Atrial fibrillation (Afib) is the most common form of cardiac arrhythmia. It is known that Afib is associated with an increased risk of stroke, heart failure, dementia, kidney failure, cardiovascular disease, and all-cause mortality. Yet as to what actually causes Afib, no one really knows. However, we do know it is a significant problem as it affects nearly 10 percent of Americans over age 65 (1).
In the absence of what actually causes Afib, its treatment usually starts after its development to treat the symptoms. This could be cardioversion, ablation of specific nerves in the heart, or lifelong use of blood thinners to prevent a potential blood clot formation that could lead to a stroke—not exactly cutting-edge preventive medicine.
However, several clues suggest that metabolic dysfunction and increased inflammation play significant roles in the development of Afib. In particular, there is a linkage between the progression of Afib and decreasing cellular energy (2). Both of these factors are strongly associated with the inhibition of AMPK activity (3, 4).
We also know that some of the common chronic conditions, such as obesity and type 2 diabetes, as well as increasing age, are also strongly associated with the development of Afib (5). All of these factors are also linked to decreased AMPK activity. While it has long been appreciated that AMPK is the master regulator of metabolism, what is not as well appreciated is the critical role AMPK also plays in controlling cardiac electrophysiology and arrhythmias (6)
Thus, the most likely suspect of the development of Afib may be decreased AMPK activity. If so, then increasing AMPK activity is a potential solution to preventing the development of Afib and the primary intervention to reduce complications after Afib has emerged. Increasing AMPK activity is the goal of Metabolic Engineering®.
The foundation of Metabolic Engineering® is lifetime calorie restriction, the most potent way to activate AMPK. However, to be genuinely effective, calorie restriction must be maintained for life without hunger or fatigue.
I patented the Zone diet more than 30 years ago to achieve such calorie restriction by providing adequate protein at each meal, balanced with low-glycemic-load carbohydrates to prevent ketosis (7). Controlled clinical studies have shown the unique protein-to-glycemic load balance to be not only effective in the remission of type 2 diabetes but also increases lean body mass in the process (8). Other studies have demonstrated that loss of AMPK activity in animal models leads to Afib (9) and that pharmacological activation of AMPK prevents Afib (10).
Finally, it appears that using GLP-1 drugs decreases the risk of new-onset Afib in diabetic patients (11, 12). The primary mechanism for this and the many other metabolic benefits of GLP-1 drugs appears to be continuous calorie restriction that activates AMPK (13).
However, calorie restriction is only one part of Metabolic Engineering®. Another critical part of Metabolic Engineering® is reducing chronic low-level inflammation. This is addressed by adequate intake of omega-3 fatty acids to lower levels of pro-inflammatory eicosanoids. It is known that there is a strong association of pro-inflammatory hormones (i.e., eicosanoids) and the development of Afib (14).
The best way to lower these inflammatory eicosanoids is to maintain an adequate intake of omega-3 fatty acids to decrease the AA/EPA ratio, as I described in my 2001 book, The OmegaRx Zone (15). Furthermore, published data suggest that increased levels of EPA and DHA in the blood are associated with a lower incidence of all-cause mortality (16). Furthermore, there was no association of increasing levels of omega-3 fatty acids and the incidence of Afib (17).
This leads to the paradox of supplementation with EPA and DHA. In clinical trials with cardiovascular patients, although there is an increase in the development of Afib with supplementation with omega-3 fatty acids, there is a far more significant decrease in stroke and a lowering of the incidence of major cardiovascular events (18). What’s going on?
It may be because they were looking at the wrong marker of inflammation. Pro-inflammatory eicosanoids are primarily controlled by the AA/EPA ratio, not by the total levels of EPA and DHA. In fact, DHA has virtually no effect on the production of pro-inflammatory eicosanoids because it is not an inhibitor of the enzymes that synthesize them. Only EPA can do that. This explains why EPA supplementation alone improves cardiovascular outcomes and reduces cardiovascular mortality better than combinations of EPA and DHA (18).
The answer to this dilemma is to take adequate intakes of omega-3 fatty acids rich in EPA to reduce the AA/EPA ratio to between 1.5 and 3, as found in the Japanese population (19). But don’t let the tail wag the dog. Before you start taking omega-3 fatty acids to reduce cardiovascular risk, activate AMPK with the Zone diet. You will begin to see benefits in your blood within a month if you monitor your insulin resistance (an indirect marker of AMPK activation).
More importantly, you will experience the benefits of a lack of hunger within days. At the end of 30 days on the Zone diet, start adding more omega-3 fatty acids to your diet until the AA/EPA ratio in your blood is reduced to between 1.5 and 3. That should take about another month. The more you activate AMPK through the Zone diet, the fewer omega-3 fatty acids you will need to lower the AA/EPA ratio.
Finally, the last component of Metabolic Engineering® is consuming adequate levels of polyphenols. However, there are more than 8,000 different polyphenols, so which ones? In terms of reducing Afib, a subgroup of polyphenols, known as delphinidins, appears to be the most effective. These are found in high concentrations in berries such as blueberries, black currant berries, and especially the maqui berry.
In animal studies, supplementation with extracts of these delphinidin-rich berries results in a significant activation of AMPK (20). However, the impact of polyphenol extracts should be considered as an addendum to following the Zone diet and supplementation with omega-3 fatty acids, as these two dietary interventions are the primary drivers of increased AMPK activity, which in turn reduces cardiovascular events associated with Afib.
Bottom line, if you want to prevent the potential consequences of existing Afib or reduce the likelihood of developing Afib in the future, then begin reprograming your metabolism today using Metabolic Engineering® to activate AMPK.
References
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2. Chakraborty P, Nattel S, Nanthakumar K. Linking cellular energy state to atrial fibrillation pathogenesis: Potential role of adenosine monophosphate-activated protein kinase. Heart Rhythm. 2020;17(8):1398-1404. doi: 10.1016/j.hrthm.2020.03.025.
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12. Lv Q, Yang Y, Lv Y, et al. Effect of different hypoglycemic drugs and insulin on the risk of new-onset atrial fibrillation in people with diabetes: a network meta-analysis. Eur J Med Res. 2024; 29:399. doi: 10.1186/s40001-024-01954-w.
13. Schooling CM, Yang G, Soliman GA, et al. A hypothesis that glucagon-like peptide-1 receptor agonists exert immediate and multifaceted effects by activating adenosine monophosphate-activated protein kinase (AMPK). Life; 2025; 15:253. doi: 10.3390/life15020253.
14. Kornej J, Qadan MA, Alotaibi M, et al. The association between eicosanoids and incident atrial fibrillation in the Framingham Heart Study. Sci Rep. 2022;12:20218. doi: 10.1038/s41598-022-21786-0.
15. Sears B. The OmegaRx Zone. Regan Books. New York, NY (2001)
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