According to Dr. Stuart Connolly, Professor of Medicine, McMaster University, and Director, Arrhythmia Service and Electrophysiology Laboratory, Hamilton Health Sciences Centre, Ontario, data from the Nurses’ Health Study showed that women with very high fish intake had half the risk of cardiovascular (CV) mortality of those whose intake was in the lowest study quintile (JAMA 2002;287(14):1815-21). Similarly, the Cardiovascular Health Study (Circulation 2004;110:368- 73) and the Physicians’ Health Study (Am J Epidemiol 1995;142(2):166-75) documented a reduced risk of sudden cardiac death (SCD) in men who ate at least five servings of fish per week vs. fewer than one per month. Elevated fish intake has also been associated with lower risk of atrial fibrillation and stroke, he noted.
  Dr. Heinz Rupp, Professor of Physiology, Philipps University, Marburg, Germany, explained that the crucial constituents of fish in this CV risk stratification are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and that in the years to come, measurement of these factors might become as important as assessment of other risk parameters such as blood pressure and cholesterol.
  The Physicians’ Health Study proved the direct relationship between these substances and SCD, determining that individuals with the highest vs. lowest blood levels had a relative risk of 0.31 (P=0.004) (New Engl J Med 2002;346(15):1113-8), Dr. Connolly stated. A related research step involved determining whether consumption of DHA and EPA could reduce the risk of clinical CV events. In the Diet and Reinfarction Trial (Lancet 1989;2(8666):757-61), increased consumption of fatty fish led to a statistically significant 29% reduction in all-cause mortality among patients with a history of myocardial infarction (MI).

The 11,323-patient GISSI-Prevenzione study (Circulation 2002;105(16):1897-903) determined that when added to proven secondary preventive agents in patients with a history of MI, dietary supplementation with 1 g of highly purified omega-3 polyunsaturated fatty acids (PUFAs) could reduce overall mortality and major CV events by 15% to 20%. The major driver of this reduction was a striking 44% reduction in SCD, Dr. Connolly remarked. This landmark study led to the approval of the pharmaceutical grade omega-3 PUFA in post-MI patients.
The recommended omega-3 PUFA dose of 1 g/day may generally be achieved with three fish oil capsules (which contain up to 30% EPA and DHA triacylglycerols) or a single daily capsule of a highly concentrated product, Omega-3, which contains more than 80% EPA and DHA ethyl esters, noted Dr. Rupp. His work suggests that Omega-3 has more prolonged action than fish oil and that after 15 to 43 days of administration, patients had higher sustained EPA and DHA levels. The resulting influx of EPA and DHA into peripheral tissues and alteration of cellular ion channels is a likely explanation for a reduced risk of SCD, he commented. The treatment benefits arise mostly from a reduction of SCD from the apparent anti-arrhythmogenic action of highly purified omega-3 PUFAs for which comparable effects are not seen with other fatty acids (J Clin Basic Cardiol 2002;5(3):209-14)..

Results from animal studies and the GISSI Prevenzione trial suggested highly purified omega-3 PUFAs might have a direct electrophysiologic activity, resulting in a higher threshold for and/or prevention of ventricular fibrillation (VF) and ventricular

tachycardia (VT), Dr. Connolly stated. A few small, randomized controlled trials testing this promising hypothesis have been reported and others are in progress.
However, a recent study by Raitt et al. (JAMA 2005;293:2884-91) found no effect on VF or VT risk in patients with implantable cardiac defibrillators (ICDs) receiving 1.8 g/ day EPA and DHA, although a trend toward benefit in patients who had only VF at study entry was observed. Similar data from the 546-patient SOFA (Study on Omega-3 Fatty Acid and Ventricular Arrhythmia) indicate fish oil is not beneficial for all patients. According to Dr. Ingeborg Brouwer, Wageningen Centre for Food Sciences and Division of Human Nutrition, Wageningen University, The Netherlands, after one year, there was no significant difference between patients receiving 2 g/ day of fish oil or placebo oil on mortality or life-threatening arrhythmia. There was a trend toward anti-arrhythmic benefit in the subgroup of patients with previous MI: 28% of treated patients and 35% in the placebo group (P=0.086) experienced arrhythmia or died.
  Dr. Connolly observed that in this respect, the SOFA results are of interest because patients in the early post-MI period are the target population for omega-3 PUFA supplementation. He noted that ICD patients are a convenient population for this type of study, but are generally not in the early phase after MI. “Typically, an ICD goes in years after infarction, and the typical arrhythmia that we see is VT related to a relatively stable re-entry circuit—probably a different mechanism from that which occurred in the early post-MI GISSI patients,” he explained. He added, “The human studies to this point are disappointing, although it’s clear we have not really looked at the disease that we want to look at in particular.”

Dr. Nancy Frasure-Smith, Professor of Psychiatry, McGill University and Senior Research Associate, Montreal Heart Institute, Quebec, observed that clinical depression is more than twice as common in patients hospitalized for coronary artery disease (CAD) than in the general population. Her research has demonstrated that clinical depression after MI or unstable angina is a significant independent risk factor for mortality in the six months after the event, chiefly due to sudden arrhythmic death. Furthermore, she noted, there is a relationship between the degree of depression during hospitalization and the risk of mortality in the five years after MI. “The adjusted relative risk is about two to four, depending on the sample. This is about the same level of risk as that of most established cardiac risk factors,” she reminded delegates.

  Depression is also a predictor for primary CAD and related events. According to a recent meta-analysis (Psychosom Med 2004;66(6):802-13), the hazard ratios for developing CAD were 1.5 and 2.7 in patients with depressive symptoms and major depression, respectively. In the Canadian-led Interheart Study (Lancet 2004;364(9438):937-52), patients who had MI were 1.56 times more likely than controls to have been depressed in the year prior to the event. “The population-attributable risk was about 9%, meaning that if we were to eliminate depression, we could reduce the number of first MIs by about 9% per year. Interestingly enough, this is about the same as the populationattributable risk of diabetes,” commented Dr. Frasure-Smith.
  Epidemiologic surveys and case control studies indicate that as is the case for CAD, there is a negative correlation between fish intake or EPA/DHA levels and depression. In addition, the incidence of death due to SCD in patients with depression and CAD is relatively high. According to Dr. Frasure- Smith, among the numerous mechanisms proposed for the link between depression and CAD are autonomic dysregulation, inflammation, endothelial dysfunction and platelet changes. Interestingly, these mechanisms may also explain how omega-3 PUFA supplementation might improve prognosis, she stated, because these substances have the potential to moderate heart rate variability, have anti-arrhythmic, anti-inflammatory and antithrombogenic properties, and promote endothelial relaxation.
  Dr. W. Emanuel Severus, Department of Psychiatry, Ludwig Maximilians University, Munich, Germany, noted that there is an urgent need for treatments that can address both depression and associated CAD, as current antidepressants (notably, the tricyclics) may have adverse effects on CV outcomes. To date, no study has specifically addressed whether omega-3 PUFAs are effective at reducing CV outcomes in patients with depression and CAD, he said. However, some small trials have determined that EPA (1 to 2 g/day), DHA (1 g/day) and a combination of the two (6.6 to 9.6 g/day) have significant antidepressant properties. Although he stressed that further trials are needed to confirm their cardioprotective and antidepressant efficacy, he suggested that adequate doses of omega-3 PUFAs might prove effective in decreasing the excess CV and other mortality risks related to depression.
  As supplements offer the most consistent way in providing high doses of omega-3 PUFAs, they may be considered as an alternative to a fish-enriched diet. As well, a highly purified pharmaceutical grade supplement will offer EPA and DHA free of mercury, pesticides and other pollutants.