Polyunsaturated Fatty Acids and Their Potential Therapeutic Role in Cardiovascular System Disorders—A Review

Abstract

Cardiovascular diseases are described as the leading cause of morbidity and mortality in modern societies. Therefore, the importance of cardiovascular diseases prevention is widely reflected in the increasing number of reports on the topic among the key scientific research efforts of the recent period. The importance of essential fatty acids (EFAs) has been recognized in the fields of cardiac science and cardiac medicine, with the significant effects of various fatty acids having been confirmed by experimental studies. Polyunsaturated fatty acids are considered to be important versatile mediators for improving and maintaining human health over the entire lifespan, however, only the cardiac effect has been extensively documented. Recently, it has been shown that omega-3 fatty acids may play a beneficial role in several human pathologies, such as obesity and diabetes mellitus type 2, and are also associated with a reduced incidence of stroke and atherosclerosis, and decreased incidence of cardiovascular diseases. A reasonable diet and wise supplementation of omega-3 EFAs are essential in the prevention and treatment of cardiovascular diseases prevention and treatment.

Full text

nutrients
Review
Polyunsaturated Fatty Acids and Their Potential
Therapeutic Role in Cardiovascular System
Disorders—A Review
Ewa Sokoła-Wysocza´nska 1, Tomasz Wysocza´nski 2, Jolanta Wagner 2,3, Katarzyna Czy˙
z4, *,
Robert Bodkowski 4, Stanisław Lochy ´nski 3,5 and Bo˙
zena Patkowska-Sokoła 4
1The Lumina Cordis Foundation, Szymanowskiego Street 2/a, 51-609 Wroclaw, Poland; sokola@libero.it
2FLC Pharma Ltd., Wroclaw Technology Park Muchoborska Street 18, 54-424 Wroclaw, Poland;
tomasz.wysoczanski@gmail.com (T.W.); jolanta.pekala@flcpharma.com (J.W.)
3Department of Bioorganic Chemistry, Faculty of Chemistry, University of Technology, Wybrzeze
Wyspianskiego Street 27, 50-370 Wroclaw, Poland; stanislaw.lochynski@pwr.edu.pl
4
Institute of Animal Breeding, Faculty of Biology and Animal Sciences, Wroclaw University of Environmental
and Life Sciences, Chelmonskiego Street 38c, 50-001 Wroclaw, Poland; robert.bodkowski@upwr.edu.pl (R.B.);
bozena.patkowska-sokola@upwr.edu.pl (B.P.-S.)
5Institute of Cosmetology, Wroclaw College of Physiotherapy, Kosciuszki 4 Street, 50-038 Wroclaw, Poland
*Correspondence: katarzyna.czyz@upwr.edu.pl; Tel.: +48-71-320-5781
Received: 23 August 2018; Accepted: 19 October 2018; Published: 21 October 2018


Abstract:
Cardiovascular diseases are described as the leading cause of morbidity and mortality in
modern societies. Therefore, the importance of cardiovascular diseases prevention is widely reflected
in the increasing number of reports on the topic among the key scientific research efforts of the
recent period. The importance of essential fatty acids (EFAs) has been recognized in the fields of
cardiac science and cardiac medicine, with the significant effects of various fatty acids having been
confirmed by experimental studies. Polyunsaturated fatty acids are considered to be important
versatile mediators for improving and maintaining human health over the entire lifespan, however,
only the cardiac effect has been extensively documented. Recently, it has been shown that omega-3
fatty acids may play a beneficial role in several human pathologies, such as obesity and diabetes
mellitus type 2, and are also associated with a reduced incidence of stroke and atherosclerosis, and
decreased incidence of cardiovascular diseases. A reasonable diet and wise supplementation of
omega-3 EFAs are essential in the prevention and treatment of cardiovascular diseases prevention
and treatment.
Keywords:
cardiovascular system; omega-3 fatty acids; alpha-linoleic acid (ALA); eicosapentaenoic
acid (EPA); docosahexaenoic acid (DHA); lipids; nutrition
1. Introduction
Fatty acids are considered to be a fundamental building material for the structural components
of cells, tissues, and organs as well as for the synthesis of certain biologically active substances.
In scientific and medical fields, omega-3 fatty acids are characterized by multidirectional effects in
humans: they present anticoagulant and antihypertensive properties, regulate lipid metabolism, and
support central nervous system functioning and eyesight. Omega-3 fatty acids also present a wide
scope of anti-inflammatory properties, which makes them efficient agents for use in patients presenting
various disorders or inflammation-based health conditions. Some researchers have also suggested that
omega-3 fatty acids may have an important role in the prevention of various types of cancer [
1
,
2
]. This
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Nutrients 2018,10, 1561 2 of 21
paper introduces the biological significance and health promoting effect of the omega-3 fatty acids
family with great focus on the cardiovascular system and its disorders.
Although there has been great progress in the prevention of cardiovascular diseases (CVDs),
circulatory system disorders and heart failures are still the leading cause of death globally. It is well
known that proper eating habits, regular physical activity, elimination of smoking, and low body
weight are essential factors in cardiovascular risk reducing, but despite this common knowledge, CVDs
are still the major cause of death worldwide, causing 17.3 million deaths per year (reported by the
World Heart Federation in the Urbanization and Cardiovascular Disease report) [3].
At the beginning of the 20th century, cardiovascular diseases were responsible for nearly 10% of
all deaths globally. Now, early in the 21st century, they account for nearly one half of all deaths in the
developed world and 25% of all deaths in developing countries. Similar data was presented by the
World Health Organization as a result of the Global Burden of Diseases Study, which stated that three
out of every ten deaths in Europe in patients younger than 65 years old were due to cardiovascular
system diseases [4].
Exposure to certain cardiovascular disease risk factors is highly affected by socioeconomic status
and the environment in which an individual lives, which means that the majority of CVDs result
from risk factors that may be controlled, treated, or modified, which include high blood pressure,
cholesterol, diabetes, tobacco use, lack of physical activity, and overweight/obesity.
Consequently, there is enough evidence to conclude that a healthy diet and lifestyle are our
best weapons in the fight against cardiovascular diseases and the most effective means in which to
prevent the occurrence of CVDs in society. A case study showed that mortality due to ischaemic heart
disease and prevalence of coronary arteriosclerosis were low in Greenlandic Inuit (Greenlanders).
Since the first description of the so-called Inuit paradox in the 1970s, the number of studies and
publications associating polyunsaturated fatty acids intake with lower risk of cardiac disorders has
grown extensively [5–7].
In the world of cardiology research, remarkably wide recognition in this matter has been obtained
as a result of the trials carried out by GISSI (Gruppo Italiano per la Studio della Sopravvivenza
nell’Infarto miocardico)—an Italian group studying survival of acute myocardial infarction (AMI). The
GISSI designed and carried out a series of large-scale clinical trials that involved more than 60,000
patients over the last 20 years. One of the research studies—the GISSI Preventzioni trial evaluated
the effectiveness of a therapy with omega-3 polyunsaturated fatty acids (PUFAs), vitamin E, and a
statin in patients with a previous AMI and demonstrated 20% mortality reduction in patients treated
with omega-3 PUFAs. Another study demonstrated that omega-3 ethyl esters have clinically proven
benefits in improving post-myocardial infarction (MI) outcomes, such as significant 15% risk reduction
for all-cause mortality together with 20% risk reduction for CVDs [
8
,
9
]. The in-hospital mortality due
to AMI has been reduced by approximately 30% over the last 20 years [
10
]. According to the current
guidelines of the European Society of Cardiology, treatment with omega-3 PUFAs may be considered a
new option to add to the shortlist of evidence-based life-prolonging therapies for heart failure [11].
2. Results
2.1. Classification of Unsaturated Fatty Acids
Unsaturated fatty acids (UFAs) are classified as either monounsaturated fatty acids (MUFAs),
because they have only one double bond (e.g., omega-7 and -9 fats), or polyunsaturated fatty acids
(PUFAs), since they have more than one double bond in their backbone (e.g., omega-3 and -6 acids) [
12
].
The most important role and significant functions are attributed to PUFAs, which possess a unique
subgroup referred to essential fatty acids (EFAs), cannot be synthesized de novo and like vitamins, and
need to be delivered with food. They can be further classified in various groups due to their chemical
structure. Omega fatty acids are classified according to the location of the first double bond—the
difference between them is expressed by the number of omega [
13
]. Two main compound groups can

Nutrients 2018,10, 1561 3 of 21
be distinguished among PUFAs: omega-3 and omega-6 families. The first double bond in the omega-3
family occurs at the third carbon from the methyl end of the chain (hence the name omega-3), and in
the case of the omega-6 family, the first double bond occurs at the sixth carbon from the methyl end of
the chain (Figure 1).
Nutrients 2018, 10, x FOR PEER REVIEW 3 of 21
the omega-3 family occurs at the third carbon from the methyl end of the chain (hence the name
omega-3), and in the case of the omega-6 family, the first double bond occurs at the sixth carbon
from the methyl end of the chain (Figure 1).
Figure 1. Classification of long-chain fatty acids.
Alpha-linolenic acid (ALA, 18:3, n-3), eicosapentaenoic acid (EPA, 20:5, n-3), and
docosahexaenoic acid (DHA, 22:6, n-3) are the prominent representatives of the omega-3 family
(Figure 1). ALA is a precursor of the omega-3 family (Figure 2) and also the only omega-3 that must
be derived from the diet, since it cannot be produced by the human body. Regarding food sources, it
is found in vegetable oils such as flaxseed (linseed), canola (rapeseed), soybean, and hemp oil, nuts,
such as walnuts, as well as in seeds (e.g., chia (Salvia hispanica)), dairy products, eggs, and algae
[14–17]. Omega-3 fatty acids can also be found in the meat of free-ranged animals (herbivores and
carnivores).
ALA serves as a precursor compound to the synthesis of other omega-3 fatty acids [18].
Although EPA and DHA can also be delivered with food, ALA can be converted to EPA and DHA in
the body and therefore has the ability to control their physiological activity. EPA and DHA are
commonly found in fish and seafood, especially in fatty fish oils, squid and krill oil, egg oil, and
seaweed, hence eicosapentaenoic and docosahexaenoic acids are frequently called “marine
omega-3s” [19]. High concentration of these molecules is not fortuitous; their role is to protect these
marine organisms from their body fluids solidifying at low temperatures [20].
Omega-6s are represented by the parent compound linoleic acid (LA, 18:2, n-6) (Figure 1). The
human body is not capable of producing LA, thus next to omega-3 alpha-linoleic acid, LA
constitutes another essential fatty acid that has to be delivered with diet. Once linoleic acid is
ingested, it is converted in a few steps into arachidonic acid (AA, 20:4, n-6) (Figure 2). The most
significant dietary plant sources of omega-6s are corn, soybean, and sunflower oil, as well as nuts,
including coconut together with coconut oil, almonds, pine-nuts, and hazelnuts. Animal origin
products that are considered to be good sources of omega-6s include, for example, pork, lard, turkey
fat, and butter [21].
Figure 1. Classification of long-chain fatty acids.
Alpha-linolenic acid (ALA, 18:3, n-3), eicosapentaenoic acid (EPA, 20:5, n-3), and docosahexaenoic
acid (DHA, 22:6, n-3) are the prominent representatives of the omega-3 family (Figure 1). ALA is a
precursor of the omega-3 family (Figure 2) and also the only omega-3 that must be derived from the
diet, since it cannot be produced by the human body. Regarding food sources, it is found in vegetable
oils such as flaxseed (linseed), canola (rapeseed), soybean, and hemp oil, nuts, such as walnuts, as well
as in seeds (e.g., chia (Salvia hispanica)), dairy products, eggs, and algae [
14
–
17
]. Omega-3 fatty acids
can also be found in the meat of free-ranged animals (herbivores and carnivores).
ALA serves as a precursor compound to the synthesis of other omega-3 fatty acids [
18
]. Although
EPA and DHA can also be delivered with food, ALA can be converted to EPA and DHA in the body
and therefore has the ability to control their physiological activity. EPA and DHA are commonly
found in fish and seafood, especially in fatty fish oils, squid and krill oil, egg oil, and seaweed, hence
eicosapentaenoic and docosahexaenoic acids are frequently called “marine omega-3s” [
19
]. High
concentration of these molecules is not fortuitous; their role is to protect these marine organisms from
their body fluids solidifying at low temperatures [20].
Omega-6s are represented by the parent compound linoleic acid (LA, 18:2, n-6) (Figure 1). The
human body is not capable of producing LA, thus next to omega-3 alpha-linoleic acid, LA constitutes
another essential fatty acid that has to be delivered with diet. Once linoleic acid is ingested, it
is converted in a few steps into arachidonic acid (AA, 20:4, n-6) (Figure 2). The most significant
dietary plant sources of omega-6s are corn, soybean, and sunflower oil, as well as nuts, including
coconut together with coconut oil, almonds, pine-nuts, and hazelnuts. Animal origin products that are
considered to be good sources of omega-6s include, for example, pork, lard, turkey fat, and butter [
21
].

Nutrients 2018,10, 1561 4 of 21
Nutrients 2018, 10, x FOR PEER REVIEW 4 of 21
Figure 2. Polyunsaturated fatty acids (PUFAs) subclasses: omega-6 and omega-3.
It has been established that PUFAs are required for the normal development and functioning of
the brain and heart, and also for the equilibrium of all tissues and organs. Studies concerning the
nutritional deficiency of omega-3 fatty acids as well as the particular roles of omega-6 and omega-3
have become the focus of numerous research groups around the world [22–26]. Deficit of omega-6
linoleic acid leads to poor growth, fatty liver, skin lesions, and reproductive failure, while the
symptoms of omega-3 fatty acids deficiency include reduced vision or abnormal electroretinogram
results. Studies in rodents have revealed significant effects of n-3 PUFAs deficiency on learning,
memory, cognition, and behavior [27]. The literature reports highlight how the increment of the
omega-6/omega-3 ratio corresponds to an increase in the occurrence of pro-inflammatory conditions.
It is crucial to maintain a proper balance of omega-3 in our bodies, since an excess of omega-6 leads
to low grade chronic systemic inflammation—recognized as the leading cause of the so-called
civilizational diseases [28–32].
2.2. EFAs Conversion
The concentration of fatty acids in blood reflects both dietary intake and biological processes.
When omega-3 and omega-6 PUFAs are consumed, they compete for incorporation into cell
membranes in all tissues of the body. Omega-3 and omega-6 fatty acids precursors, i.e., ALA and
LA, strive for the same metabolic pathways in the synthesis of longer polyunsaturated fatty acids
(such as AA, EPA, and DHA) and for the availability of the same elongase and desaturase enzymes,
particularly for Δ6-desaturase. It has been observed that too high an intake of LA would reduce the
level of Δ6-desaturase available for the metabolism of ALA [18,32].
The first step of this process involves ALA conversion into EPA, which is an active metabolic
product. This is performed through a double bond formation at the sixth and fifth position (by ∆6-
and ∆5-desaturase catalysis) and double bond elongation at the sixth position (∆6-elongase). Then,
EPA can be metabolized into DHA via ∆5-elongation and ∆4-desaturation [22]. The above process is
limited, and the only organs capable of these conversions include the liver, cerebrovascular lumen,
and astroglial cells [33,34].
DHA can be further converted into potent novel compounds with anti-inflammatory and
organ-protective properties such as the specialized pro-resolving lipid mediators (SPMs), including
D- and E-series resolvins, neuroprotectins, and maresins (Figure 2) [35–37]. The ability of ALA to be
converted into omega-3 long-chain PUFAs may be an important mechanism for maintain adequate
EPA and DHA concentrations in cell membranes and thus optimal functioning of the tissues.
Figure 2. Polyunsaturated fatty acids (PUFAs) subclasses: omega-6 and omega-3.
It has been established that PUFAs are required for the normal development and functioning
of the brain and heart, and also for the equilibrium of all tissues and organs. Studies concerning the
nutritional deficiency of omega-3 fatty acids as well as the particular roles of omega-6 and omega-3
have become the focus of numerous research groups around the world [
22
–
26
]. Deficit of omega-6
linoleic acid leads to poor growth, fatty liver, skin lesions, and reproductive failure, while the symptoms
of omega-3 fatty acids deficiency include reduced vision or abnormal electroretinogram results. Studies
in rodents have revealed significant effects of n-3 PUFAs deficiency on learning, memory, cognition,
and behavior [
27
]. The literature reports highlight how the increment of the omega-6/omega-3 ratio
corresponds to an increase in the occurrence of pro-inflammatory conditions. It is crucial to maintain
a proper balance of omega-3 in our bodies, since an excess of omega-6 leads to low grade chronic
systemic inflammation—recognized as the leading cause of the so-called civilizational diseases [
28
–
32
].
2.2. EFAs Conversion
The concentration of fatty acids in blood reflects both dietary intake and biological processes.
When omega-3 and omega-6 PUFAs are consumed, they compete for incorporation into cell membranes
in all tissues of the body. Omega-3 and omega-6 fatty acids precursors, i.e., ALA and LA, strive for
the same metabolic pathways in the synthesis of longer polyunsaturated fatty acids (such as AA,
EPA, and DHA) and for the availability of the same elongase and desaturase enzymes, particularly
for
∆
6-desaturase. It has been observed that too high an intake of LA would reduce the level of
∆6-desaturase available for the metabolism of ALA [18,32].
The first step of this process involves ALA conversion into EPA, which is an active metabolic
product. This is performed through a double bond formation at the sixth and fifth position (by
∆
6-
and
∆
5-desaturase catalysis) and double bond elongation at the sixth position (
∆
6-elongase). Then,
EPA can be metabolized into DHA via
∆
5-elongation and
∆
4-desaturation [
22
]. The above process is
limited, and the only organs capable of these conversions include the liver, cerebrovascular lumen,
and astroglial cells [33,34].
DHA can be further converted into potent novel compounds with anti-inflammatory and
organ-protective properties such as the specialized pro-resolving lipid mediators (SPMs), including
D- and E-series resolvins, neuroprotectins, and maresins (Figure 2) [
35
–
37
]. The ability of ALA to be

Nutrients 2018,10, 1561 5 of 21
converted into omega-3 long-chain PUFAs may be an important mechanism for maintain adequate
EPA and DHA concentrations in cell membranes and thus optimal functioning of the tissues.
Burdge et al., designed a study to estimate the capacity of
α
-linolenic acid to be converted into
omega-3 long-chain polyunsaturated fatty acids [
38
]. Carbon isotope labelling was used and 13C-ALA
was administered orally to six young male subjects who consumed it as part of their usual diet. The
results obtained suggested that the liver was the principal site of ALA desaturation and elongation, but
the analysis also indicated that approximately 8% of dietary ALA is converted to EPA. There was no
significant 13C enrichment of DHA above natural abundance at any of the time points measured over
21 days, thus the percentage of ALA converted to DHA was estimated to be 0–4% [
38
]. Another study
based on radioisotope-labelled ALA application suggested that its conversion to long-chain metabolites
is approximately 6% for EPA and 3.8% for DHA in the case of a diet high in saturated fat. However,
with a diet rich in n-6 PUFA, this conversion can be reduced by 40–50% [
39
]. Comparative data
have been provided in an analysis conducted by Talahalli et al., on the uptake, tissue deposition, and
conversion of ALA to its long-chain metabolites EPA and DHA, compared to EPA + DHA intake [
40
].
The level of EPA and DHA was measured in rat’s liver, heart, brain, and serum after 60 days of dietary
intake of linseed oil, fish oil, and groundnut oil. The obtained results indicated that to maintain a given
level of EPA and DHA, required amount of dietary ALA is a few times higher than the combined
amount of EPA + DHA (fish oil). Therefore, the efficacy of ALA is lower when compared to applied
EPA + DHA in elevating serum and tissue long-chain n-3 PUFA levels [40].
In the omega-6 family, LA is converted to
γ
-linolenic acid (GLA, 18:3, n-6) due to the activity of
∆
6-desaturase enzyme, and then GLA is elongated to form dihomo-GLA (DGLA, 20:3, n-6), which is
the precursor of the first series of prostaglandins (PGs). Through
∆
5-desaturase action, GLA can also be
converted to arachidonic acid (AA), which forms the precursor of the second series of prostaglandins
and thromboxanes and the fourth series of leukotrienes.
It is known that the activities of desaturases and elongases involved in the metabolism of EFAs
are affected by a number of factors, many of which contribute to reducing the activity of enzymes
responsible for ALA and EPA conversion (e.g., smoking, alcohol, stress (adrenaline), deficiencies
of certain vitamins or minerals) [
41
].
∆
6-desaturase activity is inhibited by oncogenic viruses and
radiation, while the activity of
∆
6 desaturase has been proven to reduce with age [
42
]. However, in
recent years various publications have reported on compounds that could stimulate PUFAs conversion.
Co-factors essential for normal
∆
6-desaturase activity include pyridoxine, zinc, and magnesium.
∆
6-desaturase is activated by insulin, whereas diabetics have reduced
∆
6-desaturase activity [
43
]. On
the transcriptional level, peroxisome proliferator-activated receptor-
α
(PPAR-
α
) activator WY-14.643
significantly enhanced the transcription of hepatic ∆6-desaturase by more than 500% [44].
Another study based on mice fed with diets containing either a 1.5% fatty acid preparation rich
in conjugated linoleic acid (CLA) or rich in LA revealed that dietary CLA concurrently increases the
activity and mRNA levels of enzymes involved in fatty acid synthesis and oxidation, as well as PUFAs
desaturation in the mouse liver, which appears to be mediated by both the activation of PPAR-
α
and
upregulation of SREBP-1 (sterol regulatory element binding protein-1) [45].
Omega-3s and omega-6s present various antagonistic activities. Arachidonic acid undergoes
transformation to eicosanoids (leukotrienes, thromboxanes, and the precursor of the first series of
prostaglandins), activating the inflammatory and prothrombotic processes, thus facilitating platelet
aggregation. AA and EPA also are transformed into their respective hydroxy acids, which in turn are
converted into leukotrienes (LTs). Prostaglandins and leukotrienes are highly biologically active, are
characterized by pro-inflammatory activity, and are known to be involved in various pathological
processes, such as atherosclerosis, bronchial asthma, inflammatory bowel disease, and several other
inflammatory conditions.
Hence, most omega-6 fatty acids tend to promote inflammation, whereas the omega-3 fatty acids
group has been evidenced to help reduce inflammation. It is worth emphasizing again that some of
the most potent inhibitors of desaturases are omega-6 fatty acids, which are present in the modern

Nutrients 2018,10, 1561 6 of 21
diet at about 20-fold higher levels than the omega-3s. Nowadays, in addition to saturated fats and
trans fatty acid isomers, omega-6s are the most common fat compounds in our modern Western diet,
which is rich in vegetable oils, margarine, and deep fried fast food. It has been found that the amount
and type of dietary fats in the daily diet and their improper proportions can be involved in the risk
of lifestyle diseases, such as obesity, cardiovascular diseases, and cancer, as well as immune system
weakening [46,47].
2.3. CVD Risk Factors
In its Global Atlas on Cardiovascular Disease Prevention and Control, the World Health
Organization (WHO) divided cardiovascular risk factors into modifiable and non-modifiable ones [
48
].
It reported that most cardiovascular diseases are triggered by risk factors that can be controlled, treated,
or modified, such as high blood pressure, lipid disorders, overweight/obesity, tobacco use, lack of
physical activity, and diabetes. The WHO together with World Health Federation (WHF) have been
raising concerns that in 2008, 9.8% of men and 13.8% of women were obese (with a body mass index
(BMI) higher than or equal to 30 kg/m
2
), compared to 4.8% for men and 7.9% for women in 1980. In
regard to tobacco users, the WHO estimates that there are currently about 1 billion smokers in the
world today. A higher risk of CVDs development was associated with heavy smokers, female smokers
and young male smokers [
49
]. It was emphasized in the report that cardiovascular risk increases with
elevated blood glucose values and therefore CVDs account for about 60% of all mortality in people
with diabetes.
However, in addition to the variable risk factors, there are also some major CVD factors that
cannot be controlled, which include age, gender, and genetic predisposition based on family history. It
is well-known that CVDs become increasingly common with age. As a person gets older, the heart
undergoes subtle physiologic changes, even in the absence of disease. As the heart muscle undergoes
ageing it is often unable to relax completely between beats, and as a result, the pumping chambers
become stiffer and may work less efficiently. With respect to the age factor, some studies suggest
that men are at greater risk of heart disease than pre-menopausal women. Once past menopause, a
woman’s risk is comparable to that of a man. However, the answer for whether premenopausal women
are protected from atherosclerotic disease by virtue of their hormonal status still remains inconclusive.
The same risk factors for cardiovascular diseases appear to act in women as in men, although the
general insufficiency of women presented in a large number of studies means that far less information
about the importance of these risk factors is available to us. In light of these data, the risk of stroke is
similar for men and women [50,51].
2.4. Modern Diet as a Precursor for Inflammation Progression
A healthy diet is a major factor reducing the risk of heart disease. The WHF has reported that
comparisons between a diet low in saturated fats, with plenty of fresh fruit and vegetables, and
the typical diet of someone living in the developed world show that the former can result in a 73%
reduction in the risk of major cardiac events [
48
]. Awareness regarding the importance of diet in the
development and prevention of cardiovascular disease needs to be raised.
A population study has shown that the foods typically consumed in Western diets are heavily
laden with fatty acids of the omega-6 family. The current human diet has nothing to do with the diet of
our ancestors, and it is generally accepted that hunter-gatherer societies, and other less “Westernized”
populations, exhibited superior health markers, such as body composition and physical fitness, when
compared to Western populations. Throughout 4–5 million years of hominid evolution, diets were
abundant in omega-3 fatty acids from fish and raw meat, but relatively low in omega-6 seed oils.
Simopoulos quotes several sources informing that human beings evolved on a diet with a specific
proportion of omega-6 to omega-3 fatty acids of approximately 1, whereas nowadays this ratio in
Western diets is 15/1–16.7/1 [26,52].

Nutrients 2018,10, 1561 7 of 21
Sources of omega-6 fats include the common vegetable oils used in cooking (corn, safflower,
sunflower, etc.), hydrogenated versions of these oils used to make margarine and vegetable shortening,
and animal origin food derived from livestock raised on grain, rather than on green pasture. The
volume of omega-6 sources in the average diet largely exceeds the volume of omega-3 fatty acids
sources—green vegetables, wild ocean fish, flaxseed, walnuts, and animals raised on green vegetation.
As a result, Americans usually have omega-6 to omega-3 fatty acids ratios in their tissues on a level of
10:1 to 20:1. With this preponderance of omega-6s in the diet, there is no wonder why people suffer
from the consequences of excess omega-6, which are manifested in chronic inflammation, hypertension,
as well as an increased blood clotting tendency that elevates the risk for heart attack and stroke.
2.5. Lipid Profile
Monitoring and maintaining healthy levels of lipids circulating in our blood stream is important
in prevention and early diagnosis of cardiovascular diseases. A lipid profile or lipid panel is a
group of blood tests used to evaluate the risk of developing cardiovascular problems or to control an
applied treatment.
A lipid profile typically includes total cholesterol, high-density lipoprotein (HDL) cholesterol (the
cholesterol in HDL particles), low-density lipoprotein (LDL) cholesterol (the cholesterol combined in
LDL particles), and triglycerides (TGs).
HDL cholesterol is considered to be “good” cholesterol, since it helps to remove excess cholesterol
from the arteries. HDL particles act as cleaners, carrying LDL cholesterol back to the liver, where
it is decomposed and removed from the body. Changes in lipid profile have been associated with
cardiovascular diseases due to their key role in the maintenance of the integrity of the cell membrane.
A single LDL particle formed from apolipoproteins B (apoB) is about 220–275 angstroms in
diameter, and typically transports 3000 to 6000 fat molecules including cholesterol, phospholipids, and
triglycerides (with the amounts of each varying considerably) [
53
]. Therefore, LDL, the so-called “bad”
cholesterol, deposits an excess of cholesterol in the walls of blood vessels, which can contribute
to atherosclerosis, ischemic heart disease, or, in some cases, to heart attack. As a quite simple
measurement, a lipid profile can provide important information about the progression of diseases.
Since the majority of animal studies were conducted with species that can readily convert ALA to
EPA and DHA, it is not easy to isolate the advantages of ALA per se, although there is evidence of ALA
affecting vascular function and heart condition [
54
]. It has been found that dietary flaxseed significantly
improves lipid profiles in hyperlipidemic patients and may positively affect cardiovascular risk factors
modification [
54
]. Subsequently, Egert et al., conducted a randomized strictly controlled dietary study
to compare the individual effects of dietary ALA, EPA, and DHA on low-density lipoprotein (LDL)
and fatty acid composition [
55
]. Their findings demonstrated how ALA benefited lipoprotein profiles,
but in contrast, EPA and DHA led to oxidized LDL formation [
55
]. Consistent with these results,
another study investigated the differential effects of omega-3 PUFAs on metabolic control and vascular
reactivity and documented pointed benefits of ALA [
56
,
57
]. Goyens et al., evaluated the effects of ALA
in comparison to EPA and DHA in a nutritional intervention study [
58
]. According to their conclusions,
in healthy elderly subjects, ALA might affect the levels of LDL-cholesterol and apoB more favorably
than EPA/DHA, with the intake level of ALA being of critical importance [58,59].
It is worth mentioning that lipid profile disorders also include abnormalities in triglycerides
(TGs) levels in blood plasma. Combined dyslipidemia concerns concurrent unbeneficial changes in
various subfractions of lipids, including increased levels of LDL cholesterol and TGs and a reduced
level of HDL cholesterol. It was demonstrated in numerous studies that statins, especially at higher
doses, are able to reduce blood TGs level, however, it was proved that omega-3 fatty acids are more
effective in this case [
60
]. The recent meta-analysis prepared by Alexander et al. [
61
] mentioned a
prominent effect of omega-3 long-chain PUFAs supplementation in lowering the concentration of
serum TGs, and emphasized that an elevated TGslevel is responsible for an increased CVD risk. Thus,
the combination therapy of statins and omega-3s may be useful when there is need for the optimization

Nutrients 2018,10, 1561 8 of 21
of TGs levels in the event of combined dyslipidemia [
62
]. It was demonstrated in the study by Weber
and Raederstorff [
60
] that omega-3 fatty acids supplementation may reduce serum TG levels by 20%
to 40%, and the authors suggest that this is due to lowered production of very low-density lipoprotein
(VLDLs) or an enhanced clearance of chylomicron TGs [
63
]. It was demonstrated in the study by
Davidson et al. [
64
] that the combined administration of statin (simvastatin—40 mg/d) and omega-3
supplement (465 mg EPA and 375 mg DHA per 1-g capsule) positively affected the blood plasma lipid
profile (a decrease in non-HDL-C, VLDL-C, and TG), and this effect was more profound than in the
case of statin or omega-3s alone [
64
]. Also, Micallef and Garg [
65
] concluded in their study that the
potential benefits related to blood lipid parameters such as cholesterol and TGs level can be enhanced
using omega-3s as an adjunct to statin therapy.
2.6. Atherosclerosis
Healthy arteries are flexible and elastic, but over time, the arteries’ walls can harden and the lumen
of blood vessels can become narrower. The direct cause of atherosclerosis is plaque accumulating and
building up inside the arteries. Plaque is a miscellany of cholesterol, cells, and debris that creates a
bump on the artery wall. It all begins with damage to the endothelium—a thin layer of cells lining
the interior surface of blood vessels—that can be caused by risk factors such as high blood pressure,
smoking, or high cholesterol, that afterwards leads to plaque formation.
Although atherosclerosis is often considered a heart problem, it can affect any artery in the body,
including arteries in the heart, brain, arms, legs, pelvis, and kidneys. As a result, different diseases
may develop based on which arteries are affected.
In the last decades, epidemiological, clinical, and experimental studies have demonstrated that a
diet rich in omega-3 plays a central role in atherosclerosis prevention [66–68].
Results of various research studies have shown that the suppression of atherosclerosis is associated
with reduced levels of serum lipids and antioxidant activity. A recent study hat was designed
to evaluate the effects of flaxseed oil containing
α
-linolenic acid ester of plant sterols (ALA-PS)
demonstrated that ALA-PS flaxseed oil synergistically interacted in atherosclerosis ameliorating as
well as in optimizing overall lipid levels, contracting inflammation, and lowering oxidative stress [
69
].
Another animal study suggested that ingestion of oxidized flaxseed oil increases hepatic plasma
malondialdehyde (MDA) concentration and is potentially pro-atherogenic. Mice from the control
group received fresh flaxseed oil, while the experimental population received the same diet with
heated flaxseed oil. The results obtained demonstrated that aortic wall thickness increased and lumen
and diameter parameters changed only in the experimental group [
70
]. Effects of flaxseed on serum
lipids in experimental animals have been variable—from no change to spotted reduction. In the study
conducted by Prasad, 14 g ALA per day was reported as a threshold dose [
71
]. The lower dose did not
affect inflammatory mediators, but 14 g/d or higher limited and reduced inflammatory markers. The
same study also demonstrated that flaxseed can suppress hypercholesterolemic atherosclerosis in a
rabbit model.
2.7. Cardioprotective Effects via Antithrombotic Activity
Solid experimental evidence of different effects of omega-3 fatty acids on individual components
of cardiovascular risk has been described. Multiple research studies revealed that omega-3 long-chain
fatty acids may prevent myocardial infarction and arrhythmia, decrease systolic, and diastolic blood
pressure and improve vascular function. This effect can be explained by very rapid omega-3 fatty acids
incorporation into cell membranes, thus affecting the function of cells and tissues with subsequent
impacts on the production of various vasoactive eicosanoids and other mediators [
72
]. Although the
exact mechanisms of the beneficial effect of omega-3s on cardiovascular diseases are multifactorial and
remain unclear, a series of omega-3 PUFAs action has been proven and described as mechanisms with
major importance for cardiology.

Nutrients 2018,10, 1561 9 of 21
Both anticoagulant and antiplatelet functions of omega-3 PUFAs were explored in the past
with inconsistent findings, therefore complementary studies were required [
73
,
74
]. Antiplatelet and
antithrombotic activity of omega-3 PUFAs has been documented in patients with coronary artery
disease (CAD) in an experimental study where PUFAs were distributed independently or in a combined
treatment [
75
–
77
] (e.g., with aspirin and clopidogrel [
78
,
79
]). The results obtained may be of significant
clinical importance, as they indicated the ability to improve platelet response to clopidogrel by omega-3
PUFA co-administration in coronary artery disease patients treated with angioplasty (percutaneous
coronary intervention) who are carriers of the loss-of-function CYP2C19 genetic variant. These findings
are also supported by the results of the TRITON-TIMI 38 study subanalysis [80].
Antithrombotic potential was also confirmed in a study based on dietary administration of oil-rich
fish (500 g/week for 4 weeks), which resulted in reduced platelet-monocyte aggregation in the study
group compared to the control [
81
]. Additionally, when administered concomitantly with policosanol
(10 mg/d)—a mixture of higher aliphatic primary alcohols purified from sugar-cane wax—oil-rich fish
were shown to be a safe and effective as a lipid-lowering agent [82–84].
A recent study by Mozaffarian and Wu reviewing available evidence for cardiovascular effects
of n-3 polyunsaturated fatty acid provides a compelling indication regarding the beneficial effects of
omega 3 fatty acids in reducing the risk of cardiac death [
85
]. Experimental studies confirmed that
omega-3 fatty acids may improve cardiac function due to their anticoagulant, anti-triglyceridemic,
antihypertensive, hemostatic, and antiarrhythmic properties [46,86–89].
2.8. Antiarrhythmic Properties
Antiarrhythmic properties are of particular interest to researchers. The antiarrhythmic effect of
omega-3 fatty acids has been widely described and explained by their effect on the ionic currents and
sodium channels in the plasma membrane of cardiomyocytes [
90
–
92
]. The results of previous studies
show that free PUFAs can reduce the membrane electrical excitability of heart cells. Impact on sodium
channels causes a shift in the state of dynamic balance inactivation towards hyperpolarized potentials.
Consequently, the cardiomyocytes are less susceptible to stimulation. Furthermore, it appears that
omega-3 PUFAs are characterized by even higher efficacy in arrhythmia conditions triggered by fresh
ischemia (this situation often results in ventricular fibrillation). It was also confirmed in a study
involving an animal model. A concentrate of free fish-oil fatty acids in oral administration was tested
with respect to its prevention effect on sudden cardiac death in dogs, and the obtained results indicate
that purified omega-3 fatty acids could prevent ischemia-induced ventricular fibrillation in the applied
dog model [93].
Regarding the suggestion that the cardioprotective effect of fish intake is mainly due to the
antiarrhythmic properties of marine n-3 polyunsaturated fatty acids, which modulate ion currents,
omega-3 PUFAs of vegetable origin were also examined. Epidemiological studies and dietary trials in
humans suggest that
α
-linolenic acid is a major cardioprotective nutrient [
94
,
95
]. The effects of ALA on
the specific Kv1.5 channel have also been examined. The results of the studies conducted by Dhein et
al. or Guizy et al. indicated that ALA directly blocks atria-specific Kv1.5 channels without modifying
their expression or the bilayer order. Together with the indicated influence of EPA and DHA, these
effects suggest that the antiarrhythmic potential of diets enriched with plant-derived n-3 PUFAs may
partially result from direct effects on cardiac ion channels [96,97].
2.9. Myocardial Infarction
Myocardial infarction (MI) or acute myocardial infarction (AMI), commonly known as a
heart attack, occurs due to damage to the heart muscle caused by stopped blood flow, which
prevents blood from reaching the heart—this refers to STEMI (ST-elevated myocardial infarction)
or injured heart muscle caused by major obstruction in blood flow through coronary arteries
(NSTEMI—non-ST-elevated myocardial infarction). The MI mechanism often involves the complete
blockage of a coronary artery caused by a rupture of an atherosclerotic plaque. Low density lipoprotein

Nutrients 2018,10, 1561 10 of 21
(LDL) can contain 70% total plasma cholesterol and—as mentioned previously—is considered the
foremost malefactor triggering inflammatory processes and early plaque formation, which later might
lead to MI and stroke. It was identified by Assmann and Gotto that reduction in the LDL levels
could lower the incidence of coronary heart disease (CHD), including MI, by up to one-third. HDL
(the good lipoprotein, which carries only 20% total plasma cholesterol) has also been linked to the
rates of coronary events in epidemiological and clinical studies [
98
]. Although LDL is the lipoprotein
most commonly associated with atherosclerosis and cardiovascular risk, other lipoproteins, such as
VLDL (very low-density lipoprotein), might also act as atherogenic factors. On the other hand, HDL
appears to play a protective role, and high levels of HDL particles are associated with a lower risk
of coronary artery disease. The cardioprotective effects of HDL have been attributed to its role in
reverse cholesterol transport [
99
,
100
]. The results of a clinical study on non-insulin-dependent diabetic
individuals consuming a diversified ratio of dietary polyunsaturated to saturated fatty acid (P/S)
indicated that fish oil significantly reduced plasma triacylglycerol levels (p< 0.05) and increased EPA
and DHA content of all lipoprotein lipid classes. Demonty et al., concluded that a modest intake of
omega-3 fatty acids, such as could be obtained due to regular fish consumption, would reduce plasma
triglyceride levels without affecting LDL or HDL cholesterol levels [
101
]. It is worth mentioning that
an increasing amount of data indicate that to initiate atherosclerosis, LDL has to undergo chemical
modification, such as oxidation or glycation, since these particles are more liable to retention within
the vessel wall intima [
102
]. Modified or damaged LDLs or their particular types (e.g., VLDL) have
become a subject of interest in regard to their role in CVDs. Thus, when it comes to cholesterol particles,
a high LDL level by itself cannot be considered to be the decisive factor responsible for cardiovascular
dysfunctions. Current evidence suggests that cardiovascular risk depends on the “quality” rather than
only the “quantity” of LDL [103,104].
The Lyon Diet Heart Study found plasma ALA to be associated with an improved prognosis
for recurrent myocardial infarction, but it did not find a similar association with long-chain omega-3
fatty acids. A meta-analysis of five prospective studies on ALA suggested that high ALA intake was
associated with reduced risk of fatal heart disease (relative risk 0.79, 0.60–1.04) [
105
]. The average
highest level of intake was 2 g per day versus the lowest of 0.8 g per day [
105
]. Omega-3 fatty acids
may provide rapid protective effects in patients with AMI, according to the results of a randomized,
placebo-controlled long-term trial. The effects of treatment with fish oil (eicosapentaenoic acid,
1.08 g/day
) and mustard oil (
α
-linolenic acid, 2.9 g/day) were compared for 1 year in the management
of patients divided into a fish oil group, a mustard oil group, and placebo patients with suspected
AMI. The fish oil and mustard oil groups showed a significant reduction in total cardiac arrhythmias,
left ventricular enlargement, and angina pectoris compared to the placebo group [
106
]. Sun et al., have
recently presented how plasmatic long-chain omega-3 PUFAs levels are associated with a lower risk of
AMI in Asian population [
107
]. The case-control study results did not indicate conclusive findings.
According to the authors, plasma ALA may be slightly associated with reduced AMI risk, even in
individuals with high concentrations of long-chain omega-3s, and this may be partially mediated
by lower blood pressure and LDL cholesterol level [
107
]. Contrary to the pointed importance of
the aforementioned finding, the results of the study by Derbali et al., proved that flaxseed oil has a
significant effect in heart protection against isoproterenol-induced myocardial infarction. Linum oil
pre-co-treatment was reported as an agent preventing almost all induced MI parameters through the
beneficial effect of the important ALA fraction [108].
2.10. Atrial Fibrillation
An abnormal heart rhythm characterized by irregular, commonly rapid beating, which affects
about 2 to 3 per cent of the population in Europe and North America, is another common concomitant
disease with coronary artery disease, myocardial infarction, and cardiomyopathy. This condition, i.e.,
atrial fibrillation (AF), has become one of the most important public health problems over the last
20 years, and is a significant cause of increasing health care costs in Western countries [109].

Nutrients 2018,10, 1561 11 of 21
An epidemiologic approach has been applied in order to evaluate the relationship between plasma
ALA levels, dietary ALA consumption, and AF risk. Fretts et al.’s research group investigated subjects
who were 65 years or older at study entry and detected no relationship between plasma ALA and AF
incident after correcting for age, sex, and a variety of clinical and demographic factors [
110
]. However,
a technical weaknesses of the study included plasma ALA levels measurement only occurring at a
single time point [
110
,
111
]. It should be mentioned that a similar epidemiologic study has recently
reported a beneficial effect of dietary ALA with respect to heart failure risk. Atrial fibrillation and
heart failure are frequently comorbid conditions. It seems probable that diets that substantially
increase ALA consumption with concurrent decrease in omega-6 PUFAs intake would beneficially
affect cardiovascular morbidity and mortality [
112
]. Calo et al., conducted an open-label, prospective,
randomized study in order to assess the efficacy of preoperative and postoperative treatment with
omega-3 PUFAs in preventing the occurrence of AF, which is the most coincident complication
associated with coronary artery bypass graft surgery [
113
]. The daily doses of omega-3 PUFAs
consisted of two gelatin capsules containing 850 to 882 mg EPA and DHA as ethyl esters with an
average ratio of 1:2 EPA/DHA. As a result, postoperative AF was noted in 15.2% (12 of 79) of the
patients in the PUFA group compared to 33.3% (27 of 81) of those in the control group. Additionally,
the PUFA patients were hospitalized after surgery for significantly fewer days than the controls. This
was the first study to demonstrate that individuals supplemented with omega-3 PUFAs presented a
decreased risk ratio in cardiac events, like the incidence of postoperative atrial fibrillation [
113
,
114
].
ALA’s role either in isoproterenol-treated isolated rat cardiomyocytes or in
in vivo
rat hearts was
studied, and it was demonstrated that an ALA-enriched diet protects the heart against induced fibrosis
and hypertrophy [115].
2.11. Stroke
Ischemic stroke is considered to be one of the more important reasons of death and prolonged
disability among the adults [
116
–
118
]. Commonly applied and approved stroke therapy involves the
use of tissue plasminogen activator (tPA), which, however, is substantially limited by a short temporal
window of application [
119
]. Thus, an important issue in stroke-related research is the search for
some alternative therapies that would be safe in the case of long-term prophylactic administration.
Although numerous studies have demonstrated that the brain of an adult is able to try to repair itself
in reaction to ischemic insults, no safe, efficient therapies that would enhance repair mechanisms and
thus prevent neurological deficits induced by stroke have been recognized. Therefore, attention has
been paid to neurorestorative therapies that are able to boost cerebral brain repair and concurrently
enhance post-ischemia neurological recovery [120–122].
Many studies on stroke models have shown that omega-3 fatty acids are able to protect against
ischemic brain injury [
123
–
125
], but the mechanisms of these actions have not been fully explained. It
was suggested that this inability to explain the underlying mechanisms behind the protective effect
of omega-3 fatty acids could be due to the multiple effects of these acids, i.e., anti-inflammatory
activity [
125
,
126
], oxidative stress reduction [
127
], heme oxygenase induction [
128
], or neurogenesis
and oligodendrogenesis potentiation [
124
]. Palmer et al. [
129
] also suggested that omega-3s are also
able to promote the formation of new blood vessels.
A study conducted by Wang et al. [
116
] demonstrated that an endogenous post-stroke
angiogenesis was induced by omega-3 supplementation, and this measure may be considered to
be a potential angiogenic factor enhancing endogenous tissue repair and improving long-term
functional recovery after stroke. In turn, Zhang et al. [
130
] demonstrated in their study that
prolonged administration of fish oil caused an increase in cerebral omega-3 level and provided
long-term histological and neurological protection against ischemic brain damage. This study also
demonstrated that omega-3 PUFAs derived from dietary supplementation can actively promote brain
repair due to the possibility of post-stroke brain revascularization as well as enhanced neurogenesis
and oligodendrogenesis, not only alleviate ischemic brain injury.

Nutrients 2018,10, 1561 12 of 21
The study conducted by Mozaffarian et al. [
131
] revealed that total omega-3 level in plasma
was inversely correlated with ischemic stroke risk; however, the authors did not demonstrate any
significant effect in the case of hemorrhagic stroke [
131
]. A meta-analysis of fish consumption relation
to stroke conducted by Larsson and Orsini [
132
] demonstrated that increased fish consumption (three
servings per week) was associated with a 6% lower stroke incidence [
132
]. Also, a meta-analysis of
cohort studies performed by He et al. [
133
] showed an inverse relationship between stroke (especially
ischemic one) and fish consumption. However, in another study [
134
], fish oil supplementation was
not related to a decreased stroke incidence. Also, a meta-analysis conducted by Siscovick et al. [
135
]
provided only minor evidence of stroke incidence decrease in patients supplemented with omega-3
PUFAs. Similar conclusions were reported by other meta-analyses [136–138].
It can thus be concluded based on the aforementioned evidence that fish consumption is more
efficient in stroke prevention compared to omega-3 supplements [
139
]. Also, a 12-year follow-up
study in men demonstrated a 45% lower risk of ischemic stroke, but no change in hemorrhagic stroke
incidence, in the case of fish consumption (2–4 servings/week) [
140
]. Despite the beneficial effects
related to fish consumption and stroke incidence reduction demonstrated above, some other studies
did not provide such strong evidence [
141
,
142
]. The discrepancies observed in different studies
conducted on various populations may be due to different patterns and kinds of fish consumed as
well as their preparation manners [142–144].
3. Safety Concerns
Despite abundant evidence on the beneficial activity of omega-3 fatty acids on human health,
including cardiovascular diseases, there are also some concerns regarding the safety of their
administration. The main concern is related to the possibility of an increased bleeding risk as a result
of omega-3s supplementation. According to Bays [
145
], the involvement of omega-3s in eicosanoid
metabolism may be the biochemical cause of possible increased bleeding in the case of increased
omega-3 fatty intake. The author points out, that although there is little evidence for an increased risk
for clinically significant bleeding incidence with omega-3 fatty acid supplementation, this should be
taken into account.
It was suggested that the antithrombotic effect of omega-3s can partially increase the bleeding
risk, or even a sudden cardiac death. It was suggested, moreover, that fish oil therapy can cause a
slightly higher risk of hemorrhagic stroke, but clinical evidence has not related an increased bleeding
with omega-3 fatty acid consumption, even in combination with other agents that potentially increase
bleeding (e.g., aspirin) [146]. This was confirmed in the study conducted by Watson et al. [147].
A study concerning the relationship between omega-3 fatty acid index and bleeding in the course
of AMI was conducted by Salisbury et al. [
148
]. The authors suggested that, despite numerous benefits
related to CVDs, omega-3 acids can also inhibit platelet aggregation, thus increasing the risk of bleeding.
However, following a study on a large, multicenter group of AMI patients, the authors concluded
that there is no relationship between the bleeding and omega-3 index, and thus the concerns about
bleeding should not prevent the use of omega-3 supplementation in the case of clinical indications.
Another concern related to the safety of omega-3s is the high instability of fish oil and its
susceptibility to oxidation, which may contribute to intolerance by patients and an increased risk
of toxicity [
145
,
149
,
150
]. Finally, fish consumption may also be related to the risk of poisoning with
environmental toxins like mercury, polychlorinated biphenyls, dioxins, or hypervitaminosis due to
consumption of fish oils containing high levels of fat-soluble vitamins D and A [
145
,
151
,
152
]. However,
these risks can be reduced substantially via purification processes used during fish oil supplements
and medical preparations production or supplementation with plant origin omega-3s [145].
4. Perspectives
Omega-3 fatty acids have been shown in epidemiological and clinical trials to reduce the incidence
of CVD. The daily intake of fish or plant origin oil rich in omega-3 fatty acid corresponding to

Nutrients 2018,10, 1561 13 of 21
recommended dosage may prove to be difficult, albeit valuable. Thus, an alternative method of
supplementation may be oral omega n3-PUFA therapy, which represents a potentially huge factor of
interest and motivation for the pharmaceutical industry. Pharmaceutical and biomedical companies
are increasingly interested in the subject of omega-3 fatty acids and their metabolites, and subsequently
there has been a substantial amount of research on supplements of omega-3s, particularly those found
in seafood and fish oil, and heart disease. Omega-3 fatty acid supplements usually do not have negative
side effects. When side effects do occur, they typically consist of minor gastrointestinal symptoms, such
as belching, indigestion, or diarrhea. Although the biggest group of omega-3 supplements is based on
marine or fish oils, vegetable oils have become increasingly popular and approachable in this matter,
not only for vegans and vegetarians but also for people concerned about having a healthy balanced
diet. Commonly used alternative dietary supplements based on
α
-linolenic acid include flaxseed oil
and algae oils as a source of DHA. Plant oils (source of ALA) serving as an omega-3 supplements are
as potent and effective as fish based oils (containing mainly EPA and DHA fatty acids). However, ALA
with only three double bonds is not as susceptible to oxidation as EPA (five bonds) and DHA (six
bonds). A substantial part of fish oils is oxidized during the production process, which significantly
reduces the pharmacological activity and may confer toxic properties.
5. Conclusions
Exogenous polyunsaturated fatty acids deserve special attention, given the importance of their
physiological functions, determined by the limited capacity of fatty acid desaturation by human
tissues. As is clear from the above facts, omega-3 fatty acids, particularly alpha-linolenic acid (the
pharmacologically active precursor of EPA and DHA), have a broad spectrum of anti-inflammatory
and cardio-protective activities. There is, however, still need for further research into the function
of ALA as an independent nutrient. In conclusion, the beneficial effects of omega-3 fatty acids and
their esters have been previously documented in terms of both primary and secondary prevention
of cardiovascular system disorders. It has to be highlighted, however, that the achievement of
optimal performance requires an appropriate quantitative composition and the proper proportions
of delivered fatty acids. A healthy balanced diet, especially when combined with regular physical
activity and smart supplementation of omega-3 fatty acids, has been reported as being effective in
preventing cardiovascular events, cardiac death, and coronary events, especially in persons with high
cardiovascular risk.
Author Contributions:
E.S.-W. and T.W. conceived and designed the manuscript; K.C., R.B., and T.W. collected
the data; J.W., E.S.W., and K.C. wrote the manuscript; J.W., R.B., B.P.-S., and S.L. revised drafts of the manuscript.
Funding: This research received no external funding.
Acknowledgments:
Publication supported by Wrocław Centre of Biotechnology, programme the Leading National
Research Centre (KNOW) for years 2014–2018.
Conflicts of Interest:
The authors declare that there is no conflict of interest regarding the publication of this paper.
Abbreviations
AA arachidonic acid (20:4, n-6)
AF atrial fibrillation
ALA alpha-/α-linolenic acid (18:3, n-3)
AMI acute myocardial infarction
CAD coronary artery disease
CVD cardiovascular disease
DHA docosahexaenoic acid (22:6, n-3)
EFA essential fatty acid
EPA eicosapentaenoic acid (20:5, n-3)
GLA gamma-/γ-linolenic acid (18:3, n-6)
HDL high-density lipoprotein

Nutrients 2018,10, 1561 14 of 21
IHD ischemic heart disease
LA linoleic acid (18:2, n-6)
LDL low-density lipoprotein
MI myocardial infarction
MUFA monounsaturated fatty acid
PUFA polyunsaturated fatty acid
TGs triglycerides
VLDL very low-density lipoprotein
WHF World Health Federation
WHO World Health Organization
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