Wine, beer and Chinese Baijiu in relation to cardiovascular health:the impact of moderate drinking

Qiao Kang, Jinyuan Sun,*, Bowen Wang, Baoguo Sun,*

a Beijing Laboratory for Food Quality and Safety, Beijing Technology and Business University, Beijing 100048, China

b Key Laboratory of Brewing Molecular Engineering of China Light Industry, Beijing Technology and Business University, Beijing 100048, China

Keywords:Alcohol Cardiovascular disease Distilled spirits Wine Beer Chinese Baijiu

A B S T R A C T Excessive alcohol consumption (≥15 drinks per week) causes chronic diseases and multiple other health conditions. Nevertheless, alcohol beverages have been used as a vital medicine ingredient in various cultures since ancient times. A wealth of epidemiological and experimental research has shown that light-moderate alcohol consumption, regardless of beverage type, is associated with reducing cardiovascular incidence and mortality rate. Due to the disparities in raw materials, fermentation techniques, production environment,etc., alcoholic beverages tend to possess different non-ethanol component profiles, thus resulting in varying degrees of health effects. Furthermore, bioactive compounds in alcohol are continuously discovered as well as the mechanisms underlying their cardioprotective contributions at a molecular level. This article elucidates the epidemiology of moderate alcohol consumption and various cardiovascular conditions, along with the limitations and controversies of current studies. In addition, protective effects and putative mechanisms of both ethanol and non-ethanol components of wine, beer, and Chinese Baijiu, the three most representative alcoholic beverages worldwide, are to be evaluated within the context of a rational drinking pattern.

1. Introduction

Cardiovascular diseases (CVDs) have become the No.1 global killer for decades: 31% of total deaths were attributed to CVDs,and the death number has climbed to nearly 18 million in 2016 [1].CVDs are multifactorial diseases related to genetic predisposition and multiple lifestyle risk factors such as physical inactivity, smoking,and unhealthy dietary pattern. Many healthy habits can be adopted to prevent getting CVDs. Actually, approximately 80% of coronary heart disease could be prevented by having a healthy diet along with smoking avoidance, regular physical activity, and moderate alcohol consumption (1/2-1 drink per day) [2]. A meta-analysis review of 84 prospective cohort studies also suggests that ingestion of 2.5–14.9 g of alcohol per day reduces CVD risks by 14%–25%compared with non-drinkers [3]. As those studies have suggested,moderate alcohol intake as part of a healthy lifestyle is associated with reduced cardiovascular risk compared with abstinence or heavy drinking [2,3].

Alcohol drinking has long been considered as double-edged sword. Chronic heavy drinking, generally defined as three or more standard drinks (14 g pure ethanol) per occasion [4], can cause detrimental health outcomes, including adverse cardiovascular conditions [5,6] and other alcohol-induced diseases like hepatitis [7],neurocognitive disorders [8], and certain cancers [9,10]. If a person drinks excessively on a regular basis, alcohol use disorder (AUD) is likely to occur, leading to increased all-cause mortality and disability rate along with liver cirrhosis, mental disorders, etc. [11]. By contrast, light-moderate drinking is accompanied by multiple positive consequences such as reduced risk of type 2 diabetes mellitus (T2DM),CVDs, metabolic syndrome, and certain cancers [11,12]. When emphasizing the risks of heavy drinking on human body, the positive aspects of moderate alcohol use should not be denied, and vice versa.

The concept of moderate drinking varies around the world. In the U.S., the recommended drinking standard is up to one drink(< 14.0 pure ethanol) per day for women and two for men [13]. In the U.K., an individual, regardless of gender, should drink no more than 14 drinking units (1 unit = 10 mL or 8 g pure ethanol) per week [14].Whereas in China, moderate drinking is defined as 25 g and 15 g of pure alcohol per day for men and women, respectively [15].Researchers constantly find it difficult accurately estimating alcohol consumption levels predominantly based on self-reported measures.Responders tend to underreport their drinking frequencies and amount since alcohol is usually considered an “unhealthy” food choice in common sense. Through a phone-based survey of 43 371 subjects,researchers found that spirit, beer, and wine consumptions were underreported by almost 66%, 38%, and 49%, respectively [16].The degree of under-reporting varies by age, gender, and alcohol consumption level, which further lowers the statistical power of observational studies.

Besides drinking patterns, different drink types may elicit disparate impacts on the same disease due to their diverse alcohol contents and non-ethanol profiles. As shown in Fig. 1, wine, beer, and hard liquors contain different alcohol contents (～12%–15% ABV,～5% ABV, and ～30%–40% ABV, respectively [11]), while Chinese Baijiu typically contain 42%–60% ethyl alcohol. Surprisingly, 44.8%of total alcohol is consumed in the form of distilled liquor, while beer and wine only account for 34.3% and 11.7% of total consumption,respectively [17]. In this review, Chinese Baijiu is a representative of distilled spirits due to its increasing popularity over the world and prominent health value compared to other hard liquors such as vodka [18]. To the best knowledge of authors, it is the first review that involves hard liquors in the discussion of moderate alcohol consumption and cardiovascular effects.

Fig. 1 Differences among wine, beer, and Baijiu. The raw materials, fermentation types, alcohol contents, and recommended drinking amounts are compared.

The controversy about whether moderate alcohol drinking exerts cardioprotective effects has been intensely discussed until nowadays.It has been pointed out that the association fulfills Hill’s Criteria of Causality [19], the golden standard for establishing a causal relationship.Nevertheless, researchers keep casting doubts on the causality between moderate drinking and its cardioprotective effects [20,21].Confounding factors and sample biases including smoking, diet,physical activity, socioeconomic status, education, misclassification of lifetime abstention, etc. have led to disputes on benefits brought by moderate alcohol consumption. To thoroughly elucidate how moderate drinking affects cardiovascular system,it is necessary to illustrate the probable mechanisms of action for the functional substances in different alcoholic drinks on the cardiovascular system throughin vivotesting and clinical trials. This review aims to provide an overview of current studies on how different alcoholic beverages, represented by wine, beer, and Chinese Baijiu, affects the cardiovascular system, along with the limitations and controversies constantly discussed.

2. Epidemiological studies

2.1 Alcohol consumption and different cardiovascular conditions

CVD is a general term for heart and blood vessel disorders,including hypertension (HTN), coronary heart disease (CHD), stroke,heart failure (HF), etc. [14]. Since CVDs have their unique etiology,each condition is associated with moderate alcohol consumption in different ways. The relationship between several CVDs and alcohol consumption exhibits a J- or U-shaped curve [22]. In other words,those consuming a moderate amount of alcohol on a regular basis are less likely to develop heart and vascular problems than non-drinkers.As alcohol consumption level exceeds the optimum amount, it starts to cause detrimental health consequences.

Coronary heart disease (CHD) is one of the most prevalent CVDs and a major cause of death around the world. Moderate consumption of all types of alcoholic beverages is inversely associated with CHD risks [33]. Both epidemiological and experimental studies have shown that moderate alcohol consumption is associated with a reduced risk of CHD along with other cardiovascular conditions [22,34,35].In addition, CHD remains the leading cause of death and disability for patients with diabetes [36]. A prospective cohort study assessed the CHD risk of women with T2DM and found that regular alcohol consumption of 0.1–4.9 g/day was associated with a reduced risk of nonfatal and fatal CHD incidence among diabetic patients (relative risk (RR): 0.74, 95% confidence interval (CI): 0.56–0.98) compared with non-drinkers [32]. The CHD risk is even lower for diabetic patients consuming more than 5 g/day (RR: 0.48, 95% CI: 0.32–0.72).To be noticed, drinking a small amount of alcohol with meals also benefits glycemic control by attenuating postprandial blood glucose rise and insulin response.

Alcohol has varying effects on different types of cerebrovascular accidents, or so called stroke. A recent meta-analysis study indicates that light and moderate alcohol consumption is protective against overall stroke and ischemic stroke (IS) [24]. To be noticed, heavy drinking should be avoided at all times to reduce the risk of all types of stroke. For hemorrhagic stroke, it demonstrates a monotonically increasing risk with higher intake [25]. In contrast, ischemic stroke has a J-shape relationship with alcohol consumption, suggesting that light-moderate drinkers are less likely to develop IS than non-drinkers and heavy drinkers [25].

As for myocardial infarction, which is commonly known as heart attack, a nest case-control study suggests that both gender benefit from drinking 3–4 days per week by decreasing the risk of heart attack, due to the effect of alcohol on high-density lipoprotein cholesterol (HDL-C), fibrinogen, and insulin sensitivity [29].Increased fibrinogen level is linked to the formation of atherosclerotic plaques, the rupture of which is the leading cause of heart attack.

With respect to heart failure (HF), a meta-analysis review of 8 prospective studies with 202 378 participants of both genders indicates a non-linear relationship between alcohol consumption and heart failure risk [30]. Taken non-drinkers as the reference,participants who had 7 drinks per week had a lower RR of 0.83(95% CI: 0.73–0.95) for HF than three drinks per week (RR: 0.90,95% CI: 0.84–0.96) and 14 drinks per week (RR: 0.90, 95% CI: 0.73–1.10). In a word, moderate alcohol consumption is protective against HF for both men and women (Table 1).

Table 1 Relationship between alcohol intake and cardiovascular diseases.

2.2 Alcohol consumption of different drink types

As shown by a rich amount of epidemiological studies, moderate consumption of alcoholic beverages, regardless of type, have positive effects on the cardiovascular system [37]. The famous French Paradox concept describes a paradoxical phenomenon that despite the high consumption of cholesterol and saturated fat in the French diet,French people have a much lower CHD incidence and mortality rate than any other Western countries such as the U.S. and U.K. [38]. The paradox is attributable to French people’s red wine drinking habit since alcohol consumption in a typical French diet (20–30 g/day)lowers the risk of CHD by at least 40% [38]. A prospective cohort study involving 36 250 healthy middle-aged men in France also found that moderate wine drinking (22–32 g alcohol/day) was associated with lower all-cause mortality and CVD-caused mortality rate [39].

Besides wine, numerous epidemiological studies support that beer has a protective effect against CVDs despite a lower phenolic compound level. A meta-analysis study of 13 studies involving 224 219 persons found a J-shaped relationship between beer consumption and vascular events [40]. It suggests that the vascular risk of beer drinkers (< 55 g alcohol/day) is lower than non-drinkers,and the lowest risk was observed at 43 g of alcohol per day with a RR of 0.58 (95% CI: 0.42–0.81) [40]. The ATTICA study reported that people with drinking habits weekly had a lower CVD incidence rate (14.9%) than non-drinkers (18.6%) in a 10-year follow-up period [41]. Moreover, researchers detected a strong inverse association between beer consumption equal to or less than one glass per week and CVD risks. Light-moderate beer drinkers were 57% less likely to develop CVDs than abstainers (hazard ratio (HR) 0.43, 95%CI: 0.20–0.93) [41].

As for hard liquors, Chinese Baijiu is used as a representative in this review. In fact, the total sales revenue of Baijiu has climbed to 536 383 billion yuan in 2018, which has surpassed the global sales of whisky, vodka, and rum collectively [42,43]. Several studies have shown that other popular spirits such as whisky and brandy potentially benefit cardiovascular system [44-46]. For example,Suzuki et al. found that whisky congeners produced during barrel storage period significantly promoted the production of cytoprotective heme oxygenase-1 (HO-1) enzyme in endothelial cells, thereby potentially benefits blood vessel functions [44]. Although Baijiu shows superior effect in certain health aspects such as liver health [18],as for now there is no systematic study that compares Baijiu and other hard liquors in regard of their cardioprotective effects. There is currently a lack of updated research on the health effect of other spirits, particularly cardiovascular influences, which is another reason why Baijiu was used as a representative in this review. Wu and his coworkers conducted a prospective cohort study involving 6041 subjects to elucidate how Baijiu intake in moderation affects CVD events in male patients with diabetes [47]. Results showed that moderate Baijiu drinkers (0–25 g/day) had the lowest incidence rate for cardio-cerebrovascular events (heart attack & stroke) compared to non-drinkers and heavy drinkers (≥ 25 g/day) during the followup period of 38–53 months [47]. Despite the limitations of this study,such as lacking female representation, it backed up the protective effect of moderate Baijiu ingestion against cardio-cerebrovascular diseases to some extent since the sample size was relatively large.

2.3 Limitations and controversies

All this time, potential confounders and sample biases have led to doubts of overestimating the positive effects of moderate drinking.In 1988, Shaper et al. for the first time proposed the “sick quitter”hypothesis, stating that abstainers observed in epidemiological studies might include former drinkers who quit drinking due to diagnosed illness or long-term alcohol abuse [48]. Abstainers who were actually former drinkers with severe illness, particularly cardiovascularrelated disorders tended to have increased heart disease incidence and cardiovascular mortality when compared with “healthy”occasional drinkers. Therefore, such misclassification might have resulted in the U- or J-shaped curve and was interpreted as evidence for the “protective” value of moderate drinking [49]. However,recent observational studies have shown comparable results when lifetime abstainers were used as the control group. A meta-analysis of 16 cohort studies shows that moderate alcohol intake (10 g/day)is associated with a reduced all-cause mortality rate as well as cardiovascular deaths when compared with lifetime abstainers [50].Yet, separating lifetime abstainers from former drinkers is not as easy as it seems. According to a national probability survey in the U.S.,more than 52.9% of self-reported lifetime abstainers actually reported drinking in previous surveys [51]. The controversy concerning the“sick quitter” hypothesis still exists in recent years.

Besides “sick quitters”, confounding factors might have contributed to the “cardioprotective” effects of moderate drinking as well. For example, heavy drinkers are more likely to have other risk factors such as smoking, malnutrition, and pre-existing health conditions than moderate and non-drinkers, altogether leading to an increased incidence of cardiovascular disorders [52]. On the other hand, drinkers with higher socioeconomic status, better education background, and exercise more often tend to be healthier than nondrinkers [53]. Most of the confounders involved may contribute to favorable association between moderate drinking and positive health outcomes, exaggerating the cardioprotective values of alcohol [54].Di Castelnuovo and his colleagues reevaluated a meta-analysis of 34 prospective studies after ruling out confounders such as age, gender,country, social status, and dietary pattern and reconfirmed a J-shaped relationship between moderate drinking and mortality rate in both men and women [55].

To exclude the interference of confounding factors, genetic markers were used to predict alcohol consumption levels instead of self-reporting measures in Mendelian randomization studies.To be noticed, instrumental variable analysis did not find any protective effects of moderate drinking that were often represented by a U- or J-shaped curve in conventional epidemiology [20,21]. In contrast, cardiovascular conditions (ex. stroke) and risk factors (ex.hypertension) were shown to be positively correlated with genetically predicted alcohol intake [56]. While Mendelian randomization is theoretically capable of excluding confounding influences, some researchers cast doubts to this methodology for neglecting the fact that people may keep drinking despite negative reactions like flushing or head spinning.

3. Putative mechanisms

Due to the limitations of epidemiology mentioned above, it is necessary to clarify the mechanism of actions underlying the cardioprotective effects of moderate drinking. Alcohol at low concentrations contributes to cardiovascular protection by influencing blood lipoprotein profiles [57], platelet aggregation [58], oxidative stress, insulin sensitivity [59], and endothelial function [60].

CVDs usually start with atherosclerosis, a complex multifactorial process of thickening and narrowing arterial walls caused by the accumulation of lipids, primarily oxidized low-density lipoprotein(LDL) combined with connective tissues, cell debris, deposition of calcium, and inflammatory factors (as shown in Fig. 2). It begins with endothelial injuries caused by high LDL and triglyceride (TG) levels,high blood pressure, or other oxidative stress factors. Macrophages,derived from monocytes, are summoned to the injured sites and engulf oxidized LDL, ending up as cholesterol-laden foam cells. As the process continues, exacerbated calcification and inflammation result in vascular plaques, the culprits of various CVD conditions.

To fight against atherosclerosis, HDL-C, also considered the“good” cholesterol, is responsible for transferring cholesterol from foam cells and other lipoproteins back to the liver via cholesterol esterification (EST). Cardioprotective effects of moderate alcohol intake primarily result from enhancing lipid metabolism by increasing HDL-C and EST levels [61]. A randomized, cross-over, controlled feeding trial with high-risk male subjects showed that beer intake(30 g ethanol/day) for four weeks increased plasma HDL-C,apolipoprotein A1 (ApoA-I), and Apolipoprotein A-II (ApoA-II)concentrations and decreased fibrinogen level [62]. ApoA-1 and ApoA- II are critical proteins that constitute HDL, while fibrinogen is used as biomarkers for blood clotting formation. Similarly, in a randomized, paralleled nutrition intervention study of Chinese Baijiu,subjects receiving 30 mL of traditional or tea-flavor Baijiu (45%ABV) for 28 days had significantly higher HDL-C/LDL-C ratio and ApoA1 level than the control group [63].

Fig. 2 Atherosclerosis begins with macrophage engulfment of oxidized LDL-C. Foam cells are generated and then secrete pro-inflammatory cytokines, which in turn promote the infiltration of monocytes. Moderate alcohol consumption 1) inhibits the secretion of pro-inflammatory factors;2) enhances reverse cholesterol transport by stimulating cholesterol esterification; 3) improves vessel endothelial injury conditions.

Plausible mechanisms of moderate alcohol consumption reducing CVD risks also include the mitigation of inflammation [64,65] and oxidative stress. A randomized, cross-over nutrition intervention study indicates that moderate alcohol consumption significantly decreases plasma C-reactive protein (CRP) and fibrinogen levels by 35%(P= 0.02) and 12.4% (P≤ 0.001), respectively [66]. CRP is a standard biomarker to detect inflammation in the body. Furthermore, moderate alcohol consumption decreasing the vascular oxidative damage could be explained by Akt/eNOS pathway activation, hence decreasing apoptosis and lipid peroxidation [67]. In addition, studies found that moderate drinking improves endothelial function and blood flow.

Besides the mechanisms discussed above, moderate alcohol consumption ameliorates the progression of atherosclerosis by mitigating blood vessel damages and strengthening endothelial functions. Atherosclerosis typically begins with blood vessel ruptures.A clinical trial involving 33 men at high cardiovascular risks found that moderate beer consumption may contribute to endothelial repair by enhancing the generation of circulating endothelial progenitor cells [68].The finding was in accordance with a preclinical study using Sprague-Dawley (SD) rats to study how ethanol consumption affects new blood vessel formation and recovery from ischemia injury. The study showed that ethanol ingestion promoted blood vessel density through upregulating the expression of vascular endothelial growth factor [69]. In addition, people who drink in moderation tend to have better flow-mediated dilation (FMD) condition than non-drinkers and heavy drinkers [70]. Karatzi et al. conducted a randomized, singleblinded, cross-over study with healthy, non-smoking subjects and found that beer consumption improved endothelial function assessed by a significantly increased FMD level [71]. FMD is a widely used measure of endothelial function. In conclusion, moderate alcohol consumption may exert a positive influence in the three major steps of atherosclerotic development.

Despite the progress of research in recent years, the thorough mechanisms through which moderate alcohol intake affects the cardiovascular system remain elusive. To dive deeper into that question, researchers keep discovering functional compounds in different alcohol types and how they affect heart and blood vessels after ingestion.

4. Effects of ethanol

The main components of most alcoholic beverages are ethanol and water. Ethanol itself, when ingested in moderation, exerts a positive effect on cardiomyocytes. Ethanol ingestion increases vascular endothelial nitric oxide synthase (eNOS), thereby promoting nitric oxide (NO) production [72]. NO is known to play an essential role in lowering blood pressure as a vasodilator in blood vessels.In vitrostudy using human umbilical vein endothelial cells (HUVEC) also shows a dose-dependent effect of ethanol on NO synthesis: ethanol at the concentration of 10-50 mmol/L significantly increases NO level by upregulating calcium-activated potassium channels (BKCa), while high dosage at 100–150 mmol/L inhibits NO synthesis [73].

Ethanol influences the vascular system by boosting myocardial blood flow. Ethanol-induced calcitonin gene-related peptide (CGRP),a sensory neuropeptide acting as a vasodilator, is released in coronary arteries via activated transient receptor potential vanilloid 1(TRPV1) channels on perivascular sensory nerve terminals, thereby increasing vasodilation [74]. The vasoprotective property of ethanol also attributes to the mobilization of endothelial colony-forming cells (ECFCs), which are adult endothelial progenitor cells (EPCs)that play an essential role in the regeneration of blood vessel cells in endothelial injury. Brodowski et al. found that ethanol-treated ECFCs showed markedly higher angiogenic abilities in proliferation,migration, and capillary-tube formation via enhanced VE-cadherin expression, a protein involved in cell-cell communication [60].

5. Effects of non-ethanol components

The health effects of moderate alcohol drinking largely attribute to its bioactive compounds, which have critical biological functions such as free radical-scavenging properties, inhibition of lipid peroxidation,diminishing platelet aggregation, etc. The health-promoting factors in wine and beer largely come from the raw materials, whereas in Baijiu, microbial diversity during fermentation process result in a variety of metabolic byproducts beneficial for both flavor and health.Considering the low amount and large concentration disparities of each bioactive compound in all types of alcoholic beverages, authors suggest that cardioprotective effects of moderate alcohol use can hardly attribute to one single bioactive compound. In addition, the health impact exerted by each chemical itself varies from its function in the food matrix of different alcohols due to its potential interactions with ethanol and other bioactive compounds. Thus, we noticed that currently existedin vitroandin vivoexperiments investigating the bioactivity of individual bioactive compounds cannot translate to an effective dose-effect relationship between its concentration in alcohol and the cardioprotective effects of alcohol use. Nevertheless,further research on the metabolic pathways of bioactive compounds after alcohol use is required based on the summary and critique of discovered functional factors in alcohol.

5.1 In wine

Winemaking can be traced back to ancient Iran and has thrived for thousands of years [75]. It is produced from grape juice through fermentation and composed of water, ethanol, carbohydrates, organic acids, minerals, polyphenols, and aromatics [76]. When human has little knowledge about the composition of wine, this food was used as a substitute for water to deal with sanitation problems in medieval Europe. Although pure ethanol ingestion at a low amount is negatively linked to certain cardiovascular risk factors, a blood alcohol content(BAC) of at least 0.2 g/dL is usually required [77]. By contrast, red wine requires a much lower BAC to achieve the same effect due to its non-alcoholic content, mainly polyphenolic compounds [77].

Grapes and wines constitute a critical food source of polyphenolic antioxidants, especially in Western diets [78]. Phenolic compounds in wine are critical cardioprotective factors fighting against oxidative stress and inflammation in blood vessels. In general, the concentration of non-flavonoid phenolic components in red wine ranges 60–566 mg/L [79]. A representative compound is resveratrol(3,4,5-trihydroxystilbene) (RSV) (Fig. 3), a well-studied polyphenolic compound naturally present in grapes (fruit, skin, seeds) [80], and Tempranillo is a RSV-rich grape variety for wine making [81]. The metabolism of RSV in human body is a rather complex process.Briefly, RSV quickly gets sulfatized and glucuronidated after entering enterocytes [82]. Moving through the GI tract, the conjugated forms are then metabolized by the gut microbiota into polar metabolites(dihydroresveratrol, lunularin, and 3,4’-dihydroxy-trans-stilbene),and reach the liver, kidney, and other peripheral tissues afterwards for further metabolization [82]. As for now, numerous targets of RSV relating to endothelial functions have been discovered, such as AMPactivated protein kinase (AMPK), nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB), eNOS, etc. [83].

Fig. 3 Molecular structure of resveratrol (A) and Tempranillo grapes for wine making (B).

RSV has multiple cardioprotective effects such as vasorelaxation,anti-inflammation, anti-oxidation, anti-atherosclerosis, and improving the lipid profile. Clinical trials have shown that RSV effectively improves cardiovascular functions among high-risk populations.Magyar et al. conducted a double-blind, randomized controlled trial to evaluate the cardioprotective effects of RSV in patients after having a heart attack [84]. After a 3-month follow-up period, the experimental group receiving RSV capsules (10 mg/day) every day showed improved endothelial function manifested by a significant decrease in serum LDL level (P< 0.05) and increase in FMD of the brachial artery (P< 0.05) [84]. Fujitaka et al. performed another randomized controlled trial to study how high dose (100 mg/day)modified RSV (Longevinex) impacts patients with metabolic syndrome in terms of their metabolic profile, inflammatory response,and endothelial function in patients with metabolic syndrome [85].Patients receiving Longevinex administration showed a significant increase in FMD level after three weeks [85], thereby suggesting the anti-atherosclerosis property of modified RSV, especially among the population at risk of CVDs.

RSV possesses strong anti-oxidative and anti-inflammatory properties. Romain et al. evaluated the cardioprotective effect of grapevine-shoot phenolic extract (Vineatrol 30) that contains a considerable amount of RSV (15.2%) and its oligomers using Syrian hamsters [86]. The study found that Vineatrol 30 was capable of preventing aortic fatty streak deposition (67%) and decreasing liver superoxide radicals (36%), liver tumor necrosis factor-alpha (TNF-α)(18%), and interleukin 6 (IL-6) (15%) in the high-fat diet group [86].TNF-α and IL-6 are proinflammatory cytokines associated with coronary artery disease. A study by Csiszar et al. showed similar results. In human coronary arterial endothelial cells (HCAECs),RSV at a diet relevant concentration inhibits TNF-α-induced NF-κB activation (> 50% inhibition at 6–10 mol/L), which plays a crucial role in cellular inflammation [87]. Also, RSV promotes glutathione synthesis, an antioxidant reduced by endothelial oxidative stress,along with other antioxidant enzymes [88].

Indeed, the amount of RSV in wine has been doubted to be sufficient enough to exert positive health effects considering its poor bioavailability in human body [89]. The daily dosage of RSV is about 1 gram to effectively improve health conditions [90]. However,considering the RSV concentrations in different types of wine (red:0.361–1.972 mg/L [91]; white: 0–1.089 mg/L [92]; rosé: 0.29 mg/L [93]),moderate wine drinking can hardly meet the estimated RDA of RSV. Therefore, authors suspect that RSV itself cannot fully explain the French paradox, but potentially contributes to an additive or synergistic effect with other bioactive compounds in wine. All in all, it requires further clinical trials to verify the function RSV plays in wine drinking. Besides RSV, there are other bioactive phenolic compounds(flavonoids and nonflavonoids) in wine responsible for protecting the cardiovascular system. Flavonoids (quercetins, catechins, tannins, etc.)account for over 85% of the total phenolic content in red wine [94],with a concentration varying from 150 mg/L to 650 mg/L [79].

Quercetin is a flavonoid present in wine and has the potential to protect against CVDs. The concentration of quercetin ranges from < 1.2 mg/L to 19.4 mg/L in red wines and 2.2 mg/L to 24.3 mg/L in red berry wines [95], while its RDA is 250–400 mg [96].Quercetin naturally presents in the form of glycosides or aglycones.Similar to RSV, enterobacteria and gut microbiota-derived enzymes convert quercetin into more easily absorbable molecules such as 3,4-dihydroxyphenylacetic acid, 3-(3-hydroxyphenyl)propionic acid, and 3,4-dihydroxybenzoic acid in the GI tract [97]. Quercetin metabolites are then transported to peripheral tissues via hepatic portal circulation [97]. This flavonoid family has shown anti-inflammatory,anti-atherosclerotic, anti-hypertensive, and vasodilatory activities through the mediation of interleukin-1 beta (1L-1β), TNF, mitogenactivated protein kinase (MAPK), phosphatidylinositol-3 kinase (PI3K)/AKT pathways and other intracellular targets [98,99]. Egert et al.conducted a double-blinded, randomized controlled trial with overweight or obese subjects (n= 93) to evaluate the effects of quercetin treatment on a series of CVD markers (blood pressure, lipid profile, oxidative stress, inflammation, and body composition) [100].The results showed that quercetin intake (150 mg/day) for six weeks decreased systolic blood pressure by 2.6 mmHg (P< 0.01) and significantly reduced serum HDL-C level (P< 0.001), and plasma oxidized LDL concentration (P< 0.001) in contrast to the placebo group [100].

Tannins from grape skin and seeds are another critical phenolic compound in red wine that contributes to its bitterness and astringency. Tannins content is about 544 mg/L catechin equivalents(CE) in wines with large variety difference (highest: Cabernet Sauvignon (672 mg/L CE); lowest: Pinot noir (348 mg/L CE)) [101].Hydrolyzable tannins are enzymatically digested in the stomach or small intestine into the corresponding monomers, such as ellagic acid and gallic acid [102]. As for condensed tannins, flavan-3-ols monomers, such as epicatechin and catechin, and their microbial metabolites are absorbed intact in the small intestine and undergo various conjugations before transporting to other organs, while the non-absorbed oligomers serve as substrates for colonic microbiota after passing through the upper GI tract [102]. Tannins also possess several health benefits, including antioxidant and anti-inflammatory properties [103]. Condensed tannins, or proanthocyanidins, are found to promote vasodilation by increasing endothelial NO release and c-GMP levels via NO/cGMP signaling pathway [104].

Anthocyanins, a subgroup of flavonoids naturally found in vegetables and fruits as pigments that give a red, purple, or blue color,are also detected in red wine. The typical anthocyanins content in red wine is around 500 mg/L, while the amount is above 2 000 mg/L in certain wine varieties [105]. Anthocyanins get absorbed in both the stomach and intestines, are then subject to first-pass metabolism involving conjugation reactions before entering the systemic circulation. Anthocyanins are widely recognized antioxidants that help inhibit endothelial inflammation by scavenging free radicals and reducing oxidative stress [106]. In addition, studies have shown that anthocyanins and their metabolites protect against inflammation,arteriosclerosis, and hypercholesterolemia through PI3K/AKT,MAPK, IL-1β suppression, etc. [98,107].

5.2 In beer

Beer is produced from the fermentation of malted cereals and grains, consisting of over 90% water and various nutrients, including carbohydrates, amino acids, and trace amounts of minerals and vitamins [108]. As one of the oldest beverages in human history, beer brewing was first recorded by ancient Egyptians at least 5 000 BC [75].

The polyphenols in beer originate from hops (Humulus lupulusL.)(～30%) and malt (～70%–80%) [109], where hop is one of the raw materials of beer to add aroma and flavor, and is particularly important for haze formation. It provides various phenolic compounds in beer, such as catechin, epicatechin, and proanthocyanidins [109].A recent study identified 57 phenolic compounds in craft beer,while 12 of them had never been detected [110]. Among all the polyphenolic compounds in beer, catechin, epicatechin, quercetin,proanthocyanidin, xanthohumol, and their derivatives are the most abundant types [110]. Different beer types may benefit the cardiovascular system to varying degrees. For example, brown ale seems to have higher antioxidant functions than lager beers due to its higher total phenolic compounds and flavonoid content [111].

Xanthohumol (XN) is a prenylated chalcone naturally only found in beer and hops [112] (Fig. 4). Since hop is the only known dietary source of XN, this rare health-promoting compound can only be obtained by beer drinking. XN and its two major active metabolites,isoxanthohumol (IX) and 8-prenylnaringenin (8-PN), are expected to gain more attention as anti-cancer [113], anti-atherosclerotic [114],and anti-obesity agents [115]. IX and 8-PG are often used in dietary intervention trials to assess the adherence condition of a given diet as urine markers of beer consumption [116,117]. 8-PN is converted from XN via hepatic and gut microbial enzymes, while IX is non-enzymatically converted from XN [118]. Unfortunately, the metabolism of XN and its metabolites after oral administration has not been thoroughly investigated as other common phytochemicals due to the lack of clinical expiations. The concentrations of XN,IX, and 8-PN in beer are 1.77–3.83 mg/L, 0.85–1.19 mg/L, and 0–19.8 μg/L, respectively [119,120].

Fig. 4 Molecular structure of xanthohumol (A) and hops (Humulus lupulus L.) (B).

Hirata et al. performed an animal feeding trial with cholesteryl ester transfer protein transgenic (CETP-Tg) mice model to assess the anti-atherosclerotic property of XN [121]. CETP, also known as plasma lipid transfer protein, catalyzes the transfer of cholesteryl esters from HDL to LDL and very low-density lipoprotein (VLDL),thus its elevation is linked to the development of atherosclerosis.In the study, XN administration (0.05% (m/m) for 18 weeks) in CETP-Tg mice significantly decreased aortic cholesterol accumulation and CETP activity and increased HDL-C level compared to the control group [121]. Therefore, XN seems to protect against atherosclerosis by improving lipid profile via CETP inhibition. In 2017, the same group verified the anti-atherosclerotic effect of XN using a hamster model. The study results showed that XN enhanced the mRNA expression ofcyp7a1andabcg8, as well as inhibited LDL-C oxidation and triglyceride synthesis [122].

Other plausible mechanisms of XN’s anti-atherosclerotic effect have also been discovered. Since vascular calcification (VC) is a major predictor of the initiation of atherosclerosis, Liou et al.established a vitamin D3plus nicotine induced-VC model with SD rats to study the bioactivity of XN [114]. In the study, XN-treated animals presented a significantly lower degree of vascular calcification largely due to its amelioration of oxidative stress via Nrf2/Keap1/HO-1 pathway and downregulation of bone-related factors [114]. Another animal study using apolipoprotein-E-deficient (ApoE-/-) mice also proved the atheroprotective effects of XN, primarily by decreasing pro-inflammatory factors (monocyte chemoattractant protein 1, MCP1)and improving hepatic lipid metabolism via AMPK activation [123].AMPK signaling pathway is also involved in the anti-obesity effect of XN. XN induces the browning of white adipose tissue to increase energy expenditure through thermogenesis, decreases adipogenesis (fat cell generation), and increases lipolysis partly mediated by AMPK signaling pathway [115].

5.3 In Chinese Baijiu

Chinese Baijiu, or Chinese liquor, is a traditional Chinese alcoholic beverage with a history of more than 2 000 years dating from the Western Han dynasty (202BC-8AD) [124]. It is well recognized as China’s national liquor and one of the most famous distilled liquor globally, together with brandy, gin, rum, vodka, and whiskey. “Chinese Baijiu” has recently been officially adopted in the 2021 Import and Export Tariff Code Baijiu by China Customs since it is becoming more embraced by English users over the world [125].Baijiu is typically obtained from the distillation of grains(sorghum, rice, wheat, corn, millet, peas, highland barley, etc.)after simultaneous saccharification and fermentation in solid or semi-solid states with different kinds of starter culture (Daqu, Xiaoqu,and Fuqu). Before blending and bottling for sale, Baijiu needs to undergo several years of aging to enhance the complexity of flavor.The unique manufacturing process of Chinese Baijiu endows it with distinctive aroma and bioactive molecules profile.

Since ancient times, Baijiu was used as an efficacy-enhancing ingredient in traditional Chinese medicine [126].Hanshu·Shihuozhi(Book of Han-Treatise on Food and Money), a Chinese history classic, recorded that “alcohol is the best of hundreds of medicines.”In addition to traditional drinking habits and old-time Chinese medicine classics, numerous scientific studies also support the health effects of moderate Baijiu intake, including but not limited to fighting against atherosclerosis [63], improving insulin sensitivity [127], antifatigue [128], and immunoprotective effects [129].

Water and ethanol account for approximately 98% of Baijiu,while thousands of trace components made up the rest 2%. Chinese Baijiu is far beyond a mixture of pure ethanol and water. As for 2019,2020 compounds have been detected in Baijiu, of which there are 138 health-promoting compounds, including volatile compounds like phenols,organic acids, esters, lactones, pyrazines, sulfur compounds, terpenes,furans, aldehydes, as well as non-volatile compounds such as amino acids, polyols, minerals, vitamins, and bioactive peptides [42] (Fig. 5).Volatile compounds in Baijiu are reported to protect against ethanolinduced liver damage by ameliorating gut microbiota and increasing functional intestinal fatty acid concentration [130]. On the other hand, non-volatiles like bioactive peptides have shown significant antioxidant functions in cell models [131].

Fig. 5 Health-promoting factors in Chinese Baijiu and their functions.

Phenolic compounds play critical roles in the color, taste, and aroma formation while carrying antioxidant properties in all Chinese Baijiu types. Shi et al. found that all five flavor types of Baijiu tested(strong-flavor, light-flavor, sauce-flavor, sesame-flavor, and laobaiganflavor) demonstrated free radical scavenging ability to a certain extent likely due to phenolic compounds in Baijiu. Salutary phenols identified in Baijiu include ferulic acid, gallic acid, 4-methylguaiacol,4-ethylguaiacol, catechins, etc. [132]. Ferulic acid is a natural antioxidant with antithrombotic, anti-inflammatory and analgesic effects, and has been used clinically to treat CHD, strokes, leukopenia,and thrombocytopenia disease [133]. The antioxidant effects of phenolic compounds in Baijiu, specifically 4-methylguaiacol (4-MG),4-ethylguaiacol (4-EG), and vanillin (VA), have been evaluated using multiplein vitromodels. The concentrations of 4-MG, 4-EG,and VA in Guojinggong Baijiu (a brand of strong-flavor Baijiu) are 126–1 580, 129–1 708, and 375–3 196 μg/L, respectively [134].The content of phenolics varies immensely in different flavor types and brands due to the unique manufacturing process of each type [135].It is confirmed that these phenolic compounds can alleviate or reverse AAPH-induced intracellular oxidative stress in a dose-dependent manner by enhancing the expression of antioxidant enzymes via the activation of Keap1-Nrf2 signal pathways [134,136].

Baijiu, when consumed in moderation, also improves inflammatory resistance owning to its non-alcoholic components. As introduced before, chronic inflammation of the vascular endothelium is strongly associated with atherosclerosis development, leading to various CVD conditions. 4-EG is a natural anti-inflammatory agent capable of reversing lipopolysaccharide (LPS)-induced inflammation in cell model [137]. LPS is an endotoxin that stimulates immune responses to produce pro-inflammatory mediators and cytokine, thus widely used to evaluate the efficacy of anti-inflammatory agents.What’s more, Baijiu extracts (predominantly esters, polyols, acids,aromatic compounds, furans, aldehydes, and pyrazines) have been reported to protect against LPS-induced inflammationin vitro. In the study of Liu et al., Baijiu extract was shown to significantly suppress LPS-induced NO and TNF-α secretion as well as reactive oxygen species (ROS) production in mononuclear macrophages by inhibiting the activation of MAPK and PI3K)/AKT pathways, two signaling pathways involved in anti-inflammatory activities in the body [138].

Besides phenolic compounds, another representative bioactive group found in Baijiu is pyrazines. Pyrazines are important flavor compounds in Chinese Baijiu. Wu and Xu detected nine pyrazines of which the total amount ranges from 310.35 μg/kg to 3 456.44 μg/kg using head space solid phase microextraction (HSSMPE) coupled with gas chromatography with nitrogen-phosphorus detection(GC-NPD) in strong-flavor, light-flavor, sauce-flavor,sesame-flavor, and laobaigan-flavor Baijiu [139].In vitrostudies revealed that 2-methylpyrazine and 2,3,5,6-tetramethylpyrazine are capable of decomposing triglycerides, thus may have certain benefits to lowering blood lipids and preventing thrombosis [140,141].Indeed, tetramethylpyrazine has been found to effectively protect against cardiovascular and cerebrovascular diseases [142,143].Tetramethylpyrazine is the main active ingredient of Chuanxiong(Ligusticum chuanxiongHort) (Fig. 6), which is a widely used Chinese herbal medicine to treat atherosclerosis and hypertension.Chuanxiong also contains ferulic acid, a phenolic compound mentioned above. Same bioactive compounds appearing in both Baijiu and traditional Chinese medicine may explain why this alcoholic beverage was used as a medicine enhancer in ancient times.

Since the raw ingredients of Baijiu (mainly grains) contain various proteins, Baijiu is expected to have polypeptide and amino acids with low boiling points left after microbial hydrolysis in fermentation.Accordingly, Wu and her coworkers discovered a bioactive tripeptide,Pro-His-Pro (PHP), in sesame-flavor Baijiu [144,145]. Unfortunately,the concentration is too low to be quantifiable. PHP was found to carry anin vivoangiotensin-converting enzyme (ACE) inhibiting property and protecting against APPH-induced oxidative stress in HepG2 cells via Nrf2 signaling [144], where ACE inhibitors are a class of medications commonly used to lower blood pressure. In addition, the same group identified another tetrapeptide, Ala-Lys-Arg-Ala (AKRA) in sesame-flavor Baijiu with a concentration of 8.497 μg/L [146]. AKRA also possesses an antioxidant effect in AAPH-induced oxidative stress model by suppressing ROS generation and inhibiting the formation of pro-inflammatory factors like malondialdehyde (MDA) [146]. Actually, more bioactive peptides are constantly discovered from Baijiu by-products during fermentation such as Jiuzao (residues after distillation) and Jiupei(fermented grains) [147,148]. Low bioavailability is a common challenge for food-derived bioactive peptides, and various carrier materials are developed to deliver peptides to target tissues to solve this problem [149]. Unfortunately,in vivoresearch on the afteringestion metabolization of peptide from Baijiu is currently lacking,so whether the peptides could remain intact from stomach acidity and resist digestive enzymes is still a question. More clinical trials are needed to confirm the contribution of bioactive peptides to Baijiu’s anti-atherosclerotic effects, and to find suitable delivery systems to boost bioavailability of Baijiu peptides in the future.

Fig. 6 Molecular structure of 2,3,5,6-tetramethylpyrazine (A) and Chuanxiong (Ligusticum chuanxiong Hort) (B).

6. Conclusion and outlook

In this review, findings from previous research on the cardioprotective effects of consuming different alcoholic drinks (wine,beer, and Chinese Baijiu) in moderation are summarized. What’s more, the existing limitations and controversies of current studies are discussed. Excessive alcohol use undoubtedly leads to serious adverse public health issues. Nevertheless, authors hold a neutral attitude towards alcohol drinking considering that “dose makes the poison.”As mentioned before, moderate alcohol consumption benefits not only heart and blood vessels but also other diseases such as T2DM [150],metabolic syndrome [12], and certain cancers [151]. Besides,previous studies have found a J-shaped relationship between alcohol drinking and all-cause mortality rate [152]. The health benefits of light-moderate alcohol use should not be intentionally neglected while publicizing the harmful impact of heavy drinking. Instead, pros and cons of alcohol drinking should be weighed carefully as more scientific evidence appears from both sides. To more discreetly state the health influence of alcohol drinking, well-designed clinical studies with sufficient sample size, follow-up period, and generalizability are of vital importance.

In accordance with the concept of “seeking from inside and adding from outside, reinforcing through natural fermentation [118],” the key step to improve the health value of Chinese Baijiu, as well as other alcoholic drinks, is to clarify the metabolic pathways of the functional factors both during the fermentation and post-digestion process. As more functional compounds and their forming mechanisms are fully explored, the content of health-promoting factors in alcohol could be enriched by adjusting the production process such as raw ingredient usage and fermentation techniques. To be noticed, the research of distilled spirits and health is still in infancy compared with other alcohol types. Chinese Baijiu has immense research value considering its rising global market size and exclusive bioactive molecules profile.In the future, the research of health impact of moderate drinking could emphasize on exploring health-promoting compounds in different alcoholic beverages, especially those that lack sufficient research, and the potential synergic effect they may exert on human body.Declaration of competing interest

The authors report that there is no conflict of interest.Acknowledgments

This work was supported by the National Natural Science Foundation of P.R. China (No.31972193) and the Science and Technology Program of Tibet Autonomous Region, China(XZ202001ZY0017N).