Membrane basis for fish oil effects on the heart: Linking natural hibernators to prevention of human sudden cardiac death

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.