This study was designed to evaluate the effects of omega-3 fatty acids supplements and simvastatin on lipoproteins and heart rate variability (HRV), a surrogate parameter of cardiac autonomic function, in patients with mixed dyslipidemia.
This study was a prospective, randomized, open-label study. Among the 171 patients screened, 62 who met the inclusion criteria after 6 weeks on a strict diet therapy were randomized into two treatment groups. The inclusion criteria were mixed dyslipidemia with a high triglyceride level (200–499 mg per 100 ml) and a total cholesterol level >200 mg per 100 ml. After a run-in period of 6 weeks, the patients were randomized into two groups and given a combination treatment with 4 g of omega-3 fatty acids (four 1 g Omacor (eicosapentaenoic acid, 465 mg; docosahexaenoic acid, 375 mg; other omega-3 fatty acids, 60 mg; others 100 mg, Gun-il Pharmacy, Seoul, Korea)) and 20 mg of simvastatin daily or a monotherapy of 20 mg simvastatin for 6 weeks. In the combination therapy group, seven patients dropped out, and in the simvastatin alone therapy group, five patients dropped out during the study period.
After 6 weeks of drug treatment, triglyceride levels decreased by 41.0% in the combination treatment group and 13.9% in the simvastatin monotherapy group (from 309.2±95 mg per 100 ml to 177.7±66 versus 294.6±78 mg per 100 ml to 238.3±84 mg per 100 ml, respectively, P=0.0007). No significant changes in the HRV parameters were observed in either group.
The combination of omega-3 fatty acids plus simvastatin, which achieved a significantly greater reduction of triglycerides without adverse reactions, should be considered as an optimal treatment option for patients with mixed dyslipidemia.
Omega-3 fatty acids has an important role in the prevention and treatment of coronary artery disease, because omega-3 fatty acids stabilize atheromatous plaque (Thies et al., 2003) and lower the risk of fatal ischemic heart disease in older adults (Lemaitre et al., 2003). Furthermore, omega-3 fatty acids are considered beneficial to autonomic cardiovascular function. Heart rate variability (HRV), a surrogate marker for cardiac autonomic tone, was improved in the platelets of survivors of myocardial infarction using increasing levels of docosahexaenoic acid (Christensen et al., 1997).
In patients with elevated baseline low-density lipoprotein (LDL) cholesterol (hypercholesterolemia or mixed dyslipidemia), omega-3 fatty acids decrease LDL cholesterol when the saturated fatty acid content is decreased or when they are used at high doses. However, in the patients with very low baseline LDL cholesterol and/or very high triglycerides (type IV and V dyslipidemia), omega-3 fatty acids slightly increase LDL cholesterol (Harris, 1997; Calabresi et al., 2000). Omega-3 fatty acids lower the serum triglyceride levels of normal subjects (Goyens and Mensink, 2006) and of patients with diabetes (Kabir et al., 2007), or with hypertriglyceridemia (Calabresi et al., 2004). The effect of omega-3 fatty acids on high-density lipoprotein (HDL) cholesterol varies from having no effect to slightly increasing it (Harris, 1997; Calabresi et al., 2000, 2004; Kabir et al., 2007). The HDL cholesterol concentration generally increases during omega-3 therapy in subjects with hypertriglyceridemia, but it may remain unchanged or even decline slightly in subjects without hypertriglyceridemia. Recently, as the target goals of LDL-cholesterol and triglycerides became tougher, a combination therapy of omega-3 fatty acids and statins would be a reasonable option for high-risk patients with combined or mixed dyslipidemia. We designed a study to evaluate the effects of omega-3 fatty acids administered with or without simvastatins on lipoprotein levels and HRV parameters in patients with mixed dyslipidemia, specifically in Koreans with a high carbohydrate intake showing a high prevalence of hypertriglyceridemia.
Materials and methods
This study was a prospective, randomized, open label, two-center trial that was performed in two general hospitals, the Seoul National University Hospital and the Seoul Metropolitan Boramea Hospital of Korea. Patients who had mixed dyslipidemia with high triglyceride levels (200–499 mg per 100 ml) and a total cholesterol level of over 200 mg per 100 ml were enrolled. From June 2006 to March 2008, 171 patients who initially met the inclusion criteria were kept on a strict diet therapy for 6 weeks. Among them, 62 patients who still met the criteria after the diet therapy were randomized into two treatment groups. All of the participants were instructed to follow a low cholesterol diet during the entire study period. All of the participants gave their written consent before entering the study, in accordance with a protocol approved by the Institutional Review Board of the Seoul National University Hospital and the Seoul Metropolitan Boramea Hospital. This study was also performed in accordance with the principles set forth in the Guidelines for Good Clinical Practice and the Declaration of Helsinki and its amendments.
After a run-in period of 6 weeks, eligible patients were randomly assigned to two groups using a randomization table. One group of patients received a combination treatment with 4 g of omega-3 fatty acids (two 1 g Omacor tablets (eicosapentaenoic acid, 465 mg; docosahexaenoic acid, 375 mg; other omega-3 fatty acids 60 mg; others 100 mg, Gun-il Pharmacy) twice a day) and 20 mg of simvastatin daily; the other group underwent a monotherapy with 20 mg of simvastatin for 6 weeks (Figure 1). After randomization, the study processes were not blinded.
The primary objective was to compare the change in triglyceride levels in the two groups from the baseline with week 6. The secondary objectives were to examine the changes of other lipoprotein profiles, high sensitivity C-reactive protein (hsCRP), and HRV parameters. The total cholesterol, triglycerides, LDL and HDL cholesterols, and apolipoprotein B and A1 concentrations were determined from blood samples collected just before the randomization and at the 6 week of follow-up visit. The levels of serum creatine kinase, hepatic transaminases and creatine phosphokinase, as well as hsCRP concentrations and differential blood counts were also measured.
A 24-h Holter recording was obtained from each patient using a three-channel tape recorder at the baseline (visit 2) and again at the 6-week follow-up visit (visit 3). An investigator who was fully blinded to the treatment allocation and the study phase independently analyzed the HRV data.
We defined the following standard time domain measures of HRV: (1) the standard deviation of all normal RR intervals (SDNN), (2) the standard deviation of the means of all normal RR intervals during each 5-min segment of the recording (SDANN) and (3) the root mean square of the differences of the successive RR intervals. In addition, the following frequency domain indexes were obtained using the supine 5-min recording: (1) high-frequency (HF) power (0.15–0.4 Hz), (2) low-frequency (LF) power (0.004–0.15 Hz), (3) normalized HF power, (4) normalized LF power and (5) ratio of LF/HF.
The sample size was calculated based on the primary objective of the trial, in which we detected 10% of the mean difference in triglyceride levels between the combination therapy with omega-3 fatty acids plus simvastatin versus the simvastatin only group, with a power of 80% and a two-sided significance level of P<0.05. We adjusted the sample size for an estimated follow-up loss rate of 3%, which resulted in 29 patients in each group. Data analyses were carried out according to the intention-to-treat population.
Non-normally distributed variables were analyzed using the Mann–Whitney U-test. Normally distributed data were presented as the mean±s.d. Categorical variables were expressed as percentages, and the χ2 test was used for comparison. The significance of any temporal changes in clinical, laboratory data, and HRV indexes as a result of therapy were evaluated with the paired t-test or Wilcoxon's signed rank test for both normal and non-normal data.
All statistical tests were two-sided; values of P<0.05 were considered significant. All analyses were performed with SPSS 12.0 software (SPSS Inc., Chicago, IL, USA).
Patients, adverse events and compliance
Of the 30 patients randomized to the simvastatin plus omega-3 fatty acids treatment, two were withdrawn from the study because of patient intolerance; one had a gastrointestinal disturbance and the other was withdrawn after a non-specific skin rash. No other subjects experienced any significant adverse effects in either group. Of the 31 patients randomized to the simvastatin only group, one patient was excluded because of the patient's refusal. Compliance, as assessed by counting capsules during the follow-up visit, was 92% (simvastatin) and 91% (omega-3 fatty acid) in the omega-3 fatty acids plus simvastatin group and 87% in the simvastatin only group. The clinical and demographic characteristics of the participants are given in Table 1. More female patients were allocated to the simvastatin only group (P=0.014). Patients receiving the combination treatment with omega-3 fatty acids and simvastatin had a higher alcohol use, but the difference was not statistically significant (P=0.097). These clinical parameters are known to related to triglyceride levels, but a baseline laboratory test showed no difference in baseline triglyceride levels, so we assumed that the differences were negligible.
Triglycerides and other lipoprotein profiles
The concentrations of the lipid parameters at the baseline and at 6 weeks after treatment are shown in Table 2. Percent changes from the baseline for the main lipid variables are presented in Figure 2. There was significant reduction in triglyceride levels after both treatments. Triglyceride levels decreased 41.0% with the combination treatment and 13.9% in the simvastatin monotherapy group (from 309.2 to 177.7 mg per 100 ml in the combination treatment group, from 294.6 to 238.3 mg per 100 ml in the simvastatin monotherapy group). The percent change from the baseline in triglyceride levels, the primary outcome variable, was significantly greater with omega-3 fatty acids plus simvastatin than with simvastatin alone (P=0.0007). There were significant reductions in the total or LDL cholesterol levels after both treatments. The HDL cholesterol level was not affected by either the combination therapy or by simvastatin alone. Significant reductions in apolipoprotein B and apolipoprotein E levels were observed in both treatment groups. Between the two groups, however, there was no significant difference in the changes of the LDL, HDL or total cholesterol levels.
Blood pressure and laboratory findings
The mean baseline systolic/diastolic blood pressure was 128/84 mm Hg in the combination treatment group, and 128/82 mm Hg in the simvastatin alone group. The changes in hsCRP were not significantly different between the two groups (Table 3). There were no cases of clinically significant increases in hepatic transaminase levels (>2.0 × the upper limit of normal) in either group. There was a numerically higher, but statistically insignificant, incidence of mildly elevated aspartate aminotransferase levels in the group that received omega-3 fatty acids plus simvastatin compared with the group that received simvastatin only (6.67% (2/30) versus 0% (0/31), respectively; P=0.317). Thus, the mean aspartate aminotransferase level was increased after 6 weeks of treatment with omega-3 fatty acids plus simvastatin (26.0–29.8 IU/l, P=0.009). No significant differences were observed in the serum creatine phosphokinase levels between the two groups. The mean fasting glucose level was increased after 6 weeks in the group that received omega-3 fatty acids and simvastatin. However, the incidence of an elevated fasting glucose level (>110 mg per 100 ml) after 6 weeks was the same in both groups (3.33% (1/31) versus 3.33% (1/31), baseline and 6 weeks after treatment).
Heart rate variability
As shown in Table 3, heart rates, SDNN, SDANN and RMSDD were not different before and after treatment in either group. The LF, HF and LF/HF ratio showed similar values before and after treatment (all P=NS).
Efficacy and usefulness of omega-3 fatty acids plus simvastatin in patients with mixed dyslipidemia
In this study, the efficacy and safety of 4 g of omega-3 fatty acids plus 20 mg simvastatin combination therapy were evaluated in Korean patients with mixed dyslipidemia. After 6 weeks of treatment, the triglyceride levels decreased by 41.0% in the combination treatment group and 13.9% in the simvastatin monotherapy group. These findings were consistent with previous studies in Western countries (Durrington et al., 2001; Davidson et al., 2007; Maki et al., 2008). Durrington et al. (2001) found that omega-3 fatty acids (4 g) and simvastatin (10–40 mg) decreased serum triglyceride levels significantly more than treatment with simvastatin alone (−24 versus +11% at a 12-week follow-up, P<0.005). Maki et al. (2008) reported that omega-3 fatty acids (4 g) plus simvastatin (20 mg) treatment for 6 weeks decreased triglyceride levels significantly more than treatment with a placebo plus simvastatin (−44 versus −29%) in mixed dyslipidemia patients. The combination of prescription omega-3 with simvastatin trial (Davidson et al., 2007) evaluated the efficacy of omega-3 fatty acids added to stable statin therapy in subjects with persistent hypertriglyceridemia. There was significantly greater reduction in the triglyceride levels in simvastatin 40 mg plus omega-3 fatty acids (4 g) per day versus simvastatin only (40 mg) after 8 weeks of treatment (−29.5 versus −6.3%).
To summarize the results of the previous studies and this study, the reduction of triglycerides by omega-3 fatty acids (4 g) plus variable doses of simvastatin ranges from 25 to 45%, depending on the duration and potency of the treatment as well as the baseline lipid profile. There was a trend of a greater reduction in triglycerides with longer treatment periods (Durrington et al., 2001). The dosage is also an important determinant. In the Japan Eicosapentaenoic Acid Lipid Intervention Study, with 1.8 g of eicosapentaenoic acid per day plus 10 mg of pravastatin or 5 mg of simvastatin, relatively smaller doses than in this study, triglyceride levels were decreased by 18% at the 5-year follow-up (Yokoyama et al., 2007). Finally, the patient subset is also a factor in determining efficacy. In general, 3–4 g of omega-3 fatty acids can reduce triglycerides by 25% in normal subjects and by 34% in hypertriglyceridemic patients (Harris, 1997). The combination therapy did not have any undesirable effects on LDL cholesterol in the current study or in the previous studies. In this, LDL cholesterol levels significantly decreased with a combination of omega-3 fatty acids plus simvastatin (148±32 to 95±32 mg per 100 ml, P<0.001), which was comparable with the simvastatin monotherapy (139±31 to 99±26 mg per 100 ml, P<0.001). When cholesterol synthesis was blocked by simvastatins, the unwanted effects of omega-3 fatty acids on total cholesterol and LDL cholesterol levels were kept under control in mixed dyslipidemia patients. In contrast to the potential serious side effects of combinations of statins with fibrate, a combination therapy of omega-3 fatty acids and simvastatin showed few adverse events. Thus, it could be considered as good therapeutic choice for patients with mixed dyslipidemia, lowering triglycerides by 40% without mitigating LDL cholesterol reduction by statins.
Changes in inflammatory markers with omega-3 fatty acids plus simvastatin treatment in patients with mixed dyslipidemia
Simvastatin were known to lower hsCRP (Madsen et al., 2001; Plenge et al., 2002; Meredith et al., 2007). However, this study showed no significant improvement in hsCRP levels with the use of combination therapy or simvastatin alone. In this study, in which high-risk patients were excluded, the baseline hsCRP level (0.2 mg per 100 ml) was lower than that (1.1–2.8 mg per 100 ml) of previous studies (Madsen et al., 2001; Plenge et al., 2002; Meredith et al., 2007). This difference may explain why there were no changes in the hsCRPs in either group of this study.
Indices of HRV during combination therapy of omega-3 fatty acids plus simvastatin
We evaluated HRV changes after the omega-3 fatty acids plus simvastatin combination. Depressed HRV, an indicator of autonomic nervous system impairment, has been shown to be a powerful predictor of sudden cardiac death in post-myocardial infarction patients (Kleiger et al., 1987; Perkiömäki et al., 1997; La Rovere et al., 1998). Lower HRV indices were reported in obese subjects (Chen et al., 2008), in post-myocardial infarction patients (Kleiger et al., 1987; La Rovere et al., 1998), and in patients with decreased left ventricular systolic function (Szabo et al., 1995). Depressed HRV has been well correlated with a decreased left ventricular ejection fraction and functional capacity (Szabo et al., 1995). In US adults, consumption of fish and omega-3 fatty acids was associated with specific HRV components, including higher root mean square successive differences of normal-to-normal intervals (P=0.001), higher normalized HF power (P=0.008), and a lower ratio of LF/HF (P=0.03; Mozaffarian et al., 2008). However, in this study, omega-3 fatty acids did not significantly change HRV, such as measures of circadian variation (SDNN), indices of vagal activity (normalized HF), and measures that reflect combined sympathetic and parasympathetic influences on baroreceptor function (normalized LF, LF/HF ratio). To avoid possible confusion with the short term (5 or 20 min recording) electrocardiograms of some previous studies, we collected 24-h Holter recordings at the baseline and at week 6 for analyses of the HRV parameters. Our patients had normal HRV indices; the baseline SDNN was >120 ms, which indicated normal circadian variation. Thus, the beneficial effects of omega-3 fatty acids on HRV could not be found significant in subjects with normal HRV indices. This result is consistent with a previous report from Europe (Geelen et al., 2003). To our knowledge, this is the first prospective study that reports that omega-3 fatty acids plus simvastatin combination therapy has no impact on indices of HRV in mixed dyslipidemia patients who do not have cardiovascular diseases and have normal HRV indices, especially in Asians.
There was also no significant change in the HRV of the patients receiving simvastatin only. This finding is consistent with some previous studies (Gentlesk et al., 2005; Riahi et al., 2006), although others have reported increased HRV parameters after statin therapy in hypercholesterolemia patients (Pehlivanidis et al., 2001). The pleiotropic effect of statins on autonomic nervous function was still undetermined, requiring further investigation in several disease subsets.
The lack of blinding and placebo controls for the omega-3 fatty acids are limitations of this study. We cannot exclude bias without blinding or placebos. There are also issues regarding the low statistical power of detecting differences between groups for variables other than triglycerides. LDL cholesterol levels significantly decreased with a combination of omega-3 fatty acids plus simvastatin and also with simvastatin monotherapy. Considering the potential serious side effects from the combination of statin plus fibrate, a combination therapy of omega-3 fatty acids and simvastatin is good therapeutic strategy for patients with mixed dyslipidemia. A combination therapy of omega-3 fatty acids and simvastatin showed low adverse events, and it did not alter LDL cholesterol reduction by statin.
The combination therapy with omega-3 fatty acids plus simvastatin produced a greater reduction in triglyceride levels than simvastatin monotherapy in Korean mixed dyslipidemia patients. Along with the reduction of triglycerides, LDL cholesterol was also controlled with the combination therapy without adverse events. Thus, a combination therapy of omega-3 fatty acids plus simvastatin would be considered an optimal treatment option for patients with mixed dyslipidemia.
Calabresi L, Donati D, Pazzucconi F, Sirtori CR, Franceschini G (2000). Omacor in familial combined hyperlipidemia: effects on lipids and low density lipoprotein subclasses. Atherosclerosis 148, 387–396.
Calabresi L, Villa B, Canavesi M, Sirtori CR, James RW, Bernini F et al. (2004). An omega-3 polyunsaturated fatty acid concentrate increases plasma high-density lipoprotein 2 cholesterol and paraoxonase levels in patients with familial combined hyperlipidemia. Metabolism 53, 153–158.
Chen GY, Hsiao TJ, Lo HM, Kuo CD (2008). Abdominal obesity is associated with autonomic nervous derangement in healthy Asian obese subjects. Clin Nutr 27, 212–217.
Christensen JH, Korup E, Aarøe J, Toft E, Møller J, Rasmussen K et al. (1997). Fish consumption, n-3 fatty acids in cell membranes, and heart rate variability in survivors of myocardial infarction with left ventricular dysfunction. Am J Cardiol 79, 1670–1673.
Davidson MH, Stein EA, Bays HE, Maki KC, Doyle RT, Shalwitx RA, et al., for the COMBOS Investigators (2007). Efficacy and Tolerability of Adding Prescription Omega-3 Fatty Acids 4 g/d to Simvastatin 40 mg/d in Hypertriglyceridemic Patients: An 8-Week, Randomized, Double-Blind, Placebo-Controlled Study. Clin Ther 29, 1354–1367.
Durrington PN, Bhatnagar D, Mackness MI, Morgan J, Julier K, Khan MA et al. (2001). An omega-3 polyunsaturated fatty acid concentrate administered for one year decreased triglycerides in simvastatin treated patients with coronary heart disease and persisting hypertriglyceridaemia. Heart 85, 544–548.
Geelen A, Zock PL, Swenne CA, Brouwer IA, Schouten EG, Katan MB (2003). Effect of n-3 fatty acids on heart rate variability and baroreflex sensitivity in middle-aged subjects. Am Heart J 146, E4.
Gentlesk PJ, Wiley T, Taylor AJ (2005). A prospective evaluation of the effect of simvastatin on heart rate variability in non-ischemic cardiomyopathy. Am Heart J 150, 478–483.
Goyens PLL, Mensink RP (2006). Effects of alpha-linolenic acid versus those of EPA/DHA on cardiovascular risk markers in healthy elderly subjects. Eur J Clin Nutr 60, 978–984.
Harris WS (1997). n-3 Fatty acids and serum lipoproteins: human studies. Am J Clin Nutr 65 (suppl), 1645S–1654S.
Kabir M, Skurnik G, Naour A, Pechtner V, Meugnier E, Rome S et al. (2007). Treatment for 2 mo with n-3 polyunsaturated fatty acids reduces adiposity and some atherogenic factors but does not improve insulin sensitivity in women with type 2 diabetes: a randomized controlled study. Am J Clin Nutr 86, 1670–1679.
Kleiger RE, Miller JP, Bigger JT, Moss AJ (1987). Decreased heart rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 59, 256–262.
La Rovere MT, Bigger JT, Marcus FI, Mortara A, Schwartz PJ (1998). Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. Lancet 351, 478–484.
Lemaitre RN, King IB, Mozaffarian D, Kuller LH, Tracy RP, Siscovick DS (2003). n-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study. Am J Clin Nutr 77, 319–325.
Madsen T, Skou HA, Hansen VE, Fog L, Christensen JH, Toft E et al. (2001). C-reactive protein, dietary n-3 fatty acids, and the extent of coronary artery disease. Am J Cardiol 88, 1139–1142.
Maki KC, McKenney JM, Reeves MS, Lubin BC, Dicklin MR (2008). Effects of adding prescription omega-3 acid ethyl esters to simvastatin (20 mg/day) on lipids and lipoprotein particles in men and women with mixed dyslipidemia. Am J Cardiol 102, 429–433.
Meredith KG, Horne BD, Pearson RR, Maycock CA, Lappe DL, Anderson JL et al. (2007). Comparison of effects of high (80 mg) versus low (20 mg) dose of simvastatin on C-reactive protein and lipoproteins in patients with angiographic evidence of coronary arterial narrowing. Am J Cardiol 99, 149–153.
Mozaffarian D, Stein PK, Prineas RJ, Siscovick DS (2008). Dietary fish and omega-3 fatty acid consumption and heart rate variability in US adults. Circulation 117, 1130–1137.
Pehlivanidis AN, Athyros VG, Demitriadis DS, Papageorgiou AA, Bouloukos VJ, Kontopoulos AG (2001). Heart rate variability after long-term treatment with atorvastatin in hypercholesterolaemic patients with or without coronary artery disease. Atherosclerosis 157, 463–469.
Perkiömäki JS, Huikuri HV, Koistinen JM, Mäkikallio T, Castellanos A, Myerburg RJ (1997). Heart rate variability and dispersion of QT interval in patients with vulnerability to ventricular tachycardia and ventricular fibrillation after previous myocardial infarction. J Am Coll Cardiol 30, 1331–1338.
Plenge JK, Hernandez TL, Weil KM, Poirier P, Grunwald GK, Marcovina SM et al. (2002). Simvastatin lowers C-reactive protein within 14 days: an effect independent of low-density lipoprotein cholesterol reduction. Circulation 106, 1447–1452.
Riahi S, Schmidt EB, Amanavicius N, Karmisholt J, Jensen HS, Christoffersen RP et al. (2006). The effect of atorvastatin on heart rate variability and lipoproteins in patients treated with coronary bypass surgery. Int J Cardiol 111, 436–441.
Szabo BM, Van Veldhuisen DJ, Brouwer J, Haaksma J, Lie KI (1995). Relation between severity of disease and impairment of heart rate variability parameters in patients with chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 76, 713–716.
Thies F, Garry JM, Yaqoob P, Rerkasem K, Williams J, Shearman CP et al. (2003). Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet 361, 477–485.
Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, et al., Japan EPA lipid intervention study (JELIS) Investigators (2007). Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 369, 1090–1098.
This work was supported by the Innovative Research Institute for Cell Therapy (IRICT) and the Clinical Research Center for Ischemic Heart Disease (0412-CR02-0704-0001). Dr Hyo-Soo Kim is a professor of Molecular Medicine & Biopharmaceutical Sciences, Seoul National University sponsored by World Class University Program from the Ministry of Education, Science, and Technology, Korea.
The authors declare no conflict of interest.
About this article
Cite this article
Kim, SH., Kim, MK., Lee, HY. et al. Prospective randomized comparison between omega-3 fatty acid supplements plus simvastatin versus simvastatin alone in Korean patients with mixed dyslipidemia: lipoprotein profiles and heart rate variability. Eur J Clin Nutr 65, 110–116 (2011). https://doi.org/10.1038/ejcn.2010.195
- omega-3 fatty acid
- heart rate variability
The Korean Journal of Internal Medicine (2019)
Journal of Lipid and Atherosclerosis (2019)
Effect of omega-3 long-chain polyunsaturated fatty acid supplementation on heart rate: a meta-analysis of randomized controlled trials
European Journal of Clinical Nutrition (2018)
Journal of the American College of Cardiology (2018)
Journal of Muscle Research and Cell Motility (2017)