- Email: [email protected]
Alcohol consumption and risk of heart failure: Meta-analysis of 13 prospective studies
Accepted Manuscript Alcohol consumption and risk of heart failure: meta-analysis of 13 prospective studies Susanna C. Larsson, Alice Wallin, Alicja Wolk PII:
S0261-5614(17)30168-1
DOI:
10.1016/j.clnu.2017.05.007
Reference:
YCLNU 3132
To appear in:
Clinical Nutrition
Received Date: 7 February 2017 Revised Date:
11 April 2017
Accepted Date: 8 May 2017
Please cite this article as: Larsson SC, Wallin A, Wolk A, Alcohol consumption and risk of heart failure: meta-analysis of 13 prospective studies, Clinical Nutrition (2017), doi: 10.1016/j.clnu.2017.05.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Alcohol consumption and risk of heart failure: meta-analysis of 13 prospective studies
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Susanna C. Larsson*, Alice Wallin, Alicja Wolk
Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet,
SC
Stockholm, Sweden
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*Corresponding author: Susanna C. Larsson, Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden.
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E-mail address: [email protected] (S.C. Larsson)
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ACCEPTED MANUSCRIPT ABSTRACT
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Background & Aims: Controversy exists on the association between alcohol consumption and
3
risk of heart failure (HF). We carried out a meta-analysis to summarize available prospective
4
data on alcohol consumption and HF.
5
Methods: We searched PubMed for relevant studies published until January 1, 2017. Relative
6
risk (RR) estimates from individual studies were pooled in a random-effects meta-analysis.
7
Results: A total of 13 prospective studies, with 13,738 HF cases and 355,804 participants,
8
were included in the meta-analysis. Light alcohol drinking (0.1–7 drinks/week) was inversely
9
associated with risk of HF (RR, 0.86; 95% confidence interval, 0.81–0.90). There was no
10
statistically significant association between moderate (7.1–14 drinks/week), high (14.1–28
11
drinks/week), or heavy (>28 drinks/week) alcohol consumption and HF risk. Former drinking
12
was associated with an increased risk of HF compared with never or occasional drinking (RR,
13
1.22; 95% confidence interval, 1.11–1.33).
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Conclusions: This meta-analysis found that light alcohol drinking was associated with a
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lower risk of HF. Former drinking was associated with a higher risk of HF.
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Keywords: alcohol consumption; heart failure; meta-analysis; prospective studies
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ACCEPTED MANUSCRIPT 1. Introduction
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Alcohol consumption has multiple health effects of which some are beneficial but most are
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detrimental. Among the beneficial vascular effects, alcohol consumption has been associated
21
with higher levels of high-density lipoprotein cholesterol and reduced levels of inflammatory
22
markers and fibrinogen [1-4]. In addition, observational studies have reported that light-to-
23
moderate drinking is associated with lower risk of ischemic heart disease [5] and ischemic
24
stroke [6]. On the other hand, alcohol consumption has been found to be positively associated
25
with risk of hypertension [7] and atrial fibrillation [8]. Observational studies on alcohol
26
consumption in relation to risk of heart failure (HF) have produced inconsistent results, but a
27
meta-analysis of eight prospective studies indicated an overall inverse association between
28
light to moderate drinking and HF risk [9]. No association was observed with moderate to
29
high alcohol consumption (14–21 drinks/week) [9].
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We performed an updated systematic review and meta-analysis of prospective studies to
31
investigate the associations of light and moderate alcohol consumption with risk of HF. In
32
addition, we assessed whether heavy drinking and former drinking was associated with HF,
33
which was not examined in the previous meta-analysis.
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2. Methods
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2.1. Study selection and data extraction
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The PubMed database was searched for pertinent studies published up to January 1, 2017,
38
using the following predefined search terms: “alcohol” and “consumption” or “drinking” or
39
“intake” and “heart failure”. No restrictions were imposed. The list of references in the
40
retrieved publications was also reviewed. Eligibility criteria were: 1) prospective design; 2)
41
investigated the association between alcohol (ethanol) consumption and HF incidence or HF
42
mortality; 3) the population did not have HF at baseline; 4) alcohol consumption was 3
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ACCEPTED MANUSCRIPT quantified in drinks or grams of consumption; and 5) provided relative risks (RR) with 95%
44
confidence intervals (CIs), adjusted for at least age. Studies that classified alcohol
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consumption in two groups (no/yes or nondrinkers/drinkers) were not eligible. Two authors
46
(SCL and AWa) performed the literature search and selected the studies for inclusion in the
47
meta-analysis. Any disagreement was resolved by consensus.
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The following details were recorded from each study: the last name of the first author,
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country, cohort name, follow-up time, sex, age, number of cases and participants, RRs with
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95% CIs for each category of alcohol consumption, and the variables adjusted for in the
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multivariable model. From each study, the most fully adjusted risk estimates were extracted.
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2.2. Statistical methods
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A random-effects model was applied to combine the RRs from included studies according to
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four categories of alcohol intake: light (0.1–7 drinks/week), moderate (7.1–14 drinks/week),
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high (14.1–28 drinks/week), and heavy (>28 drinks/week) based on the average consumption
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in each category and separately for men and women. The reference (comparison) group was
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the one used in the included studies, and was nondrinkers, never drinkers, or very light
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drinkers (hereafter referred to as occasional drinkers). If a study reported two or more RRs
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that fell into one of the four categories, those RRs were pooled before inclusion in the meta-
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analysis. We also conducted a meta-analysis that combined study-specific results for former
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drinkers versus never or occasional drinkers. Where alcohol consumption was reported in
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grams (two studies), the intake was converted into drinks, and one drink was assumed to
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contain 12 gram of alcohol [10]. We conducted subgroup and meta-regression analyses to
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assess possible sources of heterogeneity by sex, geographic area (North America, Europe),
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and reference group used (nondrinkers [including former drinkers], never drinkers, or
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occasional drinkers). Because the number of studies was few in the heavy drinking category,
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this category was combined with the high alcohol consumption category in the stratified
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analysis. The I2 statistic was used to quantify heterogeneity among studies [11]. Egger’s test
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was used to evaluate publication bias [12]. Stata (version 12.0, StataCorp, College Station,
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TX) was used for the statistical analyses.
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3. Results
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Our literature search identified 13 prospective studies (reported in 12 articles) [13-24] (Figure
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1) of which seven were conducted in North America and six in Europe. Study details are
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presented in Supplementary Table 1. The studies included a total of 13,738 HF cases (the
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number of cases was not reported in one study) and 355,804 participants.
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Overall, compared with the reference group (nondrinkers, never drinkers, or occasional
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drinkers), light alcohol consumption was associated with a statistically significant 14% lower
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HF risk (RR, 0.86; 95% CI, 0.81–0.91), with low between-study heterogeneity (I2 = 41.0%)
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(Figure 2). Moderate, high, and heavy alcohol consumption was not statistically significantly
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associated with HF in the overall analysis (Figure 1). There was no indication of publication
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bias (P > 0.61 for all four alcohol consumption categories).
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The association between alcohol consumption and risk of HF did not vary significantly
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by sex (P for difference by sex ≥0.58), but the only statistically significant association was
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observed between light alcohol consumption and risk of HF in women (Table 1). Light and
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moderate alcohol consumption was inversely associated with risk of HF in studies conducted
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in North America but was not associated with HF risk in European studies (P for difference =
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0.08 for the light drinking group and P for difference = 0.01 for the moderate drinking group)
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(Table 1). In analysis stratified by type of reference group, light alcohol consumption was
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associated with a lower HF risk in studies with nondrinkers or never drinkers as the reference
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group (Table 1). In addition, moderate and high-to-heavy alcohol consumption was inversely
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associated with HF in studies with never drinkers as reference group but was not associated
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with HF in studies with nondrinkers or occasional drinkers as the reference (Table 1). Eight studies provided results for former drinkers compared with never or occasional
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drinkers (Figure 3). Overall, former drinking was associated with a statistically significant
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22% increased risk of HF (RR, 1.22; 95% 1.11–1.33), with little heterogeneity among studies
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(I2 = 23.1%) (Figure 3).
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4. Discussion
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This updated meta-analysis of alcohol consumption and HF risk includes over twice as many
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cases of HF and almost twice as many participants as our previous meta-analysis [9]. This
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meta-analysis confirms a modest inverse association between light alcohol consumption (up
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to one drink daily) and risk of HF, with a 14% lower risk observed in light drinkers. This is
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the first meta-analysis to show that former drinking is associated with an increased risk of
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HF. Heavy drinking was not significantly associated with HF risk, but few studies reported
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results for heavy drinking.
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The biological mechanisms by which light alcohol drinking may lower the risk of HF are
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uncertain, but the association may partially be mediated through an influence on ventricular
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ejection fraction. A recent population-based study reported a U-shaped association between
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alcohol consumption and left ventricular ejection fraction, with light drinkers (<1 drink/day)
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having the lowest risk of moderate left ventricular dysfunction [25]. The reduced risk of HF
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associated with light drinking may also be mediated through beneficial effects of alcohol on
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coronary artery disease [16, 18].
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The observed increased risk of HF in former drinkers may reflect worse health and higher
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prevalence of hypertension and other underlying conditions for HF in former drinkers than in
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occasional or never drinkers [21, 24]. Worsening of health has been found to be associated 6
ACCEPTED MANUSCRIPT with cessation of alcohol consumption [26]. Noteworthy, the inverse association of light
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alcohol consumption with HF risk was observed not only among studies with nondrinkers
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(including former drinkers) as the reference group but also among studies with never drinkers
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(lifelong abstainers) as the reference group. The lack of association of light and moderate
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drinking with HF risk in studies with occasional drinkers as the comparison group [22, 24]
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may be related to that no further benefit of alcohol is observed when increasing the intake
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from very light (occasional drinkers) to light-to-moderate consumption.
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Few studies have provided results for different alcoholic beverages in relation to risk of
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HF [13, 16, 23]. Two studies reported similar risk estimates for consumption of wine, beer,
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and liquor [13, 23]. One study found a lower risk of HF only in wine drinkers who were men,
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and no associations with beer or liquor consumption in either men or women [16]. Although
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wine has a high content of potentially beneficial polyphenols, the association confined to
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wine in one of the studies may be explained by uncontrolled favorable user traits and
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drinking patters of wine drinkers [16].
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A strength of this meta-analysis is that we could examine the association between alcohol
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consumption and HF with high precision because of the large number of prospective studies
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included. A limitation is that some degree of misclassification of alcohol consumption in each
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study was inevitable. Alcohol consumption may be underreported, in particular among heavy
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drinkers. Another shortcoming is that all prospective studies on alcohol consumption and HF
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were conducted in North America, Northern Europe, and the United Kingdom. Findings from
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this meta-analysis may therefore not be generalizable to other populations, such as Asian and
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Mediterranean populations, with a potentially different proportion of genotypes influencing
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alcohol metabolism and different alcohol consumption pattern. Finally, the possibility that the
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observed inverse association between light drinking and HF risk may be due to uncontrolled
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confounding by lifestyle or social factors cannot be ruled out. Mendelian randomization
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studies, using genetic variants associated with alcohol consumption as unconfounded proxies
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for alcohol drinking, may provide further insight into the potential causal role of alcohol in
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the etiology of HF.
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5. Conclusion
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In this meta-analysis of 13 prospective studies, light consumption of alcohol (up to one drink
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per day) was associated with a lower risk of HF, whereas former drinking was associated
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with an increased risk. No significant association was observed with high-to-heavy drinking.
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Conflict of interest
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None.
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Acknowledgements
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This work was supported by the Swedish Research Council (grant number 2015-02302).
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Supplementary data
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This manuscript contains supplementary data (Supplementary Table 1).
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ACCEPTED MANUSCRIPT References [1]
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Brien SE, Ronksley PE, Turner BJ, Mukamal KJ, Ghali WA. Effect of alcohol consumption on biological markers associated with risk of coronary heart disease:
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meta-analysis. BMJ 2011;342:d671.
Larsson SC, Wallin A, Wolk A, Markus HS. Differing association of alcohol consumption with different stroke types: a systematic review and meta-analysis. BMC Med 2016;14:178.
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hypertension: gender differences in dose-response relationships determined through systematic review and meta-analysis. Addiction 2009;104:1981-1990. [8]
Larsson SC, Drca N, Wolk A. Alcohol consumption and risk of atrial fibrillation: a prospective study and dose-response meta-analysis. J Am Coll Cardiol 2014;64:281-
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Larsson SC, Orsini N, Wolk A. Alcohol consumption and risk of heart failure: a dose-
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ACCEPTED MANUSCRIPT [14] Walsh CR, Larson MG, Evans JC, Djousse L, Ellison RC, Vasan RS et al. Alcohol consumption and risk for congestive heart failure in the Framingham Heart Study. Ann Intern Med 2002;136:181-191. [15] Aguilar D, Skali H, Moye LA, Lewis EF, Gaziano JM, Rutherford JD et al. Alcohol consumption and prognosis in patients with left ventricular systolic dysfunction after a
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myocardial infarction. J Am Coll Cardiol 2004;43:2015-2021. [16] Klatsky AL, Chartier D, Udaltsova N, Gronningen S, Brar S, Friedman GD et al. Alcohol drinking and risk of hospitalization for heart failure with and without associated coronary artery disease. Am J Cardiol 2005;96:346-351.
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[17] Bryson CL, Mukamal KJ, Mittleman MA, Fried LP, Hirsch CH, Kitzman DW et al. The association of alcohol consumption and incident heart failure: the Cardiovascular Health Study. J Am Coll Cardiol 2006;48:305-311.
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[18] Djousse L, Gaziano JM. Alcohol consumption and risk of heart failure in the Physicians' Health Study I. Circulation 2007;115:34-39.
[19] Janszky I, Ljung R, Ahnve S, Hallqvist J, Bennet AM, Mukamal KJ. Alcohol and longterm prognosis after a first acute myocardial infarction: the SHEEP study. Eur Heart J 2008;29:45-53.
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[20] Wang Y, Tuomilehto J, Jousilahti P, Antikainen R, Mahonen M, Katzmarzyk PT et al. Lifestyle factors in relation to heart failure among Finnish men and women. Circ Heart Fail 2011;4:607-612.
[21] Goncalves A, Claggett B, Jhund PS, Rosamond W, Deswal A, Aguilar D et al. Alcohol
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consumption and risk of heart failure: the Atherosclerosis Risk in Communities Study. Eur Heart J 2015;36:939-945.
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[22] Wannamethee SG, Whincup PH, Lennon L, Papacosta O, Shaper AG. Alcohol consumption and risk of incident heart failure in older men: a prospective cohort study. Open Heart 2015;2:e000266. [23] Gemes K, Janszky I, Ahnve S, Laszlo KD, Laugsand LE, Vatten LJ et al. Light-tomoderate drinking and incident heart failure--the Norwegian HUNT study. Int J Cardiol 2016;203:553-560. [24] Larsson SC, Wallin A, Wolk A. Contrasting association between alcohol consumption and risk of myocardial infarction and heart failure: Two prospective cohorts. Int J Cardiol 2017;231:207-210 (Epub Dec 28, 2016).
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ACCEPTED MANUSCRIPT [25] Yousaf H, Rodeheffer RJ, Paterick TE, Ashary Z, Ahmad MN, Ammar KA. Association between alcohol consumption and systolic ventricular function: a population-based study. Am Heart J 2014;167:861-868. [26] Ng Fat L, Cable N, Shelton N. Worsening of health and a cessation or reduction in alcohol consumption to special occasion drinking across three decades of the life
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course. Alcohol Clin Exp Res 2015;39:166-174.
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FIGURE LEGENDS
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Figure 1. Flow chart of study selection for meta-analysis
Figure 2. Overall relative risks (RR) with 95% confidence intervals (CI) of heart failure for light (0.1–7 drinks/week), moderate (7.1–14 drinks/week), high (14.1–28 drinks/week), and
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occasional drinkers. N: number of included studies.
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heavy (>28 drinks/week) alcohol consumption compared with nondrinkers, never drinkers or
Figure 3. Forest plot of relative risks (RR) with 95% confidence intervals (CI) of heart failure for former drinkers compared with never or occasional drinkers. Squares indicate study-specific RR (size of the square reflects the study-specific statistical weight, i.e., the
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inverse of the variance); horizontal lines indicate 95% CI; diamonds indicate the overall RR
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with its 95% CI. M: men, W: women.
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Table 1. Subgroup analyses (random-effects meta-analysis) of light, moderate, and high-to-heavy alcohol consumption with risk of heart failurea
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Moderate drinking (7.1–14 drinks/wk) Nb RR (95% CI) I2 (%)c
0.88 (0.76–1.03) 0.89 (0.81–0.98) 0.91
70.9 0
6 4
0.94 (0.77–1.15) 0.95 (0.80–1.14) 0.92
7 5
0.82 (0.78–0.87) 0.92 (0.82–1.02) 0.08
0 53.1
5 6
5 5 2
0.87 (0.81–0.93) 0.80 (0.75–0.85) 1.00 (0.86–1.16)
0 0 48.7
3 5 3
High-to-heavy drinking (>14 drinks/wk) Nb RR (95% CI) I2 (%)c
65.6 0
5 3
1.02 (0.85–1.24) 0.92 (0.64–1.32) 0.58
57.4 0
0.77 (0.65–0.91) 1.06 (0.95–1.17) 0.01
48.0 0
6 4
0.91 (0.79–1.05) 1.06 (0.86–1.30) 0.14
35.4 44.4
0.90 (0.66–1.22) 0.79 (0.68–0.93) 1.07 (0.93–1.23)
62.5 45.2 0
2 5 3
0.83 (0.36–1.93) 0.89 (0.80–0.99) 1.08 (0.85–1.38)
87.4 0 50.0
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Subgroup Sex Men Women P for differenced Geographic area North America Europe P for differenced Reference group Nondrinkerse Never drinkers Occasional drinkersf
Light drinking (≤7 drinks/wk) N RR (95% CI) I2 (%)c b
The reference group in the subgroup analyses by sex and geographic area was nondrinkers, never drinkers, or occasional drinkers.
b
Number of included studies.
c
Test for between-study heterogeneity.
d
Test for difference in association between alcohol consumption and HF risk by sex or geographic area (meta-regression analysis).
e
Including former drinkers.
f
Defined as <1 drink/week in two studies and 1–6 drinks/week in one study.
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a
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Articles identified from reference lists (n = 2)
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Articles identified through PubMed search (n = 1193)
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Excluded based on title and/or abstract (n = 1177) Potentially relevant articles identified for full text review (n = 18)
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Excluded articles (n = 6): • No risk estimate for the association between alcohol consumption and HF risk (n = 3) • Included prevalent cases of HF (n = 1) • Duplicate publications (n = 2)
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Articles included in the meta-analysis (n = 12), including 13 studies
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S0261-5614(17)30168-1
DOI:
10.1016/j.clnu.2017.05.007
Reference:
YCLNU 3132
To appear in:
Clinical Nutrition
Received Date: 7 February 2017 Revised Date:
11 April 2017
Accepted Date: 8 May 2017
Please cite this article as: Larsson SC, Wallin A, Wolk A, Alcohol consumption and risk of heart failure: meta-analysis of 13 prospective studies, Clinical Nutrition (2017), doi: 10.1016/j.clnu.2017.05.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Alcohol consumption and risk of heart failure: meta-analysis of 13 prospective studies
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Susanna C. Larsson*, Alice Wallin, Alicja Wolk
Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet,
SC
Stockholm, Sweden
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*Corresponding author: Susanna C. Larsson, Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden.
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E-mail address: [email protected] (S.C. Larsson)
1
ACCEPTED MANUSCRIPT ABSTRACT
2
Background & Aims: Controversy exists on the association between alcohol consumption and
3
risk of heart failure (HF). We carried out a meta-analysis to summarize available prospective
4
data on alcohol consumption and HF.
5
Methods: We searched PubMed for relevant studies published until January 1, 2017. Relative
6
risk (RR) estimates from individual studies were pooled in a random-effects meta-analysis.
7
Results: A total of 13 prospective studies, with 13,738 HF cases and 355,804 participants,
8
were included in the meta-analysis. Light alcohol drinking (0.1–7 drinks/week) was inversely
9
associated with risk of HF (RR, 0.86; 95% confidence interval, 0.81–0.90). There was no
10
statistically significant association between moderate (7.1–14 drinks/week), high (14.1–28
11
drinks/week), or heavy (>28 drinks/week) alcohol consumption and HF risk. Former drinking
12
was associated with an increased risk of HF compared with never or occasional drinking (RR,
13
1.22; 95% confidence interval, 1.11–1.33).
14
Conclusions: This meta-analysis found that light alcohol drinking was associated with a
15
lower risk of HF. Former drinking was associated with a higher risk of HF.
SC
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Keywords: alcohol consumption; heart failure; meta-analysis; prospective studies
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2
ACCEPTED MANUSCRIPT 1. Introduction
19
Alcohol consumption has multiple health effects of which some are beneficial but most are
20
detrimental. Among the beneficial vascular effects, alcohol consumption has been associated
21
with higher levels of high-density lipoprotein cholesterol and reduced levels of inflammatory
22
markers and fibrinogen [1-4]. In addition, observational studies have reported that light-to-
23
moderate drinking is associated with lower risk of ischemic heart disease [5] and ischemic
24
stroke [6]. On the other hand, alcohol consumption has been found to be positively associated
25
with risk of hypertension [7] and atrial fibrillation [8]. Observational studies on alcohol
26
consumption in relation to risk of heart failure (HF) have produced inconsistent results, but a
27
meta-analysis of eight prospective studies indicated an overall inverse association between
28
light to moderate drinking and HF risk [9]. No association was observed with moderate to
29
high alcohol consumption (14–21 drinks/week) [9].
M AN U
SC
RI PT
18
We performed an updated systematic review and meta-analysis of prospective studies to
31
investigate the associations of light and moderate alcohol consumption with risk of HF. In
32
addition, we assessed whether heavy drinking and former drinking was associated with HF,
33
which was not examined in the previous meta-analysis.
34
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30
2. Methods
36
2.1. Study selection and data extraction
37
The PubMed database was searched for pertinent studies published up to January 1, 2017,
38
using the following predefined search terms: “alcohol” and “consumption” or “drinking” or
39
“intake” and “heart failure”. No restrictions were imposed. The list of references in the
40
retrieved publications was also reviewed. Eligibility criteria were: 1) prospective design; 2)
41
investigated the association between alcohol (ethanol) consumption and HF incidence or HF
42
mortality; 3) the population did not have HF at baseline; 4) alcohol consumption was 3
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35
ACCEPTED MANUSCRIPT quantified in drinks or grams of consumption; and 5) provided relative risks (RR) with 95%
44
confidence intervals (CIs), adjusted for at least age. Studies that classified alcohol
45
consumption in two groups (no/yes or nondrinkers/drinkers) were not eligible. Two authors
46
(SCL and AWa) performed the literature search and selected the studies for inclusion in the
47
meta-analysis. Any disagreement was resolved by consensus.
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43
The following details were recorded from each study: the last name of the first author,
49
country, cohort name, follow-up time, sex, age, number of cases and participants, RRs with
50
95% CIs for each category of alcohol consumption, and the variables adjusted for in the
51
multivariable model. From each study, the most fully adjusted risk estimates were extracted.
SC
48
M AN U
52
2.2. Statistical methods
54
A random-effects model was applied to combine the RRs from included studies according to
55
four categories of alcohol intake: light (0.1–7 drinks/week), moderate (7.1–14 drinks/week),
56
high (14.1–28 drinks/week), and heavy (>28 drinks/week) based on the average consumption
57
in each category and separately for men and women. The reference (comparison) group was
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the one used in the included studies, and was nondrinkers, never drinkers, or very light
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drinkers (hereafter referred to as occasional drinkers). If a study reported two or more RRs
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that fell into one of the four categories, those RRs were pooled before inclusion in the meta-
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analysis. We also conducted a meta-analysis that combined study-specific results for former
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drinkers versus never or occasional drinkers. Where alcohol consumption was reported in
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grams (two studies), the intake was converted into drinks, and one drink was assumed to
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contain 12 gram of alcohol [10]. We conducted subgroup and meta-regression analyses to
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assess possible sources of heterogeneity by sex, geographic area (North America, Europe),
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and reference group used (nondrinkers [including former drinkers], never drinkers, or
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occasional drinkers). Because the number of studies was few in the heavy drinking category,
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this category was combined with the high alcohol consumption category in the stratified
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analysis. The I2 statistic was used to quantify heterogeneity among studies [11]. Egger’s test
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was used to evaluate publication bias [12]. Stata (version 12.0, StataCorp, College Station,
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TX) was used for the statistical analyses.
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3. Results
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Our literature search identified 13 prospective studies (reported in 12 articles) [13-24] (Figure
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1) of which seven were conducted in North America and six in Europe. Study details are
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presented in Supplementary Table 1. The studies included a total of 13,738 HF cases (the
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number of cases was not reported in one study) and 355,804 participants.
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Overall, compared with the reference group (nondrinkers, never drinkers, or occasional
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drinkers), light alcohol consumption was associated with a statistically significant 14% lower
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HF risk (RR, 0.86; 95% CI, 0.81–0.91), with low between-study heterogeneity (I2 = 41.0%)
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(Figure 2). Moderate, high, and heavy alcohol consumption was not statistically significantly
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associated with HF in the overall analysis (Figure 1). There was no indication of publication
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bias (P > 0.61 for all four alcohol consumption categories).
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The association between alcohol consumption and risk of HF did not vary significantly
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by sex (P for difference by sex ≥0.58), but the only statistically significant association was
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observed between light alcohol consumption and risk of HF in women (Table 1). Light and
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moderate alcohol consumption was inversely associated with risk of HF in studies conducted
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in North America but was not associated with HF risk in European studies (P for difference =
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0.08 for the light drinking group and P for difference = 0.01 for the moderate drinking group)
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(Table 1). In analysis stratified by type of reference group, light alcohol consumption was
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associated with a lower HF risk in studies with nondrinkers or never drinkers as the reference
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group (Table 1). In addition, moderate and high-to-heavy alcohol consumption was inversely
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associated with HF in studies with never drinkers as reference group but was not associated
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with HF in studies with nondrinkers or occasional drinkers as the reference (Table 1). Eight studies provided results for former drinkers compared with never or occasional
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drinkers (Figure 3). Overall, former drinking was associated with a statistically significant
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22% increased risk of HF (RR, 1.22; 95% 1.11–1.33), with little heterogeneity among studies
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(I2 = 23.1%) (Figure 3).
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4. Discussion
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This updated meta-analysis of alcohol consumption and HF risk includes over twice as many
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cases of HF and almost twice as many participants as our previous meta-analysis [9]. This
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meta-analysis confirms a modest inverse association between light alcohol consumption (up
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to one drink daily) and risk of HF, with a 14% lower risk observed in light drinkers. This is
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the first meta-analysis to show that former drinking is associated with an increased risk of
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HF. Heavy drinking was not significantly associated with HF risk, but few studies reported
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results for heavy drinking.
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The biological mechanisms by which light alcohol drinking may lower the risk of HF are
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uncertain, but the association may partially be mediated through an influence on ventricular
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ejection fraction. A recent population-based study reported a U-shaped association between
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alcohol consumption and left ventricular ejection fraction, with light drinkers (<1 drink/day)
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having the lowest risk of moderate left ventricular dysfunction [25]. The reduced risk of HF
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associated with light drinking may also be mediated through beneficial effects of alcohol on
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coronary artery disease [16, 18].
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The observed increased risk of HF in former drinkers may reflect worse health and higher
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prevalence of hypertension and other underlying conditions for HF in former drinkers than in
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occasional or never drinkers [21, 24]. Worsening of health has been found to be associated 6
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alcohol consumption with HF risk was observed not only among studies with nondrinkers
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(including former drinkers) as the reference group but also among studies with never drinkers
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(lifelong abstainers) as the reference group. The lack of association of light and moderate
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drinking with HF risk in studies with occasional drinkers as the comparison group [22, 24]
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may be related to that no further benefit of alcohol is observed when increasing the intake
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from very light (occasional drinkers) to light-to-moderate consumption.
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Few studies have provided results for different alcoholic beverages in relation to risk of
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HF [13, 16, 23]. Two studies reported similar risk estimates for consumption of wine, beer,
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and liquor [13, 23]. One study found a lower risk of HF only in wine drinkers who were men,
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and no associations with beer or liquor consumption in either men or women [16]. Although
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wine has a high content of potentially beneficial polyphenols, the association confined to
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wine in one of the studies may be explained by uncontrolled favorable user traits and
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drinking patters of wine drinkers [16].
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A strength of this meta-analysis is that we could examine the association between alcohol
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consumption and HF with high precision because of the large number of prospective studies
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included. A limitation is that some degree of misclassification of alcohol consumption in each
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study was inevitable. Alcohol consumption may be underreported, in particular among heavy
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drinkers. Another shortcoming is that all prospective studies on alcohol consumption and HF
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were conducted in North America, Northern Europe, and the United Kingdom. Findings from
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this meta-analysis may therefore not be generalizable to other populations, such as Asian and
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Mediterranean populations, with a potentially different proportion of genotypes influencing
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alcohol metabolism and different alcohol consumption pattern. Finally, the possibility that the
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observed inverse association between light drinking and HF risk may be due to uncontrolled
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confounding by lifestyle or social factors cannot be ruled out. Mendelian randomization
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studies, using genetic variants associated with alcohol consumption as unconfounded proxies
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for alcohol drinking, may provide further insight into the potential causal role of alcohol in
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the etiology of HF.
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5. Conclusion
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In this meta-analysis of 13 prospective studies, light consumption of alcohol (up to one drink
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per day) was associated with a lower risk of HF, whereas former drinking was associated
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with an increased risk. No significant association was observed with high-to-heavy drinking.
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Conflict of interest
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None.
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Acknowledgements
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This work was supported by the Swedish Research Council (grant number 2015-02302).
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Supplementary data
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This manuscript contains supplementary data (Supplementary Table 1).
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[18] Djousse L, Gaziano JM. Alcohol consumption and risk of heart failure in the Physicians' Health Study I. Circulation 2007;115:34-39.
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[20] Wang Y, Tuomilehto J, Jousilahti P, Antikainen R, Mahonen M, Katzmarzyk PT et al. Lifestyle factors in relation to heart failure among Finnish men and women. Circ Heart Fail 2011;4:607-612.
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[22] Wannamethee SG, Whincup PH, Lennon L, Papacosta O, Shaper AG. Alcohol consumption and risk of incident heart failure in older men: a prospective cohort study. Open Heart 2015;2:e000266. [23] Gemes K, Janszky I, Ahnve S, Laszlo KD, Laugsand LE, Vatten LJ et al. Light-tomoderate drinking and incident heart failure--the Norwegian HUNT study. Int J Cardiol 2016;203:553-560. [24] Larsson SC, Wallin A, Wolk A. Contrasting association between alcohol consumption and risk of myocardial infarction and heart failure: Two prospective cohorts. Int J Cardiol 2017;231:207-210 (Epub Dec 28, 2016).
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ACCEPTED MANUSCRIPT [25] Yousaf H, Rodeheffer RJ, Paterick TE, Ashary Z, Ahmad MN, Ammar KA. Association between alcohol consumption and systolic ventricular function: a population-based study. Am Heart J 2014;167:861-868. [26] Ng Fat L, Cable N, Shelton N. Worsening of health and a cessation or reduction in alcohol consumption to special occasion drinking across three decades of the life
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course. Alcohol Clin Exp Res 2015;39:166-174.
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FIGURE LEGENDS
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Figure 1. Flow chart of study selection for meta-analysis
Figure 2. Overall relative risks (RR) with 95% confidence intervals (CI) of heart failure for light (0.1–7 drinks/week), moderate (7.1–14 drinks/week), high (14.1–28 drinks/week), and
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occasional drinkers. N: number of included studies.
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heavy (>28 drinks/week) alcohol consumption compared with nondrinkers, never drinkers or
Figure 3. Forest plot of relative risks (RR) with 95% confidence intervals (CI) of heart failure for former drinkers compared with never or occasional drinkers. Squares indicate study-specific RR (size of the square reflects the study-specific statistical weight, i.e., the
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inverse of the variance); horizontal lines indicate 95% CI; diamonds indicate the overall RR
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with its 95% CI. M: men, W: women.
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Table 1. Subgroup analyses (random-effects meta-analysis) of light, moderate, and high-to-heavy alcohol consumption with risk of heart failurea
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Moderate drinking (7.1–14 drinks/wk) Nb RR (95% CI) I2 (%)c
0.88 (0.76–1.03) 0.89 (0.81–0.98) 0.91
70.9 0
6 4
0.94 (0.77–1.15) 0.95 (0.80–1.14) 0.92
7 5
0.82 (0.78–0.87) 0.92 (0.82–1.02) 0.08
0 53.1
5 6
5 5 2
0.87 (0.81–0.93) 0.80 (0.75–0.85) 1.00 (0.86–1.16)
0 0 48.7
3 5 3
High-to-heavy drinking (>14 drinks/wk) Nb RR (95% CI) I2 (%)c
65.6 0
5 3
1.02 (0.85–1.24) 0.92 (0.64–1.32) 0.58
57.4 0
0.77 (0.65–0.91) 1.06 (0.95–1.17) 0.01
48.0 0
6 4
0.91 (0.79–1.05) 1.06 (0.86–1.30) 0.14
35.4 44.4
0.90 (0.66–1.22) 0.79 (0.68–0.93) 1.07 (0.93–1.23)
62.5 45.2 0
2 5 3
0.83 (0.36–1.93) 0.89 (0.80–0.99) 1.08 (0.85–1.38)
87.4 0 50.0
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Subgroup Sex Men Women P for differenced Geographic area North America Europe P for differenced Reference group Nondrinkerse Never drinkers Occasional drinkersf
Light drinking (≤7 drinks/wk) N RR (95% CI) I2 (%)c b
The reference group in the subgroup analyses by sex and geographic area was nondrinkers, never drinkers, or occasional drinkers.
b
Number of included studies.
c
Test for between-study heterogeneity.
d
Test for difference in association between alcohol consumption and HF risk by sex or geographic area (meta-regression analysis).
e
Including former drinkers.
f
Defined as <1 drink/week in two studies and 1–6 drinks/week in one study.
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a
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Articles identified from reference lists (n = 2)
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Articles identified through PubMed search (n = 1193)
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Excluded based on title and/or abstract (n = 1177) Potentially relevant articles identified for full text review (n = 18)
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Excluded articles (n = 6): • No risk estimate for the association between alcohol consumption and HF risk (n = 3) • Included prevalent cases of HF (n = 1) • Duplicate publications (n = 2)
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Articles included in the meta-analysis (n = 12), including 13 studies
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