Omega-3 polyunsaturated fatty acids (ω-3 PUFAs), which encompass eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and alpha-linolenic acid (ALA), have garnered increasing evidence for their impact on ventricular arrhythmias and sudden cardiac death. Recent studies have further suggested that ω-3 PUFAs may also influence atrial fibrillation. The mechanisms underlying the prevention and treatment of ventricular arrhythmias by ω-3 PUFAs are not fully elucidated, but potential mechanisms involve inhibiting inflammation and oxidative stress, improving myocardial cellular electrical and ventricular structural remodeling, and modulating the autonomic nervous system. In vitro studies have demonstrated that ω-3 PUFAs can increase the action potential threshold and decrease myocardial excitability, particularly pronounced in ischemia-induced arrhythmias or damaged cells. Moreover, animal experiments have shown that incorporating ω-3 PUFAs into membrane phospholipids alters the physicochemical properties of membrane microdomains and regulates numerous cellular functions, including signal transduction, protein trafficking, and changes in ion channel dynamics, all of which contribute to their potential anti-inflammatory and anti-arrhythmic effects.

1、Inhibition of Inflammation and Oxidative Stress

ω-3 PUFAs interact with several nuclear receptors and transcription factors that regulate gene expression, thereby modulating various inflammatory pathways. They can antagonize the formation of prostaglandin E2, which has a pro-inflammatory effect, and reduce the activation of nuclear factors. Additionally, ω-3 PUFAs exert anti-inflammatory effects through pro-resolving mediators derived from cyclooxygenase and lipoxygenase pathways, as well as monohydroxy epoxides generated from EPA and DHA metabolism. By inhibiting reactive oxygen species (ROS), ω-3 PUFAs reduce the activation of transcription factors such as Ik-B and NF-KB, leading to the downregulation of pro-inflammatory cytokines like interleukin-8 (IL-8) and tumor necrosis factor-α (TNF-α). ω-3 PUFAs also downregulate the expression of adhesion molecules, reduce the recruitment of macrophages in the vascular wall, and inhibit the production of prostaglandins and leukotrienes from n-6 fatty acid arachidonic acid, contributing to their anti-inflammatory effects. Studies have found that daily supplementation with 2.7g of DHA and EPA significantly reduces plasma concentrations of C-reactive protein, IL-6, IL-18, and TNF-α, while increasing adiponectin levels. Furthermore, research suggests that the anti-inflammatory mechanisms of ω-3 PUFAs are related to their derived specific pro-resolving mediators (SPMs). SPMs exert anti-inflammatory effects through a series of biological activities, including inhibiting granulocyte infiltration, stimulating bacterial phagocytosis and apoptotic cell efferocytosis in leukocytes, and activating macrophage efferocytosis.

2.Improvement of Ventricular Myocyte Electrical Remodeling

Most single-cell electrophysiological studies have revealed the inhibitory effects of ω-3 PUFAs on ionic currents, such as the rapid sodium current, ultra-rapidly activating delayed rectifier potassium current, rapidly activating delayed rectifier potassium current, and L-type calcium current. Ventricular electrical remodeling is a crucial mechanism underlying the occurrence of ventricular arrhythmias. Previous studies have shown that ω-3 PUFAs can induce changes in ion flows related to myocardial cell depolarization and repolarization, including sodium, L-type calcium, and potassium ion currents. ω-3 PUFAs can inhibit Nav and Cav ion channels, although evidence for the specific mechanisms of channel inhibition is scarce. Some scholars suggest that ω-3 PUFAs can shift the voltage-dependence (Gv) curve of Nav and Cav ion channels to the left, increasing excitability, while also shifting the steady-state inactivation curve to the left, reducing excitability. However, the changes in the steady-state inactivation curve often exceed those in the Gv curve, resulting in the inhibition of Nav and Cav channels by ω-3 PUFAs. Research suggests that ω-3 PUFAs activate the IKs channel through electrostatic effects on the voltage sensor and pore domain, increasing outward K+ current and thereby exerting an anti-ventricular arrhythmic effect. Disruption of the IKs current can lead to the most common congenital long QT syndrome (LQTS). Studies have reported that modifying the head groups of ω-3 PUFAs can adjust their efficacy on the IKs channel, potentially enabling the development of ω-3 PUFA analogues with different efficacies on the IKs channel, providing more personalized treatments for LQTS patients with varying degrees of IKs channel dysfunction. Furthermore, the incorporation of ω-3 PUFAs is positively correlated with mitochondrial proton leakage, and increasing mitochondrial DHA content through lipid transport or dietary interventions enhances proton motility.

3.Improvement of Ventricular and Atrial Structural Remodeling

Experimental animal models suggest that ω-3 PUFAs may reverse atrial structural changes mediated by atrial fibrillation (AF) through preventing the activation of mitogen-activated protein kinases, reducing matrix metalloproteinase activity, and redistributing connexins. Soluble ST2, a marker for monitoring inflammation and myocardial fibrosis, can reflect the degree of myocardial fibrosis. In a double-blind, controlled study, the intervention group receiving 2g of ω-3 PUFAs daily for 8 weeks showed significantly lower ST2 levels compared to the control group. The anti-fibrotic mechanism of ω-3 PUFAs is not fully understood, but a randomized controlled study indicated that a fish oil diet rich in ω-3 PUFAs significantly reduced myocardial fibrosis. Moreover, compared to both the control group and diabetic group, the diabetic group with a fish oil-rich diet showed significantly lower levels of transforming growth factor-β1 (TGF-β1) and cardiac p38 mitogen-activated protein kinase (p38MAPK), suggesting that ω-3 PUFAs may prevent myocardial fibrosis through the TGF-β1/MAPK signaling pathway. Some scholars believe that the anti-fibrotic effect of ω-3 PUFAs is related to specialized pro-resolving mediators (SPMs), which activate and accelerate the translocation of Nrf2 to the nucleus, thereby reducing oxidative stress and counteracting the ROS/TGF-β1/Smad2/3 pro-fibrotic pathway. Research has found that rats injected with isoproterenol for 7 days exhibited significant abnormalities in the distribution and localization of Cx43. Immunofluorescence results showed that ω-3 PUFAs treatment for 60 days significantly inhibited the lateral distribution of Cx43 compared to untreated rats, indicating that ω-3 PUFAs significantly reduced the disordered distribution and remodeling of Cx43 in isoproterenol-induced cardiomyocytes.

4.Autonomic Nervous System Function

A study randomized 132 renal transplant patients into two groups, with one group receiving three 1g ω-3 PUFAs capsules daily and the other group receiving three 1g olive oil capsules daily for 44 weeks. The 24-hour heart rate variability (HRV) of the patients was observed to assess the impact of ω-3 PUFAs on cardiac autonomic nervous system function. The results showed that compared to the olive oil group, the ω-3 PUFAs group had significantly lower low-frequency and high-frequency HRV in the standing position, and their SDNN (standard deviation of normal-to-normal intervals) was also higher than that of the control group, indicating that supplementation with marine ω-3 PUFAs may be beneficial to autonomic nervous system function.

Another study randomized 112 chronic dialysis patients to receive either 2g of ω-3 PUFAs or olive oil daily for 3 months. The results showed no significant difference in SDNN between the ω-3 PUFAs and control groups, but the average heart rate, SDNNi (standard deviation of the differences between adjacent normal RR intervals), and rMSSD (root mean square of successive differences) were significantly lower in the ω-3 PUFAs group, indicating that ω-3 PUFAs improved vagal modulation of the heart.

Although the exact mechanism underlying ω-3 PUFAs' improvement of arrhythmias remains unclear, numerous studies have shown that ω-3 PUFAs exhibit therapeutic effects on ventricular arrhythmias, sudden cardiac death (SCD), and atrial fibrillation (AF) by mechanisms such as reducing inflammation and fibrosis, influencing autonomic nervous system tone and heart rate, and prolonging the refractory period of atrial and pulmonary vein cells. While ω-3 PUFAs are essential fatty acids and vital components of cell membranes, the effective doses that confer protective effects in cell membranes, including atrial cell membranes, may be narrow and only effective under specific conditions. Experimental data suggest a U-shaped curve relationship between ω-3 PUFAs and the risk of AF occurrence.

Furthermore, ω-3 PUFAs may be more effective in the early stages of AF, particularly before advanced atrial remodeling occurs. While the application of ω-3 PUFAs in reducing postoperative AF remains controversial, they have been shown to shorten hospital stays, including intensive care unit stays, and reduce postoperative complications. Additionally, ω-3 PUFAs possess potent electrophysiological effects, inhibiting various ion channels and calcium regulatory proteins. However, their electrophysiological effects differ significantly depending on whether they are used temporarily to directly bind to ion channels or chronically integrated into cell membranes, indirectly modulating them by altering membrane properties.

Despite robust epidemiological evidence indicating a negative correlation between ω-3 PUFAs intake and cardiovascular mortality, and highly encouraging results from previous clinical prevention trials, recent studies have failed to confirm these earlier findings, specifically in relation to ω-3 PUFAs and sudden cardiac death (SCD). In fact, some studies have shown that ω-3 PUFAs increase mortality in patients with angina pectoris and even elevate the incidence of malignant arrhythmias in isolated porcine hearts with regional myocardial ischemia and canine models of SCD. However, ω-3 PUFAs can inhibit delayed depolarization in cardiomyocytes of patients with heart failure and animal models, as well as prevent triggered activity. Consequently, ω-3 PUFAs can both promote and suppress arrhythmias, depending on the underlying arrhythmic mechanism.

References:

[1] Zou Hai, He Xigan, Chen Zhenyao, et al. Clinical Research Progress on the Prevention and Treatment of Arrhythmias with ω-3 Polyunsaturated Fatty Acids [J]. Herald of Medicine, 2023, 42(11): 1704-1710.

[2] Zhang Zhiyuan, Li Feng, Qian Lingling, et al. Effects of n-3 Polyunsaturated Fatty Acids on the Occurrence of Ventricular Arrhythmias and Its Mechanisms [J]. Chinese Journal of Cardiac Pacing and Electrophysiology, 2023.

[3] Lan Yunfeng, Li Yang. Research Progress on the Anti-arrhythmic Effects and Mechanisms of Omega-3 Polyunsaturated Fatty Acids [J]. Chinese Journal of Multi-Organ Diseases in the Elderly, 2014, 000(004): 304-308.

About the Author

Xiaonisha, a food technology professional holding a Master's degree in Food Science, is currently employed at a prominent domestic pharmaceutical research and development company. Her primary focus lies in the development and research of nutritional foods, where she contributes her expertise and passion to create innovative products.