The remarkable cardioprotective effects of fish have been recognized for decades, with population-based studies linking regular fish consumption to reduced coronary artery disease incidence and mortality. Eating fish at least twice a week has been recommended as part of a healthy diet. However, the role of supplementation with marine-based omega-3 fatty acids, including eicosapentaenoic acid and docosahexaenoic acid, is less clear. More than 20 clinical trials have been undertaken with variable results. Overall, omega-3 fatty acid supplements appear to have limited utility for primary prevention of coronary artery disease but may be beneficial for secondary prevention in patients with established coronary artery disease or heart failure.
In an unexpected twist, accumulating evidence now suggests that the benefits of omega-3 fatty acid supplementation are gained at the expense of an increased risk of atrial fibrillation (AF; Figure [A]). This risk is dose-related, with the hazard ratio increasing from 1.12 (95% CI, 1.03–1.22; P=0.024) for doses ≤1 g/d up to 1.49 (95% CI, 1.04–2.15; P=0.042) for doses >1 g/d. The development of AF appears to be independent of other clinical outcomes, with increased incidence in trials with (eg, REDUCE-IT [Reduction of Cardiovascular Events With Icosapent Ethyl – Intervention Trial]) and without (eg, STRENGTH [Study to Assess Statin Residual Risk With Epanova in High Cardiovascular Risk Patients With Hypertriglyceridemia]) significant reductions in atherosclerotic event rates.
Links between omega-3 FA and AF.
A, U-shaped relationship between omega-3 FA intake and AF. B, PIEZO1 channels have a propeller-like assembly with a central pore and 3 upwardly curved blades. When mechanical force is applied, flattening of the cell membrane drives a downward motion of the blades and channel opening. Incorporation of omega-3 FA changes membrane mechanical properties. This sensitizes cells to force-dependent PIEZO1 activation and alters the kinetics of PIEZO1 inactivation. AF indicates atrial fibrillation; CAD, coronary artery disease; and FA, fatty acid.
How might omega-3 fatty acids predispose to AF? Experimental studies have shown that omega-3 fatty acids directly modify the activity of cardiac calcium, sodium, and potassium ionic currents, variably resulting in shortening or lengthening of the ventricular action potential duration. Thus, although omega-3 fatty acids may be antiarrhythmic in clinical settings that promote triggered activity, they may also facilitate re-entrant arrhythmias. Studies to date have focused mainly on ventricular electrophysiological properties, and relatively less is known about how omega-3 fatty acids might specifically affect the atria.
With this background, the award of the 2021 Nobel Prize in Physiology or Medicine to David Julius and Ardem Patapoutian is timely and relevant. Dr Julius identified a novel thermosensitive ion channel, TRPV1, involved in perception of pain. Dr Patapoutian and colleagues discovered a new class of ion channels that function as mechanical sensors in cellular membranes: PIEZO1 and PIEZO2 channels (from the Greek piesi, meaning pressure) are widely expressed and have been implicated in diverse biological processes including sensation of touch and vibration, proprioception, baroreflex regulation of blood pressure, red blood cell volume homeostasis, adipogenesis, and insulin release. How PIEZO1 might influence heart function is incompletely understood.
The heart is exquisitely sensitive to hemodynamic force on a beat-to-beat basis, and this is a key tenet of the Frank-Starling relationship that determines contractile performance and cardiac output. In conditions of volume or pressure overload, there may be progressive enlargement of the thin-walled atria. Atrial dilatation is proarrhythmic and predisposes to the development of AF. Once AF is established, structural and electric remodeling of the atrial wall set up a self-perpetuating cycle that promotes arrhythmia maintenance. Although much is known about downstream pathways, significantly less is understood about the precise nature of the trigger of atrial remodeling responses and the mechanisms by which myocardial cells sense and respond to changes in their mechanical environment. Could PIEZO channels be this missing link?
The PIEZO1/2 proteins are 2 of the largest ion channels identified to date, comprising >2500 amino acids organized into 38 transmembrane helices. These proteins assemble as homotrimeric structures with a central pore and 3 upwardly curved propeller-like blades that form a dome-like structure. In the presence of increased mechanical force, the blades flatten out, and this leads to opening of the central pore and a nonselective influx of positively charged ions including calcium (Figure [B]). Cell membrane lipids play an important role in driving the conformational rearrangements that lead to PIEZO channel opening and closure.
This is where omega-3 fatty acids come into the story. After dietary intake, omega-3 fatty acids become incorporated into cardiomyocyte surface membranes, rendering them thinner and more pliant. The effect of these changes varies with different omega-3 fatty acid types. The time course of PIEZO1 inactivation is prolonged by docosahexaenoic acid but reduced by eicosapentaenoic acid. Thus, the net effect will be determined in part by the docosahexaenoic acid:eicosapentaenoic acid ratio. A docosahexaenoic acid-predominant effect would result in PIEZO1 gain-of-function and increased influx of calcium and other cations (Figure [B]). Collectively, these changes would (1) prolong the action potential duration and increase the propensity for delayed after-depolarizations to trigger AF and (2) promote calcium-dependent signaling.
PIEZO1 channels may also mediate mechanical stress-induced signaling in other types of atrial cells including fibroblasts. PIEZO1 expression levels and activity have been shown to increase in atrial fibroblasts from patients with AF compared with those from patients with sinus rhythm, suggesting that PIEZO1 might contribute to atrial structural remodeling. The effects of omega-3 fatty acid on fibroblast functions in the context of PIEZO1 are yet to be investigated. Whether progressive myocardial stiffening caused by atrial fibrosis, hypertrophy, and extracellular matrix deposition might contribute to a dynamic feedback loop that modulates force propagation and PIEZO1 activation is unknown. Altered cell membrane properties after omega-3 fatty acid intake may extend beyond PIEZO1 channels to include changes in voltage-gated ion channels and other mechanosensitive components including ionic pumps, cell surface receptors, and extracellular matrix-cytoskeletal interactions, all of which might contribute to a proarrhythmic milieu.
The popular belief that fish oil is beneficial for heart health has fuelled a lucrative global market for omega-3 fatty acid supplements that is projected to reach $US 8.5 billion by 2025. Current data support a U-shaped curve whereby too little or too much marine-based fatty acid ingestion might predispose to AF (Figure [A]). There are numerous factors that need to be considered, including dose, type, and formulation of omega-3 fatty acids consumed (fish, dietary fish oil supplements, purified fatty acids), as well as the age, sex, clinical risk factors, and atrial mechanical milieu in individual patients. Although much remains to be learned, the groundbreaking discoveries of Ardem Patapoutian suggest new hypotheses for how omega-3 fatty acids might enhance atrial arrhythmogenesis. This may have direct relevance to the millions of individuals worldwide taking fish oil supplements on a daily basis.