A randomized clinical trial of omega-3 fatty acid and vitamin D supplementation on electrocardiographic risk profiles

Abstract

Beneficial and adverse associations with arrhythmias have been reported for omega-3 fatty acids (omega-3 FA) and Vitamin D. The 12 lead electrocardiogram (ECG) contains quantitative measures reflecting diverse aspects of electrophysiology that might provide insights into mechanisms underlying these associations. In a pre-specified ancillary study of the VITaminD and omegA-3 (VITAL) trial, we examined the effect of 1 g of marine omega-3 FA per day, comprised of 460 mg eicosapentanoic acid and 380 mg of docosahexaenoic acid, and 2000 IU VitaminD₃ per day on ECG characteristics associated with atrial and ventricular arrhythmias among individuals age 50 years or greater. A total of 911 study participants underwent ECGs at baseline and again at 2 years after the randomization. Individuals randomized to active omega-3 FA demonstrated significant net increase in PR-interval duration (p = 0.005) and P-wave duration (p = 0.03) as well significant net decrease in P-wave amplitude (p = 0.037) as compared to placebo. RMSSD increased to a greater extent in the omega-3 FA arm compared to placebo (p = 0.040). For Vitamin D₃, the Cornell voltage increased to a lesser extent in the participants assigned to active treatment as compared to placebo (p = 0.044). There were no other significant differences in QRS, QTc, Cornell voltage or heart rate. Thus, randomized treatment with omega-3 FA supplements resulted in changes on the ECG that are potentially reflective of heightened vagal tone and/or slowing of intraatrial and AV conduction. Vitamin D₃ supplementation resulted in modest reductions in progressive LV voltage suggestive of a potential antihypertrophic effect.

Trial registration ClinicalTrials.gov Identifiers: NCT01169259, NCT02178410 (06/26/2010 and 06/30/2014).

Introduction

Heart rhythm disorders are major causes of mortality and morbidity globally. Atrial fibrillation (AF) is the most common heart rhythm disturbance and the prevalence is exponentially growing¹. Sudden cardiac death (SCD) accounts for over 300,000 deaths annually in the US. Experimental^2,3 and observational studies have suggested that the intake of omega-3 polyunsaturated fatty acids (omega-3 FA) might lower the risk of ventricular arrhythmias and SCD^4,5 and vitamin D deficiency and/or PTH excess has been associated with increased SCD^6,7,8,9, whereas the observational data regarding atrial arrhythmias are mixed for both.

Three randomized trials of omega-3 FA supplementation have reported protective effects on SCD and ventricular arrhythmias, whereas the remainder have not. With respect to AF, we recently reported that omega-3 FA and/or vitamin D3 supplementation resulted in no significant difference in the risk of incident AF over a median follow up of over 5.3 years in the VITAL trial¹⁰; however, a small increased risk of AF could not be excluded. In contrast, three recent randomized trials testing various higher dose formulations of omega-3 FA found significantly increased risks of AF in participants randomized to active therapy versus placebo^11,12,13. When combined in meta-analysis with 3 additional trials of long term omega-3 FA supplementation, omega-3 FA supplementation was associated with a significant increased risk of AF compared with placebo even at lower dosages of 1 g per day¹⁴.

The mechanisms underlying this potential increased risk of AF and lower SCD risk associated with omega-3 fatty acid supplementation are unclear, although cellular electrophysiologic and autonomic mechanisms have been postulated². Several parameters on the 12-lead electrocardiogram (ECG) represent potential intermediate phenotypes for heart rhythm disorders, and thus may provide clues regarding potential mechanisms of action^15,16,17. Omega-3 FA intake has been favorably associated with several of these parameters in observational studies¹⁸, however, randomized trial data are lacking. Although Vitamin D supplementation is less well studied with respect to heart rhythm disorders, observational studies have found consistent associations between vitamin D deficiency and clinical conditions predisposing to AF and SCD, most notably including hypertension¹⁹ and heart failure²⁰.

The large-scale randomized placebo-controlled VITamin D and OmegA-3 TriaL (VITAL) primary prevention trial^21,22 provided a unique opportunity to test the effect of supplementation with omega-3 FA and vitamin D3 on ECG parameters. In a pre-specified sub-study of the VITAL Rhythm trial¹⁰, serial ECGs were performed at baseline and 2 years after randomization in a subset of 911 participants. Thus, in this present study, we report the effect of both interventions on a variety of pre-specified ECG characteristics previously associated with AF or SCD^17,23.

Results

The clinical characteristics and electrocardiographic features of study groups at baseline are presented in Tables 1 and 2, respectively. At baseline, those individuals randomized to active EPA + DHA treatment had significantly higher BMI (p = 0.023, Table 1), lower resting heart rate (p = 0.033, Table 2), and higher Cornell voltages (p = 0.049, Table 2) than those receiving the placebo treatment. Individuals randomized to vitamin D3 treatment had statistically lower diastolic blood pressure (p = 0.041, Table 1) and lower mean arterial pressure (p = 0.045, Table 1), compared to those in the placebo group. There were no differences in average age, sex distribution, race, smoking status, alcohol intake, or known clinical history of diabetes, hypertension or hyperlipidemia (Table 1) or any of the other ECG parameters (Table 2). Baseline levels of EPA + DHA and vitamin D also did not vary by baseline treatment assignment.