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Angiotensin-Converting Enzyme Gene Polymorphism Is Associated with
Vulnerability to Alcoholic Cardiomyopathy
Joaquim Ferna´ndez-Sola`, MD; Josep Marı´a Nicola´s, MD; Josep Oriola, PhD; Emilio Sacanella, MD; Ramo´n Estruch, MD; Emanuel Rubin, MD;
and Alvaro Urbano-Ma´rquez, MD
Background: Chronic alcohol abuse has a dose-dependent toxic
effect on the myocardium, leading to alcoholic cardiomyopathy.
The fact that only a minority of persons with chronic alcoholism
have this condition suggests the possibility of a genetic vulnera-
bility. In this context, polymorphism of the angiotensin-converting
enzyme (ACE) gene has been implicated in cardiac dysfunction.
Objective: To compare the ACE genotypes of alcoholic persons
who have cardiomyopathy with those of comparable alcohol abus-
ers who have normal cardiac function.
Design: Case–control study over a 2-year period.
Setting: An academic tertiary referral hospital in Barcelona,
Spain.
Patients: 30 alcoholic men with symptomatic cardiomyopathy
and 27 alcoholic men with normal cardiac function.
Measurements: Ethanol intake, cardiac status, left ventricular
ejection fraction (LVEF), and ACE gene polymorphism.
Results: The
DD
ACE genotype was present in 57% of alcoholic
persons with an LVEF less than 0.50 and in 7% of those with
normal cardiac function. Compared with persons who had an
I
allele, the odds ratio for development of left ventricular dysfunc-
tion in alcoholic persons with the
DD
genotype was 16.4.
Conclusions: Vulnerability to cardiomyopathy among chronic
alcohol abusers is partially genetic and is related to presence of
the ACE
DD
genotype. This finding demonstrates genetic suscep-
tibility to alcohol-induced myocardial damage.
Ann Intern Med. 2002;137:321-326. www.annals.org
For author affiliations, see end of text.
Approximately 15% to 40% of all cases of dilated car-
diomyopathy in western countries are related to alco-
hol abuse (1). Ethanol has a progressive and dose-depen-
dent toxic effect on cardiac function, independent of
malnutrition, thiamin deficiency, or electrolyte distur-
bances (2). We previously established a relationship be-
tween the total lifetime dose of alcohol consumed and the
depression of left ventricular ejection fraction (LVEF);
however, the quantity of alcohol consumed accounted for
only about one third of the effect of alcohol (r
2
⫽0.34)
(2). Of note, we have encountered alcoholic persons with
high levels of alcohol consumption who have no evidence
of myocardial impairment, whereas other alcoholic persons
with less consumption display considerable loss of contrac-
tile capacity. In this context, we have previously suggested
the possibility of a genetic vulnerability to the effects of
alcohol on the myocardium (3, 4).
Researchers have recently focused on the possible im-
portance of angiotensin-converting enzyme (ACE) as an
influence on skeletal muscle performance (5, 6), cardiac
hypertrophy (7–9), myocardial function (10, 11), and
overall cardiac mortality (12). Therefore, we sought to
evaluate the possibility that ACE gene polymorphism may
play a role in the development of alcoholic cardiomyopa-
thy. In this study, we compared alcoholic persons who
have depressed LVEF with alcoholic persons who showed
no evidence of cardiac dysfunction.
METHODS
Patients
Over a 2-year period (1998 to 1999), 41 men younger
than 65 years of age with chronic alcoholism (according to
criteria of Diagnostic and Statistical Manual of Mental Dis-
orders, fourth edition [13]) and signs or symptoms of heart
failure (New York Heart Association [NYHA] functional
class II to IV [14]) presented to the emergency department
at Hospital Clı´nic, Barcelona, Spain. We did not enroll 10
of these 41 patients: 2 persons with uncompensated liver
disease, 5 persons with nonalcoholic causes of heart disease
(4 with hypertension and 1 with ischemic heart disease),
and 3 persons who declined to participate. We assigned the
remaining 31 patients to group I. Of these 31 participants,
17 were admitted to the hospital’s cardiology unit because
of NYHA functional class III or IV disease; the other 14
patients, who had NYHA functional class II disease, were
studied as outpatients. All participants reported consump-
tion of at least 100 g of ethanol per day for 15 or more
years and a total lifetime dose of greater than 15 kg of
ethanol per kg of body weight. All participants had an
LVEF lower than 0.50 and a cardiothoracic index higher
than 0.5.
During the same 2-year period, 1325 asymptomatic
persons with chronic alcoholism sought assistance for end-
ing alcohol dependence at the hospital’s outpatient alco-
holism unit. Each week, the first two patients seen with a
lifetime ethanol consumption similar to that of patients in
group I were selected for the study. Of 165 such patients
seen in the outpatient clinic, we excluded 24 from the
study (19 had hypertension, 2 had coronary heart disease,
2 had uncompensated liver disease, and 1 had type 2 dia-
betes mellitus). Of the remaining 141 patients, all of whom
agreed to participate in the study, 28 (20%) had an LVEF
of 0.60 or greater and a cardiothoracic index less than 0.5.
These patients made up group II. Participants in group I
Article
© 2002 American College of Physicians–American Society of Internal Medicine E-321
were considered relatively vulnerable to the toxic effects of
ethanol on the myocardium, and those in group II were
considered relatively insensitive to these effects.
We excluded 1 patient in each group because of symp-
toms of alcohol withdrawal. Thus, 30 patients in group I
and 27 participants in group II remained in the study. All
participants gave informed consent for the various proce-
dures. The institutional review board of Hospital Clı´nic,
Barcelona, Spain, approved the study protocol. We did not
explore ethnic or racial variables because all patients were
white men of Spanish descent who lived with their families
in or around Barcelona. Most were skilled laborers or office
workers with a history of stable employment, and none
were indigent. Approximately half the patients in each
group had smoked 1 to 2 packs of cigarettes per day since
their second decade of life; none reported using illicit
drugs.
Laboratory and Nutritional Studies
Blood samples were obtained 1 day after hospital ad-
mission to measure markers of alcohol intake and nutri-
tional status. The latter was assessed as reported elsewhere
(15). Patients were considered to have caloric malnutrition
if they weighed less than 90% of their ideal weight or if
their lean body mass was more than 10% below normal.
Protein malnutrition was diagnosed when the patients had
abnormal values for three of the following variables: hemo-
globin level, lymphocyte count, total protein level, albu-
min level, prealbumin level, retinol-binding protein level,
or transferrin level (15).
Clinical and Cardiac Studies
For each patient, one of two authors obtained a de-
tailed history of ethanol intake and dietary habits using a
structured questionnaire; this history was confirmed with a
family member. The frequency and amount of ethanol in-
take were recorded. Life events, such as marriage, military
service, and positions of employment, were used as “anchor
points”to assist the patients’recollection (the time-line
follow-back method [16]). Withdrawal symptoms were
evaluated according to the Clinical Institute for With-
drawal Assessment scale (17).
Past and present signs and symptoms of heart failure
were evaluated, and NYHA functional class was deter-
mined according to the Goldman activity scale (14).
Within 3 days after admission, when test results for blood
alcohol were uniformly negative, the following cardiac ex-
aminations were performed: basal blood pressure, chest ra-
diography, conventional electrocardiography, and determi-
nation of LVEF by technetium Tc-99m-pernechnetate
radionuclide angiocardiography (Elscint SP4-HR, gamma-
camera, Haifa, Israel) by using a standard technique of
electrocardiography-gated equilibrium with an average of
400 to 450 cycles. Cardiac cycles with R-R intervals not
Table 1. Epidemiologic Data and Cardiac Function in Alcoholic Persons with Cardiomyopathy or Normal Cardiac Function*
Variable Group I: Patients with
Cardiomyopathy (
n
ⴝ30)
Group II: Patients with Normal
Cardiac Function (
n
ⴝ27)
Mean age (range), y52.8 ⫾1.6 (34–64) 52.3 ⫾1.5 (31–64)
Mean duration of alcoholism (range), y26.1 ⫾1.1 (15–45) 27.7 ⫾1.2 (20–42)
Mean daily ethanol dose at admission (range), g/d 167 ⫾6 (100–250) 173 ⫾7 (140–300)
Mean daily ethanol dose (range), g/d 169 ⫾5 (100–220) 173 ⫾6 (140–280)
Mean total lifetime dose of ethanol (range), kg of ethanol per kg
of body weight 23.2 ⫾1.5 (15–40) 25.1 ⫾1.0 (17–36)
Smoke ⱖ20 cigarettes/d, n (%) 19 (63) 17 (63)
Mean left ventricular ejection fraction (range), %0.34 ⫾0.02 (0.11–0.49) 0.65 ⫾0.01 (0.60–0.75)†
New York Heart Association functional class, n (%)
Class II 14 (46) 0 (0)
Class III or IV 16 (53) 0 (0)
Mean systolic blood pressure, mm Hg 127 ⫾3 131 ⫾2
Mean diastolic blood pressure, mm Hg 77 ⫾376⫾2
Cardiothoracic index 0.53 ⫾0.01 0.46 ⫾0.01
*Data expressed with a plus/minus sign are the mean ⫾SE.
†P⬍0.001 by using a two-tailed t-test.
Context
Although alcoholic cardiomyopathy is a dose-dependent
phenomenon, the amount of alcohol consumed accounts
for only one third of the effect of alcohol. Angiotensin-
converting enzyme (ACE) gene polymorphism may help
explain variations in cardiac vulnerability to alcohol.
Contribution
ACE genotypes of alcoholic persons with cardiomyopathy
were compared with those of persons who had similar
alcohol intake but no evidence of cardiomyopathy.
Homozygotes with the Dallele were 16.4 times as likely
to have cardiomyopathy as those with the Iallele.
Implications
Cardiac vulnerability to the adverse effects of alcohol ap-
pears to be partially under genetic control. Identification of
alcoholic persons with the DD genotype may lead to early
and novel treatments of cardiomyopathy.
–The Editors
Article ACE Genotype in Alcoholic Cardiomyopathy
E-322 3 September 2002 Annals of Internal Medicine Volume 137 •Number 5 (Part 1) www.annals.org
within 10% of the average were rejected. The mean cardiac
cycle was separated into 24 frames of a 64 ⫻64-pixel ma-
trix, with a minimum of 3 300 000 counts collected in
each frame. The LVEF was measured by using semiauto-
matic edge detection and counts with a varying region of
interest. Persons who performed the examinations had no
knowledge of the participants’history of alcoholism. To
rule out ischemic heart disease, we evaluated all patients in
group I using treadmill electrocardiography after they
received treatment for heart failure. These patients were
also studied by using echocardiography (Sonos 2500 in-
strument, Hewlett-Packard, Andover, Massachusetts).
End-diastolic and end-systolic diameters, the shortening
fraction, and the mass of the left ventricle were measured
according to the standards of the American Society of
Echocardiography (18).
ACE Gene Polymorphisms
We extracted DNA from peripheral blood leukocytes,
as described previously (19). The ACE I/D genotype was
determined by polymerase chain reaction (PCR) using
published primers 5⬘-CTG GAG ACC ACT CCC ATC
CTT TCT-3⬘and 5⬘-GAT GTG GCC ATC ACA TTC
GTC AGA T-3⬘, which flank the polymorphic region
(20). We performed PCR in a 25-
L volume containing
MgCl
2
, 1.5 mmol/L; KCl, 50 mmol/L; Tris-HCl, 10
mmol/L, at a pH of 8.3; 200
mol of each diethylnitro-
phenyl thiophosphate per L; 1-
mol/L primers; Taq poly-
merase, 1 U (Boehringer Mannhein Biochemical, Mann-
heim, Germany); and genomic DNA, 100 ng. After an
initial denaturation at 96 °C for 5 minutes, thermocycling
consisted of denaturation at 94 °C for 30 seconds, anneal-
ing at 58 °C for 30 seconds, and extension at 72 °C for 1
minute for 35 cycles, followed by a final extension for 5
minutes. Amplification products were separated on 0.5%
agarose gel/2.5% Nu Sieve (Amersham, Arlington Heights,
Illinois) and visualized by ultraviolet transillumination af-
ter ethidium bromide staining. This primer pair produced
the 480–base pair product (corresponding to the insertion,
I) or a 194–base pair fragment (corresponding to the de-
letion, D). Participants were classified as having II,DD,or
ID (heterozygous for insertion or deletion). In the past, ID
heterozygotes have been mistyped as DD because of pref-
erential amplification of the Dallele and inefficiency in the
amplification of the Iallele. Therefore, all samples found to
have the DD genotype were amplified with an insertion-
specific primer pair that recognizes the inserted sequence
5⬘-TGG GAC CAC AGC GCC CGC CAC TAC-3⬘and
5⬘-TCG CCA GCC CTC CCA TGC CCA TAA-3⬘under
identical PCR conditions except for an annealing temper-
ature of 61 °C (20). This reaction yields a 335–base pair
product in the presence of an Iallele.
Statistical Analysis
All variables are expressed as the mean (⫾SE). We
analyzed differences between the two groups using a chi-
square test, analysis of variance (ANOVA), and a two-
tailed Student t-test. We evaluated the association between
cardiomyopathy and the DD genotype using the Fisher
exact test. Odds ratios and 95% CIs were calculated. Our
analysis was performed by using the SPSS Statistical Anal-
ysis System, version 9.0 (SPSS, Inc., Chicago, Illinois), and
Stat Xact software (Cytel Software Corp., Cambridge,
Massachusetts).
Role of the Funding Sources
The funding sources had no role in the design, con-
duct, or reporting of the study or in the decision to submit
the manuscript for publication.
RESULTS
All participants were normotensive. Patients in both
groups were of similar age and reported similar amounts of
tobacco and alcohol consumption (Table 1). Clinical and
laboratory results showed no differences between the
groups other than those associated with cardiac dysfunc-
tion (Tables 1 and 2). Electrocardiographic results for the
patients in group 1 showed atrial fibrillation in 6 patients,
conduction defects in 4 patients, and premature ventricular
contractions in 9 patients. In group II, 1 patient had atrial
Table 2. Laboratory and Nutritional Data in Alcoholic Persons with Cardiomyopathy or Normal Cardiac Function*
Variable Group I: Patients with
Cardiomyopathy (
n
ⴝ30)
Group II: Patients with Normal
Cardiac Function (
n
ⴝ27)
Percentage of ideal body weight, %100.4 ⫾1.9 104.6 ⫾3.3
Tricipital skin fold thickness, cm 1.06 ⫾0.11 0.93 ⫾0.05
Lean body mass, kg 54.8 ⫾0.91 55.8 ⫾1.25
Hemoglobin level, g/dL 1460 ⫾30 1430 ⫾20
Lymphocyte count, ⫻10
6
cells/L 1962 ⫾118 2032 ⫾130
Total protein level, g/dL 704 ⫾15 685 ⫾16
Albumin level, g/dL 429 ⫾13 415 ⫾11
Prealbumin level, mg/L 308 ⫾32 295 ⫾18
Retinol-binding protein level, mg/L 55 ⫾653⫾2
Transferrin level, g/L 2.73 ⫾0.09 2.55 ⫾0.12
Aspartate aminotransferase level,
kat/L (IU/L) 0.76 ⫾0.11 (45.6 ⫾6.6) 1.04 ⫾0.13 (62.9 ⫾7.6)
Alanine aminotransferase level, nkat/L (IU/L) 698 ⫾78 (41.9 ⫾4.7) 896 ⫾127 (53.8 ⫾7.6)
␥
-glutamyl transpeptidase level,
kat/L (IU/L) 3.42 ⫾0.85 (205 ⫾51) 3.11 ⫾0.57 (187 ⫾34)
*Values are expressed as the mean ⫾SE.
ArticleACE Genotype in Alcoholic Cardiomyopathy
www.annals.org 3 September 2002 Annals of Internal Medicine Volume 137 •Number 5 (Part 1) E-323
fibrillation, 2 had minor conduction defects, and 4 had
premature ventricular contractions. The mean (⫾SE)
LVEF was 33.6% ⫾2.4% in group I and 64.9% ⫾0.8%
in group II. Group I had mean (⫾SE) values of 64.1 ⫾2.2
mm for end-diastolic diameter, 50.2 ⫾2.5 mm for end-
systolic diameter, 305 ⫾18 g for left ventricular mass, and
22.6% ⫾1.4% for shortening fraction. We found no evi-
dence of valvular disease or other structural cardiac abnor-
malities in any of these patients. In addition, results of the
treadmill test showed no evidence of ischemic heart disease
in any patient from group I.
Cirrhosis of the liver was diagnosed in 8 patients in
group I (27%) and in 7 patients in group II (26%). How-
ever, none of the patients showed signs or symptoms of
liver disease (Child–Pugh grade A) (21). Evidence of mild
caloric malnutrition was observed in 5 (17%) patients in
group I and 3 (11%) patients in group II; slight protein
malnutrition was diagnosed in 3 (10%) patients in group I
and in 4 (15%) in group II. No relation was observed
between nutrition and the cardiac and genotype variables
evaluated.
Patients were treated according to their NYHA func-
tional class. For the patients in group I, we recommended
abstinence from alcohol consumption and a dietary so-
dium intake of less than 100 mmol/d. In addition, patients
in group I were treated with an ACE inhibitor (captopril,
25 mg three times daily). Six patients with NYHA class III
or IV disease who presented with congestive heart failure
received furosemide, 20 to 40 mg twice daily, and spirono-
lactone, 25 mg/d. The 7 patients with atrial fibrillation also
received digoxin, 0.25 mg/d. No patient was treated with

-blockers or hydralazine.
The Iand Dalleles were identified in 36% and 65%,
respectively, of the patients in group I and in 63% and
37%, respectively, of the patients in group II. Of the 57
total alcoholic participants in the study, 19 (33%) were
homozygous for the ACE deletion allele (DD), 26 (45%)
were heterozygous (ID), and 12 (21%) were homozygous
for the insertion allele (II). This distribution of genotypes
is similar to that of the general population of the Barcelona
region (19) and of Spain in general (22).
Age and amounts of alcohol consumed were similar
among the genotypes (Table 3). Seventeen of 19 (89%)
patients with the DD genotype had cardiomyopathy. By
contrast, 13 of the 38 (34%) participants who carried an I
allele (II or ID) had impaired cardiac function. As shown
in Table 4, more than half (57%) of the patients in group
I were homozygous for the deleted version (DD)ofthe
ACE gene, whereas among those in group II, only 7% had
this variant (two-sided Pvalue ⬍0.001). We observed the
same pattern when we restricted the analysis to the 17
patients in group I with an LVEF lower than 0.40. Thus,
compared with carriers of the Iallele, alcoholic persons
with the DD phenotype had an odds ratio of 16.4 (CI, 3.0
to 158) for the development of left ventricular dysfunction.
Echocardiographic results showed that group I patients
with the DD phenotype had somewhat greater end-systolic
diameter, end-diastolic diameter, and left ventricular mass
and had lower shortening fractions than group I carriers of
an Iallele, although the differences were not statistically
significant.
DISCUSSION
We compared two groups of patients with chronic
alcoholism—one with cardiomyopathy and one with nor-
mal cardiac function. No significant laboratory abnormal-
ities other than modest elevations of hepatic enzyme levels
were found in either group, and malnutrition was not a
factor in cardiac impairment. We excluded patients with
causes of cardiac dysfunction other than ethanol consump-
tion (for example, coronary artery disease, heart valve dis-
ease, diabetes mellitus, or hypertension). Thus, the only
Table 3. Epidemiologic Data in Alcoholic Persons, according to Angiotensin-Converting Enzyme Genotype*
Variable Patients with
II
Genotype (
n
ⴝ12)
Patients with
ID
Genotype (
n
ⴝ26)
Patients with
DD
Genotype (
n
ⴝ19)
Age, y51.2 ⫾2.5 (31–62) 52.5 ⫾1.5 (35–64) 53.7 ⫾2.1 (34–64)
Duration of alcoholism, y26.6 ⫾1.9 (20–40) 27.0 ⫾1.1 (16–42) 26.7 ⫾1.6 (15–45)
Daily ethanol dose at admission, g/d 157 ⫾5 (125–200) 179 ⫾8 (100–300) 165 ⫾7 (100–250)
Amount of ethanol consumed daily, g/d†168 ⫾6 (125–220) 170 ⫾7 (100–280) 171 ⫾7 (100–260)
Total lifetime dose of ethanol, kg of ethanol
per kg of body weight 23.3 ⫾1.5 (17–33) 24.5 ⫾1.1 (17–40) 24.0 ⫾1.9 (15–40)
*Data are expressed as the mean ⫾SE (range). No statistically significant differences were observed among the groups, according to analysis of variance. ACE ⫽
angiotensin-converting enzyme.
†According to patient self-report at history-taking.
Table 4. Distribution of Angiotensin-Converting Enzyme
Genotypes among Alcoholic Persons with or
without Cardiomyopathy*
Variable Group I: Patients with
Cardiomyopathy
(
n
ⴝ30)
Group II: Patients with
Normal Cardiac Function
(
n
ⴝ27)
Mean LVEF 0.336 0.649
ACE genotype, n (%)
II 3 (10) 9 (33)
ID 10 (33) 16 (59)
DD 17 (57) 2 (7)†
*ACE ⫽angiotensin-converting enzyme; LVEF ⫽left ventricular ejection frac-
tion.
†P⬍0.001 for the difference in DD genotype between the groups I and II.
Article ACE Genotype in Alcoholic Cardiomyopathy
E-324 3 September 2002 Annals of Internal Medicine Volume 137 •Number 5 (Part 1) www.annals.org
phenotypic difference that was evident between the two
groups was the presence of alcoholic cardiomyopathy.
The distribution of ACE genotypes in the general pop-
ulation varies according to geographic location and race
(23, 24). The distribution of ACE alleles among the alco-
holic participants in this study was similar to that observed
in Barcelona (19) and Spain (22), indicating that it is not
involved in genetic or acquired susceptibility to alcoholism.
However, this distribution in the general population does
not necessarily apply to specific patient groups because the
participants in the current study were selected according to
their vulnerability to cardiomyopathy. We studied the dis-
tribution of the ACE gene polymorphism because it has
been implicated in other cardiac disorders (25). Some al-
leles of this gene contain an inserted sequence (I), whereas
in other alleles, the sequence is deleted (D). The Dpoly-
morphism has been associated with higher circulating lev-
els of ACE and angiotensin II than those seen with the I
variety (26, 27); however, local autocrine or paracrine ef-
fects may be of greater importance (25, 28). The Dallele
has also been linked to idiopathic cardiomyopathy (29, 30)
and cardiac hypertrophy secondary to hypertension (31) or
aortic stenosis (32). In patients homozygous for the Dal-
lele, regression of cardiac hypertrophy after valve replace-
ment (33) or control of hypertension (33) is not as efficient
as in patients with the Iallele. The contribution of ACE
polymorphism to the course of ischemic heart disease (11,
34, 35) or essential hypertension (19, 36) is still controversial.
In the current study, we have demonstrated an associ-
ated vulnerability to cardiomyopathy among chronic alco-
holic persons homozygous for the Dallele of the ACE
gene. In terms of susceptibility to the cardiotoxic effects of
ethanol, it appears that a single copy of the Iallele is suf-
ficient to eliminate the 16.4-fold excess risk associated with
the DD genotype. In this context, the presence of the I
allele has been shown to increase the efficiency of muscular
contraction (6). However, even alcoholic carriers of the I
allele may develop left ventricular dysfunction and should
be advised that they are not invulnerable to this complica-
tion. The precise mechanism by which the absence of the I
allele contributes to the previously demonstrated cardio-
toxic effect of chronic alcohol abuse (2, 3) is a subject for
further study. This demonstration of a genetic vulnerability
to alcohol-induced myocardial damage suggests that alco-
holic injury to other organs may also show a genetic influ-
ence. Because the sample of alcoholic persons we studied
was ethnically homogeneous and did not include binge
drinkers or indigent persons, further studies are needed to
extend these findings to the general population of alcohol
abusers. In additional, future studies should assess other
genotypes related to the ACE system that may affect the
development of cardiomyopathy.
Grant Support: By Fondo de Investigacio´n Sanitaria (grants 98/0330,
99/0115, and 99/0318) and Generalitat de Catalunya (grant CUR 2001/
SGR/00379).
Requests for Single Reprints: Emanuel Rubin, MD, Department of
Pathology, Anatomy, and Cell Biology, Jefferson Medical College, 1020
Locust Street, Suite 279, Philadelphia, PA 19107; e-mail, emanuel.rubin
@mail.tju.edu.
Potential Financial Conflicts of Interest: Grants Received: J. Ferna´ndez-
Sola`, J.M. Nicola´s, E. Sacanella, R. Estruch, A. Urbano-Ma´rquez.
Current Author Addresses: Drs. Ferna´ndez-Sola`, Nicola´s, Oriola,
Sacanella, Estruch, and Urbano-Ma´rquez: Alcohol Research and Cardiac
Units, Department of Medicine, Hospital Clı´nic i Provincial, University
of Barcelona, Villaroel, 170 08036, Barcelona, Spain.
Dr. Rubin: Department of Pathology and Cell Biology, Jefferson Med-
ical College, Thomas Jefferson University, 1020 Locust Street, Suite 279,
Philadelphia, PA 19107-6799
Author Contributions: Conception and design: J. Ferna´ndez-Sola`, J.
Marı´a Nicola´s, E. Rubin, A. Urbano-Ma´rquez.
Analysis and interpretation of the data: J. Ferna´ndez-Sola`, J. Marı´a Nico-
la´s, E. Rubin.
Drafting of the article: J. Ferna´ndez-Sola`, J. Marı´a Nicola´s, E. Rubin, A.
Urbano-Ma´rquez.
Critical revision of the article for important intellectual content: E. Rubin
Final approval of the article: A. Urbano-Ma´rquez.
Provision of study materials or patients: E. Sacanella, R. Estruch.
Statistical expertise: J. Marı´a Nicola´s.
Obtaining of funding: J. Ferna´ndez-Sola`, J. Marı´a Nicola´s, R. Estruch,
E. Rubin.
Administrative, technical, or logistic support: J. Oriola.
Collection and assembly of data: E. Sacanella.
Current author addresses and author contributions are available at www
.annals.org.
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Article ACE Genotype in Alcoholic Cardiomyopathy
E-326 3 September 2002 Annals of Internal Medicine Volume 137 •Number 5 (Part 1) www.annals.org
