Background: Myocardial infarction (MI) elicits an intense acute inflammatory response that is essential for cardiac repair. However, an excessive inflammatory response also favors myocardial apoptosis, cardiac remodeling, and cardiovascular mortality. Omega-3 polyunsaturated fatty acids (ω-3) bear anti-inflammatory effects, which may mitigate the inflammatory response during MI. This study investigated whether ω-3 intake is associated with attenuation of the MI-related inflammatory response and cardiac remodeling. Methods: ST-elevation MI (STEMI) patients (n = 421) underwent clinical, biochemical, nutritional, 3D echocardiogram, Cardiac Magnetic Resonance imaging (CMRi) at 30 days and 3D echocardiogram imaging at six months after the MI. Blood tests were performed at day one (D1) and day five (D5) of hospitalization. Changes in inflammatory markers (ΔD5-D1) were calculated. A validated food frequency questionnaire estimated the nutritional consumption and ω-3 intake in the last 3 months before admission. Results: The intake of ω-3 below the median (< 1.7 g/day) was associated with a short-term increase in hs-C-reactive protein [OR:1.96(1.24–3.10); p = 0.004], Interleukin-2 [OR:2.46(1.20–5.04); p = 0.014], brain-type natriuretic peptide [OR:2.66(1.30–5.44); p = 0.007], left-ventricle end-diastolic volume [OR:5.12(1.11–23.52)]; p = 0.036] and decreases in left-ventricle ejection fraction [OR:2.86(1.47–6.88); p = 0.017] after adjustment for covariates. No differences were observed in the extension of infarcted mass obtained by CMRi. Conclusion: These findings suggest that a reduced daily intake of ω-3 may intensify outcome-determining mechanisms after STEMI, such as acute inflammatory response and late left ventricular remodeling. Trial registration: Clinical Trial Registry number and website: NCT02062554.
Keywords: Omega-3; Inflammatory response; Cardiac remodeling; STEMI
Myocardial infarction (MI) elicits an intense acute inflammatory response due to mechanical stress and ischemia-reperfusion injury [[
Omega-3 (ω-3) are polyunsaturated fatty acids whose interactions with human physiology have been reported, particularly for α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA components bear anti-inflammatory effects through two complementary actions: (i) reducing the content of arachidonic acid products and (ii) downregulating the expression of pro-inflammatory cytokines via NF-κB and AP-1 inhibition [[
Participants from the Brasília Heart Study (BHS) database were used for this analysis (n = 421). BHS is a an ongoing prospective observational cohort composed of STEMI patients admitted to Hospital de Base do Distrito Federal (Brasília, Brazil) since 2006 [[
Graph: Fig. 1Diagram flow of study design
Patients enrolled into the study underwent therapies based on current guidelines for treatment of acute coronary disease, as indicated by Table 1 data [[
Baseline characteristics of clinical and laboratory data of participants
Characteristics < 1.7 g ≥1.7 g Daily intake of ω-3 at admission (g) 1.0(0.7) 2.7(1.3) < 0.001 Daily intake of ω-3 at 3 months (g) 1.1(0.9) 1.9(1.5) < 0.001 Age, (years) 60 ± 10 58 ± 11 0.256 Gender: female n(%) 52(26) 52(24) 0.717 Diabetes mellitus, n(%) 31(15) 55(25) 0.010 Hypertension, n(%) 113(56) 141(65) 0.044 Previous myocardial infarction, 21(10) 22(10) 0.957 Previous stroke, 11(5) 11(5) 0.881 Coronary reperfusion therapy, 171(84) 194(89) 0.012 Percutaneous coronary intervention (PCI), 94(46) 100(46) 0.479 Fibrinolytic therapy, 125(61) 151(70) 0.052 PCI and fibrinolytic therapy, 53(26) 65(30) 0.190 Current smoking, 78(38) 83(39) 0.970 Ex smoking, 59(29) 70(33) 0.440 Drugs previously in use: Statin, 13(6) 13(6) 0.861 Calcium channel blocker, 20(10) 22(10) 0.922 Beta-blocker, 40(20) 32(14) 0.139 Angiotensin inhibitor drugs (ACEi or ARB), 66(32) 93(43) 0.026 Aspirin, 34(17) 33(15) 0.666 HbA1c, (%) 6.0(0.8) 6.1(1.2) 0.830 Glomerular filtration rate, (mL/min) 70(24) 69(25) 0.173 Triglycerides, (mg/dL) 118(90) 147(126) 0.001 LDL-C, (mg/dL) 118 ± 38 121 ± 48 0.538 HDL-C, (mg/dL) 38(13) 36(13) 0.150 Systolic blood pressure, (mmHg) 130(37) 140(40) 0.016 Diastolic blood pressure, (mmHg) 80(30) 85(26) 0.063 Heart rate, (bpm) 75(18) 75(25) 0.415 Time between MI onset and medical care, (minutes) 120(255) 90(182) 0.126 Killip >I, 20(10) 26(12) 0.470 Peak CK-MB, (UI/L) 161(243) 200(268) 0.070 Troponin, (ng/mL) 2.40(22.36) 1.52(20.16) 0.468 Body Mass Index, (kg/m2) 25.9(5.1) 26.8(5.0) 0.234 Waist circumference, (cm) Female 95(14) 93(9) 0.164 Male 95(13) 98(12) 0.173
Participants underwent a structured detailed clinical questionnaire, anthropometric measurements, blood collection for biochemical analysis, nutritional, and imagining evaluation. Ex-smoking status, diabetes and hypertension were previously defined elsewhere [[
Blood samples were obtained within the first 24 h of MI symptoms (D1) and at day five of hospitalization (D5). High-sensitivity C-reactive protein (hs-CRP), urea, creatinine, triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glomerular filtration rate (GFR) were obtained as described elsewhere [[
A food frequency intake questionnaire (FFQ) was used to estimate nutritional composition and ω-3 intake [alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)] within the previous 3-month period. The questionnaire was applied at admission and at the 3rd month of follow-up. The food intake was clustered in 62 items divided into 10 groups (dairy products, eggs and meats, oils, snacks and canned foods, cereals and vegetables, greens and fruits, desserts and candies, beverages, diet and light products and spices). Approximate portions of usual intake of each item was recalled by patients with the aid of a photographic record for dietary surveys and the portion size was, subsequently, quantified into weights [[
Participants underwent 3D Echocardiography at the first- and sixth-month following MI (iE 33 system; Philips Medical Systems, Andover, MA) according to current guidelines [[
Cardiac Magnetic Resonance imaging (CMRi) and CMRi data analysis were performed according to descriptions shown in a previous study [[
Normally distributed data were presented as mean ± SD and skewed data as median and interquartile range (IQR). Participants were stratified into two groups according to daily consumption of ω-3 (below or above the median). Chi-square or two-tailed t tests were used for comparison of baseline data. Analyses of covariance (ANCOVA) was used to assess the association between ω-3 consumption and the change (Δ) of hs-CRP, IL-2 and BNP levels between D1 and D5. ANCOVA adjusted by covariates was also used to compare infarcted mass and the change in LVEF and LVEDV between 30 and 180 days. All analyses of the changes between D1 and D5 or between the 30th and the 180th day were additionally adjusted for the baseline levels in order to attenuate the effect of regression toward the mean. Multivariate binary logistic regression was used to evaluate the association between the dichotomous dependent variable ω-3 intake below or above the median and the independent variables Δhs-CPR, ΔIL-2, ΔBNP, ΔLVEF and ΔLVEDV. These dependent variables were categorized into below or above their respective medians to bypass the non-normal distribution and as a strategy to level their effects sizes, allowing direct comparability between variables. Stepwise selection of variables was used to reach the final model using the covariates. The following covariates were used for ANCOVA and regression analyses and were selected using bootstrapping based on t test analysis (Table 1): age, gender, diabetes mellitus, hypertension, coronary reperfusion therapy, and use of ACE inhibitors/ARBs. Restricted cubic spline models were used to assess the relationship between daily consumption of ω-3 and hs-CRP levels. Splines were adjusted by the GRACE score [[
Baseline characteristics are shown in Table 1. Participants who had a daily intake of ω-3 above the median (≥1.7 g/day) at admission had higher systolic blood pressure, higher levels of triglycerides and higher frequency of diabetes mellitus, hypertension, and coronary reperfusion therapy as well as the use of ACE inhibitors/ARBs than their counterparts.
Three months after STEMI, the food questionnaire was reapplied in order to evaluate the intake of ω-3 in this interlude. Participants who originally presented with ω-3 intake below the median (< 1.7 g/day) had no changes in their ω-3 intake during follow-up (from 1.0(0.7) to 1.1(0.9) g/day; p = 0.572). However, participants who originally had an intake of ω-3 above the median (≥1.7 g/day) reduced their ω-3 intake after STEMI (from 2.7(1.3) to 1.9(1.5) g/day; p < 0.001). Due to the natural limitation of the FFQ tool, it is not possible to specify the difference of 30% (0.8 g). Regardless, after 3 months, the higher intake group were still consuming significantly higher amounts of ω-3 (Table 1).
Comparative analyses of inflammatory markers are shown in Table 2. Participants who consumed ω-3 above or below the median had equivalent levels of hs-CRP at D1. Participants who consumed ω-3 above the median had higher levels of IL-2 at D1 than their counterparts. The increase in both hs-CRP and IL-2 levels from D1 to D5 were smaller among those who consumed ω-3 above the median than their counterparts. All these comparative results remained significant after adjustment for covariates as indicated above.
Comparative levels of inflammatory markers, BNP levels, LVEF and infarcted mass
Characteristics < 1.7 g ≥1.7 g ANCOVAa Inflammatory markers hs-CRP at 1st day, (mg/L) 0.60(1.11) 0.60(0.97) 0.820 0.648 hs-CRP at 5th day, (mg/L) 4.10(6.90) 2.90(4.62) 0.005 0.027 Δhs-CRP, (mg/L)b + 2.80(5.50) + 1.57(4.14) 0.001 0.004 IL-2 at 1st day, (pg/mL) 0.04(1.24) 1.34(2.60) < 0.001 0.036 IL-2 at 5th day, (pg/mL) 5.83(6.55) 5.46(6.30) 0.110 0.224 +5.36(6.18) + 3.87(6.17) 0.003 0.013 Cardiac remodeling marker BNP at 1st day, (ng/mL) 0.18(0.13) 0.17(0.17) 0.208 0.099 BNP at 5th day, (ng/mL) 0.35(0.32) 0.21(0.26) < 0.001 0.056 ΔBNP, (ng/mL)b + 0.14(0.27) + 0.07(0.18) 0.003 0.029 Cardiac Magnetic Resonance Imaging and Echocardiography Infarcted mass, (%) 12.6 ± 7.3 11.8 ± 7.1 0.311 0.406 Infarcted mass, (g) 15.6(9.3) 14.6(11.9) 0.628 0.798 LVEF at 1st month, (%) 55.0 ± 14.8 53.7 ± 13.8 0.590 0.900 LVEF at 6th month, (%) 54.7 ± 12.8 59.9 ± 10.6 0.189 0.609 ΔLVEF, (%)b −1.9 ± 10.7 + 4.5 ± 13.6 0.165 0.010 LVEDV at 1st month, (mL) 89.8 ± 38.0 96.6 ± 32.6 0.580 0.960 LVEDV at 6th month, (mL) 99.2 ± 43.5 85.6 ± 22.9 0.223 0.848 ΔLVEDV, (%)b + 13.2 ± 22.8 −8.8 ± 14.7 0.001 0.011
Binary logistic regression models are shown in Table 3 and were used to assess the association between the intake of ω-3 and study endpoints. The intake of ω-3 was inversely associated with increase in hs-CRP and IL-2 levels (Δhs-CRP and ΔIL-2 – Model 1). Both associations remained significant after full adjustment for covariates (Model 2). The addition of smoking habit as covariate did not change the results.
Binary logistic regression to assess the association between daily consumption of omega-3 and Δhs-CRP, ΔIL-2, ΔBNP, ΔLVEF and ΔLVEDV
OR(95%CI); Omega-3 < 1.7 g Model 1 1.819(1.226–2.699);0.003 Model 2 1.958(1.238–3.097);0.004 OR(95%CI); ΔIL-2 ≥ + 4.642 pg/mL Omega-3 < 1.7 g Model 1 2.092(1.123–3.897);0.020 Model 2 2.464(1.205–5.038);0.014 OR(95%CI); ΔBNP ≥ + 0.10 ng/mL Omega-3 < 1.7 g Model 1 2.481(1.300–4.737);0.006 Model 2 2.660(1.300–5.443);0.007 OR(95%CI); ΔLVEF < + 1.2% Omega-3 < 1.7 g Model 1 4.115(1.150–14.723);0.030 Model 2 5.119(1.114–23.518);0.036 OR(95%CI); ΔLVEDV ≥ -3.248% Omega-3 < 1.7 g Model 1 5.250(1.093–25.211);0.038 Model 2 2.857(1.467–6.877);0.017
Model 1: Unadjusted; Model 2: Adjusted for diabetes mellitus, hypertension, coronary reperfusion therapy, use of ACEi/ARBs drugs, triglycerides, systolic blood pressure, diastolic blood pressure and peak CK-MB
Restricted cubic spline models were used to assess the relation between the daily consumption of ω-3 across changes in hs-CPR levels (Fig. 2). The consumption of ω-3 was inversely associated with the change in hs-CRP levels even after fully adjusted analysis (p = 0.01).
Graph: Fig. 2Restricted cubic spline curves to assess for relationship between daily consumption of ω-3 and change in hs-CRP (a), IL-2 (b) and BNP levels (c) during acute phase of STEMI (ΔCRP = D5 – D1). Splines were adjusted by the Global Registry of Acute Coronary Events (GRACE) score and plasma peak CKMB level
Comparative analyses of BNP levels, infarcted mass, LVEF, LVEDV and SI are shown in Table 2. No difference in plasma levels of BNP was observed at D1. However, BNP levels significantly increased in both subgroups from D1 to D5 (p < 0.001 and p = 0.032 for subgroups below and above the median, respectively). In the subgroup analysis, those who consumed ω-3 levels above the median had lower levels of BNP at D5 than their counterparts. Accordingly, participants who consumed ω-3 levels above the median had a smaller change in BNP levels (ΔD5-D1) than their counterparts; this difference remained significant after adjustment.
No differences were observed in the extension of infarcted mass obtained by CMRi neither in the LVEF at first and sixth months after STEMI. However, participants who consumed ω-3 levels above the median had an increase of LVEF from the first to the sixth month after STEMI while their counterparts had a decrease of LVEF in this period of time. Also, LVEDV was not different between the groups at the first and sixth month after STEMI. Nevertheless, participants who consumed ω-3 levels above the median had a decrease in LVEDV from the first to the sixth month while their counterparts had an increase in LVEDV in the same period.
The associations between the intake of ω-3 and the changes in the levels of BNP, LVEF and LVEDV measures were tested by binary logistic regression models as shown in Table 3. The intake of ω-3 below the median was inversely associated with increase in BNP levels. Conversely, the intake of ω-3 below the median was directly associated with reduction in LVEF and decrease in LVEDV. Both associations remained significant after full adjustment for covariates.
In short, this study indicates that an increased daily intake of ω-3 (at least 1.7 g) is associated with attenuated inflammatory response and ventricular remodeling after STEMI.
Excessive increase in pro-inflammatory cytokines secretion after MI have been associated with a higher risk for mortality [[
Higher intake of ω-3 before MI was associated with higher late gain of LVEF and decreased late gain of LVEDV, indicating a lower degree of remodeling. As the nutritional reanalysis of these individuals three months after STEMI continued to point to a higher consumption of ω-3, we cannot rule out the possibility that persistently increased consumption also contributed to this outcome. We also cannot exclude the possibility of a play of chance due to the observational design of this study, precluding the balance between the groups for variables not measured or not known. Nevertheless, the treatment of high-dose of ω-3 after STEMI has been shown to be associated with a reduction in left ventricular remodeling, myocardial fibrosis, and systemic inflammation in a prospective randomized controlled trial [[
Some limitations must be considered when reading this study. Firstly, as commented above, our findings must be considered as hypothesis generating due to the observational design and hence the impossibility to exclude selection bias. Randomized controlled trials (RCT) are required to exclude unbalance between the arms and the healthy cohort effect. However, consistency with RCT and mechanistic data deem this finding plausible. Other limitation that should be considered is the recall bias due to FFQ application, since participants are asked to report their food intake retrospectively in a prolonged period of time.
In conclusion, the findings of the present study suggest that a reduced daily intake of ω-3 may intensify outcome-determining mechanisms after STEMI, such as acute inflammatory response and late left ventricular remodeling.
Not applicable.
BHS proceedings were in accordance with the Helsinki Declaration and the study was approved by the local Ethics Committee (083/06). Participants were only enrolled after signing informed consent. BHS is registered at
This work was supported by a grant from the Brazilian National Research Council (CNPq) grant number 308550/2010–2. Prof. Sposito is recipient of a Research Career Awards from the CNPq.
The datasets generated and/or analyzed during the current study are not publicly available due to ongoing proprietary work but are available from the corresponding author on reasonable request. The authors had full access to all of data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.
AMCS, APRC and SNS collected outpatient data, conducted data analyses and prepared the manuscript. LSFC, FAM, ORCF, WN, JQS and ACS reviewed the manuscript. ACS is the guarantor of this work. All authors read and approved the final manuscript.
All authors consent the submission of the manuscript as it is.
There are no financial and non-financial competing interests for all authors, who declare that they do not have a conflict of interest regarding the study.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
• ACEi
- Angiotensin-converting enzyme inhibitors
• ANCOVA
- Analysis of covariance
• AP-1
- Activator Protein-1
• ARB
- Angiotensin II receptor blockers
• BHS
- Brasília Heart Study
• BNP
- B-type natriuretic peptide
• CK-MB
- Creatine kinase myocardial bound
• CMRi
- Cardiac Magnetic Resonance imaging
• D1
- First day of hospitalization
• D5
- Fifth day of hospitalization
• FFQ
- Food frequency questionnaire
• hs-CRP
- High-sensitivity C-reactive protein
• IL-2
- Inteleucin-2
• LVEDD
- Left ventricle end-diastolic diameter
• LVEDV
- Left ventricle end-diastolic volume
• LVEF
- Left ventricle ejection fraction
• LVESD
- End-systolic diameter
• LVESV
- Left ventricle end-systolic volume
• MI
- Myocardial infarction
- NF-κB
- Nuclear Factor κB
• PD
- Posterior wall diastolic thickness
• SD
- Septum diastolic thickness
• STEMI
- ST-elevation myocardial infarction
- ΔD5-D1
- Change from fifth to first day of hospitalization
- ω-3
• Omega-3
By Alessandra M. Campos-Staffico; Ana Paula R. Costa; Luiz Sérgio F. Carvalho; Filipe A. Moura; Simone N. Santos; Otavio R. Coelho-Filho; Wilson Nadruz; José C. Quinaglia e Silva and Andrei C. Sposito
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