Commentary :
There
have been various discussions of MonounsaturatedFatty Acids (MUFA) and Polyunsaturated Fatty Acids (PUFA) for influencing
atherosclerosis. MUFA seems to have beneficial effects on the risk of coronary
heart disease and atherosclerosis [1], and the authors have reported the
marine-derived long-chain MUFA decrease atherosclerosis lesion development and
total cholesterol
in mouse [2]. On
contrast, n-3 PUFA has been studied by GISSI-P trial, which was the Gruppo
Italiano Per Lo Studio Della Sopravvivenza Nelllnfarto Miocardio-Prevenzione
(GISSI-P) Trial [3]. It
included 11,324 subjects who had myocardial infarction followed up for 3.5
years. Administration of n-3 PUFA significantly lowered the risk of primary
endpoint by 10%, suggesting beneficial effect statistically. Consecutive study
showed the clinical effects for death, combined death, stroke and non-fatal myocardial
infarction. Furthermore, it attributed the reduced risk of the events for
overall by 20%, cardiovascular by 30%, and sudden death by 45% [4]. From
historical aspect of lipids and atherosclerosis,
there were observational studies concerning risk of heart disease and
consumption of fish. They indicated the inverse relationship between heart
disease and intake of fish [5]. After that, eating fish about 40-60g per day
would be effective for the reducing cardiovascular mortality approximately half
level. This amount is compatible for intake of about 0.2 to 1.0g of n-3 fatty
acids [6]. Consecutively,
there was a report by Japan EPA Lipid Intervention Study (JELIS) [7]. Subjects
(n=18, 645) were assigned to receive either 1800mg of EPA with statin (EPA
group) or statin only (control group) for 5 years. After treatment, LDL-C
levels reduced 25% in both groups. In contrast, EPA group showed 19% of
reduction of major coronary events compared with the control group. Thus, EPA
seemed to prevent coronary events, especially non-fatal coronary events. Thus,
various researches have been found concerning intake of fatty food and
particular types of vascular events such as heart failure, arrhythmia
and coronary
heart disease. Among them, there have been controversies as to the
randomized trials of supplement with n-3 fatty element. A protocol was that
supplement with a combination of EPA and DHA were provided for 40 months [8].
Further, continuous administration of n-3 fatty acids 1g/day was tried for 12,536
subjects for 6.2 years in average [9]. As
the results, the rate of cardiovascular events was not decreased in patients at
high risk. Furthermore, meta-analysis of 10 trials involving 77,917 individuals
has performed [10]. In this analysis, there were not identified significant
beneficial effects of n−3 fatty acid on major vascular events. As
to the guideline of American Heart Association (AHA), n-3 fatty acid
supplements have been currently recommended for secondary prevention of
coronary heart disease [11]. Similarly, n-3 fatty acid intake is also
beneficial for primary prevention of cardiovascular
disease [12]. In
the clinical practice, blood lipid control has been continued for long [13].
Its purpose is to prevent arteriosclerotic diseases, such as coronary heart
disease. As one of the intervention tests, the JELIS trial has been conducted
in Japan, in which the effect of inhibiting cardiovascular events was studied
by administration of eicosapentaenoic
acid (EPA) [7]. Based
on this result, the Japan Atherosclerosis Society (JAS) announced
"Guidelines for Preventing Arteriosclerotic
Diseases (2012 Edition)". In the guideline, it was judged that the
effectiveness of EPA was confirmed. Furthermore, it was evaluated to be the
recommendation level IIa (rather effective and utility), and evidence level A
(data based on many RCT and meta-analysis). Thereafter,
re-evaluation was done from the results of various reports, and two important
research papers were cited in the 2017 edition, which were Alpha Omega test [8]
and ORIGIN (Outcome Reduction With An Initial Glargine Intervention) trial [9].
From these results, it was concluded as follows: In a recent large-scale
clinical trial, the effect of inhibiting cardiovascular events by
administration of n-3 (ω-3) PUFA could not be demonstrated." Recently,
some important papers have been published. Among them, results of a
cardiovascular event inhibition test by n-3 PUFA were reported. Out of the results
of three reports, two cases were unable to prove their effect, and one was
found to be effective. These results will be meaningful for evaluating the
effect of n-3 PUFA for the future prevention of arterioscleroticdiseases. The
first report is the ASCEND (A Study of Cardiovascular
Events in Diabetes) test [13]. This is a RCT study comparing EPA/DHA and
olive oil in diabetic patients by the Clinical Research Department of Oxford
University in England. The group was divided into 4 groups by 2 randomizations.
One randomization is the n-3 group [EPA 460 mg and DHA 380 mg] and the placebo
group (matching olive oil). The other randomization is the aspirin group
(aspirin 100 mg) and the placebo group. The
primary end point was 4 situations, including nonfatal myocardial infarction,
stroke excluding cerebral hemorrhage, cardiovascular death excluding cerebral
hemorrhage, and Transient
Ischemic Attack (TIA). As a result, cardiovascular protective effect was
not observed when 15,480 patients were followed for 7.4 years. Further, no
difference was found between the two groups (rate ratio 0.97, P = 0.55) as a
result of the main endpoint. These
results were compared the results of the JELIS trial [7] and the guidelines of
the American Society of Cardiology [14]. The latter showed the secondary
preventive effect of n-3 PUFA on cardiovascular
disease [14]. According to these evidence and comparison, they concluded
that there was no preventive effect for cardiovascular disease by n-3 PUFA administration.
ASCEND test had also included the study of two groups whether aspirin was daily
administrated or not [15]. The
incidence of the main endpoint was significantly lower in the aspirin group
(8.5% vs. 9.6%), but conversely the rate of onset for bleeding as an adverse
effects was high (4.1% vs. 3.2%). This result suggested that evaluation and
judgment should be considered carefully associated with various factors and
their balance in both situations. How
should we consider these results? As a conventional evaluation, the
GISSI-PREVENZIONE test had the effect of recurrence prevention [16], and the
JELIS test had the effect of initial prevention [7]. Therefore, n-3 PUFA seemed
to have preventive effect against cardiovascular
disease [17] from multi-faceted action. Future task would be the problems
of EPA alone, combined DHA/EPA, the influence of α-linolenic acid and others. In
contrast, recent clinical research seems to show a little different result as
compared with before. There were unremarkable effect in the Alpha Omega test
[8] and the Origin test [9]. Moreover, recent studies revealed no effectiveness
in RCT blinding in meta-analysis [10]. The results showed that cardiovascular
inhibitory effect was not significantly different between n-3 and control
groups, from the viewpoint of non-fatal myocardial infarction, coronary artery
disease death, and total coronary
artery disease [10]. There is a meaningful report, which was the PREDIMED
test in 2013 and also 2018 [18]. In this study, olive oil was administered to
the control group. Three kinds of diets were: i)
Mediterranean
diet with extra-virgin olive oil ii)
Mediterranean
diet with mixed nuts, and iii)
Control
diet with reduced dietary fat. The results were
that i) and ii) showed lower incidence of major cardiovascular events in the
persons at high cardiovascularrisk [18]. In summary, recent several reports shows that n-3 PUFA cannot
always have clinical effects for arteriosclerotic
diseases in primary and secondary prevention aspects. Consequently, further
research in this field will be expected with the specific protocol to clarify
detail relationships among lots of factors. 1. Joris
PJ and Mensink RP. Role of cis-monounsaturated fatty acids in the prevention of
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ZH, Bando M, Sakurai T, Chen Y, Emma-Okon B, et al. Long-chain monounsaturated
fatty acid-rich fish oil attenuates the development of atherosclerosis in mouse
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N Engl J Med 379:1387-1389. https://doi.org/10.1056/NEJMoa1800389 Citation:
Bando M and Bando H. The influence of unsaturated fatty acids for
atherosclerosis in recent years (2019) J Obesity and Diabetes 3:9-11 Atherosclerosis, Unsaturated Fatty acids, Coronary
heart disease, DiabetesThe Influence of Unsaturated Fatty Acids for Atherosclerosis in Recent Years
Masahiro Bando and Hiroshi Bando
Abstract
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