Crtitique 276 – Alcohol Consumption, High-Density Lipoprotein Particles and Subspecies, and Risk of Cardiovascular Disease: Findings from the PREVEND Prospective Study

Authors

Kunutsor SK; Bhattacharjee A; Connelly MA; Bakker SJL; Dullaart RPF

Citation

Int J Mol Sci (2024), 25, 2290. https://doi.org/10.3390/ijms25042290

Author’s Abstract

Background The associations of HDL particle (HDL-P) and subspecies concentrations with alcohol consumption are unclear.

Objective(s) We aimed to evaluate the interplay between alcohol consumption, HDL parameters and cardiovascular disease (CVD) risk.

Methods In the PREVEND study of 5151 participants (mean age, 53 years; 47.5% males), self-reported alcohol consumption and HDL-P and subspecies (small, medium, and large) by nuclear magnetic resonance spectroscopy were assessed. Hazard ratios (HRs) with 95% CIs for first CVD events were estimated. In multivariable linear regression analyses, increasing alcohol consumption increased HDL-C, HDL-P, large and medium HDL, HDL size, and HDL subspecies (H3P, H4P, H6 and H7) in a dose-dependent manner. During a median follow-up of 8.3 years, 323 first CVD events were recorded.

Results Compared with abstainers, the multivariable adjusted HRs (95% CIs) of CVD for occasional to light, moderate, and heavy alcohol consumers were 0.72 (0.55–0.94), 0.74 (0.54–1.02), and 0.65 (0.38–1.09), respectively. These associations remained consistent on additional adjustment for each HDL parameter. For CVD, only HDL-C was associated with a statistically significant decreased risk of CVD in a fully adjusted analysis (HR 0.84, 95% CI 0.72–0.97 per 1 SD increment). For coronary heart disease, HDL-C, HDL-P, medium HDL, HDL size, and H4P showed inverse associations, whereas HDL-C and HDL size modestly increased stroke risk. Except for H6P, alcohol consumption did not modify the associations between HDL parameters and CVD risk. The addition of HDL-C, HDL size, or H4P to a CVD risk prediction model containing established risk factors improved risk discrimination.

Conclusions Increasing alcohol consumption is associated with increased HDL-C, HDL-P, large and medium HDL, HDL size, and some HDL subspecies. Associations of alcohol consumption with CVD are largely independent of HDL parameters. The associations of HDL parameters with incident CVD are generally not attenuated or modified by alcohol consumption.

Forum Comments

Background

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide, imposing a significant burden on economies and health systems. Established risk factors for CVD include hypertension, diabetes, smoking, obesity and dyslipidaemia. The role of yet another risk factor on CVD risk, namely alcohol consumption, is more complex (Ding et al., 2021; Yoon et al., 2020). Extensive epidemiological research indicates that a J-shaped association exists between alcohol consumption and CVD risk.  In other words, moderate alcohol consumption is associated with a reduced risk of CVD mortality whereas high alcohol consumption is not. Better understanding and documenting the mechanisms that underly this association would further substantiate the causal relation between moderate alcohol consumption and CVD.

CVD develops over several decades, in part by unbalances in an individual’s lipoproteins. Lipoproteins are the transporters of hydrophobic lipids, namely triglycerides and cholesterol, within the body. Lipoproteins are essential contributing factors of CVD. Whereas the lipoprotein low-density lipoprotein (LDL) provides cells of the vascular wall with cholesterol for growth, the lipoprotein high-density lipoprotein (HDL) disposes of the surplus of cholesterol in these cells or disposes of cholesterol erroneously deposited in other cells like macrophages. Enhanced cholesterol uptake by macrophages, leads into foam cell formation and ultimately results in plaque formation and inflammation (Bhargava et al. 2022, Das and Ingole, 2023).

One of those lipoproteins, HDL is the lipoprotein under consideration in the Dutch prospective cohort Prevention of Renal and Vascular End-stage Disease (PREVEND) study, reported on by Kunutsor et al. (Kunutsor et al., 2024). HDL was discovered approximately 70 years ago, and approximately 60 years ago, the Framingham Heart Study reported the inverse relationship between plasma levels of these lipoproteins and atherosclerosis (Wilson et a., 1980).

So, HDL, generally considered a protective factor for CVD (Huang et al., 2017; Pullinger et al., 2021), removes excess cholesterol from cells, especially macrophages in the artery wall, through a process called reverse cholesterol transport (Lee et al., 2021). Reverse cholesterol transport is considered important in the protection against the process of atherogenesis. In addition, HDL has an anti-inflammatory capacity and protects against inflammatory processes in the vascular wall, which is also important in the prevention of cardiovascular events (Jia et al., 2021).

Critique

The International Journal of Molecular Sciences, an advanced forum for biochemistry, molecular and cell biology, molecular biophysics, molecular medicine, and all aspects of molecular research in chemistry, published a paper on a longitudinal epidemiological study analysing HDL subspecies by NMR spectroscopy. Support for assessment of precise HDL subspecies came from an earlier assessment of HDL and incident vascular events that showed that two of seven HDL size-based subspecies modestly improved risk prediction for myocardial infarction and composite vascular end points (Deets et al. 2023).

The authors conclude that alcohol consumption affects various HDL characteristics and is associated with a lower risk for CVD, but the lower risk association is independent of specific HDL parameters. Similarly, the beneficial association between some HDL parameters and CVD outcome is unaffected by alcohol consumption.

This conclusion may seem somewhat confusing. HDL which is increased in moderate alcohol consumers, and which has been reported to protect against CVD, seems not to be affecting the alcohol–CVD association.

Let us consider the alcohol- HDL-CVD relationship further. Plasma levels of HDL-cholesterol (HDL-C) are strongly associated with CVD. This observation is strong, graded and coherent across the populations studied (Boekholdt et al., 2013). In recent years, Mendelian randomization experiments and drug interventions increasing plasma levels of HDL-C have casted doubt on the causal link (Voight et al., 2012). Furthermore, drugs that increase plasma levels HDL-C have failed to show improved cardiovascular outcomes (Probstfield et al., 2018). One possible explanation for this discrepancy is that cholesterol mass within HDL is an indicator but not a cause of its beneficial effects.

Numerous nutrition intervention studies (Sierksma et al., 2002, Wilkens et al., 2022) and large scale longitudinal epidemiological studies (Rimm et al., 1999) (Trius-Soler et al., 2024) have shown that moderate alcohol consumption results in, and is associated with, increased HDL-C concentrations. Moderate alcohol consumption not only increases HDL-C but also protein and enzyme activities that may or may not accompany this increase in HDL-C. It has been shown, initially in nutrition intervention trials, that not only the composition of the HDL particles changes during alcohol consumption, but also the functionality of the particle (Carmont et al. 2011). One important, previously mentioned, a function of the HDL particle is the removal of excess cholesterol from macrophages in the vascular wall, which has been shown stimulated in interventions with moderate alcohol consumption  (Beulens et al., 2004; Sierksma et al., 2002, 2004).

Also, epidemiological research has shown that not the quantity of HDL-C but the functioning of the reverse cholesterol transport may be the real protection that HDL has to offer in CVD (Rohatgi et al., 2014, Adorni et al. 2021, Badita et al. 2023). Other epidemiological studies have estimated the importance of HDL increases in CVD protection from moderate alcohol consumption and showed that up to 50% of the protective effect is attributable to the alcohol-induced HDL increase (Mukamal et al., 2005).

However, measuring HDL-C is easier than analysing HDL function. In clinical practice, the standard measure of HDL is the cholesterol content in HDL particles after precipitation of apolipoprotein-B containing lipoproteins; apoB-containing lipoproteins within the arterial wall is the key initiating event in the pathobiology of atherosclerosis leading to CVD. More refined techniques to determine HDL-C in serum include amongst others ultracentrifugation, electrophoresis, and nuclear magnetic resonance (NMR). NMR is used to obtain a better characterization of these particles aiming to better predict CVD risk. Moreover, using nuclear magnetic resonance (NMR) spectroscopy is relatively easy.  It has previously been shown that HDL particles and subspecies characterized by this technique vary in their associations with incident CVD (Potočnjak et al., 2017) and type 2 diabetes (Deets et al., 2023; Sokooti et al., 2021). Indeed, an earlier PREVEND Study publication assessing the association of HDL particle subspecies with incident Diabetes Type 2 (T2D) in the general population, showed in an initial crude model, that higher levels of HDL-C, HDL-P, large, medium HDL particles, and HDL size were associated with a lower risk of T2D. It was further found that greater HDL size and lower levels of H4P (medium HDL size) were associated with a lower risk, whereas higher levels of H2P (small HDL size) were associated with a higher risk of developing T2D (Sokooti et al. 2021). It had been previously established that HDL-C is also inversely associated with risk of developing T2D (Wilson et al., 2007, Abbasi et al., 2013), and that, moderate alcohol consumption is also inversely associated with risk of developing T2D (Joosten et al. 2011, Ma et al. 2022).

One difficulty with the techniques that exist to measure HDL, HDL-C and HDL functionality is that they lack mutual validation. So, in the case of the PREVEND study by Kunutsor et al. (2024), the authors may not have found clear associations between alcohol consumption and HDL particles affecting CVD incidence, because HDL functionality was not directly nor indirectly evaluated. This issue was mentioned by the authors in the last sentence of their discussion section.

Also, numerous associations were not significant. Although the authors claim that a strength of the study was the large sample size (8,592 subjects) and the prolonged follow-up period (1997 onwards of five follow-up screening rounds with 3-to-4-year intervals), whereas only 323 CVD events occurred evaluating some 43,000 person years. Further, lack of ethnic diversity and inadequate representation of women in some previous studies limit generalizability of those findings.

Therefore, this interesting study shows that HDL changes with moderate alcohol consumption. The suggestion that there may not be a mediating role for the beneficial moderate alcohol–CVD relationship is not explained by the parameters analysed in this study but is most likely explained by other characteristics of the HDL particle, namely its function in reverse cholesterol transport.

Specific Comments from Forum Members

Forum member Skovenborg reminds us that “While an increasing TC/HDL-C ratio is a powerful predictor of CHD risk in men and women (Calling et al., 2019), randomized trials of HDL-C modifying drugs have not shown the anticipated benefit (Riaz et al., 2019), and results of Mendelian randomization analyses also challenge the concept that raising plasma HDL-C will translate into reductions in risk of MI (Voight et al., 2012). However, HDL is not simply a carrier of cholesterol taken from cells for redistribution and removal from the body; HDL is a complex constellation of many proteins and phospholipids organized into HDL subspecies with diverse physiochemical properties and metabolic actions. The main protein on HDL is apolipoprotein A1 that lends structural stability to the particle and stimulates efflux of cholesterol from cells to HDL, enlarging the particles. However, ongoing research has focused on apolipoprotein C3 as a potentially important protein that may modulate HDL function. ApoC3 is present on 6% to 15% of HDL, and several cohort studies found HDL that contains apoC3 associated with a higher risk of CHD: pooled relative risk per standard deviation, 1.09 (95% CI 1.01-1.18), whereas HDL that lacks apoC3 was associated with lower risk: relative risk 0.76 (0.70-0.83) (Jensen et al., 2018).

HDL containing apoC3 is associated with metabolic risk factors, such as diabetes mellitus, obesity, and blood glucose. In contrast, HDL lacking apoC3 is associated with favourable levels of these risk factors. Regarding lifestyle, HDL containing apoC3 levels were 0.9% lower (95% CI: –1.7, –0.1) per each 20 MET hours/week higher physical activity while HDL not containing apoC3 levels were 1.6% (0.8-2.3) higher per 15 g/day higher alcohol consumption (Koch et al., 2017).  The MR approach, having thus far focused on HDL cholesterol or apoA1 levels, may not capture the functional properties of HDL that play a role in the disease pathology (Sacks and Jensen, 2018).”

Calling S., Johansson. S-E., Wolff, M., Sundquist, J., Sundquist, K. (2019), “The ratio of total cholesterol to high density lipoprotein cholesterol and myocardial infarction in Women’s health in the Lund area (WHILA): a 17-year follow-up cohort study”, BMC Cardiovascular Disorders Vol. 19 No. 1, 239, https://doi.org/10.1186/s12872-019-1228-7.

Riaz, H., Khan, S.U., Rahman, H., Shah, N.P., Kaluski, E., Lincoff, A.M., Nissen, S.E. (2019), “Effects of high-density lipoprotein targeting treatments on cardiovascular outcomes: A systematic review and meta-analysis”, European Journal of Preventive Cardiology, Vol. 26 No. 5, pp. 533-543, https://doi.org/10.1177/2047487318816495.

Voight, B.F., Peloso, G.M., Orho-Melander, M., Frikke-Schmidt, R., Barbalic, M., Jensen, M.K. et al. (2012), “Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study”, Lancet Vol. 380 No. 9841, pp. 572-580, https://doi.org/10.1016/S0140-6736(12)60312-2.

Jensen, M.K., Aroner, S.A., Mukamal, K.J., Furtado, J.D., Post, W.S., Tsai, M.Y., Tjønneland, A., Polak, J.F., Rimm, E.B., Overvad, K., McClelland, R.L., Sacks, F.M. (2018), “HDL subspecies defined by presence of apolipoprotein C-III and incident coronary heart disease in four cohorts”, Circulation Vol. 137 No. 13, pp. 1364-1373, https://doi.org/10.1161/CIRCULATIONAHA.117.031276.

Koch, M., Furtado, J.D., Jiang, G.Z., Gray, B.E., Cai, T., Sacks, F., Tjønneland, A., Overvad, K., Jensen, M.K. (2017), “Associations of anthropometry and lifestyle factors with HDL subspecies according to apolipoprotein C-III”, Journal of Lipid Research, Vol. 58 No. 6, pp. 1196-1203, https://doi.org/10.1194/jlr.P073288

Sacks, F., Jensen, M.K. (2018), “From High-Density Lipoprotein Cholesterol to Measurements of Function”, Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 38 No. 3, pp. 487-499, https://doi.org/10.1161/ATVBAHA.117.307025.  

Forum member Harding found this study confusing. “Its conclusion that light to moderate alcohol consumption is protective for CHD and that this is accompanied by an increase in HDL-C is consistent with numerous studies over recent decades.  This is obviously important because of its implications for causality.  But then on further analysis of the sub-fractions (‘parameters’) of HDL, the study finds no association of any of them with alcohol consumption and CVD.  I assume that it is this finding that justifies the sentence, in the Abstract and in the Conclusion, ‘Furthermore, the associations of these HDL parameters with cardiovascular outcomes appear not be attenuated or modified to a considerable extent by alcohol consumption.’

I did get the overall impression that the authors are seeking to place as little emphasis on alcohol’s cardio-protective effect as possible.  For example, in the introduction, the sentence, ‘A number of studies have shown that moderate alcohol consumption is associated with a higher risk of adverse cardiovascular outcomes’ is justified by reference to two studies, Bell et al. (2017) and Mostofsky et al. (2016).  In the Bell et al. (2017) paper, I am unable to find any cardiovascular outcomes for which moderate drinkers are at higher risk.  The Mostofsky et al. (2016) paper is mainly concerned with increased cardiovascular events in the 24 hours after any consumption of alcohol, but also finds protection from moderate drinking in the longer term.  Both can’t be right for moderate drinkers.  So, the authors are struggling to justify their statement.

Further, the study found that moderate alcohol consumption was protective for coronary heart disease (CHD), with associations for HDL-C and most of its ‘parameters’ but was also associated with a higher risk for stroke.  But the definition for stroke in section 4.3 is, ‘Stroke encompassed subarachnoid haemorrhage, intracerebral haemorrhage, other specified and unspecified intracranial haemorrhages, occlusions and stenoses of precerebral or cerebral arteries, and carotid artery obstruction.  So ‘stroke’ includes both ischemic and haemorrhagic stroke.  It is well known that alcohol consumption (moderate or not) is a risk factor for haemorrhagic stroke, but moderate consumption is protective for ischemic stroke.  The authors mention the relatively low incident rate of stroke.  Even so, as this study did not distinguish between the two, the overall conclusions relating to stroke and CVD (encompassing CHD and all strokes) can be safely ignored.

The authors go on to say in section 3.3 that both CHD and stroke are conditions both mediated by atherosclerosis.  Given their definition of stroke, I am not sure they are.  In section 3.2, they say that in previous work, the various parameters of HDL were associated with lower risk of ischemic stroke.  In this section they say, ‘Our key finding of a protective effect of occasional to light alcohol consumption on cardiovascular risk is consistent with previous studies [23,26,27]’.  They don’t express this key finding in the Abstract or Conclusion.

Forum members Harding and Ellison similarly have concerns with the heterogenous nature of the heavy drinkers’ category. “Having such a small number of heavy drinkers in the top category of alcohol intake, it is unclear how these subjects were included in the overall analyses.  The number of subjects in that category was much, much lower than in the three middle groups.  There were large numbers of subjects in the middle groups of no alcohol and two groups of “moderate” drinkers from which reasonable estimates of effect of alcohol could be evaluated. The heavy drinking group was very different in numerous lifestyle and metabolic factors (e.g., smoking, waist circumference, CRP, risks of CHD by alcohol).  Further, there were only 11 CHD events in this group. This was especially shown in Table 3 of associations of alcohol with CHD (the effects on CVD are ignored, as outlined below); in the unadjusted model, there was a level or gradual change in risk associated with increasing alcohol intake, while when certain adjustments were made for different varieties of HDL, there was an abrupt change (often a change in direction of effect) for the highest category of alcohol intake.  Such changes suggest that subjects in the top group (> 30 g/day of alcohol) were very different in many characteristics and not representative of the effects just of increasing alcohol consumption.  It is uncertain how (or if) this had strong effects on their results.”

Forum member Ellison had three further comments on this paper. The first was noted by Forum member Harding and other Forum members that it is a confusing paper. “At one point the authors state that moderate drinking reduces coronary heart disease (CHD) then that alcohol increases some cardiovascular conditions, and the paper seems to focus more on potentially harmful aspects of alcohol consumption.  Second, the combining in their analyses on CHD with other cardiovascular diseases (CVD) doesn’t really make sense, as they state that the risk of stroke is increased by alcohol, but the risk of CHD is decreased, so combining CHD risk with stroke risk would tend to block any favourable or adverse effects when combined.  (Note also that they did not separate ischemic stroke, which is reduced by moderate alcohol, from haemorrhagic stroke, the risk of which is usually found to be increased by alcohol.)

Finally, reporting that certain varieties of HDL increase or decrease with alcohol consumption is interesting, but I am not sure how much this means for the potential prevention of CHD.  Epidemiologic studies have consistently (almost always) shown that regular, moderate alcohol intake, especially with food, reduces the risk of CHD and total mortality significantly, and total HDL is one (but only one) of the mechanisms leading to this protective effect.  If the authors want to describe alcohol’s overall effect on disease, they need to also consider the dozens (or even hundreds) of other mechanisms related to the effects of alcohol intake before reaching conclusions that apparently suggest to them that alcohol does not affect CHD risk.”

Concluding comments

The clinical relevance of HDL reverse cholesterol transport is indeed well highlighted by many studies, in which an inverse relationship has been detected between reverse cholesterol transport and the prevalence of atherosclerosis, inflammation, and the promotion of plaque stability, as well as the incidence of CV events such as acute myocardial infarction, occurring independently of plasma HDL-C level (Soria-Florido et al., 2020, Rohargi et al. 2014, 2021). The ability of HDL to promote reverse cholesterol transport therefore appears to be more related to its size and composition in terms of proteins and lipids, than to HDL-C plasma levels, where identifying efficacy should move to HDL function measurement, that is, reverse cholesterol transport, instead of plasma levels. This paper thus continues to support the clinical relevance of HDL as a major player in the modulation of the complex and multifactorial atherosclerotic process underlying CVD. Further clinical studies are therefore encouraged to also provide data on cholesterol efflux capacity values at baseline, after alcohol consumption or treatments, or the effect of cholesterol efflux on outcomes. As suggested by Ballantyne and Nambi (2024), “of all the HDL therapeutics, those that could reliably promote cholesterol efflux and reverse cholesterol transport offer the most potential and promise to be the answer to the question that most cardiovascular clinicians have been asked at some point in time: “is there not a treatment that can clear out the plaque from the artery?… perhaps A reconceptualization is needed that focuses on developing better assays for characterizing HDL functions that can be used in conjunction with genomics, metabolomics, proteomics, and transcriptomics to identify new targets and the correct population in which to test therapies to improve cholesterol efflux and the functionality of HDL.”

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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

Richard Harding, PhD, Formerly Head of Consumer Choice, Food Standards and Special Projects Division, Food Standards Agency, UK R. Curtis Ellison, MD, Section of Preventive Medicine/Epidemiology, Boston University School of Medicine, Boston, MA, USA