Main topic

Herz B. Maisch DOI 10.1007/s00059-016-4469-6 Herz- und Gefäßzentrum Marburg (HGZ) und Philipps Universität Marburg, Marburg, Deutschland © The Author(s) 2016. This article is available at SpringerLink with Open Access. Alcoholic The result of dosage and individual predisposition

Alcoholism—use and abuse both mental and physical—in particular, 4 Beer: 12 fluid ounces of 5 % beer = gastrointestinal [9], neurological [10, 355 ml fluid = 17.5 ml 100 % . According to the definition of the World 11], and cardiological [12, 13]. The 4 Wine: 5 fluid ounces of 12 % wine = HealthOrganization(WHO), relationship of alcohol with heart dis- 148 ml fluid = 17.76 ml of 100 % is subgrouped in two categories: alcohol ease or dementia is complicated by the alcohol. abuse and [1]. This fact that moderate alcohol consumption 4 Distilled spirits: 1.5 fluid ounces of corresponds roughly with the concept of was shown not only to be detrimental ~40%liquor=44ml=17.6mlof the American Psychiatric Association [2, buttoacertaindegreealsoprotective 100 % alcohol. 3]. describes the psycho- against [14]orto logical dependence on for ad- cognitive function in predementia. A historical perspective equate functioning together with occa- We reviewed the effects of ethanol on sional heavy consumption, while alcohol the cardiovascular system in 1996 [15], For more than 3000 years, alcoholic bev- dependence is defined as an increased including aspects of inflammation [16], erages have been consumed in multiple together with physical rhythm disturbances [17], and hyperten- societies through the centuries and cul- symptoms upon withdrawal. In Western sion [18]. In 2001 we updated the data tures. The name alcohol is much younger countries it is estimated that up to 10 % on the ambivalent relationship between than the many beverages containing it. of the adult population suffers from al- alcohol and the heart [19] and in 2008 Pulverized antimony was used as eye coholism [4]. The highest prevalence is added new evidence on a larger cohort shadow by Egyptian women and named detected in the third to fifth decade of of patients with different forms of car- al-Kol. In the 16th century Paracelsus life, and alcoholism is seen in all races, diomyopathy and increased alcohol in- Theophrastus Bombastus from Hohen- ethnic groups, and socioeconomic strata. take from the German competence net- heim used this term for distilled liquor Germany with a total population of work on [20]. and called it alcohol [15]. The benefi- 81 million inhabitants is a permissive This review revisits our past and deals cial cardiovascular effects of alcohol have society with respect to the drinking of withourcurrentthinkingontheepidemi- been appreciated, e. g., in medieval times, alcohol. Alcohol consumption is part ology, pathophysiology, clinical charac- when people took advantage of the va- of the local culture. About 40 million teristics, and treatments available for al- sodilating properties of alcohol to treat individuals drink alcohol. The per capita coholic cardiomyopathy. pectoris or heart failure. So Hilde- alcohol consumption of 9.7 l pure ethanol gard von Bingen (1098–1179), one of the and the early onset of regular or episodic Methods most prominent mysticians of her time, intensive drinking among young people recommended her heart wine as a uni- in Germany consequently leads to high This review assembles and selects per- versal remedy. One liter of wine was alcohol-related morbidity and mortality tinent literature on the ambivalent re- cooked for 4 min with 10 fresh pars- [5]. lationship of ethanol and the cardiovas- ley stems, 1 spoon of vinegar, and 300 g More than 1.8 million individuals cular system, including guidelines, meta- honey and then filtered [11]. This recipe in Germany with a total population of analyses, Cochranereviews, originalcon- is still in use today. 81 million inhabitants are alcohol de- tributions, and data from the Marburg Over the centuries “the good and the pendant. For an additional 1.6 million Cardiomyopathy registry. bad” of alcohol were evaluated clinically persons the use of alcohol is harmful [6, Drinksasmeasuresofalcoholareoften and scientifically. As early as 1855, Wood 7]. In a world-wide setting, alcohol use given in ounces (oz), whereby 1 oz equals incriminated alcohol as a cause of heart disorders show similarities in developed 28.35 g or 29.57 ml. failure. In 1861, Friedrich reported id- countries, where alcohol is cheap and Examples for 100 % alcohol in ml of iopathic hypertrophy as associated with readily available [8]. The many com- one drink in consumed beverages are be- alcoholism. In 1873, Walshe described plications of alcohol use and abuse are tween 17.6 to 17.76 ml: myocardial cirrhosis in alcoholics, which

Herz Main topic

Fig. 1 8 a Left ventricle from a 49-year-oldmanwithchronic alcohol abuse. Myofibers show partly hypertrophy andatrophy. Fibrosis is present as reparative interstitial and perivascular fibrosis.HE ×320. b Electron microscopy of an endomyocardial septalbiopsyfromapatientwithalcoholiccardiomyopathydemonstratingmyofibrillarreductionandvariablemitochondriae in size but increased in number.×2190. (With kind permission from H. Frenzel and B. Schwartzkopff [22])

holism as a cause of cardiac dilatation and hypertrophy, as did Sir William Osler in 1892 in his textbook Principles and Practices of Medicine. In 1893, Graham Steell, well known for the Graham Steell murmur due to pulmonary regurgitation in pulmonary hypertension or in mi- tral stenosis, reported 25 cases in whom he recognized alcoholism as one of the causes of muscle failure of the heart. He found it “a comparatively common one” [25]. In his 1906 textbook The Study of the Pulse, William MacKenzie described cases of heart failure attributed to alcohol andfirstusedtheterm“alcoholicheart Fig. 2 8 a Otto von Bollinger. (© de.wikipedia.org). b Munich beer heart.(© Philipp Mansmann disease” [26]. in http://www.bayerische-staatszeitung.de/staatszeitung/kultur/detailansicht-kultur/artikel/ In his 1972 review article, Bridgen was bierherz.html) the first to introduce the term alcoholic cardiomyopathy [27]. includes a spectrum of hepatic derange- In 1884, the pathologist and veterinarian ments that occur in the setting of right- Otto von Bollinger (. Fig. 2a) described Nutritional causes of “alcoholic” sided heart failure. Conversely cirrhosis the “Munich beer heart” with fibrosis, cardiomyopathy (fibrosis) was found both in heart and hypertrophy, and fatty degeneration in liver. Highcardiacoutputinpatientswith postmortem cardiac tissue of alcoholics Beriberi heart disease liver cirrhosis may have contributed to who consumed an estimated average of this cardiomyopathy in a vicious circle. 432 liters of beer per year (. Fig. 2b;[23]). Thiamine deficiency is common feature The term “wine heart” (Tübinger Wein- At that time every 10th necropsy in men inamalnourishedand/oralcoholicpopu- herz) originated in 1877 by Münzinger at the Munich pathology institute named lation. Thus, theconceptofberiberiheart [21], a German pathologist at Tübin- cardiac dilatation and fatty degeneration disease dominated thinking about alco- gen university. This entity we would as “Bierherz” being its underlying cause. hol and the heart for decades and caused call nowadays “alcoholic cardiomyopa- For comparison, the mean annual beer many to doubt that alcohol was actu- thy” with histologic features of dilata- consumption in Bavaria is nowadays es- ally cardiotoxic [28]. But vitamin B1 tion, myofibrillar necrosis and fibrosis timated to be 145 l and in the rest of (thiamine) deficiency is accompanied by (. Fig. 1a), and ultrastructural changes Germany around 100 l beer per person an elevated cardiac output and dimin- such as reduction of myofibrils and mi- and year [24]. ished peripheral vascular resistance [29, tochondriosis in a great variability of size In 1887, Maguire reported on 2 pa- 30]. According to its central hemody- and form (. Fig. 1b;[22]). tients with severe alcohol consumption namics, it can be classified as hyper- In Munich, the annual consumption who benefitted from abstinence. He sug- dynamic cardiomyopathy or high output of beer reached 245 l per capita and year gested that alcohol was poisoning the failure with a cardiac output >8 l/min in the last quarter of the 19th century. heart. In 1890, Strümpell listed alco- or a cardiac index >3.9 l/min/m2 [31,

Herz Abstract · Zusammenfassung

32]. In contrast, alcoholic cardiomyopa- Herz DOI 10.1007/s00059-016-4469-6 thy is characterized by a low cardiac out- © The Author(s) 2016. This article is available at SpringerLink with Open Access. put, associated with systemic vasocon- striction [4]. However, the high output B. Maisch state can lead to cardiac dilation, thus, Alcoholic cardiomyopathy. The result of dosage and individual representing a characteristic subentity of predisposition cardiomyopathy different from low out- put . Therefore, Abstract thiamine deficiency per se is just a his- The individual amount of alcohol consumed Chronic heavy alcohol abuse will also increase acutely or chronically decides on harm or blood pressure and cause a downregulation torical nutritional anomaly in the history benefit to a person’s health. Available data of the immune system that could lead to of alcoholic cardiomyopathy. suggest that one to two drinks in men and one increased susceptibilityto infections, which in drink in women will benefit the cardiovascular turn could add to the development of heart Manchester arsenic-in-beer system over time, one drink being 17.6 ml failure. Myocardial tissue analysis resembles 100 % alcohol. Moderate drinking can reduce idiopathic cardiomyopathy or chronic myo- epidemic the incidence and mortality of coronary artery . In the diagnostic work-up of alcoholic disease, heart failure, diabetes, ischemic and cardiomyopathy, the confirmation of alcohol In 1900, the Manchester arsenic-in-beer hemorrhagic stroke. More than this amount abuse by carbohydrate deficient transferrin epidemic was a serious food poisoning can lead to alcoholic cardiomyopathy, which (CDT) and increased liver enzymes, and the outbreak affecting several thousand peo- is defined as alcohol toxicity to the heart involvement of the heart by markers of heart ple across the North-West and Midlands muscle itself by ethanol and its metabolites. failure (e.g., NT-proBNP) and of necrosis Historical examples of interest are the (e.g., troponins or CKMb) is mandatory. ofEngland,withmanycasesprovingfatal. Munich beer heart and the Tübingen wine Treatment of alcoholic cardiomyopathy The arsenic had come from the glucose heart. Associated with chronic alcohol consists of alcohol abstinence and heart for which sulphuric acid was used in the abuse but having different etiologies are failure medication. sugarproductionprocessofa companyin beriberi heart disease (vitamin B1 deficiency) Leeds. Brewers had been using this sugar, and cardiac cirrhosis as hyperdynamic Keywords , arsenic poising in the Atrial fibrillation · Beriberi · Cirrhotic thus, unknowingly poisoning the beer Manchester beer epidemic, and cobalt cardiomyopathy · Hypertension · and as a result their customers for many intoxication in Quebec beer drinker’s disease. years even prior to the epidemic [33]. Ar- senic poising caused a multisystem dis- ease in over 6000 cases with more than Alkoholische Kardiomyopathie. Eine Folge der Dosis und der 70 deaths [34]. The syndrome included individuellen Prädisposition the usual signs and symptoms of ar- senic poisoning, with skin, nervous sys- Zusammenfassung nach Quebec benannte Bierherzerkrankung tem, and gastrointestinal manifestations. Die individuelle Menge akut oder chronisch getrunkenen Alkohols ist für den gesundheit- infolge einer Kobaltintoxikation. Chronischer Unusual in arsenic poisoning, but espe- lichen Schaden oder Nutzen entscheidend. Alkoholabusus erhöht den Blutdruck und cially prominent in this epidemic, were Grenzdosen für Männer sollten 1–2 Getränke verursacht eine Downregulation des Im- the cardiovascular findings. In his clin- à 17,6 ml reinen Alkohols sein, für Frauen munsystems mit erhöhter Infektanfälligkeit. ical description, Ernest Reynolds wrote ein Getränk. Mäßiger Alkoholkonsum kann Histologisch ist die alkoholische nicht von der idiopathischen Kardiomyopathie und einer that “cases were associated with so much die Inzidenz und Mortalität von koronarer Herzerkrankung, Herzinsuffizienz, Diabetes chronischen Myokarditis zu unterscheiden. heart failure and so little pigmentation mellitus, ischämischem und hämorrhagi- Alkoholabusus wird durch Bestimmung that they were diagnosed as beri-beri schem Schlaganfall vermindern. Größere des carbohydratdefizienten Transferrins ...”. He also found that “undoubtedly Mengen Alkohol führen zur alkoholischen (CDT) und erhöhter Leberenzyme bestätigt, the principal cause of death has been Kardiomyopathie, bedingt durch die Toxizität die Herzinsuffizienz durch Biomarker wie NT-proBNP und die Myozytolyse durch cardiac failure. In postmortem exami- von C2H5OH und seinen Metaboliten auf den Herzmuskel. Historische Beispiele sind Troponine und CKMb. Die Behandlung der nations, the only prominent signs were das Münchener Bier- und das Tübinger alkoholischen Kardiomyopathie besteht in the interstitial nephritis and the dilated Weinherz. Nicht auf die reine Alkoholwirkung der Alkoholabstinenz und medikamentöser flabby heart” (p. 169, [35]). This outbreak zurückzuführen sind aufgrund ihrer andersar- Therapie der Herzinsuffizienz. had been the first known trace metal car- tigen Ätiologie das Beriberi-Herz bei Mangel Schlüsselwörter diotoxic syndrome. an Thiamin (Vitamin B1) und die kardial mitbedingte Leberzirrhose als hyperdyname Vorhofflimmern · Beriberi · Zirrhosebedingte In 2013, the issue of arsenic in beer Kardiomyopathien, die Arsenvergiftung bei Kardiomyopathie · Hochdruck · Myokarditis and wine was again prominent, when der Manchester Biertrinkerepidemie und die MehmetCoelhan, aresearcherattheWei- henstephan research center at the Tech- nical University of Munich, reported at a meeting of the American Chemical So- ciety that many of the nearly 360 beers tested in Germany had trace amounts of

Herz Main topic arsenic. The source was identified to be the team of J. Schäfer suspected cobalt short- and long-term pressor effects me- the filter of choice for wine and beer, intoxication as the cause of heart failure, diated by the renin–aldosterone system i.e., diatomaceous earth [36]. The Ger- which clinically mimicked Quebec‘s beer and plasma vasopressin have been de- man word for it is Kieselguhr, a beige drinker disease [43]. One should note, scribed [47, 48]. powder made up of the skeletons of di- however, that cobalt is needed in minute The long-term hypertensive effect of atoms. The trace amounts of arsenic have amounts of 0.0003 mg/day in vitamin alcoholhasbeenconfirmedinmanystud- not been comparable to the arsenic-in- B12 (cobalamine) to avoid megaloblastic ies [49–52]. Remarkably, alcohol also in- beer endemic in Manchester but may still anemia. teracts with brain stem receptors and ex- reach up to 10-times the amount admit- erts thereby central hypertensive effects ted for arsenic in drinking water in the Cardiac cirrhosis or cirrhotic [18]. The apparent threshold amount of European Union and the US. cardiomyopathy drinking associated with higher blood pressure is approximately 3 drinks/day. Quebec‘s beer drinker disease The heart and liver interact in several Most studies show no increase in blood different ways. Acute or chronic right pressure with lighter drinking; several In the mid-1960s, another unexpected heart failure leads to elevation of liver show an unexplained J-shaped curve in heart failure epidemic among chronic, enzymes most likely due to liver conges- women with lowest blood pressures in heavybeerdrinkersoccurredintwocities tion, whereas cirrhosis due to cardiac lighter drinkers. There seems to be inde- intheUSA,inQuebec,Canada,andin disease is infrequent. Chronic liver dis- pendence from adiposity, salt intake, ed- Belgium. It was characterized by con- ease such as cirrhosis may in turn affect ucation, smoking, beverage type (wine, gestive heart failure, pericardial effusion, the heart and the whole cardiovascular liquor, or beer), and several other poten- and an elevated hemoglobin concentra- system, leading to a syndrome named tial confounders. tion. The explanation proved to be the cirrhotic cardiomyopathy (CCM). Thus, Clinical observation confirmed that addition of small amounts of cobalt chlo- CCM has been introduced as an new several days to weeks of drinking show ride. Cobalt was used as a foam stabi- entity separate of the cirrhosis etiology. higher and weeks of abstinence lower lizer by certain breweries in Canada and Increased cardiac output due to hy- pressures. Alcohol intake may also in- in the USA. In 1966 McDermott et al. perdynamic circulation, left ventricular terfere with the drug and dietary treat- [37] described the syndrome as myocar- dysfunction (systolic and diastolic), and ment of hypertension. This altogether dosis with heart failure, Kestelott et al. certain electrophysiological abnormal supports a causal relationship between [38] added pericardial involvement and findings are pathophysiological features alcohol consumption and a hypertensive named it alcoholic pericardiomyopathy, of the disease. The underlying mecha- state. and Morin and Daniel [39]inQuebec nisms might include the impaired β-re- tracked downthe etiologytocobaltintox- ceptor and calcium signaling, altered Alcoholic cardiomyopathy: ication to what become known as Quebec cardiomyocyte membrane physiology, Cytotoxicity of alcohol beer-drinkers cardiomyopathy. Human elevated sympathetic nervous tone and on heart muscle pathologywasfirstdescribedbyBonefant increased activity of vasodilatory path- et al. [40]. Animal models investigated ways [44]. In pathophysiological terms, The 1989 landmark report of Urbano- ultrastructure [41] and treatment e. g. by heart failure in liver cirrhosis belongs to Marquez et al. [53] showed a clear re- selenium [42]. Removal of the cobalt ad- the hyperdynamic cardiomyopathies. lation of lifetime alcohol consumption ditive ended the epidemic in all locations. to structural and functional myocardial and alcohol together Hypertension and skeletal muscle abnormalities in al- acted synergistically in these patients. As coholics. The amount of consumed al- the syndrome could be attributed to the As early as in 1915, Lian [45]reportedin cohol was large—the equivalent of >80 g toxicity of this trace element, the additive middle-aged French servicemen during alcohol/day for 20 years. Further evi- was prohibited thereafter. the first world war that heavy drinking dencecamefromdataonacutealcohol Not alcohol but cobalt itself recently couldleadtohypertension.Ittookalmost effects [54] and from clinical observation caused severe heart failure in a 55-year- 60 years before further attention was paid [55–57]. old man, who was referred to the uni- to the complex interaction between the In 1996, cardiomyopathies were de- versity hospital in Marburg to rule out heart and the peripheral vasculature in fined as diseases ”affecting the my- coronaryarterydisease as the cause ofhis various cross-sectional and prospective ocardium with associated cardiac dys- heart failure. He had become almost deaf epidemiologic studies, which have em- function“ [58] and primary and sec- and blind, with fever of unknown cause, pirically confirmed this early report. One ondary forms were distinguished in this hypothyroidism, and enlarged lymph is aware today that alcohol may cause an context. After consumption of large nodes. Both his hips had been replaced, acute but transient vasodilation, which quantities of alcohol over years the clin- the left side by a CoCrMo Protasul metal may lead to an initial fall in blood pres- ical picture of heavy alcohol drinkers prosthesis. Remembering a similar case sure probably mediated by the atrial na- could be indistinguishable from other in an episode of the TV series Dr. House, triuretic peptide (ANP) [46]. But also forms of dilated or familial cardiomy-

Herz Fig. 3 8 a Left ventricle (LV) biopsy of a 53-year-old individual with an alcohol consumption of >5 drinks/day for 32 years. Perivascular increase of leukocytes and fibrosis, myocytes in variable sizes with some myocytolysis.HE ×160. b LV biopsy of the 53-year-old alcoholic with increased ICAM (intercellular adhesion molecule) expression in capillaries and small vessels. ×320. c Circulating antimyosin antibodies in the 53-year-old patient with alcoholic abuse.Indirect immunofluorescent test. Titer 1:160 ×640 opathy. Alcohol is still suspected to of the action potential duration [67–71]. to exhibit sparse lymphocytic infiltrates be the major cause or contributory Isolated cardiomyocytes of alcohol-fed with myocyte degeneration and focal factor of secondary nonischemic di- rats did not maintain ATP levels upon necrosis and increased HLA (human lated cardiomyopathy being involved in energy demand due to an inadequate leukocyte antigen) or ICAM (intercel- up to one third of all cases of dilated increase in mitochondrial ATP-synthase lular adhesion molecule) expression cardiomyopathy [59–61]. In alcoholic activity, which led altogether to further (. Fig. 3;[16, 84]). cardiomyopathy, dilation and impaired myocyte loss [72, 73]. Ultrastructural This may have to do with the suscep- contraction of the left or both ventri- disarray of the contractile apparatus [74] tibility for infections due to a suppressed cles is observed [4]. Left ventricular is associated with a depressed myofib- immune system in a compromised hu- enddiastolic diameters are increased rillar and sarcoplasmic protein synthesis man host and also in experimental an- compared to age- and weight-matched in after ethanol exposure imal [85]. Ethanol can alter lympho- controls [62], the left ventricular mass [75–77]. This reduces contractile car- cytefunctions, inhibitneutrophilchemo- index is increased [63], and the left ven- diac filaments with subsequent negative taxis, and suppress the production of cy- tricular ejection fraction is well below inotropic effects on heart contractility tokines, which are involved in regulating normal (<45 %). Thus, the diagnosis of [78, 79]. An apoptotic effect of ethanol acute inflammatory responses to infec- alcoholic cardiomyopathy is still based on cardiac muscle has also been de- tious challenges [86–88]. Furthermore, on the coincidence of heavy alcohol scribed, which could be counteracted by autoimmunity and circulating autoanti- consumption and a global myocardial insulin-like growth factor (IGF)-I [80] bodies seem to be associated in some dysfunction, which cannot be explained and confirmed in later studies [81, 82]. patients with chronic alcohol consump- by any other underlying myocardial dis- In a study in rats that were fed with tion [16, 20, 84]. ease [64]. However, the prevalence of two different doses of alcohol (5 mM alcoholic cardiomyopathy may be un- [low alcohol], 100 mM [high alcohol] and derestimated, as autopsy findings reveal or in pair-fed nonalcohol controls for atherosclerosis pathologic changes of the heart in indi- 4–5 months), caspase-3 activity as puta- viduals with no clinical symptoms [65], tive marker of apoptosis was decreased The beneficial heart wine as universal when analyzing in large cross-sectional in the low alcohol diet, which went along remedy in medieval ages by Hildegard studies. with increased or normal contractility, von Bingen [11] found its later corre- Further evidence suggests that not whereas high doses of ethanol showed lates in many observations at the begin- only ethanol but also the first metabolite increased caspase activity, wall thinning, ning of modern medicine when coronary acetaldehyde may directly interfere with and a reduction of shortening velocity artery disease (CAD) and its risk factors cardiac and skeletal muscle homeostasis [83]. Of note, rats are a relatively alcohol and symptoms received more attention. [53, 66]. In vitro studies have further resistant species. Heberden [89] described angina so ele- elucidated the direct effect of ethanol gantly in 1786 and also added that ”con- on electromechanical coupling, indicat- Alcohol and myocarditis siderable relief“ through ”wine and spir- ing a decrease in myofilament–calcium ituous liquors“ could be expected. This sensitivity during alcohol consumption, Alcohol abuse coinciding with myocardi- observation led to the erroneous belief changes in the transmembrane action tis was reported in 1902 by McKenzie that alcohol is an immediate coronary va- potential, the amplitude of the cytosolic [26]. In endomyocardial biopsies of alco- sodilator. Alcohol is not a direct coronary calcium transients, and the shortening holics up to 30 % of patients were found vasodilator [90]. Symptomatic relief of

Herz Main topic angina could be through the anesthetic in vitro to platelet inhibition in a dose- Clinical work-up for alcoholic effect of ethanol or through peripheral dependent manner [100] and has shown cardiomyopathy vasodilation, which could transiently re- effects on all-cause mortality in a com- duce oxygen demand of the heart. munity-based study [101]. Polyphenols Habitual drinkers often hide their alcohol In 1819 the Irish physician Dr. Samuel of red barrique wines and flavonoids dependence fairly effectively. They may Black, who had a special interest in have been shown to inhibit endothe- admitdrinkingatsocialeventsbutnotthe angina pectoris described what is proba- lin-1 synthase [102] and PDGF-induced abuse inthe firstcontact. Patientswithal- bly the first commentary pertinent to the vasoproliferation thus also contributing coholic cardiomyopathy, therefore, usu- ”French Paradox“ [91]. This refers to the to cardiovascular protection [103]. ally present with symptoms of heart fail- finding in the last century that moderate ure, i. e., dyspnea, orthopnea, , alcohol consumption could be the rea- Signal transduction and beta- , and . Echocardio- son for the relatively low cardiovascular receptors graphy may reveal a mild or severe de- disease incidence in wine-drinking re- pression of cardiac function and ejection gions [92]. Renaud and de Lorgeril [93] In alcoholic cardiomyopathy, similar fraction or even show hypertrophy in the suggested that the inhibition of platelet to idiopathic dilated cardiomyopathy beginning [109]. Heart failure symptoms reactivity by wine may be one explana- (DCM), beta 1-adrenergic and mus- maybeduetoearlydiastolicortolatersys- tion for protection from CAD in France. carinic receptors are reduced in the tolic dysfunction. At later stages, due to However, there was further evidence on myocardium itself and reduced respon- atrialfibrillation, thrombiarenotuncom- this and other dietary mechanisms with siveness of the adenyl cyclase was shown, moninthedilatedatria.Mitralregurgi- the observation that France and Fin- whereas catecholamine levels in the cir- tation is found in up to two thirds of cases land have similar intakes of cholesterol culation may be elevated [104]. As a net [110]. Atrial fibrillation and supraven- and saturated fat, but consumption of effect, negative inotropism may result tricular tachyarrhythmias are common vegetables and vegetable oil containing and contribute to heart failure. findings in 15–20 % of patients [111], monounsaturated and polyunsaturated whereas ventricular are rare fattyacidsisgreaterinFrancethanin and stroke [112]. On ECG, unspecific abnormali- Finland. ties like complete or incomplete left bun- This inverse relation on mortality re- Acute effects of alcohol can result in dle branch block, atrioventricular con- sembles in most population based stud- rhythm disturbances. Since this hap- duction disturbances, alterations in the ies a U- or J-shaped curve: Total absti- pens often on weekends and holidays, ST segment, and P wave changes can be nence has a slightly increased mortal- Ettinger and Regan coined the term ”hol- found comparable to those in idiopathic ity when compared to low or moder- iday heart syndrome“, when they de- DCM [113]. ate alcohol consumption. It is present scribed 32 habitual drinkers with an ad- On endomyocardial biopsy, a dis- in individuals with and without overt ditional ingestion of ethanol prior to the crimination between idiopathic, chronic CAD, with diabetes, and with hyperten- [59, 105]. Atrial fibrillation inflammatory and alcoholic cardiomy- sion and has been underlined by a large wasthecommonestmanifestation, which opathy is virtually impossible since number of studies [94, 95]. The car- resolved with abstinence. In the Kaiser common features such as fibrosis, hy- dioprotective effect of alcohol can be at- Permanente Study, atrial arrhythmias in pertrophy of cardiac myocytes, and tributed to the increase in total high-den- 1322 persons reporting >6 drinks per day alterations of nuclei are present at light sitylipoproteins(HDL),and especiallyby were compared to arrhythmias in 2644 microscopy in the alcoholic cardiomy- an increase in subfractions HDL2 and matched light drinkers, showing a dou- opathy [114]aswellasinchronicmy- HDL3, whereas established cardiovascu- bledrelativeriskforheavydrinkers[106]. ocarditisaccordingtotheDallascriteria lar risk factors like low-density lipopro- Apartfromdirectcardiotoxicity,hyper- [115] or the World Heart Federation/ teins (LDL) or lipoprotein(a) are thought tension causing atrial stretch the arrhyth- International Society and Federation of to be moderately decreased [96]. Mod- mogenic potential of alcohol may come Cardiomyopathy (WHF/ISFC) defini- erate alcohol intake also exerts beneficial from the lowering the resting membrane tion of myocarditis [116]. Although the effects on the blood coagulation system. potential [107]andtheprolongationof severity of histological alterations on Itleadstoanincreaseofendogenousplas- conduction [108]. endomyocardial biopsy correlates with minogen activators [97], or a decrease in Studies of alcohol and stroke are com- thedegreeofheartfailureinoneofour fibrinogen concentrations [98]. plicated by the various contributing fac- studies, biopsy is not in common use In the Caerphilly prospective heart tors to stroke. Heavier drinkers are ap- for prognostic purposes [117]. Even the disease study, platelet aggregation in- parently at a higher risk of hemorrhagic recovery after abstinence of alcohol is duced by adenosine diphosphate was also stroke, whereasmoderate drinkingmight hard to predict based on morphometric inhibited in subjects who drank alco- be neutral or even result in a reduced risk evaluation of endomyocardial biopsies hol [99]. Assessing differences between of ischemic stroke. [118]. various forms of alcoholic beverages it CardiacMRImaybehelpfulinthedif- should be noted that resveratrol leads ferential diagnosis to hypertrophic car-

Herz Table 1 Clinical work-up in alcoholic cardiomyopathy Work-up of Criteria/findings Cardiacsymptoms Fatigue,dyspnea,edema,nocturia,tachycardia Noncardiac physi- Mental state (, depression, anxiety, psychosis) cal examination Neurology (cognitive decline, cerebellar degeneration, peripheral neuropathy, proximal ) 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 LV dilatation or hypertrophy, atrial dilatation, reduced shortening and ejection fraction, small pericardial effusion, mitral and tricuspid regurgitation, atrial thrombi in atrial fibrillation Endomyocardial Similar to dilated cardiomyopathy with myocyte hypertrophy or loss, reparative fibrosis, low grade leukocyte infiltration, vari- biopsy able, sometimes increase in Major HistocompatibilityComplex(MHC) class I and II expression, immunoglobulin binding to sarcolemma and myosin; helpful in differential diagnosis of other forms of cardiomyopathies, theoretically suited for follow-up or improvement but not in common use for this purpose Cardiac MRI Helpful in ruling out other cardiomyopathies, e. g. hypertrophic cardiomyopathy, myocarditis, constrictive 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 Monitor abstinence Alcohol concentration In acute 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 Acute myocyte destruction 1–3 days No MCV mean corpuscular volume, GGT gamma-glutamytransferase, GOT glutamic oxalacetic transaminase, GPT glutamic pyruvic transaminase, CDT carbohydrate-deficient transferrin, NT-proBNP n-terminal pro brain natriuretic peptide, CKMB creatinin kinase, muscle, brain subunit diomyopathy, storage diseases, and in- which best detects chronic alcohol con- even with moderate consumption an im- flammatory cardiomyopathy. For a com- sumption alone [122, 123]orincombina- mediately higher cardiovascular risk was prehensive overview see . Table 1 (com- tion with the other markers such as GGT attenuated after 24 h. It then became bined data from [6, 8, 24, 28]). [8, 124]. Markers such as ethyl sulphate, protective for and phosphatidyl ethanol, and fatty acid ethyl hemorrhagicstrokewitha30 %lowerrisk Laboratory findings esters are not routinely done. For a com- and protective against ischemic stroke prehensive overview see . Table 2 with within one week. In contrast, heavy al- Measuring blood alcohol concentration combined data from [6, 8, 24, 28]. cohol drinking continued to be associ- in an acute intoxication gives baseline Biomarkers of heart failure such as ated with higher cardiovascular risk in information but does not permit deduc- NT-proBNP and of myocardial necrosis the followingday(RR=1.3–2.3)andweek tions to chronic misuse. Markers for suchasthe troponinsand CKMB indicate (RR =2.25–6.2). chronic alcohol consumption rely on liver heart failure or myocytolysis. enzymes such as gamma-glutamyltrans- Prognosis and treatment ferase (GGT) [119], glutamic oxalacetic Is there an immediate risk of transaminase (GOT), and glutamic pyru- alcohol intake? Prognosis in individuals with low or victransaminase(GPT).Elevationsofthe moderate consumption up to one or two transaminases (GOT, GPT), especially In a recent meta-analysis, Mostofsky et drinks per day in men and one drink in a ratio of GOT/GPT higher than 2 might al. [125] analyzed if independent from women is not different from people who be indicative of in- habitual moderate or heavy alcohol con- do not drink at all. In CAD, diabetes, steadofliverdiseasefromotheretiologies sumption an immediate risks exists fol- and stroke prevention the J-type mor- [120, 121]. An excellent marker is car- lowingalcoholintake. Datafrom23stud- tality curves even indicate some benefit bohydrate deficient transferrin (CDT), ies with 20,457 participants showed that apart from the social ”well-being“. In

Herz Main topic

Table 3 Treatment of alcoholism and alcoholic cardiomyopathy Medication Treatment goal Dosage Adverse reaction Evidence Pharmacological for maintaining abstinence Naltrexone Abstinence 50–100 mg/day (oral) Nausea, headache, dizziness, joint and High 380 mg i. m. per month muscle pain Acamprosate Abstinence 666 mg three times daily Diarhea, pruritus, rash, altered libido High Disulfiram Abstinence 200 mg/day (oral) Dizziness, rash, headache, polyneuritis, Mixed, needs super- impotence, hepatotoxicity vision Nalmefene Reduced drinking or absti- 18 mg/day (oral) Dizziness, rash, headache, nausea, vomit- Moderate nence ing 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 HF+ prognosis As needed – High in HF Digitalis Rate control According to digoxin or Avoid overdosage Moderate in atrial digitoxin level fibrillation (AF) Anticoagulants Avoid stroke INR 1.8–2.2 in AF Bleeding High in AF patients with chronic alcohol use disor- alcohol use acetaldehyde accumulation Corresponding address ders and severe heart failure prognosis and symptoms such as nausea, flushing, is poor, since continued alcohol abuse sweating, and tachycardia or by selective Prof. Dr. B. Maisch results in refractory congestive heart serotonin re-uptake inhibitors (SSRI) [8, Herz- und Gefäßzentrum Marburg (HGZ) und failure. Death might also be sudden due 130, 131]. To treat the alcohol prob- Philipps Universität Marburg to arrhythmias, heart conduction block, lem, a combined approach comprising Feldbergstr. 45, 35043 Marburg, Deutschland [email protected] and systemic or pulmonary embolism. pharmacologic and psychosocial therapy In these patients, only early and abso- involving self-help groups or Alcoholics lute abstinence of alcohol can reverse Anonymous is essential. myocardial dysfunction [56, 57, 126] Treatment of alcoholic cardiomyopa- Compliance with ethical which in a historic study by McDonald thy follows the usual regimen for ther- guidelines and Burch was achieved with prolonged apy of heart failure, including ACE in- bedrest for several months without fur- hibitors, betablockers, diuretics includ- Conflict of interest. B. Maisch states that he has no ther access to alcoholic beverages. This ing spironolactone or eplerinone, and competing interest. was an excellent result long before ACE digitalis in atrial fibrillation for rate con- This article quotes studies with human participants or inhibitors or betablockers were avail- trol together with anticoagulation, when- animals. See references with the contributing author able for heart failure treatment [57]. ever appropriate (. Table 3). Caution for on human studies. Mortality can otherwise reach 40–50 % anticoagulation is warranted due to the OpenAccess. Thisarticleisdistributedundertheterms within a 4–5 year period in the non- problemsofnoncompliance, trauma, and of the Creative Commons Attribution 4.0 International abstinent patients [127], whereas after overdosage especially in hepatic dysfunc- License (http://creativecommons.org/licenses/by/ withdrawal from alcohol hemodynamic tion. 4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give and clinical improvement or at least appropriate credit to the original author(s) and the a slower progression of disease com- Conclusion source, providealinktotheCreativeCommonslicense, pared to the idiopathic form of dilated and indicate if changes were made. cardiomyopathy was shown [128, 129]. The individual amount of alcohol con- To maintain abstinence, recent inves- sumption decides on harm or benefit. References tigations suggest the benefits of adjuvant The preponderance of data suggests that medications, e. g., naltrexone, which is drinking one to two drinks in men and 1. Madden JS (1993) The definition of alcoholism. Alcohol28:617–620 an opiate receptor antagonist that blocks one drink in women will benefit the car- 2. Schuckit MA, Hesselbrock V, Tipp J et al (1994) endogenous reward and reduces diovascular system over time. More than A comparison of DSM-III-R, DSM-IV and ICD-10 alcohol-cue-conditioned reinforcement this amount can lead to alcoholic car- substance use disorders diagnoses in 1922 men andwomen subjects in the COGA study. Addiction signals; acamprosate, an agent that ex- diomyopathy. Moderate drinking below 89:1629–1638 erts action through excitatory amino that threshold might even reduce the in- 3. Hasin D, McCloud S, Li Q, Endicott J (1996) acids; by disulfiram, an aldehyde de- cidence of coronary artery disease, dia- Cross-system agreement among demographic subgroups: DSM-III, DSM-III-R, DSM-IV and ICD-10 hydrogenase inhibitor, which causes in betes, and heart failure.

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