 705.
37 Chakrabarti A, Grag SK, Sharma PL. A preliminary study on the interaction between ethanol and
propranolol in normal human subjects. Indian J. Phvsiol. Pharmacol. 1992; 36(3): 209212.
38 Kulkosky PJ, Allison TG, Carr BA. Angiotensin II reduces alcohol intake and choice in water- or Iood-
restricted rats. Alcohol JulyAugust 1996; 13(4): 359363.
39 Spinosa G, Perlanski E, Leenen FH, Stewart RB, Grupp LA. Angiotensin converting enzyme inhibition:
Animal experiments suggest a new pharmacological treatment Ior alcohol abuse in human. Alcohol Clin.
Exp. Res. 1988; 12: 6570.
40 Lingham T, Perlanski E, Grupp LA. Angiotensin converting enzyme inhibitors reduce alcohol
consumption: Some possible mechanisms and important conditions Ior its therapeutic use. Alcohol Clin.
Exp. Res. 1990; 14: 9299.
41 Hubbell C, Chrisbacher GA, Bilski EJ, Reid LD. Manipulation oI the reninangiotensin system and
intake oI a sweetened alcoholic beverage among rats. Alcohol 1992; 9(1): 5361.
42 Tracy HA Jr, Wayner MJ, Armstrong DL. Losartan improves the perIormance oI ethanol-intoxicated
rats in an eight-arm radial maze. Alcohol SeptemberOctober 1997; 14(5): 511517.
43 Regan TJ, Levinson GE, Oldewurtel HA. Ventricular Iunction in non-cardiacs with alcoholic Iatty liver:
Role oI ethanol in the production oI cardiomyopathy. J. Clin. Invest. 1969; 48: 397407.
44 Posner P, Baker SP, Issacson RL. Potentiation oI the negative chronotropic action oI verapamil by
ethanol. J. Cardiovasc. Pharmacol. 1986; 8: 697699.
45 Martinez JL, Penna M. InIluence oI changes in calcium concentration and verapamil on the cardiac
depressant eIIect oI ethanol in cat papillary muscle. Gen. Pharmacol. 1992; 23: 10511056.
46 Perez-Reyes M et al. Interaction between ethanol and calcium channel blockers in humans. Alcohol
Clin. Exp. Res. 1992; 16: 769.
47 Bauer LA et al. Verapamil inhibits ethanol elimination and prolongs the perception oI intoxication. Clin.
Pharmacol. Ther. 1992; 52: 6.
48 Dul B, Gajkowska B. The inIluence oI the calcium channel antagonist, verapamil and ethanol on the
myocardial ultrastructure in rat. Exp. Toxic. Pathol. 1997; 49(6): 493496.
49 Brown RA, Sundareson AM, Lee MM, Savage AO. DiIIerential eIIects oI chronic calcium channel
blocker treatment on the inotropic response oI diabetic rat myocardium to acute ethanol exposure. Life
Science 1996; 59(10): 835847.
50 Pierce GN, Jutryk MJB, Dhalla NS. Alterations in calcium binding by and composition oI the cardiac
sacrolemmal membrane in chronic diabetes. Proc. Natl. Acad. Sci. USA 1983; 80: 54125416.
51 Dhalla NS, Pierce GN, Innes IR, Beamish RE. Pathogenesis oI cardiac dysIunction in diabetes mellitus.
Can. J. Cardiol. 1985; 1: 263281.
52 Littleton JM, Little HJ, Whittington MA. EIIect 1991s oI dihydropyridine calcium channel antagonists
in ethanol withdrawal; doses required, stereospeciIicity and action oI Bay K 8644. Psvchopharmacologv
1990; 100: 387392.
53 Little HJ, Dolin SJ, Whittington MA. Calcium channel antagonists prevent adaptive responses to
ethanol. Alcohol Alcohol. 1993; 2 (Suppl.): 263267.
54 Qureshi S et al. EIIect oI an acute dose oI alcohol on the pharmacokinetics oI oral niIedipine in humans.
Pharm. Res. 1992; 9: 683.
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55 Engel JA, Fahke C, Hulthe P, Hard E, Johannessen K, Snape B, Svensson L. Biochemical and
behavioral evidence Ior an interaction between ethanol and calcium channel antagonists J. of Neural Trans.
1988; 74: 181193.
56 Tuna RK, Eroglu L. EIIects oI Bay K 8644 and niIedipine on locomotor activity and striatal
homovanillic acid concentration in acutely ethanol-treated rats. Alcohol Alcohol. 1991; 26: 465471.
57 Dul B, Gajkowska B. The inIluence oI ethanol and calcium channel antagonist, niIedipine on
myocardial ultrastructure in the rat. Exp. Toxic. Pathol. 1998; 50: 2730.
58 Dolin SJ, Little HJ. Augmentation by calcium channel antagonists oI general anesthetic potency in mice.
Br. J. Pharmacol. 1986; 88: 909914.
59 Rush CR, Pazzaglia PJ. Pretreatment with isradipine, a calcium channel blocker, does not attenuate the
acute behavioral eIIects oI ethanol in human. Alcohol Clin. Exp. Res. 1998; 22: 539547.
60 Lima CJ, Guiha NH, Lekagul O, Cohn JN. Impaired leIt ventricular Iunction in alcoholic cirrhosis with
ascites. IneIIectiveness oI ouabain. Circulation 1974; 49: 755760.
61 Rich EC, Siebold C, Campion B. Alcohol-related acute atrial Iibrillation: a case-control study and
review oI 40 patients. Arch. Intern. Med. 1985; 145: 830833.
62 Filipek B, Krupinska J, Librowski T, Piekoszewski W. The interaction between ethanol and amiodarone,
in the model oI adrenaline arrhythmia in the rat. Polish Journal of Pharmacologv & Pharmacv MayJune
1989; 41(3): 213218.
63 Olsen H, Bredesen JE, Lunde PKU. EIIect oI ethanol intake on disopyramide elimination by healthy
volunteers. Eur. J. Clin. Pharmacol. 1983; 25: 103105.
64 Kater RMH, Roogin G, Tobon F, Zieve P, ad Iber FL. Increased rate oI clearance oI drugs Irom the
circulation oI alcoholics. Am. J. Med. Sci. 1969; 258: 3539.
65 Sandor P, Seller EM, Dumbrell M, Klouw V. EIIect oI short- and long-term alcohol use on phenytoin
kinetics in chronic alcoholics. Clin. Pharmacol. Ther. 1981; 30: 390397.
66 Olsen H, Morland J. Ethanol interaction with drug acetylation in vivo and in vitro. Pharmacol. Biochem.
Behav. 1983; 18(Suppl. 1): 295300.
67 Hansten PD. Procainamide and ethanol. Drug Interactions Newsletter, Applied Therapeutics. Inc, San.
Francisco. CA 1982; 2: 23.
68 Orszulak MD, Polakowski P. InIluence oI ethanol on pharmacokinetic parameters oI procainamide in
rabbits. Die Pharmacie 1988; 43(40): 260261.
69 Guthrie SK, Wilde DW, Brown RA, Savage AO, Bleske B. Interactions oI ethanol and quinidine on
contractility and myocyte action potential in the rat ventricle. Journal of Electrocardiologv January 1995;
28(1): 3947.
70 Belkin GA. Cocktail purpura: An unusual case oI quinine sensitivity. Ann. Intern. Med. 1967; 66: 583
587.
71 Siroty RR. Purpura on the rocks-with a twist. JAMA 1976; 235(23): 25212522.
72 Udall JA. Drug interIerence with warIarin therapy. Clin. Med. 1970; 77: 20.
73 O`Reilly RA. Lack oI eIIect oI IortiIied wine ingestion during Iasting and anticoagulant therapy. Arch.
Intern. Med. 1981; 141: 458.
74 Kater RHM et al. Increased rate oI clearance oI drugs Irom the circulation oI alcoholic. Am. J. Med. Sci.
1969; 258: 35.
75 Breckenridge A. Pathophysiological Iactors inIluencing drug kinetics. Acta Pharmacol. Toxicol. 1971;
29(Suppl. 3): 225.
76 Pelkonen O, Sataniemi E. Drug metabolism in alcoholics. Pharmacol. Ther. 1982; 16(2): 261268.
77 Brecher AS, Hellman K, Basista MH. Coagulation protein Iunction VI: augmentation oI anticoagulant
Iunction by acetaldehyde-treated heparin. Digestive Diseases & Sciences. July 1999; 44(7): 13491355.
78 Deykin D et al. Ethanol potentiation oI aspirin-induced prolongation oI the bleeding time. N. Engl. J.
Med. 1982; 306: 852.
79 Melander O, Liden A, Melander A. Pharmacokinetic interaction oI alcohol and acetylsalicylic acid.
European J. of Clin. Pharm. 1995; 48(2): 151153.
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Chapter 6
Alcohol abuse and hemorrhagic stroke
Seppo Juvela
INTRODUCTION
Prognosis Ior both spontaneous intracerebral hemorrhage (ICH) |14| and aneurysmal subarachnoid
hemorrhage (SAH) |47|, despite improvements in medical and neurosurgical treatment, has largely remained
unaIIected. Outcome oI both these main hemorrhagic stroke subtypes, which together account Ior
approximately 20 oI all strokes, is still determined mainly by the severity oI bleeding, and overall case-
Iatality still reaches 4050 |2,3,7|. Hence, identiIication oI modiIiable risk Iactors Ior ICH and SAH as well
as Ior impaired outcome aIter these strokes has been important in order to inIluence the incidence and outcome
oI these stroke subtypes as well as to understand better the pathogenesis oI these hemorrhages.
Alcohol consumption has been shown to increase the risk Ior both ICH |4,814| and SAH |11,1517|.
Hypertension increases the risk Ior ICH |8,12,14|, but its signiIicance as a risk Iactor Ior SAH seems to be less
important than Ior other stroke subtypes |1618|. Cigarette smoking seems to increase the risk Ior SAH |16
19| but is less likely to increase the risk Ior ICH |8,12,14,19,20|.
Other potential risk Iactors Ior hemorrhagic stroke include anticoagulant treatment |2,3,14,21|, aspirin use
|14,17,22|, thrombolytic therapy |3,23|, and use oI amphetamines or cocaine |3,11,16|. These may also
synergize with each other, e.g., ethanol potentiates aspirin-induced prolongation oI bleeding time |24|, and
anticoagulant treatment increases the risk oI hemorrhage associated with thrombolytic therapy |23|. In
addition, alcohol consumption, cigarette smoking, hypertension, sex, and age are correlated either directly or
inversely with each other so that multivariate analyses must be used to reveal independent role oI each oI them
as a risk Iactor Ior hemorrhagic stroke subtypes |4,11|.
In most risk-Iactor studies, ICH and SAH have been combined to Iorm the category hemorrhagic stroke
|9,11,19,22,23|, which likely causes bias by either overestimation or underestimation oI the signiIicance oI
risk Iactors Ior diIIerent stroke subtypes. In addition, studies oI hemorrhagic stroke have also included
hemorrhages oI diIIerent etiologies, such as non-aneurysmal SAH, arteriovenous malIormation, unspeciIic
stroke or likely also brain injuries. It is recommended that spontaneous ICH and aneurysmal SAH should not
be combined in epidemiological and clinical studies because these hemorrhages have diIIerent risk Iactors as
well as age and sex distributions |4|.
This review deals with spontaneous ICH and aneurysmal SAH the two most common and severe Iorms oI
hemorrhagic stroke in regard to the modiIiable risk Iactors commonly associated with hemorrhagic stroke
and recovery aIter bleeding including alcohol
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consumption and other health-related habits, previous diseases, and use oI antithrombotic and other medicines.
SUBARACHNOID HEMORRHAGE
Prevalence of intracranial aneurysms
Intracranial aneurysms in the general population have been studied mostly in autopsy series. Depending on
whether the aneurysms were sought or merely noted as incidental Iindings, prevalence appears to be 25
(range 0.29) |2527 |. More than halI oI these aneurysms were unruptured beIore death. On the other hand,
aneurysm size is at least 3060 greater beIore death than its size measured aIter death beIore Iixation |28|.
The prevalence oI small aneurysms may thus be greater than reported in autopsy series.
Reported Irequencies oI unruptured aneurysms in angiographic series range Irom 1.16.5 |26,27,29|. The
variance in prevalence has been explained by the age distributions oI the diIIerent series as well as by racial
diIIerences |25,26|. Incidence oI multiple aneurysms depends primarily on completeness oI diagnostic
procedures and can be estimated at about 30 |30,31|. Small aneurysms, which cannot be seen in
angiography, may also be observed during surgery.
Aneurysms seem to be acquired degenerative lesions as a result oI hemodynamic stress, but may sometimes be
Iamilial (c. 10 oI cases) or associated with connective tissue diseases |25,27,32|. Many Iactors may increase
the risk oI aneurysm Iormation or subarachnoid hemorrhage, mainly through unknown mechanisms. These
include hypertension, atherosclerosis, Iemale sex, aging, cigarette smoking, alcohol consumption, use oI oral
contraceptives, arterial deIiciency in collagen Type III, asymmetry oI the Circle oI Willis, cerebral
arteriovenous malIormations, viral inIections, pituitary tumors, and certain HLA-associated Iactors
|4,16,17,19,25,32,33|. Although age, sex, and hypertension may be risk Iactors Ior aneurysm Iormation, their
association with rupture oI the aneurysm itselI is unlikely |3437|.
Incidence of subarachnoid hemorrhage
Incidence oI SAH varies widely throughout the world, but 10/100,000/year is the generally accepted estimate
Ior western countries |3,25,38|, with the highest incidence rates (~13/ 100,000/year) Ior Finland and Japan
|7,25,26,39|. During last decades, the incidence oI SAH has declined somewhat |7,38,39|, which is mostly
explained by a greater proportion oI patients investigated with computerized tomography (CT) scan. However,
at least part oI this decline can be explained by a well-known decrease oI cigarette smoking and perhaps by
improved treatment oI hypertension.
Aneurysms develop during adulthood, risk Ior SAH increasing linearly with age |3,7,25,40|. Subarachnoid
hemorrhage also is the most common Iorm oI stroke and cause oI stroke mortality among young adults |40|.
Although the incidence oI SAH has been higher in women than in men overall |7,25,39|, its incidence among
young adults has been higher in men |7,17,25,40|. Proneness to SAH among young men might be partly
contributed by their heavier drinking and smoking habits |17|. In recent studies, the Iemale-to-male ratio has
been approximately one also among young adults |41|. This may be due to increased smoking among young
women.
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Since Iemale preponderance Ior SAH is not signiIicant until the IiIth decade |7,25,41|, the overrepresentation
oI their aneurysm Iormation is thought to be secondary to hormonal Iactors |41|; it has been presumed that
estrogen has an inhibitory eIIect on aneurysm Iormation; cigarette smoking also has antiestrogenic properties.
The collagen content oI cerebral arteries may also diminish aIter menopause, Iavoring aneurysm Iormation
|41|.
Risk factors for subarachnoid hemorrhage
Indisputable independent modiIiable risk Iactors Ior SAH seems to be only cigarette smoking, alcohol
consumption, and to a lesser extent, hypertension |4,16,17,19,33|. Risk Iactors may also diIIer according to
race and age, with young adults having risk Iactors diIIerent Irom those oI elderly people |17|.
Cigarette smoking is an independent and the most important risk Iactor Ior SAH, which has already been
proved in several cohort and case-control studies |4,1619,33,42,43|. In North America and Europe, the
prevalence oI smoking in SAH patients ranges Irom 4575, whereas in the general adult population it is only
2035. Men and younger age groups smoke more than others both in SAH patients and in general
populations |17,43|. Although cigarette smoking is decreasing in western countries, incidence oI SAH does
not necessarily change because oI improved diagnostic methods and aging oI populations. OI SAH cases, 38
48 can be attributed to cigarette smoking |16,17,42|. Smoking is also associated more strongly with SAH
than with other Iorms oI stroke |19|.
It is also well known that heavy smokers start smoking at an earlier age, have smoked longer, and have more
rarely ceased smoking than those who smoke only occasionally or less than 20 cigarettes per day |4446|. In
agreement with this, patients with SAH are more oIten heavy smokers |16,17|, had smoked longer |17|, and
had ceased smoking less oIten |17| than controls. In addition, cigarette smoking increases the risk Ior SAH in
a doseresponse manner |16,17,19|, but the mechanism by which smoking increases the risk has remained
unknown.
Blood-pressure values are generally lower in smokers than in nonsmokers |19|, but smoking a cigarette causes
an acute increase in blood pressure Ior approximately three hours |16|. Transient increase in blood pressure
caused by smoking may cause rupture oI an aneurysm. It is also possible that long-lasting smoking can cause
aneurysm Iormation and growth by weakening the walls oI cerebral arteries. This can happen, Ior example, iI
increased amounts oI proteolytic enzymes are released into the systemic circulation by smoking |4,17|. This
concept is supported by some reports suggesting that Iormer smokers also have an increased risk, which is,
however, lower than that oI current smokers |16,19|.
DiIIerences between SAH patients either with a single aneurysm or with multiple aneurysms can also be risk
Iactors Ior aneurysm Iormation, since the presence oI multiple aneurysms does not seem to increase the risk
Ior rupture oI an aneurysm |34,35,37|. The risk Iactors Ior aneurysm Iormation may only be more augmented
in the patients with multiple aneurysms. OI several potential risk Iactors Ior multiple intracranial aneurysms,
only two studies have used multivariate statistics to reveal independent risk Iactors |30,31|. Cigarette smoking
|30,31|, Iemale sex |30,31|, and possibly also age |31|, but not hypertension, were independent risk Iactors Ior
multiple intracranial aneurysms and thus possibly also Ior aneurysm Iormation. The theory that cigarette
smoking causes Iormation oI aneurysms through atherosclerosis is unlikely because atherosclerosis-promoting
Iactors such as hypertension, and diabetes, as well as cardiovascular and ischemic cerebrovascular diseases, do
not correlate with multiple aneurysms |30,31|.
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AIter diagnosis oI an unruptured aneurysm, size oI aneurysm |34,35,37,47|, and possibly age inversely
|35,36,47| and cigarette smoking |47| are independent predictors Ior subsequent aneurysm rupture. Cigarette
smoking also seems to be the most important independent risk Iactor Ior subsequent rupture oI an unruptured
aneurysm, irrespective oI aneurysm size, oI gender, and oI age oI the patient at diagnosis |47|. The relative
risk oI cigarette smoking, tested as a time-dependent covariate in the Cox model, increased iI the patient
continued smoking during Iollow-up |47|.
In a recent study, cigarette smoking and Iemale gender were only signiIicant independent Iactors aIIecting
both aneurysm Iormation and growth (Juvela et al. Stroke 2001; 32: 485491). Women in particular were at
high risk Ior aneurysm Iormation, and cigarette smoking hastened aneurysm growth. These Iindings are
important since aneurysms grow beIore the rupture |35|. The Iaster the growth, the more likely is rupture.
Cigarette smokers` serum elastase/alpha-1-antitrypsin imbalance (i.e., increased elastase activity and/or
decreased alpha-1-antitrypsin activity) may contribute either to aneurysm Iormation or to SAH |48,49|.
Cigarette smoking has also been shown to increase elastase activity in the wall oI the rabbit aorta |50|. Perhaps
the strongest evidence is that topical application oI elastase (but oI neither collagenase nor papaverine)
experimentally to the artery wall has caused saccular aneurysm Iormation, growth, and even rupture |51|.
Thus, it is quite probable that regular cigarette smoking increases elastase activity in the artery wall, and this,
together with hemodynamic stress, can cause aneurysm Iormation and even hastens aneurysm growth, leading
to rupture.
The role oI alcohol as a risk Iactor Ior SAH has not been as well established as smoking. Several cohort and
case-control studies have shown that alcohol consumption increases independently oI cigarette smoking,
age, and history oI hypertension risk Ior both ICH |4,814| and SAH |11,1517,52|, even in women
|13,14,17,52|. In two studies |9,13|, alcohol consumption was associated with a signiIicantly increased risk Ior
ICH but not with an increased risk Ior SAH, while in another study |15| the situation was opposite. Long-term
heavy alcohol intake and problem drinking also are more inIrequent in SAH patients than in ICH patients |4|.
Approximately 13 oI subarachnoid hemorrhages could be attributed to recent heavy drinking |17|.
The risk Ior SAH seems to be increased when average alcohol intake is more than 150 g within a week,
obtained with use oI interview |11,1517,52|. Intake oI alcohol more than 40 g at a time increases the risk Ior
SAH during subsequent 24 hours |17|. Above these limits, alcohol intake increases risk Ior SAH in a linear
doseresponse manner, and especially binge drinking is more risky than intake oI corresponding amount oI
alcohol within a longer time period |16,17|. According to case-control studies |16,17|, those with a lower
alcohol intake than 150 g within a week do not seem to have an increased risk Ior SAH but cohort studies
suggest that they have |15,52|. AIter adjustment Ior cigarette smoking, the association oI heavy alcohol intake
with risk Ior SAH has not been shown to be signiIicant both by use oI laboratory markers oI alcohol intake and
by interview with CAGE questionnaire which relates not merely to amount oI alcohol consumed but also to
abnormal drinking behavior (e.g., drinking on waking) and alcohol-induced problems |17|. Use oI these
parameters oI alcohol intake also show that current and Iormer heavy drinking as well as problem drinking are
more common in ICH patients than in SAH patients |4,14,17|. Thus, it seems that moderate or high amount oI
alcohol intake has a relative short-time harmIul eIIect on risk Ior SAH.
In a recent study, alcohol consumption was not an independent risk Iactor Ior aneurysm growth or Iormation
(Juvela et al. Stroke 2001; 32: 485491). It was not even a signiIicant
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risk Iactor in univariate analysis, except Ior a correlation between number oI positive CAGE responses and
aneurysm growth rate, although alcohol consumption is known to correlate with smoking |4,16,17|. Alcohol
consumption is also not an independent risk Iactor Ior multiple aneurysms |30,31|. Thus, it is quite likely that
alcohol intake does not cause aneurysm Iormation.
Blood pressure is raised independently by age, body mass index, pulse rate, amount oI regular alcohol use, and
sodium intake |5357|. Daily drinking oI alcohol results in a dose-dependent gradual elevation oI blood
pressure within a Iew days to weeks |54,55|. AIter cessation oI drinking blood pressure is normalized.
Although short-term occasional drinking may not consistently elevate blood pressure, it has been reported that,
in normotensive subjects, acute consumption oI alcohol can transiently raise both systolic and diastolic blood
pressure |58,59|. The maximum response occurs at peak blood alcohol concentration. A reactive Iorm oI
hypertension associated with increased catecholamines and vascular hyperresponsiveness is a well-known
eIIect during alcohol withdrawal |60|. In social drinkers, binge drinking causes a transient increase in blood
pressure and pulse rate only during intoxication, since blood pressure values, but not pulse rate, are even
decreased aIter drinking and are normalized during hangover |59|. In heavy drinkers, a high variability oI
alcohol consumption (episodic drinking) seems to increase blood pressure values more than a low variability
oI alcohol intake |57|.
Blood-pressure levels, which are transiently increased during alcohol intake and withdrawal, may prove to be
an important mechanism Ior SAH |4,16,17|; such a transient increase in systemic blood pressure, together with
cerebral arteriolar vasoconstriction during alcohol exposure |61|, may contribute to rupture oI an existing
aneurysm without causing Iormation oI an aneurysm. Use oI illicit drugs amphetamines and cocaine may
increase risk Ior SAH by this same mechanism |11,16|, since presence oI multiple aneurysms does not
correlate with the use oI such drugs |30|.
History oI hypertension as a risk Iactor Ior SAH seems to be less crucial than Ior other stroke subtypes
|4,16,17,25,42|. The prevalence oI hypertension among SAH patients (2030) has been suggested to be only
slightly higher than in the general population; aIter adjustment Ior age, gender, cigarette smoking, and alcohol
consumption, history oI hyper-tension has not been shown in case-control studies to increase risk Ior SAH
|16,17|. Smoking and alcohol consumption have thus been considered to increase risk Ior SAH by
mechanisms other than chronic hypertension; hypertension does not even seem to increase risk Ior aneurysm
rupture |34,35,37,47|. In a recent study, patients with hypertension did not have de novo aneurysms or
aneurysm growth more oIten than did the non-hypertensive, nor did BP values correlate with aneurysm
Iormation or growth (Juvela et al. Stroke 2001; 32: 485491).
Recently, patients oI working age with hypertension also had more aneurysms than did the normotensive,
although prevalence oI multiple aneurysms has not been higher overall in hypertensive patients |31|.
ThereIore, patients with hypertension who are subject to intracranial aneurysm Iormation may more Irequently
have more than two aneurysms. The association oI hypertension with SAH could be due to study populations
including ICH patients been used in SAH studies |11,18,32,33|. This inclusion was possible especially in
studies perIormed beIore the CT era, and occurred because ICH is the more common type oI stroke in most
populations |2,3,7|.
Recently, Iamily history oI intracranial aneurysms has been suggested to be evidence Ior genetic causality oI
cerebral aneurysms |27,62|. However, cigarette smoking and other health-related habits should be analyzed as
a conIounding Iactor Ior this association since
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correlation oI these habits between Iamily members is higher than in the general population |62,63|. In
addition, 3848 oI subarachnoid hemorrhages can be attributed to current smoking |16,17,42|, whereas risk
attributable to aIIected Iirst-degree relatives accounts Ior only 5 |62|. Furthermore smoking and alcohol-
intake behaviors may even to some degree be inIluenced by genetic Iactors |63|, although tobacco-associated
premature death Irom lung cancer and cardiovascular diseases does not seem to be inIluenced by genetic or
Iamilial predisposition |64|.
Risk factors for poor outcome after subarachnoid hemorrhage
The outcome aIter aneurysmal SAH is determined by the severity oI bleeding assessed by the clinical
condition and amount oI subarachnoid, intracerebral, and intraventricular blood on the CT scan, as well as by
the occurrence oI rebleeding or delayed cerebral ischemia (symptomatic vasospasm) |6,6568|. Advanced age
seems to impair outcome independently oI Iactors mentioned above |67|.
The risk oI delayed cerebral ischemia is best predicted by the amount oI subarachnoid and intraventricular
blood amount |65,66,68|, as well as by previous hypertension |66,68|, irrespective oI clinical condition on
admission or hydrocephalus. Cigarette smoking has also been shown to increase the risk oI symptomatic
vasospasm |43| and oI cerebral inIarction aIter SAH |68|.
Alcohol consumption seems not to increase the risk oI death due to primary bleed although heavy drinking
may increase mortality and morbidity because oI severe rebleeding and delayed cerebral ischemia aIter SAH
|6|. Poor outcome in heavy drinkers is caused mainly by an increase in mortality and morbidity due to
rebleeding and delayed ischemia although Irequency and time oI onset oI rebleeding and delayed ischemia are
not aIIected by drinking habits |6|.
There can be several mechanisms by which heavy drinking and ethanol withdrawal can predispose to a severe
rebleeding or symptomatic vasospasm aIter SAH. These include the eIIects on blood pressure, platelet
Iunction, clotting Iactors, alcohol-induced cardiac arrhythmias, and changes in cerebral blood Ilow |6,10,54
60,69|. Long term severe heavy drinking can cause thrombocytopenia, reduced platelet aggregability and
thromboxane Iormation capacity, increase in prostacyclin production in the endothelium, and deIects oI
clotting Iactors |6,10|. In addition, cerebral autoregulation is impaired aIter SAH leading to an increase in
cerebral blood Ilow iI blood pressure is elevated |25|. Increase in blood pressure, together with cerebral
arteriolar vasoconstriction during alcohol exposure |61|, may increase blood pressure in large cerebral arteries.
All these Iactors together could explain the severity oI rebleeding and presence oI intracerebral hematoma in
heavy drinkers. Cessation oI alcohol abuse results in rebound thrombocytosis and increased thromboxane
Iormation by platelets within two weeks thus Iavoring thrombosis Iormation and severe delayed cerebral
ischemia |6,69|.
INTRACEREBRAL HEMORRHAGE
Incidence of intracerebral hemorrhage
Incidence oI spontaneous ICH also varies widely throughout the world being most common in Asia, but 15
30/100,000/year is the generally accepted estimate Ior western countries
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|2,3,39,70|. Although incidence oI ICH is higher than that oI SAH, the incidence oI SAH is higher in people
aged 60 or less, especially in Finland |2,7|. The incidence oI SAH increases linearly by age |3,7|, while that oI
ICH increases exponentially |2,3|. ICH also is clearly more common among men than among women.
Risk factors for intracerebral hemorrhage
Most spontaneous hematomas are attributed to chronic arterial hypertension |14,8,12,14|. Other risk Iactors
Ior ICH include alcohol consumption |4,814|, anticoagulant treatment |3,4,14,21|, and to a lesser extent,
aspirin use |14,22|, thrombolytic therapy |3,23|, use oI amphetamines or cocaine |3,11|, and possibly also
diabetes mellitus |4|. These Iactors increase risk Ior ICH especially in young and middle-aged adult people,
whereas amyloid angiopathy is an important cause oI ICH in the older age groups. Cigarette smoking, which is
the most important risk Iactor Ior SAH, seems not to increase independently oI hypertension and alcohol
consumption the risk Ior ICH, although its prevalence may be higher among ICH patients than in the general
population |8,12,14,19,20|. Thus, ICH seems, contrary to SAH, to have a multiIactorial pathogenesis.
History oI hypertension as a risk Iactor Ior ICH is well known |14,8,12,14,20,70|. Its occurrence among ICH
patients varies Irom 4570, whereas the prevalence oI hypertension in the general adult population is about
20. The risk is even substantially higher among those who have ceased their antihypertensive therapy
|14,70|. Approximately 20 oI ICH patients had not used the hypertensive medicines, which were prescribed
to them beIore hemorrhage or these were stopped by a physician within Iew weeks to months beIore ICH |14|.
The mechanism is thought to involve a hypertension-induced degeneration oI the walls oI small arteries
(lipohyalinosis and Iibrinoid necrosis or microaneurysm) that leaves them prone to rupture. Both insulin-
dependent and non-insulin-dependent diabetes mellitus has been suggested, independently oI chronic
hypertension and other risk Iactors, to increase risk Ior ICH partly by this same mechanism: vasculopathy oI
perIorating cerebral arteries, the walls oI which are weakened by lipid and hyaline material (lipohyalinosis and
Iibrinoid necrosis), microaneurysm, and/or microangiopathy |4|.
Several studies have shown that alcohol consumption increases the risk Ior ICH in a dose response manner
independent oI chronic hypertension |4,814| even in women |13,14|. Evidence Ior this has been obtained
using diIIerent interview methods and laboratory markers oI alcohol intake |14|. Alcohol intake seems to be
more common among patients with spontaneous ICH than among those oI a similar age with aneurysmal SAH
|4,9,13|. The amount oI alcohol used within the previous 24 hours seems to be similar in both hemorrhage
types |4|. However, recent heavy drinking (~300 grams) within the previous week as well as problem drinking
are more common in male ICH patients than in male SAH patients independent oI their history oI
hypertension |4|. When the risk Ior SAH seems to be increased when average alcohol intake is more than 150
g within a week, risk Ior ICH seems to be increased already at lower levels oI alcohol intake |4,11,14,17|.
Average alcohol intake oI 100 g within a week |71| or oI less than 40 g at a time |14| seems to not increase
the risk.
This alcohol-associated risk Ior ICH is oI relative short duration. This theory is supported by the observation
that recent drinking, within 24 hours oI ICH, was more important as a risk Iactor than the amount oI alcohol
consumed within 1 week, and that previous drinking was not a risk Iactor |14|. The association oI recent
drinking and ICH is not inIluenced by
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sex, age, body mass index, smoking status, hypertension or other previous diseases, or by use oI nonsteroidal
anti-inIlammatory drugs or anticoagulants |14|.
The pathophysiologic mechanisms by which alcohol could contribute to ICH include hypertension |5460|,
impaired hemostasis |69,72,73|, decreased circulating levels oI clotting Iactors produced by the liver |72,74|,
excessive Iibrinolysis |75|, disseminated intravascular coagulation |10|, and changes in cerebral blood Ilow
|76|. Because even anticoagulant treatment with a low- or moderate-intensity warIarin regimen seems not to
increase the risk oI intracranial bleeding |77|, and the prevalence oI thrombocytopenia as a cause oI ICH
seems to be uncommon |14|, liver dysIunction or thrombocytopenia must be severe iI bleeding or clotting
disorders can be considered as the sole cause oI ICH. Clotting and bleeding disorders together with alcohol-
induced transient elevation oI blood pressure |5860| and plasminogen activator activity |75| could increase
the risk oI ICH |14|.
It is unlikely that chronic hypertension is the mechanism by which alcohol consumption increases the risk Ior
ICH, because the alcohol-associated risk has remained signiIicant aIter adjustment Ior hypertension
|8,9,12,13,14|. On the other hand, the transient increase in blood pressure during alcohol intake and
withdrawal may prove to be an important mechanism |14|. Such a transient increase in systemic blood
pressure |5860| together with cerebral arteriolar vasoconstriction |61| during alcohol exposure might
contribute to rupture oI small cerebral arteries. Since alcohol intake is more abundant in ICH patients than in
SAH patients |4,9,13|, it is possible that alcohol may increase the risk oI ICH also by other mechanisms than
only by a transient elevation oI blood pressure. Use oI illicit drugs amphetamines and cocaine may increase
risk Ior SAH by this same mechanism. During as well as aIter alcohol or drug intake, cerebral autoregulation,
especially in patients with hypertensive cardiovascular disease, may be altered leading to arteriolar dilatation
and increased cerebral blood Ilow even at moderately increased blood pressure levels. This may result in
vascular rupture(s) |11,76,78 |. Illicit drugs may also cause ICH by abrupt increase in blood pressure and by
vasculitis |14|.
Anticoagulant treatment has been shown to be a risk Iactor Ior ICH causing a low per cent oI cases
|4,14,21,77|. Intracranial bleeding caused by anticoagulant is more common in the elderly because they are
treated more oIten by anticoagulants. Risk oI hemorrhage is also directly associated with intensity oI
anticoagulation. Bleeding that occurs when the international normalized ratio (INR) is 3.0 is uncommon and
Irequently associated with an obvious underlying disease |14,77|.
Use oI aspirin or other nonsteroidal anti-inIlammatory drugs (NSAIDs) seems to increase somewhat risk Ior
ICH |14|. According to a meta-analysis oI aspirin trials |22|, although aspirin increases slightly (1.5-Iold) but
signiIicantly (p 0.05) the risk oI hemorrhagic stroke, which type oI hemorrhage it increases remained
unknown. It is likely that aspirin increases only the risk oI ICH, since most oI those SAH patients who had
used NSAIDs beIore hemorrhage had used those agents Ior symptoms consistent with minor leakage, which
have been suggested occurring in approximately 2030 oI SAH cases |4,5|.
The risk oI ICH associated with the use oI thrombolytic agents has been shown to be low aIter myocardial
inIarction. This low risk may be increased somewhat by use oI anticoagulants and among elderly people |23|.
Thrombocytopenia as a cause oI ICH also is uncommon |2,3,14|. These observations suggest that liver
dysIunction or hemostatic disorders must be severe iI bleeding or clotting disorders can be considered as the
sole cause oI ICH.
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Risk factors for poor outcome after intracerebral hemorrhage
The short-term outcome (30-day mortality) aIter ICH is determined independently by the severity oI bleeding
as assessed by the initial level oI consciousness, the volume oI hematoma and the presence oI intraventricular
blood |7984|; and the long-term Iunctional outcome also depends on location oI the hematoma, the age oI
patient, and the amount oI alcohol consumed within one week beIore ICH |81,83,84|. Hematomas, which are
outside the basal ganglia and brain stem are associated independently oI other Iactors with a better prognosis
than the central hematomas |84|.
Patients with a subcortical or cerebellar hematoma at least 3 cm in diameter and impaired consciousness are
generally considered to beneIit Irom surgical removal oI clot, which reduces both mortality and morbidity
|1,84|. Patients with the most common intracerebral hematomas, which are located in the putamen are not
generally accepted as candidates Ior surgery. Although surgery may reduce mortality oI stuporous or semi-
comatose patients it seems to leave these patients severely disabled |1,84,85|.
Alcohol intake is not associated with case Iatality due to initial bleeding but it is associated with long-term
outcome |84|. Poor outcome, as well as overall outcome, are directly associated with the amount oI alcohol
used within the last week beIore ICH as well as with a laboratory marker oI alcohol intake, erythrocyte mean
corpuscular volume (MCV), suggesting that both recent drinking and long-term heavy alcohol intake impair
outcome. At no level oI alcohol intake is the outcome better in users than in abstainers |84|.
Although alcohol intake and MCV were associated with variables predicting a Iavorable outcome (better
clinical condition, younger patient age, superIicial location oI hematoma), they are also associated directly but
non-signiIicantly with volume oI hematoma, especially MCV |84|. A possible reason Ior this is that patients
who are long-term heavy drinkers have cerebral atrophy |86|, rendering it possible that the hematoma must
enlarge more in them than in those with less alcohol intake to produce similar symptoms. This might later
cause more cerebral edema in heavy drinkers than expected on the basis oI clinical condition owing to both the
size oI hematoma and the cytotoxic metabolites released Irom it |87|.
Enlargement oI the hematoma or rebleeding, which impairs clearly the outcome, occurs in 1020 oI patients
when the initial CT scan is perIormed within 46 hours Irom the onset |84,85,88|. Enlargement oI hematoma
seems to be associated with initial volume oI hematoma, time period between the onset oI symptoms and Iirst
CT scan (inversely), heavy alcohol drinking, low level oI Iibrinogen, and elevated MCV |84,88|.
Presence oI cerebral atrophy or hematoma enlargement because oI liver dysIunction could, however, not
explain why patients with light or moderate recent alcohol intake have an increased risk oI impaired outcome.
CAGE positiveness (problem drinking), and heavy drinking were not important determinants oI outcome aIter
exclusion oI amount oI recent alcohol intake Irom the logistic models |84|. Cerebral atrophy as well as liver
dysIunction seem to be reversible, which could in part explain why previous heavy drinking does not seem to
impair outcome |84,86|.
Pathophysiologic mechanisms by which alcohol could contribute to impaired outcome include also the same
Iactors that increase risk Ior ICH: (transient) hypertension |5460|, impaired hemostasis |69,72,73|, decreased
circulating levels oI clotting Iactors produced by the liver |72,74|, excessive Iibrinolysis |75|, disseminated
intravascular coagulation |10|, and changes in cerebral blood Ilow |76|. Transient increase in blood pressure
|5860|
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together with cerebral arteriolar vasoconstriction during alcohol exposure |61|, and/or impaired hemostasis
could cause additional ruptures oI small cerebral arteries causing enlargement oI hematoma.
CONCLUSIONS
Cigarette smoking, alcohol consumption, and hypertension are important modiIiable risk Iactors Ior
hemorrhagic stroke and impaired outcome aIter the bleeding. Cigarette smoking and moderate to heavy
alcohol consumption increase risk Ior SAH. Hypertension and alcohol consumption are risk Iactors Ior
spontaneous ICH. Cigarette smoking may impair somewhat the outcome aIter SAH but alcohol consumption
impairs Iunctional recovery both aIter SAH and aIter ICH. Thus, cessation oI smoking and avoiding heavy
alcohol drinking, in particular binge drinking, are important Iactors to reduce incidence and partly also
impaired outcome oI these severe Iorms oI hemorrhagic stroke.
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66 hman J, Servo A, Heiskanen O. Risk Iactors Ior cerebral inIarction in good-grade patients aIter
aneurysmal subarachnoid hemorrhage and surgery: a prospective study. J. Neurosurg. 1991; 74: 1420.
67 Lanzino G, Kassell NF, Germanson TP, Kongable GL, Truskowski LL, Torner JC, Jane JA, the
Participants. Age and outcome aIter aneurysmal subarachnoid hemorrhage: why do older patients Iare
worse? J. Neurosurg. 1996; 85: 410418.
68 Juvela S. Plasma endothelin concentrations aIter aneurysmal subarachnoid hemorrhage. J. Neurosurg.
2000; 92: 390400.
69 Haselager EM, Vreeken J. Rebound thrombocytosis aIter alcohol abuse: A possible Iactor in the
pathogenesis oI thromboembolic disease. Lancet 1977; i: 774775.
70 ThriIt AG, McNeil JJ, Forbes A, Donnan GA. Three important subgroups oI hypertensive persons at
greater risk oI intracerebral hemorrhage. Hvpertension 1998; 31: 12231229.
71 Berger K, Ajani UA, Kase CS, Gaziano JM, Buring JE, Glynn RJ, Hennekens CH. Light-to-moderate
alcohol consumption and the risk oI stroke among U.S. male physicians. N. Engl. J. Med. 1999; 341: 1557
1564.
72 Ragni MV, Lewis JH, Spero JA, Hasiba U. Bleeding and coagulation abnormalities in alcoholic
cirrhotic liver disease. Alcoholism Clin. Exp. Res. 1982; 6: 267274.
73 Hillbom M, Neiman J. Platelet thromboxane Iormation capacity aIter ethanol withdrawal in chronic
alcoholics. Haemostasis 1988; 18: 170178.
74 Niizuma H, Suzuki J, Yonemitsu T, Otsuki T. Spontaneous intracerebral hemorrhage and liver
dysIunction. Stroke 1988; 19: 852856.
75 Hendriks HFJ, Veenstra J, Velhuis-te Wierik EJM, SchaaIsma G, KluIt C. EIIect oI moderate dose oI
alcohol with evening meal on Iibrinolytic Iactors. BMJ 1994; 308: 10031006.
76 Berglund M, Risberg J. Regional cerebral blood Ilow during alcohol withdrawal. Arch. Gen. Psvchiatrv
1981; 38: 351355.
77 Hirsh J. Oral anticoagulant drugs. N. Engl. J. Med. 1991; 324: 18651875.
78 Kibayashi K, Mastri AR, Hirsch CS. Cocaine induced intracerebral hemorrhage: analysis oI
predisposing Iactors and mechanism causing hemorrhagic strokes. Hum. Pathol. 1995; 26: 659663.
79 Portenoy RK, Lipton RB, Berger AR, Lesser ML, Lantos G. Intracerebral haemorrhage: a model Ior
prediction oI outcome. J. Neurol. Neurosurg. Psvchiatrv 1987; 50: 976979.
80 Tuhrim S, Dambrosia JM, Price TR, Mohr JP, WolI PA, Hier DB, Kase CS. Intracerebral hemorrhage:
external validation and extension oI a model Ior prediction oI 30-day survival. Ann. Neurol. 1991; 29: 658
663.
81 Franke CL, van Swieten JC, Algra A, van Gijn J. Prognostic Iactors in patients with intracerebral
haematoma. J. Neurol. Neurosurg. Psvchiatrv 1992; 55: 653657.
82 Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume oI intracerebral hemorrhage: A
powerIul and easy-to-use predictor oI 30-day mortality. Stroke 1993; 24: 987993.
83 Daverat P, Castel JP, Dartigues JF, Orgogozo JM. Death and Iunctional outcome aIter spontaneous
intracerebral hemorrhage: a prospective study oI 166 cases using multivariate analysis. Stroke 1991; 22: 1
6.
84 Juvela S. Risk Iactors Ior impaired outcome aIter spontaneous intracerebral hemorrhage. Arch. Neurol.
1995; 52: 11931200.
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85 Fujitsu K, Muramoto M, Ikeda Y, Inada Y, Kim I, Kuwabara T. Indications Ior surgical treatment oI
putaminal hemorrhage. Comparative study based on serial CT and time-course analysis. J. Neurosurg.
1990; 73: 518525.
86 Charness ME, Simon RP, Greenberg DA. Ethanol and the nervous system. N. Engl. J. Med. 1989; 321:
442454.
87 Yang G-Y, Betz L, Chenevert TL, Brunberg JA, HoII JT. Experimental intracerebral hemorrhage:
relationship between brain edema, blood Ilow, and blood-brain barrier permeability in rats. J. Neurosurg.
1994; 81: 93102.
88 Fujii Y, Takeuchi S, Sasaki O, Minakawa T, Tanaka R. Multivariate analysis oI predictors oI hematoma
enlargement in spontaneous intracerebral hemorrhage. Stroke 1998; 29: 11601166.
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Chapter 7
Alcohol abuse and ischemic stroke
Matti Hillbom
INTRODUCTION
Alcohol consumption has been reported to show a U-shaped |1|, J-shaped |2| or linear |3| association with the
incidence oI total stroke, including ischemic stroke. A J-shaped association has also been observed between
alcohol intake and blood pressure, the major risk Iactor Ior ischemic stroke |4|. It now seems to be generally
accepted that light-to-moderate drinking does not cause any cerebrovascular harm and may even protect
against atherothrombotic stroke. However, heavy drinking clearly increases the risk oI both ischemic and
hemorrhagic stroke.
Alcohol abuse is known to cause both hypertension and atrial Iibrillation. Alcohol abuse shows a rather high
(530) estimated prevalence in the western industrialized countries, but only a modest increasing eIIect on
the risk oI ischemic stroke compared to hypertension and atrial Iibrillation |5|. The impact oI hypertension on
the incidence oI stroke is much greater than that oI alcohol |6,7|. The population-attributable risk Ior stroke
caused by hypertension has been estimated to be ten-Iold compared to that caused by heavy alcohol
consumption |7|. However, alcohol remains among the many risk Iactors oI ischemic stroke.
DiIIerent drinking habits certainly contribute to the diversity oI observations. For example, alcohol seems to
carry a much higher risk Ior deep cerebral inIarct (lacunar stroke) in Spain than in Finland |8,9|. Regular daily
drinking is much more common in the Mediterranian countries than in Scandinavia. However, the
Scandinavian pattern oI heavy binge drinking may be more hazardous Ior some other types oI ischemic stroke.
The aim oI the present chapter is to discuss the relationship between heavy drinking and several subtypes oI
ischemic stroke with particular reIerence to the drinking pattern. The nature oI the relationship will be
highlighted with case histories whenever possible. At the end oI the chapter, the possible protective eIIect oI
light alcohol drinking will also be discussed.
CARDIOGENIC BRAIN EMBOLISM
Stroke admission rates have been observed to be high among heavy drinkers |10|. Some studies also suggest
that alcohol abuse may associate with ischemic stroke recurrence |11,12|. A study on recent alcohol intake
showed that heavy drinking is an independent risk Iactor Ior most subtypes oI ischemic stroke and particularly
a risk Iactor Ior cardiogenic brain embolism |13|.
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Table 7.1 Previously published and new case histories illustrating several diIIerent mechanisms that could
link alcohol abuse to an increased risk oI ischemic brain inIarct
Cases [reference] Number of cases Tvpe of stroke Mechanism or underlving disease Drinking pattern
|14|* 1 Cardioembolic Alcoholic cardiomyopathy Regular
|18|* 1 Cardioembolic Atrial Iibrillation Binge
|19|* 1 Cardioembolic Atrial Ilutter Binge
Case 1 1 Cardioembolic Atrioventricular block Binge
Case 2 1 Cardioembolic Myocardial inIarct Binge
Case 3 1 Cardioembolic LeIt atrial thrombus Regular
Case 4 1 Cardioembolic Myocardial inIarct Regular
|22|* 1 Paradoxical Atrial septal deIect Regular
Case 5 1 Paradoxical Patent Ioramen ovale Binge
Case 6 1 Paradoxical Patent Ioramen ovale Binge
|23|* 1 Undetermined Rebound thrombocytosis Regular
Case 7 1 Tandem embolism Large-artery disease Binge
Case 8 1 Lacunar inIarct Small-vessel occlusion Regular
|37|* 1 Dissection Hypertension Binge
|22|* 1 Dissection Neck trauma Binge
|38|* 3 Dissection? Alcoholic stupor Binge?
|39|* 1 Dissection Vertebral occlusion Binge
|40|* 1 Compression Alcoholic coma Binge?
Case 9 1 Dissection Neck compression Binge
|41|* 2 Cryptogenic Unknown Binge
|42|* 1 Cryptogenic Unknown Binge
* See reIerence Ior details oI the cases. In case 23 investigations to detect cardiac and vascular abnormalities were not
perIormed.
The association between alcohol abuse with cardiogenic brain embolism suggests several mechanisms via
which heavy drinking could precipitate brain inIarct. First, there is the possibility oI alcoholic heart muscle
disease. Excessive chronic alcohol consumption leads to dilated cardiomyopathy, which oIten results in heart
Iailure. In some countries, alcohol is the identiIiable cause oI chronic heart Iailure in 23 oI cases.
Embolism to the brain is a Irequent complication oI the disease |14|. Although case histories are inIrequently
reported (Table 7.1), alcoholic patients with dilated cardiomyopathy are common. In Spain, where regular
daily alcohol intake is the prevailing drinking pattern oI heavy drinkers, alcoholic cardiomyopathy has been
observed in one-third oI both male and Iemale alcoholics |15|.
Atrial Iibrillation is certainly the commonest cause oI cardiogenic brain embolism, and about 0.4 oI the
population have atrial Iibrillation. The relative risk oI ischemic stroke in subjects with atrial Iibrillation is 5- to
7-Iold compared to subjects without this condition. Alcohol abuse has been estimated to account Ior a
substantial portion (30) oI the new-onset cases |16| and to precipitate atrial Iibrillation even in healthy
nonalcoholic subjects |17|. Alcohol-induced atrial Iibrillation |18| and atrial Ilutter |19| have been reported as
causes oI cardiogenic brain embolism in nonalcoholic young adults. These cases were young men with neither
cardiomyopathy nor coronary disease, and the strokes were precipitated by acute alcoholic intoxication.
Autopsy oI a patient who had two episodes oI embolic stroke, both precipitated by acute alcohol drinking, did
not show
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any cardiac abnormality |19|. These two cases illustrate that even occasional heavy drinking may precipitate
cardiac arrhythmias leading to stroke. The Iollowing case history conIirms that subjects prone to severe
cardiac arrhythmias should avoid drinking Ior intoxication.
Case 1
In June 1988, a 31-year-old nonsmoking man showed transient dysphasia shortly aIter having ingested several
glasses oI beer. Subsequent examinations suggested cardiogenic brain embolism. Computed tomography oI
the head showed a small leIt temporo-parietal brain inIarct. His heart was in a normal position, the leIt
ventricle was slightly enlarged (63/ 43 mm), and precordial echocardiography did not reveal any intracardiac
thrombi, but a 17-hour Holter monitoring revealed severe bradyarrhythmias (heart rate varying Irom 30 to 58
beats with several asystoles ~4 seconds), single ventricular extras and a third-degree atrioventricular block.
The diagnosis oI a congenital heart conduction deIect was made. The subject was put on continuous aspirin
treatment.
On the aIternoon oI October 4th 1991, while working, the subject suddenly developed right homonymous
quadrantanopia and dysphasia. He had been taking aspirin regularly, but on the preceding evening he had
ingested a large amount oI alcohol (180 g ethanol). The short CAGE questionnaire |20| suggested that he was
a problem drinker, and his serum gammaglutamyl transIerase was clearly above normal. His total alcohol
intake during the preceding week amounted to 450 grams oI ethanol. He was a nonsmoker and had no other
risk Iactors Ior stroke except the previously diagnosed congenital heart conduction deIect and alcohol abuse.
The examination revealed a new leIt parietal brain inIarct, but transesophageal echocardiography (TEE)
showed no pathological Iindings. The patient was put on continuous anticoagulant treatment and warned
against drinking alcohol.
Other conditions, such as post-inIarct abnormalities oI the leIt ventricle and hypertensive heart disease have
also been observed in subjects with alcoholic ischemic stroke. The Iollowing three case histories suggest that
patients with these conditions should be warned against heavy drinking.
Case 2
In August 1992, a 57-year-old nonsmoking man, while trying to sleep aIter having ingested a large amount oI
alcohol (120 grams ethanol), suddenly became unconscious Ior a short moment and simultaneously developed
leIt hemiparesis. On admission into the local hospital, a couple oI hours later, his blood ethanol concentration
was 40 mmol/L. Subsequent examinations revealed a large right hemispheric brain inIarct (a dense media sign
was visible in the Iirst CT oI the head) together with severe brain edema and herniation. The patient, who was
used taking a binge once a month, died three days later. Autopsy was not perIormed. According to the hospital
records, he had hypertension, coronary artery disease and a large anterolateral myocardial inIarct resulting into
inIero-posterior and antero-apical hypokinetic segments. The patient had also Iallen down, because oI his
intoxication a Iew hours beIore going to bed. ThereIore, a traumatic carotid arterial dissection could not be
excluded, but cardiogenic brain embolism was also possible.
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Case 3
In April 1994, a 60-year-old nonsmoking man who had diabetes and untreated hypertension, but who did not
use any medication, suddenly developed right hemiparesis and a visual Iield deIect several hours aIter getting
out oI bed in the morning. He was an episodic heavy drinker and had ingested a large amount oI alcohol on the
preceding evening (150 g ethanol). His usual weekly alcohol intake averaged 300 g oI ethanol. On admission,
he had atrial Iibrillation. During the preceding month, he had both an upper respiratory inIection and a
bacterial dental inIection, and two weeks beIore the index stroke he experienced symptoms suggestive oI a
transient ischemic attack. A computed tomography head scan showed a new leIt temporo-occipital brain
inIarct and an older leIt deep capsular inIarct. Duplex imaging oI the carotid and vertebral arteries did not
suggest any signiIicant stenoses, but TEE showed an enlarged leIt atrium with a moving appendicular
thrombus.
Case 4
In March 1990, a 42-year-old man known to be an episodic heavy drinker and regular smoker suddenly
developed a right visual Iield deIect caused by a leIt occipital brain inIarct. A Iew weeks prior to the index
stroke he had an anteroseptal and inIerior myocardial inIarct, and aIter discharge Irom hospital, he had started
to drink large amounts oI alcohol daily. In April 1995, he developed a right occipital brain inIarct. This
accident` was again preceded by a drinking bout oI about two weeks (900 g ethanol per week). On admission,
clinical examination showed tubular vision. A computed tomography head scan revealed two separate inIarcts
located on the leIt and right occipital lobes. Duplex imaging oI the carotid and vertebral arteries showed
neither occlusions nor signiIicant stenoses, but transthoracic echocardiography (TTE) showed leIt ventricular
inIerior and anteroapical hypokinetic segments without any thrombi. Three days aIter the onset oI the latter
stroke, the patient`s platelet count amounted to 604, suggesting rebound thrombocytosis due to the recent
cessation oI prolonged heavy alcohol drinking. This patient was later diagnosed Ior a clinically deIinite
mitochondrial disorder, but the presumed etiology oI his strokes was probable cardiogenic embolism |21|.
PARADOXICAL EMBOLISM
Paradoxical embolism has also been reported as an apparent cause oI a brain inIarct in a heavy drinker |22|.
Two Iurther cases oI possible paradoxical embolism triggered in connection with binge drinking are described
below.
Case 5
In July 1990, an obese 39-year-old man who was a smoker and inIrequent weekend drinker suddenly Ielt
severe headache and developed right hemiparesis together with right hemianopia shortly aIter getting up Irom
bed in the morning. He had been healthy and was not using any medication, although slightly elevated blood
pressure values had been measured. He had ingested a large amount oI alcohol (150 g ethanol) during the
preceding evening.
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On admission in the morning oI the stroke onset, his blood alcohol level was still 20 mmol/L. A computed
tomography head scan showed a leIt parietal subcortical brain inIarct. An arch angiogram revealed neither any
signiIicant stenoses nor other abnormalities in his arteries. TEE showed a slightly enlarged leIt atrium, no
thrombi, but a patent Ioramen ovale without any spontaneous right-to-leIt shunt. Venography showed a deep
venous thrombosis in his right leg.
Case 6
In March 1996, a 26-year-old healthy nonsmoking man who was an inIrequent weekend drinker woke up at 8
a.m., and three hours later, while jogging, suddenly developed a right visual Iield deIect. He had been drinking
alcohol during the preceding evening (alcohol intake amounted to 150 g oI ethanol), and had experienced
distinct signs and symptoms oI hangover and vomited that morning. An arch angiogram was normal, but TEE
showed a moderate-to-large patent Ioramen ovale, but not spontaneous right-to-leIt shunt. Venography was
not perIormed, but a hematologic examination revealed resistance to protein C (APC resistance, heterozygous
Ior the prothrombin gene).
The latter case suggests that paradoxical embolism could have been transported via a patent Ioramen ovale
during a Valsalva manouver precipitated by vomiting, a common consequence oI intoxication and hangover.
Thrombocytosis and associated platelet hyperactivity have been considered as contributing Iactors Ior alcohol-
induced ischemic strokes |22,23|. Case 4 and the case reported by Neiman |23| suggest a relationship between
alcohol-induced rebound thrombocytosis and the onset oI ischemic stroke. Although rebound thrombocytosis
coincided with the onset oI stroke in these cases, we still lack direct prooI oI a causal relation. Such Iactors as
rebound thrombocytosis, decreased Iibrinolytic activity, APC resistance, etc., could well be considered to
promote the development oI thrombi, but it has remained unclear whether any particular drinking pattern, such
as episodic heavy drinking, precipitates thrombus Iormation via these mechanisms.
LARGE-ARTERY ATHEROSCLEROSIS
It is generally thought that thromboembolic strokes are mainly caused by atherosclerotic disease.
Atherosclerotic disease is less prevalent among populations regularly consuming alcohol than among binge-
drinking populations. The high risk oI stroke in a population with a high alcohol intake does not seem to be
due to large-artery atherosclerosis |24|, but may be caused by other diseases promoting the onset oI stroke, i.
e., alcoholic cardiomyopathy. On the other hand, the age-adjusted relation between alcohol intake and carotid
artery atherosclerosis has been reported to be U-shaped, with light drinkers Iacing a lower atherosclerosis risk
than either abstainers or heavy drinkers |25|.
A strong positive relation between alcohol consumption and the risk oI mortality Irom stroke is apparent |26|.
In the Scandinavian countries, binge drinking has been observed to associate with both an increased risk Ior
ischemic stroke mortality |27| and the progression oI atherosclerosis |28|. It is thereIore not surprising that a
weak association has been observed even between large-artery atherosclerotic stroke and recent heavy
drinking |13|. An artery-to-artery embolism (tandem embolism) may easily be detached Irom an existing
thrombus attached to an atherosclerotic vessel wall because oI the abrupt increase in
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blood Ilow caused by acute alcoholic intoxication. The Iollowing case history suggests such a mechanism.
Case 7
In February 1996, a 66-year-old previously healthy, heavily smoking man suddenly developed dysphasia and
right hemiparesis while getting up Irom a couch in the aIternoon. He was an episodic drinker and had suIIered
Irom sleep apneas. He had been drinking since the preceding night, and the total amount oI alcohol ingested
during the index bout amounted to 150 g ethanol. On admission into hospital on the same evening, a computed
tomography head scan excluded the possibility oI hemorrhagic stroke, but did not show a leIt hemispheric
inIarct, either. His blood alcohol concentration was 30 mmol/L. He did not have atrial Iibrillation or any other
signs or symptoms oI cardiac disease (normal electrocardiogram), but an arch angiogram showed a major leIt
internal carotid arterial stenosis (80) with a rough atheromatous plaque. A diagnosis oI large-artery
atherosclerotic brain inIarct was made, and the patient was remitted Ior carotid endarterectomy.
SMALL-VESSEL OCCLUSION
Small-vessel occlusions, i.e., thrombosis oI a single perIorating cerebral artery, cause lacunar ischemic
strokes. A lacunar inIarct usually occurs in the internal capsule or thalamus and presents clinically as a pure
motor stroke, pure sensory stroke, sensomotor stroke, dysarthria clumsy hand or ataxic hemiparesis. Patients
with typical lacunar inIarct syndromes account Ior approximately 20 oI all ischemic strokes, and
hypertensive small-vessel disease seems to be the most important etiology |29|. Because heavy drinking oI
alcohol is a Irequent cause oI arterial hypertension, it is assumed to associate with small-vessel occlusion as
well. However, conIlicting observations have also been reported. Some studies have not shown alcohol to be a
signiIicant risk Iactor |2931|, whereas others have |9,32|. The study oI You et al. included a rather large
series oI young adults with lacunar inIarcts |33|. This study suggested that long-term heavy alcohol
consumption is a risk Iactor Ior ischemic brain inIarct, whereas recent heavy drinking is not. The Iollowing
case history suggests a relationship between alcohol drinking and the onset oI lacunar brain inIarct.
Case 8
In October 1994, a 55-year-old heavily smoking man with treated diabetes and hypertension suddenly
developed leIt sensomotor hemiparesis, while sitting at home in the evening. He was a habitual heavy drinker
with a regular weekly consumption oI 500 g ethanol. During the aIternoon preceding the onset oI stroke, he
had ingested 10 bottles oI beer (120 g ethanol) in a pub. On admission into hospital immediately aIter the
onset oI the stroke, his blood pressure was 110/75 mmHg and blood alcohol 20 mmol/L. Duplex imaging oI
the carotid and vertebral arteries did not show any signiIicant stenoses, and precordial echocardiography was
unremarkable. A computed tomography head scan later conIirmed the presence oI a small brain inIarct in the
area oI the right lentiIorm and caudate nuclei.
A Iew similar subjects with classical risk Iactors Ior lacunar stroke have been seen at our department during
the recent years. One patient had recurrent lacunar brain inIarcts
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during heavy binge drinking. Some recent reports oI interest should be mentioned here, because they may help
to orient Iuture investigations. First, apolipoprotein E phenotype seems to signiIicantly inIluence the blood-
pressure-increasing eIIect oI alcohol consumption |34| and the risk oI recurrent lobar intracerebral hemorrhage
|35|. Studies relating apolipoprotein E phenotype to the occurrence oI strokes triggered by heavy drinking are
not yet available. Second, a line oI experimental studies have demonstrated alcohol-induced cerebrovascular
spasms in relation to stroke-like events |36|. This mechanism oI probable importance has been described in
other chapters oI this book. Third, it could be possible that alcohol inIluences cerebrovascular autoregulation
in a manner that promotes the onset oI lacunar stroke. Further studies are needed to demonstrate such an
eIIect.
CERVICAL ARTERIAL DISSECTION
Cervical arterial dissection is probably one oI the most common causes oI ischemic stroke in young
subjects. It is diagnosed by imaging with conventional or MR angiography and typically occurs aIter major
trauma, but may also occur spontaneously or aIter trivial injury. Needless to say, alcoholic intoxication is a
major risk Iactor Ior all types oI trauma. ThereIore, it is not surprising that cervical arterial dissections have
also been described to have occurred in connection with alcohol abuse |22,37|. Some reports have emphasized
that extracranial vessel compression due to unusual posturing during alcoholic stupor or coma could also result
in a brain inIarct |3840|, but it has remained unclear whether cervical arterial dissection is the underlying
mechanism or not. In at least one oI the reported cases dissection was excluded |40|.
Surprisingly, case-control studies have not yet been able to prove alcohol as a risk Iactor Ior ischemic stroke
caused by cervical arterial dissection |13|. Injury oI the neck arteries may easily occur during a drunken Iight
or Ialling, but the onset oI ischemic stroke is oIten delayed. In Iact, the onset oI cervical trauma may have
occurred long beIore the onset oI stroke, and the relationship is thereIore diIIicult to establish. To show a
relationship, we will need to question the subjects with dissection about their experienced trauma and violence
oI all kinds as well as about alcohol drinking. The Iollowing case report illustrates the problem.
Case 9
One Friday evening in May 1993, a 36-year-old man, aIter having been drinking heavily (180 g ethanol),
started to wrestle with a drunken companion. During the Iight, this man was strangled, particularly on the right
hand side oI his neck. The man did not Ieel any symptoms immediately aIter the Iight, but later on he Ielt pain
on his right neck and got a headache. AIter a Iortnight, while turning his Iace to right, he suddenly developed a
right Horner`s sign and temporal hyperalgesia. AIter admission into hospital, an arch angiogram revealed a 3-
cm-long tight stenosis with aneurysms at both ends in the extracranial part oI his right internal carotid artery.
A diagnosis oI traumatic carotid arterial dissection was made. He was treated with anticoagulants and made
good recovery without any complications.
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CRYPTOGENIC STROKE
Finally, ischemic brain inIarcts oI unknown origin (cryptogenic stroke) have also been described in connection
with heavy drinking oI alcohol |41,42|. Alcohol also has complex eIIects on cerebral blood Ilow and
autoregulation. Whether or not these mechanisms play a signiIicant role is unclear. Thus Iar, we have not
Iound an alcoholic binge to result in marked hypotension and watershed inIarcts. We believe that many oI the
cryptogenic ischemic brain inIarcts are due to emboli oI unknown origin.
EFFECTS OF LIGHT DRINKING
Several studies have shown regular light (1020 g oI ethanol daily) or moderate (less than 300 g oI ethanol per
week) drinking to associate with a decreased risk Ior ischemic stroke oI atherothrombotic origin |4345|, but
the observations on the eIIects oI light and moderate alcohol consumption on stroke mortality have been
conIlicting |27,46,47|. For example, one study showed light-to-moderate drinking to be associated with a 36
reduction in deaths Irom ischemic heart disease, but had no eIIect on death Irom stroke |47|. A recent study
|48| reported that light-to-moderate alcohol consumption reduces the overall risk oI stroke and the risk oI
ischemic stroke in men. The beneIit was apparent with as little as one drink per week. More abundant
consumption, up to one drink per day, did not increase the observed beneIit.
Several possible mechanisms have been proposed to explain the beneIicial eIIect oI light-to-moderate alcohol
consumption |49|. However, almost all oI the proposed mechanisms are unable to explain a protective eIIect
with such small amounts oI alcohol as a Iew drinks per week. The only exception could be the increasing
eIIect oI alcohol on estrogen levels, which protects against atherogenesis. On the other hand, accurate and
reliable data on alcohol consumption are hard to Iind in epidemiological studies, because drinking patterns
have usually not been inquired.
In Iact, some investigators have pointed out that there is no convincing evidence to show that light or moderate
drinking is protective against stroke |50|. Nor does light-to-moderate drinking seem to protect against
mortality Irom stroke when compared with not drinking |47|. Although many studies have taken into account
several potential conIounding Iactors, others still exist. The ones that have been poorly controlled include
physical activity, psychosocial conIounders and dietary Iactors. For example, it has been observed that
moderate drinkers who do not smoke are more likely than nondrinkers to engage in regular leisure time
physical activity |51|. At the moment, we cannot recommend regular drinking oI small amounts oI alcohol Ior
the prevention oI ischemic stroke. We know that any increase in alcohol consumption in a population is
associated with a corresponding increase oI heavy drinking, which has untoward consequences.
CONCLUSIONS
Heavy drinking oI alcohol is a risk Iactor Ior brain inIarct. This has been observed particularly in young and
middle-aged men, who are Irequently heavy drinkers. In many cultures, women and elderly people do not
drink Ior intoxication and are seldom heavy drinkers.
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Although in some studies, adjustment Ior hypertension has abolished the independent role oI alcohol as a risk
Iactor, suggesting that the risk is increased through an elevated blood pressure, other studies have shown that
recent heavy drinking also increases the risk independently. The ultimate mechanisms leading to the increased
risk are still unclear. Several actions oI alcohol could explain why precisely recent heavy drinking increases
the risk oI ischemic stroke. Trauma to the neck, which Irequently occurs during alcoholic intoxication, is
certainly one reason. Another is alcohol-induced cardiac arrhythmias, which predispose to cardiogenic brain
embolism. Some oI the examples presented as case histories above may equally well suggest a coincidence as
a causal relationship. Several Iactors have been proposed to explain the beneIicial eIIect oI light-to-moderate
drinking seen in epidemiological investigations. However, direct prooI oI their signiIicance is still lacking, and
some counIounding Iactors have not yet been adequately controlled Ior.
REFERENCES
1 Truelsen T, Gronbk M, Schnohr P, Boysen G. Intake oI beer, wine, and spirits and risk oI stroke. The
Copenhagen City Heart Study. Stroke 1998; 29: 24672472.
2 Sacco RL, Elkind M, Boden-Albala B, I-Feng Lin, Kargman DE, Hauser WA, Shea S, Paik MC. The
protective eIIect oI moderate alcohol consumption on ischemic stroke. JAMA 1999; 281: 5360.
3 Leppl JM, Paunio M, Virtamo J, Fogelholm R, Albanes D, Taylor PR, Heinonen OP. Alcohol
consumption and stroke incidence in male smokers. Circulation 1999; 100: 12091214.
4 Gillman MW, Cook NR, Evans DA, Rosner B, Hennekens CH. Relationship oI alcohol intake with blood
pressure in young adults. Hvpertension 1995; 25: 11061110.
5 Sacco RL. Risk Iactors and outcomes Ior ischemic stroke. Neurologv 1995; 45(Suppl. 1): S10S14.
6 Jiang He, Klag MJ, Zhenglai Wu, Whelton PK. Stroke in the People`s Republic oI China I. Geographic
variations in incidence and risk Iactors. Stroke 1995; 26: 22222227.
7 Gorelick PB. Stroke prevention, an opportunity Ior eIIicient utilization oI health care resources during the
coming decade. Stroke 1994; 25: 220224.
8 Caicoya M, Rodriquez T, Corrales C, Cuello R, Lasheras C. Alcohol and stroke: a community case-
control study in Asturias, Spain, J. Clin. Epidemiol. 1999; 52: 677684.
9 Mntyl R, Aronen HJ, Salonen O, Pohjasvaara T, Korpelainen M, Peltonen T, Standertskjld-
Nordenstam C-G, Kaste M, Erkinjuntti T. Magnetic resonance imaging white matter hyperintensities and
mechanisms oI ischemic stroke. Stroke 1999; 30: 20532058.
10 Starr JM, Thomas B, Whalley LJ. Population risk Iactors Ior hospitalization Ior stroke in Scotland. Int.
J. Epidemiol. 1996; 25: 276281.
11 Sacco RL, Shi T, Zamanillo MC, Kargman DE. Predictors oI mortality and recurrence aIter hospitalized
cerebral inIarction in an urban community: the Northern Manhattan Stroke Study. Neurologv 1994; 44:
626634.
12 Moroney JT, Bagiella E, Tatemichi TK, Paik MC, Stern Y, Desmond DW. Dementia aIter stroke
increases the risk oI long-term stroke recurrence. Neurologv 1997; 48: 13171325.
13 Hillbom M, Numminen H, Juvela S. Recent heavy drinking oI alcohol and embolic stroke. Stroke 1999;
30: 23072312.
14 Gonzales MRM, Donderis AC, Sanhauja JJ, Rieger JS. Cardiomyopathy, alcoholism and cerebral
embolism. Rev. Clin. Esp. 1988; 182: 7980.
15 Urbano-Marquez A, Estruch R, Fernandez-Sola J, Nicolas JM, Pare JC, Rubin E. The greater risk oI
alcoholic cardiomyopathy and myopathy in women compared with men. JAMA 1995; 274: 149154.
16 Lip GYH, Beevers DG, Sing SP, Watson RDS. ABC oI atrial Iibrillation, etiology, pathophysiology,
and clinical Ieatures. BMJ 1995; 311: 14251428.
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17 Thornton JR. Atrial Iibrillation in healthy non-alcoholic people aIter an alcoholic binge. Lancet 1984; 2:
10131014.
18 Rosolacci T, DeIaux D, Neuville V. Complete arrhythmia, caused by atrial Iibrillation, causing ischemic
cerebral vascular accident Iollowing acute alcoholic intoxication in a young subject. Presse. Med. 1995; 24:
1911.
19 Gras P, Abdoul Karim A, Grosmaire N, Borsotti JP, Giroud M, Blettery B, Dumas R. Multiple brain
embolism in acute alcohol intoxication, a clinico-pathological case. Rev. Neurol. 1992; 148: 215217.
20 MayIield D, McLeod G, Hall P. The CAGE questionnaire: validation oI a new alcoholism screening
instrument. Am. J. Psvchiatrv 1974; 131: 11211123.
21 Majamaa K, Turkka J, Krpp M, Winqvist S, Hassinen IE. The common MELAS mutation A3243G in
mitochondrial DNA among young patients with an occipital brain inIarct. Neurologv 1997; 49: 13311334.
22 Hillbom M, Kaste M. Alcohol abuse and brain inIarction. Ann. Med. 1990; 22: 347352.
23 Neiman J. Association oI transient ischaemic attack in alcohol withdrawal with changes in haemostasis.
Br. J. Addiction 1988; 83: 14571459.
24 Reed DM. The paradox oI high risk oI stroke in populations with low risk oI coronary heart disease. Am.
J. Epidemiol. 1990; 131: 579588.
25 Kiechl S, Willeit J, Egger G, Oberhollenzer M, Aichner F. Alcohol consumption and carotid
atherosclerosis: evidence oI dose-dependent atherogenic and antiatherogenic eIIects. Results Irom the
Bruneck Study. Stroke 1994; 25: 15931598.
26 Hart CL, Smith GD, Hole DJ, Hawthorne VM. Alcohol consumption and mortality Irom all causes,
coronary heart disease, and stroke: results Irom a prospective cohort study oI Scottish men with 21 years oI
Iollow up. BMJ 1999; 318: 17251729.
27 Hansagi H, Romelsj A, Gerhardsson de Verdier M, Andreasson S, LeiIman A. Alcohol consumption
and stroke mortality, a 20-year Iollow-up oI 15,077 men and women. Stroke 1995; 26: 17681773.
28 Kauhanen J. Pattern oI alcohol drinking and progression oI atherosclerosis. Arterioscler. Thromb. Jasc.
Biol. 1999; 19: 30013006.
29 You R, McNeil JJ, O`Malley HM, Davis SM, Donnan GA. Risk Iactors Ior lacunar inIarction
syndromes. Neurologv 1995; 45: 14831487.
30 Ferro JM, Crespo M, Ferro H. Role oI vascular risk Iactors in lacunar and unexplained strokes in young
adults: a case-control study. Cerebrovasc. Dis. 1995; 5: 188193.
31 Janssens E, Mounier-Vehier F, Hamon M, Leys D. Small subcortical inIarcts and primary subcortical
haemorrhages may have diIIerent risk Iactors. J. Neurol. 1995; 242: 425429.
32 Qureshi AI, SaIdar K, Patel M, Janssen RS, Frankel MR. Stroke in young black patients: risk Iactors,
subtypes, and prognosis. Stroke 1995; 26: 19951998.
33 You RX, McNeill JJ, O`Malley HM, Davis SM, ThriIt AG, Donnan GA. Risk Iactors Ior stroke due to
cerebral inIarction in young adults. Stroke 1997; 28: 19131918.
34 Kauma H, Savolainen MJ, Rantala AO, Lilja M, Kervinen K, Reunanen A, Kesniemi YA.
Apolipoprotein E phenotype determines the eIIect oI alcohol on blood pressure in middle-aged men. Am. J.
Hvpertens. 1998; 11: 13341343.
35 O`Donnell HC, Rosand J, Knudsen KA, Furie KL, Segal AZ, Chiu RI, Ikeda D, Greenberg SM.
Apolipoprotein E genotype and the risk oI recurrent lobar intracerebral hemorrhage. New Engl. J. Med.
2000; 342: 240245.
36 Altura BM, Altura BT. Association oI alcohol in brain injury, headaches, and stroke with brain-tissue
and serum levels oI ionized magnesium: a review oI recent Iindings and mechanisms oI action. Alcohol
1999; 19: 119130.
37 Hess DC, Sethi KD, Nichols FT. Carotid dissection: a new Ialse localising sign. J. Neurol. Neurosurg.
Psvchiatrv 1990; 53: 804805.
38 Prendes JL. Cerebral inIarction and alcohol. Lancet 1979; 1: 219.
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Page 82
39 Derlon JM, Charbonneau P, Theron J, Houtteville JP, Bazin C. Edematous soItening oI cerebellar oI the
young. Neurochirurgie 1983; 29: 423428.
40 Jockers-Scherubl M, Vogel HP, Marx P. Cerebral inIarct caused by compression oI the carotid artery in
an alcohol intoxicated patient. Nervenar:t 1993; 64: 401403.
41 Wilkins MR, Kendall MJ. Stroke aIIecting young men aIter alcoholic binges. BMJ 1985; 291: 1342.
42 Sangla I, Bille-Turc F, Pouget J, Serratrice G. Ischemic cerebral vascular accident with simultaneous
acute alcoholic intoxication in a young subject. Presse. Med. 1995; 24: 827.
43 Palomki H, Kaste M. Regular light-to-moderate intake oI alcohol and the risk oI ischemic stroke; is
there a beneIicial eIIect? Stroke 1993; 24: 18281832.
44 Jamrozik K, Broadhurst RJ, Anderson CS, Stewart-Wynne EG. The role oI liIestyle Iactors in the
etiology oI stroke, a population-based case-control study in Perth, Western Australia. Stroke 1994; 25: 51
59.
45 Camargo CA, Jr. Case-control and cohort studies oI moderate alcohol consumption and stroke. Clin.
Chem. Acta 1996; 246: 107119.
46 Knuiman MW, Vu HTV. Risk Iactors Ior stroke mortality in men and women: the Busselton Study. J.
Cardiovascular Risk 1996; 3: 447452.
47 Yuan J-M, Ross RK, Gao Y-T, Henderson BE, Yu MC. Follow up study oI moderate alcohol intake and
mortality among middle aged men in Shanghai, China. BMJ 1997; 314: 1823.
48 Berger K, Ajani UA, Kase CS, Gaziano M, Buring JE, Glynn RJ, Hennekens CH. Light-to-moderate
alcohol consumption and the risk oI stroke among U.S. male physicians. New Engl. J. Med. 1999; 341:
15571564.
49 Hillbom M, Juvela S. Alcohol and risk Ior stroke. In: Zakhari S, WasseI M. (Eds.) Alcohol and the
Cardiovascular Svstem, Washington DC, National Institute on Alcohol Abuse and Alcoholism, NIAAA
Research Monograph No. 31. 1996; 6383.
50 Wannamethee SG, Shaper AG. Patterns oI alcohol intake and risk oI stroke in middle-aged British men.
Stroke 1996; 27: 10331039.
51 Barrett DH, Anda RF, CroIt JB, Serdula MK, Lane MJ. The association between alcohol use and health
behaviors related to the risk oI cardiovascular disease: the South Carolina Cardiovascular Prevention
Project. J. Stud. Alcohol 1995; 56: 915.
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Chapter 8
Alcohol consumption and the risk of stroke: the role
of tobacco?
Jaana M. Leppl
INTRODUCTION
Studies on alcohol and smoking are numerous and the epidemiologic evidence on their eIIects on
cardiovascular diseases is overwhelming. The knowledge oI their eIIects on diIIerent subtypes oI stroke has
cumulated as well, especially during the last decade, but the interaction between alcohol and tobacco with
respect to the risk oI stroke is mostly unexplored. This is the subject oI this chapter.
ALCOHOL CONSUMPTION AND THE RISK OF STROKE
There is plenty oI evidence that heavy drinking (~60 g/day) is related to increased risk oI both hemorrhagic |1
9| and ischemic strokes |1,3,7,8,1012|. In contrast, light (24 g/day Ior men and 12 g/day Ior women) and
moderate (2560 g/day Ior men and 1348 g/day Ior women) drinking does not seem to increase and may even
decrease the risk oI stroke compared with non-drinking |7,13,14|. However, in order to understand the
relationship between alcohol and the risk oI stroke, one has to separately examine the eIIects oI alcohol on
each stroke subtype (i.e., subarachnoid and intracerebral hemorrhage, and cerebral inIarction), the dose
response curve most probably diIIering Irom one subtype to another. The risk oI subarachnoid hemorrhage
seems to increase steeply with increasing alcohol consumption |7,15|. The relationship between alcohol and
the risk oI intracerebral hemorrhage is poorly known but may be U-shaped with lowest risk among light to
moderate drinkers |79|, and that oI ischemic stroke appears to be J-shaped, with non-drinkers and heavy
drinkers having a higher risk than light drinkers |7,8,15,16|.
Alcohol causes many changes in physiological Iunctions which may modiIy the risk oI stroke. It increases
blood pressure |1720| and serum HDL cholesterol levels |7,18,2026|, and there is some evidence that these
two Iactors mediate the eIIect oI alcohol on the risk oI stroke |7,15|. Alcohol seems to have a U-shaped
association with Iibrinogen levels |27|, moderate alcohol consumption increases |28| but ethanol intoxication
decreases |29| Iibrinolytic activity, and immediate heavy alcohol intake decreases platelet aggregation |30|
but, in binge drinkers and alcoholics, platelet aggregation is increased aIter alcohol withdrawal |30,31|.
Cerebral blood Ilow is increased immediately aIter alcohol intake |32|. In addition, ethanol has both anti- |33|
and pro-oxidant activity |34|, but it has been speculated that constituents other than alcohol (e.g., Ilavonoids
and hydroxystilbenes) might inIluence the
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development oI atherosclerosis |34,35|. Alcohol also interIeres with glucose metabolism, moderate alcohol
consumption being associated with a decreased risk oI diabetes |36|. Alcohol seems to increase insulin
sensitivity and glucose tolerance |26|, even though alcoholics are usually resistant to insulin |18,26|.
CIGARETTE SMOKING AND THE RISK OF STROKE
Heavy smoking (~20 cigarettes/day) increases both the incidence |3741| and mortality Irom stroke |40,41|.
Cigarette smoking is a major modiIiable risk Iactor Ior subarachnoid hemorrhage |4248|. In contrast,
evidence concerning the role oI tobacco in the risk oI intracerebral hemorrhage is still controversial, yet it
appears that heavy, but not light-to-moderate cigarette smoking, increases the risk |9,38,49,50|. Smoking is
dose-dependantly associated with the risk oI ischemic stroke |38,46|. Cessation oI smoking reduces stroke risk
|37,39|, with major reduction within 25 years aIter cessation |37,39,46|, indicating that part oI the eIIects oI
smoking is reversible. The risk oI stroke seems to return to the level oI never-smokers in light smokers, but
heavy smokers seem to retain an increased risk even though also they beneIit Irom cessation |37|.
There are several mechanisms by which smoking may cause stroke. Cigarette smoking causes an immediate,
yet reversible increases in blood pressure |42,5155| and cerebral blood Ilow |56|. In epidemiologic studies,
however, it has consistently been associated with reduced blood pressure in normotensive people |18,52,57
60|, although blood pressure has been elevated in diabetic |61| and hypertensive smokers |62|, and cerebral
blood Ilow has been decreased in chronic smokers |40| compared with respective nonsmokers. It is not
plausible that smoking decreases blood pressure, but smokers may initially have lower blood pressure than
those who remain nonsmokers |63|. They may also have a reduced white coat eIIect`, which would lead to
artiIicially low measurements oI blood pressure in clinics |59|. There is no evidence that smoking causes
hypertension, but in heavy smokers the rise in blood pressure may persist during waking hours because oI
Irequent smoking Iactually causing a hypertensive state |55|. Even though smoking may not be causally
related to hypertension, it clearly modiIies the eIIect oI hypertension on stroke |40,51| and other
cardiovascular risks |64| which are much higher in hypertensive than normotensive smokers.
Cigarette smoking is associated with reduced levels oI serum HDL cholesterol |18,20,51,57, 58,60,65,66| and
increased levels oI serum triglycerides |18,57,6567|. It increases platelet activity |51,53,68,69|, plasma
Iibrinogen levels |27,51,57|, hematocrit |57,65|, and blood viscosity |57|. It is also associated with endothelial
dysIunction |57,70,71|. Cigarette smoking increases the risks oI carotid stenosis |72,73| and diabetes |36|,
which both are risk Iactors Ior ischemic stroke.
Tobacco smoke has over 4000 compounds, the eIIects oI which are mostly unknown |51|. Many oI the eIIects
oI smoking are attributed to nicotine, which increases systolic and diastolic blood pressure and heart rate in a
doseresponse manner |74,75|. Despite these hemodynamic eIIects, nicotine does not appear to enhance
thrombosis |75,76|, and the mechanism by which smoking is related to thrombogenesis is unclear. Besides
nicotine, carbonmonoxide is a potential mediator oI the eIIects oI tobacco smoke on cardiovascular diseases
|51,77|. It may injure the vascular endothelium |77| and thus promote atherogenesis. The causal role oI
smoking in the development oI atherosclerosis is plausible but so Iar unproven.
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Page 85
THE EFFECT MODIFICATION OF ALCOHOL BY SMOKING
There are only two epidemiologic studies on the eIIect modiIication oI alcohol by smoking and neither oI
them examines it in relation to the risk oI stroke. In a Japanese cohort oI 19,231 men, alcohol consumption and
all-cause mortality had a J-shaped association in nonsmokers but not in smokers |78|. In a cross-sectional
study oI 5,312 German men and women, the rise in blood pressure associated with drinking was higher in
smokers than in nonsmokers |79|. Some studies have instead examined the eIIect modiIication oI smoking by
alcohol. In a cohort oI 22,071 US male physicians, alcohol attenuated the linear eIIect oI smoking on the risk
oI total stroke |38|. In a Japanese cohort oI 1,775 men, a dose-dependent decrease in diastolic blood pressure
and serum HDL cholesterol by increasing cigarette smoking was evident in nondrinkers but not in drinkers
|67|.
The eIIects oI both alcohol and tobacco are maniIold, which makes them complicated to examine and
understand. The eIIects may be additive or synergistic, or counteract each other either directly via the same
mechanisms or indirectly inIluencing the same phenomena but through diIIerent mechanisms. Both alcohol
intake and cigarette smoking increase blood pressure |1720,42,5155|, even though the relationship between
smoking and hypertension is controversial |18,52,55,5762|. Alcohol consumption increases serum HDL
cholesterol |17,18,2026| whereas cigarette smoking has been consistently associated with reduced levels oI
HDL cholesterol |18,20,51,57,58,60,65,66|. Alcohol decreases platelet activity and Iibrinogen levels and
increases Iibrinolysis |27,30|, whereas smoking increases platelet aggregability and Iibrinogen levels
|27,51,53,57,68,69|. It is very plausible that smoking substantially modiIies the eIIects oI drinking on stroke
risk, but it remains to be studied what the actual net eIIects oI all these physiological mechanisms involved are
and how smoking modiIies the doseresponse relationships between alcohol and each stroke subtype.
METHODOLOGICAL PROBLEMS IN STUDIES ON ALCOHOL AND
TOBACCO
Studies on interactions between alcohol and tobacco are most challenging, not only because oI the complexity
oI the eIIects oI either Iactor, but also because oI many inherent methodological problems. Epidemiologic
studies on alcohol and tobacco are prone to imprecision in measurements and various biases, their interactions
thus being even harder to evaluate in a reliable and valid manner. Alcohol consumption and smoking are
usually selI-reported and the measurement oI either habit is susceptible to both recall and response bias. The
reporting oI alcohol use especially tends to be diIIerential, heavy drinkers more likely reporting themselves as
moderate-to-light drinkers than nondrinkers |24|. DiIIerential misclassiIication is likely to lead to biased
estimates oI relative risks, and the amount and direction oI such bias is hard to evaluate. Furthermore, the
classiIication oI alcohol intake and cigarette smoking, and the selection oI respective reIerence categories (e.
g., current nondrinkers vs. never-drinkers, and current nonsmokers vs. never-smokers) inIluence the risk ratios
and, consequently, the interpretations oI study results. DiIIerent category boundaries make it diIIicult to
compare studies with each other and drawing uniIorm conclusions becomes unsubstantial. Alcohol and
tobacco have both immediate and cumulative eIIects, the assessment and diIIerentiation oI which may be
diIIicult or even impossible. This is reIlected
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Page 86
in the use oI composite indices such as pack-years oI smoking, such indices being appealing to use but causing
considerable problems in the causal interpretation oI results. There is no consensus on the most preIerable way
to simultaneously take into account both current use and the duration oI habit.
CONCLUSIONS
Alcohol consumption and cigarette smoking are both independent risk Iactors Ior stroke, and their eIIects seem
to vary by stroke subtype, the average daily amount oI drinking and smoking, and duration oI habit. It is likely
that smoking modiIies the eIIects oI alcohol on the risk oI stroke, depending on both stroke subtype and the
relative role oI each Iactor in the occurrence oI subtype in question. However, there are no studies that have
speciIically examined this interaction and the risk oI stroke, even though some studies have addressed this
issue with respect to some other cardiovascular diseases. This multi-Iaceted relationship between alcohol and
smoking clearly needs more research.
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7 Leppl JM, Paunio M, Virtamo J, Fogelholm R, Albanes D, Taylor PR, Heinonen OP. Alcohol
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control study in Asturias, Spain. J. Clin. Epidemiol. 1999; 52(7): 677684.
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11 Palomki H, Kaste M. Regular light-to-moderate intake oI alcohol and the risk oI ischemic stroke. Is
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Page 87
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oxidants that might inIluence the development oI atherosclerotic cardiovascular disease?
Neuroepidemiologv 1999; 18: 292302.
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35 Goldberg DM, Soleas GJ, Levesque M. Moderate alcohol consumption: The gentle Iace oI Janus. Clin.
Biochem. 1999; 32(7): 505518.
36 Rimm EB, Chan J, StampIer MJ, Colditz GA, Willett WC. Prospective study oI cigarette smoking,
alcohol use, and the risk oI diabetes in men. BMJ 1995; 310: 555559.
37 Wannamethee SG, Shaper AG, Whincup PH, Walker M. Smoking cessation and the risk oI stroke in
middle-aged men. JAMA 1995; 274: 155160.
38 Robbins AS, Manson JE, Lee IM, SatterIield S, Hennekens CH. Cigarette smoking and stroke in a
cohort oI U.S. male physicians. Ann. Intern Med. 1994; 120: 458462.
39 Kawachi I, Colditz A, StampIer MJ, Willett WC, Manson JE, Rosner B, Speizer FE, Hennekens CH.
Smoking cessation and decreased risk oI stroke in women. JAMA 1993; 269(2): 232236.
40 Higa M, Davanipour Z. Smoking and stroke. Neuroepidemiologv 1991; 10: 211222.
41 Lund Hheim L, Holme I, Hjermann I, Leren P. Smoking habits and risk oI Iatal stroke: 18 years Iollow
up oI the Oslo study. J. Epidemiol. Comm. Health 1996; 50: 621624.
42 Longstreth WT Jr, Koepsell TD, Yerby MS, van Belle G. Risk Iactors Ior subarachnoid hemorrhage.
Stroke 1985; 16(3): 377385.
43 Fogelholm R, Murros K. Cigarette smoking and subarachnoid haemorrhage: A population-based case-
control study. J. Neurol. Neurosurg. Psvchiatrv 1987; 50: 7880.
44 Knekt P, Reunanen A, Aho K, Helivaara M, Rissanen A, Aromaa A, Impivaara O. Risk Iactors Ior
subarachnoid hemorrhage in a longitudinal population study. J. Clin. Epidemiol. 1991; 44(9): 933939.
45 Teunissen LL, Rinkel GJE, Algra A, van Gijn J. Risk Iactors Ior subarachnoid hemorrhage: A
systematic review. Stroke 1996; 27(3): 544549.
46 Sacco RL. Risk Iactors, outcomes, and stroke subtypes Ior ischemic stroke. Neurologv 1997; 49 (Suppl.
4): S39S44.
47 Weir BKA, Kongable GL, Kassell NF, Schultz JR, Truskowski LL, Sigrest A, and the Investigators.
Cigarette smoking as a cause oI aneurysmal subarachnoid hemorrhage and risk Ior vasospasm: A report oI
the Cooperative Aneurysm Study. J. Neurosurg. 1998; 89: 405411.
48 Morris KM, Shaw MDM, Foy PM. Smoking and subarachnoid haemorrhage: A case control study. Br.
J. Neurosurg. 1992; 6: 429432.
49 Fogelholm R, Murros K. Cigarette smoking and risk oI primary intracerebral haemorrhage: A
population-based case-control study. Acta Neurol. Scand. 1993; 87: 367370.
50 ThriIt AG, Donnan GA, McNeil JJ. Epidemiology oI intracerebral hemorrhage. Epidemiol. Rev. 1995; 17
(2): 361381.
51 Rigotti NA, Pasternak RC. Cigarette smoking and coronary heart disease. Cardiol. Clin. 1996; 14(1):
5168.
52 Omvik P. How smoking aIIects blood pressure. Blood Pressure 1996; 5: 7177.
53 Sleight P. Smoking and hypertension. Clin. Experim. Hvperten. 1993; 15(6): 11811192.
54 Hashimoto H. Enhanced elevation oI blood pressure during cigarette smoking in the elderly. Jpn. Circ.
J. 1993; 57: 955959.
55 Groppelli A, Giorgi DMA, Omboni S, Parati G, Mancia G. Persistent blood pressure increase induced
by heavy smoking. J. Hvperten. 1992; 10: 495499.
56 Morioka C, Kondo H, Akashi K, Matsumura K, Ochi N, Makinaga G, Furukawa T. The continuous and
simultaneous blood Ilow velocity measurement oI Iour cerebral vessels and a peripheral vessel during
cigarette smoking. Psvchopharmacologv 1997; 131: 220229.
57 Price JF, Mowbray PI, Lee AJ, Rumley A, Lowe GDO, Fowkes FGR. Relationship between smoking
and cardiovascular risk Iactors in the development oI peripheral arterial disease and coronary artery
disease: Edinburgh Artery Study. Eur. Heart J. 1999; 20: 344353.
58 Hughes K, Leong WP, Spothy SP, Lun KC, Yeo PPB. Relationships between cigarette smoking, blood
pressure and serum lipids in the Singapore general population. Int. J. Epidemiol. 1993; 22(4): 637643.
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59 Mikkelsen KL, Wiinberg N, Hoegholm A, Christensen HR, Bang LE, Nielsen PE, Svendsen TL,
Kampmann JP, Madsen NH, Bentzon MW. Smoking related to 24-h ambulatory blood pressure and heart
rate: A study in 352 normotensive Danish subjects. Am. J. Hvperten. 1997; 10: 483491.
60 Imamura H, Tanaka K, Hirae C, Futagami T, Yoshimura Y, Uchida K, Tanaka A, Kobata D.
Relationship oI cigarette smoking to blood pressure and serum lipids and lipoproteins in men. Clin.
Experim. Pharmacol. Phvsiol. 1996; 23: 397402.
61 Poulsen PL, Ebbehoj E, Hansen KW, Mogensen CE. EIIects oI smoking on 24-h ambulatory blood
pressure and autonomic Iunction in normoalbuminuric insulin-dependent diabetes mellitus patients. Am. J.
Hvperten. 1998; 11: 10931099.
62 Verdecchia P, Schillaci G, Borgioni C, Ciucci A, Zampi I, Battistelli M, Gattobigio R, Sacchi N,
Porcellati C. Cigarette smoking, ambulatory blood pressure and cardiac hypertrophy in essential
hypertension. J. Hvperten. 1995; 13: 12091215.
63 Charlton A, While D. Blood pressure and smoking: Observations on a national cohort. Arch. Dis. Child
1995; 73: 294297.
64 Beilin LJ. LiIestyle and hypertension: An overview. Clin. Experim. Hvperten. (New York) 1999; 21(5
6): 749762.
65 Vriz O, Nesbitt S, Krause L, Majahalme S, Lu H, Julius S. Smoking is associated with higher
cardiovascular risk in young women than in men: The Tecumseh Blood Pressure Study. J. Hvperten. 1997;
15: 127134.
66 Connelly PW, Petrasovits A, Stachenko S, MacLean DR, Little JA, Chockalingam A. Prevalence oI
high plasma triglycerids combined with low HDL-C levels and its association with smoking, hypertension,
obesity, diabetes, sedentariness and LDL-C levels in the Canadian population. Can. J. Cardiol. 1999; 15
(4): 428433.
67 Handa K, Tanaka H, Shindo M, Kono S, Sasaki J, Arakawa K. Relationship oI cigarette smoking to
blood pressure and serum lipids. Atherosclerosis 1990; 84: 189193.
68 Rngemark C, Benthin G, Granstrm EF, Persson L, Winell S, Wennmalm A. Tobacco use and urinary
excretion oI thromboxane A
2
and prostacyclin metabolites in women stratiIied by age. Circulation 1992;
86: 14951500.
69 Gleerup G, Winther K. Smoking Iurther increases platelet activity in patients with mild hypertension.
Eur. J. Clin. Invest. 1996; 26: 4952.
70 Drexler H, Hornig B. Endothelial dysIunction: A novel therapeutic target: Endothelial dysIunction in
human disease. J. Mol. Cell. Cardiol. 1999; 31: 5160.
71 Pepine CJ. Clinical implications oI endothelial dysIunction. Clin. Cardiol. 1998; 21(11): 795799.
72 Mast H, Thompson JLP, Lin IF, HoImeister C, Hartmann A, Marx P, Mohr JP, Sacco RL. Cigarette
smoking as a determinant oI high-grade carotid artery stenosis in Hispanic, black, and white patients with
stroke or transient ischemic attack. Stroke 1998; 29: 908912.
73 Wilson PWF, Hoeg JM, D`Agostino RB, Silbershatz H, Belanger AM, Poehlmann H, O`Leary D, WolI
PA. Cumulative eIIects oI high cholesterol levels, high blood pressure, and cigarette smoking on carotid
stenosis. New Engl. J. Med. 1997; 337: 516522.
74 Netter P, Mller MJ, Neumann A, Kamradik B. The inIluence oI nicotine on perIormance, mood, and
physiological parameters as related to smoking habit, gender, and suggestibility. Clin. Investig. 1994; 72:
512518.
75 Benowitz NL. The role oI nicotine in smoking-related cardiovascular disease. Prev. Med. 1997; 26: 412
417.
76 Blann AD, Steele C, McCollum CN. The inIluence oI smoking and oI oral and transdermal nicotine on
blood pressure, and haematology and coagulation indices. Thromb. Haemost. 1997; 78(3): 10931096.
77 Kochar MS, Bindra RS. The additive eIIects oI smoking and hypertension: More reasons to help your
patients kick the habit. Postgrad. Med. 1996; 100(5): 147160.
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78 Tsugane S, Fahey MT, Sasaki S, Baba S, Ior the JPHC Study Group. Alcohol consumption and all-cause
and cancer mortality among middle-aged Japanese men: Seven-year Iollow-up oI the JPHC Study Cohort I.
Am. J. Epidemiol. 1999; 150(11): 12011207.
79 Keil U, Chambless L, Filipiak B, Hrtel U. Alcohol and blood pressure and its interaction with smoking
and other behavioural variables: Results Irom the MONICA Augsburg Survey 19841985. J. Hvperten.
1991; 9: 491498.
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Chapter 9
Alcohol, vascular cells and hemodynamic forces
Eileen M. Redmond and Paul A. Cahill
INTRODUCTION
Over the past two decades important inIluences oI ethanol on the cardiovascular system have been recognized.
Several epidemiological studies have demonstrated a consistent doseresponse relationship between increasing
alcohol consumption and decreasing incidence oI coronary heart disease, despite an increase in mortality due
to a number oI other diseases |13|. More recently, in vivo animal studies have demonstrated an inhibitory
eIIect oI ethanol on neointimal Iormation Iollowing balloon injury |4,5|. These observations have prompted
Iurther investigation into the direct eIIect oI ethanol on vascular endothelial and smooth muscle cell Iunction.
In vivo, cells oI the blood vessel wall are continuously subjected to hemodynamic Iorces due to Ilowing blood
that are now recognized as eliciting critical biologic responses that result in modulation oI vessel Iunction and
structure |68|. Thus, it is important to consider these Iorces in any study oI ethanol and vascular cells. The
object oI this chapter is to Iocus on some key Iunctions oI vascular cells that are modulated by hemodynamic
Iorces (e.g., endothelial nitric oxide production; smooth muscle cell migration and proliIeration), and how
ethanol has been reported to aIIect these responses.
MECHANICAL FORCES AND VASCULAR CELLS
In vivo, cells oI the blood vessel wall are continuously subjected to mechanical Iorces associated with blood
Ilow. These hemodynamic Iorces can be resolved into two components; shear stress, the tangential Irictional
Iorce acting at the endothelial cell surIace, and pressure-stretch acting perpendicular to the vascular wall. In
the arterial circulation, where blood Ilow is pulsatile, the endothelial cell is the recipient oI most oI the shear
stress, whereas both the endothelial and smooth muscle cells, together with the underlying matrix, are
subjected to stretch (cyclic strain) |68|. It is now recognized that hemodynamic Iorces directly inIluence
vascular cell biology and play an important role in the acute control oI vascular tone, vascular remodeling and
the Iocal development oI atherosclerotic lesions |68|. A large number oI studies have veriIied the hypothesis
that mechanical stresses and strains contribute to the development oI vascular diseases. It has been
demonstrated that increased tensile stress and strain due to hypertension may induce and/or Iacilitate vascular
hypertrophy, whereas oscillatory low Iluid shear stress and/or altered shear gradients due to eddy blood Ilow
(typically near branches, biIurcations, regions oI arterial narrowings and curvature) may
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initiate or promote Iocal atherosclerosis and intimal hyperplasia |9|. In most large-size vessels, one can
estimate the magnitude oI the Iluid shear stress (t), t 4nQ/ar
3
(Hagen-Poiseuille law), as being proportional
to viscosity (n) and Ilow rate (Q) and inversely proportional to the third power oI the internal vessel radius (r).
This relation highlights the Iact that relatively small decreases in vessel diameter at constant Ilow can
markedly increase shear stress at the endothelial surIace.
SHEAR STRESS AND ENDOTHELIAL CELLS
The endothelium occupies a strategic location and acts as an interIace between the blood stream and the vessel
wall. Because oI this location, Iluid shear stress is one oI the most important mechanical Iorces acting upon
vascular endothelium. Shear stress can inIluence a variety oI endothelial cell Iunctions including the
production oI vasoactive mediators, activation oI transcriptional regulatory Iactors, and the expression oI
cellular adhesion molecules |6,10,11|. The molecular mechanism(s) responsible Ior transduction oI shear
stimuli and the relevant intracellular signalling pathways in endothelium are not Iully deIined, but likely
involve the activation oI integrins, guanine nucleotide-binding proteins (G-proteins) and cascades oI protein
kinases |10,11|.
It is now well established that endothelial cells respond to increases in Ilow by modulating their release oI
vasoactive agents such as the vasorelaxants nitric oxide (NO) and prostacyclin (PGI
2
), and the vasoconstrictor
endothelin (Figure 9.1). Indeed, shear stress is thought to be the premiere physiological stimulus Ior NO |10|.
Nitric oxide is synthesized
Figure 9.1 Hemodynamic Iorces directly inIluence vascular cell biology. Fluid shear
stress and/ or pressure (cyclic stretch) can modulate the production oI vasoactive
mediators such as nitric oxide (NO), prostacyclin (PGI
2
) and endothelin (ET) Irom
the endothelium, which in turn inIluence smooth muscle cell structure and Iunction.
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Figure 9.2 Shear stress stimulates nitric oxide (NO) production by endothelial cells.
By a mechanism thought to involve a pertussis toxin-sensitive G protein (G) and a K
channel, shear stress stimulates nitric oxide synthase (NOS) activity in endothelial
cells. The resulting NO can stimulate soluble guanylyl cyclase (GC) in adjacent
smooth muscle cells, leading to increased levels oI cGMP and subsequent
vasorelaxation and inhibition oI proliIeration.
by the heme-containing enzyme nitric oxide synthase (NOS) Irom L-arginine in a reaction that produces
stoichiometric amounts oI L-citrulline |12|. Three isoIorms oI NOS have been identiIied by gene cloning. Two
are constitutively expressed and one, the inducible NOS (iNOS) is produced de novo in response to
inIlammatory cytokines |12|. Activation oI NOS and release oI NO results in stimulation oI a soluble guanylyl
cyclase leading to a proIound increase in intracellular cGMP levels within most target cells |12| (Figure 9.2).
NO is a multiIunctional molecule and plays a pivotal role in regulating blood Ilow by inhibiting smooth
muscle contraction as well as platelet aggregation and adhesion |12|. In addition, NO has been shown to
inhibit vascular smooth muscle cell proliIeration |13,14|. G-proteins Iunction as transducers oI signals across
the cell membrane by coupling diverse receptors to eIIectors and thus play a central role in signal transduction
and cell biology |15,16|. Recent evidence suggests that both inhibitory G-proteins (Gio1,2,3), which are
pertussis toxin sensitive, and Goq may play a role in both agonist- and shear stress-induced activation oI
constitutive NOS (eNOS) in EC |17,18|. Stimulation oI these G-proteins triggers a number oI signal
transduction cascades, including activation oI K
(mitoK
ATP
) channels. Originally puriIied
Irom inner mitochondrial membranes in beeI heart, these channels are important regulators oI mitochondrial
matrix volume |37|. Opening oI cardiac mitoK
ATP
channels leads to membrane depolarization, matrix
swelling, and accelerated respiration |38|. Diazoxide has been identiIied as a selective mitoK
ATP
channel
opener |39|, and diazoxide treatment oI both isolated cardiac myocytes |39| and intact myocardium |40|
induces protection against ischemia-reperIusion injury. Diazoxide also reduces calcium paradox injury in
isolated rat heart |41|, a protective eIIect comparable to that observed with acute ethanol exposure |12|. 5-
hydroxydecanoate (5-HD) has been identiIied as a selective inhibitor oI mitoK
ATP
channels |39|,
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and 5-HD pretreatment oI intact rat heart abolishes ischemic preconditioning |42|. Protein kinase C appears to
modulate mitoK
ATP
channel activity because treatment oI isolated rabbit cardiac myocytes with the PKC
activator phorbol 12-myristate 13-acetate (PMA) potentiates the eIIects oI diazoxide |43| and because
chelerythrine treatment oI isolated rat heart abolishes diazoxide-induced protection |40|. Importantly, ischemic
preconditioning was recently shown to redistribute c protein kinase C to mitochondria in rabbit myocardium
|44|.
We recently completed a study in which we tested the hypothesis that chronic moderate alcohol consumption
reduces cardiac ischemia-reperIusion injury by activation oI mitoK
ATP
channels |45|. Adult male Sprague-
Dawley rats received a diet oI rodent chow and 18 ethanol (vol/vol) in their drinking water Ior 10 months, a
Ieeding schedule previously reported to induce cardiac protection |27|. At the end oI the treatment period,
there were no diIIerences in body weight, heart weight, baseline LV developed pressure, or coronary Ilow
between ethanol-Ied rats and age-matched controls. Serum ethanol levels were measured prior to each
experiment and averaged 15 + 1 mg/dL (3 mM) |45|. Hearts Irom control and treated rats were isolated and
perIused using a modiIied LangendorII method. AIter a 20 minute equilibration period, hearts were subjected
to 45 minutes oI no-Ilow ischemia and 48 minutes oI reperIusion. LV developed pressure recovered to 45 oI
pre-ischemic levels in hearts Irom ethanol-Ied animals compared to only 20 in controls (p 0.01). Creatine
kinase release was lower Irom hearts oI ethanol-Ied animals compared with controls (14 + 1 vs. 26 + 1 U/min/
gww, p 0.01). Treatment oI control hearts with 100 M 5-HD Ior 10 minutes immediately prior to ischemia-
reperIusion had no eIIect on subsequent recovery oI LV developed pressure or on creatine kinase release.
However, 5-HD treatment abolished resistance to ischemia-reperIusion injury in hearts Irom ethanol-Ied rats,
supporting a critical role Ior mitoK
ATP
channel activation in ethanol-induced protection |45|. Studies to
determine how moderate alcohol exposure modulates mitoK
ATP
channel activity are currently underway.
CONCLUSIONS
Numerous epidemiological studies support a beneIicial eIIect oI light-to-moderate alcohol consumption in
decreasing the risk oI myocardial inIarction and death due to coronary heart disease. In rodent heart models,
moderate ethanol exposure directly protects cardiac myocytes through signal transduction pathways involving
activation oI protein kinase C. Acute exposure oI hearts to low concentrations oI ethanol (10 mM) rapidly
induces powerIul protective mechanisms against ischemia-reperIusion injury. ThereIore, there may be
considerable therapeutic potential Ior the administration oI physiological concentrations oI ethanol to patients
prior to elective procedures that involve myocardial ischemia, such as coronary angioplasty and cardiac
surgery. Chronic exposure oI hearts to low concentrations oI ethanol induces sustained protection against
ischemia-reperIusion injury. Public health recommendations are designed to reassure current light-to-moderate
drinkers but do not encourage new drinkers because oI concerns regarding alcohol abuse and the exacerbation
oI co-existing medical conditions such as diabetes mellitus. Further examination oI the cellular mediators oI
ethanol-induced cardiac preconditioning may lead to the development oI novel therapeutic agents Ior the
prevention and treatment oI coronary heart disease.
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ACKNOWLEDGMENT
Studies in the authors` laboratories were supported by National Institute on Alcohol Abuse and Alcoholism
grants #AA11147 (D.M-R.) and #AA11135 (M.O.G).
REFERENCES
1 Lieber CS. Medical disorders oI alcoholism. N. Engl. J. Med. 1995; 333: 1058.
2 Pearson TA. AHA Medical/ScientiIic Statement. Alcohol and heart disease. Circulation 1996; 94: 3023.
3 Friedman LA, Kimball AW. Coronary heart disease mortality and alcohol consumption in Framingham.
Am. J. Epidemiol. 1986; 124: 481.
4 Fuchs CS, StampIer MJ, Colditz GA, Giovannucci EL, Manson JE, Kawachi I, Hunter DJ, Hankinson
SE, Hennekens CH, Speizer FE, Willett WC. Alcohol consumption and mortality among women. N. Engl.
J. Med. 1995; 332: 1245.
5 Thun MJ, Peto R, Lopez AD, Monaco JH, Henley SJ, Heath CW, Doll R. Alcohol consumption and
mortality among middle-aged and elderly U.S. adults. N. Engl. J. Med. 1997; 337: 1705.
6 Yang T, Doherty TM, Wong ND, Detrano RC. Alcohol consumption, coronary calcium, and coronary
heart disease events. Am. J. Cardiol. 1999; 84: 802.
7 Gaziano JM, Gaziano TA, Glynn RJ, Sesso HD, Ajani UA, StampIer MJ, Hennekens CH, Buring JE.
Light-to-moderate alcohol consumption and mortality in the physicians` health study enrollment cohort. J.
Am. Coll. Cardiol. 2000; 35: 96.
8 Criqui MH, Cowan LD, Tyroler HA, Bangdiwala S, Heiss G, Wallace RB, Cohn R. Lipoproteins as
mediators Ior the eIIects oI alcohol consumption and cigarette smoking on cardiovascular mortality.
Results Irom the Lipid Research Clinics Follow-up Study. Am. J. Epidemiol. 1987; 126:629.
9 Langer RD, Criqui MH, Reed DM. Lipoproteins and blood pressure as biologic pathways Ior the eIIect oI
moderate alcohol consumption on coronary heart disease. Circulation 1992; 85: 910.
10 Renaud SC, Beswick AD, Fehily AM, Elwood PC. Alcohol and platelet aggregation: the Caerphilly
Prospective Heart Disease Study. Am. J. Clin. Nutr. 1992; 55: 1012.
11 Ridker PM, Vaughan DE, StampIer MJ, Glynn RJ, Hennekens CH. Association oI moderate alcohol
consumption and plasma concentration oI endogenous tissue-type plasminogen activator. JAMA 1994; 272:
929.
12 AuIIermann W, Wu S, Parmley W, Wikman-CoIIelt J. Ethanol protects the heart against the calcium
paradox injury. Cell Calcium 1990; 11: 47.
13 Simkhovich BZ, Przyklenk K, Kloner RA. Role oI protein kinase C as a cellular mediator oI ischemic
preconditioning: a critical review. Cardiovasc. Res. 1998; 40: 9.
14 Kloner RA, Yellon D. Does ischemic preconditioning occur in patients? J. Am. Coll. Cardiol. 1994; 24:
1133.
15 Billinger M, Fleisch M, Eberli FR, Garachemani A, Meier B, Seiler C. Is the development oI myocardial
tolerance to repeated ischemia in humans due to preconditioning or to collateral recruitment? J. Am. Coll.
Cardiol. 1999; 33: 1027.
16 Laskey WK. BeneIicial impact oI preconditioning during PTCA on creatine kinase release. Circulation
1999; 99: 2085.
17 Speechly-Dick ME, Grover GJ, Yellon DM. Does ischemic preconditioning in the human involve
protein kinase C and the ATP-dependent K
channels modulate cardiac mitochondrial Iunction. Am. J. Phvsiol. 1998; 275: H1567.
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Page 113
39 Liu Y, Sato T, O`Rourke B, Marban E. Mitochondrial ATP-dependent potassium channels: novel
eIIectors oI cardioprotection? Circulation 1998; 97: 2463.
40 Wang Y, Hirai K, AshraI M. Activation oI mitochondrial ATP-sensitive K
channels by protein
kinase C. Circ. Res. 1998; 83: 110.
44 Zhang J, Bolli R, Lalli J, Tang XL, Li RCX, Zheng Y, Pass J, Ping P. Ischemic preconditioning and
phorbol ester redistribute protein kinase C c to the nucleus, sarcolemmal membranes, and mitochondria in
rabbit myocardium. Circulation 1999; 100: I-325.
45 Zhou P, Zhou HZ, Gray MO. Mitochondrial K-ATP channel activation is necessary Ior chronic cardiac
preconditioning in a rat model oI moderate alcohol consumption. Circulation 2000; 102 (Suppl. S): 1410.
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Chapter 11
Alcohol and smoking: synergism in heart disease?
Jin Zhang and Ronald Watson
INTRODUCTION
It is well known that cigarette smoking is a strong risk Iactor Ior developing cardiovascular disease (CVD) |1|.
Moderate wine drinking has cardioprotective eIIects while alcohol abuse causes cardiomyopathy, hypertension
and stroke in most cases. Epidemiologic studies suggest that current and Iormer alcoholic adults are at greater
risk Ior some deleterious health eIIects oI smoking, particularly cancer and cardiovascular disease, than are
members oI the general smoking and nonsmoking populations. More alcoholics die Irom tobacco-related
diseases than Irom alcoholism |2|. Although many studies have Iound individual eIIects oI tobacco smoke or
alcohol in promoting cardiovascular disease, Iew studies have investigated the synergisms during concomitant
use oI alcohol and tobacco. It is really very complicated and conditional since it depends on the dosage and
types oI alcohol and tobacco use, as well as other aspects oI health condition. Most heavy alcohol users also
smoke or have smoked superIrequently.
CIGARETTE SMOKING AND CARDIOVASCULAR DISEASE
Cigarette smoking-related cardiovascular diseases have been described widely. However, the mechanisms oI
their eIIects on cardiovascular system were not totally clear. The eIIects oI nicotine and carbon monoxide on
blood vessel walls, unIavorable lipid proIiles, increased myocardial work and the decreased oxygen carrying
capacity oI the blood oI smokers contribute to the overall eIIect oI cigarette smoking on cardiovascular disease
|3|. OI the increased cardiovascular risk caused by smoking, it is estimated that approximately one-tenth oI
this is due to smoking-induced changes in serum lipid |4|. The majority oI studies indicate elevations in serum
cholesterol, phospholipids, triglycerides, low-density lipoprotein (LDL) and increased hepatic lipase activity in
smokers, with decreased serum high-density lipoprotein (HDL) cholesterol |5|.
A mechanism to explain the link between smoking and some oI the observed changes in serum lipid and
lipoprotein concentrations includes the pharmacological eIIects oI nicotine in stimulating sympathetic nervous
activity and release oI catecholamines. Catecholamines mediate lipolysis, causing an increase in plasma
concentrations oI Iree Iatty acids and very low-density lipoprotein triglycerides. Free Iatty acids stimulate
hepatic secretion oI very low-density lipoprotein and hence triglycerides and high-density lipoprotein
concentrations vary inversely with low-density lipoprotein concentrations in serum |6|. On the other hand,
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smokers had higher levels oI Iibrinogen, plasminogen activator inhibitor 1 (PAI-1) activity and Iasting and
steady-state C-peptide levels during the clamp. They also showed insulin resistance and lipid intolerance with
an impaired triglyceride clearance aIter a mixed test meal. Insulin resistance is an important reason Ior
promoting the increased cardiovascular morbidity in smokers |7|.
OI thousands oI cigarette smoke compounds, many are capable oI generating reactive oxygen species (ROS)
during metabolism. ROS can initiate a serial oI cellular responses, such as activation oI nuclear Iactor kappa B
(NF-kB), which plays an important role in the proinIlammatory process. NF-kB can induce IL-1 beta, platelet-
activating Iactor (PAF) and tumor necrosis Iactor (TNF) |8|. IL-1 beta is well known as an inducer oI several
other proinIlammatory enzymes such as the inducible cyclooxygenase-2 (COX-2); PAF is shown to beneIit
platelet aggregation. These are two Iactors involved in atherogenesis |9|. TNF may decrease myocardial
contraction through enhancing inducible nitric oxide synthase (iNOS) and nitric oxide (NO) production or by
inducing myocardial apoptosis |10|.
In addition, cigarette smoking is associated with unhealthy eating patterns, including increased intakes oI
alcohol, total Iat, cholesterol, saturated Iat, a lower consumption oI Ioods with Iibers such as Iruits and
vegetables that may lower cholesterol levels, as well as deIiciencies oI vitamin C, E and beta-carotene
|11,12|. These Iactors make smokers and heavy alcohol users more predisposed to cardiovascular disease.
CARDIOPROTECTIVE EFFECT OF MODERATE WINE DRINKING
There is evidence that moderate wine consumption protects against CAD. Two studies linked the beneIicial
eIIects oI moderate drinking only to wine |13,14|. Red wine contains several Ilavonoids and phenolic
compounds with signiIicant antioxidant properties. The protection eIIects against atherogenesis suggested that
antioxidants in wine might play a role through modiIication oI LDLs |15|. However, it seems unlikely that the
cardioprotective eIIects are due solely to the antioxidant properties oI these compounds, since the orally
ingested phenolic antioxidants may not reach suIIiciently high plasma levels to aIIect the oxidizability oI LDL
in humans |16|. Moreover, the majority oI epidemiological studies have shown that all alcohol beverage types
(beer, wine, and distilled spirits) conIer some cardioprotective eIIects |17|.
What is the mechanism oI alcohol cardioprotection? The beneIicial eIIects oI moderate drinking have been
addressed on Iactors involved in atherogenesis |17|. First oI all, alcohol increases plasma HDL level and
activity oI lipoprotein lipase, which showed an inverse relationship with the risk oI CAD. Secondly, in animal
models, ethanol reduced atherogenic plaques by inIluencing the inIlammatory process oI endothelial lesions.
Alcohol interIeres with the expression oI vascular adhesion molecules such as VCAM-1 and ICAM-1 by
inhibiting the transcription Iactor NF-kB |18|. Additionally, inhibition oI the enzyme HMG-CoA reductase, a
key enzyme in the synthesis oI cholesterol, results in the reduction oI plasma cholesterol. Furthermore alcohol
has antithrombotic eIIects which could contribute to its cardioprotective eIIects. Possible Iactors responsible
Ior the eIIects oI moderate alcohol consumption on clotting include an increase in the prostacyclin/
thromboxane ratio, decreased platelet aggregability in response to most agonists, increased release oI
plasminogen activator, and lowered Iibrinogen levels |19|. Certainly, some alcoholic drinks, especially wine,
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Page 116
supply phytochemical isoIlavenoids, vitamins which have powerIul antioxidant eIIects. These eIIects include
inhibition oI low-density lipoprotein oxidation as well as reduction in coagulation and improved thrombolysis.
Most importantly, the beneIicial protective eIIects oI a moderate alcohol intake are Iound only in non-smokers
|20|.
ALCOHOL ABUSE AND CARDIOVASCULAR DISEASE
Although there is considerable evidence that moderate drinking protects against mortality and morbidity Irom
coronary heart disease |21,22|, heavy consumption is shown to have deleterious cardiovascular eIIects. It
exerts its adverse eIIects by increasing the risks oI cardiomyopathy, hypertension, and stroke |23|. Chronic
ethanol consumption has been linked to the prevalence oI hypertension, which contributes to an increased
incidence oI stroke. Heavy drinkers have a 10 mmHg higher systolic blood pressure than non-drinkers even
though the relationship may diIIer between men and women |24|. Stroke is a leading cause oI death and
morbidity. Alcohol may increase the risk oI stroke through various mechanisms that include hypertension,
hypercoagulable states, cardiac arrhythmias, and cerebral blood Ilow reductions |25|. Hypertension, including
borderline hypertension, is probably the most important stroke risk Iactor based on degree oI risk and
prevalence. Furthermore, cardiac morbidity, cigarette smoking, diabetes, physical inactivity, and high levels oI
alcohol consumption are also strongly related to stroke risk |26|. Recently, chronic consumption oI alcohol has
proven detrimental to heart tissue and can lead to alcohol-induced heart muscle disease, a major cause oI non-
ischemic cardio-myopathy in Western society |27|. Alcohol-induced heart muscle disease yields abnormal
contractile Iunction and energy metabolism, sometimes resulting in arrhythmias, cardiomegaly, and congestive
heart Iailure. A molecular mechanism underlying observed alcohol-induced heart Iailure is a nonoxidative
pathway Ior alcohol metabolism in several target tissues including heart. Normally the mitochondria
manuIactures most oI the cell`s energy ATP via the tricarboxylic acid cycle (TCA cycle), beta-oxidation oI
Iatty acids and oxidative phosphorylation. The very high-energy requirements oI heart muscle are mostly met
by beta-oxidation oI Iatty acids. Fatty acids bound to albumin or Irom chylonmicrons and very low-density
lipoproteins enter the myocyte where they are converted to acetyl CoA through beta-oxidation in the
mitochondria matrix. Acetyl CoA then enters the TCA cycle. The products oI TCA cycle will enter the
electron transport chain oI the inner mitochondrial membrane, where most oI the cell`s ATP is produced. In
alcoholics, it turns out that nonesteriIied Iatty acids are esteriIied with ethanol to produce Iatty acid ethyl esters
(FAEEs), which can attach to mitochondria and uncouple oxidative phosphorylation and disrupt the energy
process. Furthermore, electron-microscopic and histochemical analysis have revealed shrunken, disorganized
myocytes, loss oI myoIibrils, a dilated and disordered sarcoplasmic reticulum, excessive accumulation oI
lipids, and enlarged mitochondria with chaotic cristae. It has also been indicated that chronic alcohol
administration decreases activity oI the Na
), alkoxyl (RO
RO
, and H
2
O
2
are thereIore conveniently classed as reactive oxygen species (ROS). In general, Iree radicals are continuously
Iormed in all cells as unwanted (and potentially damaging) by-products oI normal aerobic metabolism. In
some instances they may perIorm beneIicial actions e.g., generation during phagocytic action, and Nitric
Oxide in the regulation oI vascular tone. However, the beneIicial eIIects are comparatively Iew compared to
the damaging eIIects oI ROS. Included in the category oI ROS are singlet oxygen (
1
O
2
), ozone (O
3
) |16|.
Nitric oxide (NO
OH
). Normally, Fe
2
or Cu
2
are sequestered by binding
proteins in vivo. DNA, proteins and lipids are potential biomolecular targets Ior Iree radical attack, with lipids
being particularly susceptible to peroxidative chain reactions, resulting in damage to cell membranes and
subcellular organelles.
Cells are protected Irom Iree radical induced damage by a variety oI Iree radical scavenging antioxidants.
Antioxidants enzymes, which are capable oI eliminating Iree radical species that cause tissue damage, include
catalase, glutathione peroxidase and superoxide dismutase (also termed preventative antioxidants |17|). Thus,
with regards the enzyme superoxide dismutase: . The hydrogen peroxide generated in
this or other reactions can be converted into water and oxygen (2H
2
O
2
2H
2
OO
2
) via catalase, whilst
glutathione peroxidase reduces peroxides (ROOH2GSHROHH
2
OGSSG). These
Table 12.1 Reactive oxygen species
Superoxide radical
Singlet oxygen
1
O
2
Hydrogen peroxide H
2
O
2
Hypochlorous acid HOCl
Alkoxyl radicals RO
Peroxyl radicals
Hydroxyl radical OH
Source: Adapted Irom |228|.
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enzymatic reactions contrast with the non-enzyme antioxidants such as urate, biothiols such as glutathione,
reduced coenzyme Q
10
, ascorbate, carotenoids, Ilavonoids, lycopenes and the tocopherols which have chain-
breaking or radical trapping properties and may also be capable oI directly repairing anti-oxidants |17|. Some
plasma proteins such as Ierritin and albumin can also be considered as antioxidants as they bind metal ions
such as Fe
2
and Cu
2
thereby minimizing the potential Ior OH
hydroxyl radical
RO
alkoxyl radical
R
peroxyl radical
H
2
O
2
hydrogen peroxide
1
O
2
singlet oxygen
O
3
ozone
NO
nitric oxide
ONOO
peroxynitrite
N
nitrogen dioxide radical
RNS reactive nitrogen species
LDL low density lipoprotein
ALD alcoholic liver disease
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219 Turner RJ, Wheatley LE, Beck NF. Impaired mitogen responses in lambs with white muscle disease.
Res. Jet. Sci. 1984; 37: 357358.
220 Higuchi T, Ichijo S, Osame S, Ohishi H. Studies on serum selenium and tocopherol in white muscle
disease oI Ioal. Nippon Juigaku Zasshi 1989; 51: 5259.
221 Hoshino Y, Ichijo S, Osame S, Takahashi E. Studies on serum tocopherol, selenium levels and blood
glutathione peroxidase activities in calves with white muscle disease. Nippon Juigaku Zasshi 1989; 51:
741748.
222 Osame S, Ohtani T, Ichijo S. Studies on serum tocopherol and selenium levels and blood glutathione
peroxidase activities in lambs with white muscle disease. Nippon Juigaku Zasshi 1990; 52: 705710.
223 de Gritz BG, Rahko T, Korpela H. Diet-induced lipoIuscin and ceroid Iormation in growing pigs. J.
Comp. Pathol. 1994; 110: 1124.
224 de Gritz BG. Copper-zinc superoxide dismutase (CuZnSOD) in antioxidant deIicient pigs. Zentralbl
Jeterinarmed A 1995; 42: 561573.
225 Dickerson B, McKnight A, Middleton J, Tyler JW, Bagley R, Valdez R. Electromyographic evaluation
oI a calI with white muscle disease. Jet. Rec. 1997; 140: 431432.
226 LoIstedt J. White muscle disease oI Ioals. Jet. Clin. North Am. Equine Pract. 1997; 13: 169185.
227 Walsh DM, Kennedy DG, Goodall EA, Kennedy S. Antioxidant enzyme activity in the muscles oI
calves depleted oI vitamin E or selenium or both . Br. J. Nutr. 1993; 70: 621630.
228 Halliwell B, Aeschbach R, Loliger J, Aruoma OI. The characterization oI antioxidants. Food Chem.
Toxicol. 1995; 33: 601617.
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Chapter 13
Alcohol and platelet function
Adam K. Mvers, Kabita Das and Qing-Hui Zhang
INTRODUCTION
Coronary heart disease (CHD) and its maniIestations account Ior approximately halI a million deaths annually
in the United States, 25 oI the nation`s total mortality |1|. Much progress has been made in deIining the
mechanisms involved in the pathogenesis and progression oI CHD, devising new therapeutic approaches Ior
the treatment and prevention oI CHD, and identiIying Iactors that promote susceptibility to this disease.
Important liIestyle Iactors aIIecting CHD risk include exercise, smoking, diet and alcohol consumption |2|.
Moderate drinking reduces risk oI CHD mortality, and although it is generally accepted that about halI oI the
risk reduction might be due to a beneIicial eIIect oI moderate consumption oI alcohol or alcoholic beverages
on plasma lipids |35|, the eIIects oI alcohol on other parameters undoubtedly contribute. Although there are
many deIinitions oI moderate alcohol consumption` the United States Departments oI Agriculture and Health
and Human Services deIine moderate drinking as no more than one drink per day Ior women and no more
than two drinks per day Ior men` (a standard drink contains approximately 12 grams oI ethanol, which is the
amount present in a 12 oz bottle oI beer, a 5 oz serving oI table wine, or 1.5 ounces oI 80 prooI distilled
spirits) |6|. The eIIects oI alcohol on platelet aggregation and subsequent thrombus Iormation have been
studied by several laboratories including our own |714|, and is the topic oI the present review. Platelets are
oI substantial interest because oI their role in CHD-related mortality. Myocardial inIarction (MI) most oIten
results Irom thrombotic occlusion oI stenosed coronary vessels. In this scenario, the blockage is due to the
rupture oI an atherosclerotic plaque, which exposes a thrombogenic surIace to platelets. Adherence oI platelets
and subsequent thrombus Iormation eventually blocks Ilow through the aIIected coronary artery, causing
ischemia, acute MI and potentially death |15|. An inhibitory eIIect oI alcohol on platelet aggregation is
thereIore a potential Iactor in the reduced risk oI CHD-related death with moderate drinking. In addition,
studies have suggested that alcohol consumption might have a role in inhibiting the progression oI
atherosclerosis, a process that involves both plasma lipids and platelets |16|. While this chapter Iocuses mainly
on the possibly beneIicial aspects oI moderate alcohol consumption on the hemostatic system, it is recognized
that there are complex issues associated with drinking, which can vary Irom individual to individual. Some oI
these are discussed elsewhere in this volume.
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MECHANISMS OF HEMOSTASIS
In order to consider the eIIects oI alcohol on platelet aggregation and their mechanisms, it is Iirst necessary to
provide a brieI background on the coagulation and Iibrinolytic systems responsible Ior normal hemostasis.
Vascular injury leads to activation oI platelets and adhesion to the vessel wall. Platelet receptors Ior
subendothelial components such as collagen, Iibronectin, or laminin promote adhesion to the injured vessel
wall; under high shear conditions, these interactions are not adequate and von Willebrand Iactor and its platelet
receptor are required Ior adhesion |17|. During primary hemostasis, this adhesion oI platelets to the vascular
wall produces activation, which is characterized by platelet morphological and biochemical changes,
aggregation oI platelets to each other, and the secretion oI platelet granule contents (the platelet release
reaction). The end result is the primary hemostatic plug. The subsequent Iormation oI Iibrin around the
primary platelet plug constitutes secondary hemostasis, and is the end result oI a series oI biochemical
reactions involving the coagulation Iactors oI plasma and the platelet surIace.
Stimulation oI platelets involves multiple pathways oI activation. One major biochemical pathway, which can
be activated by receptor binding oI several agonists including collagen, thrombin, platelet activating Iactor,
and thromboxane A2, is the phospholipase C-mediated second messenger system. Phosphatidylinositol (4,5)
bis-phosphate is broken down to inositol triphosphate (IP3) and diacylglycerol by phospholipase C when such
agonists bind to their receptors. IP3 causes an increase in cytosolic-Iree calcium, a central event in platelet
activation and aggregation, initially resulting in platelet shape change Irom a discoid-shaped Iormed element
to a spherical body with pseudopods. Diacylgylcerol activates protein kinase C directly, which in concert with
the elevated calcium is responsible Ior platelet aggregation and secretion oI granule contents. These granule
contents are numerous and serve a variety oI Iunctions, important among them support oI hemostasis and
vascular repair. Notably, amine storage granules release ADP, which is a platelet agonist and thereIore recruits
Iurther platelets Ior aggregation |17|.
A second major stimulatory pathway is mediated by phospholipase A2, an enzyme that is activated when
intraplatelet Ca
2
is elevated and to some extent by agonist-receptor interactions. This enzyme releases the
Iatty acid Irom the sn-2 position oI membrane phospholipids; when the Iatty acid is arachidonic acid, it is
metabolized rapidly in platelets to thromboxane A2 (TXA2), a potent platelet agonist. Thus, TXA2 ampliIies
platelet responses. Arachidonic acid can also be released subsequent to the activation oI phospholipase C, as a
result oI the breakdown oI diacylglycerol by diglyceride lipase, but this pathway probably contributes a minor
amount oI arachidonic acid compared to the phospholipase A2 pathway |18|.
Platelet activation can be inhibited by both the cAMP and cGMP signal transduction pathways. A major
physiological agonist Ior adenylyl cyclase activation and cAMP production in platelets is prostacyclin.
Although platelets do not synthesize prostacyclin, its production by vascular endothelium inhibits platelet
activation. Nitric oxide produced by vascular tissues activates guanylyl cyclase in platelets and stimulates
cGMP production; platelets can also directly produce nitric oxide as a negative Ieedback mechanism during
activation |19|. Interestingly, alcohol stimulates vascular prostacyclin synthesis under some experimental
conditions |20|, although the relevance oI this to the in vivo hemostatic system has not been adequately
demonstrated.
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Regardless oI the mechanism or stimulus Ior platelet activation, the Iinal common pathway involves
expression oI glycoprotein (Gp) IIb-IIIa on the platelet surIace, which results in binding and cross-linking oI
platelets with Iibrinogen |17|. Activation also produces the expression on the platelet surIace oI binding sites
Ior coagulation Iactors and enzymes, accelerating the rate oI thrombin Iormation. Thrombin converts
Iibrinogen to Iibrin, which adheres to damaged surIaces oI blood vessels enmeshing platelets, blood cells, and
plasma to Iorm the secondary hemostatic plug. During the process oI platelet activation, the initial stage oI
aggregation (primary platelet aggregation) is reversible, but once platelets have undergone secondary
aggregation and release oI granule contents, the aggregation is irreversible.
The platelet-Iibrin plug can eventually be broken down and removed through the process oI Iibrinolysis, which
involves the plasmin/plasminogen system. Plasminogen is converted to plasmin by activators generated by
endothelial and smooth muscle cells: tissue type plasminogen activator (t-PA) and urokinase type plasminogen
activator (u-PA). Plasmin is a proteolytic enzyme resembling trypsin, which digests Iibrin Iibers as well as
Iibrinogen and clotting Iactors |21|. By secreting plasminogen activator inhibitor (PAI-1), platelets serve to
protect the clot Irom degradation and inhibit Iibrinolysis.
Thus, many sites exist at which alcohol might interact with the hemostatic system, and possibly aIIect
parameters related to risk oI CHD. The Iollowing is an overview oI work done to date by our laboratory, as
well as a review oI the Iield in general. In many oI these studies, the primary methodology used was optical
density platelet aggregometry, in which platelet rich plasma or platelets resuspended in buIIer are stimulated
by agonists and changes in optical density oI the platelet preparation are measured as platelets become
activated and Iorm aggregates. In our own studies, we have also incorporated whole blood platelet
aggregometry. In this technique, whole blood is stimulated with a platelet agonist, and increased electrical
impedance is measured as platelets aggregate on a pair oI metal electrodes. SpeciIically, our interest has been
in the eIIects oI ethanol itselI on platelets, as opposed to eIIects oI other biologically active compounds
contained in various alcoholic beverages (the latter are considered elsewhere in this volume).
ACTIONS OF / N v/ 7RD ALCOHOL ON PLATELETS
The immediate Iunctional eIIect oI ethanol usually observed under experimental conditions is inhibition oI
platelet aggregation in response to most agonists such as thrombin, ADP, epinephrine and collagen |79|. This
eIIect has been generally consistent across both animal and human studies in in vitro, in vivo and ex vivo
preparations with various methods oI ethanol administration. Despite such broad evidence, questions have
remained regarding the relevance oI the eIIect to moderate alcohol consumption in humans, due to the doses oI
alcohol used in those studies, the method oI administration, and various other Iactors. For this reason, our own
laboratory has sought to systematically evaluate the eIIects oI ethanol in animal and human studies, with both
in vitro addition oI alcohol and alcohol consumption, using multiple platelet agonists and multiple
concentrations oI alcohol. Here, we review our own Iindings, in the context oI the broader literature.
In vitro platelet studies in several species including man have generally |13,22,23| but not always |12,24,25|
demonstrated an inhibitory eIIect oI alcohol on aggregation or other measures oI activation. In the Iirst study
in our laboratory, we actually observed that alcohol could promote platelet aggregation under some
experimental conditions |12|. We made the
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serendipitous observation that when alcohol was added directly to whole blood but not platelet rich plasma
(PRP), it directly induced aggregation oI platelets at Iinal concentrations as low as 34 mM, as measured by
impedance aggregometry. This concentration is equivalent to blood alcohol oI 156 mg; lower concentrations
were not tested. Further experiments demonstrated that the pro-aggregatory action oI alcohol in whole blood
was dependent upon the direct injection oI ethanol into whole blood, achieving a locally high concentration oI
alcohol that produces lysis oI red blood cells. Consequently, the ADP released during hemolysis activates
platelets. Thus, that early study had limited relevance to health eIIects oI moderate alcohol consumption, but
may be related to the hematological abnormalities occurring as a result oI binge drinking and acute alcohol
toxicity |23|. Observations that alcohol might activate platelets in vitro under some circumstances have been
usually made when platelets were exposed to the ethanol in high Iinal concentrations (inconsistent with blood
alcohol levels attained during consumption) or, as discussed above, high local concentrations during alcohol
delivery |12,24,25|. When working with a multiIunctional and potentially toxic agent such as ethanol, careIul
interpretations oI results, taking into account the physiological and pharmacological relevance oI alcohol
concentrations and delivery modality, is obviously important.
Our subsequent study |13| is an example oI the more commonly observed, inhibitory eIIect oI in vitro alcohol
on platelets. We systematically examined a more physiologically relevant` range oI alcohol concentrations (1
85 mM, equivalent to 5391 mg), added as a dilute solution (7.8 w/v) to human and rat PRP and whole
blood. Aggregation responses to collagen, ADP and arachidonic acid were studied. Collagen-induced platelet
aggregation was inhibited by the short term exposure to alcohol, at concentrations as low as 4.25 mM (20 mg
) in rat whole blood (higher concentrations were required Ior signiIicant eIIects in human samples, perhaps
owing to the small sample size oI 6 in this study).
It is generally accepted that the major mechanism Ior the inhibitory eIIect oI ethanol (though not necessarily
Ior other components oI alcoholic beverages) on platelet aggregation involves inhibition oI phospholipase A2
and, as a result, inhibition oI thromboxane A2 synthesis |18,26|. For this reason, most studies, including ours
|13|, have observed a greater eIIect when secondary aggregation (which involves thromboxane A2 synthesis)
is induced, by agonists such as collagen or in human platelets, higher concentrations oI ADP. Alcohol does not
inIluence platelet shape change or primary aggregatory responses to ADP because these activities are not
closely associated with phospholipase A2 activity but rather with phospholipase C (in Iact, concentrations oI
ethanol well beyond physiological levels can actually induce shape change in human platelets) |25|. When
arachidonic acid is used as the platelet agonist, the phospholipase A2 step is bypassed and alcohol is a less
eIIicacious inhibitor |13|. An interesting possibility has been noted regarding the inhibition oI phospholipase
A2 activity by alcohol, in that increased membrane Iluidity could be a Iactor in this inhibition because this
enzyme is membrane bound. II increased platelet membrane Iluidity is associated with drinking |26|, this may
be especially beneIicial in subjects who consume a diet high in saturated Iats, contributing to the well-known
eIIects oI the French paradox oI low incidence oI CHD despite a diet rich in saturated Iats |7|.
Another platelet signal transduction system that is modulated in vitro by ethanol is the nitric oxide (NO)-
cGMP system. We originally perIormed studies based on the hypothesis that alcohol might inhibit platelet
aggregation and release reaction in part by enhancing cGMP production, but instead observed that platelet
guanylyl cyclase activity and cGMP
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production in response to the nitric oxide donor sodium nitroprusside is actually inhibited by alcohol |10|.
Such an action would theoretically potentiate platelet activation (contrary to the inhibition by alcohol actually
observed), suggesting that other actions oI ethanol in platelets (Ior example, inhibition oI phospholipase A2)
are Iunctionally more important, because the actual eIIect oI alcohol in vitro is to inhibit platelet activation.
/ N v/ vD ALCOHOL EXPOSURE IN ANIMALS AND PLATELET
FUNCTION
In the next phase oI our systematic evaluation oI ethanol and platelet Iunction, our laboratory investigated the
eIIects oI acute, in vivo exposure oI rats to ethanol through inhalation |11|. We Iocused on eIIects on whole
blood platelet aggregation, based on the apparent sensitivity oI this technique in the earlier in vitro
experiments |13|. By varying alcohol delivery rate and time oI exposure, blood alcohol concentrations (BAC)
can be controlled. Ex vivo platelet aggregation tests were perIormed aIter animals had been exposed to a
speciIic atmospheric ethanol environment Ior either 3, 6, or 9 hours which produced to BAC oI 127 + 15, 259
+ 21 mg, and 453 + 16 respectively. At the highest BAC (453 + 16 mg), responses to three doses oI
collagen (1, 3 or 5 g/ml) were signiIicantly inhibited, with the eIIects oI the two lower concentrations being
inhibited by more than 50. At 259 + 21 mg/, responses to the two lower collagen concentrations were
inhibited, while at BAC oI 127 + 15 mg/, the response to the low collagen concentration was signiIicantly
attenuated. Results with ADP and arachidonic acid were less consistent and less marked. Thus, these results
illustrated that acute in vivo alcohol exposure had eIIects very similar to those observed with in vitro addition
oI alcohol to whole blood or PRP, although the BACs tested in our study are substantially higher than those
associated with moderate alcohol consumption in humans.
Littleton et al. had previously studied the chronic eIIects on ethanol vapor inhalation in rats |27|. When
ethanol was given to the rats over a period oI 57 days to attain plasma level oI 50 mM (230 mg) ex vivo
aggregation responses to collagen were reduced in PRP. More proIound platelet inhibition and
thrombocytopenia were observed aIter 30 days oI inhalation; plasma ethanol concentrations in those rats
ranged Irom 80120 mM (368552 mg). Although these early experiments oI Littleton et al. involved long-
term intoxication associated with high plasma alcohol levels, the general result (inhibition oI platelet
aggregation aIter in vivo alcohol exposure by various routes, particularly in response to collagen) has been
conIirmed in several studies including ours described above.
Ex vivo platelet aggregation measurements can be a simple and convenient surrogate Ior analysis oI thrombotic
tendency in vivo, but, importantly, studies on the eIIects oI alcohol consumption on aggregation have been
supported by results oI in vivo thrombosis models, Ior example, in a rabbit experimentally induced arterial
thrombosis model |28|. Rabbits were given alcohol by gastric intubation, resulting in blood levels oI 48 or 100
mM (221 or 460 mg), and a catheter was used to produce arterial wall injury to stimulate platelet activation
and thrombosis. The dry weights oI thrombi were reduced in alcohol-treated rabbits compared to controls. In
addition to testing the eIIects oI ethanol, Rand et al. in a previous study demonstrated that it is the aggregation
and not adhesion to the vessel wall that is inhibited by ethanol |22|.
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ALCOHOLIC BEVERAGE CONSUMPTION AND HUMAN PLATELET
FUNCTION
As discussed elsewhere in this volume, quite a Iew epidemiological studies have examined the association
between morbidity and mortality Irom CHD and moderate alcoholic beverage consumption, and an inverse
association has been established in studies involving nearly a million subjects |29|. One example oI such
reports is a study oI American Cancer Society volunteers, which showed that the rate oI death Irom all
cardiovascular diseases was 3040 lower among men and women who consumed at least one alcoholic drink
daily than among nondrinkers. While it should be emphasized that alcohol consumption is associated with
higher death rates Irom injuries, violence, suicide, cirrhosis, certain cancers and hemorrhagic stroke |30|, the
incidence oI death Irom heart disease is much greater compared to these other causes, making any role oI
platelets potentially important.
Cross-cultural studies have shed light onto the French paradox involving the Mediterranean diet. A
Mediterranean diet typically consists oI high Iruit, vegetable, and grain intake, while also including one to two
drinks per day. The daily intake oI Iats and meat is also higher among those who consume this type oI diet, but
yet, the rate oI coronary heart disease is low |31|. This has led to studies such as the Caerphilly Prospective
Heart Disease Study |32| oI 1600 men aged 4966 years. This study is particularly noteworthy in the present
context, because along with other parameters related to CHD risk, platelet responses in PRP were measured
using thrombin, collagen and ADP. There was a decreased CHD risk associated with increased alcohol
consumption, and secondary aggregation to ADP was the aggregation test most closely associated with the
occurrence oI MI. In contrast, there was no inhibitory eIIect oI alcohol against thrombin induced aggregation;
in Iact, Ior each level oI alcohol intake, the response oI platelets to thrombin was higher than in nondrinkers
|32|. The eIIects oI alcohol or drinking on thrombin-induced platelet aggregation are complex; withdrawal
Irom alcohol in alcoholics as well as binge drinking has been associated with a platelet-rebound eIIect |33,34|,
with hypersensitivity oI platelets to physiological agonists, particularly thrombin.
The rebound eIIect may explain the rate oI sudden death and ischemic stroke in this subset oI the population.
In a related animal study perIormed by RuI et al. |35|, rats drank diluted alcohol, and aggregation to thrombin
was reduced substantially. However, aIter deprivation oI alcohol Ior 18 hours, platelet activation by thrombin
was more than doubled compared to the original response. This was also observed among men in the
Caerphilly study, with the rebound eIIect also seen in ADP-induced aggregation one to two hours aIter
consumption oI alcohol.
The issue oI how drinking aIIects platelet Iunction is complicated even more by the Iact that the non-alcoholic
components oI alcoholic beverages may also have eIIects on platelets (this aspect is discussed more Iully
elsewhere). Among wine drinking Iarmers lower platelet response to thrombin was observed compared to non-
drinkers, even aIter alcohol deprivation Ior 10 hours |37|. Similarly, in rats, the rebound to thrombin-induced
aggregation does not occur when animals are Ied red wine as opposed to ethanol beIore deprivation |38|. This
may be related to a reduction in lipid peroxidation by grape tannins.
Pikaar and colleagues investigated the eIIect oI moderate red wine consumption on twelve male volunteers |5|.
Four standardized amounts oI wine were consumed during 5-week intervals in randomized order. The doses
consisted oI 0, 2, and 4 glasses oI red wine a day (corresponding to 0, 23, and 46 grams oI alcohol a day). The
eIIects oI binge drinking`
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were also tested (14 glasses consumed over three days). Little diIIerence was seen between binge and daily
drinking, but collagen-induced aggregation was reduced with wine consumption compared to abstention.
Some studies have speciIically examined the potential role oI red wine Ilavanoids such as quercetin and
resveratrol in platelet inhibition and potential reduction oI CHD risk by wine consumption, based in part on
the observation that the compounds may prevent lipid oxidation |37|. Bertellini et al. demonstrated a dose-
dependent inhibition oI collagen induced aggregation by in vitro exposure oI platelets to resveratrol |38|. The
mechanisms involved have been postulated to involve suppression oI TXA2 production by trans-resveratrol
and an inhibition oI phospholipase C by quercetin. The in vivo relevance oI various red wine components to
platelet Iunctional parameters is only now being sorted out, and is discussed in more depth elsewhere in this
volume.
SPECIFIC EFFECTS OF ETHANOL CONSUMPTION ON PLATELETS
From the Ioregoing, although it is clear that consumption oI alcoholic beverages inhibits platelet Iunction in
humans, several questions remain regarding the nature oI the eIIect. Duration oI the eIIect and doseresponse
relationships, Ior example, are not established, and even the Iundamental question oI whether ethanol itselI has
a direct role in the eIIects oI alcoholic beverages on platelet Iunction has not been suIIiciently investigated.
Thus, we recently perIormed a study in human volunteers, who consumed ethanol in the Iorm oI grain alcohol,
at doses equivalent to one or two alcoholic beverages (0.25 or 0.5 ml ethanol/kg, respectively)
|14|. Aggregation oI platelets was measured in both PRP and whole blood, collected beIore and one hour aIter
consumption, in response to ADP, arachidonic acid and collagen, with sample size oI at least 16 Ior each
statistical comparison. This study demonstrated that alcohol itselI, at levels relevant to moderate consumption,
dose-dependently inhibited platelet aggregation. The response was most pronounced when collagen was the
agonist and aggregation was measured in whole blood, at the higher alcohol dose (blood alcohol concentration
one hour aIter consumption was only 38 mg). Interestingly, we observed that the eIIects were more evident
in women than in men.
While these observations suggest that an anti-platelet eIIect oI ethanol could contribute to the reduced risk oI
CHD-related mortality in drinkers, it must be emphasized that any contribution oI a platelet action oI ethanol
must be viewed in the context oI other actions oI ethanol and alcoholic beverage components. Furthermore,
the duration oI the antiplatelet eIIect is not known, nor are the eIIects oI chronic vs. acute alcohol consumption
or pattern oI consumption (regular consumption vs. binge drinking). Nonetheless, this is the Iirst clear
demonstration oI dose-dependent, inhibitory eIIects oI acute, moderate alcohol consumption on platelet
Iunction.
EFFECTS OF ACETALDEHYDE ON PLATELETS
An obvious question when considering eIIects oI drinking on platelet Iunction is whether the degradation
products oI alcohol, particularly acetaldehyde, have a role in the observed eIIects. InsuIIicient work has been
published to support Iirm conclusions, but some studies in rat and human suggest that acetaldehyde, like
ethanol, might reduce platelet responses to
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agonists |39,40|. We have been recently perIorming studies on acetaldehyde, and Iind little iI any eIIect oI
acetaldehyde, added in vitro, on human platelet aggregation at concentrations consistent with levels in humans
aIter ethanol consumption (unpublished data Irom our laboratory). More work is needed in this area.
ETHANOL AND OTHER ASPECTS OF HEMOSTASIS
Because a variety oI hemostatic Iactors beyond those associated with platelets also contribute to the
complications associated with coronary heart disease, it is important to consider the above inIormation on
platelets in the context oI some oI these other observations. One oI the strongest risk Iactors Ior myocardial
inIarction is elevated plasma Iibrinogen level |41|. The association oI Iibrinogen and alcohol consumption was
evaluated by Mennen and colleagues |42|. Alcohol consumption was associated with plasma Iibrinogen levels
in a U-shaped Iashion Ior men only, with Iibrinogen being the lowest in those subjects who drank 2059
grams oI alcohol per day. Fibrinogen levels were greater Ior nondrinkers and those who consumed over 60
grams oI alcohol per day. The type oI alcohol consumed also apparently played a role, with a lower level oI
Iibrinogen in those who drank wine and spirits as opposed to those who drank beer and cider (in which no
association was Iound).
Endothelial cells provide a stage Ior both coagulation and Iibrinolysis by synthesizing proteins involved in
both processes. With regard to other Iactors involved in hemostasis, an association has been observed between
alcohol exposure and the transcription oI t-PA, u-PA and PAI-1 |43|. It was demonstrated that a relatively low
concentration oI ethanol (0.010.10, v/v) increased surIace-localized Iibrinolytic activity, as well as t-PA
and u-PA antigen and mRNA levels, while decreasing PAI-1 antigen and mRNA levels. Pre-incubation oI
cultured endothelial cells produced time- and concentration-dependent eIIects; notably, increased Iibrinolytic
activity could be sustained Ior a Iull 24 hours aIter a brieI exposure oI endothelial cells to less than 0.1
ethanol. II this mechanism is operant in vivo, Irequent consumption oI a moderate amount oI alcohol could
result in a reduced risk oI vascular disorders by eIIects on the Iibrinolytic system.
CONCLUSIONS
In conclusion, a broad array oI circumstantial evidence now suggests that platelet inhibitory eIIects oI alcohol
might contribute to the reduced risk oI CHD mortality among moderate drinkers. This evidence includes
epidemiological data, in vitro data on eIIects oI alcohol on platelets, and studies on ex vivo platelet Iunction
aIter alcohol consumption in animal models and human volunteers. While the eIIects oI multiple components
oI alcoholic beverages might contribute, it is likely that ethanol itselI is partially responsible Ior the inhibition
oI platelet Iunction aIter consumption. The primary mechanism oI this inhibition likely involves eIIects oI
ethanol on platelet mediators and signaling, due to inhibition oI phospholipase A2, and consequently reduced
thromboxane synthesis.
Despite the circumstantial evidence, however, there is a need Ior deIinitive studies oI several aspects oI this
issue. SpeciIically, studies must be perIormed to more Iully deIine the time-action and dose-dependence oI
ethanol`s eIIects on the hemostatic system. Furthermore, the relative balance between platelet inhibition and
possible rebound eIIects
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aIter alcohol consumption should be Iully examined, and the role oI pattern oI drinking behavior must be
elucidated. Ultimately, there is a need Ior prospective human studies on the relationship between alcoholic
beverage consumption and CHD mortality and morbidity.
Finally, caution must be exercised in interpreting Iindings oI potential beneIits oI drinking. Risks associated
with alcohol consumption are substantial, and vary considerably between individuals and populations.
Although CHD-related risk is reduced in moderate drinkers, and although it is important to deIine the
mechanisms involved, development oI any speciIic recommendations regarding appropriate levels oI
individual alcohol consumption will be a diIIicult task.
REFERENCES
1 American Heart Association. Heart and Stroke Facts. 1995 Statistical Supplement. American Heart
Association, Dallas, TX, 1994.
2 Hennekens CH. Alcohol and risk oI coronary events. In Alcohol and the Cardiovascular Svstem,
Research Monograph-31, Zakhari S, WasseI M. (Eds.) National Institute oI Health, Washington DC 1996,
pp. 1524.
3 Fraser GE, Anderson JT, Foster N, Goldberg R, Jacobs D, Blackburn H. The eIIect oI alcohol on serum
high density lipoprotein (HDL): A controlled experiment. Atherosclerosis 1983; 46: 275286.
4 Willet W, Hennekens CH, Siegel AJ, Adner MM, Castelli WP. Alcohol consumption and high-density
lipoprotein cholesterol in marathon runners. New Eng. J. Med. 1980; 303: 11591162.
5 Pikkar NA, Wedel M, van der Beek EJ, van Dokkum W, Kempen HJM, KluIt C, Ockhuizen T, Hermus
RJJ. EIIect oI moderate alcohol consumption on platelet aggregation, Iibrinolysis, and blood lipids.
Metabolism 1987; 36: 538543.
6 Zakhari S, Gordis E. Moderate drinking and cardiovascular health. Proc. Assoc of Amer. Phvsicians
1999; 111: 148158.
7 Renaud SC, RuI JC. EIIects oI alcohol on platelet Iunctions. Clin. Chim. Acta 1996; 246: 7789.
8 Rubin R. EIIect oI ethanol on platelet Iunction. Alcohol Clin. Exp. Res. 1999; 23: 11141118.
9 Rubin R, Rand ML. Alcohol and platelet Iunction. Alcoholism. Clin. Exp. Res. 1994; 18: 105110.
10 Dong QS, Wroblewska B, Myers AK. Inhibitory eIIect oI alcohol on cyclic GMP accumulation in
human platelets. Thromb. Res. 1995; 80: 143151.
11 Dong QS, Karanian JW, Wesely L, Myers AK. Inhibition oI platelet aggregation in whole blood aIter
exposure oI rats to alcohol inhalation. Alcohol 1997; 14: 4954.
12 Abi-Younes SA, Ayers ML, Myers AK. Mechanism oI ethanol-induced aggregation in whole blood.
Thromb. Res. 1991; 63: 481489.
13 Torres-Duarte AP, Dong QS, Young J, Abi-Younes S, Myers AK. Inhibition oI platelet aggregation in
whole blood by alcohol. Thromb. Res. 1995; 78: 107115.
14 Zhang QH, Das K, Siddiqui S, Myers AK. EIIects oI acute, moderate ethanol consumption on human
platelet aggregation in platelet-rich plasma and whole blood. Alcoholism. Clin. Exp. Res. 2000; 24: 528
534.
15 Fuster V. Mechanisms leading to myocardial inIarction: insights Irom studies oI vascular biology.
Circulation 1994; 90: 21262140.
16 Ducimetiere P, Guize L, Marciniak A, Milon H, Richard J, RuIat P. Arteriographically documented
CAD and alcohol consumption in French men. The Corali Study. Eur. Heart J. 1993; 14: 727733.
17 Bennett JS. Mechanisms oI platelet adhesion and aggregation: an update. Hospital Practice 1992: 70
86.
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18 Stubbs CD, Rubin R. EIIect oI ethanol on platelet phospholipase A
2
. Lipids 1992; 27: 255260.
19 Riddel DR, Owens JS. Nitric oxide and platelet aggregation. Jitamins Hormones 1999; 57: 2548.
20 LandolIi R, Steiner M. Ethanol raises prostacyclin in vivo and in vitro. Blood 1984; 64: 679682.
21 Kwaan HC. The biological role oI components oI the plasminogenplasmin system. Prog. in
Cardiovasc. Dis. 1992; 34: 309316.
22 Rand ML, Groves HM, Kinlough-Rathbone RL, Packham MA, Mustard JF. EIIects oI ethanol on rabbit
platelet responses to collagen in vitro and ex vivo and on platelet adhesion to de-endothelialized aortae in
vivo. Thromb. Res. 1987; 48: 379388.
23 Haut MJ, Cowan DH. The eIIect oI ethanol on hemostatic properties oI human blood platelets. Amer. J.
Med. 1974; 56: 2233.
24 Rubin R, Hoek JB. Alcohol-induced stimulation oI phospholipase C in human platelets requires G-
protein activation. Biochem. J. 1988; 254: 147153.
25 Rubin R, Ponnappa BC, Thomas AP, Hoek JB. Ethanol stimulates shape change in human platelets by
activation oI phosphoinositide-speciIic phospholipase C
1
. Arch. Biochem. Biophv. 1988; 260: 480492.
26 Rubin R. Ethanol interIeres with collagen-induced platelet activation by inhibition oI arachidonic acid
mobilization. Arch. Biochem. Biophvs. 1989; 270: 99113.
27 Littleton JM, Fenn CG, Ummney ND, Yazdanbakhsh M. EIIects oI ethanol administration on platelet
Iunction in the rat. Alcoholism. Clin. Exp. Res. 1982; 6: 512519.
28 Rand ML, Groves HM, Packham MA, Mustard JF, Kinlough-Rathbone RL. Acute administration oI
ethanol to rabbits inhibits thrombus Iormation induced by indwelling aortic catheters. Lab. Invest. 1990; 63:
742745.
29 Renaud S, Criqui MH, Farchi G, Veenstra J. Alcohol drinking and coronary heart disease. In Health
Issues Related to Alcohol Consumption, Verschuren PM (Ed.), ILSI Press, Washington DC 1993, pp. 81
123.
30 Thun MJ, Peto R, Lopez AD, Monaco JH, Henley SJ, Heath CW, Doll R. Alcohol consumption and
mortality among middle-aged and elderly U.S. adults. New Eng. J. Med. 1997; 337: 17051714.
31 Rimm EB, Ellison RC. Alcohol in the Mediterranean diet. Amer. J. Clin. Nutr. 1995; 61: 1378S1382S.
32 Renaud SC, Beswick AD, Fehily AM, Sharp DS, Elwood PC. Alcohol and platelet aggregation: the
Caerphilly prospective heart disease study. Amer. J. Clin. Nutr. 1992; 55: 10121017.
33 Hillbom M, Kangasaho M, Kaste M, Numminen H, Vapaatalo H. Acute ethanol ingestion increases
platelet reactivity: is there a relationship to stroke? Stroke 1985; 16: 1923.
34 Hillbom M, Kangasaho M, Hjelm-Jager M. Platelet aggregation and thromboxane B2 Iormation aIter
ethanol abuse: is there a realtionship to stroke? Acta Neurol. Scand. 1984; 70: 432437.
35 RuI JC, Berger J, Renaud S. Platelet rebound eIIect oI alcohol withdrawal and wine drinking in rats.
Arterioscler. Thromb. Jasc. Biol. 1995; 15: 140144.
36 Renaud S, Dumont E, Godsey F, Supplisson A, Thevenon C. Platelet Iunctions in relation to dietary Iats
in Iarmers Irom two regions oI France. Thromb. and Haemostas. 1979; 40: 518531.
37 RuI JC. Wine and polyphenols related to platelet aggregation and atherothrombosis. Drugs Exper. Clin.
Res. 1999; 25: 125131.
38 Bertelli AAE, Giovannini L, De Caterina R, Bernin W, Migliori M, Fregoni M, Bavaresco L, Bertelli A.
Antiplatelet activity oI cis-resveratrol. Drugs Exper. Clin. Res. 1996; 22: 6163.
39 Zoucas E, Bengmark S. EIIects oI acetaldehyde on rat platelet aggregation in vivo and in vitro. Res. Exp.
Med. 1987; 187: 4348.
40 Spertini O, Hauert J, Bachmann F. Reaction oI acetaldehyde with human platelets. Thromb. Haemostas.
1992; 67: 126130.
41 Ma J, Hennekens CH, Ridker PM, StampIer MJ. A prospective study oI Iibrinogen and risk oI
myocardial inIarction in the Physicians Health Study. Journal of the Amer. Coll. Cardiol. 1999; 33: 1347
1352.
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42 Mennen LI, Balkau B, Vol S, Caces E, Eschwege E. Fibrinogen a possible link between alcohol
consumption and cardiovascular disease? Arteriosclerosis Thromb. Jascular Biol. 1999; 19: 887892.
43 Booyse FM, Aikens ML, Grenett HE. Endothelial cell Iibrinolysis: transcriptional regulation oI
Iibrinolytic protein gene expression (t-PA, u-PA, and PAI-1) by low alcohol. Alcoholism. Clin. Exp.
Res. 1999; 23: 11191124.
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Chapter 14
Fatty acid ethyl esters: role in alcohol cardiotoxicity
Leo Hsu, Marv E. Beckemeier and Puran S. Bora
INTRODUCTION
Alcohol is the most Irequently used mind-altering drug except Ior caIIeine. HalI oI Americans, aged 12 years
and older, use alcohol on a regular basis and approximately 10 oI these Americans are regarded to be
alcoholics |1|. More pertinent to the heart, chronic alcohol abuse has been Iound to be the chieI source oI
secondary cardiomyopathy (termed alcoholic cardiomyopathy or alcohol-induced heart muscle disease) in the
Western world |2,3|. Furthermore, patients with alcohol-induced heart muscle disease who continue in chronic
alcohol abuse have 50 mortality rates |4|. Despite, the severity and prevalence oI alcohol`s role in
cardiotoxicity, research was previously hindered due to a lack oI knowledge oI any existing biochemical
mechanisms. The most commonly known catabolic pathway Ior alcohol is catalyzed by the enzyme alcohol
dehydrogenase (ADH) to the toxic metabolite acetylaldehyde. Although this mechanism may partially explain
liver damage associated with alcohol intake, it does not account Ior the presence oI extrahepatic damage. Only
the liver possesses this oxidative metabolic pathway to a suIIicient degree |5|.
A connection between extrahepatic organ damage and chronic abuse oI alcohol has been made with the
discovery oI a nonoxidative pathway Ior alcohol metabolism. This pathway has been identiIied in the heart,
pancreas, brain, and tissues such as blood |616|. Furthermore, the pathway creates a toxic metabolite named
Iatty acid ethyl ester (FAEE). FAEEs are neutral molecules that are thought to accumulate in the mitochondria
and have been shown to produce mitochondrial dysIunction in vitro in rabbit hearts, and in vitro and in vivo in
rat hearts. The uncoupling oI the mitochondria`s energy transduction process can result in an ineIIicient energy
production as well as cell damage, providing a link between ethanol ingestion and the subsequent development
oI alcohol-induced end-organ damage. In addition, the FAEEs are able to induce myocardial cell damage in rat
and rabbit hearts. |11,12,16,17|
The enzyme responsible Ior the production oI the potentially toxic ethyl esters, named Iatty acid ethyl ester
synthase (FAEES), exhibits its highest activity in heart, brain, and pancreas, those extrahepatic organs most
commonly damaged by alcohol abuse |18,19|. Four FAEESs, labeled synthase-I, synthase-II, synthase-III and
synthase/carboxylesterase have been puriIied to homogeneity and have also been characterized |610,12
14,20,21|. This chapter will discuss the potential toxicity oI FAEEs, and examine the role oI synthase/
carboxylesterase on cardiotoxicity and its genetics. Further inIormation on the other FAEESs can be Iound in a
recent review article |22|.
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FATTY ACID ETHYL ESTERS
The majority oI ingested alcohol is rapidly absorbed Irom the small intestine into the bloodstream, and is
distributed to tissues that possess high water content and blood Ilow, e.g., myocardium |5|. Once ethanol has
reached myocardium, it has been shown to aIIect both the sarcolemma (muscle cell membrane) and the
sarcoplasmic reticulum (SR). In rat myocytes, chronic alcohol intake creates sarcolemma leaking along with
an intracellular calcium increase |23,24|. Several studies also exhibited decreased Ca
2
binding and uptake by
the SR |2529|. Normal Iunction oI these components is essential Ior proper contraction oI the heart. Indeed,
several investigators have reported depressed cardiac Iunction with acute and chronic exposure to ethanol
|26,3034|.
A decreased capacity to produce metabolic energy was observed in many investigations |3035|. It was noted
that ethanol increases basal metabolic rates and oxygen consumption |35|. Changes in phosphate/O
2
and
respiratory control ratios was also demonstrated with ethanol intake |30,3638|. In addition, mitochondrial
cristae disruption, swelling, and existence oI dense inclusion bodies was detected in laboratory animals
receiving chronic ethanol intake |26,3941|. The toxic metabolite acetylaldehyde does not appear to cause
these results Ior reasons discussed above. However, recent research on FAEEs may help elucidate the
mechanism Ior ethanol`s eIIect on the sarcolemma, SR, and cellular respiration.
It was previously thought that the heart was unable to metabolize ethanol. More recently, however, isolated
perIused hearts have exhibited a non-oxidative metabolism oI ethanol |16|. As shown in Figure 14.1, ethanol
(ETOH) is esteriIied with Iatty acids to produce the neutral molecule, FAEE. FAEE synthesis and
accumulation oI ethyl esters was observed in organs commonly damaged by chronic ethanol abuse |18|. This
putative toxic metabolite is produced in the myocardium, brain, pancreas and blood |616|. Furthermore,
uncoupling oI oxidative phosphorylation was shown to linearly decrease with concentrations oI ethyl oleate (a
FAEE) below 4050 M |17|.
Although Iatty acids are known uncouplers oI oxidative phosphorylation, they are usually bound to Iatty acid
binding proteins as seen in Figure 14.1. ThereIore, they are unable to produce the uncoupling eIIect under
physiological conditions. However, it was hypothesized that FAEEs act as a shuttle Ior the toxic Iatty acids to
reach mitochondria |17|. FAEEs are less likely to bind Iatty acid binding proteins compared to Iatty acids due
to their lack oI negative charge. Once the FAEEs are produced, they are believed to bind mitochondria. This is
supported by the Iinding that 72 oI the FAEEs produced intracellularly were bound to mitochondria |17|.
Furthermore, 60 minute incubation oI rabbit myocardium in ethyl |
3
H| oleate resulted in a linear increase in
mitochondrial binding oI the FAEE |11|.
AIter the FAEEs bind to mitochondria, they are thought to be hydrolyzed into Iatty acids. These Iatty acids
have been shown to uncouple oxidative phosphorylation in concentrations _5 M |17,42,43|. Bora et al. have
indeed demonstrated that when ethyl |
3
H| oleate was injected into rat myocardium, the ratio oI ethyl |
3
H|
oleate:|
3
H| oleate (FAEE:FA) was 1:8. In addition, miniscule amounts oI |
3
H| oleate were Iormed in the
absence oI mitochondria |11|. These results were conIirmed by Szczepiokowski et al., who revealed that 90
oI FAEEs were hydrolyzed to Iatty acids in HepG2 cells |44|. ThereIore, it was concluded that the majority oI
the uncoupling eIIect was due to the Iatty acids, and that mitochondria possess an esterase that substantially
hydrolyzes FAEEs into toxic Iatty acids. Carboxylesterase was also noted to be partly responsible Ior this
hydrolysis |20|.
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Figure 14.1 Fatty acids (FA) are Iound linked to Iatty acid binding proteins (FABP)
and are thereIore prevented Irom entering the mitochondria. However, FA can react
with ethanol (ETOH) to produce Iatty acid ethyl esters (FAEE) via Iatty acid ethyl
ester synthase. Once inside the mitochondria, FAEE can cause direct damage, but
also their hydrolysis to Iatty acids can lead to uncoupling oI oxidative
phosphorylation.
To determine the accumulation oI FAEEs in the body, Lange et al. have measured the amount oI the ethyl
esters in autopsy samples |18|. They have reported FAEE concentrations ranging Irom 9115 M in human
leIt ventricles. The autopsy samples were taken Irom patients exposed to acute or chronic alcohol. In addition,
ventricles Irom patients that had abstained Irom alcohol contained no ethyl esters |45|. Presence oI FAEE
persisted in the autopsy samples despite undetectable alcohol levels in the blood. Furthermore, the biological
halI liIe (t
1/2
) has been estimated to be between 2024 hours |17|. ThereIore, FAEEs are thought to collect in
tissues, such as the heart, with chronic ethanol intake and may play a pathologic role. This has been Iurther
corroborated by Yamazaki et al.`s Iinding that heart FAEE concentrations in autopsy samples were higher in
alcoholics despite low blood ethanol concentrations |46|.
Besides its uncoupling eIIect, evidence oI FAEE`s toxicity has been reported by several other studies. One
such study revealed that FAEEs can be a direct cause oI membrane Iluidity aberrations |47|. In addition,
pancreatic lysosomes incubated with FAEEs have shown increased instability |48|. Decreases in protein
synthesis and cell Iormation were also observed in HepG2 cells which had taken in ethanol |44|. Histologic
changes were also observed by light microscopy just 4 days aIter 3050 L injections oI 50 M oleic acid
ethyl ester solution. 30 days aIter the injection, myocytes had Iurther increased in size and deIormity |11|
(Figure 14.2).
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Figure 14.2 (A) Histopathological analyses oI control rat myocardium with 30 l
phosphate-buIIered saline (PBS) 0.01 dimethylsulIoxide. Sections stained with
Mason trichrome. No cell damage is observed (original magniIication 300). (B)
Histopathological analyses oI rat myocardium injected with 30 L oI 50 M FAEE.
Sections stained with Mason trichrome. The signiIicant cell damage was observed
aIter 30 days. The cells were enlarged and irregular in shape (original magniIication
300).
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Szczepiorkowski et al. reported a histologic distinction between human hepatoblastoma cells with and without
FAEEs |44|. In vivo damage to pancreatic tissue was also noted. FAEEs in reconstituted LDLs were inIused
intra-arterially to rats. Pancreatic injury Irom the inIused ethyl esters was indicated by pancreatic trypsinogen-
activation peptide increases, creation oI pancreatic edema, and acinar cell ultrastructural changes |49|. It is
important to point out, however, that no histological alterations or edema were observed in the myocardium.
These results may be conIounded due to the nonuse oI ethanol in the study. II ethanol was given to the rats, it
is reasonable to believe that FAEE concentrations would be signiIicantly higher due to endogenous synthesis
oI FAEEs.
Although, the oxidative metabolite, acetylaldehyde, exists in low concentrations in blood |50|, notable
concentrations oI FAEEs have been located in human blood serum Iollowing ethanol intake |51|. In Iact,
FAEEs in the circulation have been commonly proposed as a marker Ior ethanol exposure. Furthermore, a
recent study suggests that plasma FAEEs are produced by lipoprotein lipase |52|, rather than in tissue or cells
as Doyle |51| and Gorski |15| hypothesize. Lipoprotein lipase (LPL) was previously reported to have Iatty
acid ethyl ester synthase (FAEES) capability |53|. AIter perIusion oI isolated rat hearts with chylomicrons (a
LPL substrate), Chang et al. observed that the majority oI the ethyl esters were Iound in the perIusate rather
than in the myocardium itselI. Apo CII (co-Iactor Ior LPL) levels were signiIicantly increased, supporting the
hypothesis that plasma FAEEs are synthesized by LPL |52|.
Serum FAEE appear to Iavor lipoprotein vs. albumin binding during increased concentrations oI the ethyl
esters. FAEEs also display a lack oI competition with Iree Iatty acids Ior albumin binding |54|. Gorski et al.
have shown that FAEES ability also exists within leukocytes. The highest synthase levels were measured in
the natural killer (NK) cells. CD4