Critique #284 – Alcohol and arterial stiffness in middle-aged and older adults: Cross-sectional evidence from the UK Biobank study

Authors

Schutte, R., Zhang, J., Kiran, M., Ball G.

Citation

Alcohol: Clinical Experimental Research 2024 48:1915–1922. https://doi.org/10.1111/acer.15426

Author’s Abstract

Background The association between arterial stiffness and alcohol consumption is still controversial. We investigated this relationship by performing continuous analysis in men drinking only beer/cider, and women drinking only red wine.

Methods This cross-sectional study involved participants aged 40–69 years consisting of 9029 men who drank only beer/cider, and 6989 women drinking only red wine. Alcohol consumption was captured by a self-reported questionnaire and reported as units per week, where one unit is equal 10 mL pure ethanol. Arterial stiffness index (ASI) was estimated using photoplethysmography.

Results In men consuming a mean 17.8 (5th and 95th percentiles, 2.6–76.7) units/week, ASI increased by heptiles (sevenths) of alcohol captured from beer/cider consumptionand after adjusting for age (9.14, 9.40, 9.51, 9.53, 9.80, 9.80, 10.00 m/s; p-trend< 0.001) and after full adjustment (9.29, 9.46. 9.55, 9.55, 9.73, 9.73, 9.75 m/s;p-trend= 0.013). Similarly, in women consuming a mean 8.1 (1.6–29.3) units/week,ASI increased by heptiles of alcohol captured from red wine consumption and afteradjusting for age (8.05, 8.05, 8.05, 8.11, 8.17, 8.30, 8.45 m/s; p-trend

= 0.012) and borderline significant after full adjustment (8.05, 8.07, 8.05, 8.07, 8.11, 8.22, 8.43 m/s; p-trend = 0.055). These associations were confirmed in multivariable-adjusted regression analysis in all men, men younger and older than 50 years, and when consuming more than 14 units per week. Similarly, these associations were confirmed in all women, women older than 50 years, and in those consuming more than 14 units per week.

Conclusions Positive linear relationships exist between arterial stiffness and alcohol, irrespective of whether captured from beer/cider consumption in men or red wine consumption in women. No evidence existed to support the notion that our arteries benefit from any level of alcohol consumption.

Forum Summary

Increased arterial stiffness is a degenerative vascular aging process contributing to cardiovascular disease. Schutte et al. (2024) suggest that alcohol consumption has no protective effect on arterial stiffness. Their conclusions are however contradictory to those of previous studies. Their study does not use an appropriate control group, has several other methodological flaws, omits to indicate that arterial stiffness is not the main contributor to cardiovascular disease and has poor assessment of alcohol consumption in terms of quantity and quality.

Forum comments

Background

Increased arterial stiffness is a degenerative vascular aging process. It mainly affects the extracellular matrix of elastic arteries and results in a reduced capability of arteries to expand and contract in response to pressure changes, leading to the development and progression of cardiovascular diseases (CVD) (Marti et al. 2012, Anderson et al. 2012 Lyle and Raaz, 2017, Cecelja and Chowienczke, 2016, Van Bortel 2016).

Large artery (aortic) stiffening has important consequences on systolic hypertension and may damage the microvasculature of organs operating at low vascular resistance. Large artery stiffness is now recognized as a major contributor to systolic hypertension in the elderly and outcomes for particularly heart failure patients remain suboptimal. (Marti et al., 2012, Chirinos et al., 2019). Arterial health, or in other words, healthily functioning arteries, is difficult to evaluate since various characteristics of arteries determine their functioning. Intervening in vascular aging may delay and prevent CVD mortality in an increasingly aging global population (Ahmed et al. 2024).

Aging and related processes are the main determinants of stiffness in elastic arteries, which are correlated with nutritional and lifestyle factors and subsequent age-associated disorders, such as metabolic syndrome, type 2 diabetes, hypertension, atherosclerosis, and renal disease, thus implying metabolic factors in its pathogenesis [Avolio, 2013, Sell and Monnier, 2012, Li et al., 2017, Wu et al., 2015). Accumulating evidence demonstrates that diet and nutrition may prevent or reverse the development of arterial aging (La Rocca et al., 2017) Generally, diets and nutrients that reduce oxidative stress and inflammation, such as diets high in fruits and vegetables, grains, nuts, seeds, legumes, low-fat meat, and fish, with limited amounts of refined foods are associated with reduced arterial stiffness [La Rocca et al., 2017, Mozos et al., 2017). In a recent review on the effect of polyphenols in grape juice (monomeric and oligomeric flavan-3-ols) on CVD risk factors, a strong and clinically significant relationship between daily total polyphenol dose and change in flow-mediated dilation was suggested (Blumberg et al. 2015, De Bruyne et al. 2019).

It is, therefore, both important and interesting to know how diet and lifestyle factors like alcohol consumption affect arterial health and consequently, CVD (Colpani et al., 2018), given CVD is still one of the two major global causes of death.

That is probably why Schutte et al. (2024) investigated the association between alcohol consumption and arterial stiffness. Their hypothesis is clearly stated at the end of their introduction, namely that the authors intended to show that no level of alcohol consumption will show a protective relationship with arterial stiffness. This is interesting given that Del Giorno et al. (2022) conclude that “despite the variable findings across studies, the current [systematic literature] review provides preliminary evidence that light-to-moderate alcohol consumption is associated with arterial stiffness values lower than expected, and evidence that high doses accelerate arterial ageing.” Similarly, Hwang et al. (2022) conclude that “while making specific conclusions regarding this relationship is tenuous; the data suggest that excessive alcohol consumption or a binge drinking pattern is associated with increased arterial stiffness, where Mahmud and Feely (2002) suggest that “alcohol, when ingested acutely, may reduce arterial stiffness, although alcohol when ingested chronically, in excess, increases it”. These data also suggest that the relationship between arterial stiffness is dependent on both the amount and pattern of alcohol consumption.

Critique

The intention to show that no level of alcohol consumption has a protective effect on arterial stiffness may in part be achieved by not using the correct control group, namely the non-drinkers or never-drinkers, instead “performing superior continuous analysis in drinkers”. The authors claimed that in doing this, they were “avoiding biases embedded in epidemiological evidence”, that is, not to “include participants abstaining from alcohol due to health reasons”, which “creates an inappropriate high-risk reference group forcing the trough of the curve with consequent reporting of cardiovascular benefit from low to moderate alcohol consumption (Fillmore et al., 2007)”.  This rationale has been thoroughly debunked by, for example, Klatsky and Udaltsova (2007, 2010, 2013) Holahan et al. 2010 and Ronksley et al., 2011.

In general, when one is interested in the effect of e.g. physical activity on a health outcome, it is correct and state-of-the-art in epidemiology to compare those active with those not. Of course, such a control group may be contaminated with those active occasionally, but an effect of the lifestyle factor of physical activity will appear when relevant. Simply not including that control group removes the possibility of a correct comparison. As has been reported in our previous critiques #214, #283 and #245, also based on UK biobank-based data (Wood et al. 2018, Jani et val., 202, Ortolá et al., 2024), the non-drinkers and never-drinkers were present in the UK biobank study and could have easily been incorporated in Schutte et al.’s (2024) analyses. Surprisingly, this seems to be the new standard for alcohol studies in the UK Biobank: comparisons without a control group.

Furthermore, as referred to by Boyd et al. (2023) in their analysis of the UK Biobank data to investigate the contribution of health-related factors, such as drinking history and beverage type, to the differences in alcohol-attributable harm between socio-economic groups, a “limitation…is the cross-sectional nature of the behavioural data. Measurement of alcohol consumption at baseline is effectively a proxy for lifetime consumption which is common to most epidemiological studies on alcohol-related health risks. The absence of longitudinal data on drinking…behaviours could [over or] underestimate the true impact”

Based on their results, Schutte et al. (2024) show that the Arterial Stiffness Index (ASI) increases in beer/cider-drinking men and red wine-drinking women. The reason for choosing these groups is partially provided but unbalanced: for men, it is stated that they drink beer and cider mainly (while cider seems to be the most gender-balanced alcoholic drink in the UK[1]) and for women drinking only red wine it is stated that wine is popular amongst women and a prominent polyphenol effect of red wine is expected. It would have been more logical to compare red wine drinkers (separating men from women) with beer and cider drinkers (again separating men and women) to study beverage-specific effects. This would have resulted in a better, more balanced design. It is also unclear if the mainly beer and cider-drinking men did not drink any red wine and it is unclear how it was assessed that the only red wine-drinking women, never really drank any other alcoholic beverage (mark the contradiction with choosing to exclude the non-drinkers and never-drinkers’ groups). The choice of the groups used for analysis is probably subject to bias, which may have affected the conclusions reached.

Another important issue concerns the relevance of arterial stiffness for CVD outcomes. CVDs are many, and the main CVD that has an inverse association with light to moderate alcohol consumption is mainly determined by atherosclerosis (Hendriks, 2020). Atherosclerosis results from three consecutive processes including inflammation and high blood pressure leading to vascular damage, an LDL and HDL-cholesterol disbalance leading to oxidized LDL-cholesterol deposition in the arterial wall, and clotting tendencies leading to closure of the blood vessel. Arterial stiffness contributes to atherosclerosis by vascular calcification and remodelling of the extracellular matrix lining the arteries (Chen et al., 2020). Vascular calcification leads to reduced arterial elasticity and decreased vessel wall compliance. So, whereas atherosclerosis is considered the main cause of the leading CVD with beneficial effects of light to moderate alcohol consumption on all three main processes, arterial stiffness is recognized as one of many contributing factors.

Moreover, the association between arterial stiffness and cardiovascular diseases is controversial as reported by the authors. Some researchers report a positive, some a negative association, and some report a J-shaped relation. The discrepancies observed may relate to the methodology used. The UK Biobank study applies the ASI using finger photoplethysmography as an indicator for arterial stiffness. The method calculates the ASI from the shape of the waveform obtained during a 10-15-second measurement at the index finger. The ASI methodology is validated against other techniques like Pulse Wave Velocity (PWV), which is considered the gold standard. PWV uses the time delay between two pressure waveforms from two recording sites, viz. the large arteries: the carotid and the femoral artery. Several of these studies using the golden standard for arterial stiffness assessment find J-shaped or negative associations with alcohol consumption (Sierksma, Lebrun, et al., 2004; Sierksma, Muller, et al., 2004; Van Den Elzen et al., 2005).

Referencing in general is tendentious and incorrect. It is tendentious to refer to papers like the one by Mukamal (2020) as promoting the J-curve; this was a scientific review providing a balanced overview on the safety of alcohol consumption concerning dietary guideline development. Referencing is incorrect because, e.g. the Global Burden of Disease study of 2016 (GBD Alcohol Collaborators 2016, 2018) was referred to stating that the level of alcohol consumption that minimized harm across health outcomes was zero. In contrast, the same group of researchers showed in the subsequent Global Burden of Disease study of 2020 that among individuals aged 40 years and older, the burden-weighted relative risk curve was J-shaped for all regions (GBD Alcohol Collaborators 2020, 2022).

Also, another important issue is to evaluate how much arterial stiffness attributed to alcohol consumption may contribute to the overall cardiovascular disease risk. A paper by Vallee (2023), also based on the UK biobank study investigates this issue and does use the correct control group of non-drinkers and never-drinkers. The FDR logworth was calculated to assess the order of the strength relationship between all the covariates with ASI levels in men and women. Vallee et al. (2023) concluded that alcohol consumption per day was positively associated with higher levels of ASI in both sex but with a lesser relationship. This was formulated as follows: “After age and mean BP, smoking pack years was the third mainly factor associated with ASI levels in men and also in women after age and heart rate. … However, alcohol consumption was in the factors which were the less correlated with ASI levels in both men and women”. So, whereas age, heart rate, blood pressure, BMI and smoking have FDRs varying between 21 and 300, alcohol consumption had an FDR of 2.8. This raises the question of how relevant the observed increase in arterial stiffness is.

The study was intended to show that no protective effect would be present for alcohol consumption on arterial stiffness but was phrased in the abstract conclusion as “No evidence existed to support the notion that our arteries benefit from any level of alcohol consumption”. This conclusion is unfortunately not supported by the data. First, arteries benefit from light or moderate alcohol consumption by its counteracting effects on the atherosclerotic process. Second, arterial stiffness due to alcohol consumption is still contradictory and probably has a limited contribution to cardiovascular diseases. Third, the results obtained in this UK biobank-based study may have resulted from minor deviations in their model adjustments or any other issues like the absence of a control group and group choice (including differences in drinking pattern and dietary background), the cross-sectional nature of the study, measurement issues, alcohol self-report, and low response rate, to mention a few.

Specific Comments from Forum Members

Forum member Harding agrees that “the authors seem to have set out to prove their hypothesis that alcohol has no beneficial effect on arterial stiffness, as expressed in the last sentence of the introduction.  They say they “hypothesized that irrespective of these beverage types or sex, no level of alcohol consumption will show an inverse or protective relationship with arterial stiffness.”  They then conducted a study that could neither prove nor disprove this hypothesis.  Epidemiology of this type might show an association, or it might not, depending on how it is conducted, as Stockwell et al. have demonstrated so convincingly.

Other epidemiological studies have indicated a protective effect of moderate alcohol consumption, but to establish whether this observed association is causal, different approaches are needed such as intervention studies.  I have not conducted an exhaustive literature search for such intervention studies, but have found three (Mahmud and Feely, 2002, Karatzi et al., 2005, Nishiwaki et al., 2017).  Two gave their subjects either red wine or de-alcoholised red wine (indeed quite a lot), and one gave their subjects beer.  All three studies showed an improvement in arterial stiffness, and the researchers in these studies concluded that it was the alcohol in the drinks that was responsible.

I also agree that the lack of a control group is hard to understand.  Their last statement of the Conclusions (page 1915), “No evidence existed to support the notion that our arteries benefit from any level of alcohol consumption”, is not justified by their study and in the context of other studies, is not true.

It is hard to see what contribution the Schutte et al. (2024) study makes to the sum of human knowledge.”

Forum member de Gaetano states “in Figure 1B, I see an L- curve rather than a linear one. In the presence of the missing value of abstainers, a J-curve would have possibly appeared.

They quote a paper by our Research Group, (De Curtis et al., 2005), but they report that our study was in humans, while our experiments were only on hyperlipidemic rats. Moreover, we only showed that alcohol-free red wine effectively prevented experimental arterial thrombosis, suggesting an important beneficial role of wine polyphenols. We did not perform any experiment on pure alcohol or whole wine and thus Schutte et al. (2024) cannot say that our Research Group’s study supports their conclusions on the danger of alcohol. What a superficial and inaccurate citation!”

Forum member Ellison was frustrated that, “once again, a group of supposedly unbiased investigators stated that they had carried out an analysis to judge the effects of alcohol consumption on arterial stiffness but did not include as a control group non-drinkers or never-drinkers.  We should immediately know, without further analysis of the paper, that the results could not answer the question. 

Those of us, however, who conducted a detailed reading of the paper found other problems as well.  For example, it is surprising that these authors continue to refer to a 2007 paper by Fillmore et al. (2006, 2007) where the authors created their criteria for an ‘unbiased’ paper and subsequently used those criteria to exclude 54 of the 58 papers they reviewed. Their final analysis reported the four remaining (all rather atypical) studies as showing no beneficial effects on CVD mortality from moderate drinking, although there was no statistically significant effect.  That paper has been repeatedly found to be completely erroneous in its conclusions.

There are other problems:

(1) They included in their ‘lowest drinking’ group subjects with higher than recommended levels of alcohol consumption (the average intake for a strangely constructed men’s group was 17.8 drinks/week and for women, it was an average intake of 8 drinks/week); and

(2) They note in their results that there were no statistically significant effects of alcohol among either men or women who consumed less than 14 drinks/week (the upper recommended limit for men and double the recommended women for women). 

Thus, the lowest alcohol intake group was not even an appropriate group for ‘healthy levels of intake,’ but included many subjects drinking more.  Interestingly, the authors do not highlight these effects using <14 drinks/week as a light-drinking group. 

Because of these problems, it is not possible to judge from the present analyses whether light-to-moderate alcohol consumption in the general public has either beneficial or adverse effects on arterial stiffness.  Many previous studies have found that high levels of alcohol intake adversely affect arterial disease, but we cannot determine from this paper the effects on arterial stiffness of light-to-moderate drinking, as practiced by the large majority of people.”

Forum member Waterhouse states, “I would like to emphasize the seemingly deliberate exclusion of the proper control group”. 

Concluding comments

This cross-sectional analysis is flawed. It adds little to the current knowledge on the association between alcohol consumption and arterial stiffness, mainly because no proper control group was included in the analysis. Also, the results do not support the conclusion drawn that “…arteries do not benefit from any level of alcohol consumption”, because the association between alcohol consumption and arterial stiffness is controversial with opposite results from longitudinal studies using better techniques, and because arterial stiffness is not a main contributor to cardiovascular disease.

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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:

Henk Hendriks, PhD, Netherlands

Creina Stockley, PhD, MBA, Independent consultant and Adjunct Senior Lecturer in the School of Agriculture, Food and Wine at the University of Adelaide, Australia

Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board, Aarhus, Denmark

Ulrich Keil, MD, PhD, Professor Emeritus, Institute of Epidemiology & Social Medicine, University of Muenster, Germany

Richard Harding, PhD, Formerly Head of Consumer Choice, Food Standards and Special Projects Division, Food Standards Agency, UK

Giovanni de Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy iovanni

R. Curtis Ellison, MD, Section of Preventive Medicine/Epidemiology, Boston University School of Medicine, Boston, MA, USA Curt

Andrew L. Waterhouse, PhD, Department of Viticulture and Enology, University of California, Davis, California, USA

Mladen Boban, MD, PhD, Professor and Head of the Department of Pharmacology, University of Split School of Medicine, Croatia

Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway

Matilda Parente, MD, consultant in molecular pathology/genetics and emerging technologies, San Diego, CA, USA

Pierre-Louis Teissedre, PhD, Faculty of Oenology–ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France

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[1] https://www.beveragedaily.com/Article/2019/02/15/Cider-succeeds-with-men-women-and-millennials-but-faces-retention-challenge#:~:text=Cider%20reaches%20an%20even%20audience,%25%20male%20and%2047%25%20female.