Peter L McLennan

Dietary fish oil prevents ventricular fibrillation following coronary artery occlusion and reperfusion.

Coronary artery occlusion and reperfusion in the anesthetized rat was used as a whole animal model of arrhythmia and sudden cardiac death to examine the influence of long-term dietary lipid modulation of myocardial membrane fatty acids on the development of cardiac arrhythmias. Feeding rats a diet supplemented with tuna fish oil significantly reduced the incidence and severity of arrhythmias, preventing ventricular fibrillation during both occlusion and reperfusion. Dietary sunflower seed oil reduced arrhythmias during occlusion but not in reperfusion. Dietary fat can modify the vulnerability of the myocardium to arrhythmic stimuli. The efficacy of tuna fish oil in reducing vulnerability to both ischemic and reperfusion arrhythmias suggests a potential beneficial effect of dietary n-3 fatty acids in addition to their influence on hemostasis, plasma lipids, and atherosclerosis that may contribute to their proposed role in lowering cardiovascular disease mortality and morbidity.

The cardiovascular protective role of docosahexaenoic acid

Dietary fish oils rich in n-3 polyunsaturated fatty acids can modulate a diverse range of factors contributing to cardiovascular disease. This study examined the relative roles of eicosapentaenoic acid (20:5 n-3; EPA) and docosahexaenoic acid (22:6 n-3; DHA) which are the principal n-3 polyunsaturated fatty acids regarded as candidates for cardioprotective actions. At low dietary intakes (0.4-1.1% of energy (%en)), docosahexaenoic acid but not eicosapentaenoic acid inhibited ischaemia-induced cardiac arrhythmias. At intakes of 3.9-10.0%en, docosahexaenoic acid was more effective than eicosapentaenoic acid at retarding hypertension development in spontaneously hypertensive rats (SHR) and inhibiting thromboxane-like vasoconstrictor responses in aortas from SHR. In stroke-prone SHR with established hypertension, docosahexaenoic acid (3.9-10.0%en) retarded the development of salt-loading induced proteinuria but eicosapentaenoic acid alone was ineffective. The results demonstrate that purified n-3 polyunsaturated fatty acids mimic the cardiovascular actions of fish oils and imply that docosahexaenoic acid may be the principal active component conferring cardiovascular protection.

Cardiac Membrane Fatty Acid Composition Modulates Myocardial Oxygen Consumption and Postischemic Recovery of Contractile Function

Background—Regular fish consumption is associated with low cardiovascular disease morbidity and mortality. Fish oils modify cardiac membrane phospholipid fatty acid composition with potent antiarrhythmic effects. We tested the effects of dietary fish oil on ventricular hemodynamics and myocardial oxygen consumption (MVO2). Methods and Results—Male Wistar rats were fed for 16 weeks on a reference diet rich in n-6 polyunsaturated fatty acids (PUFA), a diet rich in saturated animal fat (SAT), or a diet rich in n-3 PUFA from fish oil. Isolated working hearts were perfused with porcine erythrocytes (40% hematocrit) at 75 mm Hg afterload with variable preload (5 to 20 mm Hg) or with low coronary flow ischemia with maintained afterload, preload, and heart rate, then reperfused. MVO2 was low and coronary perfusion reserve high in n-3 PUFA hearts, and cardiac output increased with workload. The n-3 PUFA reduced ischemic markers—acidosis, K+, lactate, and creatine kinase—and increased contractile recovery during reperfusion. SAT hearts had high MVO2, low coronary perfusion reserve, and poor contractile function and recovery. Dietary differences in MVO2 were abolished by KCl arrest (basal metabolism) or ruthenium red (3.4 &mgr;mol/L) but not by ryanodine (1 nmol/L). Fish oil or ryanodine, but not ruthenium red, prevented ventricular fibrillation in reperfusion. Conclusions—Dietary fish oil directly influenced heart function and improved cardiac responses to ischemia and reperfusion. The n-3 PUFA reduced oxygen consumption at any given work output and increased postischemic recovery. Thus, direct effects on myocardial function may contribute to the altered cardiovascular disease profile associated with fish consumption.

Dietary lipid modulation of ventricular fibrillation threshold in the marmoset monkey

Programmed electrical stimulation was used to examine the ability of long-term dietary lipid modulation to influence myocardial vulnerability to the induction of ventricular fibrillation in adult marmoset monkeys (Callithrix jacchus). Marmosets fed diets supplemented (to a total of 28.5% of the energy as fat) with polyunsaturated fatty acid (PUFA)-rich tuna fish oil or sunflower seed oil had significantly elevated mean ventricular fibrillation threshold compared with those fed a saturated animal fat supplemented diet or a reference diet not supplemented with fat (11.2% of the energy as fat). Fibrillation threshold was reduced during acute myocardial ischemia induced by coronary artery occlusion but still remained higher in the PUFA-fed animals than either the control or the ischemic threshold in reference or saturated fat supplemented animals. Dietary tuna fish oil was associated with a low incidence of sustained fibrillation episodes and no fatalities. These results indicate that myocardial substrate vulnerability to arrhythmic stimuli is increased during ischemia in a nonhuman primate model but dietary PUFA can reduce vulnerability under both normal and ischemic conditions. Reduced dietary fat intake alone was without effect.

Myocardial membrane fatty acids and the antiarrhythmic actions of dietary fish oil in animal models

Epidemiologic studies, animal studies, and more recently, clinical intervention trials all suggest a role for regular intake of dietary fish oil in reducing cardiovascular morbidity and mortality. Prevention of cardiac arrhythmias and sudden death is demonstrable at fish or fish oil intakes that have little or no effect on blood pressure or plasma lipids. In animals, dietary intake of fish oil [containing both eicosapentaenoic acid (EPA, 20∶5n−3) and docosahexaenoic acid (DHA, 22∶6n−3)] selectively increases myocardial membrane phospholipid content of DHA, whereas low dose consumption of purified fatty acids shows antiarrhythmic effects of DHA but not EPA. Ventricular fibrillation induced under many conditions, including ischemia, reperfusion, and electrical stimulation, and even arrhythmias induced in vitro with no circulating fatty acids are prevented by prior dietary consumption of fish oil. The preferential accumulation of DHA in myocardial cell membranes, its association with arrhythmia prevention, and the selective ability of pure DHA to prevent ventricular fibrillation all point to DHA as the active component of fish oil. The antiarrhythmic effect of dietary fish oil appears to depend on the accumulation of DHA in myocardial cell membranes.

Role of fat amount and type in ameliorating diet‐induced obesity: insights at the level of hypothalamic arcuate nucleus leptin receptor, neuropeptide Y and pro‐opiomelanocortin mRNA expression

Aims:  Dietary fatty acid profile, independent of caloric percent of fat, is a major regulator of body adiposity. This study examined the effects of dietary fat amount and types on fat storage and hypothalamic gene expression in the mouse model of chronic diet‐induced obesity.

Fish oil reduces heart rate and oxygen consumption during exercise

Dietary omega-3 polyunsaturated fatty acids (PUFAs) are readily incorporated into heart and skeletal muscle membranes where, in the heart, animal studies show they reduce O2 consumption. To test the hypothesis that omega-3 PUFAs alter O2 efficiency in humans, the effects of fish oil (FO) supplementation on O2 consumption during exercise were evaluated. Sixteen well-trained men (cyclists), randomly assigned to receive 8 × 1 g capsules per day of olive oil (control) or FO for 8 weeks in a double-blind, parallel design, completed the study (control: n = 7, age 27.1 ± 2.7 years; FO: n = 9, age 23.2 ± 1.2 years). Subjects used an electronically braked cycle ergometer to complete peak O2 consumption tests (VO2peak) and sustained submaximal exercise tests at 55% of peak workload (from the VO2peak test) before and after supplementation. Whole-body O2 consumption and indirect measurements of myocardial O2 consumption [heart rate and rate pressure product (RPP)] were assessed. FO supplementation increased omega-3 PUFA content of erythrocyte cell membranes. There were no differences in VO2peak (mL kg−1 min−1) (control: pre 66.8 ± 2.4, post 67.2 ± 2.3; FO: pre 68.3 ± 1.4, post 67.2 ± 1.2) or peak workload after supplementation. The FO supplementation lowered heart rate (including peak heart rate) during incremental workloads to exhaustion (P < 0.05). In addition, the FO supplementation lowered steady-state submaximal exercise heart rate, whole-body O2 consumption, and RPP (P < 0.01). Time to voluntary fatigue was not altered by FO supplementation. This study indicates that FOs may act within the healthy heart and skeletal muscle to reduce both whole-body and myocardial O2 demand during exercise, without a decrement in performance.

Dietary fish oil dose- and time-response effects on cardiac phospholipid fatty acid composition.

Fish consumption is associated with reduced cardiovascular mortality, and elevated myocardial long-chain n−3 polyunsaturated FA (PUFA) content is implicated in this cardioprotection. This study examined the dose and time responses for incorporation of n−3 PUFA into cellular membranes in rats fed fish oil (FO)-containing diets. For the time course study, rats were fed a 10% FO diet for periods ranging from 0 to 42 d, after which myocardial and erythrocyte membrane fatty acid composition was determined. For the dose response study, rats (n=3) were fed 0, 1.25, 2.5, 5, or 10% FO for 4 wk, with myocardial, erythrocyte, and skeletal muscle membrane FA determined. Myocardial DHA (22∶6n−3) levels doubled in 2 d, stabilizing at levels ≈200% higher than control after 28 d feeding with 10% FO. By comparison, DHA levels doubled after 4 wk of 1.25% FO feeding. In myocardium and skeletal muscle, EPA (20∶5n−3) levels remained low, but in erythrocytes EPA levels reached 50% of DHA levels. The n−3 PUFA were incorporated at the expense of n−6 PUFA in myocardium and skeletal muscle, whereas erythrocytes maintained arachidonic acid levels, and total n−3 PUFA incorporation was lower. This study shows that low doses of FO produce marked changes in myocardial DHA levels; maximal incorporation takes up to 28 d to occur; and while erythrocytes are a good indicator of tissue n−3 incorporation in stable diets, they vary greatly in their time course and pattern of incorporation.

Comparative Changes in the Fatty-Acid Composition of Rat Cardiac Phospholipids after Long-Term Feeding of Sunflower Seed Oil- or Tuna Fish Oil-Supplemented Diets

The fatty-acid composition of rat heart phospholipids was examined after long-term, i.e. more than 12 months, feeding of diets supplemented with n-6 fatty acids as sunflower seed oil (SSO), or n-3 fatty acids as tuna fish oil (TFO) which is a particularly rich source of docosahexenoic acid (DHA). Although some small changes occurred in the relative proportions of palmitic and stearic acids and in the ratio of total saturates to total unsaturates, the most important changes were in the relative proportions of 18:2 n-6 and 20:4 n-6 to 20:5 n-3 and 22:6 n-3. In general, the n-6/n-3 ratio of phosphatidylcholine (PC), phosphatidylethanolamine (PE) and diphosphatidyl glycerol (DPG) was altered in favour of the family of fatty acids administered, although the proportions of the individual long-chain polyunsaturated fatty acids which contributed to this ratio varied from one class of phospholipids to another. In cardiac PC and PE, feeding TFO supplements reduced the proportions of arachidonic acid (AA) and significantly elevated (p less than 0.01) the proportions of DHA but produced relatively little change in those of eicosapentenoic acid (EPA). In DPG, feeding TFO led to a significant increase in the proportion of AA as well as an increase in DHA. The level of EPA was relatively low in PC, PE and DPG even after TFO feeding and never reached comparable levels with that of either AA or DHA. Nevertheless the n-6/n-3 ratio in all these classes of major cardiac phospholipids was significantly reduced by feeding TFO compared to the SSO diet or the commercial rat chow (CC) reference group. In contrast to the reports of other workers who have studied the fatty-acid composition of platelet membranes after feeding various fish oil supplements, in the rat heart the major effect of tuna fish oil is an increase in the proportion of DHA rather than EPA in the cardiac phospholipids.

Dietary modulation of lipid metabolism and mechanical performance of the heart

Sudden Cardiac Death resulting from sustained ventricular fibrillation or malignant cardiac arrhythmia has been linked to the type of dietary fat intake in several economically well developed countries where high levels of saturated fatty acids are common. Experimental studies with the small non-human primate marmoset monkey have clearly demonstrated the health benefit of substituting polyunsaturated fatty acids (PUFAs) for dietary saturated fatty acids. Heart rate and blood pressure are lowered, while the left ventricular ejection fraction and the electrical threshold for the induction of ventricular fibrillation are both increased after prolonged feeding of PUFA enriched diets. All these changes in heart function reduce the risk of developing malignant cardiac arrhythmias.The fatty acid composition of cardiac membrane phospholipids is profoundly altered by these changes in dietary lipid intake. In particular the proportions of arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexae noic acid (DHA) are altered in such a way that the production of myocardial eicosanoids is affected. Although the changes in proportion of these long-chain PUFAs in cardiac phosphatidyl ethanolamine and phosphatidyl inositol are not identical, the shift in balance between these substrates or inhibitors of cyclo-oxygenase activity leads to relatively greater production of prostacyclin (PGI2) than thromboxane (TXA2).The effect of the omega-3 PUFAs of fish oil is proportionally greater than that of linoleic acid (LA; 18:2, ω6) rich sunflower seed oil, particularly during ischaemia, and probably reflects the different nutritionally induced changes in cardiac membrane fatty acid composition by these different types of dietary PUFAs. (Mol Cell Biochem 116: 19–25, 1992).