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Herz 2016 · 41:484–493DOI 10.1007/s00059-016-4469-6Published online: 31 August 2016© The Author(s) 2016. This article is available atSpringerLink with Open Access.

B. MaischHerz- und GefäßzentrumMarburg (HGZ) und Philipps Universität Marburg, Marburg, Deutschland

Alcoholic cardiomyopathyThe result of dosage and individualpredisposition

Alcoholism—use and abuse

According to the definition of the WorldHealthOrganization(WHO), alcoholismis subgrouped in two categories: alcoholabuse and alcohol dependence [1]. Thiscorresponds roughly with the concept ofthe American Psychiatric Association [2,3]. Alcohol abuse describes the psycho-logical dependence on ethanol for ad-equate functioning together with occa-sional heavy consumption, while alcoholdependence is defined as an increasedalcohol tolerance together with physicalsymptoms upon withdrawal. In Westerncountries it is estimated that up to 10%of the adult population suffers from al-coholism [4]. The highest prevalence isdetected in the third to fifth decade oflife, and alcoholism is seen in all races,ethnic groups, and socioeconomic strata.

Germany with a total population of81 million inhabitants is a permissivesociety with respect to the drinking ofalcohol. Alcohol consumption is partof the local culture. About 40 millionindividuals drink alcohol. The per capitaalcohol consumptionof 9.7 l pure ethanoland the early onset of regular or episodicintensive drinking among young peoplein Germany consequently leads to highalcohol-related morbidity and mortality[5].

More than 1.8 million individualsin Germany with a total population of81 million inhabitants are alcohol de-pendant. For an additional 1.6 millionpersons the use of alcohol is harmful [6,7]. In a world-wide setting, alcohol usedisorders show similarities in developedcountries, where alcohol is cheap andreadily available [8]. The many com-plications of alcohol use and abuse are

both mental and physical—in particular,gastrointestinal [9], neurological [10,11], and cardiological [12, 13]. Therelationship of alcohol with heart dis-ease or dementia is complicated by thefact that moderate alcohol consumptionwas shown not only to be detrimentalbut to a certain degree also protectiveagainst cardiovascular disease [14] or tocognitive function in predementia.

We reviewed the effects of ethanol onthe cardiovascular system in 1996 [15],including aspects of inflammation [16],rhythm disturbances [17], and hyperten-sion [18]. In 2001 we updated the dataon the ambivalent relationship betweenalcohol and the heart [19] and in 2008added new evidence on a larger cohortof patients with different forms of car-diomyopathy and increased alcohol in-take from the German competence net-work on heart failure [20].

This review revisits our past and dealswithourcurrentthinkingontheepidemi-ology, pathophysiology, clinical charac-teristics, and treatments available for al-coholic cardiomyopathy.

Methods

This review assembles and selects per-tinent literature on the ambivalent re-lationship of ethanol and the cardiovas-cular system, including guidelines, meta-analyses,Cochranereviews, originalcon-tributions, and data from the MarburgCardiomyopathy registry.

Drinksasmeasuresofalcoholareoftengiven in ounces (oz), whereby 1 oz equals28.35 g or 29.57 ml.

Examples for 100% alcohol in ml ofone drink in consumed beverages are be-tween 17.6 to 17.76 ml:

4 Beer: 12 fluid ounces of 5% beer =355 ml fluid = 17.5 ml 100% alcohol.

4 Wine: 5 fluid ounces of 12% wine =148 ml fluid = 17.76 ml of 100%alcohol.

4 Distilled spirits: 1.5 fluid ounces of~40% liquor = 44 ml = 17.6 ml of100% alcohol.

A historical perspective

For more than 3000 years, alcoholic bev-erages have been consumed in multiplesocieties through the centuries and cul-tures. The name alcohol ismuch youngerthan the many beverages containing it.Pulverized antimony was used as eyeshadow by Egyptian women and namedal-Kol. In the 16th century ParacelsusTheophrastus Bombastus from Hohen-heim used this term for distilled liquorand called it alcohol [15]. The benefi-cial cardiovascular effects of alcohol havebeenappreciated, e. g., inmedieval times,when people took advantage of the va-sodilating properties of alcohol to treatanginapectorisorheart failure. SoHilde-gard von Bingen (1098–1179), one of themost prominent mysticians of her time,recommended her heart wine as a uni-versal remedy. One liter of wine wascooked for 4 min with 10 fresh pars-ley stems, 1 spoon of vinegar, and 300 ghoney and then filtered [11]. This recipeis still in use today.

Over the centuries “the good and thebad” of alcohol were evaluated clinicallyand scientifically. As early as 1855,Woodincriminated alcohol as a cause of heartfailure. In 1861, Friedrich reported id-iopathic hypertrophy as associated withalcoholism. In 1873, Walshe describedmyocardial cirrhosis in alcoholics, which

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Fig. 18 a Left ventricle froma49-year-oldmanwithchronic alcohol abuse.Myofibers showpartly hypertrophyandatrophy.Fibrosis is present as reparative interstitial and perivascular fibrosis.HE ×320.b Electronmicroscopy of an endomyocardialseptalbiopsyfromapatientwithalcoholiccardiomyopathydemonstratingmyofibrillarreductionandvariablemitochondriaein size but increased in number.×2190. (With kind permission fromH. Frenzel and B. Schwartzkopff [22])

Fig. 28 aOtto von Bollinger. (© de.wikipedia.org). bMunich beer heart. (© PhilippMansmannin http://www.bayerische-staatszeitung.de/staatszeitung/kultur/detailansicht-kultur/artikel/bierherz.html)

includes a spectrum of hepatic derange-ments that occur in the setting of right-sided heart failure. Conversely cirrhosis(fibrosis) was found both in heart andliver. Highcardiacoutput inpatientswithliver cirrhosis may have contributed tothis cardiomyopathy in a vicious circle.The term “wine heart” (Tübinger Wein-herz) originated in 1877 by Münzinger[21], a German pathologist at Tübin-gen university. This entity we wouldcall nowadays “alcoholic cardiomyopa-thy” with histologic features of dilata-tion, myofibrillar necrosis and fibrosis(. Fig. 1a), and ultrastructural changessuch as reduction of myofibrils and mi-tochondriosis in a great variability of sizeand form (. Fig. 1b; [22]).

In Munich, the annual consumptionof beer reached 245 l per capita and yearin the last quarter of the 19th century.

In 1884, the pathologist and veterinarianOtto von Bollinger (. Fig. 2a) describedthe “Munich beer heart” with fibrosis,hypertrophy, and fatty degeneration inpostmortem cardiac tissue of alcoholicswho consumed an estimated average of432 liters of beerper year (. Fig. 2b; [23]).At that time every 10th necropsy in menat theMunich pathology institute namedcardiac dilatation and fatty degenerationas “Bierherz” being its underlying cause.For comparison, the mean annual beerconsumption in Bavaria is nowadays es-timated to be 145 l and in the rest ofGermany around 100 l beer per personand year [24].

In 1887, Maguire reported on 2 pa-tients with severe alcohol consumptionwho benefitted from abstinence. He sug-gested that alcohol was poisoning theheart. In 1890, Strümpell listed alco-

holism as a cause of cardiac dilatationandhypertrophy, as did SirWilliamOslerin 1892 in his textbook Principles andPractices of Medicine. In 1893, GrahamSteell, well known for the Graham Steellmurmur due to pulmonary regurgitationin pulmonary hypertension or in mi-tral stenosis, reported 25 cases in whomhe recognized alcoholism as one of thecauses of muscle failure of the heart. Hefound it “a comparatively common one”[25]. In his 1906 textbook The Study ofthe Pulse, William MacKenzie describedcases of heart failure attributed to alcoholand first used the term “alcoholic heartdisease” [26].

In his 1972 review article, Bridgenwasthe first to introduce the term alcoholiccardiomyopathy [27].

Nutritional causes of “alcoholic”cardiomyopathy

Beriberi heart disease

Thiamine deficiency is common featureinamalnourishedand/oralcoholicpopu-lation. Thus, the conceptofberiberiheartdisease dominated thinking about alco-hol and the heart for decades and causedmany to doubt that alcohol was actu-ally cardiotoxic [28]. But vitamin B1(thiamine) deficiency is accompanied byan elevated cardiac output and dimin-ished peripheral vascular resistance [29,30]. According to its central hemody-namics, it can be classified as hyper-dynamic cardiomyopathy or high outputfailure with a cardiac output >8 l/minor a cardiac index >3.9 l/min/m2 [31,

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32]. In contrast, alcoholic cardiomyopa-thy is characterized by a low cardiac out-put, associated with systemic vasocon-striction [4]. However, the high outputstate can lead to cardiac dilation, thus,representing a characteristic subentity ofcardiomyopathy different from low out-put dilated cardiomyopathy. Therefore,thiamine deficiency per se is just a his-torical nutritional anomaly in the historyof alcoholic cardiomyopathy.

Manchester arsenic-in-beerepidemic

In 1900, the Manchester arsenic-in-beerepidemic was a serious food poisoningoutbreak affecting several thousand peo-ple across the North-West and MidlandsofEngland,withmanycasesprovingfatal.The arsenic had come from the glucosefor which sulphuric acid was used in thesugarproductionprocessofa company inLeeds. Brewershadbeenusing this sugar,thus, unknowingly poisoning the beerand as a result their customers for manyyears evenprior to the epidemic [33]. Ar-senic poising caused a multisystem dis-ease in over 6000 cases with more than70 deaths [34]. The syndrome includedthe usual signs and symptoms of ar-senic poisoning, with skin, nervous sys-tem, and gastrointestinal manifestations.Unusual in arsenic poisoning, but espe-cially prominent in this epidemic, werethe cardiovascular findings. In his clin-ical description, Ernest Reynolds wrotethat “cases were associated with so muchheart failure and so little pigmentationthat they were diagnosed as beri-beri. . . ”. He also found that “undoubtedlythe principal cause of death has beencardiac failure. In postmortem exami-nations, the only prominent signs werethe interstitial nephritis and the dilatedflabbyheart” (p. 169, [35]). Thisoutbreakhad been the first known trace metal car-diotoxic syndrome.

In 2013, the issue of arsenic in beerand wine was again prominent, whenMehmetCoelhan, aresearcherattheWei-henstephan research center at the Tech-nical University of Munich, reported ata meeting of the American Chemical So-ciety that many of the nearly 360 beerstested in Germany had trace amounts of

Abstract · Zusammenfassung

Herz 2016 · 41:484–493 DOI 10.1007/s00059-016-4469-6© The Author(s) 2016. This article is available at SpringerLink with Open Access.

B. Maisch

Alcoholic cardiomyopathy. The result of dosage and individualpredisposition

AbstractThe individual amount of alcohol consumedacutely or chronically decides on harm orbenefit to a person’s health. Available datasuggest that one to twodrinks inmen andonedrink inwomenwill benefit the cardiovascularsystem over time, one drink being 17.6 ml100% alcohol. Moderate drinking can reducethe incidence andmortality of coronary arterydisease, heart failure, diabetes, ischemic andhemorrhagic stroke. More than this amountcan lead to alcoholic cardiomyopathy, whichis defined as alcohol toxicity to the heartmuscle itself by ethanol and its metabolites.Historical examples of interest are theMunich beer heart and the Tübingen wineheart. Associated with chronic alcoholabuse but having different etiologies areberiberi heart disease (vitamin B1 deficiency)and cardiac cirrhosis as hyperdynamiccardiomyopathies, arsenic poising in theManchester beer epidemic, and cobaltintoxication in Quebec beer drinker’s disease.

Chronic heavy alcohol abuse will also increaseblood pressure and cause a downregulationof the immune system that could lead toincreased susceptibility to infections, which inturn could add to the development of heartfailure. Myocardial tissue analysis resemblesidiopathic cardiomyopathy or chronic myo-carditis. In the diagnostic work-up of alcoholiccardiomyopathy, the confirmation of alcoholabuse by carbohydrate deficient transferrin(CDT) and increased liver enzymes, and theinvolvement of the heart by markers of heartfailure (e.g., NT-proBNP) and of necrosis(e.g., troponins or CKMb) is mandatory.Treatment of alcoholic cardiomyopathyconsists of alcohol abstinence and heartfailure medication.

KeywordsAtrial fibrillation · Beriberi · Cirrhoticcardiomyopathy · Hypertension · Myocarditis

Alkoholische Kardiomyopathie. Eine Folge der Dosis und derindividuellen Prädisposition

ZusammenfassungDie individuelle Menge akut oder chronischgetrunkenen Alkohols ist für den gesundheit-lichen Schaden oder Nutzen entscheidend.Grenzdosen für Männer sollten 1–2 Getränkeà 17,6 ml reinen Alkohols sein, für Frauenein Getränk. Mäßiger Alkoholkonsum kanndie Inzidenz und Mortalität von koronarerHerzerkrankung, Herzinsuffizienz, Diabetesmellitus, ischämischem und hämorrhagi-schem Schlaganfall vermindern. GrößereMengen Alkohol führen zur alkoholischenKardiomyopathie, bedingt durch die Toxizitätvon C2H5OH und seinen Metaboliten aufden Herzmuskel. Historische Beispiele sinddas Münchener Bier- und das TübingerWeinherz. Nicht auf die reine Alkoholwirkungzurückzuführen sind aufgrund ihrer andersar-tigen Ätiologie das Beriberi-Herz bei Mangelan Thiamin (Vitamin B1) und die kardialmitbedingte Leberzirrhose als hyperdynameKardiomyopathien, die Arsenvergiftung beider Manchester Biertrinkerepidemie und die

nach Quebec benannte Bierherzerkrankunginfolge einer Kobaltintoxikation. ChronischerAlkoholabusus erhöht den Blutdruck undverursacht eine Downregulation des Im-munsystemsmit erhöhter Infektanfälligkeit.Histologisch ist die alkoholische nicht von deridiopathischen Kardiomyopathie und einerchronischen Myokarditis zu unterscheiden.Alkoholabusus wird durch Bestimmungdes carbohydratdefizienten Transferrins(CDT) und erhöhter Leberenzyme bestätigt,die Herzinsuffizienz durch Biomarker wieNT-proBNP und die Myozytolyse durchTroponine und CKMb. Die Behandlung deralkoholischen Kardiomyopathie besteht inder Alkoholabstinenz und medikamentöserTherapie der Herzinsuffizienz.

SchlüsselwörterVorhofflimmern · Beriberi · ZirrhosebedingteKardiomyopathie · Hochdruck · Myokarditis

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arsenic. The source was identified to bethe filter of choice for wine and beer,i.e., diatomaceous earth [36]. The Ger-man word for it is Kieselguhr, a beigepowder made up of the skeletons of di-atoms. The trace amounts of arsenic havenot been comparable to the arsenic-in-beer endemic inManchester butmay stillreach up to 10-times the amount admit-ted for arsenic in drinking water in theEuropean Union and the US.

Quebec‘s beer drinker disease

In the mid-1960s, another unexpectedheart failure epidemic among chronic,heavybeerdrinkersoccurred intwocitiesin the USA, in Quebec, Canada, and inBelgium. It was characterized by con-gestive heart failure, pericardial effusion,and an elevated hemoglobin concentra-tion. The explanation proved to be theaddition of small amounts of cobalt chlo-ride. Cobalt was used as a foam stabi-lizer by certain breweries in Canada andin the USA. In 1966 McDermott et al.[37] described the syndrome as myocar-dosis with heart failure, Kestelott et al.[38] added pericardial involvement andnamed it alcoholic pericardiomyopathy,and Morin and Daniel [39] in Quebectrackeddowntheetiology tocobalt intox-ication towhat becomeknownasQuebecbeer-drinkers cardiomyopathy. HumanpathologywasfirstdescribedbyBonefantet al. [40]. Animal models investigatedultrastructure [41] and treatment e. g. byselenium [42]. Removal of the cobalt ad-ditive ended the epidemic in all locations.Cobalt poisoning and alcohol togetheracted synergistically in these patients. Asthe syndrome could be attributed to thetoxicity of this trace element, the additivewas prohibited thereafter.

Not alcohol but cobalt itself recentlycaused severe heart failure in a 55-year-old man, who was referred to the uni-versity hospital in Marburg to rule outcoronary artery disease as the cause of hisheart failure. He had become almost deafand blind, with fever of unknown cause,hypothyroidism, and enlarged lymphnodes. Both his hips had been replaced,the left side by a CoCrMo Protasul metalprosthesis. Remembering a similar casein an episode of the TV seriesDr. House,

the team of J. Schäfer suspected cobaltintoxication as the cause of heart failure,which clinicallymimickedQuebec‘s beerdrinker disease [43]. One should note,however, that cobalt is needed in minuteamounts of 0.0003 mg/day in vitaminB12 (cobalamine) to avoid megaloblasticanemia.

Cardiac cirrhosis or cirrhoticcardiomyopathy

The heart and liver interact in severaldifferent ways. Acute or chronic rightheart failure leads to elevation of liverenzymes most likely due to liver conges-tion, whereas cirrhosis due to cardiacdisease is infrequent. Chronic liver dis-ease such as cirrhosis may in turn affectthe heart and the whole cardiovascularsystem, leading to a syndrome namedcirrhotic cardiomyopathy (CCM). Thus,CCM has been introduced as an newentity separate of the cirrhosis etiology.Increased cardiac output due to hy-perdynamic circulation, left ventriculardysfunction (systolic and diastolic), andcertain electrophysiological abnormalfindings are pathophysiological featuresof the disease. The underlying mecha-nisms might include the impaired β-re-ceptor and calcium signaling, alteredcardiomyocyte membrane physiology,elevated sympathetic nervous tone andincreased activity of vasodilatory path-ways [44]. In pathophysiological terms,heart failure in liver cirrhosis belongs tothe hyperdynamic cardiomyopathies.

Hypertension

As early as in 1915, Lian [45] reported inmiddle-aged French servicemen duringthe first world war that heavy drinkingcould leadtohypertension. It tookalmost60 years before further attentionwas paidto the complex interaction between theheart and the peripheral vasculature invarious cross-sectional and prospectiveepidemiologic studies, which have em-pirically confirmed this early report. Oneis aware today that alcohol may cause anacute but transient vasodilation, whichmay lead to an initial fall in blood pres-sure probably mediated by the atrial na-triuretic peptide (ANP) [46]. But also

short- and long-term pressor effects me-diated by the renin–aldosterone systemand plasma vasopressin have been de-scribed [47, 48].

The long-term hypertensive effect ofalcoholhasbeenconfirmedinmanystud-ies [49–52]. Remarkably, alcohol also in-teracts with brain stem receptors and ex-erts thereby central hypertensive effects[18]. The apparent threshold amount ofdrinking associated with higher bloodpressure is approximately 3 drinks/day.Most studies show no increase in bloodpressure with lighter drinking; severalshow an unexplained J-shaped curve inwomen with lowest blood pressures inlighter drinkers. There seems to be inde-pendence from adiposity, salt intake, ed-ucation, smoking, beverage type (wine,liquor, or beer), and several other poten-tial confounders.

Clinical observation confirmed thatseveral days to weeks of drinking showhigher and weeks of abstinence lowerpressures. Alcohol intake may also in-terfere with the drug and dietary treat-ment of hypertension. This altogethersupports a causal relationship betweenalcohol consumption and a hypertensivestate.

Alcoholic cardiomyopathy:Cytotoxicity of alcoholon heart muscle

The 1989 landmark report of Urbano-Marquez et al. [53] showed a clear re-lation of lifetime alcohol consumptionto structural and functional myocardialand skeletal muscle abnormalities in al-coholics. The amount of consumed al-cohol was large—the equivalent of >80 galcohol/day for 20 years. Further evi-dence came from data on acute alcoholeffects [54] and from clinical observation[55–57].

In 1996, cardiomyopathies were de-fined as diseases ”affecting the my-ocardium with associated cardiac dys-function“ [58] and primary and sec-ondary forms were distinguished in thiscontext. After consumption of largequantities of alcohol over years the clin-ical picture of heavy alcohol drinkerscould be indistinguishable from otherforms of dilated or familial cardiomy-

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Fig. 38 a Left ventricle (LV) biopsy of a 53-year-old individualwith an alcohol consumption of >5 drinks/day for 32 years.Perivascular increase of leukocytes and fibrosis,myocytes in variable sizeswith somemyocytolysis.HE ×160. b LV biopsy ofthe 53-year-old alcoholic with increased ICAM (intercellular adhesionmolecule) expression in capillaries and small vessels.×320. c Circulating antimyosin antibodies in the 53-year-old patientwith alcoholic abuse. Indirect immunofluorescent test.Titer 1:160 ×640

opathy. Alcohol is still suspected tobe the major cause or contributoryfactor of secondary nonischemic di-lated cardiomyopathy being involved inup to one third of all cases of dilatedcardiomyopathy [59–61]. In alcoholiccardiomyopathy, dilation and impairedcontraction of the left or both ventri-cles is observed [4]. Left ventricularenddiastolic diameters are increasedcompared to age- and weight-matchedcontrols [62], the left ventricular massindex is increased [63], and the left ven-tricular ejection fraction is well belownormal (<45%). Thus, the diagnosis ofalcoholic cardiomyopathy is still basedon the coincidence of heavy alcoholconsumption and a global myocardialdysfunction, which cannot be explainedby any other underlying myocardial dis-ease [64]. However, the prevalence ofalcoholic cardiomyopathy may be un-derestimated, as autopsy findings revealpathologic changes of the heart in indi-viduals with no clinical symptoms [65],when analyzing in large cross-sectionalstudies.

Further evidence suggests that notonly ethanol but also the first metaboliteacetaldehyde may directly interfere withcardiac and skeletal muscle homeostasis[53, 66]. In vitro studies have furtherelucidated the direct effect of ethanolon electromechanical coupling, indicat-ing a decrease in myofilament–calciumsensitivity during alcohol consumption,changes in the transmembrane actionpotential, the amplitude of the cytosoliccalcium transients, and the shortening

of the action potential duration [67–71].Isolated cardiomyocytes of alcohol-fedrats did not maintain ATP levels uponenergy demand due to an inadequateincrease in mitochondrial ATP-synthaseactivity, which led altogether to furthermyocyte loss [72, 73]. Ultrastructuraldisarray of the contractile apparatus [74]is associated with a depressed myofib-rillar and sarcoplasmic protein synthesisin cardiac muscle after ethanol exposure[75–77]. This reduces contractile car-diac filaments with subsequent negativeinotropic effects on heart contractility[78, 79]. An apoptotic effect of ethanolon cardiac muscle has also been de-scribed, which could be counteracted byinsulin-like growth factor (IGF)-I [80]and confirmed in later studies [81, 82].In a study in rats that were fed withtwo different doses of alcohol (5 mM[low alcohol], 100 mM [high alcohol]or in pair-fed nonalcohol controls for4–5 months), caspase-3 activity as puta-tive marker of apoptosis was decreasedin the low alcohol diet, whichwent alongwith increased or normal contractility,whereas high doses of ethanol showedincreased caspase activity, wall thinning,and a reduction of shortening velocity[83]. Of note, rats are a relatively alcoholresistant species.

Alcohol andmyocarditis

Alcohol abuse coincidingwithmyocardi-tis was reported in 1902 by McKenzie[26]. In endomyocardial biopsies of alco-holics up to 30% of patients were found

to exhibit sparse lymphocytic infiltrateswith myocyte degeneration and focalnecrosis and increased HLA (humanleukocyte antigen) or ICAM (intercel-lular adhesion molecule) expression(. Fig. 3; [16, 84]).

This may have to do with the suscep-tibility for infections due to a suppressedimmune system in a compromised hu-man host and also in experimental an-imal [85]. Ethanol can alter lympho-cyte functions, inhibitneutrophil chemo-taxis, and suppress the production of cy-tokines, which are involved in regulatingacute inflammatory responses to infec-tious challenges [86–88]. Furthermore,autoimmunity and circulating autoanti-bodies seem to be associated in somepatients with chronic alcohol consump-tion [16, 20, 84].

Coronary artery disease andatherosclerosis

The beneficial heart wine as universalremedy in medieval ages by Hildegardvon Bingen [11] found its later corre-lates in many observations at the begin-ning ofmodernmedicinewhen coronaryartery disease (CAD) and its risk factorsand symptoms received more attention.Heberden [89] described angina so ele-gantly in 1786 and also added that ”con-siderable relief “ through ”wine and spir-ituous liquors“ could be expected. Thisobservation led to the erroneous beliefthat alcohol is an immediate coronary va-sodilator. Alcohol isnotadirect coronaryvasodilator [90]. Symptomatic relief of

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angina could be through the anestheticeffect of ethanol or through peripheralvasodilation, which could transiently re-duce oxygen demand of the heart.

In 1819 the Irish physicianDr. SamuelBlack, who had a special interest inangina pectoris described what is proba-bly the first commentary pertinent to the”French Paradox“ [91]. This refers to thefinding in the last century that moderatealcohol consumption could be the rea-son for the relatively low cardiovasculardisease incidence in wine-drinking re-gions [92]. Renaud and de Lorgeril [93]suggested that the inhibition of plateletreactivity by wine may be one explana-tion for protection from CAD in France.However, there was further evidence onthis and other dietary mechanisms withthe observation that France and Fin-land have similar intakes of cholesteroland saturated fat, but consumption ofvegetables and vegetable oil containingmonounsaturated and polyunsaturatedfatty acids is greater in France than inFinland.

This inverse relation on mortality re-sembles in most population based stud-ies a U- or J-shaped curve: Total absti-nence has a slightly increased mortal-ity when compared to low or moder-ate alcohol consumption. It is presentin individuals with and without overtCAD, with diabetes, and with hyperten-sion and has been underlined by a largenumber of studies [94, 95]. The car-dioprotective effect of alcohol can be at-tributed to the increase in total high-den-sity lipoproteins (HDL), andespeciallybyan increase in subfractions HDL2 andHDL3, whereas established cardiovascu-lar risk factors like low-density lipopro-teins (LDL) or lipoprotein(a) are thoughtto be moderately decreased [96]. Mod-erate alcohol intake also exerts beneficialeffects on the blood coagulation system.It leads toan increaseof endogenousplas-minogen activators [97], or a decrease infibrinogen concentrations [98].

In the Caerphilly prospective heartdisease study, platelet aggregation in-ducedbyadenosinediphosphatewas alsoinhibited in subjects who drank alco-hol [99]. Assessing differences betweenvarious forms of alcoholic beverages itshould be noted that resveratrol leads

in vitro to platelet inhibition in a dose-dependent manner [100] and has showneffects on all-cause mortality in a com-munity-based study [101]. Polyphenolsof red barrique wines and flavonoidshave been shown to inhibit endothe-lin-1 synthase [102] and PDGF-inducedvasoproliferation thus also contributingto cardiovascular protection [103].

Signal transduction and beta-receptors

In alcoholic cardiomyopathy, similarto idiopathic dilated cardiomyopathy(DCM), beta 1-adrenergic and mus-carinic receptors are reduced in themyocardium itself and reduced respon-siveness of the adenyl cyclasewas shown,whereas catecholamine levels in the cir-culation may be elevated [104]. As a neteffect, negative inotropism may resultand contribute to heart failure.

Arrhythmias and stroke

Acute effects of alcohol can result inrhythm disturbances. Since this hap-pens often on weekends and holidays,Ettinger andRegan coined the term ”hol-iday heart syndrome“, when they de-scribed 32 habitual drinkers with an ad-ditional ingestion of ethanol prior to thearrhythmia [59, 105]. Atrial fibrillationwas thecommonestmanifestation,whichresolved with abstinence. In the KaiserPermanente Study, atrial arrhythmias in1322 persons reporting >6drinks per daywere compared to arrhythmias in 2644matched light drinkers, showing a dou-bled relative risk forheavydrinkers [106].Apart from direct cardiotoxicity, hyper-tension causing atrial stretch the arrhyth-mogenic potential of alcohol may comefrom the lowering the resting membranepotential [107] and the prolongation ofconduction [108].

Studies of alcohol and stroke are com-plicated by the various contributing fac-tors to stroke. Heavier drinkers are ap-parently at a higher risk of hemorrhagicstroke,whereasmoderatedrinkingmightbe neutral or even result in a reduced riskof ischemic stroke.

Clinical work-up for alcoholiccardiomyopathy

Habitual drinkers oftenhide their alcoholdependence fairly effectively. They mayadmitdrinkingat socialeventsbutnot theabuse in thefirst contact. Patientswithal-coholic cardiomyopathy, therefore, usu-ally present with symptoms of heart fail-ure, i. e., dyspnea, orthopnea, edema,nocturia, and tachycardia. Echocardio-graphy may reveal a mild or severe de-pression of cardiac function and ejectionfraction or even show hypertrophy in thebeginning [109]. Heart failure symptomsmaybeduetoearlydiastolicortolatersys-tolic dysfunction. At later stages, due toatrialfibrillation, thrombiarenotuncom-mon in the dilated atria. Mitral regurgi-tation is found inup to two thirds of cases[110]. Atrial fibrillation and supraven-tricular tachyarrhythmias are commonfindings in 15–20% of patients [111],whereas ventricular tachycardias are rare[112]. On ECG, unspecific abnormali-ties like complete or incomplete left bun-dle branch block, atrioventricular con-duction disturbances, alterations in theST segment, and P wave changes can befound comparable to those in idiopathicDCM [113].

On endomyocardial biopsy, a dis-crimination between idiopathic, chronicinflammatory and alcoholic cardiomy-opathy is virtually impossible sincecommon features such as fibrosis, hy-pertrophy of cardiac myocytes, andalterations of nuclei are present at lightmicroscopy in the alcoholic cardiomy-opathy [114] as well as in chronic my-ocarditis according to the Dallas criteria[115] or the World Heart Federation/International Society and Federation ofCardiomyopathy (WHF/ISFC) defini-tion of myocarditis [116]. Although theseverity of histological alterations onendomyocardial biopsy correlates withthe degree of heart failure in one of ourstudies, biopsy is not in common usefor prognostic purposes [117]. Even therecovery after abstinence of alcohol ishard to predict based on morphometricevaluation of endomyocardial biopsies[118].

CardiacMRImaybehelpful in thedif-ferential diagnosis to hypertrophic car-

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Table 1 Clinical work-up in alcoholic cardiomyopathy

Work-up of Criteria/findings

Cardiac symptoms Fatigue, dyspnea, edema, nocturia, tachycardia

Noncardiac physi-cal examination

Mental state (delirium tremens, depression, anxiety, psychosis)Neurology (cognitive decline, cerebellar degeneration, peripheral neuropathy, proximal myopathy)Respiratory function (aspiration pneumonitis, pneumonia, tuberculosis, smoking)Gastrointestinal tract (malnutrition, liver disease, pancreatic disease)Endocrine function: pseudo-Cushing’s syndrome, hypogonadism

ECG Atrial fibrillation, complete or incomplete left or right bundle branch blocks, ST-segment and T-wave alterations

Echocardiography LV dilatation or hypertrophy, atrial dilatation, reduced shortening and ejection fraction, small pericardial effusion, mitral andtricuspid regurgitation, atrial thrombi in atrial fibrillation

Endomyocardialbiopsy

Similar to dilated cardiomyopathy with myocyte hypertrophy or loss, reparative fibrosis, low grade leukocyte infiltration, vari-able, sometimes increase in Major HistocompatibilityComplex(MHC) class I and II expression, immunoglobulin binding tosarcolemma andmyosin; helpful in differential diagnosis of other forms of cardiomyopathies, theoretically suited for follow-upor improvement but not in common use for this purpose

Cardiac MRI Helpful in ruling out other cardiomyopathies, e. g. hypertrophic cardiomyopathy, myocarditis, constrictive pericarditis

Cardiac CT Only as noninvasive method to exclude coronary disease

Table 2 Markers of alcoholism and cardiac involvement

Laboratory marker Indicative for Time to normalize Monitorabstinence

Alcohol concentration In acute alcohol intoxication Hours Yes

Mean corpuscular volume of red blood cells (MCV) Increased 3 months No

GGT, GOT, GPT, GOT/GPT ratio Liver disease in patients with alcohol abuse 4 weeks No

CDT (carbohydrate-deficient transferrin) Chronic alcohol abuse 4 weeks No

Ethyl glucuronide and ethyl sulphate High-risk drinkers 2 days Yes

Phosphatidyl ethanol High-risk drinkers 4 weeks No

NT-proBNP Heart failure, helpful in follow-ups Several weeks No

Troponins, CKMB Acutemyocyte destruction 1–3 days No

MCV mean corpuscular volume, GGT gamma-glutamytransferase, GOT glutamic oxalacetic transaminase, GPT glutamic pyruvic transaminase, CDTcarbohydrate-deficient transferrin, NT-proBNP n-terminal pro brain natriuretic peptide, CKMB creatinin kinase, muscle, brain subunit

diomyopathy, storage diseases, and in-flammatory cardiomyopathy. For a com-prehensive overview see . Table 1 (com-bined data from [6, 8, 24, 28]).

Laboratory findings

Measuring blood alcohol concentrationin an acute intoxication gives baselineinformation but does not permit deduc-tions to chronic misuse. Markers forchronic alcohol consumption rely on liverenzymes such as gamma-glutamyltrans-ferase (GGT) [119], glutamic oxalacetictransaminase (GOT), andglutamic pyru-vic transaminase (GPT).Elevationsof thetransaminases (GOT, GPT), especiallya ratio of GOT/GPT higher than 2 mightbe indicative of alcoholic liver disease in-steadof liverdisease fromotheretiologies[120, 121]. An excellent marker is car-bohydrate deficient transferrin (CDT),

which best detects chronic alcohol con-sumptionalone [122, 123]or incombina-tion with the other markers such as GGT[8, 124]. Markers such as ethyl sulphate,phosphatidyl ethanol, and fatty acid ethylesters are not routinely done. For a com-prehensive overview see . Table 2 withcombined data from [6, 8, 24, 28].

Biomarkers of heart failure such asNT-proBNP and of myocardial necrosissuchas the troponinsandCKMBindicateheart failure or myocytolysis.

Is there an immediate risk ofalcohol intake?

In a recent meta-analysis, Mostofsky etal. [125] analyzed if independent fromhabitual moderate or heavy alcohol con-sumption an immediate risks exists fol-lowingalcohol intake. Data from23stud-ies with 20,457 participants showed that

evenwith moderate consumption an im-mediately higher cardiovascular risk wasattenuated after 24 h. It then becameprotective for myocardial infarction andhemorrhagic strokewitha30 %lowerriskand protective against ischemic strokewithin one week. In contrast, heavy al-cohol drinking continued to be associ-ated with higher cardiovascular risk inthe followingday (RR=1.3–2.3)andweek(RR =2.25–6.2).

Prognosis and treatment

Prognosis in individuals with low ormoderate consumption up to one or twodrinks per day in men and one drink inwomen is not different from people whodo not drink at all. In CAD, diabetes,and stroke prevention the J-type mor-tality curves even indicate some benefitapart from the social ”well-being“. In

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Table 3 Treatment of alcoholism and alcoholic cardiomyopathy

Medication Treatment goal Dosage Adverse reaction Evidence

Pharmacological formaintaining abstinence

Naltrexone Abstinence 50–100 mg/day (oral)380 mg i. m. per month

Nausea, headache, dizziness, joint andmuscle pain

High

Acamprosate Abstinence 666 mg three times daily Diarhea, pruritus, rash, altered libido High

Disulfiram Abstinence 200 mg/day (oral) Dizziness, rash, headache, polyneuritis,impotence, hepatotoxicity

Mixed, needs super-vision

Nalmefene Reduced drinking or absti-nence

18 mg/day (oral) Dizziness, rash, headache, nausea, vomit-ing

Moderate

Diazepam Avoid delirium As needed Dizziness, sleepiness Only symptomatic

Pharmacological for heart failure (HF)

ACE inhibitors HF+ prognosis As tolerated – High in HF

Betablockers HF+ prognosis As tolerated – High in HF

Diuretics HF+ prognosis As needed – High in HF

Digitalis Rate control According to digoxin ordigitoxin level

Avoid overdosage Moderate in atrialfibrillation (AF)

Anticoagulants Avoid stroke INR 1.8–2.2 in AF Bleeding High in AF

patients with chronic alcohol use disor-ders and severe heart failure prognosisis poor, since continued alcohol abuseresults in refractory congestive heartfailure. Death might also be sudden dueto arrhythmias, heart conduction block,and systemic or pulmonary embolism.In these patients, only early and abso-lute abstinence of alcohol can reversemyocardial dysfunction [56, 57, 126]which in a historic study by McDonaldand Burch was achieved with prolongedbedrest for several months without fur-ther access to alcoholic beverages. Thiswas an excellent result long before ACEinhibitors or betablockers were avail-able for heart failure treatment [57].Mortality can otherwise reach 40–50%within a 4–5 year period in the non-abstinent patients [127], whereas afterwithdrawal from alcohol hemodynamicand clinical improvement or at leasta slower progression of disease com-pared to the idiopathic form of dilatedcardiomyopathy was shown [128, 129].

To maintain abstinence, recent inves-tigations suggest the benefits of adjuvantmedications, e. g., naltrexone, which isan opiate receptor antagonist that blocksendogenous opioid reward and reducesalcohol-cue-conditioned reinforcementsignals; acamprosate, an agent that ex-erts action through excitatory aminoacids; by disulfiram, an aldehyde de-hydrogenase inhibitor, which causes in

alcohol use acetaldehyde accumulationand symptoms such as nausea, flushing,sweating, and tachycardia or by selectiveserotonin re-uptake inhibitors (SSRI) [8,130, 131]. To treat the alcohol prob-lem, a combined approach comprisingpharmacologic and psychosocial therapyinvolving self-help groups or AlcoholicsAnonymous is essential.

Treatment of alcoholic cardiomyopa-thy follows the usual regimen for ther-apy of heart failure, including ACE in-hibitors, betablockers, diuretics includ-ing spironolactone or eplerinone, anddigitalis in atrial fibrillation for rate con-trol togetherwith anticoagulation, when-ever appropriate (. Table 3). Caution foranticoagulation is warranted due to theproblemsofnoncompliance, trauma, andoverdosage especially inhepatic dysfunc-tion.

Conclusion

The individual amount of alcohol con-sumption decides on harm or benefit.The preponderance of data suggests thatdrinking one to two drinks in men andone drink in women will benefit the car-diovascular system over time. More thanthis amount can lead to alcoholic car-diomyopathy. Moderate drinking belowthat threshold might even reduce the in-cidence of coronary artery disease, dia-betes, and heart failure.

Corresponding address

Prof. Dr. B. MaischHerz- und Gefäßzentrum Marburg (HGZ) undPhilipps Universität MarburgFeldbergstr. 45, 35043Marburg, Deutschlandbermaisch@gmail.com

Compliance with ethicalguidelines

Conflict of interest. B.Maisch states that he has nocompeting interest.

This article quotes studieswith humanparticipants oranimals. See referenceswith the contributing authoronhuman studies.

OpenAccess. Thisarticle isdistributedunderthetermsof the Creative CommonsAttribution 4.0 InternationalLicense (http://creativecommons.org/licenses/by/4.0/), which permits unrestricteduse, distribution,and reproduction in anymedium, provided yougiveappropriate credit to the original author(s) and thesource, providea link totheCreativeCommons license,and indicate if changesweremade.

References

1. Madden JS (1993) The definition of alcoholism.Alcohol28:617–620

2. Schuckit MA, Hesselbrock V, Tipp J et al (1994)A comparison of DSM-III-R, DSM-IV and ICD-10substance use disorders diagnoses in 1922 menandwomensubjects in theCOGAstudy. Addiction89:1629–1638

3. Hasin D, McCloud S, Li Q, Endicott J (1996)Cross-system agreement among demographicsubgroups: DSM-III, DSM-III-R, DSM-IV and ICD-10

Herz 6 · 2016 491

Main topic

diagnoses of alcohol use disorders. Drug AlcoholDepend41:127–135

4. Preedy VR, Atkinson LM, Richardson PJ, Peters TJ(1993) Mechanisms of ethanol-induced cardiacdamage. BrHeart J69:197–200

5. Batra A, Müller CA, Mann K, Heinz A (2016)Abhängigkeit und schädlicher Gebrauch vonAlkohol. DtschArztebl113:301–310

6. MannK,HochE, BatraA (2015) S3-Leitlinie Screen-ing, Diagnose undBehandlung alkoholbezogenerStörungen. Springer,Heidelberg

7. Wodarz N, Mann K, Hoch E et al (2016) S3Leitlinie: Alkoholbezogene Störungen, Screening,Diagnose und Behandlung. Bayerisches Ärztebl2016(4):144–149

8. Connor JP, Huber PS, Hall WD (2016) Alcohol usedisorders. Lancet387:988–998

9. Rocco A, Compare D, Angrisani D et al (2014)Alcoholic disease: Liver and beyond. World JGastroenterol20:14652–14659

10. Solfrizzi V, D‘Introno A, Colacicco AM et al (2007)Alcohol consumption,mild cognitive impairment,and progression to dementia. Neurology68(21):1790–1799

11. Panza F, Capurso C, D’Introno A et al (2009)Alcohol drinking, cognitive functions in olderage, predementia, and dementia syndromes.JAlzheimersDis17(1):7–31

12. Gonçalves A, Claggett B, Jhund PS, RosamondW (2015) Alcohol consumption and risk of heartfailure: The Atherosclerosis Risk in Communitiesstudy. EurHeart J36:939–945

13. Goncalves A, Jhund PS, Glaggett B et al (2015)Relationship between alcohol consumption andcardiac structure and function in the elderly. Theatherosclerosis risk in communities study. CircCardiovasc Imaging 8:e002846. doi:10.1161/CIRCIMAGING.114.002846

14. George A, Figueredo VM (2011) Alcoholic car-diomyopathy: A review. JCardiacFail 17:844–849

15. Maisch B (1996) Alcohol and the heart. Herz21:207–212

16. WilkeA,KaiserA, Ferency I,MaischB (1996)Alcoholandmyocarditis. Herz21:248–257

17. Menz V, Grimm W, Hoffmann J, Maisch B (1996)Alcohol and rhythm disturbance: The HolidayHeart syndrome. Herz21:227–231

18. Rupp H, Brilla CG, Maisch B (1996) Hypertensionand alcohol: Central and peripheral mechanisms.Herz21:258–264

19. Schoppet M, Maisch B (2001) Alcohol and theheart. Herz26:345–352

20. Maisch B, Gelbrich G, Pankuweit S et al (2008)Alcohol and heart failure. Eur Heart J 29(AbstrSuppl):553

21. Münzinger (1877) Das Tübinger Herz. Ein Beitragzur Lehre von der Überanstrengung des Herzens.DtschArchKlinMed19:449

22. Frenzel H, Schwartzkopff B (2000) ToxischeSchädendesHerzensdurchAlkohol,Anthrazyklineund Kokain. In: Hort W (ed) Pathologie desEndokard, der Kranzarterien und des Myokard,1stedn. vol22/2. Springer,Berlin,pp1175–1228

23. von Bollinger O (1884) Über die Häufigkeit undUrsachen der idiopathischenHerzhypertrophie inMünchen. DtschMedWochenschr10:180

24. https://www.hdbg.eu. Accessed8Aug201625. Steell G (1893) Heart failure as a result of chronic

alcoholism.MedChronManchester18:1–2226. MacKenzie J (1902) The Study of the Pulse. Y. J.

Pentland,Edinburgh,p23727. Brigden W, Robinson J (1964) Alcoholic heart

disease. BritMedJ2:1283–1289

28. Aalsmeer WC, Wenckebach KF (1929) Herz undKreislaufbei derBeri Beri Krankheit. WienArch InnMed16:193–272

29. Akbarian M, Yankopoulos NA, Abelmann WH(1966) Hemodynamic studies in Beriberi heartdisease. AmJMed414(2):197–212

30. Djoenaidi W, Notermans SL, Dunda G (1992)Beriberi cardiomyopathy. Eur J Clin Nutr46:227–234

31. MehtaPA,DubreySW(2009)Highoutput failure. QJMed102:235–241

32. Hunt SA, Abraham WT, Chin MH et al (2005)ACC/AHA2005guideline update for the diagnosisand management of chronic heart failure inthe adult-summary article a report of theAmerican College of Cardiology/American HeartAssociation Task Force on practice guidelines(writing committee toupdate the2001Guidelinesfor the Evaluation and Management of HeartFailure). JAmCollCardiol46:1116–1143

33. Kelynack TN, KirkbyW (1901) Arsenical poisoninginbeerdrinkers. Baillière, Tyndall&Cox, London

34. Royal Commission Appointed to Inquire intoArsenical Poisoning fromtheConsumptionofBeerand other Articles of Food or Drink (1903) ”FinalReport“Part I.WymanandSons, London

35. Reynolds ES (1901) An account of the epidemicoutbreak of arsenical poisoning occurring in beerdrinkers in the north of England and themidlandcounties in1900. Lancet157(4038):166–170

36. http://www.npr.org/sections/thesalt/2013/04/08/176587506/arsenic-in-beer-may-come-from-widely-used-filtering-process. Accessed 8 Aug2016

37. McDermott PH, Delaney RL, Egan JD, Sullivan JF(1966) Myocardosis and cardiac failure in men.JAMA198(3):253–256

38. Kesteloot H, Terryn R, Bosmans P, Joossens JV(1966)Alcoholicperimyocardiopathy. ActaCardiol21(3):341–357

39. Morin Y, Daniel P (1967) Quebec beer-drinkers‘cardiomyopathy: Etiologic considerations. CanMedAssocJ97:926–928

40. Bonenfant JL,MillerG, RoyPE (1967)Quebecbeer-drinkers’ cardiomyopathy: pathologicstudies. CanMedAssocJ97:910–916

41. Sandusky GE, Henk WG, Roberts ED (1981)Histochemistry and ultrastructure of the heart inexperimental cobalt cardiomyopathy in the dog.ToxicolApplPharmacol61:89–95

42. Van Vleet JF, Rebar AH, Ferrans VJ (1977)Acute cobalt and isoproterenol cardiotoxicityin swine: Protection by selenium-vitamin Esupplementation and potentiation by stress-susceptiblephenotype. AmJVetRes38:991–1002

43. Dahms K, Sharkowva Y, Heitland P et al (2014)Cobalt intoxication diagnosedwith the help of DrHouse. Lancet383:574

44. Møller S, Henriksen JH (2010) Cirrhotic cardiomy-opathy. JHepatol53:179–190

45. Lian C (1915) L‘alcoholisme cause d’hypertensionarterielle. BullAcadMed74:525–528

46. Abe H, Kawano Y, Kojima S et al (1994) Biphasiceffectsofrepeatedalcoholintakeon24-hourbloodpressure in hypertensive patients. Circulation89:2626–2633

47. WigleDA,PangSC,Sarda IR, a (1993)Acuteethanolingestionmodifies the circulatingplasma levels ofatrialnatriureticpeptide. Alcohol10:275–280

48. Guillaume P, Jankowski M, Gianoulakis C,Gutkowska J (1996) Effect of chronic ethanolconsumption on the atrial natriuretic system ofspontaneously hypertensive rats. Alcohol Clin ExpRes20:1653–1661

49. Potter JF, Beevers DG (1984) Pressor effect ofalcohol inhypertension. Lancet1:119–122

50. MacMahon S (1987) Alcohol consumption andhypertension. Hypertension9:111–121

51. Klatsky AL (1996) Alcohol and hypertension. ClinChimActa246:91–105

52. Klatsky AL (2000) Alcohol and hypertension. In:Operil S, Weber M (eds) Hypertension, 2nd edn.WB.SaundersCo,Philadelphia,pp211–220

53. Urbano-Marquez A, Estrich R, Navarro-Lopez F etal (1989) The effects of alcoholismon skeletal andcardiacmuscle. NEngl JMed320:409–415

54. Wendt VE, Ajluni R, Bruce TA et al (1966) Acuteeffectsofalcoholonthehumanmyocardium. AmJCardiol17:804–812

55. Regan TJ, Levinson GE, Oldewurtel HA (1969)Ventricular function in noncardiacs with alcoholicfatty liver: Role of ethanol in the production ofcardiomyopathy. JClin Invest48:397–407

56. Burch GE, Giles TD (1971) Alcoholic cardiomyopa-thy. Conceptof thediseaseand its treatment. AmJMed50:141–145

57. McDonald CD, Burch GE,Walsh JJ (1971) Alcoholiccardiomyopathy managed with prolonged bedrest. Ann InternMed74:681–691

58. Richardson P, McKenna W, BristowM et al (1996)Report of the 1995 World Health Organization/InternationalSocietyandFederationofCardiologyTask Force on the definition and classification ofcardiomyopathies. Circulation93:841–842

59. Regan TJ (1990) Alcohol and the cardiovascularsystem. JAMA264:377–381

60. Rubin E, Urbano-Marquez A (1994) Alcoholiccardiomyopathy. AlcoholClinExpRes18:111–114

61. Piano MR, Schwertz DW (1994) Alcoholic heartdisease: A review. HeartLung23:3–17

62. HenryWL, Gardin JM, Ware JH (1980) Echocardio-graphic measurements in normal subjects frominfancytooldage. Circulation62:1054–1061

63. Kupari M, Koskinen P, Suokas A (1991) Leftventricular size, mass and function in relation tothe duration and quantity of heavy drinking inalcoholics. AmJCardiol67:274–279

64. FabrizioL,ReganTF(1994)Alcoholiccardiomyopa-thy. CardiovascDrugsTher8:89–94

65. Steinberg JD, Hayden MT (1981) Prevalenceof clinically occult cardiomyopathy in chronicalcoholism. AmHeart J101:461–464

66. Fernandez-Sola J, Estruch R, Grau JM et al(1994) The relation of alcoholic myopathy tocardiomyopathy. Ann InternMed120:529–536

67. Guarnieri T, Lakatta EG (1990) Mechanism ofmyocardial contractile depression by clinicalconcentrations of ethanol. A study in ferretpapillarymuscles. JClin Invest85:1462–1467

68. Danziger RS, Sakai M, Capogrossi MC et al (1991)Ethanol acutely and reversibly suppresses excita-tioncontraction coupling in cardiacmyocytes. CircRes68:1660–1668

69. ThomasAP, RozanskiDJ, RenardDC, RubinE (1994)Effectsofethanolonthecontractile functionof theheart: A review. AlcoholClinExpRes18:121–131

70. Kojima S, Wu ST, Wikman-Coffelt J, Parmley WW(1993)Acuteeffects of ethanol oncardiac functionand intracellular calcium in perfused rat heart.CardiovascRes27:811–816

71. Tepper D, Capasso JM, Sonnenblick EH (1986) Ex-citation-contraction coupling in rat myocardium:Alterationswith long term ethanol consumption.CardiovascRes20:369–374

72. Das AM, Harris DA (1993) Regulation of themitochondrial ATP-synthase is defective in ratheart during alcohol-induced cardiomyopathy.BiochimBiophysActa1181:295–299

492 Herz 6 · 2016

73. Capasso JM, Li P, Guideri G et al (1992)Myocardialmechanical, biochemical, and structural alter-ations inducedbychronicethanol ingestion in rats.CircRes71:346–356

74. Segel LD, Rendig SV, Choquet Y et al (1975)Effects of chronic gradedethanol consumption onthe metabolism, ultrastructure, and mechanicalfunctionof the ratheart. CardiovascRes9:649–663

75. Siddiq T, Richardson PJ, Mitchell WD et al(1993) Ethanolinduced inhibition of ventricularprotein synthesis in vivo and the possible role ofacetaldehyde. CellBiochemFunct11:45–54

76. Preedy VR, Peters PJ (1990) Changes in protein,RNA, and DNA and rates of protein synthesisin muscle-containing tissues of the mature ratin response to ethanol feeding: A comparativestudy of heart, small intestine and gastrocnemiusmuscle. AlcoholAlcohol25:489–498

77. Lang CH, Frost RA, Kumar V, Vary T (2000)Impaired myocardial protein synthesis inducedby acute alcohol intoxication is associated withchanges in eIF4F. Am J Physiol Endocrinol Metab279:1029–1038

78. PreedyVR,PatelVB,WhyHJetal (1996)Alcoholandthe heart: Biochemical alterations. Cardiovasc Res31:139–147

79. Patel VB, SandhuG, Corbett JMet al (2000) A com-parative investigation into the effect of chronicalcohol feeding on themyocardiumof normoten-sive andhypertensive rats: Anelectrophoretic andbiochemical study. Electrophoresis21:2454–2462

80. Chen DB, Wang L, Wang PH (2000) Insulin-like growth factor I retards apoptotic signalinginduced by ethanol in cardiomyocytes. Life Sci67:1683–1693

81. Fernández-Solà J, Fatjó F, Sacanella E et al (2006)Evidenceofapoptosisinalcoholiccardiomyopathy.HumPathol37(8):1100–1110

82. Hajnoczky G, Buzas CJ, Pacher P et al (2005)Alcohol and mitochondria in cardiac apoptosis:Mechanisms and visualization. Alcohol Clin ExpRes29:693–701

83. RodriguezA, ChawlaK,UmohNAetal (2015)Alco-hol and apoptosis: Friends or foes? Biomolecules5:3193–3203

84. Vasiljevic JD, Kanjuh V, Seferovic P et al (1990)The incidence of myocarditis in endomyocardialbiopsy samples from patients with congestiveheart failure. AmHeart J120:1370–1377

85. Morin Y, Roy PE, Mohiuddin SM, Taskar PK (1969)The influence of alcohol on viral and isoproterenolcardiomyopathy. CardiovascRes3(3):363–368

86. Bernstein IM, Webster KH, Williams RC, StricklandRG (1974) Reduction in circulating T lymphocytesinalcoholic liverdisease. Lancet2:488–490

87. ArbabiS,Garcia I,BauerGJ,MaierRV(1999)Alcohol(ethanol) inhibits IL-8 and TNF: role of the p38pathway. J Immunol162:7441–7445

88. Cook RT (1998) Alcohol abuse, alcoholism, anddamage to the immune system–a review. AlcoholClinExpRes22:1927–1942

89. HeberdenW (1786) Some account of a disorder ofthe breast. Med Trans R Coll Physicians (london)2:59–67

90. Klatsky AL, Friedman GD, Siegelaub AB (1974) Al-cohol consumption before myocardial infarction.Results from the Kaiser-Permanente epidemio-logic study of myocardial infarction. Ann InternMed81:294–301

91. Black S (1819) Clinical and pathological reports.AlexWilkinson,Newry,pp1–47

92. Renaud S, de Lorgeril M (1992) Alcohol, platelets,andtheFrenchparadox forcoronaryheartdisease.Lancet339:1523–1526

93. Artaud-Wild SM, Connor SL, Sexton G et al (1993)Differences in coronarymortality canbeexplainedby differences in cholesterol and saturated fatintakes in 40 countries but not in France andFinland. Aparadox. Circulation88:2771–2779

94. Pearson TA, Terry P (1994)What to advise patientsaboutdrinkingalcohol: Theclinician‘sconundrum.JAMA272:967–968

95. FriedmanGD, KlatskyAL (1993) Is alcohol good foryourhealth? NEngl JMed329:1882–1883

96. Gaziano JM, Buring JE, Breslow JL et al (1993)Moderate alcohol intake, increased levels of high-density lipoprotein and its subfractions, anddecreased risk of myocardial infarction. N Engl JMed329:1829–1834

97. Ridker PM, Vaughan DE, Stampfer MJ et al (1994)Associationofmoderatealcoholconsumptionandplasma concentration of endogenous tissue-typeplasminogenactivator. JAMA272:929–933

98. Mennen LI, Balkau B, Vol S et al (1999) Fibrinogen:Apossible link between alcohol consumption andcardiovascular disease? Arterioscler ThrombVascBiol19:887–892

99. Renaud SC, Beswick AD, Fehily AM et al (1992)Alcohol and platelet aggregation: The CaerphillyProspective Heart Disease study. Am J Clin Nutr55(5):1012–1017

100. Pace-Asciak CR, Hahn S, Diamandis EP et al (1995)The red wine phenolics trans-resveratrol andquercetin block human platelet aggregation andeicosanoid synthesis: Implications for protectionagainst coronary heart disease. Clin Chim Acta235(2):207–219

101. Semba RD, Ferrucci L, Bartali B et al (2014)Resveratrol levels and all-causemortality in oldercommunity-dwelling adults. JAMA Intern Med174(7):1077–1084

102. Corder R, Douthwaite JA, Lees DM et al (2001)Entothelin-1synthesisreducedbyredwine.Nature414(6866):863–864

103. Rosenkranz S, Knirel D, Dietrich H et al (2002)Inhibition of the PDGF receptor by red wineflavonoids provides a molecular explanation forthe”Frenchparadox“. FASEBJ16(14):1958–1960

104. StrasserRH,Nuchter I, RauchBetal (1996)Changesin cardiac sinal transduction systems in chronicethanol treatment preceding the development ofalcoholiccardiomyopathy. Herz21:232–240

105. Ettinger PO, Wu CF, De La Cruz C, Weisse AB,Ahmed SS, Regan TJ (1978) Arryhthmias andthe ”Holiday Heart“: Alcohol-associated cardiacrhythmdisorders. AmHeart J1978(95):555–562

106. Klatsky AL (2005) Alcohol and cardiovasculardiseases: A historical review and 2005 up-date. http://www.aim-digest.com/gateway/pages/heart/articles/CVD/klatsky1105.htm. Ac-cessed8Aug2016

107. Patterson E, Dormer KJ, Scherlag BJ et al (1987)Long-term intracoronary ethanol administrationelectrophysiologic and morphologic effects.Alcohol4:375–384

108. Greenspon AJ, Schaal SF (1983) The ”HolidayHeart“: Electrophysiologic studies of alcoholeffects inalcoholics. Ann InternMed98:135–139

109. Kasper EK, Agema WR, Hutchins GM et al(1994) The causes of dilated cardiomyopathy:A clinicopathologic review of 673 consecutivepatients. JAmCollCardiol23:586–590

110. Johnson RA, Palacios I (1982) Dilated cardiomy-opathiesof theadult. NEngl JMed307:1051–1058

111. Engler R, Ray R, Higgins CB (1982) Clinicalassessmentandfollow-upof functional capacity inpatientswith chronic congestive cardiomyopathy.AmJCardiol1982(49):1832–1837

112. Follansbee WP, Michelson EL, Morganroth J(1980) Nonsustained ventricular tachycardiain ambulatory patients: Characteristics andassociationwith suddencardiacdeath. Ann InternMed92:741–747

113. Marriott HJL (1964) Electrocardiographic abnor-malities, conduction disorders and arrhythmias inprimary myocardial disease. Prog Cardiovasc Dis7:99–114

114. Teragaki M, Takeuchi K, Takeda T (1993) Clinicaland histologic features of alcohol drinkers withcongestiveheart failure. AmHeart J125:808–817

115. Aretz HT, BillinghamME, EdwardsWD et al (1987)Myocarditis. A histopathologic definition andclassification. AmJCardiovascPathol1:3–14

116. MaischB,Portic I, RisticADetal (2000)Definitionofinflammatory cardiomyopathy (myocarditis): Onthewaytoconsensus. Herz25(3):200–209

117. Maisch B, Bauer E, Hufnagel G (1988) The use ofendomyocardialbiopsies inheart failure. EurHeartJ9(SupplH):59–71

118. La Vecchia LL, Bedogni F, Bozzola L et al (1996)Predictionof recoveryafterabstinence inalcoholiccardiomyopathy: Role of hemodynamic andmorphometricparameters. ClinCardiol19:45–50

119. Leggett BA, Powell LW, Halliday JW (1989)Laboratory markers of alcoholism. Dig Dis7:125–134

120. Cohen JA, KaplanMM(1979) The SGOT/SGPT ratio– an indicator of alcoholic liver disease. DigDis Sci24:835–838

121. Williams AL, Hoofnagle JH (1988) Ratio ofserum aspartate to alanine aminotransferasein chronic hepatitis. Relationship to cirrhosis.Gastroenterology95:734–739

122. SalaspuroM (1999) Carbohydrate-deficient trans-ferrin as compared toothermarkers of alcoholism:Asystemic review. Alcohol19:261–271

123. Arndt T (2001) Carbohydrate-deficient transferrinas a marker of chronic alcohol abuse: A criticalreviewof preanalysis, analysis, and interpretation.ClinChem47:13–27

124. ReynaudM, Schellenberg F, Loisequx-Meunier NNet al (2000) Objective diagnosis of alcohol abuse:Compared values of Carbohydrate-DeficientTransferrin (CDT), Gamma-Glutamyl Transferase(GGT), and Mean Corpuscular Volume (MCV).AlcoholClinExpRes24:1414–1419

125. Mostofsky E, Chalhal HS, Mukamal KJ et al (2016)Alcohol and immediate risk of cardiovascularevents: A systematic review and dose-responsemeta-analysis. Circulation133(10):979–987

126. Nethala V, Brown EJ, Timson CR, Patcha R (1993)Reversal of alcoholic cardiomyopathy in a patientwith severe coronary artery disease. Chest104:626–632

127. Pathak SK, Kukreja RC, Hess M (1996) Molecularpathologyofdilatedcardiomyopathies. Curr ProblCardiol21:99–144

128. Guillo P, Mansourati J, Maheu B et al (1997)Long-term prognosis in patients with alcoholiccardiomyopathyandsevereheart failureafter totalabstinence. AmJCardiol79:1276–1278

129. Prazak P, Pfisterer M, Osswald S et al (1996)Differences of disease progression in congestiveheart failure due to alcoholic as compared toidiopathic dilated cardiomyopathy. Eur Heart J17:251–257

130. Litten RZ, Allen JP (1998) Advances in develop-ment of medications for alcoholism treatment.Psychopharmacology (Berl)139:20–33

131. Garbutt JC, West SL, Carey TS et al (1999) Phar-macological treatment of alcohol dependence:a reviewof theevidence. JAMA281:1318–1325

Herz 6 · 2016 493