Discerning whether and how long-chain, n-3 fatty acids lower blood pressure: a comment on Skulas-Ray et al.

A plethora of epidemiologic evidence links consumption of fish and n-3 fatty acids with reduced morbidity and mortality from atherosclerotic cardiovascular disease [1]. What is not at all clear is how such benefits accrue, how long diet must be changed, and what quantity of n-3 fatty acids confers disease protection. An important, randomized clinical trial recently found no reduction in major cardiovascular events from a margarine providing the relatively low dose of 400 mg daily of n-3 fatty acids for 40 months [2]. In the current issue, Skulas-Ray and colleagues report a clinical experiment examining the dose–response relationship between n-3 fatty acid supplementation and BP at rest and during acute mental stress [3]. BP was reduced comparably at rest and during stress by 3,400 mg/day for 8 weeks, whereas the lower dose of 850 mg had no effect. BP reduction was proportional to the increase in circulating n-3 fatty acids, corroborating the existence of a presumably linear, dose–response relationship. The authors further report a robust reduction in stroke volume, which in conjunction with a reduced heart rate (found in prior studies), yields a notable decline in resting cardiac output. Several caveats about the study design warrant mention. Subjects were normotensive, and the BP reduction of about 2 mmHg from high-dose supplementation may be larger in persons with high-normal or hypertensive BP. The duration of 8 weeks may be insufficient to fully characterize the effects of a diet change since tissue levels may require more than 4 months to plateau [4]. Finally, the use of a cross-over design has efficiencies at the cost of susceptibility to carry-over effects. The latter two issues could have conspired to produce null findings for the low dose but would not have biased the findings. In the context of extant literatures, Skulas-Ray's study indicates that BP declines with n-3 consumption in normotensives, extending the relatively robust evidence for such effects in persons with hypertension [5]. This suggests a role for fish and n-3 intake in hypertension prevention [6]. The manner in which BP falls could involve cardiovascular autonomic control or direct effects on the heart and vasculature. Research on n-3 fatty acids and heart rate variability, an index of cardiac autonomic control, is rather mixed, perhaps due to effect modification by concurrent health behaviors, such as exercise [7]. The current findings of reduced heart rate, stroke volume, and cardiac output, and lengthened pre-ejection period, all point to modulation of cardiac autonomic control. This collection of alterations in cardiovascular function at rest begs the question of how n-3 fatty acids affect cardiovascular responses, given our inconstant environmental stimuli and demands. The lack of a change in reactivity to mental stress reported here conflicts with the blunting of stress-induced BP elevation reported recently by Ginty and Conklin [8]. With respect to oxygen delivery at rest and during exercise, the decline in resting cardiac output implies a reduction in tissue oxygen demand, itself a provocative suggestion. Such may indeed be the case, as oxygen consumption during exercise has been reported to fall with fish oil supplementation [9]. Therefore, this paper adds evidence of multifaceted and dose-dependent changes in cardiovascular physiology from dietary n-3 fatty acids. It supports a role for increased fish and n-3 fatty acid consumption in hypertension prevention and should stimulate further research to untangle the various mechanisms of these micronutrients in human disease pathogenesis.