Effects of Omega-3 Intake in Cardiovascular

Diseases: Literature Review

Introduction:
In industry rich areas the mortality rate due to atherosclerotic diseases mainly myocardial
infarction (MI) is very high and in US mortality rate was 20% as reported in 1995. [1]
Epidemiological studies over the countries with different rates of atherosclerotic MI, focus point
on the difference in the lifestyle (majorly dietary habits). In a study done in 7 countries [2],
findings revealed that mortality rate in Japan and Mediterranean countries was lower because of
usage of unsaturated fatty acids their diets than in the Northern European countries and US.
According to these findings, another Canadian, Greenlandic and Alaskan Eskimos study proved
that omega-3 fatty acids (Ω-3 FAs) were essential in prevention from atherosclerotic disorders.
[3-6]. Many epidemiological researches, clinical trials and systematic review were done in order
to find the importance of Ω-3 FAs in diet for better health after these studies, revealing that
intake of Ω-3 FAs reduces the risk of cardiovascular disease (CVD) in individuals. [7,8].
In Japan first eicosapentaenoic acid preparation (purified) was prepared for use in human, in
1983. [9]. In addition to atherosclerotic diseases, Ω-3 FAs are now also well recognized for its
role in other diseases of the CNS including dementia and CV system including cardiac heart
failure and arrhythmia, autoimmune diseases such as psoriasis and rheumatoid arthritis and
carcinogenesis, and also in defense from infection. Due to number of studies done on importance
of Ω-3 FAs and recent advances, it’s a good time to analyze recent studies with a history of
forgoing studies. Studies with high-impact conducted during the last 50 years on
pharmacological characteristics and actions, disease control mechanisms of Ω-3 FAs and its
clinical effects in relation to CVD were reviewed in this article along with the findings of studies
of different preparations of Ω-3 FAs such as purified eicosapentaenoic acid-ethyl ester (EPA-E;
Epadel) and eicosapentaenoic acid-ethyl ester/docosahexaenoic acid-ethyl ester (Lotriga)
[10,11].
2. Pharmacology and Physiological Effects of Ω-3 FAs on CV Risk:
In the body, Ω-3 FAs preparations docosapentaenoic acid (DPA) is less abundant as compared to
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). [12] In GI tract, Ω-3 FAs are
absorbed into the chylomicron triglycerides (TG) where EPA and DHA are absorbed into TG [as
very-low-density lipoproteins (VLDL)] and released into the blood. Large amount of Ω-3 FAs
are present in bound form to albumin while very small amount of it is present as free fatty acids.
[13]. Along with hypercholesterolemia (recognized as an important risk factor for CV)
hypertriglyceridemia was also an additional risk factor for CV according to some studies [14,15].
Ω-3 FAs decrease serum TG in hypertriglyceridemia patients [16] and in a dose-dependent
manner, decreases small dense low-density lipoprotein (LDL) cholesterol while enhance high-
density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol. Such
useful effects are challenging to attain with diet rich in Ω-3 FAs as well as with low dose of Ω-3
FAs but intake of large doses of Ω-3 FAs are required. Decreased synthesis and secretion of
hepatic very-low-density lipoprotein-triglyceride and enhanced clearance of TG from
chylomicrons and VLDL particles causes reduction in TG concentration, according to the
evidences. [17]. Presence of highly atherogenic, small, dense LDL particles and reduced high-
density lipoprotein cholesterol concentrations (both relating to cause increased risk of CVD)
were the factors associated to increased concentration of TG. [18].
Genetic studies of apo-lipoprotein (Apo) CIII (lipoprotein lipase inhibitor) that affect the
breakdown of triglyceride revealed that triglycerides are included in causing CHD and
atherosclerosis [19]. Reduction in triglycerides and Apo C-III without raising LDL-C in high
triglycerides patients as well as in high triglycerides patients being treated with statins, EPA
plays an important role. [20,21]. In a study of Japan, it was revealed that Lotoriga enhances ratio
of mean particle size of LDL and LDL-cholesterol/Apo B, and decreases apo-lipoprotein CIII
[22]. According to systematic review of different studies [23], fish oil supplements have been
reported to reduce blood pressure moderately after intake of fish oil, probably due to reduced
systemic vascular resistance but not decreased cardiac output.
High consumption of the Ω-3 FAs cause increased level of NO formation which in turn increases
the endothelial nitric oxide synthase enzyme expression. Many studies suggested that
consumption of Ω-3 FAs lead to serum indicators of endothelial dysfunction improvement (such
as endothelial selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1)
[24,25]. Systematic review on the use of Ω-3 FAs revealed that, along with other endothelial
function parameters, its consumption also help in improvement of flow-mediated vasodilation
[26]. In adults with metabolic syndrome along with parallel anti-inflammatory effect, flow-
mediated dilation (FMD) and arterial stiffness by carotid-femoral pulse wave velocity (PWV),
were also used for analysis of the endothelial function, which are improved by intake of Ω-3
FAs, as reported by Tousoulis et al. [27] in his study. In patients having an intermediate-high
cardiovascular risk, Ω-3 FAs also enhanced function of peripheral artery, analyzed using small
artery reactive hyperemia index (saRHI).
In another study conducted by Chan et al. [29], it was proposed that, in patients with familial
hypercholesterolemia treated by statin therapy, intake of Ω-3 FAs also helped in the developed
arterial elasticity calculated by pulse contour analysis of the radial artery. In his study, Tagetti et
al. [30], reported that there was no significant interaction between omega-6 and Ω-3 FAs
consumption or their ratio with reduction in blood pressure, but they observed an association
among CYP4F2 V433M genotype and total omega-3, alpha-linolenic acid and linoleic/alpha-
linolenic ratio. Consumption of Higher omega-3 polyunsaturated fatty acid (PUFA) was reported
to be involved in the reduction of the blood pressure in 433VV genotype subjects. Heart rate was
also reported to be improved after intake of fish oil in several randomized studies [31]. The
linear response of even low doses of Ω-3 FAs for reduction of blood pressure was not visible in
case of heart rate improvement. Direct effect of fish oil and Ω-3 FAs occur on the
cardiomyocytes leading to reduction in the heart rate [32,33] while indirect effect is on the
circulatory dynamics (ventricular diastolic filling and vagal tone). In Japanese population, in
cardiovascular mortality risk, intake of the Ω-3 FAs proved to reduce effect of high resting heart
rate. [34] Association between heart rate and CV events, suggest that reduction in the heart rate
by Ω-3 FAs effect lead to improvements in CV events on consumption of Ω-3 FAs.
Consumption of fish leads to reduction in the risk of life threatening MI and risk of sudden
cardiac deaths due to CHD [35], and their anti-arrhythmic characteristics are of main concern.
Effect of Ω-3 FAs on the electrophysiology of ventricular and atrial cardiomyocytes (particularly
EPH/DHA), improved the excitability of cardiomyocyte and change concentration of Ca 2+
intracellularly by blockade of Na+ and Ca2+ channels in cardiomyocytes [33]. But this result is
not clear to be associated with Ω-3 FAs solely because such effects were also visible with usage
of omega-6 fatty acid too. Fibrinolytic and coagulation systems were also reported to be effected
by Ω-3 FAs intake. Bleeding time can be increased at the dose of 0.27 to 4.8 g/day of EPA or
EPA + DHA while there is no regular relation with clinical bleeding [36]. Association of intake
of omega-3 polyunsaturated fatty acid dose (even at the dose of 4g) to increased risk of bleeding
is not clear. Anti-inflammatory properties are also seen in Ω-3 FAs. Eskimos consuming fish,
had very rare chances of autoimmune diseases (such as bronchial asthma and psoriasis), as
reported in a study in Greenland [37]. Different animal and human studies revealed that Ω-3 FAs
(particularly EPA) show anti-inflammatory properties as well as immunomodulatory properties
[38,39]. Cell membranes store house for Ω-3 FAs arachidonic acid (AA). It is released after
stimulation of cell and metabolized prostaglandin and leukotriene (pro-inflammatory lipid
mediators) in the AA cascade, leading to increased inflammation, present already. Just like
arachidonic acid (AA), Ω-3 FAs is also stored in the cell membranes lead to reduction in storage
of AA by replacing it. On the other hand, Ω-3 FAs are also metabolized in the AA cascade by
pro-inflammatory lipid mediators into metabolites less active as compared to those of AA, thus
maintaining the balance for inhibition of inflammation. [40]. Administration of EPA suppresses
the atherosclerosis [42] in the leukotriene receptor B-knockout mice [41]. According to recent
reports, the effect of DHA-rich fish oil is higher than EPA-rich fish oil in decreasing
inflammation [43]. Survival of mouse with systemic lupus erythematosus (a typical autoimmune
disease), is extended by the DHA-rich fish oil [44]. Resolvins and neuroprotectins properties of
Ω-3 FAs (DHA in particular) have also been identified in the end of inflammatory process. [45].
These Ω-3 FAs metabolites are effective anti-inflammatory lipid mediators (Figure 1) [46]. Over
production of 12/15-lipoxygenase suppress the atherosclerosis by increased production of these
anti-inflammatory lipid mediators in the mice [47]. Nevertheless, the roles of these anti-
inflammatory mediators are fixed in the atherosclerosis in case of humans. CVD is the main
factor for mortality in cases of end-stage renal disease (ESRD). CVD related mortality rate, in
patients with ESRD is 10–20 times more than general population [48,49]. In the patients on
dialysis, the mortality and morbidity rate increases as atherosclerosis aggravates. Clinical studies
were conducted by Kajbaf et al. [50] in order to analyze the effect of 3g of omega-3
supplementation daily dose in the patients with atherosclerosis [by measuring carotid intima-
media thickness (cIMT)] in hemodialysis (HD) patients, and reported considerable reduction in
cIMT by use of omega-3 supplementation.
3. Ω-3 FAS and CVD:
Diseased condition of the patient defines the amount of fish oil supplements required for clinical
effect on CVD and duration of action. Moreover, the clinical effects of fish oil supplements are
determined by the endpoint used for analyzing its efficiency. Ω-3 FAS are reported to be
effective in reduction in risk of CHD-related mortality and sudden cardiac death by lowering the
risk of CVD. It was reported in the several randomized studies (large-scale prospective cohort
studies) [35], that Ω-3 FAs were beneficial in lowering the risk of CHD-related mortality and
sudden cardiac death by intake of the fish oil, but these effects does not show any linear dose–
response association. Intake of oil supplementation leads to decrease in risk of sudden cardiac
deaths, but after adjustment for multiple covariates this effect was not significant. According to
findings the Japanese general population consumption of Ω-3 FAs was inversely and
independently related with long-term total CVD mortality risk [52]. In a study, De Oliveira Otto
et al. [53] proposed that except alpha-linolenic acid or n-6 PUFAs, eicosapentaenoic acid and
docosahexaenoic acid (both dietary and circulating) were indirectly related to the CVD
incidence. Findings of such studies conclude that life threatening MI or sudden cardiac death can
be reduced but intake of fish oil. Patients receiving ACE inhibitors, aspirin, beta-antagonists, and
statins did not show any benefit from Ω-3 FAs as per secondary prevention trials. In a study
conducted at large scale, Risk and Prevention Study [56], it was revealed that patients with
multiple CVD risk factors did not have clear effect of Ω-3 FAs in lowering CHD-related
mortality. Reason of inability of Ω-3 FAs in reduction of CVD may be due to severe
pharmacotherapy in patients participated in the such secondary prevention studies. Authors of
different studies suggested that to attain statistically significant results, large scale studies with
large sample size must be required. In a study, a group of women without previous risk of
cardiovascular disease, consumption of tuna and dark fish, ALA, or marine Ω-3 FAs was not
related to with risk of major CVD in case of primary prevention [57]. It was revealed from
nineteen group studies that the omega-3 biomarkers (ALA, DHA and DPA) were related to the
less fatal CHD risk [58]. In some studies it was observed that MI (non-fatal) and acute coronary
syndrome were related consumption of the fish oil and Ω-3 FAs, while few large scale
randomized studies show mixed findings. Some studies reported that Ω-3 FAs as most important
in reducing CV death [63-65] while other did not reported such benefits. [54,55,66]. Patients
consuming fish oil proved to have low risk of CVD (non-fatal) but no significant decrease was
reported in a systematic review of randomized trials. [51] Due to this reason the benefits of Ω-3
FAs are not clear in non-fatal CVD. In a study, when findings of cohort study were compared it
was concluded that the MI patients had lower levels of total PUFAs, total omega-3 PUFAs and
total omega-6 PUFAs than the controlled group with matching indications. [67]. It suggests that
along with omega-3, total omega-6 blood levels were also associated with CV risk. In Chinese
population high intake of marine e.g. EPA/DHA and plant e.g. alpha-linolenic acid were reported
to be associated with the lowering of CV mortality risk. [68]. In a current study it was revealed
that in Japanese population EPA/AA ratio was considered to be a predictive marker of major
cardiac events. [69]. In general population microalbuminuria is another well known risk factor
for CV morbidity and mortality [70,71]. Mortality associated to CV was higher than non-CV in
patients with high concentration of urinary albumin while risk of both CV and non-CV death was
increased in these patients. In his study Fukami et al. [72], he reported that the EPA/AA ratio
was strongly associated to microalbuminuria. [72] Albuminuria has also been reported to be
associated with the vascular abnormalities such as decreased vascular dilatation, arterial stiffness
and venous thromboembolism [73,74], and it is now known as an indicator for endothelial
dysfunction. These effects of albuminuria as endothelial dysfunction and subclinical
inflammation may associate albuminuria to the cardiovascular disease [75]. The inverse relation
of the serum EPA/AA ratio with prevalence of microalbuminuria proposes that increased
EPA/AA ratio had protective effect on endothelial dysfunction. There is no any clear evidence
showing any pathophysiological significance of serum EPA/AA ratio for prediction of risk CV,
the composition of the EPA/AA ratio has been seen to be correlated with Ω-3 FAs in red cell
membrane (organic cell membrane), cell function may be affected by whom. [76]. Inverse
relation has been shown between omega-3 polyunsaturated fatty acids concentration in blood and
rate of CHF in old patients, according to a prospective cohort study. Other such studies reported
that except of fried fish consumption of boiled or grilled fish help preventing CHF onset. [31,78]
In cases with new onset of CHF studies have proved that omega-3 polyunsaturated fatty acids
have been proved to be protective. More data is required for the primary prevention settings
while a large-scale data, from randomized, double-blind, placebo-controlled trial of a large
number of patients (7,046) with CHF (pre-existing) [8] during 3 years and 9 months reported
benefits of Ω-3 FAs, mainly Lotriga, in survival from CHF along with left ventricular ejection
rate improvements, was found for secondary prevention[79]. According to American College of
Cardiology/American Heart Association (ACC/AHA) guidelines, Ω-3 FAs was proved to be
effective against the CHF on the basis this study. [80] Mixed findings were achieved on the
effectiveness of fish oil, in few small scale randomized studies, on patients with defibrillators
implanted for ventricular tachycardia [81,82]. Mata-analysis of different studies with varied
designs, also reported no significant benefits of intake of fish oil in these conditions. [83] Due to
this reason new and more developed studies are needed in order to achieve better definitive
findings. In a study conducted in patients with atrial fibrillation (AF), it was reported that
consuming fish oil helped in reduction of risk of AF [84] while a similar randomized, large-scale
study reported no reduction in postoperative AF in patients [85]. Systematic review of different
such studies showed that intake of fish oil and omega- 3 fatty acids did not have any beneficial
effect against AF. [85, 86] These findings concluded that the effect of fish oil in AF
(postoperative as well as pre-existing) is not clear. Due to this large scale studies are required in
order to determine the effectiveness of fish oil in prevention from new-onset AF in non-AF
patients. No correlation of fish oil intake with the hemorrhagic stroke white inverse correlation
with incidence of ischemic stroke, in patients receiving moderate consumption of fish oil, was
found on systematic review of large prospective cohort studies [87,88]. But, prospective
intervention studies generated inconsistent findings. In a sub-analysis of JELIS trial [89], it was
reported that highly purified EPA i.e. Epadel had no beneficial effect in primary prevention,
however showed benefits in secondary prevention of stroke. No protective effect of Ω-3 FAs
against onset of stroke has also been reported in some studies. [54, 56]. In OMEGA-REMODEL,
Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling after Acute Myocardial Infarction
trial, it was reported that patients with acute MI being treated with Ω-3 FAs (4g for 6 months)
along with standard therapy had reduction in the left ventricular end-systolic volume index
(LVESVI) and non-infarct myocardial fibrosis [90]. In a comparative prospective, multicenter,
double-blind, placebo-controlled study done on placebo group and Ω-3 FAs receiving group,
showed that former group received 4g of Ω-3 FAs had decrease in the LVESVI by 5.4% while in
later group it was increased by 1.2% which received corn oil. On the other hand in the Ω-3 FAs
group non-infarct myocardial fibrosis was decreased by 2.1% while in placebo group it was
increased by 3.4%. No significant difference in improvement of the size of infarct and left
ventricular ejection fraction were reported. Group of patients receiving Ω-3 FAs had shown a
decrease in the Myeloperoxidase (a biomarker of inflammation) and ST2 (a biomarker of
myocardial fibrosis) as compared to placebo group. Thus the study concluded that intake of Ω-3
FAs during the recovery phase following acute MI, by suppressing inflammation at both
systemic and myocardial levels, improved left ventricular remodeling and non-infarct myocardial
fibrosis. End point used in the treatment of CVD with the fish oil determine the variation in the
effects and maybe due to difference in dose of Ω-3 FAs and duration of usage, along with
patients related factors such as disease severity and use of other parallel medications during the
study. In simple systematic review the benefits of Ω-3 FAs may be masked, and it may not
provide adequately potent protection against CVD. In a review, Mozaffarian and Rimm [35], it
was reported that the different conditions lead to variation in the dose of EPA and DHA used for
treatment of pathological conditions such as arrhythmia and hypertriglyceridemia and ratio of
EPA and DHA has also been unclear. All of these aspects must be considered while conducting
another study or interpreting the results for a particular study.
4. Molecular mechanism of action of Ω-3 FAs on heart disease
Ω-3 FAS, EPA and DHA are synthesized form alpha-linolenic acid (ALA) and are not formed
inside the human or other mammals body endogenously. The mechanism of action of Ω-3 FAs,
consumed for improving the heart failure is still not known. Different pro-resolving mediators
(resolvins, protectins and maresins) were derived from Ω-3 FAs when lipidomic analysis was
done using advanced liquid chromatography-mass spectrometry (LC-MS). These mediators are
also known as specialized pre-resolving mediators (SPMs) (Figure 1) and due to their distinct
structures and ability to exert of anti-inflammatory effects in a stereospecific manner, they have
attracted attention in past few years. The resolvin E (RvE) series are derived from EPA by
conversion of 18-hydroxyeicosapentaenoic acid (18-HEPE) with the help of enzyme aspirin-
acetylated COX2 or CYP450 monooxygenase. RvE1 resolve acute inflammation by actively
stopping the trafficking of leukocytes, enhance clearance of the inflammation cells and debris,
and inhibit cytokine production. [91] Protectins, resolvin D series and maresins are mediators
synthesized from DHA by 15-lipoxygenase (15-LOX) in humans or by 12/15-LOX in mice. In
recent few studies in-vivo action of SPMs as cardio-protective was reported as per gathered
evidences. According to a study conducted by Keyes et al. [92], it was reported that in rats with
ischemia/reperfusion injury, RvE1 administration reduced the infarct size. In another study it was
concluded that administration of RvD1, in mice with acute inflammation following MI, enhanced
the production of SPMs in spleen and switch off the inflammatory M2 macrophages in the left
ventricle to avoid myocardial fibrosis and maintain cardiac function [93]. Histopathological
remodeling (such as myocardial hypertrophy, inflammatory cell infiltration, and interstitial
fibrosis) occurs on increasing the pressure on heart that leads to heart failure eventually. A
research was done by Endo et al. [94] over fat-1 transgenic mice expressing Caenorhabditis
elegans n-3 fatty acid desaturase enzyme, which converts n-6 PUFAs to n-3 PUFAs. Cardiac
hypertrophy occurred when they stimulated the aortic valve stenosis in the mice by surgical
procedure, resulting in pressure overload. Cardiomyocyte hypertrophy was similar in the
pressure overload-induced transgenic mice and that in the wild type mice, while even after
pressure loading the heart’s contractile ability was maintained even at four weeks. Moreover,
interstitial fibrosis and macrophage infiltration were noticeably inhibited. Ω-3 FAS showed
cardioprotective action when mediated by the CD68-positive macrophages extracted from the
bone marrow during the experiment over transplanting bone marrow cells of fat-1 transgenic
mice into wild type mice. Co-culture experiments of macrophages with cardiac fibroblasts
reported marked increases of metabolites synthesized from EPA, in particular18-HEPE, in
macrophages extracted from fat-1 transgenic mice. Furthermore, addition of 18-HEPE to cardiac
fibroblasts caused dose-dependent suppression of IL-6 production.
5. Large-scale Clinical Studies of Ω-3 FAS and Issues to be Resolved:
Endpoint used in the treatment of CVD with the fish oil determine the variation in the effects and
maybe due to difference in dose of Ω-3 FAs and duration of usage, along with patients related
factors such as disease severity and use of other parallel medications during the study. Ω-3 FAS
have been available in many countries from almost 20 years and a large number of studies have
been conducted to examine their effects. [7,8,56,64,66] (Table 1). In earlier studies it was
reported that Ω-3 FAs was effective in secondary prevention of cardiovascular events [7, 64] and
reduce the incidence of the mortality relating to the CHF in patients. [8]. In several studies due to
limitations such as use of low dose of Ω-3 FAs, admission of patients with normal or nearly
normal baseline triglyceride levels and insufficient statistical power [95], Omacor was reported
to be non-effective. [56,66]. Prescription-strength of Ω-3 FAs at high dose was investigated in
two ongoing large scale CV interventional outcome studies. Vescepa (containing high-purity
icosapent ethyl, the ethyl ester of EPA) and Epanova (containing EPA as the free fatty acid) were
investigated in the REDUCE-IT (NCT01492361) trial and STRENGTH (NCT02104817) trial
respectively and assessed the reduction in CV events in high risk patients at statin therapy and
have high levels of triglyceride persistently. The role of Ω-3 FAs in reduction of CV risk was
expected to be clarified by the findings of these two trials.
6. Relationship between statins and ω3 fatty acids:
As mentioned earlier, many research studies have been done in order to identify the beneficial
effects of Ω-3 FAs. Significant reduction in CV risk has been reported in large number of large-
scale epidemiological studies, clinical outcome trials, and systematic review. Along with the
synthesis of the mediators, vascular functions regulation is also dependent upon the balance
between EPA or DHA and AA in the body of the human. In the study in general population [96],
as well as in a post-hoc analysis of the results of a clinical trial [69] showed the serum EPA to
AA ratio (EPA/AA) has been a good biomarker for predicting the risk of CV disease. The
effectiveness of the stains used for both primary and secondary prevention of CV disease has
been recognized [97], and statins along with low-density-lipoprotein cholesterol (LDL-C)-
lowering therapy has been used as first-line therapy. Even with treatment with statin lowers the
LDL-C levels but the risk of CV risk still remains [98], and attention has been given to other risk
factors as low level of HDL-C and high level of triglycerides. According to particular findings
patients being treated with statins showed enhanced in plasma AA concentration and reduced in
plasma Ω-3 FAs concentration and/or plasma omega-3/AA ratio [99] and these may be related to
the residual risk after beginning of statin treatment. These results suggest that use of statins help
in regulation of endogenous breakdown of long-chain polyunsaturated fatty acids (LCPUFAs).
Position-specific desaturation and carbon-chain elongation reactions produce LCPUFAs by
endogenous breakdown of omega-6 and omega-3 PUFA precursors [100]. The AA-dominant
endogenous synthesis of LCPUFAs leading to decreased plasma omega-3 concentration and/or
omega-3/AA ratio during statin therapy may be clinically very important, as in general
population [96], as well as in a post-hoc analysis of the results of a clinical trial [69] showed the
serum EPA to AA ratio (EPA/AA) has been a good biomarker for predicting the risk of CV
disease. Consequently, patients on statin treatment it seems rational to recommend omega-3
LCPUFA supplementation, for maintaining the plasma omega-3 concentration and omega-3/AA
ratio.
7. Conclusion
Effectiveness of the Ω-3 FAs for prevention of atherosclerotic diseases, particularly CHD-related
life threatening myocardial infarction and sudden cardiac death have been investigated in the
large number of epidemiological studies of Greenlandic, Canadian and Alaskan Eskimos were
published in the late 1970s, several epidemiological/observational and large-scale randomized
studies. But the patients being aggressively treated the effectiveness of Ω-3 FAs has not been
established for secondary prevention of non -fatal MI and CHD as these in such patients the
effects are prone to be weakened or masked. However, Ω-3 FAs have a wide range of therapeutic
properties including improvement of lipid breakdown, lowering blood pressure and heart rate,
counteract arrhythmia, improvement in vascular endothelial function, and counteract clotting and
inflammation.