Background Elevated resting heart rate (HR) has emerged as a new risk factor for all-cause and cardiovascular mortality. The effect of marine-derived omega-3 long-chain polyunsaturated fatty acid (n−3 LCPUFAs) supplementation on HR was investigated as an outcome in many clinical trials. The present study was to provide an updated meta-analysis on the HR- slowing effect of n−3 LCPUFAs, and to differentiate the chronotropic effect between eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Methods PubMed and Cochrane databases were searched for relevant articles examining the effects of n−3 PUFAs on HR through May 2017. A random-effects model was used to generate the pooled effect sizes and 95% conﬁdence intervals (CIs). The pooled effect sizes were presented as weighted mean differences (WMDs). Results A total of 51 randomized controlled trials (RCTs) with approximately 3000 participants were included in this meta- analysis. Compared to placebo, n−3 PUFA supplementation mildly but signiﬁcantly reduced HR (−2.23 bpm; 95% CI: −3.07, −1.40 bpm). Moderate evidence of heterogeneity was observed among included trials (I = 49.1%, P heterogeneity o 0.001). When DHA and EPA were separately administered, modest HR reduction was observed in trials that supple- mented with DHA (−2.47 bpm; 95% CI: −3.47, −1.46 bpm), but not in trials with EPA. Conclusions The present meta-analysis provides strong clinical evidence demonstrating the effect of heart rate reduction by n−3 LCPUFA supplementation. When DHA or EPA administered alone, heart rate was slowed by DHA rather than by EPA. Introduction The potential cardioprotective effects of marine-derived omega-3 long-chain polyunsaturated fatty acids (n−3 LCPUFAs) and ﬁsh intake have been investigated in Electronic supplementary material The online version of this article numerous studies [1, 2]. Findings from a prospective study (https://doi.org/10.1038/s41430-017-0052-3) contains supplementary of male physicians without a history of pre-existing cardi- material, which is available to authorized users. ovascular disease suggest that those who consumed ﬁsh at * Li-Qiang Qin least once per week had a lower risk of sudden cardiac death firstname.lastname@example.org (SCD) . Moreover, baseline blood levels of n−3 * Weiguo Zhang LCPUFAs were also inversely associated with SCD in this email@example.com population . Similarly, n−3 LCPUFAs from fatty ﬁsh firstname.lastname@example.org consumption or ﬁsh oil supplementation have been shown to lower the risk of SCD in several secondary prevention Department of Nutrition and Food Hygiene, School of Public studies [4–7]. Although the exact physiologic mechanisms Health, Soochow University, Suzhou 215123, China underlying this preventive effect of n−3 LCPUFAs on SCD DSM Nutritional Products, Human Nutrition and Health, 4303 remain unclear, it has been suggested that n−3 LCPUFAs Kaiseraugst, Switzerland may exert its protective effect on SCD by reducing heart DSM Nutritional Products, Human Nutrition and Health, rate (HR) . Elevated resting HR is a potential risk factor Beijing 100020, China 1234567890 806 K. Hidayat et al. for cardiovascular morbidity and mortality [9–12], particu- −3 LCPUFAs (i.e., fatty ﬁsh) and being compared with larly SCD. Therefore, any agent with HR-reducing effect placebo; (3) trials reported effects on HR; and (4) the mean and relatively no side effect may serve as a valuable can- age of participants was ≥18 years. didate in SCD prevention. To this end, the effect of n−3 LCPUFA supplementation on HR has been investigated in a Data extraction and assessment of bias large number of randomized controlled trials (RCTs) [13– 63], with most of the RCTs showing HR reduction com- Using a standardized data collection form, the following pared to placebo. In 2005, Mozaffarian et al.  published study characteristics were abstracted from each study: (1) a meta-analysis including 30 RCTs and reported that n−3 ﬁrst author’s last name, year of publication; (2) participant PUFA supplementation reduced HR by 1.6 beats per minute characteristics including the mean age, sex, and health (bpm). Although 21 additional RCTs [43–63] have been status; (3) trial characteristics including the trial design, published since then, no updated meta-analysis has been number of participants in intervention or control groups, performed. Furthermore, several RCTs have separately total dose of EPA plus DHA, ratio of EPA to DHA, trial investigated the effects of two major n−3 LCPUFAs, duration, type of control, dropout rate, and blinding; and (4) namely eicosapentaenoic acid (EPA) and docosahexaenoic methods of HR assessment. Cochrane tool for assessing the acid (DHA), on HR [30, 31, 33–36, 40, 45, 54, 56]. risk of bias was used to evaluate the risk of bias among the However, whether EPA or DHA similarly results in HR included studies (Supplementary Table S1) . Two reduction has not been systematically analyzed. authors (KH and JY) independently performed the database In order to provide updated evidence on the effect of n search, data extraction, and quality assessment. Any dis- −3 LCPUFAs on HR reduction and to differentiate the crepancies regarding inclusion were resolved by group chronotropic effect between EPA and DHA when they were discussion. separately administered, we carried out this meta-analysis and systematic review. Statistical analysis Omega-3 PUFA was considered as the intervention arm in Methods this meta-analysis. If the multi-arm interventions included multiple doses of n−3 LCPUFAs, we included those with Search strategy the highest dose in the meta-analysis. The mean changes of HR in both intervention and control groups were reported as This present meta-analysis was planned, conducted, and differences between mean values at baseline and ﬁnal. The reported in accordance with the preferred reporting items for standard deviations (SDs) for changes from baseline in each systematic reviews and meta-analyses guidelines (PRISMA) group were obtained from each trial. If not reported, the . PubMed and Cochrane databases were searched for standard errors (SEs), conﬁdence intervals (CIs), and P- relevant articles examining the effects of n−3 LCPUFAs on values were all converted to SDs using a standard formula HR through May 2017. The following search terms were . If only SDs for the baseline and ﬁnal values were employed to identify relevant articles in the databases: provided, we computed SDs for net changes using the (omega 3 fatty acids OR omega 3 OR polyunsaturated fatty method proposed by Follmann et al.  in which a cor- acids OR PUFA OR ﬁsh oil OR marine oil OR eicosa- relation coefﬁcient of 0.5 was assumed. The degree of pentaenoic acid OR EPA OR docosahexaenoic acid OR heterogeneity across trials was assessed using Q and I DHA) AND (heart rate OR HR OR pulse). The search statistics. For the Q statistic, P o 0.1 was considered sta- strategy had no restriction on language, publication date, or tistically signiﬁcant; and for the I statistic, the following article type. The reference lists of the previous meta- conventional cut-off points were used: o25% (low het- analyses were reviewed to complement the database sear- erogeneity), 25–75% (moderate heterogeneity), and 475% ches. Additionally, we also attempt to contact the authors of (severe heterogeneity). Potential publication bias was the original studies for unreported HR data. assessed using both Begg’s rank correlation test and Egger’s linear regression . If the publication bias was detected, Selection and inclusion of RCTs the trim and ﬁll method was performed to correct the bias . A random-effects model was used to generate the The studies eligible for inclusion in this meta-analysis had pooled effect sizes and 95% CIs . The pooled effect to meet the following inclusion criteria: (1) RCTs lasted at sizes were presented as weighted mean differences least 2 weeks; (2) one or more intervention groups received (WMDs). To explore the possible inﬂuences of trial and n−3 LCPUFA supplementation (i.e., ﬁsh oil (EPA plus participant characteristics on the pooled effect sizes, pre- DHA), puriﬁed EPA, puriﬁed DHA) or food containing n deﬁned subgroup and meta-regression analyses were Effect of Omega-3 on Heart Rate 807 performed according to the trial design (parallel vs. cross- participants with at least one chronic condition, such as over), mean age of participants (o55 vs. ≥55), health status coronary artery disease, renal failure, hypertension, hyper- of participants (generally healthy vs. chronic condition), lipidemia, type 2 diabetes mellitus, frequent premature baseline HR (o69 vs. ≥69), total dose of EPA plus DHA ventricular contraction, epilepsy, psoriatic arthritis, severely (o3.5 vs. ≥3.5 g/day), individual n−3 PUFA supple- accident injured, and age-related cognitive decline; 19 trials mentation (EPA vs. DHA), EPA to DHA ratio (o1.5 vs. were conducted exclusively in men, 2 in women, and the 41.5), methods of HR measurement (single vs. multiple remaining included both sexes; the duration of trials ranged average vs. ambulatory/continuous), and type of control from 2 weeks to 1 year; the mean age of participants ranged (olive oil vs. other). In addition, sensitivity analyses were from 22.45 to 70 years; HR of the participants in almost all performed to investigate the inﬂuence of a single trial on the trials was within the normal range (i.e., 60–100 bpm). The overall effect estimated by omitting one trial in each turn. dose of EPA plus DHA ranged from 0.5 to 15 g/d, with the All analyses were performed using STATA version 11.0 ratio of EPA to DHA from 0.1 to 4.9. Ten studies separately (StataCorp, College Station, TX, USA). A P-value o 0.05 examined the differential effects of EPA and DHA. Placebo was considered to be statistically signiﬁcant, unless other- was chosen from corn oil, olive oil, safﬂower oil, soybean wise speciﬁed. oil, sunﬂower oil, or mixed oil for control groups. The single HR measurement was used in 18, the average of multiple HR measurement in 23, and the average of Results ambulatory or continuous monitoring in 25 intervention trials. Most of the trials reported no signiﬁcant side effect of Trial characteristics LCPUFA. A ﬂowchart of study selection, including reasons for Effect of n−3 PUFAs on HR exclusion, is presented in Fig. 1. Totally, 51 RCTs were eligible for this meta-analysis, in which 4 trials had two The net changes in HR between the intervention and control separated intervention groups and approximately 3000 sub- groups ranged from 0 to 10 bpm. Compared to placebo, n jects participated. The trials were published between 1988 −3 LCPUFA supplementation mildly but signiﬁcantly and 2016. In term of the trial classiﬁcation, 11 trials were reduced HR (−2.23 bpm; 95% CI: −3.07, −1.40 bpm; Fig. crossover designed and 40 parallel designed; 3 trials were 2). Moderate evidence of heterogeneity was observed with single-blind treatment, 2 open-labeled, and the among included trials (I = 49.1%, P heterogeneity o remaining double blind; 24 intervention groups were con- 0.001). Neither Begg’s rank correlation nor Egger’s linear ducted in healthy participants, whereas the other 32 in test observed the presence of publication bias (P Begg’s = 0.591, P Egger’s = 0.450; Table 1). Subgroup and sensitivity analyses The results of subgroup analyses according to mean age of participants, the health status of participants, baseline HR, total dose of EPA plus DHA, individual n−3 PUFA sup- plementation, EPA to DHA ratio, methods of HR mea- surement, type of control, and Jadad score are presented in Table 2. The effect of n−3 LCPUFA supplementation on HR appeared to be inﬂuenced by speciﬁcn−3 LCPUFA supplementation (P meta-regression o 0.01). When com- paring the separate effects of EPA and DHA supple- mentations on HR, modest HR reduction was observed in trials that supplemented with DHA (−2.47 bpm; 95% CI: −3.47, −1.46 bpm; Fig. 3), whereas statistically signiﬁcant effect was not observed with EPA supplementation (1.19 bpm; 95% CI: −0.30, 2.67 bpm; Fig. 3). The sensitivity analysis restricted to double-blind trials, and by using dif- ferent values of the correlation coefﬁcient R (0.25 and 0.75) did not materially alter the observed results. Moreover, the Fig. 1 Flowchart of study selection sensitivity analysis by omitting one trial in each turn 808 K. Hidayat et al. Fig. 2 Forest plot of the change in heart rate resulting from n−3 PUFA supplementation revealed that the overall ﬁndings were free from the inﬂu- The risk of bias ence of a single study. In addition, the overall results remained statistically signiﬁcant (−2.24 bpm; 95% CI: The risk of bias in included studies is presented in supple- −3.08, −1.39 bpm) after omission of trials with duration mentary table S1. In these trials, 17.6% presented adequate less than 6 weeks. random sequence generation, 88% reported allocation Effect of Omega-3 on Heart Rate 809 Table 1 Characteristics of the included 56 intervention groups (51 RCTs) Reference Design Mean Male (%) Health status No. of No. of EPA+DHA EPA/ Duration Control HR Dropout Blinding age ﬁsh oil control (g/d) DHA (week) measurement (%) (year) (n) (n) (ratio) Mehta et al. Crossover 63 100 CAD 8 … 5.5 1.4 4 Not available Single 0 d 1988  Mills et al. 1989 Parallel 28 100 Healthy 10 10 2.6 1.6 4 Olive Single 0 d  Vacek et al. Crossover 54 63 CAD 6 … 9.0 1.5 6 Palm and Single 25 d 1989  cottonseed Levinson et al. Parallel 56 81 Hypertension 8 8 15.0 1.5 6 Palm and corn Multiple 6d 1990  average Mills et al. 1990 Parallel 23 100 Healthy 10 10 1.3 1.6 4 Safﬂower Multiple 9d  average Solomon et al. Parallel 56 80 CAD 5 5 4.6 1.5 12 Olive Single 0 d 1990  Wing et al. Crossover 61 35 Hypertension 20 … 4.5 1.5 8 Olive Multiple 17 d 1990  average Bairati et al. Parallel 54 80 CAD 66 59 4.5 1.5 26 Olive Single 39 d 1992  Deslypere et al. Parallel 56 100 Healthy 14 14 2.9 4.9 52 Oleic Multiple 0d 1992  average Landmark et al. Crossover 42 100 Hypertension with 18 … 4.6 0.6 4 Olive Single 0 d 1993  hyperlipidemia Vandogen et al. Parallel 46 100 Healthy 16 18 4.3 1.5 12 Olive, palm, Multiple 13 d 1993  safﬂower average Leaf et al. 1994 Parallel 63 79 CAD 201 205 6.9 1.4 12 Corn Single 26 d  McVeigh et al. Crossover 53 80 T2DM 20 … 3.0 1.1 6 Olive Single 0 d 1994  Toft et al. 1995 Parallel 54 64 Hypertension 37 39 3.4 1.6 16 Corn Single 10 d  Christensen Parallel NA NA CAD 26 23 4.3 1.5 12 Olive 24-h- 11 d et al. 1996  continuous Gray et al. 1996 Parallel 56 100 Hypertension 9 10 3.5 1.6 8 Corn Multiple 10 d  average Christensen Parallel 52 59 Renal failure 11 6 4.2 1.0 12 Olive 24-h- 41 d et al. 1998  continuous Conquer and Parallel 30 100 Healthy 9 10 3.0 Puriﬁed 6 Omega 6 Single 5 d Holub, 1998 DHA  810 K. Hidayat et al. Table 1 (continued) Reference Design Mean Male (%) Health status No. of No. of EPA+DHA EPA/ Duration Control HR Dropout Blinding age ﬁsh oil control (g/d) DHA (week) measurement (%) (year) (n) (n) (ratio) Grimsgaard Parallel 44 100 Healthy 72 77 3.8 Puriﬁed 7 Corn Multiple 4d et al, 1998  DHA average Grimsgaard Parallel 44 100 Healthy 75 77 3.6 Puriﬁed 7 Corn Multiple 4d et al. 1998  EPA average Christensen Parallel 38 58 Healthy 20 20 5.9 1 12 Olive 24-h- 0d et al. 1999  continuous Mori et al. 1999 Parallel 49 100 Overweight, 17 20 3.7 Puriﬁed 6 Olive 24-h- 5d  hyperlipidemia DHA ambulatory Mori et al. 1999 Parallel 49 100 Overweight, 19 20 3.8 Puriﬁed 6 Olive 24-h- 5d  hyperlipidemia EPA ambulatory Miyajima et al. Crossover 45 100 Hypertension 17 … 2.7 Puriﬁed 4 Linoleic Multiple 4d 2001  DHA average Nestel et al. Parallel 58 55 Hyperlipidemia 12 14 2.8 Puriﬁed 7 Olive Single 7 d 2002  DHA Nestel et al. Parallel 58 55 Hyperlipidemia 12 14 3.0 Puriﬁed 7 Olive Single 7 d 2002  EPA Woodmann Parallel 61 76 T2DM 17 16 3.7 Puriﬁed 6 Olive 24-h 15 d et al. 2002  DHA ambulatory Woodmann Parallel 61 76 T2DM 17 16 3.8 Puriﬁed 6 Olive 24-h 15 d et al. 2002  EPA ambulatory Geelen et al. Parallel 59 49 Healthy 39 35 1.3 1.2 12 Oleic Multiple 2d 2003  average Dyerberg et al. Parallel 39 100 Healthy 24 25 3.2 1.5 8 Palmitic 24-h 10 d 2004  continuous Monahan et al. Parallel 25 56 Healthy 9 9 5.0 1.5 4.3 Olive Single 0 d 2004  Stark and Crossover 57 0 Healthy 32 … 2.8 Puriﬁed 4 Corn, soy Multiple 16 d Holub, 2004 DHA average  Geelen et al. Parallel 64 60 Frequent PVCs 41 43 1.3 1.2 14 Oleic 24-h 9d 2005  continuous O’Keefe et al. Crossover 68 100 CAD 18 … 0.8 0.4 16 Corn, olive 1-h continuous 44 d 2005  Harris et al. Crossover 49 72 Cardiac transplant 18 4 3.4 1.1 20 NA Single 0 d 2006  recepient (median) Shah et al. 2007 Parallel 31 65 Healthy 14 12 0.5 1.5 2 Corn oil Single 4 s  Effect of Omega-3 on Heart Rate 811 Table 1 (continued) Reference Design Mean Male (%) Health status No. of No. of EPA+DHA EPA/ Duration Control HR Dropout Blinding age ﬁsh oil control (g/d) DHA (week) measurement (%) (year) (n) (n) (ratio) Theobald et al. Crossover 48.65 50 Healthy 38 … 0.7 Puriﬁed 12 Olive oil Multiple 0.05 d 2007  DHA average DeGiorgio et al. Crossover 42.5 NA Epilepsy 11 … 2.88 1.5 12 Soybean oil 1-h continuous 0 d 2008  Ninio et al. Parallel 50.25 37 Overweight, mild 13 14 1.92 0.2 12 Sunﬂower oil Multiple 14 d 2008  hypertension, average hyperlipidemia Peoples et al. Parallel 25.15 100 Healthy 9 7 3.2 0.3 8 Olive oil 1-h continuous 88 d 2008  Walser et al. Parallel 34.75 66 Healthy 12 9 5 1.5 6 Safﬂower oil 24-h 9d 2008  continuous Buckley et al. Parallel 22.45 100 Healthy 12 13 1.92 0.2 5 Sunﬂower oil Multiple 14 d 2009  average Nodari et al. Parallel 62.95 91 Idiopathic dilated 22 22 0.85–0.88 0.6 24 Olive oil Single 0.07 d 2009  cardiomyopathy Carney et al. Parallel 57.35 86 Depressed with CHD 36 36 2 1.2 10 Corn oil Single 33 d 2010  Sjoberg et al. Parallel 53 51 Overweight 17 17 1.91 0.2 12 Sunola oil Multiple 11 d 20109  average Yurko-Mauro Parallel 70 42 Age-related cognitive 242 243 0.9 Puriﬁed 24 Corn oil and soy Single 10 d et al. 2010  decline DHA oil Kim et al. 2011 Parallel 58.5 41 Hyperlipidemia 30 31 3.3 1.2 6 Simvastatin 24-h 0.04 o  continuous Sagara et al. Parallel 52.5 100 Hypertension and 15 23 2 Puriﬁed 5 Olive oil Multiple 32 d 2011  hypercholesterolemia DHA average Noreen et al. Parallel 35 100 Healthy 20 20 2.4 2 6 Safﬂower oil Multiple 0d 2012  average Carter et al. Parallel 24 68 Healthy 34 33 2.7 1.4 8 Olive oil Single 0 d 2012  Hansen et al. Parallel 41 100 Healthy 42 43 3.6 0.5 23 Chicken, pork or Single 12 o 2014  beef Logan and Parallel 66 0 Healthy ‘12 12 3 1 12 Olive oil Multiple 0s Spriet, 2015 average  Cottin et al. Parallel 26.5 100 Healthy 15 15 3 Puriﬁed 6 Olive oil 24-h 0.02 s 2016  DHA continuous 812 K. Hidayat et al. concealment, 88% had blinded participants and study investigators (7 of 10), 88% had blinded assessment of outcomes, 100% had low risk of attrition bias, 84% had low risk of reporting bias, and 78% had low risk of other bias. In general, four studies were considered to be of poor quality, while the remaining studies were considered to be of fair or good quality. Discussion The novel major ﬁndings from the present meta-analysis are twofold. First, by pooling the results from 51 RCTs, our study provided the latest evidence that n−3 LCPUFA supplementation reduced HR compared to placebo (−2.23 bpm; 95% CI: −3.07, −1.40 bpm); Second, by pooling results from EPA and DHA administration trials separately, our study demonstrated that DHA rather than EPA reduced HR compared to placebo (−2.47 bpm with DHA; 95% CI: −3.47, −1.46 bpm), thereby more ascribable to the negative chronotropic effect. The effect of n−3 LCPUFA supplementation on HR was previously analyzed by Mozaffarian et al.  in 2005; however, it included only 30 RCTs with 1678 participants compared with 51 RCTs with approximately 3000 partici- pants in our present meta-analysis. With more RCTs included than the previous one, this present meta-analysis provides more updated and comprehensive review of the current literature concerning the effect of n−3 LCPUFA supplementation on HR. The change in weight across trials was observed because of the signiﬁcant difference in the total number of included trials. Compared to the previous meta-analysis, our ﬁndings were relatively more stable and less inﬂuenced by individual trials because a large number of additional trials were included. Moreover, our meta- analysis showed that the magnitude of HR reduction was somewhat greater than the previous meta-analysis (−2.23 bpm; 95% CI: −3.07, −1.40 bpm vs. −1.55 bpm; 95% CI: −2.51, −0.59 bpm). Furthermore, the previous meta- analysis combined multiple doses of intervention (com- pared to the same control) in the same meta-analysis. This approach could be problematic due to a double or triple counting of the control group, and these effect sizes from a single study might not be independent of each other. In contrast, we only included the intervention group with the highest dose to avoid this issue. Besides, several studies suggested that EPA and DHA had differential effects on HR [30, 31, 33–36, 40, 45, 54, 56], but the clariﬁcation on these issues has not been examined in the previous meta-analysis. Nonetheless, we further examine the effects of EPA and DHA supplementations on HR. On the population level, n−3 LCPUFAs and dietary ﬁsh intake have been reported to be associated with a greater Table 1 (continued) Reference Design Mean Male (%) Health status No. of No. of EPA+DHA EPA/ Duration Control HR Dropout Blinding age ﬁsh oil control (g/d) DHA (week) measurement (%) (year) (n) (n) (ratio) Cottin et al. Parallel 26.5 100 Healthy 14 15 3 Puriﬁed 6 Olive oil 24-h 0.02 s 2016  EPA continuous Kristensen et al. Parallel 62 41 Psoriatic arthritis 58 56 1.6 2 24 Olive oil Single 21 d 2016  Matsumura Parallel 39.3 83 Severely accident injured 37 46 1.6 0.1 12 Rapeseed oil, Multiple 25 d et al. 2016  soybean oil, olive average oil, and ﬁsh oil CAD coronary artery disease, CHD coronary heart disease, d double blind, NA not available, o open label, PVC premature ventricular contraction, s single blind, T2DM type 2 diabetes mellitus Intentional addition of 63 mg ﬁsh oil to the placebo served to prevent both participants and even researchers from identifying Effect of Omega-3 on Heart Rate 813 Table 2 Subgroup analyses of the effect of n−3 PUFA supplementation on HR according to predeﬁned study characteristics Characteristic Intervention groups, n Effect on HR (95% CI), P meta-regression bpm Design Parallel 45 −2.11 (−3.06, −1.15) 0.53 Crossover 11 −2.97 (−4.30, −1.63) Mean age, year o55 35 −2.20 (−3.50, −0.90) 0.91 ≥55 21 −2.12 (−3.02, −1.22) Health status Generally healthy 24 −2.21 (−3.58, −0.85) 0.93 Chronic condition 32 −2.27 (−3.31, −1.23) Baseline HR, bpm o69 26 −1.81 (−3.20, −0.42) 0.34 ≥69 30 −2.50 (−3.26, −1.74) EPA+DHA, g/d o3.5 34 −2.10 (−2.82, −1.39) 0.70 ≥3.5 22 −2.55 (−4.41, −0.70) Individual n−3 supplementation DHA 10 −2.47 (−3.47, −1.46) o 0.01 EPA 6 1.19 (−0.30, 2.67) EPA/DHA (ratio) o1.5 21 −2.24 (−3.25, −1.23) 0.72 ≥1.5 19 −2.19 (−4.23, −0.14) HR measurement Single 18 −2.09 (−3.70, −0.48) Multiple average 23 −2.03 (−3.37, −0.69) 0.52 Ambulatory/continuous 15 −1.99 (−3.01, −0.99) Control Olive oil 25 −2.60 (−3.92, −1.27) 0.37 Other 29 −1.96 (−3.06, −0.87) reduction in HR [71–73], which is approximated by n−3 from pharmacological drugs, lifestyle (e.g., physical ﬁtness, LCPUFA supplementation that reduced HR by 2.23 bpm psychological status, and diet or nutrition) and environment and DHA supplementation that reduced HR by 2.47 in this (e.g., noise and temperature) also modulates cardiac rhythm meta-analysis. It should also be further noted that the HR of [8, 12, 64]. In vitro evidence showed that n−3 LCPUFAs the majority of participants included in this meta-analysis directly modulated the functions of ion channels leading to was within normal range—the state where reducing HR is reversible elevation in action potential threshold, lowering conventionally not a medical indication . At the popu- resting membrane potential and the duration of the refrac- lation level however, such HR reduction may have sig- tory period, and ﬁnally resulting in reduction of membrane niﬁcant public health implications, as a reduction of 3.2 electrical excitability of cardiac myocytes [8, 12, 64]. bpm HR would roughly correspond to 7.5% lower risk of Speciﬁcally, the inhibitory effect of n−3 LCPUFAs on SCD . Given the fact that both previous and present funny channel current (i.e. I ), which lengthens spontaneous meta-analyses showed greater HR reduction trend in those depolarization in cardiac pacemaker cells (i.e. sinoatrial with higher baseline HR, future trials may compare the node), is highly attributable to causing HR reduction [12, effect of n−3 LCPUFA supplementation on different levels 64]. of baseline HR, particularly in those with tachycardia It is important to clarify the relative effects of EPA and (resting HR4 100 bpm) or high–normal [12, 74]. DHA on various health outcomes in this era where n−3 The regulation of HR in humans involves multiple sys- LCPUFA supplements are available. The effects of indivi- tems (e.g., cardiovascular, metabolic, endocrine, and auto- dual components of n−3 LCPUFAs on HR remain poorly nomic nervous/neural systems) and their interactions. Aside understood, as majority of the studies used the combination 814 K. Hidayat et al. Fig. 3 Forest plot of the change in heart rate resulting from DHA and EPA supplementations of DHA and EPA (i.e., ﬁsh oil), and more importantly, the than DHA (−4.61 vs. −1.27 mm Hg in systolic blood proportion of EPA and DHA in n−3 LCPUFA supplements pressure) as shown by a meta-analysis on hypertension varied among trials. An animal study by McLennan et al. treatment with omega-3 . The pronounced blood pres- [33, 75] showing that DHA but not EPA prevented sure reduction by EPA can activate baroreceptor reﬂex [79, ischemia-induced cardiac arrhythmia in rats. Moreover, 80], thereby offsetting the HR-slowing effect of EPA if despite the fact that animals were given ﬁsh oil in which there is any. EPA is the dominant component, DHA appeared as the This meta-analysis has several limitations that are worth major n−3 LCPUFAs to be incorporated into myocardial mentioning. First, moderate degree of heterogeneity was membranes . To date, only limited trials have examined observed across the included trials. Therefore, the ﬁndings the separate effects of DHA and EPA, with most studies from this meta-analysis should be interpreted with caution. showed that DHA but not EPA reduced HR [30, 31, 33–36, Given that most of the trials showed a clear pattern towards 40, 45, 54, 56]. Concordantly, a cross-sectional study in the reduction of HR, the observed heterogeneity across European men reported that DHA content of erythrocyte, studies was potentially due to the difference in statistical but not EPA and other fatty acids, was inversely associated signiﬁcance between trials rather than due to the difference with HR; however, the association was slightly attenuated in direction of the effect size. Second, the characteristics of after further adjustment . Furthermore, the inverse participants and trials varied widely across trials, and this association between dietary ﬁsh intake and HR in obser- can lead to underestimation or overestimation of the true vational studies [71–73] could possibly due to higher DHA intervention effect. However, the predeﬁned subgroup and content in some ﬁsh . While in our general analysis, n sensitivity analyses showed that the characteristics of par- −3 LCPUFA caused HR reduction, in our subgroup ana- ticipants and trials did not affect the overall effect size. lysis, DHA but not EPA reduced HR. This may be partially Third, the effect of individual n−3 LCPUFAs on HR was explained by a greater blood pressure-lowing effect of EPA inconclusive because these ﬁndings were based on the Effect of Omega-3 on Heart Rate 815 limited evidence from RCTs. Despite these limitations, this supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association. present meta-analysis can have valuable public health and Circulation. 2017;135:e867–884. clinical implications for incorporation of n−3 LCPUFA 3. Albert CM, Hennekens CH, O’Donnell CJ, Ajani UA, Carey VJ, supplementation as a lifestyle modiﬁcation for reducing all- Willett WC, et al. Fish consumption and risk of sudden cardiac cause mortality among general populations , and for death. JAMA. 1998;279:23–28. 4. Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, reducing the risk of sudden cardiac death, particularly in Willett WC, et al. Blood levels of long-chain n-3 fatty acids and those who do not consume enough fatty ﬁsh on a regular the risk of sudden death. N Engl J Med. 2002;346:1113–8. basis. 5. Burr ML, Fehily AM, Gilbert JF, Rogers S, Holliday RM, Sweetnam PM, et al. Effects of changes in fat, ﬁsh, and ﬁbre intakes on death and myocardial reinfarction: Diet and Reinfarc- tion Trial (DART). Lancet. 1989;2:757–61. Conclusions 6. GISSI-Prevenzione. Dietary supplementation with n-3 poly- unsaturated fatty acids and vitamin E after myocardial infarction: The present meta-analysis provides strong and updated results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet. clinical evidence demonstrating the effect of heart rate 1999;354:447–55. reduction by n−3 LCPUFA supplementation. In analyzing 7. Marchioli R, Barzi F, Bomba E, Chieffo C, Di Gregorio D, Di trials with DHA or EPA alone, our study demonstrates that Mascio R, et al. Early protection against sudden death by n-3 DHA rather than EPA is more ascribable to such chrono- polyunsaturated fatty acids after myocardial infarction: timecourse analysis of the results of the Gruppo Italiano per lo Studio della tropic effect. Future investigations may evaluate whether Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione. Cir- heart rate reduction with n−3 LCPUFAs in general and culation. 2002;105:1897–903. with DHA in speciﬁc is associated with improved outcomes 8. Kang JX. Reduction of heart rate by omega-3 fatty acids and the in clinical patients or with better health proﬁle of the public. potential underlying mechanisms. Front Physiol. 2012;3:416. 9. Kannel WB, Kannel C, Paffenbarger RS Jr, Cupples LA. Heart rate and cardiovascular mortality: the Framingham Study. Am Acknowledgements Heart J. 1987;113:1489–94. 10. Wannamethee G, Shaper AG, Macfarlane PW, Walker M. Risk Author contributions KH, L-QQ and WZ designed the research. KH factors for sudden cardiac death in middle-aged British men. and JY performed the literature search, data extraction, and quality Circulation. 1995;91:1749–56. assessment. KH performed the data analyses and wrote the paper. ZZ 11. Shaper AG, Wannamethee G, Macfarlane PW, Walker M. Heart and G-CC assisted with the literature search and selection. KH, WZ, rate, ischaemic heart disease, and sudden cardiac death in middle- ME, and L-QQ had primary responsibility for the ﬁnal content. All aged British men. Br Heart J. 1993;70:49–55. authors read and approved the ﬁnal manuscript. 12. Zhang GQ, Zhang W. Heart rate, lifespan, and mortality risk. Ageing Res Rev. 2009;8:52–60. Compliance with ethical standards 13. Mehta JL, Lopez LM, Lawson D, Wargovich TJ, Williams LL. Dietary supplementation with omega-3 polyunsaturated fatty acids Conﬂict of interest ME and WZ are presently employed by DSM, a in patients with stable coronary heart disease: effects on indices of manufacture of omega-3 fatty acids. The other authors declare that platelet and neutrophil function and exercise performance. Am J they have no conﬂict of interest. Med. 1988;84:45–52. 14. Mills DE, Prkachin KM, Harvey KA, Ward RP. 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