Fish oil for atrial fibrillation prevention: Can we intervene soon enough to make a difference?

The atria have dual physiologic roles, serving both to facilitate ventricular filling and acting as sensors for blood volume, releasing natriuretic peptides that promote renal sodium excretion when filling pressures are elevated. While the atria typically operate with low diastolic pressures, they adapt rapidly to increased pressures with the development of chamber thinning and dilatation. Dilatation is limited by fibroblast proliferation and extracellular matrix accumulation that increases atrial stiffness. Atrial structural remodeling in response to hemodynamic overload is characterized by matrix metalloprotease activation, fibroblast proliferation, and increased abundance of extracellular matrix components.¹

Atrial structural remodeling can constitute both a risk factor for the development of atrial fibrillation (AF) and a response to the presence of AF. In individuals with AF, atrial structural remodeling contributes to the transition from paroxysmal to persistent AF, as a result of increased tissue area for reentry, and of heterogeneous and slowed conduction. Heterogeneity, whether of conduction or repolarization, is critical for reentrant electrical activity. While electrical remodeling (altered refractory period) tends to predominate as the earliest response to atrial tachycardia, atrial structural remodeling is typically the earliest response to increased atrial pressures and cardiac hemodynamic overload. In recognition of the significance of atrial structural remodeling, investigators have sought to identify interventions that can help to minimize its occurrence.

In experimental animal models that increase atrial pressures (heart failure, myocardial infarction, hypertension, valvular dysfunction), several mechanistically distinct interventions have been shown to attenuate the development of atrial fibrosis. In a canine heart failure model induced by ventricular tachypacing, pretreatment with enalapril² (an angiotensin-converting enzyme inhibitor) or simvastatin³ attenuated but did not eliminate the development of atrial fibrosis. In a rat model of heart failure induced by myocardial infarction, increased left atrial fibrosis was attenuated by spironolactone (an aldosterone antagonist) but not by an angiotensin-converting enzyme inhibitor or beta-adrenergic receptor blocker.⁴ In a canine heart failure model due to ventricular tachypacing, pretreatment with omega-3 polyunsaturated fatty acids (ω3-PUFAs) attenuated ventricular tachypacing-induced hemodynamic dysfunction and significantly decreased the development of atrial fibrosis, the heterogeneity of conduction, and the duration of induced AF episodes.⁵ Similarly, in a canine model of 2 weeks simultaneous atrial and ventricular pacing (SAVP), pretreatment with ω3-PUFAs reduced the abundance of collagen in the atrial appendage, decreased matrix metalloprotease 9 activation, and decreased the inducibility of AF induced with an extrastimulus protocol.⁶ Pretreatment with ω3-PUFA appears to be an effective strategy for preventing the development of a substrate for AF in response to increased atrial pressures.

In this issue of HeartRhythm, Ramadeen and colleagues⁶ extend their group’s work in the SAVP model.^7,8 The authors now show that prophylactic ω3-PUFA reduced the presence of inflammatory cells in the atria following 2 days of pacing. This result is consistent with a recent report from our laboratory documenting reduced atrial inflammation in dogs pretreated with ω3-PUFA prior to cardiac surgery.⁹ Early atrial injury and inflammation may be a key step initiating the gene expression response to increased atrial pressure that promotes atrial structural remodeling, characterized by myocyte hypertrophy and the development of atrial fibrosis.

Concentrated ω3-PUFA preparations are approved by the Food and Drug Administration for the treatment of hypertriglyceridemia, and the side-effect profile of these drugs is relatively benign. The efficacy of ω3-PUFAs in modifying the substrate for AF when given before the development of experimental heart failure raises an obvious and important question. Would the administration of ω3-PUFAs affect heart failure symptoms, atrial fibrosis, AF inducibility, or AF persistence when given after a sustained increase in atrial pressure?

Ramadeen et al⁶ also directly address this clinically important question. They report that when ω3-PUFA treatment was initiated 7 days after the onset of tachypacing, treatment had no detectable impact on the extent of atrial fibrosis or atrial vulnerability to AF induced with burst pacing after 2 weeks of SAVP.

The authors previously reported that ω3-PUFA pretreatment for 7 days prior to and 14 days following the onset of SAVP was associated with downregulation expression of hypertrophic and profibrotic genes (Akt, epidermal growth factor, JAM3, myosin heavy chain α-subunit, and CD99) in the treated relative to untreated control SAVP animals.¹⁰ In this study, they show that the first 7 days of SAVP were associated with increased atrial expression of Akt, SMAD7 (a profibrotic signaling molecule), and epidermal growth factor compared with unpaced animals. The early changes in gene expression may have been sufficient to initiate persistent changes in atrial gene expression. The initiation of ω3-PUFA treatment after 7 days of pacing had no apparent impact on the expression of collagen isoforms I and III. Thus, to the extent that the beneficial effects of ω3-PUFA treatment are dependent on a suppression of collagen expression, late initiation of treatment (for patients with significant atrial fibrosis) might be expected to have little benefit.

In addition to the lack of benefit with respect to atrial collagen expression profiles, the authors noted that ω3-PUFA treatment was associated with a modestly increased risk of proarrhythmia in unpaced animals subjected to atrial burst pacing, with 21 days of treatment leading to an increase in episodes of tachyarrhythmia (>5-s duration) from ~1% to ~6% (Figure 5). In the absence of a hemodynamic load on the atria, this effect was unlikely to be due to a modification of atrial structure. While the significance of burst pacing as a trigger for AF might be questioned and no significant difference in AF incidence was detected, more serious ventricular proarrhythmic responses to ω3-PUFA treatment have also recently been reported in dogs treated following myocardial infarction.¹¹

A large randomized clinical trial recently evaluated the impact of ω3-PUFAs for the prevention of AF recurrence following cardioversion in groups of patients with either paroxysmal or persistent AF.¹² Somewhat surprisingly, this study reported no benefit of ω3-PUFA treatment with respect to the recurrence of AF in patients with either paroxysmal or persistent AF. In view of the important results reported by Ramadeen et al, it seems likely that sufficient atrial structural remodeling had occurred prior to the onset of ω3-PUFA treatment, limiting the potential for treatment benefit. In the presence of preexisting atrial structural remodeling, accumulating clinical and preclinical evidence suggests that short-term dietary supplementation (weeks to months) with concentrated ω3-PUFA preparations is unlikely to provide significant clinical benefit.¹³

Epidemiologic studies suggest that populations that consume more food-based ω3-PUFAs (from plants or fish) and less ω6-PUFAs have a lower incidence of AF and experience fewer cardiovascular deaths.¹⁴ Exercise has similar cardiovascular benefits.¹⁵ While dietary counseling and exercise programs are more difficult to implement and monitor, long-term programs that focus early and more holistically on modifying diet and lifestyle may have a greater impact on cardiovascular health than programs that narrowly focus on the acute pharmacologic modulation of ω3-PUFA intake after the development of AF.