Critique 266: Reduced stress-related neural network activity mediates the effect of alcohol on cardiovascular risk

Authors Mezue K; Osborne MT; Abohashem S; Zureigat H; Gharios C; Grewal SS; Radfar A; Cardeiro A; Abbasi T; Choi KW; Fayad ZA; Smoller JW; Rosovsky R; Shin L; Pitman R; Tawakol A

Citation Journal of the American College of Cardiology, 81(24):2315-2325; 2023.

Author’s Abstract

Background: Chronic stress associates with major adverse cardiovascular events (MACE) via increased stress-related neural network activity (SNA). Light/moderate alcohol consumption (ACl/m) has been linked to lower MACE risk, but the mechanisms are unclear.

Objectives: The purpose of this study was to evaluate whether the association between ACl/m and MACE is mediated by decreased SNA.

Methods: Individuals enrolled in the Mass General Brigham Biobank who completed a health behaviour survey were studied. A subset underwent 18F-fluorodeoxyglucose positron emission tomography, enabling assessment of SNA. Alcohol consumption was classified as none/minimal, light/moderate, or high (< 1, 1-14, or >14 drinks/week, respectively).

Results: Of 53,064 participants (median age 60 years, 60% women), 23,920 had no/minimal alcohol consumption and 27,053 ACl/m. Over a median follow-up of 3.4 years, 1,914 experienced MACE. ACl/m (vs none/minimal) associated with lower MACE risk (HR: 0.786; 95% CI: 0.717-0.862; P < 0.0001) after adjusting for cardiovascular risk factors. In 713 participants with brain imaging, ACl/m (vs none/minimal) associated with decreased SNA (standardized beta -0.192; 95% CI: -0.338 to -0.046; P = 0.01). Lower SNA partially mediated the beneficial effect of ACl/m on MACE (log OR: -0.040; 95% CI: -0.097 to -0.003; P < 0.05). Further, ACl/m associated with larger decreases in MACE risk among individuals with (vs without) prior anxiety (HR: 0.60 [95% CI: 0.50-0.72] vs 0.78 [95% CI: 0.73-0.80]; P interaction = 0.003).

Conclusions: ACl/m associates with reduced MACE risk, in part, by lowering activity of a stress-related brain network known for its association with cardiovascular disease. Given alcohol’s potential health detriments, new interventions with similar effects on SNA are needed.

Forum Summary

The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioural and physiological responses to the stressor. A new study aimed to investigate the whether the association between light to moderate consumption (1-2 standard drinks/day) and lower risk of cardiovascular events such as heart attacks and strokes. The study suggested that while heavier alcohol consumption acts on the amygdala to increase stress related neural activity that increases blood pressure and heart rate, light to moderate alcohol consumption effectively decreases stress related neural activity and hence the risk of major cardiovascular events.

In addition, and importantly, this study points to alcohol-mediated effects on the brain, which may not only be relevant for risk of major cardiovascular disease events but also for various neurological disorders currently occurring in increasingly higher incidence such as dementia and Parkinson’s disease. Despite the usual limitations of self-reported intake at enrolment, which did not distinguish between beverage type or customary drinking pattern but with statistical adjustments for age, sex, and CVD risk factors, the study substantiates a > 20% decrease in major adverse cardiovascular events (MACE) in light/ moderate drinkers compared to those who drank no/minimal alcohol Notably, the investigators’ sensitivity analyses on the nondrinking subset defangs the usual ‘sick quitter’ arguments.

Forum comments

Background including previous results

The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioural and physiological responses to the stressor. The adult as well as developing brain possesses a remarkable ability to show structural and functional plasticity in response to stressful and other experiences. Stress can however, cause an imbalance of neural circuitry. This imbalance, in turn, affects systemic physiology via neuroendocrine, autonomic, immune and metabolic mediators (McEwen 2017).

Cardiovascular diseases (CVDs) have collectively remained the leading causes of death worldwide and substantially contribute to loss of health and excess health system costs (Vaduganathan et al. 2022). The Global Burden of Disease study suggests that the following are the leading environmental, metabolic, and behavioural risks for CVDs: ambient particulate matter air pollution, household air pollution from solid fuels, lead exposure, low or high temperature, high systolic blood pressure, high low-density lipoprotein cholesterol (LDL-C), high body mass index (BMI), high fasting plasma glucose, kidney dysfunction, dietary risks, tobacco smoking, second-hand tobacco smoke, harmful alcohol consumption, and low physical activity.

Chronic stress, both at the individual and environmental level, is also known to be associated with CVD risk (Pedersen et al. 2017). Specifically, chronic psychological stress has been associated with higher risk of obesity (Scott et al. 2012), hypertension (Rod et al. 2009), diabetes (Falco et al. 2015, Novak et al. 2013), and poor CVD outcomes, including myocardial infarction (Alcantara et al. 2015, Rosengren et al. 2004, Bot et al. 2017), and stroke (Booth at al. 2015). Perceived adverse neighbourhood environment conditions as a type of chronic psychosocial stress has also been associated with obesity (Scott et al. 2012, Powell-Wiley et al. 2012) and other CVD risk factors (Diez Roux et al. 2016).

Since chronic psychosocial stress is associated with many metabolic and behavioural risk factors such as obesity and hypertension, chronic psychosocial stress may either have a direct or an indirect effect on CVD risk. So far, experimental studies have provided evidence that moderate alcohol consumption will have direct metabolic effects, which may beneficially contribute to a reduced risk for CVD. These metabolic changes include an increased HDL cholesterol levels with increase cholesterol efflux activities (Beulens et al. 2004), improved glucose homeostasis resulting in decreased HbA1c levels (Schrieks et al. 2015), reduced levels of fibrinogen (Sierksma et al. 2002)resulting in a decreased clotting tendency of the circulation and increased antioxidant and reduced inflammatory activities (Arranz et al. 2012). These metabolic changes may well explain a considerable part of the mechanistic basis for CVD protection provided by moderate alcohol consumption (Mukamal et al. 2005).

Chronic psychosocial stress may also contribute to CVD risk in a direct way. Some limited experimental research may suggest that stress hormones may be beneficially affected by a moderate dose of alcohol with dinner after a mental stress test (Schrieks et al. 2016). Similarly, unpleasant ambiance-induced mood may be improved by moderate alcohol consumption through autonomic nervous system activity (Schrieks et al. 2014).

Efforts to identify additional direct mechanisms by which chronic psychosocial stress may increase CVD risk have recently focused on identifying parts of the brain that may be activated by chronic stress (Miller et al. 2011).  The amygdala has been shown to be an important part of the neural network that responds to threatening situations and its activity appears to be heightened in the setting of social stressors related to peer evaluation with associated increases in pro-inflammatory cytokines (Muscatell et al. 2015). Recent work has also demonstrated that resting amygdalar activity is associated with worsening aortic vascular inflammation and greater risk for subsequent CVD events (Tawakol et al. 2007). Powell-Wiley et al. (2021) has subsequently shown that amygdalar activity or chronic stress-related neural activity, associates with subclinical CVD risk in a community-based cohort.

Chronic stress-related neural activity may in part be mediated by various brain systems. Apart from the amygdala, the brain cerebrospinal fluid system was also suggested to play an important role in moderate alcohol induced improvement of the brain and brain functioning. Experimental rat studies showed that acute low dosages of alcohol increased the diffusive movement of waste metabolites via an increased arterial endothelial-smooth muscle cell dilative reactivity without affecting blood brain barrier integrity. Prolonged induction of this system under chronic high alcohol exposure conditions, however, caused oxidative damage of the arterial endothelial-smooth muscle layers resulting in cerebral amyloid-like angiopathy leading to dysfunction of the blood brain barrier and impaired waste metabolites movement (Cheng et al. 2019).

The current epidemiological study was undertaken to assess whether there is a relationship between chronic stress-related neural activity and major adverse cardiovascular events (MACE) and moreover to assess whether this association was partially mediated by an alcohol-induced decrease in stress-related neural network activity.

Comments on current methodology

The main group of patients consisted of over 50,000 individuals of the Mass General Brigham (MGS) Biobank recruiting people of about 60 years of age through hospitals. Alcohol consumption was assessed by questionnaire distinguishing between none/minimal (<1 drink/week), light/moderate (1-14 drinks/week) and high (>14 drinks/week) alcohol consumption during the previous year. Analysis within this main group showed a reduced relative risk for major adverse cardiovascular events (MACE) being associated with light to moderate alcohol consumption and as compared to the none/minimal drinking group. This beneficial association was not significantly different for the various MACE outcomes; a roughly 25% risk reduction was observed for coronary MACE, acute coronary syndrome MACE, heart failure, peripheral vascular disease and stroke. Summarily, the authors mention that all cancer risk was increased in light/moderate alcohol consumers. Heavier alcohol consumers were excluded from this specific analysis since the group was very small and the group was irrelevant in terms of hypothesis testing.

Interestingly though, the authors investigated whether potential abstainer bias may have played a role in the analysis. Using a sensitivity analysis excluding non-drinkers yielded similar results both when comparing light/moderate alcohol consumption versus minimal alcohol consumption excluding abstainers as well as comparing light alcohol consumption versus none/minimal alcohol consumption.

The second part of the study consisted of a subpopulation of 754 participants that underwent PET/CT analysis (an imaging test that shows the metabolic or biochemical function of your brain) for cancer surveillance or diagnosis excluding those with brain tumours. Subject characteristics have been shown for the total MGS population, but unfortunately not for the specific subgroup of patients that were evaluated for their stress-related neural network activity (SNA), specifically unfortunate since subject characteristics were already different between the none/minimal drinking group and the light/moderate drinking group in the first overall analysis. Also, the first analysis of the larger group used a slightly different set of covariables than those applied for the alcohol stress-associated neural network activity analysis.

The subpopulation showed a U-shaped association between alcohol consumption and SNA, whereby SNA is the ratio of the amygdalar activity per ventromedial prefrontal cortex activity. The ratio change was caused by a changed amygdala activity rather than an overall change in brain activity (represented by the ventromedial prefrontal cortex activity). Metabolic brain activity tended to be reduced in high alcohol consumers though.

Interestingly, persons with a prior history of anxiety (greater chronic stress), a higher ANS and increased risk of MACE, showed a greater relative decrease in incident MACE associated with light/moderate alcohol consumption.

This study suggests that the benefit of light/moderate alcohol consumption on CVD risk may be partly related to its ability to attenuate stress-related neural network activity. However, we should be aware that this associative relation would have to meet several conditions such as temporal relationships, strength and dose-dependency of the association, consistency, specificity and biological plausibility as pointed out in the accompanying editorial (de Gaetano et al. 2023). Biological plausibility may be further substantiated in more experimental settings showing cause and effect relationship.

Alternatively, and importantly, this study points to alcohol-mediated effects on the brain, which may not only be relevant for MACE. Various neurological disorders currently occurring in increasingly higher incidences may be associated with moderate alcohol consumption possibly through the mechanism investigated in this study. These neurological disorders include amongst others dementia (Ruitenberg et al. 2002,  Zhong et al. 2022) and possibly Parkinson’s disease (Jiménez-Jiménez et al. 2019).

Specific comments from Forum members

Forum Member Ellison commented that “as someone working with alcohol and health for many decades, I have often been asked: “I know you have said that moderate wine consumption may lower the risk of heart disease, but how much of this is just due to relaxation and the lowering of stress that may result from a glass or two of wine with dinner?”  My answer was always: “We know that much of the reduction in risk of heart disease is due to specific effects of alcohol and polyphenols, but we just don’t know about stress.”  Now, with this paper by Mezue et al. (2023), we have some proof that alcohol modifies a number of brain functions related to stress. 

As described by other Forum members, sustained stress effects on brain function have been shown to be risk factors for obesity, hypertension, and diabetes, all of which increase the risk of cardiovascular disease.  Thus, part of the adverse effects of these factors may ultimately be related to stress.  In addition, in regard to possible mechanisms, the authors describe a number of interconnected neural networks that are adversely affected by stress, and show that they may have direct effects on the risk of cardiovascular disease.  Moderate drinking appears to decrease such adverse effects.

As stated well in the Editorial Comment in the journal stimulated by this paper, “The discovery of a new possible mechanism of action suggests that moderate alcohol consumption can improve cardiovascular health by lowering the activity of a brain network associated with cardiovascular disease: a stimulating link among alcohol, brain, and the heart that deserves closer attention in future investigations” (de Gaetano 2023).

Forum Member Parente adds that “this important study offers a putative mechanism for the link between low and moderate alcohol consumption and decreased cardiovascular disease (CVD) risk. Despite the usual limitations of self-reported intake at enrolment, which did not distinguish between beverage type or customary drinking pattern but with statistical adjustments for age, sex, and CVD risk factors, the study substantiates a > 20% decrease in major adverse cardiovascular events (MACE) in light/ moderate drinkers compared to those who drank no/minimal alcohol (HR: 0.786; 95% CI: 0.717-0.862; P < 0.0001). Notably, the investigators’ sensitivity analyses on the nondrinking subset defangs the usual ‘sick quitter’ arguments.

Apart from cardiovascular effects conferred by modest drinking, the authors’ mechanistic findings regarding the neural network in this study further support wider adoption of methods that promote the relaxation response in people with hypertension and cardiovascular disease. A decade has passed since an American Heart Association study group’s tepid IIb classification of recommendation (COR) of transcendental meditation (TM) as a nonpharmacologic method of lowering blood pressure (Brook et al. 2013) – despite an effect size equivalent to that of aerobic exercise and other AHA-recommended methods, which might have warranted a IIa designation (Schneider 2013). Support for nonpharmacologic anxiolytic methods was given another boost in 2017 in an AHA scientific statement by Levine et al., entitled “Meditation and Cardiovascular Risk Reduction”, awareness of which has escaped at-risk populations, and perhaps their physicians. With the current study by Mezue et al., we now gain important insights into the effects of modest alcohol consumption on the downregulation of neural networks and neural-leukopoietic-arterial axes to lower CVD risk.

Forum Member Skovenborg recounts that “the Swedish neuroscientist and pioneer of cerebral blood flow studies in man, Professor David H. Ingvar, M.D., Ph.D., (1985) wrote a paper on “memory of the future”. Evidence is summarized that the frontal/prefrontal cortex handles the temporal organization of behaviour and cognition, and that the same structures house the action programs or plans for future behaviour and cognition. As these programs can be retained and recalled, they might be termed “memories of the future”. It is suggested that they form the basis for anticipation and expectation as well as for the short and long-term planning of a goal-directed behavioural and cognitive repertoire. This repertoire for future use is based upon experiences of past events and the awareness of a Now-situation, and it is continuously rehearsed and optimized. Professor Ingvar (1998) is also co-author of a study of the effect of moderate doses of alcohol on the brain. He suggested that a small dose of alcohol (one to two drinks) had the effect of associating problems of the past with a reduced sense of guilt. At the same time the small dose of alcohol renders the anticipation and expectations regarding the future more optimistic and less influenced by anxiety. A combination of these effects would have a stress-reducing and mood lifting effect.”

Forum Member Mattivi considers that “this is a very interesting article for the results highlighted, which requires, in my view, further work to investigate the putative mechanisms. It might be useful to specifically study the levels of brain chemical compounds that act as neurotransmitters at chemical synapses, such as serotonin, dopamine and GABA, whose pathways (and receptors) are affected by ethanol exposure, as demonstrated by conclusive animal experiments as reviewed by McBride and Li (1998). Also in humans, as the neuroscientists team of University of Heidelberg have reviewed (Vengeliene et al. 2008), virtually all brain neurotransmission seems to be affected by alcohol consumption, which suggests in my view that further molecular pharmacology studies could be important also to better investigate and understand the mechanisms of anti-stress effects.”

Forum Summary

The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as the behavioural and physiological responses to the stressor. A new study aimed to investigate the whether the association between light to moderate consumption (1-2 standard drinks/day) and lower risk of cardiovascular events such as heart attacks and strokes. The study suggested that while heavier alcohol consumption acts on the amygdala to increase stress related neural activity that increases blood pressure and heart rate, light to moderate alcohol consumption effectively decreases stress related neural activity and hence the risk of major cardiovascular events.

In addition, and importantly, this study points to alcohol-mediated effects on the brain, which may not only be relevant for risk of major cardiovascular disease events but also for various neurological disorders currently occurring in increasingly higher incidence such as dementia and Parkinson’s disease. Despite the usual limitations of self-reported intake at enrolment, which did not distinguish between beverage type or customary drinking pattern but with statistical adjustments for age, sex, and CVD risk factors, the study substantiates a > 20% decrease in major adverse cardiovascular events (MACE) in light/ moderate drinkers compared to those who drank no/minimal alcohol Notably, the investigators’ sensitivity analyses on the nondrinking subset defangs the usual ‘sick quitter’ arguments.

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Forum members contributing to this critique

Henk Hendriks, PhD, Netherlands

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

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

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

Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy

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

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

Fulvio Mattivi, MSc, Head of the Department Food Quality and Nutrition, Research and Innovation Centre, Fondazione Edmund Mach, in San Michele all’Adige, Italy

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