COMMENTARIES

Fish intake and QTc protection

Christina Chrysohoou, M.D., Ph.D., Registrar Cardiologist, 1st Cardiology Clinic University of Athens,
Hippokration Hospital, 144 Vas. Sofias, 11528 Athens,
Greece
E-mail: chrysohoou@usa.net

The Mediterranean type of diet has been proved to have a significant beneficial impact on the progression of cardiovascular diseases. Fish is one of the main components of this diet; while many epidemiological studies and clinical trials have indicated its antioxidant and anti-inflammatory properties and its beneficial effects on the clinical outcome in patients with cardiovascular disease [1,2]. Furthermore, many studies have shown long-chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFAs), which comprise the most important components of fish diet, may protect against heart disease mortality and morbidity. One way that long-chain omega-3 polyunsaturated fatty acids reduce the chance of sudden cardiac death is by reducing abnormal heart rhythms. The Q-T interval on the electrocardiogram measures the duration of polarization and repolarization of ventricular myocardium; while studies in the general population have revealed that longer QTc interval correlates with an increased mortality risk. We tried to evaluate the effects of chronic fish consumption on QT duration in free-eating population [1]; for the purpose of this study we used the data from ATTICA study that enrolled 3,042 persons without any evidence of cardiovascular disease, from the general population. All participants answered a detailed food frequency questionnaire, blood was taken, and a surface electrocardiogram was recorded where heart rate and the duration of ventricular polarization and depolarization corrected for heart rate (QTc duration) was measured. In this population, fish consumption was associated with age and obesity, but inversely with years of school and hypertension. About 90% of participants reported eating fish at least once/week, mainly sardines, goatfish, giltheads, and tope. Fish intake was divided into 4 categories: none or very rare; rare (< 150 g or about 5 oz/week); moderate, 150-300 g/week; and frequent, > 300 g or nearly 11 oz/week. Fish consumption was also inversely related to serum triglyceride levels and systolic blood pressure. Furthermore, we observed a strong inverse relationship between fish consumption and QTc duration in resting ECG recording, in cardiovascular disease-free subjects. These associations remained significant even after various adjustments were made, including nut intake that is rich in n-3 fatty acids, sex, age, body mass index, smoking, diabetes mellitus, lipids levels, smoking, and physical status. In particular an increase in consumption of 2 servings (i.e. 300 g) of fish per week was associated with 0.01 sec lower QTc interval. When the relationship between fish consumption and QTc interval was adjusted for several potential confounders (e.g. nut intake, age, sex, BMI, education, smoking, physical activity, hypertension, hypercholesterolemia, diabetes), QTc remained significantly and inversely related to fish intake. Those findings come in accordance with the report of the National Heart, Lung and Blood Family Heart Study, where participants who were in the highest tertile of alpha-linolenic acid consumption had shorter QT interval [3]; while Geelen A et al., in a clinical trial where 1.5 g n-3 fatty acids or placebo were given daily for 14 weeks, found no effect on QTc duration and other characteristics of the electrocardiogram in the participants [4]. Other observational studies and randomized trials have also indicated clinical benefits of fatty fish or fish oil consumption at relatively modest intake, 1 to 2 servings per week or 500 to 1000 mg/d eicosapentaenoic acid and docasohexaenoic acid, respectively. In the meta-analysis by Mozaffarian et al. [5], the lowest eicosapentaenoic acid and docasohexaenoic acid doses were 1 g/d, and it is possible that a dose-response effect may exist at lower (e.g. dietary) levels of intake. A recent study from the same investigators in a large population-based sample revealed the beneficial impact of tuna or other boiled or baked fish consumption on cardiac electrocardiographic parameters related to arrhythmic risk, including a 46% lower likelihood of prolonged QT interval [6].  In ATTICA study a nearly 30% lower likelihood of having QTc > 0.45 sec was revealed when people consume more than 300 g of fish per week. This finding is modest compared to other studies, but the population of this work is free-eating individuals in the Mediterranean region, where the fish consumption mainly involves small lean fat fish, and other natural sources of n-3 fatty acids were also taken into account in the analysis (i.e. nuts). Furthermore, the potential confounding effect of other habits of the studied Mediterranean sample, such as the way of cooking and serving fish, with vegetables, legumes, fruits, and especially olive oil, may play a role in the different impact of fish consumption on the investigated cardiac electrocardiographic parameters.

          The possible mechanisms that n-3 fatty acids modify cardiovascular risk may be through the modulation of L-type calcium channels in the sarcolemma of cardiac myocytes, or the suppression of plasma levels metabolites of linoleic acid, such as thromboxane A2 which stimulates vasoconstriction and platelet aggregation. So, in that way fish consumption has antithrombotic properties. Another possible mechanism is that fish intake which is rich in alpha-linoleic acid promotes the formation of prostaglandin I3, which acts as a vasodilator, and thromboxane A3, which is less active. Thus a limited amount of linolenic acid is converted to eicosapentaenoic fatty acid which competes with arachidonic acid. The final result is the inhibition of the production of thrombaxane A2 that causes vasoconstriction and platelet aggregation, reducing the risk for ventricular arrhythmia and cardiac arrest.

          Furthermore, omega-3 express anti-inflammatory properties, while the dietary intake of linolenic acid in foods, where is predominantly in alpha-form, as in flaxseed, linseed, canola oil, soybean oil, green leafy vegetables and fish is inversely associated with QTc and JTc intervals in a dose-response manner in both sexes. The shortening of QTc duration limits the possibility of the occurrence of ventricular arrhythmia and sudden cardiac death.

          Some limitations in our study may exist. For example, the design of the study is cross-sectional and therefore we cannot make assumptions for causal relationships. Fish intake was evaluated by self-reports through food frequency questionnaires and therefore, information about the amount of fish consumed could be over- or under-estimated. Finally, large, randomized, double-blind controlled trials of purified n-3 LC-PUFAs in free eating population and patients following an acute myocardial infarction could provide more insights in this matter.

References

1.    Chrysohoou C, Panagiotakos DB, Pitsavos C, et al. Long-term fish consumption is associated with protection against arrhythmia in healthy persons in a Mediterranean region-the ATTICA study. Am J Clin Nutr 2007;85:1385-91.
2.    Zampelas A, Panagiotakos DB, Pitsavos C, et al. Fish consumption among healthy adults is associated with decreased levels of inflammatory markers related to cardiovascular disease: the ATTICA study. J Am Coll Cardiol 2005;46:120-24.
3.    Djousse L, Rautaharju PM, Hopkins PN, et al, on behalf of the investigators of the NHLBI family heart study. Dietary linolenic acid and adjusted QT and JT intervals in the national heart lung, and blood institute family heart study. J Am Coll Cardiol 2005;45:1716-22.
4.    Geelen A, Zock PL, Brouwer IA, et al frequent premature ventricular complexes. Br J Nutr 2005;93:787-90.
5.    Mozaffarian D, Gottdiener JS, Siscovick DS. Intake of tuna or other broiled or baked fish versus fried fish and cardiac structure, function, and hemodynamics. Am J Cardiol 2006;97:216-22.
6.    Mozaffarian D, Prineas RJ, Stein PK, Siscovick DS. Dietary fish and n-3 fatty acid intake and cardiac electrocardiographic parameters in humans. J Am Coll Cardiol 2006;48:478-84.