Statins are well-known as the first-line drugs in the treatment of hyper-LDL cholesterolemia. Large-scale, prospective, randomized clinical trials have demonstrated that statins improve clinical cardiovascular outcomes and reduce mortality in both primary and secondary prevention [18
]. However, in the real world, despite that clinical evidence, CHD including acute MI can occur even among dyslipidemia patients currently taking a statin with an LDL goal of less than 100 mg/d [23
]. Therefore, combining omega-3 fatty acids with a statin induces further triglyceride reduction for patients with high triglyceride levels despite achieving target LDL cholesterol goals. However, little is known about further prevention of cardiovascular events in hypercholesterolemia patients without hypertriglyceridemia, especially with the addition of fish oil capsules to statin therapy. A study did report, however, that there was a further decrease in nonfatal coronary events or unstable angina in patients with hypercholesterolemia, especially in secondary prevention with the use of statins and EPA in combination therapy [24
]. This was the first study to show an additional clinical benefit of long-term combination therapy with omega-3 fatty acids and statins without serious adverse effects compared to statins only. However, this trial was not designed as a double-blind study. Also, unfortunately, the study did not show RBC fatty acid composition, investigated only EPA and not a DHA effect on coronary events, and revealed no additional benefit for acute MI.
Omega-3 fatty acids are known to cause improvement in lipid profiles without inducing serious hepatotoxicity or myopathy. Unlike previous studies, our study was specifically designed to evaluate the fatty acid composition of RBC and lifestyle factors such as alcohol consumption and smoking status in patients who developed acute STEMI, although they were taking statins and had achieved their LDL cholesterol control. The findings of this study can give us better understanding of the effectiveness and limitation of statin use for primary prevention of acute MI.
In the present study, the average omega-3 index in healthy controls was about 11%, which was similar to figures from previous studies in Koreans [14
], and slightly higher than those reported by previous studies performed in Japan [26
]. Recent studies have shown that the Japanese have an omega-3 index of 7-11%, and the index tends to rise along with increasing age [26
]. Our study did not show a correlation between omega-3 index and age.
Recently, two case-control studies were conducted to reveal the omega-3 index of RBCs in patients with acute MI or metabolic syndrome in Korea. One study found that patients with acute MI have a lower omega-3 index (9.6%) in comparison to healthy controls, and total trans
-fatty acids are associated with an increased risk of MI. However, the result did not have adequate statistical power due to a wide confidence interval of the odds ratio of MI risk estimate. The other study reported that patients with (11.8%) and without metabolic syndrome (12.4%) have similar omega-3 indices. In the present study, we found that patients who experienced acute STEMI, even though they were taking statins and had achieved their LDL cholesterol control goal, had an omega-3 index of 8.8%, which was significantly lower than that of controls (11.1%), while no difference in total trans
-fatty acids was observed between the two groups. Previous studies have provided inconsistent data on whether trans
fat intakes are associated with MI risk according to levels of intake [28
]. On the other hand, the present study found that omega-6 fatty acids such as linoleic acid were increased in patients with acute STEMI compared to controls, which was in accordance with a previous study [31
]. Linoleic acid was frequently inversely associated with risk for coronary heart disease events in Western people [32
]. However, the present study found that omega-6 fatty acids such as linoleic acid were increased in patients with acute STEMI compared to controls. Previous studies from Korea and Japan showed that there were no differences of linoleic acid level between MI cases and controls [25
]. Although it is not yet known why, possible mechanisms underlying the ethnic difference in linoleic acid concentrations include differences in fat distribution, fatty acid interactions with genetic polymorphisms, and diet. Replication studies with larger sample size would be needed to confirm our study results.
The American Heart Association recommends that healthy people should eat two servings of a variety of (preferably oily) fish per week [11
]. The present study showed an association between fish consumption and the omega-3 index (r = 0.269, P = 0.026), although two sample t
-test revealed only a borderline difference of average fish consumption (servings/week) between cases and controls (2.1 vs. 3.1, P = 0.059), although the consumption was greater than that in most Western populations. A Japanese study also showed that a very high level of fish intake was significantly associated with a lower risk of nonfatal CHD [17
Harris et al. [13
] suggest the omega-3 index (EPA + DHA as a percent of total fatty acid in RBC membranes) as a novel risk factor for CHD. The studies have shown that a higher omega-3 index than a value of 8-10% is desirable for its cardio-protective benefits, because of the relationship between a lower average omega-3 index and the development of CHD in Caucasians [13
]. Interestingly, Korean patients with acute STEMI already had an omega-3 index of 8%, which is a cardio-protective goal for Western people. Therefore, we suggest that a higher cut-off point of omega-3 index than 8-10% for preventing CHD is needed, and an omega-3 index of 11% or above could be appropriate in Korea. This discrepancy between Korean and Western people could be explained in large part by the fact that most Korean people have higher fish consumption than people of Western populations. Korean consumes fish species such as mackerel, salmon which are very high in omega-3 [34
]. In addition, there may be ethnic differences in the threshold of omega-3 index and underlying mechanism of development of CHD. Using multivariable adjusted regression analysis, our study showed that lower omega-3 index was independently associated with acute STEMI after adjusting for age, sex, and BMI. Subjects in the lowest quartile of omega-3 index was positively associated with almost six times odds for being a case, even after adjusting for all confounding variables, than the highest quartile subgroup (Table ). That finding is concordant with previous case-control studies about EPA and DHA levels that found significantly lower EPA and DHA in patients with acute coronary syndrome compared to healthy control people [29
]. A case-control follow-up study also provides evidence of a plasma concentration of EPA and DPA associated with a lower incidence of nonfatal MI among American women [30
], despite their current lower fish intake than that of typical Korean and Japanese people.
Cigarette smoking is an important risk factor for cerebro-cardiovascular diseases. Epidemiologic, clinical, and experimental data have revealed that smoking is prothrombotic, atherogenic, and causative factors in the development of CHD [36
]. In the present study, we also found that smoking was a major associated factor for acute STEMI development in patients taking statins who had achieved their goal LDL cholesterol. Our results were consistent with a previous study using Japanese data that revealed an association of cigarette smoking with CVD mortality in patients, despite their lower total cholesterol level [37
]. The relationship between omega-3 index and smoking status is a controversial topic [38
]. In additional analysis, we found no difference in the omega-3 index between smokers and non-smokers within each group (data not shown).
There is no single cause for CHD. CVD is caused by a constellation of risk factors, including environmental factors, such as sedentary lifestyle, genetic predisposition, advancing age, smoking, an atherogenic diet, and underlying conditions or diseases including insulin resistance or type 2 diabetes, hypertension, and dyslipidemia. In this view, interestingly, the present study showed that smoking, a lower omega-3 index, and advancing age together among those factors may work together to cause acute STEMI despite statin-induced low LDL cholesterolemia. Another Korean study also reported that, compared to survivors, non-survivors of acute MI had a lower level of total cholesterol, triglycerides, and LDL-cholesterol, while the opposite was observed with plasma omega-3 fatty acids [39
]. However, the researchers did not explain why non-survivors from acute MI had lower lipid levels than survivors. It is obvious, however, that certain cardiovascular events still occur even among patients reaching target levels of LDL-cholesterol [30
]. Therefore, relative to controls, STEMI cases are more likely to be smokers and to have a lower omega-3 index, even though the LDL cholesterol target is achieved with a statin in the cases with dyslipidemia. Patients should be asked to quit smoking and eat more fish or take omega-3 supplements as well as reach their LDL-cholesterol target on a statin.
Our study is limited by its cross-sectional study design. Further investigation with a cohort study is warranted. Another limitation is the wide confidence interval due to a relatively small sample size. Koreans usually have a fish intake that is several times higher than Western people, which limits the generalizability of those results to other population groups.
In summary, subjects with acute STEMI had a lower omega-3 index and higher smoking rate after adjusting for age, gender, and BMI than controls, although they are currently receiving a statin with an LDL goal of less than 100 mg/d and normal triglyceride levels. Nevertheless, acute STEMI patients have an omega-3 index of 8.8% that is higher than that of people of Western populations. This means that the cut-off point for the omega-3 index for preventing CVD might be tailored for the Korean population. Thus, at present, we suggest a suitable level of an omega-3 index of 11% or above for prevention of coronary artery disease in the Korean population. However, replication studies with a larger sample size are needed to confirm our first stage study results for current practice in the field.