linoleic-acid and Arrhythmias--Cardiac

It has long been recognized from epidemiological studies that Greenland Eskimos have substantially reduced rates of acute myocardial infarction (MI) compared with Western controls. From these epidemiological observations, the benefits of fatty fish consumption have been explored in cell culture and animal studies, as well as randomized controlled trials investigating the cardioprotective effects of omega-3 fatty acids. Dietary omega-3 fatty acids seem to stabilize the myocardium electrically, resulting in reduced susceptibility to ventricular arrhythmias, thereby reducing the risk of sudden death. These fatty acids also have potent anti-inflammatory effects, and may also be antithrombotic and anti-atherogenic. Furthermore, the recent GISSI-Prevention study of 11 324 patients showed a marked decrease in risk of sudden cardiac death as well as a reduction in all-cause mortality in the group taking a highly purified form of omega-3 fatty acids, despite the use of other secondary prevention drugs, including beta-blockers and lipid-lowering therapy. The use of omega-3 fatty acids should be considered as part of a comprehensive secondary prevention strategy post-myocardial infarction.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Dogs; Fatty Acids, Omega-3; Female; Forecasting; Humans; Linoleic Acid; Male; Nutritional Physiological Phenomena; Randomized Controlled Trials as Topic; Rats; Risk Factors; Treatment Outcome

Leukotoxin (Lx), an epoxide derivative of linoleic acid, has been suggested to be a toxic mediator of multiple organ failure in burn patients and of acute respiratory distress syndrome. Lx production was recently shown during myocardial ischemia/reperfusion. However, a recent study suggested that to be toxic Lx must be metabolized to Lx-diol. In the present study, isolated adult rat ventricular myocytes were studied with the whole-cell patch-clamp technique to determine the effects of these compounds on cardiac electrical activity. Measurements of action potentials showed that neither linoleic acid nor Lx (100 microM) caused any significant changes in action potential properties. However, Lx-diol in the range of 10-100 microM produced a dose dependent increase in duration and a decrease in overshoot of the action potential. Subsequent voltage clamp experiments isolating Na current (INa) and transient outward K current (Ito) revealed that Lx-diol inhibited INa and Ito by about 80% at 100 microM, while linoleic acid and Lx had no effect on these currents at the same concentration. While Lx-diol produced the same inhibition of INa and Ito at 100 microM, its effects were more potent on Ito with significant inhibition at 10 microM. Lx-diol also hastened the activation kinetics of Ito but not INa. The action of Lx-diol was rapid (reaching steady state in 3-5 min) and was reversible in 5-10 min following washout. Thus, Lx-diol could favor arrhythmias or cardiac arrest in intact heart and may be responsible for the cardiac problems seen in systemic inflammatory response syndrome. These results further support the suggestion that Lx is not toxic in the heart but rather must be metabolized to Lx-diol to produce toxic effects on cardiac muscle.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Cells, Cultured; Dose-Response Relationship, Drug; Exotoxins; Heart Ventricles; Linoleic Acid; Mass Spectrometry; Myocardium; Patch-Clamp Techniques; Potassium; Rats; Sodium; Stearic Acids

A novel series of 2-O-alkylascorbic acids (5a-u) was synthesized, and their scavenging activities against active oxygen species as well as their suppressive effects on the arrhythmias in rat heart ischemia-reperfusion models were evaluated. Some 2-O-alkylascorbic acids (5e-1) exhibited potent inhibiting activities against lipid peroxidation in rat brain homogenates and in alleviating effects in the ischemia-reperfusion models. Studies on the structure-activity relationship demonstrated that a free 3-enolic hydroxyl group and the longer alkyl chains substituted on the 2-hydroxyl group of ascorbic acid were beneficial for the biological and pharmacological activities. 2-O-Octadecylascorbic acid (5k, CV-3611), one of the most potent and promising compounds, markedly inhibited lipid peroxidation (IC50 = 4.3 X 10(-6) M) and alleviated myocardial lesions induced by ischemia-reperfusion at an oral dose of 1 mg/kg in rats.

Topics: Animals; Arrhythmias, Cardiac; Ascorbic Acid; Heart Rate; Ligation; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Male; Micelles; Oxygen; Rats; Structure-Activity Relationship

Dietary lipid supplements high in either saturated fatty acids derived from sheep perirenal fat or polyunsaturated fatty acids (65% linoleic acid) derived from sunflower seed oil were fed to marmoset monkeys (Callithrix jacchus) for 20 months. The effect of these long-term dietary lipid supplements on myocardial contractile function and their influence on responses to isoprenaline and external calcium concentration were examined using isolated papillary muscles and atria. Isoprenaline potency was increased by the sheep fat-supplemented diet, which induced significant three- to eightfold leftward parallel shifts of isoprenaline dose-response curves for papillary muscle and left atrial inotropy and right atrial chronotropy. The antagonist potency of propranolol was not influenced by diet. The incidence of isoprenaline-induced spontaneous tachyarrhythmias in electrically driven papillary muscles and left atria was reduced by the sunflower seed oil-supplemented diet and increased by the sheep fat diet, as were the spontaneous beat rate and calcium-dependent automaticity of right atria. These results show that dietary lipids can significantly modify stimulus-response coupling and alter the susceptibility to arrhythmogenesis in the heart of the nonhuman primate, and indicate that nutritional interventions may modify responses to cardioactive drugs as well as influence the development of cardiac disease.

Topics: Animals; Arrhythmias, Cardiac; Calcium; Callitrichinae; Dietary Fats; Heart; Heart Rate; Isoproterenol; Linoleic Acid; Linoleic Acids; Male; Myocardial Contraction; Propranolol; Receptors, Adrenergic, beta

Cardioprotective drugs are agents that prevent or moderate harmful consequences of impaired cardiac energetics, such as sudden coronary death (SCD) due to early post-occlusion ventricular fibrillation (EPVF), development of incapacitating myocardial necrosis. Cardioprotection may be due to anti-ischaemic action, correcting the imbalance between vascular supply and myocardial demand for blood, but also to cytoprotective effect, preserving cellular integrity in the presence of factors damaging structure and function of the cardiac cell membrane such as ischaemia, ionic imbalance and that of pH, etc. Neither anti-ischaemic nor cytoprotective effect alone, or in combination, are sufficient to warrant full cardioprotection, i.e. both prevention of SCD and limitation of infarct size. Thus the beta-blocker pindolol which is anti-ischaemic in its effect reducing myocardial O2 demand and protects from SCD and EVFP, failed to limit infarct size. Even interventions of a mainly cytoprotective type of action protecting from SCD and EPVF, such as the linoleic acid-rich diet, or lidocaine, were unable to limit infarct size, 7-oxoPGI2 (anti-ischaemic and cytoprotective) failed to protect from SCD, VF and did not limit infarct size. On the other hand the nonsteroidal anti-inflammatory drugs which, like salicylates or sulfinpyrazon, reduce myocardial O2 demand and protect from post-occlusion SCD and EPVF, effectively limiting infarct size.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Death, Sudden; Dietary Fats; Epoprostenol; Humans; Lidocaine; Linoleic Acid; Linoleic Acids; Myocardial Infarction; Pindolol

Male rats were fed for 3-4 months (short-term) or 12-15 months (long-term) on a standard laboratory diet alone (control) or supplemented with sunflower seed oil (SSO, 12% w/w) or sheep kidney fat (SKF, 12% w/w). Papillary muscles were electrically driven (1 Hz, 5 ms, supramaximal voltage) at 37 degrees C in Krebs-Henseleit solution, and contractions were measured isometrically. Both the positive inotropic responses to CA++ and the incidence of spontaneous tachyarrhythmias under catecholamine stress were increased by short-term SKF feeding and with age in control and SKF groups, whereas SSO prevented these changes. The results show a marked effect of age upon ventricular myocardial function in the rat, which appears to be accelerated by the consumption of animal (saturated) fat while polyunsaturated vegetable oil provides some degree of protection. It is suggested that changes in membrane lipid composition can alter the Ca++ handling characteristics of myocardial cells.

Topics: Age Factors; Animals; Arrhythmias, Cardiac; Blood Pressure; Calcium; Cardiomyopathies; Dietary Fats; Heart Rate; In Vitro Techniques; Isoproterenol; Linoleic Acid; Linoleic Acids; Lipidoses; Male; Myocardial Contraction; Papillary Muscles; Rats; Rats, Inbred Strains

Experiments on 77 white random-bred male rats weighing 200 +/- 10 g have shown that combinations of high unsaturated fatty acids (HUFA) containing the precursors of prostaglandin synthesis, arachidonic and linoleic acids, produce a powerful antiarrhythmic action during transitory coronary insufficiency. The effect was seen not only during ischemia but also during subsequent myocardial reperfusion. The combination of HUFA containing arachidonic and linoleic acids as precursors of prostaglandin synthesis exerted a more demonstrable antiarrhythmic action than that without arachidonic acid. The degree of the ischemia-induced depression of contractile process was less versus control, provided HUFA combinations contained arachidonic acid.

Topics: Animals; Arachidonic Acid; Arachidonic Acids; Arrhythmias, Cardiac; Coronary Disease; Fatty Acids, Unsaturated; Linoleic Acid; Linoleic Acids; Male; Prostaglandins; Rats