Cell Biochem Biophys DOI 10.1007/s12013-014-0407-5
ORIGINAL PAPER
Omega-3 Fatty Acids and Primary and Secondary Prevention of Cardiovascular Disease Yong Cao • Lei Lu • Jun Liang • Min Liu Xianchi Li • RongRong Sun • Yi Zheng • Peiying Zhang
•
Ó Springer Science+Business Media New York 2014
Abstract The prevalence of cardiovascular disease (CVD) is increasing dramatically especially in developing countries like India. CVD is a leading cause of morbidity and mortality. There has been a growing awareness of the role of nutrients in the prevention of CVD. One specific recommendation in the battle against CVD is the increased intake of omega-3 fatty acids, which are polyunsaturated fatty acids. Studies have reported inverse associations of CVD with dietary intake of omega-3 fatty acids, suggesting that omega-3 fatty acids supplementation might exert protective effects on CVD. They exert their cardioprotective effect through multiple mechanisms. Omega-3 fatty acid therapy has shown promise as a useful tool in the primary and secondary prevention of CVD. This review briefly summarizes the effects of omega-3 fatty acids in primary and secondary prevention of CVD.
Yong Cao, Lei Lu, and Jun Liang have contributed equally to this work. Y. Cao L. Lu M. Liu R. Sun Y. Zheng Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China J. Liang Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou 221009, Jiangsu, China X. Li P. Zhang (&) Department of Cardiology, Xuzhou Central Hospital, Affiliated Xuzhou Hospital of Medical School of Southeast University, Xuzhou Clinical Medical College of Nanjing University of Chinese Medicine, 199# South Jiefang Road, Xuzhou 221009, Jiangsu, China e-mail: [email protected]
Keywords Cardiovascular disease Polyunsaturated fatty acids Omega-3 fatty acids
Nutrition and Cardiovascular Disease Recent years have witnessed greater emphasis on prevention of chronic diseases with focus on societal lifestyles, cultural attitudes toward health, and dietary influences on health conditions [1]. The major cardiovascular diseases (CVD) affecting the developed world have at their core atherosclerosis and hypertension, both of which are profoundly affected by diet and can be approached, at least in part, from a nutritional point of view [2]. Studies have shown that cardioprotective nutrients, if routinely incorporated in a healthy diet, would markedly reduce the population risk of coronary heart disease (CHD) [3]. Therapeutic lifestyle changes, effected through a cardiac rehabilitation program comprising regular exercise and the intake of a combination of dietary nutrients [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), oleic acid, folic acid, and vitamins A, B6, D and E], reduced various risk factors in myocardial infarction (MI) patients, which support the rationale for nutritional programs in the secondary prevention of CHD [4]. Vitamins have antioxidant effects and thus have favorable effects. Although beneficial to the heart, they do not provide the all-round cardioprotection that is required. Interest in omega-3 fatty acids has grown steadily since the observation that Greenland Eskimos have a low incidence of CVD in the setting of a diet rich in fatty fish. Recent research has highlighted their effects, including potential clinical advantages [1]. In this review, we briefly discuss the evidence demonstrating the effects of omega-3 fatty acids in the primary and secondary prevention of CVD [5].
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Omega-3 Fatty Acids
Primary Prevention of CVD
Omega-3 fatty acids are long-chain polyunsaturated fatty acids (PUFAs). The major dietary sources of omega-3 fatty acids are fish containing EPA and DHA, as well as nuts, seeds, and vegetable oils containing a-linolenic acid (ALA). Omega-3 fatty acids, especially those derived from marine sources, may be a useful tool for the primary and secondary prevention of CVD [1]. As the only dietary source of omega-3 PUFA, ALA is considered to be inadequate because humans convert typically \5 % of ALA to EPA and even less to DHA [6].
The evidence for the role of omega-3 PUFA in the primary prevention of CVD is limited by the lack of randomized controlled trials (RCTs). Most of the evidence for the use of omega-3 PUFA comes from case–control studies and prospective cohort studies, with not all studies showing benefit [8]. A study that investigated the relation between fish consumption and CHD in 852 middle-aged men without CHD in the town of Zutphen, the Netherlands showed that consumption of as little as one or two fish dishes per week may be of preventive value in relation to CHD. The study found an inverse dose–response relation between fish consumption in 1960 and death from CHD during 20 years of follow-up. Mortality from CHD was [50 % lower among those who consumed at least 30 g of fish per day than among those who did not eat fish [9]. Three large prospective cohort studies have shown differing results as to any possible benefits of omega-3 PUFA intake. The Health Professional Study included 44,895 male healthcare professionals aged 40–75 years, free of CVD, who completed dietary questionnaires and were followed up for 6 years showed no significant reduction in the risk of CVD even with 5–6 servings of fish per week [9, 10]. The two large prospective cohort studies which did show some cardiovascular benefit were the Physicians’ Health Study and the Nurses’ Health Study [9]. The Physicians’ Health Study studied the effects of weekly fish consumption (at least one fish meal per week) on 21,185 healthy male physicians aged 40–85 years followed up for 11 years. Eating fish once a week, compared to fish consumption less than once a month, decreased the risk of sudden cardiac death (SCD) and all-cause mortality. There was, however, no risk reduction for MIs or total cardiac mortality [9, 11]. The Nurses’ Health Study was conducted in 84,688 healthy female nurses aged 34–59 years who were followed up for 16 years. A higher consumption of fish and omega-3 fatty acids was associated with a lower risk of CHD, and deaths due to CHD [9, 12]. Further epidemiological evidence has been obtained from the analysis of the multiple risk factor intervention trial (MRFIT) database. MRFIT was a multifactorial risk factor intervention study, which randomized 12,866 middle-aged men at high risk of CHD in the USA to either an intervention group or usual care group, and followed them up for 10.5 years. Study of the ‘usual care’ group demonstrated no association between dietary intake of ALA (the predominant dietary PUFA) and risk of CHD deaths. A reduction in 10-year mortality rates was observed with increased intake of PUFAs [9, 13]. Similar positive effects of fish consumption on cardiovascular (CV) outcomes were
Cardioceuticals Cardioceuticals contain all essential nutrients including vitamins, minerals, omega-3-fatty acids, and other antioxidants like a-lipoic acid and coenzyme Q10 in an appropriate proportion and provides all-round cardioprotection. Cardioceuticals improve different parameters that contribute to a healthy heart such as increasing oxygenation, protection of artery walls, clot prevention antioxidant effect, maintaining healthy rhythm of the heart, and cholesterol lowering. By virtue of these effects, they reduce the risk factors of the heart and subsequently cost of treatment in the high-risk patients by reducing need for re-hospitalization, improve the quality of living, and reduce the mortality rates in the high-risk population. Mechanism of Action Omega-3s exert their cardioprotective effects through multiple mechanisms, including reducing arrhythmias and altering production of prostaglandins, which reduces inflammation and improves platelet and endothelial function. To date, no serious adverse effects of omega-3s have been identified, despite extensive study [1]. In addition, there appear to be additional benefits to the use of fish oil, including lowering significantly elevated triglyceride levels, preventing atrial fibrillation (AF), reducing mortality rates in congestive heart failure patients, and perhaps stabilizing atherosclerotic plaques [7]. The American Heart Association (AHA) recommends the use of omega-3 PUFA at a dose of approximately 1 g/day of combined DHA and EPA, either in the form of fatty fish or fish oil supplements (in capsules or liquid form) in patients with documented CHD [6], and at least 500 mg/day for individuals without disease [5]. Omega-3 PUFA therapy has shown great promise in primary and particularly in secondary prevention of CVD.
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noticed in the Honolulu Heart Program, where heavy smokers with high fish consumption were at lower risk for CHD mortality than those who smoked heavily and had low fish consumption. The Honolulu Heart Program began in 1965 to follow a cohort of 8,006 Japanese-American men aged 45–65 years who lived on Oahu, Hawaii, in 1965 [5, 14]. The Japan EPA Lipid Intervention Study (JELIS), a primary (n = 14,981) and secondary (n = 3,664) prevention trial concluded that EPA is a promising treatment for prevention of major coronary events, and especially nonfatal coronary events, in Japanese hypercholesterolemic (total cholesterol C6.5 mmol/l) patients. In patients with no history of coronary artery disease, EPA treatment reduced major coronary events by 18 % [5, 15].
Secondary Prevention OF CVD Coronary Artery Disease The GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell’ Infarto Miocardico)-Prevenzione study randomized 11,323 post-MI patients to receive a fish oil supplement (1 g daily containing 850 mg of concentrated EPA and DHA) versus no supplement, 300 mg of a vitamin E supplement versus no supplement, and both supplements versus no supplements. The primary combined efficacy endpoint was death, nonfatal MI, and stroke. At the end of 1-year of follow-up, patients taking the fish oil supplement had a 15 % reduction in the primary endpoint, including 21 and 30 % reductions in total and CV mortality, respectively [16]. The major factor in the mortality reduction by omega-3 PUFAs was shown to be a striking 45 % reduction in SCDs, which had not been a stated primary endpoint for the GISSI-Prevenzione trial [17]. Assessment of the time course of the benefit of omega-3 PUFAs in post-MI patients showed that the reduction in risk of sudden death was specifically relevant and statistically significant already at 4 months. A similarly significant, although delayed, pattern after 6–8 months of treatment was observed for cardiovascular, cardiac, and coronary deaths [18]. In a subgroup analysis of findings from the GISSI trial, Macchia et al. found that the magnitude of reduction in mortality due to SCD increased with progressively worsening left ventricular (LV) systolic function. The effect of omega-3 PUFA treatment on SCD was related to the degree of systolic dysfunction, with the benefit on SCD reduction in patients with ejection fraction (EF) B40 % being fourfold higher than in those with EF [50 % [19]. The secondary prevention arm of the JELIS trial suggested that the reduction of nonfatal CHD events may require
higher doses (2–3 g/day of DHA ? EPA) and/or a longer duration of treatment (3–5 years) [15]. The Diet and Reinfarction Trial (DART) was the first RCT of dietary fish intake in secondary cardiovascular prevention of MI in 2,033 men who recovered from a recent MI [5, 20]. These patients were allocated to three different dietary advice groups: fat advice group, in which participants were advised to reduce dietary fat intake to 30 % of total energy and to increase the polyunsaturated/ saturated (P/S) ratio to 1. Fiber advice group, in which participants were advised to increase their intake of cereal fiber to 18 g daily. Fish advice group, in which participants were instructed to either eat at least 2 weekly portions (200–400 g) of fatty fish or to take a daily fish oil supplement. At 2 years, there was a reduction of 29 % in all-cause mortality after MI among men that followed a high fish intake diet and 16 % reduction in the risk of ischemic heart disease events compared to the remaining two groups. The reduction in CV events was particularly impressive in the subgroup that took the fish oil supplement as opposed to simply increasing dietary fish consumption. The benefit of the high fish intake group started to manifest early and persisted throughout study duration [5, 21]. The Indian Study on Infarct Survival also demonstrated a significant effect of omega-3 fatty acid therapy on mortality in patients who had an MI. In this study, 360 Indian patients were randomized within 24 h following an MI into three groups: (a) Fish oil capsules (providing 1.8 g of EPA ? 0.72 g/d of DHA daily), (b) a mustard oil group 20 g/day (providing 2.9 g ALA daily), and (c) a placebo group. At 1-year follow-up, there were significant reductions in total CHD events and nonfatal MI and a 50 % reduction in SCD in the fish oil and mustard oil groups when compared with the placebo group. The fish oil and mustard oil groups also showed significant reductions in total cardiac arrhythmias, LV enlargement, and angina pectoris compared with the placebo group. Total cardiac deaths showed no significant reduction in the mustard oil group; however, the fish oil group had significantly less cardiac deaths compared with the placebo group (11.4 vs. 22.0 %). The study population significantly differed from those in other published studies in that they were enrolled within 24 h of MI and were predominantly vegetarian. Also, they received no aggressive treatment typical of modern post-MI therapies [22]. The Lyon Diet Heart Study also demonstrated a decline in the nonfatal MIs and cardiac deaths with Mediterranean diet at an extended follow-up (with a mean of 46 months per patient). Also, the protective effect of a Mediterranean dietary pattern was maintained up to 4 years after the first infarction [23].
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The randomized, double-blind Study on Prevention of Coronary Atherosclerosis by Intervention with Marine Omega-3 fatty acids (SCIMO) in 223 patients with angiographically proven coronary artery disease found that dietary intake of omega-3 fatty acids modestly decreases the course of coronary atherosclerosis in humans. Comparison of baseline versus post-treatment angiograms showed that coronary segments in the fish oil group showed less progression and more regression than segments in the placebo group [24].
Arrhythmias It has been shown that for individuals at high risk of fatal ventricular arrhythmias, regular daily ingestion of fish oil fatty acids may significantly reduce potentially fatal ventricular arrhythmias [25]. Anand et al. also suggest that any patient with documented CHD and those with risk factors for SCD, such as LV dysfunction, LV hypertrophy, prior MI or high-grade ventricular dysrhythmias, should consider fish oil supplementation [26].
Hypertension A meta-analysis of 31 placebo-controlled trials on 1,356 subjects demonstrated a dose–response effect of fish oil on blood pressure (BP), of -0.66/-0.35 mmHg/g omega-3 fatty acids. The hypotensive effect may be the strongest in hypertensive subjects and those with clinical atherosclerotic disease or hypercholesterolemia [27]. Results of another meta-analysis of controlled clinical trials suggest that diet supplementation with a relatively high dose of omega-3 PUFA (C3 g/day) can lead to clinically relevant BP reductions in individuals with untreated hypertension. In the six studies that enrolled untreated hypertensives (n = 291), significant reductions of systolic BP and diastolic BP were present in two and four trials, respectively [28]. INTERMAP observational data on food omega-3 PUFA and BP noted that omega-3 fatty acids from foods such as fish, nuts, seeds, and vegetable oils have a small but important antihypertensive effect. INTERMAP was an international cross-sectional epidemiologic study conducted in almost 5,000 men and women in China, Japan, the United Kingdom, and the United States. In the study, omega-3 PUFA intake related inversely to BP, including in non hypertensive persons. Food omega-3 PUFA may thus contribute to prevention and control of adverse BP levels [29].
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Atrial Fibrillation Omega-3 fatty acids can be used to prevent AF post bypass particularly in patients with contraindications to sotalol or b-blockers (i.e., chronic obstructive lung disease or bradycardia) [5]. Calo` et al. investigated the effect of preoperative and postoperative treatment with omega-3 fatty acids in preventing the occurrence of AF after bypass surgery in 160 patients with no prior history of AF. They demonstrated that omega-3 fatty acids supplementation during hospitalization in patients undergoing coronary artery bypass graft substantially reduced the incidence of postoperative AF and was associated with a shorter hospital stay. New-onset postoperative AF was noticed in 33.3 % of the control group and in 15.2 % of the omega-3 fatty acids group [30].
Conclusion Heart disease is the leading cause of death worldwide and a major public health problem. Data now support the contention that appropriate nutritional interventions may have an important effect in preventing or delaying the appearance of CVD. One specific recommendation in the battle against CVD is the increased intake of omega-3 fatty acids, which are PUFAs. The nutritionally essential omega-3 fatty acids are ALA, EPA, and DHA. The omega-3 PUFAs of particular interest for the prevention of CVD include EPA and DHA are found predominantly in fish and fish oils. The association between fish consumption and risk of CVD has been extensively studied, and there is abundant evidence for the cardioprotective nature of omega-3 fatty acids. Several mechanisms explaining the cardioprotective effect of omega-3 PUFAs have been suggested, including antiarrhythmic, hypolipidemic, and antithrombotic roles. The AHA currently recommends consumption of 1 g/day of a DHA and EPA combination in patients with established CHD. In patients without CHD, at least 500 mg/day of EPA ? DHA is recommended; this goal can be met by eating two fish meals per week, with an emphasis on fatty fish.
References 1. Defilippis, A. P., Blaha, M. J., & Jacobson, T. A. (2010). Omega3 fatty acids for cardiovascular disease prevention. Current Treatment Options in Cardiovascular Medicine, 12, 365–380. 2. Getz, G. S., & Reardon, C. A. (2007). Nutrition and cardiovascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology, 27, 2499–2506. 3. Kris-Etherton, P. M., Hu, F. B., Ros, E., & Sabate´, J. (2008). The role of tree nuts and peanuts in the prevention of coronary heart
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18. Marchioli, R., Barzi, F., Bomba, E., Chieffo, C., Di Gregorio, D., Di Mascio, R., et al. (2002). GISSI-Prevenzione Investigators. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: Time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Circulation, 105, 1897–1903. 19. Macchia, A., Levantesi, G., Franzosi, M. G., Geraci, E., Maggioni, A. P., Marfisi, R., et al. (2005). Left ventricular systolic dysfunction, total mortality, and sudden death in patients with myocardial infarction treated with n-3 polyunsaturated fatty acids. European Journal of Heart Failure, 7, 904–909. 20. Burr, M. L., Fehily, A. M., Gilbert, J. F., Rogers, S., Holliday, R. M., Sweetnam, P. M., et al. (1989). Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and reinfarction trial (DART). Lancet, 2, 757–761. 21. Patel, J. V., Tracey, I., Hughes, E. A., & Lip, G. Y. (2009). Omega-3 polyunsaturated fatty acids: A necessity for a comprehensive secondary prevention strategy. Vascular Health and Risk Management, 5, 801–810. 22. Singh, R. B., Niaz, M. A., Sharma, J. P., Kumar, R., Rastogi, V., & Moshiri, M. (1997). Randomized, double-blind, placebo-controlled trial of fish oil and mustard oil in patients with suspected acute myocardial infarction: The Indian experiment of infarct survival-4. Cardiovascular Drugs and Therapy, 11, 485–491. 23. de Lorgeril, M., Salen, P., Martin, J. L., Monjaud, I., Delaye, J., & Mamelle, N. (1999). Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: Final report of the Lyon Diet Heart Study. Circulation, 99, 779–785. 24. von Schacky, C., Angerer, P., Kothny, W., Theisen, K., & Mudra, H. (1999). The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial. Annals of Internal Medicine, 130, 554–562. 25. Leaf, A., Albert, C. M., Josephson, M., Steinhaus, D., Kluger, J., Kang, J. X., et al. (2005). Fatty Acid Antiarrhythmia Trial Investigators. Prevention of fatal arrhythmias in high-risk subjects by fish oil n-3 fatty acid intake. Circulation, 112, 2762–2768. 26. Anand, R. G., Alkadri, M., Lavie, C. J., & Milani, R. V. (2008). The role of fish oil in arrhythmia prevention. Journal of Cardiopulmonary Rehabilitation and Prevention, 28, 92–98. 27. Morris, M. C., Sacks, F., & Rosner, B. (1993). Does fish oil lower blood pressure? A meta-analysis of controlled trials. Circulation, 88, 523–533. 28. Appel, L. J., Miller, E. R, 3rd, Seidler, A. J., & Whelton, P. K. (1993). Does supplementation of diet with ‘fish oil’ reduce blood pressure? A meta-analysis of controlled clinical trials. Archives of Internal Medicine, 153, 1429–1438. 29. Ueshima, H., Stamler, J., Elliott, P., Chan, Q., Brown, I. J., Carnethon, M. R., et al. (2007). INTERMAP Research Group. Food omega-3 fatty acid intake of individuals (total, linolenic acid, long-chain) and their blood pressure: INTERMAP study. Hypertension, 50, 313–319. 30. Calo`, L., Bianconi, L., Colivicchi, F., Lamberti, F., Loricchio, M. L., de Ruvo, E., et al. (2005). N-3 fatty acids for the prevention of atrial fibrillation after coronary artery bypass surgery: A randomized, controlled trial. Journal of the American College of Cardiology, 45, 1723–1728.
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ORIGINAL PAPER
Omega-3 Fatty Acids and Primary and Secondary Prevention of Cardiovascular Disease Yong Cao • Lei Lu • Jun Liang • Min Liu Xianchi Li • RongRong Sun • Yi Zheng • Peiying Zhang
•
Ó Springer Science+Business Media New York 2014
Abstract The prevalence of cardiovascular disease (CVD) is increasing dramatically especially in developing countries like India. CVD is a leading cause of morbidity and mortality. There has been a growing awareness of the role of nutrients in the prevention of CVD. One specific recommendation in the battle against CVD is the increased intake of omega-3 fatty acids, which are polyunsaturated fatty acids. Studies have reported inverse associations of CVD with dietary intake of omega-3 fatty acids, suggesting that omega-3 fatty acids supplementation might exert protective effects on CVD. They exert their cardioprotective effect through multiple mechanisms. Omega-3 fatty acid therapy has shown promise as a useful tool in the primary and secondary prevention of CVD. This review briefly summarizes the effects of omega-3 fatty acids in primary and secondary prevention of CVD.
Yong Cao, Lei Lu, and Jun Liang have contributed equally to this work. Y. Cao L. Lu M. Liu R. Sun Y. Zheng Graduate School, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China J. Liang Department of Endocrinology, Xuzhou Central Hospital, Xuzhou Clinical School of Xuzhou Medical College, The Affiliated XuZhou Hospital of Medical College of Southeast University, Xuzhou 221009, Jiangsu, China X. Li P. Zhang (&) Department of Cardiology, Xuzhou Central Hospital, Affiliated Xuzhou Hospital of Medical School of Southeast University, Xuzhou Clinical Medical College of Nanjing University of Chinese Medicine, 199# South Jiefang Road, Xuzhou 221009, Jiangsu, China e-mail: [email protected]
Keywords Cardiovascular disease Polyunsaturated fatty acids Omega-3 fatty acids
Nutrition and Cardiovascular Disease Recent years have witnessed greater emphasis on prevention of chronic diseases with focus on societal lifestyles, cultural attitudes toward health, and dietary influences on health conditions [1]. The major cardiovascular diseases (CVD) affecting the developed world have at their core atherosclerosis and hypertension, both of which are profoundly affected by diet and can be approached, at least in part, from a nutritional point of view [2]. Studies have shown that cardioprotective nutrients, if routinely incorporated in a healthy diet, would markedly reduce the population risk of coronary heart disease (CHD) [3]. Therapeutic lifestyle changes, effected through a cardiac rehabilitation program comprising regular exercise and the intake of a combination of dietary nutrients [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), oleic acid, folic acid, and vitamins A, B6, D and E], reduced various risk factors in myocardial infarction (MI) patients, which support the rationale for nutritional programs in the secondary prevention of CHD [4]. Vitamins have antioxidant effects and thus have favorable effects. Although beneficial to the heart, they do not provide the all-round cardioprotection that is required. Interest in omega-3 fatty acids has grown steadily since the observation that Greenland Eskimos have a low incidence of CVD in the setting of a diet rich in fatty fish. Recent research has highlighted their effects, including potential clinical advantages [1]. In this review, we briefly discuss the evidence demonstrating the effects of omega-3 fatty acids in the primary and secondary prevention of CVD [5].
123
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Omega-3 Fatty Acids
Primary Prevention of CVD
Omega-3 fatty acids are long-chain polyunsaturated fatty acids (PUFAs). The major dietary sources of omega-3 fatty acids are fish containing EPA and DHA, as well as nuts, seeds, and vegetable oils containing a-linolenic acid (ALA). Omega-3 fatty acids, especially those derived from marine sources, may be a useful tool for the primary and secondary prevention of CVD [1]. As the only dietary source of omega-3 PUFA, ALA is considered to be inadequate because humans convert typically \5 % of ALA to EPA and even less to DHA [6].
The evidence for the role of omega-3 PUFA in the primary prevention of CVD is limited by the lack of randomized controlled trials (RCTs). Most of the evidence for the use of omega-3 PUFA comes from case–control studies and prospective cohort studies, with not all studies showing benefit [8]. A study that investigated the relation between fish consumption and CHD in 852 middle-aged men without CHD in the town of Zutphen, the Netherlands showed that consumption of as little as one or two fish dishes per week may be of preventive value in relation to CHD. The study found an inverse dose–response relation between fish consumption in 1960 and death from CHD during 20 years of follow-up. Mortality from CHD was [50 % lower among those who consumed at least 30 g of fish per day than among those who did not eat fish [9]. Three large prospective cohort studies have shown differing results as to any possible benefits of omega-3 PUFA intake. The Health Professional Study included 44,895 male healthcare professionals aged 40–75 years, free of CVD, who completed dietary questionnaires and were followed up for 6 years showed no significant reduction in the risk of CVD even with 5–6 servings of fish per week [9, 10]. The two large prospective cohort studies which did show some cardiovascular benefit were the Physicians’ Health Study and the Nurses’ Health Study [9]. The Physicians’ Health Study studied the effects of weekly fish consumption (at least one fish meal per week) on 21,185 healthy male physicians aged 40–85 years followed up for 11 years. Eating fish once a week, compared to fish consumption less than once a month, decreased the risk of sudden cardiac death (SCD) and all-cause mortality. There was, however, no risk reduction for MIs or total cardiac mortality [9, 11]. The Nurses’ Health Study was conducted in 84,688 healthy female nurses aged 34–59 years who were followed up for 16 years. A higher consumption of fish and omega-3 fatty acids was associated with a lower risk of CHD, and deaths due to CHD [9, 12]. Further epidemiological evidence has been obtained from the analysis of the multiple risk factor intervention trial (MRFIT) database. MRFIT was a multifactorial risk factor intervention study, which randomized 12,866 middle-aged men at high risk of CHD in the USA to either an intervention group or usual care group, and followed them up for 10.5 years. Study of the ‘usual care’ group demonstrated no association between dietary intake of ALA (the predominant dietary PUFA) and risk of CHD deaths. A reduction in 10-year mortality rates was observed with increased intake of PUFAs [9, 13]. Similar positive effects of fish consumption on cardiovascular (CV) outcomes were
Cardioceuticals Cardioceuticals contain all essential nutrients including vitamins, minerals, omega-3-fatty acids, and other antioxidants like a-lipoic acid and coenzyme Q10 in an appropriate proportion and provides all-round cardioprotection. Cardioceuticals improve different parameters that contribute to a healthy heart such as increasing oxygenation, protection of artery walls, clot prevention antioxidant effect, maintaining healthy rhythm of the heart, and cholesterol lowering. By virtue of these effects, they reduce the risk factors of the heart and subsequently cost of treatment in the high-risk patients by reducing need for re-hospitalization, improve the quality of living, and reduce the mortality rates in the high-risk population. Mechanism of Action Omega-3s exert their cardioprotective effects through multiple mechanisms, including reducing arrhythmias and altering production of prostaglandins, which reduces inflammation and improves platelet and endothelial function. To date, no serious adverse effects of omega-3s have been identified, despite extensive study [1]. In addition, there appear to be additional benefits to the use of fish oil, including lowering significantly elevated triglyceride levels, preventing atrial fibrillation (AF), reducing mortality rates in congestive heart failure patients, and perhaps stabilizing atherosclerotic plaques [7]. The American Heart Association (AHA) recommends the use of omega-3 PUFA at a dose of approximately 1 g/day of combined DHA and EPA, either in the form of fatty fish or fish oil supplements (in capsules or liquid form) in patients with documented CHD [6], and at least 500 mg/day for individuals without disease [5]. Omega-3 PUFA therapy has shown great promise in primary and particularly in secondary prevention of CVD.
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noticed in the Honolulu Heart Program, where heavy smokers with high fish consumption were at lower risk for CHD mortality than those who smoked heavily and had low fish consumption. The Honolulu Heart Program began in 1965 to follow a cohort of 8,006 Japanese-American men aged 45–65 years who lived on Oahu, Hawaii, in 1965 [5, 14]. The Japan EPA Lipid Intervention Study (JELIS), a primary (n = 14,981) and secondary (n = 3,664) prevention trial concluded that EPA is a promising treatment for prevention of major coronary events, and especially nonfatal coronary events, in Japanese hypercholesterolemic (total cholesterol C6.5 mmol/l) patients. In patients with no history of coronary artery disease, EPA treatment reduced major coronary events by 18 % [5, 15].
Secondary Prevention OF CVD Coronary Artery Disease The GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell’ Infarto Miocardico)-Prevenzione study randomized 11,323 post-MI patients to receive a fish oil supplement (1 g daily containing 850 mg of concentrated EPA and DHA) versus no supplement, 300 mg of a vitamin E supplement versus no supplement, and both supplements versus no supplements. The primary combined efficacy endpoint was death, nonfatal MI, and stroke. At the end of 1-year of follow-up, patients taking the fish oil supplement had a 15 % reduction in the primary endpoint, including 21 and 30 % reductions in total and CV mortality, respectively [16]. The major factor in the mortality reduction by omega-3 PUFAs was shown to be a striking 45 % reduction in SCDs, which had not been a stated primary endpoint for the GISSI-Prevenzione trial [17]. Assessment of the time course of the benefit of omega-3 PUFAs in post-MI patients showed that the reduction in risk of sudden death was specifically relevant and statistically significant already at 4 months. A similarly significant, although delayed, pattern after 6–8 months of treatment was observed for cardiovascular, cardiac, and coronary deaths [18]. In a subgroup analysis of findings from the GISSI trial, Macchia et al. found that the magnitude of reduction in mortality due to SCD increased with progressively worsening left ventricular (LV) systolic function. The effect of omega-3 PUFA treatment on SCD was related to the degree of systolic dysfunction, with the benefit on SCD reduction in patients with ejection fraction (EF) B40 % being fourfold higher than in those with EF [50 % [19]. The secondary prevention arm of the JELIS trial suggested that the reduction of nonfatal CHD events may require
higher doses (2–3 g/day of DHA ? EPA) and/or a longer duration of treatment (3–5 years) [15]. The Diet and Reinfarction Trial (DART) was the first RCT of dietary fish intake in secondary cardiovascular prevention of MI in 2,033 men who recovered from a recent MI [5, 20]. These patients were allocated to three different dietary advice groups: fat advice group, in which participants were advised to reduce dietary fat intake to 30 % of total energy and to increase the polyunsaturated/ saturated (P/S) ratio to 1. Fiber advice group, in which participants were advised to increase their intake of cereal fiber to 18 g daily. Fish advice group, in which participants were instructed to either eat at least 2 weekly portions (200–400 g) of fatty fish or to take a daily fish oil supplement. At 2 years, there was a reduction of 29 % in all-cause mortality after MI among men that followed a high fish intake diet and 16 % reduction in the risk of ischemic heart disease events compared to the remaining two groups. The reduction in CV events was particularly impressive in the subgroup that took the fish oil supplement as opposed to simply increasing dietary fish consumption. The benefit of the high fish intake group started to manifest early and persisted throughout study duration [5, 21]. The Indian Study on Infarct Survival also demonstrated a significant effect of omega-3 fatty acid therapy on mortality in patients who had an MI. In this study, 360 Indian patients were randomized within 24 h following an MI into three groups: (a) Fish oil capsules (providing 1.8 g of EPA ? 0.72 g/d of DHA daily), (b) a mustard oil group 20 g/day (providing 2.9 g ALA daily), and (c) a placebo group. At 1-year follow-up, there were significant reductions in total CHD events and nonfatal MI and a 50 % reduction in SCD in the fish oil and mustard oil groups when compared with the placebo group. The fish oil and mustard oil groups also showed significant reductions in total cardiac arrhythmias, LV enlargement, and angina pectoris compared with the placebo group. Total cardiac deaths showed no significant reduction in the mustard oil group; however, the fish oil group had significantly less cardiac deaths compared with the placebo group (11.4 vs. 22.0 %). The study population significantly differed from those in other published studies in that they were enrolled within 24 h of MI and were predominantly vegetarian. Also, they received no aggressive treatment typical of modern post-MI therapies [22]. The Lyon Diet Heart Study also demonstrated a decline in the nonfatal MIs and cardiac deaths with Mediterranean diet at an extended follow-up (with a mean of 46 months per patient). Also, the protective effect of a Mediterranean dietary pattern was maintained up to 4 years after the first infarction [23].
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The randomized, double-blind Study on Prevention of Coronary Atherosclerosis by Intervention with Marine Omega-3 fatty acids (SCIMO) in 223 patients with angiographically proven coronary artery disease found that dietary intake of omega-3 fatty acids modestly decreases the course of coronary atherosclerosis in humans. Comparison of baseline versus post-treatment angiograms showed that coronary segments in the fish oil group showed less progression and more regression than segments in the placebo group [24].
Arrhythmias It has been shown that for individuals at high risk of fatal ventricular arrhythmias, regular daily ingestion of fish oil fatty acids may significantly reduce potentially fatal ventricular arrhythmias [25]. Anand et al. also suggest that any patient with documented CHD and those with risk factors for SCD, such as LV dysfunction, LV hypertrophy, prior MI or high-grade ventricular dysrhythmias, should consider fish oil supplementation [26].
Hypertension A meta-analysis of 31 placebo-controlled trials on 1,356 subjects demonstrated a dose–response effect of fish oil on blood pressure (BP), of -0.66/-0.35 mmHg/g omega-3 fatty acids. The hypotensive effect may be the strongest in hypertensive subjects and those with clinical atherosclerotic disease or hypercholesterolemia [27]. Results of another meta-analysis of controlled clinical trials suggest that diet supplementation with a relatively high dose of omega-3 PUFA (C3 g/day) can lead to clinically relevant BP reductions in individuals with untreated hypertension. In the six studies that enrolled untreated hypertensives (n = 291), significant reductions of systolic BP and diastolic BP were present in two and four trials, respectively [28]. INTERMAP observational data on food omega-3 PUFA and BP noted that omega-3 fatty acids from foods such as fish, nuts, seeds, and vegetable oils have a small but important antihypertensive effect. INTERMAP was an international cross-sectional epidemiologic study conducted in almost 5,000 men and women in China, Japan, the United Kingdom, and the United States. In the study, omega-3 PUFA intake related inversely to BP, including in non hypertensive persons. Food omega-3 PUFA may thus contribute to prevention and control of adverse BP levels [29].
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Atrial Fibrillation Omega-3 fatty acids can be used to prevent AF post bypass particularly in patients with contraindications to sotalol or b-blockers (i.e., chronic obstructive lung disease or bradycardia) [5]. Calo` et al. investigated the effect of preoperative and postoperative treatment with omega-3 fatty acids in preventing the occurrence of AF after bypass surgery in 160 patients with no prior history of AF. They demonstrated that omega-3 fatty acids supplementation during hospitalization in patients undergoing coronary artery bypass graft substantially reduced the incidence of postoperative AF and was associated with a shorter hospital stay. New-onset postoperative AF was noticed in 33.3 % of the control group and in 15.2 % of the omega-3 fatty acids group [30].
Conclusion Heart disease is the leading cause of death worldwide and a major public health problem. Data now support the contention that appropriate nutritional interventions may have an important effect in preventing or delaying the appearance of CVD. One specific recommendation in the battle against CVD is the increased intake of omega-3 fatty acids, which are PUFAs. The nutritionally essential omega-3 fatty acids are ALA, EPA, and DHA. The omega-3 PUFAs of particular interest for the prevention of CVD include EPA and DHA are found predominantly in fish and fish oils. The association between fish consumption and risk of CVD has been extensively studied, and there is abundant evidence for the cardioprotective nature of omega-3 fatty acids. Several mechanisms explaining the cardioprotective effect of omega-3 PUFAs have been suggested, including antiarrhythmic, hypolipidemic, and antithrombotic roles. The AHA currently recommends consumption of 1 g/day of a DHA and EPA combination in patients with established CHD. In patients without CHD, at least 500 mg/day of EPA ? DHA is recommended; this goal can be met by eating two fish meals per week, with an emphasis on fatty fish.
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