Omega-3 Fatty Acids reduce rate and QT-interval, but increase electrical instability in cardiomyocytes

Omega-3 fatty acids (n-3 FAs) are well known for their cardiovascular benefits but have also been linked to atrial fibrillation (AF)1. The REDUCE-IT trial associated high-dose EPA (4 g/day) with increased AF risk, while other studies found no link between EPA and non-paroxysmal AF2-4. Higher DHA and total n-3 FAs levels correlate with slower heart rates and animal studies suggest a protective role against AF5. However, the underlying electrophysiological mechanisms remain unclear.

To investigate the direct effects of EPA and DHA on the electrical activity of cardiomyocytes

Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes were treated with varying concentrations of EPA and DHA and assessed at multiple time points (Fig.1A). Multielectrode array (MEA) recordings were used to measure the heart rate, QTc interval and conduction properties including electrical variability.

DHA and EPA both significantly reduced heart rate and shortened QT interval duration, with distinct temporal patterns. DHA lowered heart rate by approximately 40% within 24 hours, progressing to nearly 60% by 48 hours, with a tendency toward a stronger effect at higher concentrations. EPA followed a similar trend initially; however, by 48 hours, 10 µM EPA resulted in only a 20% reduction, whereas 100 µM EPA produced a 60% decrease, comparable to DHA (Fig. 1B). Similarly, DHA shortened the QT interval by about 25% within 24 hours, reaching its maximal effect at 48 hours, largely independent of dose. EPA at 10 μM initially mimicked this response but either reversed or remained unchanged at 48 hours, whereas 100 μM EPA followed a pattern similar to DHA (Fig.1C). Additionally, DHA and EPA both increased short-term variability (STV) of the R–R interval over 48 hours, with higher concentrations (100 µM) exerting a more pronounced effect (Fig.2). This elevated STV indicates heightened electrical instability, suggesting a greater proarrhythmic risk.

Both EPA and DHA acutely shorten the QT interval and reduce heart rate in hiPSC-derived cardiomyocytes. However, they lead to electrical instability that may predispose to arrhythmia.