Response to the Letter of Hester Den Ruijter and Ruben Coronel Regarding the Article “The Role of n-3 PUFAs in Preventing the Arrhythmic Risk in Patients with Idiopathic Dilated Cardiomyopathy”

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We thank Drs Hester M. Den Ruijter and Ruben Coronel for their valuable comments [1]. Consumption of fish or fish oil is associated with lower risk of arrhythmic outcomes including sudden death and atrial fibrillation [2]. However, the mechanisms underlying these relationships are not well established and may include direct or indirect effects on myocardial electrophysiology, which may apply to numerous potential arrhythmogenic substrates (heart failure, acute ischemia, infarct scar and hibernated/ stunned myocardium). Of note, n-3 PUFAs may worsen arrhytmic events based on re-entry circuits activation as in the presence of large infarct scar or hibernated/stunned myocardium, but may also reduce risk of ventricular arrhythmias in implantable cardioverter defibrillator patients without coronary artery disease [3]. Trials evaluating fish oil have shown controversial results, possibly due to different sample size and duration of intake or variable pharmacological doses of fish oil, dietary intake of n-6 fatty acids and concomitant medication [4]. Different arrhythmogenic substrates may be a cause of divergent results, as well. In our patients, with idiopathic dilated cardiomyopathy, the predominant arrhythmogenic substrate is a non-reentrant mechanism that likely involves triggered activity from delayed after depolarizations in response to catecholamines. Recent work by Drs Den Ruijter and Coronel has shown that triggered arrhythmias are inhibited by fish oil in isolated myocytes of patients with end-stage heart failure as a result of cardiac action potential shortening, decreased diastolic and systolic intracellular calcium levels and a reduced response to β-adrenergic stimulation [5]. Probably in heart failure patients also other favorable biological effects of n-3 PUFAs, as we observed in our study (reduction of heart rate, inflammatory pathways and catecholamine plasma levels, increase of heart rate variability, etc), may indirectly contribute to antiarrhythmic result of the fish oil treatment. Certainly, as Dr Raitt has emphasized in his editorial, an improvement in markers of risk may not translate to improvement in outcome and large prospective trials assessing the n-3 PUFA effects on mortality or severe ventricular arrhythmias need to be performed [6]. We agree with Drs Den Ruijter and Coronel and hypothesize that habitual consumption of fish and long-chain n-3 fatty acid intake would be associated with more favorable outcomes just in selected populations. According to the available evidence, trial designs in heart failure patients have to take into account not only the different aetiology, but also the severity of heart failure, as the relative importance of the arrhythmogenic mechanisms may change over time with the progression of disease. …