This study aimed to assess the balance of serum n-3 to n-6 polyunsaturated fatty acids (PUFAs) in patients with acute coronary syndrome (ACS). We enrolled 1,119 patients who were treated and in whom serum PUFA level was evaluated in 5 divisions of cardiology in a metropolitan area in Japan. Serum levels of PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA), were compared between patients with and without ACS. We also evaluated the balance of serum n-3 to n-6 PUFAs, including EPA/AA and DHA/AA ratios. EPA/AA values were 0.46 ± 0.32 and 0.50 ± 0.32 in the ACS and non-ACS groups, respectively. DHA/AA values were 0.95 ± 0.37 and 0.96 ± 0.41 in the ACS and non-ACS groups, respectively. Next, we divided the patients into 3 groups based on the tertiles of EPA/AA or tertiles of DHA/AA to determine the independent risk factors for ACS. According to multivariate logistic regression analysis, the group with the lowest EPA/AA (≤0.33) had a greater probability of ACS (odds ratio 3.14, 95% confidence interval 1.16 to 8.49), but this was not true for DHA/AA. In conclusion, an imbalance in the ratio of serum EPA to AA, but not in the ratio of DHA to AA, was significantly associated with ACS.
Lipid control with statins reduces the risk of acute coronary syndrome (ACS) through the regression or stabilization of coronary artery plaques. However, patients treated with statins may still develop ACS. Sachdeva et al analyzed a large cohort of patients hospitalized with coronary artery disease (CAD) and found that >1/2 were readmitted, although they had low-density lipoprotein cholesterol levels <100 mg/dl. Therefore, we need to focus on the residual risks in patients on statin therapy to further reduce cardiovascular events. Several observational studies reported that n-3 polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), contributed to reduction in the risk of CAD in healthy subjects. It is well known that PUFAs play important roles in the initiation and progression of CAD. In the Japan EPA Lipid Intervention Study, which reported the beneficial effect of pure EPA administration for reducing coronary events, a high EPA/arachidonic acid (AA) ratio was associated with a low incidence of coronary events. Based on these previous studies, n-3 PUFAs and the balance of n-3 to n-6 PUFAs may play important roles in residual cardiovascular risk reduction. However, it is still unclear which n-3 PUFA and the balance of which n-3 PUFA to n-6 PUFAs play an important role in the development of ACS. This study aimed to assess serum levels of PUFAs and the balance of n-3 to n-6 PUFAs, including EPA, DHA, AA, and dihomo-γ-linolenic acid in patients with ACS.
Methods
This was a multicenter observational study performed at 5 centers (4 university hospitals and 1 community hospital) located in Tokyo. We enrolled 1,119 patients who were treated in the divisions of cardiology at these 5 centers from January 2004 to May 2011. All these patients had evaluation of serum PUFAs. This cohort consisted of 1,037 patients without ACS and 72 patients with ACS. Acute myocardial infarction was defined as a transient increase of the MB fraction of creatine kinase or troponin T level in patients with ischemic symptoms and/or typical electrocardiographic findings (ST elevation). Unstable angina was defined as angina at rest, accelerated exertional angina combined with typical electrocardiographic changes (ST depression), or an increase in the intensity of anti-ischemic therapy. Patients were excluded if they were receiving hemodialysis or taking pure EPA. Patients with ongoing congestive heart failure, severe liver dysfunction, or other systemic diseases, including malignancy and collagen disease, were also excluded. Patients with a medical history of percutaneous coronary intervention, coronary artery bypass grafting, and old myocardial infarction were also excluded. We also evaluated the use of the following medications: statins, antiplatelet agents, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, β blockers, and hypoglycemic agents. This study was approved by the institutional ethics committee of each hospital, and all subjects gave informed consent.
Fasting blood samples were obtained in the morning, and serum levels of EPA, DHA, AA, and dihomo-γ-linolenic acid were measured at an external laboratory (SRL Inc., Tokyo, Japan). We also evaluated the following laboratory parameters: total cholesterol, fasting triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio, fasting plasma glucose, hemoglobin A1c, uric acid, serum creatinine (Cr), and estimated glomerular filtration rate. The estimated glomerular filtration rate was calculated based on the Japanese equation that uses serum Cr level, age, and gender as follows: estimated glomerular filtration rate (ml/min/1.73 m 2 ) = 194 × Cr −1.094 × age −0.287 (female × 0.739). Blood samples from patients with ACS were obtained during admission and those from outpatients were obtained at the outpatient clinic.
Patients were stratified into 3 groups based on the tertiles of EPA/AA ratio (tertile cut-off values: 0.33 and 0.55) or DHA/AA ratio (tertile cut-off values: 0.78 and 1.06). The risk of ACS in patients in the different tertiles of EPA/AA and DHA/AA was compared using crude odds ratios (ORs) and their 95% confidence intervals. To adjust ORs for patients’ clinical characteristics, we used a multivariate logistic regression model that included age, gender, body mass index, hypertension, diabetes mellitus, dyslipidemia, smoking, family history of CAD, serum Cr level, and the use of statins, antiplatelet agents, renin-angiotensin system inhibitors, calcium channel blockers, β blockers, or hypoglycemic agents. Patients with missing information for each variable were excluded in the multivariate analysis. The α level for all statistical tests was set at 0.05; thus, all confidence intervals were presented at the 95% level. All analyses were carried out with SAS, version 9.2 (SAS Institute, Cary, North Carolina).
Results
In all 1,119 subjects, the mean ± SD serum levels of EPA, AA, DHA, and dihomo-γ-linolenic acid were 76.4 ± 47.8, 159.9 ± 54.3, 146.9 ± 55.0, and 33.4 ± 12.4 μg/ml, respectively. EPA/AA ratio was 0.498 ± 0.320 and DHA/AA ratio was 0.962 ± 0.408. EPA/AA ratio was 0.456 ± 0.321 and 0.501 ± 0.320 in the ACS and non-ACS groups, respectively. DHA/AA ratio was 0.951 ± 0.368 and 0.963 ± 0.411 in the ACS and non-ACS groups, respectively.
Tables 1 and 2 list a comparison of the clinical data among the patient groups stratified according to the tertiles of EPA/AA or tertiles of DHA/AA. There was an inverse trend between the magnitude of EPA/AA and the incidence of ACS, but there was no such trend for DHA/AA. A positive trend was observed between the magnitudes of both EPA/AA and DHA/AA and the average number of conventional coronary risk factors, including age (≥65 years), obesity (body mass index ≥25 kg/m 2 ), hypertension, diabetes mellitus, dyslipidemia, smoking history, and family history of CAD. Table 3 lists the risk of ACS in each EPA/AA group based on the OR determined by logistic regression analysis, and Table 4 lists the same analysis for DHA/AA group. According to the results of multivariate logistic regression analyses, the patients in the group with the lowest EPA/AA (≤0.33) were more likely to have ACS, but this was not true for DHA/AA. A multivariate logistic regression analysis demonstrated that apart from low EPA/AA, diabetes mellitus (OR 3.88, 95% confidence interval 1.54 to 9.73) showed significant and positive correlations with ACS risk.
| Variable | No. of Measurements | EPA/AA ≤0.33 (n = 366) | 0.33 < EPA/AA ≤ 0.55 (n = 386) | 0.55 < EPA/AA (n = 367) | p |
|---|---|---|---|---|---|
| Age (yrs) | 1,119 | 59.3 ± 13.6 | 65.4 ± 11.1 | 67.1 ± 8.9 | <0.001 ∗ |
| Men | 1,119 | 69.1 | 69.7 | 77.9 | 0.011 ∗ |
| Body mass index (kg/m 2 ) | 1,059 | 24.5 ± 4.3 | 24.3 ± 3.3 | 24.2 ± 3.1 | 0.514 |
| Hypertension | 1,119 | 52.5 | 53.1 | 58.3 | 0.217 |
| Diabetes mellitus | 1,119 | 29.0 | 35.0 | 37.9 | 0.034 ∗ |
| Dyslipidemia | 1,119 | 64.8 | 66.3 | 65.1 | 0.894 |
| Family history of ischemic heart disease | 1,119 | 16.1 | 16.1 | 13.6 | 0.56 |
| Smoking | 1,119 | 38.0 | 39.6 | 38.1 | 0.875 |
| Number of risk factors | 1,119 | 2.9 ± 1.4 | 3.2 ± 1.4 | 3.3 ± 1.4 | 0.001 ∗ |
| Total cholesterol (mg/dl) | 893 | 198.0 ± 36.6 | 196.5 ± 38.2 | 194.4 ± 33.2 | 0.47 |
| Triglyceride (mg/dl) | 913 | 153.7 ± 90.1 | 153.7 ± 130.0 | 137.2 ± 74.8 | 0.07 |
| Low-density lipoprotein cholesterol (mg/dl) | 924 | 115.6 ± 31.6 | 114.0 ± 31.4 | 112.0 ± 29.1 | 0.343 |
| High-density lipoprotein cholesterol (mg/dl) | 917 | 53.8 ± 17.6 | 53.5 ± 18.3 | 54.8 ± 17.9 | 0.607 |
| Low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio | 917 | 2.4 ± 1.0 | 2.4 ± 1.0 | 2.3 ± 0.9 | 0.218 |
| Fasting blood sugar (mg/dl) | 903 | 113.6 ± 50.0 | 112.9 ± 35.9 | 116.6 ± 33.4 | 0.495 |
| Hemoglobin A1c (%) | 898 | 6.1 ± 1.2 | 6.2 ± 1.0 | 6.2 ± 0.9 | 0.363 |
| Serum Cr (mg/dl) | 917 | 0.9 ± 0.3 | 0.8 ± 0.3 | 0.8 ± 0.3 | 0.736 |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 917 | 64.8 ± 19.6 | 63.8 ± 16.8 | 63.3 ± 16.9 | 0.549 |
| EPA (μg/ml) | 1,119 | 38.8 ± 16.5 | 67.9 ± 19.7 | 122.7 ± 51.6 | <0.001 ∗ |
| AA (μg/ml) | 1,119 | 175.5 ± 75.3 | 158.3 ± 40.7 | 146.1 ± 34.3 | <0.001 ∗ |
| DHA (μg/ml) | 1,119 | 112.4 ± 38.2 | 147.6 ± 43.2 | 180.5 ± 59.1 | <0.001 ∗ |
| Dihomo-γ-linolenic acid (μg/ml) | 1,119 | 38.9 ± 13.4 | 33.7 ± 11.7 | 27.5 ± 9.2 | <0.001 ∗ |
| Statin | 1,119 | 40.2 | 41.5 | 46.9 | 0.149 |
| Antiplatelet agent | 1,119 | 39.1 | 48.4 | 53.1 | <0.001 ∗ |
| Renin-angiotensin system inhibitor | 1,119 | 7.9 | 11.1 | 6.8 | 0.089 |
| Calcium channel blocker | 1,119 | 43.2 | 42.2 | 56.1 | <0.001 ∗ |
| β Blocker | 1,119 | 31.4 | 33.9 | 32.2 | 0.749 |
| Hypoglycemic agents | 1,119 | 15.8 | 17.1 | 19.1 | 0.508 |
| ACS | 1,119 | 8.2 | 6.0 | 5.2 | 0.224 |
| Stable CAD | 1,119 | 37.4 | 47.2 | 45.2 | 0.182 |
∗ p <0.05. p Values are from analysis of variance for continuous data and from Mantel-Haenszel “analysis of variance” test of 2 degrees of freedom for presence-absence data.
| Variable | No. of Measurements | DHA/AA ≤0.78 (n = 371) | 0.78 < DHA/AA ≤ 1.06 (n = 384) | 1.06 < DHA/AA (n = 364) | p |
|---|---|---|---|---|---|
| Age (yrs) | 1,119 | 58.7 ± 13.6 | 65.7 ± 10.4 | 67.3 ± 9.3 | <0.001 ∗ |
| Men | 1,119 | 68.5 | 72.1 | 76.1 | 0.069 |
| Body mass index (kg/m 2 ) | 1,059 | 24.6 ± 4.3 | 24.1 ± 3.3 | 24.4 ± 3.1 | 0.213 |
| Hypertension | 1,119 | 53.1 | 53.9 | 56.9 | 0.558 |
| Diabetes mellitus | 1,119 | 28.8 | 36.2 | 36.8 | 0.039 ∗ |
| Dyslipidemia | 1,119 | 63.6 | 66.1 | 66.5 | 0.668 |
| Family history of ischemic heart disease | 1,119 | 12.4 | 19.5 | 13.7 | 0.015 ∗ |
| Smoking | 1,119 | 33.7 | 39.8 | 42.3 | 0.047 ∗ |
| Number of risk factors | 1,119 | 2.8 ± 1.4 | 3.2 ± 1.4 | 3.3 ± 1.3 | <0.001 ∗ |
| Total cholesterol (mg/dl) | 893 | 199.2 ± 35.2 | 193.9 ± 39.5 | 195.7 ± 33.0 | 0.185 |
| Triglyceride (mg/dl) | 913 | 140.0 ± 84.1 | 140.3 ± 100.0 | 165.6 ± 118.1 | 0.002 ∗ |
| Low-density lipoprotein cholesterol (mg/dl) | 924 | 115.1 ± 30.8 | 113.7 ± 33.4 | 112.7 ± 27.7 | 0.635 |
| High-density lipoprotein cholesterol (mg/dl) | 917 | 57.3 ± 19.0 | 53.5 ± 17.8 | 51.1 ± 16.2 | <0.001 ∗ |
| Low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratio | 917 | 2.2 ± 1.0 | 2.3 ± 1.0 | 2.4 ± 0.9 | 0.06 |
| Fasting blood sugar (mg/dl) | 903 | 114.6 ± 49.3 | 112.2 ± 31.2 | 116.3 ± 38.0 | 0.462 |
| Hemoglobin A1c (%) | 898 | 6.1 ± 1.1 | 6.2 ± 1.1 | 6.2 ± 0.9 | 0.207 |
| Serum Cr (mg/dl) | 917 | 0.8 ± 0.3 | 0.8 ± 0.3 | 0.9 ± 0.3 | 0.968 |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) | 917 | 64.3 ± 18.7 | 64.3 ± 18.0 | 63.3 ± 16.5 | 0.69 |
| EPA (μg/ml) | 1,119 | 48.5 ± 26.3 | 72.8 ± 35.7 | 108.5 ± 56.1 | <0.001 ∗ |
| AA (μg/ml) | 1,119 | 182.8 ± 72.8 | 154.9 ± 37.8 | 141.9 ± 36.0 | <0.001 ∗ |
| DHA (μg/ml) | 1,119 | 109.9 ± 36.1 | 141.0 ± 33.4 | 190.9 ± 58.6 | <0.001 ∗ |
| Dihomo-γ-linolenic acid (μg/ml) | 1,119 | 37.8 ± 13.3 | 31.7 ± 10.8 | 30.6 ± 11.9 | <0.001 ∗ |
| Statin | 1,119 | 43.7 | 43.5 | 41.2 | 0.754 |
| Antiplatelet agent | 1,119 | 33.7 | 52.1 | 54.9 | <0.001 ∗ |
| Renin-angiotensin system inhibitor | 1,119 | 8.6 | 7.3 | 10.2 | 0.378 |
| Calcium channel blocker | 1,119 | 43.1 | 44.5 | 53.8 | 0.007 ∗ |
| β Blocker | 1,119 | 28.0 | 35.4 | 34.1 | 0.072 |
| Hypoglycemic agents | 1,119 | 14.6 | 17.7 | 19.8 | 0.169 |
| ACS | 1,119 | 5.7 | 7.8 | 5.8 | 0.397 |
| Stable CAD | 1,119 | 29.4 | 48.4 | 52.2 | <0.001 ∗ |
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