Membrane Basis for Fish Oil Effects on the Heart: Linking Natural Hibernators to Prevention of Human Sudden Cardiac Death

Abstract

The concept that diet-induced changes in membrane lipids could modify heart function partly arose from observations that membrane composition and physical properties were closely associated with the capacity of the heart to respond appropriately to torpor and hibernation. Observations of natural hibernators further revealed that behavior of key membrane-bound enzymes could be influenced through the lipid composition of the cell membrane, either by changing the surrounding fatty acids through reconstitution into a foreign lipid milieu of different composition, or by alteration through diet. Myocardial responsiveness to beta-adrenoceptor stimulation, including initiation of spontaneous dysrhythmic contractions, was altered by both hibernation and dietary modulation of membrane fatty acids, suggesting modified vulnerability to cardiac arrhythmia. Subsequent studies using whole-animal models recognized that vulnerability to ventricular fibrillation decreased as the polyunsaturated: saturated fat (P:S) ratio of the diet increased. However, dietary fish oils, which typically contain at least 30% saturated fatty acids and only 30% long-chain n-3 (omega-3) polyunsaturated fatty acids (PUFA), exhibit antiarrhythmic effects that exceed the predicted influence of the P:S ratio, suggesting properties unique to the long-chain n-3 PUFA. Large-scale clinical trials and epidemiology have confirmed the arrhythmia prevention observed in vitro in myocytes, papillary muscles, and isolated hearts and in whole-animal models of sudden cardiac death. Some progress has been made towards a biologically plausible mechanism. These developments highlight nature's ability to provide guidance for the most unexpected applications.

α-Linolenic Acid-Enriched Diet Prevents Myocardial Damage and Expands Longevity in Cardiomyopathic Hamsters

“…41,42 In addition, EPA induces the suppression of tumor necrosis factor-␣ and interleukin-1␤ production, 43 the inhibition of platelet aggregation, 44 and the generation of -3-derived mediators (resolvins and protectins) that could provide novel mechanisms of tissue damage repair. 12,45 Furthermore, EPA also modulates gap junction 10 and cell signaling by influencing intracellular trafficking and the localization of membrane proteins. In CMPH/FS hearts, the tissue-specific synthesis of EPA (not detectable in CMPH/FS plasma nor in GSH/PT and CMPH/PT plasma or cardiac tissue) and the remarkable consensual decrease in AA boosted the EPA/AA ratio; this could reduce the myocardial risk of inflammatory injuries and of further structural and functional damages.…”

“…In addition, most investigations have been performed using marine-derived -3 PUFAs, 9 and only a few epidemiological studies have evaluated ALA's potential against cardiovascular diseases. Furthermore, although the cardioprotective ability of -3 PUFAs has been mainly related to anti-arrhythmic and anti-fibrillatory effects, 10 and among others, recent studies indicate that they could act by altering lipid composition 11 and plasma membrane structure to regulate intracellular signaling 12 and metabolism, 13 further in-depth research is needed to establish the amount of dietary -3 PUFAs that maximally affects the greatest number of cardiovascular risk factors and to determine the exact cellular and molecular mechanisms through which -3 PUFAs elicit their beneficial effects on the cardiovascular system.…”

Low dietary fish-oil threshold for myocardial membrane n-3 PUFA enrichment independent of n-6 PUFA intake in rats

“…In terms of relative human intake, we calculated this estimated threshold to be equivalent to a single 1 g capsule of fi sh oil per week ( Table 4 ). Moreover, long chain n-3 PUFA intake in the rat, equivalent in humans to only two meals of fatty fi sh per week, was suffi cient to double the myocardial concentration of DHA, the principle myocardial n-3 fatty acid in the heart of many species ( 14 ). This equates to an n-3 PUFA intake consistently associated with low risk of cardiovascular disease mortality ( 28,29 ).…”

“…It is increased by low intake of fi sh oil in humans ( 39 ) now demonstrated in rats, showing for the fi rst time that both human and rat hearts respond within a similar low dietary range. Other similarities between humans and rats include increased myocardial DHA concentrations associated with chronic stress leading to sudden death ( 43 ), lowering sudden death risk with dietary fi sh oil ( 14 ), and reduced heart rate with dietary-induced increases in myocardial DHA concentration ( 14,44 ).…”

“…Cardiovascular benefi ts ascribed to regular fi sh consumption include slowed resting heart rate ( 6-8 ) and reduced risk for cardiac arrest ( 9,10 ), heart failure ( 11,12 ), and atrial fi brillation ( 13 ). These can all be attributed to direct effects in the heart on the basis of experimental observations ( 14 ).…”