The only way to keep your health is to eat what you don't want, drink what you don't like, and do what you'd rather not

Mark Twain

The complex conundrum between diet and cardiovascular disease has been the focus on innumerable research projects.1 Indeed, substantial epidemiologic evidence supports the beneficial impact of nutrition-related factors and micronutrients in particular on cardiovascular morbidity and mortality.2 However, we cannot buy at face value, the concept that apparently healthy diet including ample amounts of micronutrients is wholly beneficial. Instead, it is appropriate to disentangle this veritable conundrum focusing on specific nutrition-related factors and micronutrients, on 1 hand, specific cardiovascular conditions, on the other, and exploiting appropriate research study designs.

In fact, focusing on the impact of micronutrients on the risk of atrial fibrillation (AF), a burdensome cardiovascular condition with high prevalence and severe morbidity and mortality tolls, we welcome the work by Huang published in this issue of the Journal, analyzing the relationship between blood levels of nutrition-related factors and incident AF, building on previous work suggesting indeed that AF risk is lower in subjects with adequate intake of micronutrients (eg, vitamins, copper, iron, and zinc), and instead higher in those with no or low intake of such nutrition-related factors.1–3

Notably, Huang3 performed a genome-wide association study, using a Mendelian randomization design and including 60,620 cases of incident AF and 970,216 controls, to explore the association between AF risk and individual micronutrients. Disappointingly, he did not identify any significant mediating effect of circulating concentrations of vitamin B12 (regression coefficient [β] = 0.000, standard error [SE] = 0.021, P = 0.994), vitamin E (β = 0.080, SE = 0.152, P = 0.600), retinol (β = 0.098, SE = 0.397, P = 0.806), folate (β = −0.006, SE = 0.052, P = 0.901), β-carotene (β = 0.014, SE = 0.025, P = 0.560), iron (β = −0.009, SE = 0.072, P = 0.905), zinc (β = 0.038, SE = 0.032, P = 0.239), and copper (β = −0.012, SE = 0.023, P = 0.589) on AF. Accordingly, his conclusion was that these micronutrients are unlikely to significantly impact on the risk of AF, implying that previously reported associations might be prevalently because of residual confounding.

Before taking these results for granted, it is imperative though to elaborate on further details on the chosen study design, for strengths and weaknesses. Indeed, genome-wide association study is usually used to detect associations between genetic variants and traits in large population samples, with the main aim of these studies being to better clarify the biology of disease.4 Similarly, Mendelian randomization analysis, which exploits genetic variability to explore causal associations by purportedly reducing reverse causation and confounding, helped to identify lots of causal effects in many cardiometabolic diseases in the past years (Fig. 1).5 However, beyond the putative causal relationship of each nutrition-related factor with incident AF, the epigenetic modulation of single-nucleotide polymorphisms is crucial because the pathogenesis of many cardiometabolic diseases is complex and multifactorial, and it accounts for interindividual phenotypic presentation and disease susceptibility.6 In this context, many variables that may influence the risk of developing AF have not been considered by Huang, including clinical characteristics (eg, obesity, chronic obstructive pulmonary disease, or hyperthyroidism) and concomitant drug therapy (eg, statins or antiarrhythmic drugs).

FIGURE 1.:

Rationale of studies with Mendelian randomization design and their application to the appraisal of micronutrients and risk of incident atrial fibrillation (AF).

Indeed, among the compounds included in the analysis by Huang, many have been shown to possess important antioxidant and antithrombotic properties, and many foods rich in antioxidants have been associated with a lower incidence of AF.7,8 In addition, antioxidant supplementation has been proposed to reduce the incidence of AF.9 Accordingly, antioxidant treatments have been shown to reduce the risk of new-onset AF in patients undergoing coronary artery bypass graft surgery, especially ascorbic acid (relative risk: 0.716 [95% confidence interval: 0.57–0.90]; P = 0.005) or N-acetylcysteine (relative risk: 0.775 [95% confidence interval: 0.63–0.94]; P = 0.013).9 This strategy would have the key advantage of limiting intrinsic adverse effects and avoiding major pharmacological interactions.

Furthermore, there is now clear evidence that it is paramount to adhere to a wholly healthy diet regimen, rather than focusing on a single-nutrient consumption. Indeed, many of the antioxidant nutrients analyzed by Huang are well-represented in the Mediterranean diet, which has been proven as very beneficial to prevent cardiovascular disease, including AF.10 For instance, in a case–control study including 800 subjects, 400 with a first episode of AF, adherence to the Mediterranean diet was significantly lower in patients who developed AF compared with controls.11 This was also evident for the estimated intake of total antioxidants (13.5 ± 8.3 vs. 18.2 ± 9.4 mmol/d; P < 0.001). Moreover, spontaneous conversion of AF was more frequent in patients in the highest quartile of Mediterranean diet score. Finally, the post hoc analysis of the PREDIMED trial also showed that a Mediterranean diet enriched with extra-virgin olive oil was associated with a reduction in the risk of AF (hazard ratio = 0.62 [95% confidence interval: 0.45–0.88]).12

Globally, these findings suggest that the adherence to a healthy antioxidant-rich dietary pattern may have a beneficial effect because nutrients (including micronutrients) may interact with each other simultaneously targeting multiple pathogenetic pathways involved in the onset of AF.13 This is also suggested by the analysis of this study because there was no overlap among single nucleotide polymorphisms of the 8 tested nutrition-related factors. Similar interactions can be envisioned between nutrition-related factors and drugs. Indeed, among cardiovascular drugs, statin therapy has been associated with lower incidence and recurrence of AF.14 This effect may possibly be mediated by an improvement in the antioxidant status, particularly increasing vitamin E serum levels.15

In conclusion, while welcoming the relevant and valid work by Huang, we believe that beyond the causal relationship between antioxidant nutrients and the risk of AF, a major role is played by the epigenetic modulation of circulating levels of different antioxidant compounds which may greatly affect the risk of AF in the general population and in patients at risk for cardiovascular disease.

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