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The focus of this review is on the effects of alcohol on the myocardium and its role as a cause of
heart failure due to dilated cardiomyopathy (DC). For nearly 150 years, alcohol consumption has
been associated with a variety of cardiovascular diseases. Observations during the second half of
the 19th century described cardiac enlargement seen at autopsy and heart failure symptoms in
persons who had consumed excessive amounts of alcohol.
During the first half of the 20th century, the concept of beriberi heart disease (ie, thiamine
deficiency) was present throughout the medical literature, and the idea that alcohol had any
direct effect on the myocardium was doubted. Epidemics of heart failure in persons who had
consumed beer contaminated with arsenic in the 1900s and cobalt in the 1960s also obscured the
observation that alcohol could exhibit a direct toxic effect. In the 1950s, evidence began to
emerge that supported the idea of a direct toxic myocardial effect of alcohol, and research during
the last 25 years has been particularly productive in characterizing the disease entity of alcoholic
cardiomyopathy (AC).
Ultimately, AC is a clinical diagnosis made in a patient presenting with a constellation of
findings that includes a history of excessive alcohol intake, possible physical signs of alcohol
abuse (eg, parotid disease, telangiectasia or spider angiomata, mental status changes, cirrhosis),
heart failure, and supportive evidence consistent with DC. Hypertension due to alcohol may be a
confounding comorbidity in that it may contribute to LV dysfunction; therefore, LV dysfunction
due to hypertension must be differentiated from pure AC.
Proposed mechanisms of injury in AC include the following:
Inhibition of protein synthesis
Inhibition of oxidative phosphorylation
Fatty acid ester accumulation
Free radical damage
Inhibition of calcium-myofilament interaction
Inflammatory and immunologic factors
Receptor abnormalities
Disruption of cell membrane structure
Coronary vasospasm
Synergy with concomitant conditions
Activation of the renin-angiotensin system [1]
Alcohol use has also been shown to have numerous effects on the cardiovascular system other
than heart failure. It has been associated with arrhythmia (eg, atrial fibrillation, atrial flutter,
other supraventricular arrhythmia, premature ventricular contractions), hypertension, stroke, and
sudden death.[2] In addition, the literature reports alcohol withdrawal being associated with
takotsubo, or stress-induced, cardiomyopathy. However, numerous studies have demonstrated
that light to moderate alcohol consumption (ie, 1-2 drinks per d or 3-9 drinks per wk) decreases
the risk of cardiac events such as myocardial infarction.

Cardiac Effect of Alcohol

Long-term alcohol use has been implicated as the etiology of left ventricular (LV) dysfunction in
as many as one third of cases of DC. The mechanism by which alcohol causes cardiac damage
remains unclear. Over many years, several theories have arisen based on clinical and scientific
data obtained in human and animal studies, including oxidative stress, apoptosis, mitochondrial
dysfunction, derangements of fatty acid metabolism/transport, and accelerated protein
The original theories regarding the mechanism focused on nutritional deficiencies (eg, thiamine
deficiency), secondary exposures (eg, tobacco, cobalt, arsenic), and other comorbidities (eg,
hypertension). However, although these mechanisms may play a role in selected patients, most
evidence in the literature indicates that the effects of alcohol on the myocardium are independent
of these factors and that the effect is a direct toxic result of ethanol or its metabolites.
Some studies have suggested that a genetic vulnerability exists to the myocardial effects of
alcohol consumption. Individuals with certain mitochondrial deoxyribonucleic acid (DNA)
mutations and angiotensin-converting enzyme (ACE) genotypes (DD genotype) may be
particularly susceptible to the damaging effects of alcohol. Exactly how these genetic variables
create this higher risk is not known.
Mitochondrial dysfunction is known to have a significant role in the development and
complications of alcoholic cardiomyopathy. Long-term alcohol use has been linked to damage of
mitochondrial DNA, increasing the risk of mutations.[4]
In addition, alcohol has been shown to have a negative effect on net protein synthesis. Many
studies have shown this result, and it remains a topic of ongoing investigation and speculation.
The exact manner in which alcohol produces this effect is not known, but the effect is consistent,
is observed throughout the heart, and may be exaggerated under stressful conditions.
To identify the causative agent of alcoholic cardiomyopathy, investigators administered ethanol
to rats pretreated with inhibitors of ethanol metabolism. Use of ethanol alone or ethanol with an
alcohol dehydrogenase inhibitor resulted in a 25% decrease in protein synthesis. When the rats
were given an inhibitor of acetaldehyde dehydrogenase to increase levels of the ethanol
metabolite acetaldehyde, an 80% decrease in protein synthesis occurred. Based on these data,
acute ethanol-induced injury appears to be mediated by ethanol and acetaldehyde; the latter may
play a more important role.
Acetaldehyde is a potent oxidant and, as such, increases oxidative stress, leading to the formation
of oxygen radicals, with subsequent endothelial and tissue dysfunction. Acetaldehyde may also
result in impairment of mitochondrial phosphorylation. Mitochondria play an essential role in
cellular metabolism, and disruption of their function can have profound effects on the entire cell.
The myocyte mitochondria in the hearts of persons exposed to alcohol are clearly abnormal in
structure, and many believe that this may be an important factor in the development of AC.
A study in a rat model using an alcohol dehydrogenase transgene that results in elevated levels of
acetaldehyde demonstrated a change in calcium metabolism at the intracellular level and a
decrease in peak shortening and shortening velocity. This was interpreted by the authors as

suggesting that acetaldehyde plays a key role in the cardiac dysfunction seen after alcohol intake.
Others have suggested that an acute decrease in mitochondrial glutathione content may play a
role in mitochondrial damage and implicate oxidative stress as a contributor in this process.
The formation of fatty acid ethyl esters during the metabolism of alcohol and specific genetic
defects in fatty acid ethyl ester synthase (which metabolizes these esters and may predispose
individuals to these toxic effects) have been proposed to result in further impairment of
mitochondrial phosphorylation. Acetaldehyde has also been associated with coronary vasospasm
and the release of troponin T in the acute setting. The latter effect can be blocked by the
administration of propranolol, implicating beta-adrenergic stimulation as an effect of
Other proposed mechanisms of injury include a direct inhibition of calcium-myofilament
interaction, free radical induced lipopigment accumulation within the myocyte and inhibition of
protein synthesis, an inflammatory or myocarditislike response (possibly secondary to antibodies
formed against protein-acetaldehyde adducts), reduced receptor expression, abnormal membrane
structure, disruption of zinc homeostasis, and an increase in myocardial superoxide dismutase
activity (resulting in an antioxidant imbalance).[5]
Quantity of alcohol intake in cardiac disease
Excessive intake of alcohol may result in increased systemic blood pressure in a dose-response
relationship, and this may contribute to chronic myocardial dysfunction. Patients who consume
more than 2 drinks per day have a 1.5- to 2-fold increase in hypertension compared with persons
who do not drink alcohol, and this effect is most prominent when the daily intake of alcohol
exceeds 5 drinks. Because hypertension may directly contribute to left ventricular (LV)
dysfunction, this may be a confounding comorbidity in persons who abuse alcohol, and it should
be differentiated from pure forms of AC.
In 1989, Urbano-Marquez et al reported on 48 men with alcohol abuse with a mean daily intake
of 243 g of alcohol and showed (1) an inverse relationship between total lifetime intake and
ejection fraction and fractional shortening and (2) a direct relationship between total lifetime
intake and LV mass. In persons who consumed 70 g of ethanol (or the equivalent of 7 oz of
whiskey, 20 oz of wine, or 72 oz of beer [ie, six 12-oz cans]) per day for 20 years, 36% had an
abnormal ejection fraction. Age and nutritional status appeared to play little or no role.[6]
In a 1986 study, Richardson et al concluded that continuous, rather than episodic, drinking was a
major risk factor for the development of heart failure and that this effect was unrelated to the
hypertensive effect of alcohol. In the study, the authors evaluated 38 patients with nonischemic
DC. Of these persons, 18 were classified as heavy drinkers (ie, 80 g/d or a lifetime dose of 250
kg), and 20 were classified as abstinent or light drinkers. Those classified as heavy drinkers all
were men who predominantly drank beer.[7]
Other studies and reviews have also quoted quantities similar to those mentioned above, and the
type of beverage consumed appeared to be irrelevant.
Binge drinking induces a systemic inflammatory reaction, which may lead to alcohol-induced
myocardial inflammation. One study indicated that patients who repeatedly expose themselves to
excessive amounts of alcohol may demonstrate evidence on magnetic resonance imaging (MRI)

scans of alcohol-induced myocardial inflammation but not show deterioration in indices of LV

performance. The study did not provide evidence of an absolute acute risk of cardiac events
involved with binge drinking, and the clinical significance of the findings requires further
Sex-related demographics
Currently available data indicate that certain aspects of alcoholic cardiomyopathy(AC) are
affected by the patient's sex. Several authors have reported that although AC is a disease that
affects males more often than females (due to a higher rate of alcohol abuse in men), females
may be more sensitive to alcohol's cardiotoxic effects.
In 1997, Fernandez-Sola and colleagues evaluated 10 women and 26 men who were alcohol
abusers and reported a similar prevalence of cardiomyopathy in the males and females, despite a
lower total lifetime alcohol dose in the women.[9]
In 1995, Urbano-Marquez described similar results in a study of 50 women and 100 men who
abused alcohol. The authors reported a lifetime dose of alcohol in the female group that was 60%
of that in the male group, but they found an equal incidence of cardiomyopathy and myopathy in
the males and females.[10]
Based on their work with a rat model, Jankala and colleagues suggested a link between lower
levels of p53 mRNA expression and female susceptibility to the development of AC.[11]
Age-related demographics
Alcoholic cardiomyopathy is a disease that primarily affects persons of at least middle age and is
observed less commonly in those younger than age 40 years, although preclinical cardiac
abnormalities have been demonstrated in persons engaging in chronic alcohol abuse. This is
believed to be due primarily to the fact that alcohol must be consumed excessively for at least 10
years to have a clinically relevant effect on the myocardium.
The natural history of patients with alcoholic cardiomyopathy depends greatly on each patient's
ability to cease alcohol consumption completely. Multiple case reports and small retrospective
and prospective studies have clearly documented marked improvement in or, in some patients,
normalization of cardiac function with abstinence. The following reports and studies provide
impressive data on the utility of abstinence and the confirmation of alcohol consumption as a
cause of DC.
Nakanishi et al identified 11 patients with AC and reported significant improvement in 8 of them
after they abstained from alcohol use. In addition, a marked worsening was seen in the 3 patients
who continued to abuse alcohol, including death from heart failure in 2 patients.[12]
A 12-month observational study of 20 patients with AC noted smaller cavity diameters, better
clinical evaluation findings, and fewer hospitalizations in the 10 patients who abstained from
alcohol use.
Guillo and colleagues evaluated 14 patients with AC over a 3-year period with serial
examinations, electrocardiograms (ECGs), stress tests, echocardiograms, and MUGA scans. Of

the 3 patients who continued to drink, 1 was lost to follow-up and 2 died. One patient underwent
heart transplantation within the 3 years of follow-up observation, and 1 patient died from
tamponade after an endomyocardial biopsy. Nine of the original 14 patients completed the 36month follow-up period, 6 patients had marked improvement in symptoms and increased ejection
fractions. The other 3 patients had no change in ejection fraction, one patient cut back alcohol
consumption, and another patient resumed use after a period of abstinence.[13]
A 1- and 4-year follow-up study of 55 men with alcoholism showed that abstinence and
controlled drinking of up to 60 g/day (4 drinks) resulted in comparable improvement in LV
ejection fraction. Ten patients who continued to drink higher amounts of alcohol all died during
the follow-up period.
Demakis and colleagues found that, overall, the 2 factors that were associated with a better
prognosis in AC were abstinence and a shorter duration of symptoms before the initiation of
therapy. In their study, perhaps the largest evaluation of the natural history of AC, the
investigators prospectively followed 57 patients with AC and divided them into 3 groups: 15
patients who improved clinically, 12 patients who remained stable, and 30 patients whose
conditions deteriorated. Of the 39 patients who continued to drink, only 4 patients improved.
Eleven of the 18 patients who abstained improved; however, the condition of 3 patients who
abstained continued to deteriorate.[14]
In 1996, Prazak et al conducted a retrospective study comparing 23 patients with AC to 52
patients with idiopathic DC and found that the 1-, 5-, and 10-year survival rates for AC were
100%, 81%, and 81%, respectively, compared with 89%, 48%, and 30%, respectively, for
idiopathic DC. When transplant-free survival was compared between the 2 groups, the difference
was more impressive, with 10-year survival rates of 81% and 20% for the AC and idiopathic DC
patients, respectively. The 2 groups had similar ejection fractions, New York Heart Association
class symptoms, and overall LV volume. The sole endpoint was all-cause mortality.[15]
In contrast to the Prazak study, a 1993 study by Redfield et al showed no difference in mortality
between patients with AC and those with idiopathic DC.[16]Prazak et al speculated that the
outcomes in the reports may have differed because the patients in their study observed more
complete abstinence and underwent aggressive medical therapy.[15]