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• W1946812879 abstract "In 1978, a report from the Chief Medical Officer in Greenland documented that coronary heart disease (CHD) was responsible for only 3.5% of all deaths in Greenland Eskimos [1], a strikingly small number compared to the typical figures found in the Western countries. Seeking potential explanations for such low frequency of cardiac events, investigators at the University of Aalborg, in Denmark, noted that the serum lipids of Eskimos was enriched in omega-3 fatty acids, that is, polyunsaturated fatty acids with the first double bond found in position 3 when the molecule is scanned from its methyl (-CH3) end (n-3 PUFA) [2, 3]. They then identified fish oil as the primary source of n-3 PUFA in Eskimos’ diet [4], in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), whose abundance in plasma and platelets has antihemostatic, hence antithrombotic effects [5]. These molecules consequently became the target of a wealth of studies aimed at explaining their preventive effects against cardiovascular diseases. In 1985, Kromhout et al. evaluated the long-term impact of dietary n-3 PUFA on a cohort of 852 healthy men in the town of Zutphen, in the Netherlands. After 20 years of follow-up they found a 50% reduction in CHD-related deaths in subjects consuming at least 30 g of fish per day, as compared to the rest of the population [6]. Spurred by these findings in humans, later studies in small and large animal models sought to determine the mechanisms responsible for the beneficial impact of n-3 PUFA consumption on cardiovascular mortality. Reiner et al. reported a reduction of aortic atherosclerosis in mice with saturated fat diet supplemented with n-3 PUFA, and attributed it to the modulation of the expression and secretion of several macrophage effector molecules [7]. Other studies confirmed the reduction of atherogenesis in rodents and dog models of hypercholesterolemia or vascular injury subjected to fish oil rich diet, and highlighted the positive modulation of platelet function as a possible mechanism of action of n-3 PUFA [8-11]. The above mentioned evidences seemed solid enough to justify the launch, in 1989, of a large randomized clinical trial testing the protective effects of fish oil consumption in CHD patients. The early Diet And Reinfarction Trial (DART) was conducted in men undergoing secondary prevention for myocardial infarction. In the group advised to increase the dietary intake of fatty fish, it was observed a 29% reduction in all-cause mortality over the first 2 years of follow-up. Conversely, the dietary fish oil enrichment did not affect reinfarction and CHD-related death rate [12]. These surprising results suggested, for the first time in humans, a potential preventive action of n-3 PUFA against life-threatening arrhythmias, in addition to the expected antiatherosclerotic effect. Ten years later, the GISSI-P (Gruppo Italiano per lo Studio della Streptochinasi nell`Infarto Miocardico – Prevenzione) trial randomized 11,324 patients, enrolled within 3 months after acute myocardial infarction, for treatment with n-3 PUFA, vitamin E, n-3 PUFA+vitamin E, or placebo. The authors found that a daily dietary supplement with high-dose (850 mg) EPA and DHA reduced cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke altogether by 20%, despite the lack of benefits on atherosclerotic–thrombotic events. This reduction was mainly driven by a 45% fall in sudden cardiac death rate. No differences in the rate of myocardial reinfarction were detected among groups. This large prospective trial further supported the hypothesis that the benefit of n-3 PUFA consumption is mainly due to antiarrhythmic effects, also because a drop in death rate within the first 4 months of follow-up can be hardly explained by a reduction in atherosclerotic processes [13]. More recently, the same reduction in mortality could not be confirmed in patients with angina enrolled in the Diet and Angina Randomized Trial (DART 2). Proposed explanations for such inconsistency were the lower rate of malignant arrhythmias and the different proarrhythmic predisposing conditions in this lower risk subset of patients [14]. Finally, a very recent trial, the Japan EPA Lipid Intervention Study (JELIS), showed that a supplement of 1800 mg/day of EPA was effective to reduce the composite endpoint of sudden cardiac death, myocardial infarction, unstable angina, and revascularization procedures in a population of Japanese hypercholesterolaemic patients. Of note, EPA was added to a diet that is already about 10-fold richer in n-3 PUFA compared to the American one. Despite the study cohort was composed for over the 80% by patients without cardiovascular history, the investigators found a significant reduction of the primary endpoint in both primary and secondary prevention groups [15]. After the DART results were published, several experimental studies have been undertaken to explore the potential antiarrhythmic effects of n-3 PUFA. In animal models of ischemic sudden cardiac death, n-3 PUFA reduced malignant arrhythmias, particularly those associated with coronary occlusion/reperfusion. This protective action was present either after prolonged oral administration or intravenous injection immediately before induction of the arrhythmias [16-18]. A likely antiarrhythmic mechanism identified in cultured cardiomyocytes was PUFAs incorporation into the sarcolemma, where they might modulate the conductivity of several ion channels. In particular, n-3 PUFA might inhibit (1) the L-type Ca2+ current, thereby reducing the cytosolic Ca2+ fluctuations that trigger arrhythmias, and (2) the voltage-dependent Na+ current that decrease the resting membrane potential in the partially depolarized cardiomyocytes at the periphery of the ischemic area [19-21]. A general scheme summarizing these mechanisms is displayed in Figure 1. Proposed antiarrhythmic effects of n-3 PUFA. These intriguing experimental and clinical findings led to the hypothesis that n-3 PUFA prevent ventricular arrhythmias not only in the specific setting of postinfarction cardiomyopathy, but also in all patients at high risk of sudden death. Over the last two decades, the advent and the wide use of implantable cardioverters/defibrillators (ICD) allowed a more in-depth evaluation of the antiarrhythmic effects of n-3 PUFA. ICD are designed to record life-threatening arrhythmias such as ventricular tachycardia, mostly underestimated in the pre-ICD era when sudden cardiac death was the only arrhythmic endpoint evaluated. In 2005, a randomized trial analyzed the outcome of a regular daily consumption of fish oil fatty acids in patients implanted with ICD. The time to the first arrhythmic event requiring ICD response (sustained ventricular tachycardia or ventricular fibrillation) or to death from any cause was the primary endpoint of the study and was reduced by 28% in the treated group. Despite the risk reduction became significant only when probable arrhythmic events were added to the analysis, this study strongly supported a relevant antiarrhythmic action of n-3 PUFA in high-risk patients [22]. One year later, the SOFA (Study on Omega-3 Fatty Acids) trial failed to confirm prognostic improvements due to fish oil dietary supplement in a large cohort of patients with ICD and previous malignant ventricular arrhythmias [23]. A subgroup analysis indicated that the highest benefit in terms of time to the first arrhythmic event was present in the subpopulation of patients with prior myocardial infarction, despite the markedly variable time elapsed between infarction and randomization. Conversely, another recent randomized trial by Raitt et al. showed that n-3 PUFA do not reduce the risk of ventricular tachycardia and fibrillation in patients with ICD who had experienced a recent episode of ventricular malignant arrhythmia, and may even be proarrhythmic in some of them characterized by recurrent episodes of ventricular tachycardia [24]. The authors hypothesized the existence, in these patients, of an underlying electrophysiological proarrhythmic substrate other than ischemia and more likely related to a scar-based reentry. A recent meta-analysis conducted by Brouwer et al. on the most recent and largest trials, including 1148 patients with ICD, failed to demonstrate any protective effect of n-3 PUFAs against malignant tachyarrhythmias [25]. Focusing their analysis on subgroups, the authors concluded that n-3 PUFA might be effective in preventing arrhythmias caused by triggered activity and prolonged action potentials, whereas potentially harmful in patients with reentry arrhythmias. This electrophysiological interpretation might explain the contrasting results of the GISSI and the DART 2 trials. After so many studies in the field and clear evidence of some beneficial effects of n-3 PUFA on CHD, the lack of univocal results has not allowed drawing definite and universally accepted conclusions. That is probably why the 2006 AHA Diet and Lifestyle recommendations state that two servings per week of fish high in EPA and DHA reduce the risk of sudden death and death from CHD, whereas oily fish consumption is still a class IIbB recommendation in the current AHA/ACC guidelines for secondary prevention after myocardial infarction [26-28]. A question to be addressed is the effective dose and the way of intake of n-3 PUFA. Current guidelines suggest for patients with known CHD an amount of 800–1000 mg/day of EPA/DHA. This quantity is comparable to the GISSI trial dose, but significantly lower than the one used in the JELIS trial. Another key question regards the main beneficial effect of n-3 PUFA, whether antiatherosclerotic, antiaggregant, or antiarrhythmic. At present, no definitive answers to these questions. The authors declare no conflict of interests." @default.
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• W1946812879 title "Omega-3 Fatty Acids for the Prevention of Myocardial Infarction and Arrhythmias" @default.
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