Hindawi Publishing Corporation
Cardiology Research and Practice
Volume 2012, Article ID 729670, 11 pages
Omega-3Fatty Acidsand VitaminD inCardiology
Norbert G¨ uttler,1KirilaZheleva,1MarianaParahuleva,1RidvanChasan,1
Mehmet Bilgin,2ChristianeNeuhof,3Mehmet Burgazli,4Bernd Niemann,5
1Department of Cardiology and Angiology, University Hospital Giessen, 35390 Giessen, Germany
2Department of Radiology, Bezmialem University of Istanbul, Istanbul, Turkey
3Department of Cardiology, University of Giessen, 35390 Giessen, Germany
4Department of Internal Medicine, University of Giessen, 35390 Giessen, Germany
5Department of Cardiac Surgery, University of Giessen, 35390 Giessen, Germany
6Department of Cardiovascular Surgery, University Hospital Giessen, 35390 Giessen, Germany
Correspondence should be addressed to Mehmet Bilgin, firstname.lastname@example.org
Received 17 April 2012; Revised 15 August 2012; Accepted 7 September 2012
Academic Editor: Hugo ten Cate
Copyright © 2012 Norbert G¨ uttler et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Dietary modification and supplementation play an increasingly important role in the conservative treatment of cardiovascular
disease. Current interest has focused on n-3 polyunsaturated fatty acids (PUFA) and vitamin D. Clinical trial results on this
subject are contradictory in many aspects. Several studies indicate that n-3 PUFA consumption improves vascular and cardiac
hemodynamics, triglycerides, and possibly endothelial function, autonomic control, inflammation, thrombosis, and arrhythmia.
production of anti-inflammatory mediators. Clinical trials evaluating a possible reduction in cardiovascular disease by n-3 PUFA
have shown different results. Supplementation of vitamin D is common regarding prevention and treatment of osteoporosis. But
vitamin D also seems to have several effects on the cardiovascular system. Vitamin D deficiency appears to be related to an increase
in parathyroid hormone levels and can predispose to essential hypertension and left ventricular hypertrophy, increased insulin
resistance, and eventually to atherosclerosis and adverse cardiovascular events. Randomized prospective clinical trials are needed
to determine whether vitamin D and omega-3 FA supplementation therapy should be recommended as a routine therapy for
primary or secondary prevention of cardiovascular disease.
There are different ways of preventing and treating car-
diovascular disease. Besides drug therapy and lifestyle
changing dietary modification and supplementation play an
increasingly important role in the conservative treatment
of cardiovascular disease. Current interest has focused on
n-3 polyunsaturated fatty acids (PUFA) and vitamin D
. Their potential cardiovascular risk reduction has been
subject of many studies. n-3 PUFA seems to play a role
in the treatment of coronary artery disease (CAD), cardiac
arrhythmias, and heart failure. There are indications that
they can also be used as an addition to the standard therapy
of hypertriglyceridemia and diabetes. The results of some
clinical studies are promising concerning cardiovascular
outcomes. The GISSI-P study, for example, has shown that
in addition to medical therapy daily supplementation with
omega-3 fatty acids (FA) can reduce cardiac and all-cause
mortality in patients after myocardial infarction .
The vitamin D receptor (VDR) is expressed in most
tissues.Bioactivevitamin D belongsto agroup of secosteroid
molecules which are traditionally associated with bone and
calcium metabolism . The human body can synthesize
vitamin D under influence of sunlight exposure out of 7-
dehydrocholesterol, which is the major source (80% to 90%)
of this substance in humans under natural conditions .
2 Cardiology Research and Practice
Vitamin D may potentially affect the treatment and pre-
vention of hypertensive vascular disease, coronary artery
disease, cardiac arrhythmias, peripheral vascular disease,
lipid metabolism, and diabetes mellitus. Accumulating epi-
associated with an increased risk of cardiovascular events [5,
6], and experimental data generally support the hypothesis
that vitamin D has a protective role in cardiovascular health
This paper willexamine the relevanceof omega-3 FA and
2.DietarySources of n-3PUFA
Fish is the major food source of long-chain n-3 PUFA,
including eicosapentaenoic acid (EPA), docosahexaenoic
acid (DHA), and, in smaller amounts, docosapentaenoic
acid (DPA), a long-chain n-3 PUFA metabolite of EPA .
The fact that the correlation between DPA levels and fish
consumption is low suggests that DPA levels in humans
are predominantly determined by endogenous metabolism
rather than diet. Alpha-linolenic acid is a plant-derived n-
3 FA, which cannot be synthesized in humans and so is an
essential dietary fatty acid. ALA is found in some sorts of
seeds, nuts, and their oils. Some reports suggest that ALA
might have cardiovascular benefits as well as EPA and DHA,
but further studies of ALA’s effects are urgently needed.
Biochemical pathways to convert ALA to EPA and EPA to
DHA are limited in humans, so that EPA and DHA levels are
primarily determined by direct dietary consumption.
There has been a discussion if fish consumption or fish
chain n-3 PUFA, fish contains specific proteins, vitamin D,
selenium, and other minerals and elements. Most studies of
death caused by coronary heart disease in generally healthy
populations evaluated fish consumption, not fish oil sup-
plementation. Because of the other mentioned ingredients
of fish besides n-3 PUFA, this policy is reasonable, and the
consumption of fish should be preferred. For individuals
who cannot consume sufficient amounts of fish, fish oil
supplementation is an alternative.
3.Effects of n-3 PUFAon
by the influence of n-3 PUFA on multiple relevant molecular
pathways (Figure 1). Cellular and organelle functions are
strongly influenced by membrane lipid environments. Lipid
microdomains contribute to the modulation of numerous
cellular functions like signal transduction, protein and
membrane trafficking, and ion channel kinetics. The incor-
poration of n-3 PUFA in cell and organelle membrane
structures alters their physicochemical properties and influ-
ences the localization, function, and signaling of membrane-
associated proteins . This might contribute to potential
anti-inflammatory and antiarrhythmic effects.
In animal-experimental and in vitro studies, n-3 PUFA
tion of membrane sodium channel, L-type calcium channel,
and sodium-calcium exchanger. This might contribute to
reduced myocyte excitability and cytosolic calcium fluctu-
ations especially in ischemic or damaged cells. However,
specific effects in experimental studies have not always been
Also some clinical trials for arrhythmia and sudden
death after ischemia suggest that omega-3 FA has a direct
electrophysiological effect on the myocardium. It is hypoth-
esized that during ischemia, a reduction in the sodium ion
current protects hyperexcitable tissue, and a reduction in the
calcium ion current reduces arrhythmogenic depolarizing
currents . Whereas accumulating evidence suggests that
incorporation of n-3 PUFA into and resultant changes in
lipid membranes contributes to effects on ion channels, and
that n-3 PUFA might also directly interact with membrane
channels and proteins, the potential relevance of these
effects on humans is not fully established.
n-3 PUFAs are natural ligands of several nuclear recep-
tors and transcription factors regulating gene expression in
multiple tissues [11, 12]. These receptors regulate cellular
functions related to cardiovascular disease, including lipid
metabolism, glucose-insulin homeostasis, and inflamma-
tion. n-3 PUFA can also affect activation of transcription
Another anti-inflammatory effect may be contributed to
the lowering of arachidonic acid-(AA-) derived eicosanoids
caused by n-3 PUFA consumption [13, 14].
Some n-3 PUFA-derived eicosanoids, in contrary, have
an anti-inflammatory effect and seem to play a role in
cardiovascular protection .
4.Benefits of n-3PUFA Consumption for
Physiological effects of n-3 PUFA that might influence
the risk of cardiovascular disease (CVD) are depicted in
Figure 2. Randomized trials assessed the efficacy of fish oil
supplementation in a population after myocardial infarction
(GISSI-P) study randomized 11,324 patients to n-3 PUFA
within three months after MI. Results demonstrated relative
risk reductions in overall mortality (20%), cardiac mortality
(30%), and sudden cardiac death (SCD, 45%) with 1g/day
of highly purified omega-3 acid ethyl esters (Omacor) over
a 3.5-year period . Significant benefits emerged within
three to four months especially in those with extensive left
ventricular dysfunction. Some studies suggest that n-3 PUFA
improves heart rate variability as a marker of autonomic
function [16, 17]. Holter monitor recordings showed an
increase in heart rate variability (HRV) in the fish oil group
. Observational studies have linked omega-3 FA with
the prevention of sudden cardiac death (SCD). Heart rate
variability has been shown to be one of the best predictors of
the risk of SCD. The data showed clearly that n-3 fatty acids
Cardiology Research and Practice3
Figure 1: Molecular pathways affected by n-3 PUFA . AA: arachidonic acid; COX: cyclooxogenase; cPLA2: cytosolic phospholipase A2;
CYP450: cytochrome P450; DHA: docosahexaenoic acid; DNA: deoxyribonucleic acid; ERK: extracellular signal-regulated kinase; GPR
120: G-protein-coupled receptor 120; HNF: hepatic nuclear factor; LOX: lipoxygenase; mRNA: messenger ribonucleic acid; n-3 FA: n-3
fatty acids; NF-κB: nuclear factor-kappaB; PGE2: prostaglandin E2; PMN: polymorphonuclear leukocyte; PPAR: peroxisome proliferator-
activated receptor; RXR: retinoid X receptor; SREBP-1c: sterol regulatory element binding protein-1c.
increase HRV. This supports the hypothesis that an increased
intake of n-3 fatty acids may reduce the risk of SCD .
However, in a larger cohort assessed in the Japan EPA lipid
intervention study (JELIS) there was lack of an effect of fish
Atrial fibrillation (AF) is the most common sustained
arrhythmia and is associated with considerable morbidity
and mortality . The role of omega-3 FA and its potential
antiarrhythmic effect in the prevention of AF have been
postulated. AF is a common complication after coronary
artery bypass grafting operation (CABG). A prospective
randomized study showed the efficacy of fish oil on AF after
CABG. Perioperative intravenous infusion of polyunsatu-
rated fatty acids (PUFA) reduced the incidence of AF after
CABG leading to a shorter stay in the intensive care unit
(ICU) and in hospital . However, outcome of clinical
results of the OMEGA, a randomized, placebo-controlled
trial to test the effect of highly purified omega-3 FA on
top of modern guideline-adjusted therapy after myocardial
infarction, showed a low rate of SCD, total mortality, and
major adverse cerebrovascular and cardiovascular events
within 1 year of followup after guideline- adjusted treatment
and secondary prevention of acute myocardial infarction
. The results of this study should be interpreted carefully,
because it was substantially underpowered. Alpha omega
(study of omega-3 fatty acids and coronary mortality)
studied n-3 PUFA supplemented margarine in post-MI
patients . The study outcome was neutral, the study was
underpowered as well.
4 Cardiology Research and Practice
effects on glucose
Arterial wall compliance
Production of arachidonic
acid derived eicosanoids
Production of n-3 derived
Myocardial efficiency (e.g
reduce oxygen consumption
at given work output)
Left ventricular diastolic
Autonomic function vagal tone
Dose response relationship not established.
Effects appears linear across a wide range of intakes (at least up to 7 g/d).
additional effects at higher levels.
Effect appears linear within ranges of typical dietary intake (<750mg/d), with smaller
Effects only appears potentially relevant of higher supplemental intakes (>4g/d).
Figure 2: Physiological effects of n-3 PUFA that might influence cardiovascular disease (CVD) risk .
GISSI-heart failure (GISSI-HF) was a large adequately
powered trial evaluating n-3 PUFA in heart failure .
Results demonstrated a significant and clinically important
reduction of all-cause mortality with 1g Omacor in a heart
failure population. n-3 PUFA supplementation showed an
absolute risk reduction of 1.8% in all-cause mortality seen
over two years of followup. There was little benefit in
atherothrombotic events, such as MI or stroke.
Another effect of n-3 PUFA is lowering of plasma
like reduced hepatic very low-density lipoprotein synthesis,
increased fatty acid beta-oxidation, reduced delivery of
nonesterified fatty acids to the liver, reduced hepatic enzyme
activity for triglyceride synthesis, and increased hepatic
synthesis of phospholipids rather than triglycerides.
n-3 PUFA consumption reduces heart rate and systolic
and diastolic blood pressure [28, 29]. The decrease of heart
rate is probably caused by direct effects on electrophysiologic
pathways  and by indirect effects like the improving of
left ventricular diastolic filling or an augmented vagal tone
. According to some trials the reduction of blood pres-
sure is a consequence of increased nitric oxide production,
a mitigated vasoconstrictive response to norepinephrine
and angiotensin II, enhanced vasodilatory responses, and
improved arterial compliance [30, 31].
The suspected antithrombotic effects of n-3 PUFA seen
in some studies could not be confirmed in some human
trials, where n-3 PUFA had no relevant effect on platelet
aggregation and coagulation factors [32, 33].
Several trials found an improvement of endothelial
function in some studies decreased markers of endothelial
dysfunction were measured after n-3 PUFA consumption
. The normalization could partly mediate a protective
effect against CVD.
In some studies n-3 PUFA consumption improved car-
diac filling and myocardial efficiency measured by a reduced
Cardiology Research and Practice5
Potential effects of n-3 PUFA
Improvement of autonomic function
Decreased platelet aggregation
Decreased blood pressure and heart rate
Improvements in endothelial function
Improvement of vascular and cardiac hemodynamics
workload-specific oxygen demand . In two trials n-3
PUFA even improved left ventricular function in patients
with heart failure [36, 37].
The trial results concerning the influence of n-3 PUFA
on insulin resistance and diabetes are still contradictory.
While some trials found a modestly higher incidence of type
2 diabetes caused by n-3 PUFA consumption, most of the
trials did not see any consistent effects on fasting glucose
or hemoglobin A1c in patients with non-insulin-dependent
Because of the above-mentioned
inflammatory properties of n-3 PUFA, fish oil is already
used as an adjunctive therapy for several inflammatory
diseases like rheumatoid arthritis . Nevertheless, the
clinical impact of such anti-inflammatory effects, especially
at usual dietary doses, is still unclear and will have to be
subject of further studies. Possible effects of n-3 PUFA in the
cardiovascular system are listed in Table 1.
According to numerous meta-analyses, all these possible
benefits of n-3 PUFA seem to lead to a significant reduction
of mortality by chronic heart disease (CHD) .
Adverse effects of omega-3 FA were also documented. The
food and drug administration (FDA) product label on
Lovaza (omega-3-acid ethyl esters) warns against potential
bleeding complications when administered in combination
with anticoagulants . This warning is based on obser-
vational studies that suggested a prolonged bleeding time
in populations ingesting high levels of fish oil . On the
other hand, in randomized clinical trials of patients under-
going coronary artery bypass graft surgery, percutaneous
transluminal coronary angioplasty, and endarterectomy and
diagnostic angiography, no adverse bleeding-related events
have been demonstrated . However, no serious adverse
events in patients receiving antiplatelet and anticoagulant
therapy in addition to fish oil supplementation have been
Besides, there have been concerns about possible con-
taminants present in some fish species, like methylmer-
cury, dioxins, and polychlorinated biphenyls (PCBs). The
concentration of these contaminants in some fish species
has been under examination in the USA . In most fish
species, mercury levels are quite low, only in selected few
species they were moderate or even near the US. Food and
Drug Administration action level of 1μg/g (e.g., tilefish,
swordfish, shark, and Mexico King mackerel). Mercury
exposure levels common in the USA have no relation to
higher CVD risks . PCB and dioxin levels are usually
low in commercially sold fish and according to the results
of one US analysis contribute approximately 9% to total
dietary exposure. So for general adult population the health
benefits of modest fish consumption significantly overweigh
the potential risks. There are special recommendations for
sensitive subpopulations like young children and women of
There are several dietary guidelines for FA . In these
guidelines there is convergence recommending at least
250mg/day EPA + DHA or at least 2 servings/week of fish,
preferably oily fish. For pregnant women, nursing mothers,
and young children, these recommendations are modified.
The American Heart Association 2020 Strategic Impact
Goals defined consumption of at least 2 3.5-oz servings/week
rics that characterized ideal cardiovascular health . The
2010 US. Dietary Guidelines for Americans recommended
for individuals with higher and average CVD risk 2 4-oz
seafood servings/week, which should provide an average of
at least 250mg/day EPA + DHA (1,750mg/week) . At
present in most countries EPA + DHA intakes are much
lower than recommended.
7.Sources of VitaminD andRisk Factors
There are two forms of vitamin D: Vitamin D2 (ergo-
calciferol) is an ultraviolet B (UVB) radiation product of
ergosterol. It can be consumed as supplement or in fortified
foods. Vitamin D3 (cholecalciferol) is a product of UVB
radiation of 7-dehydrocholesterol, is synthesized in the
human epidermis, and can be consumed in oily fish, fortified
foods, or a supplement. In the liver vitamin D is converted
to 25(OH)D, which is the major circulating metabolite and
which should be measured to clinically assess vitamin D
is produced primarily in one organ, the kidney, and then cir-
culated throughout the body, where it exerts several impor-
tant effects. It crosses the cell membrane and cytoplasm and
reaches the nucleus, where it binds to the vitamin D receptor
(VDR), which is present in most tissues including endothe-
lium, vascular smooth muscle, and myocardium. Directly
or indirectly, 1,25(OH)2D regulates more than 200 genes,
including those involved in renin production in the kidney,
insulin production in the pancreas, release of cytokines from
lymphocytes, and growth and proliferation vascular smooth
muscle cells as well as cardiomyocytes [6, 47].
6Cardiology Research and Practice
Risk factors for vitamin D deficiency
Darkly pigmented skin
Institutionalized of homebound
Increased distance from equator
Cover-up clothing and/or sunscreen
Medications: anticonvulsants, glucocorticoids, antirejection, and
immunodeficiency virus medications
The synthesis of vitamin D3 in response to UVB
radiation in sunlight depends on many factors, including
latitude, altitude, time of year and day, weather, age, skin
pigmentation type, clothing, activity, and other aspects of
the environment like air pollution. Modern human cultures
produce less vitamin D cutaneously, in part because of
increasingly indoor lifestyles and the avoidance of sun
exposure by using sunscreen and other strategies. Sunscreen
with a sun protection factor of 15 blocks approximately 99%
of cutaneous vitamin D production. Other factors associated
with vitamin D deficiency are poor nutrition, chronic illness,
and renal failure.
Risk factors for vitamin D deficiency are pointed out in
8.Effects of VitaminDand VitaminD
Deficiency on the CardiovascularSystem
The ubiquity of the VDR and tissue 25(OH)D-1α-
hydroxylase provides insight into several pathobiologic
pathways through which hypovitaminosis D may mediate
emulating vitamin D deficiency, displays increased blood
pressure, serum angiotensin, and tissue renin . In in
vitro studies vitamin D analogs directly suppress renin gene
expression via a vitamin D response element that is present
in the renin gene . Vitamin D analogs have been shown
to inhibit the production of several proinflammatory Th-
1 cytokines, such as IL-2 and IFN-γ, while stimulating
the effects of Th-2 lymphocytes, leading to a reduction in
matrix metalloproteinase and reducing plaque production
and instability. Furthermore, it has been shown to have
immunosuppressive effects reducing the proliferation of
lymphocytes and the production of cytokines, which have
been identified as playing an important role in atherogen-
esis. VDR agonists have also been shown to downregulate
plasminogen activator inhibitor 1 in human aortic smooth
muscle cells but not endothelial cells. Besides, vitamin D
seems to have a dose-dependent role in the inhibition of
vascular calcification .
Chronic kidney disease (CKD) has been recognized as
a powerful cardiovascular risk factor. Agarwal et al. found
that the administration of an activated vitamin D analog
(paricalcitol) reduced proteinuria in 51% of the 57 patients
with CKD in comparison with only 25% of the 61 study
participants who received placebo (P = 0.004), suggesting a
direct vascular effect of vitamin D . Some observational
studies have reported an increased risk for death in patients
with CKD and low serum 25(OH)D levels. Other studies
have shown an association between treatment with activated
vitamin D and lower all-cause and cardiovascular mortality
in patients with CKD.
9.Benefits of VitaminD for
A wide range of cardiovascular diseases has been associated
with vitamin D deficiency involving multiple potential
mechanisms. Essential hypertension is a major risk factor for
blood pressure control via multiple pathways and is inversely
related to serum renin activity . The results of clinical
studies have shown that vitamin D levels were inversely
associated with systolic and diastolic blood pressure, and
vascular resistance [50, 51]. Conversely, in another study
there was no association between vitamin D levels in newly
diagnosed patients with hypertension and their matched
controls . The NHANES III study also observed the
correlation between vitamin D levels and peripheral vascular
disease. Low vitamin D levels were associated with a higher
prevalence of peripheral arterial disease . Vitamin D
deficiency is also strongly associated with increased thickness
Many coronary risk factors, including hypertension,
diabetes mellitus, and lipid levels are affected by vitamin
D: Multiple studies evaluated the relation of vitamin D
prospectively with long-term cardiovascular outcomes in
subjects without history of cardiovascular disease . In
healthy males between the ages of 40 and 75 years without
history of coronary artery disease, vitamin D deficiency was
associated with an increased rate of myocardial infarction
over a 10-year period . Similarly, in the Framingham
Offspring study subjects without history of cardiovascular
disease and vitamin D deficiency had increased risk for
developing a first-cardiovascular event after 5 years of
followup compared with subjects with optimal vitamin D
levels (>15ng/mL) . Vitamin D can also indirectly affect
calcium levels . It has been noted that osteoporosis,
osteopenia, and low vitamin D levels are common in patients
with congestive heart failure . Observational studies
have shown that there is ethnic variation in the incidence
of heart failure and serum vitamin D levels. For example,
vitamin D deficiency and hyperparathyroidism are more
common in African American patients, and heart failure in
Cardiology Research and Practice7
this population is characterized by greater incidence, disease
severity, and overall mortality compared to other popu-
Possible mechanisms of increased cardiovascular (CV)
risk from vitamin D deficiency are shown in Figure 3. Vita-
system, can predispose to hypertension and left ventricular
hypertrophy. It causes an increase in parathyroid hormone,
which increases insulin resistance and is associated with
diabetes, hypertension, inflammation, and increased cardio-
vascular risk  (Table 3).
Multiple, recent studies have shown an association
vascular outcome parameters [62–64].
A meta-analysis of 18 randomized controlled trials
comprising 57,000 individuals showed that a vitamin D
intake >500IU/day improved all-cause mortality, in part by
decreasing cardiovascular (CV) deaths . Data regarding
both efficacy and CV safety for vitamin D appear to be
superior to that for calcium supplements.
Currently, most experts define vitamin D deficiency as
a 25(OH)D level of <20ng/mL (50mmol/L) and vitamin D
insufficiency as 21 to 29ng/mL. The optimal concentration
of 25(OH)D is at least 30ng/mL .
Excessive use of vitamin D supplements can cause progres-
sive accumulation and toxic effects, presenting as hyper-
calcemia and renal damage. Clinical symptoms include
anorexia, nausea, and vomiting, followed by polyuria, poly-
dipsia, pruritus, and eventually even renal failure . As
to the present knowledge such toxic effects occur only
with prolonged (at least several months) daily intake of
more than 1,000μg (40,000IU). Excessive sunlight exposure
vitamin D3to biologically inert isomers.
Up to 95% of the body’s vitamin D requirement comes from
the synthesis in the epidermis in response to sun exposure.
The remaining 5% are ingested from dietary sources. Studies
indicate that the average U. S. adult consumes approximately
230IU vitamin D per day, whereas an estimated daily intake
of 1,000 to 2,000IU would be necessary to satisfy the body’s
needs for most people.
The recommended dosage of supplemental vitamin D
has increased within the last years. Currently US Govern-
ment recommends 600IU daily for children and adults up
to the age of 70 years and 800IU for seniors above 70 years
6,000IU for pregnant women and lactating mothers. The
tolerable upper intake level (UL) is set at 4,000IU per day by
the US Government, but according to many experts should
be raised to 10,000IU per day.
Potential effects of vitamin D deficiency on the cardiovascular
Activation of renin-angiotensin-aldosterone system
Predisposition to hypertension and left ventricular hypertrophy
Increase in parathyroid hormone
Increase in insulin resistance
Association with diabetes, hypertension, and inflammation
Increase in lipid levels
Increased thickness of the intima-media in carotid arteries
Increased rate of myocardial infarction
Decrease of cardiac function
There are several trials underway to fill some gaps in the
understanding of intervention with n-3 PUFA and vitamin
D in cardiovascular disease.
The ongoing vitamin D and omega-3 trial (VITAL)
is a large randomized, double-blind, placebo-controlled, 2
× 2 factorial trial of vitamin D and marine omega-3 FA
supplements in the primary prevention of cancer and car-
diovascular diseases (CVD) among a multiethnic population
of 20,000 US men aged ≥50 and women aged ≥55. Vitamin
D is used in the form of vitamin D3 (cholecalciferol) and
2,000IU/day and omega-3 FA is used as Omacor fish oil,
1g/day. The mean treatment period will be five years the
study is expected to be completed in 2016. Baseline blood
samples are collected in at least 16,000 participants, with
followup blood collection in about 6,000 participants. Yearly
followup questionnaires will assess treatment compliance,
use of nonstudy drugs or supplements, occurrence of
endpoints will be confirmed by medical record review by
physicians blinded to treatment assignment, and deaths
will be ascertained through national registries and other
sources. Ancillary studies are planned to investigate the
effect of vitamin D and omega-3 FA on other multiple
diseases like for example diabetes, glucose intolerance, and
hypertension. The results of VITAL are expected to influence
individual decisions, clinical recommendations, and public
health guidelines regarding the use of vitamin D and marine
omega-3 FA supplements for the primary prevention of
cancer and CVD .
GISSI-R&P was launched in 2004 and is an ongoing
large-scale, randomized-controlled trial conducted in Italian
general practice to assess the efficacy and safety of omega-
3 PUFAs in reducing cardiovascular mortality (including
sudden death) and hospitalization for cardiovascular reasons
in patients at high CVD risk but without history of
myocardial infarction. The secondary epidemiological aim
is to assess the feasibility of adopting current guidelines in
strategies in people at high cardiovascular risk.
8Cardiology Research and Practice
Figure 3: Possible mechanism of increased cardiovascular (CV) risk from vitamin D deficiency. PTH: parathyroid hormone; RAAS: renin-
a randomized study, which should provide reliable evidence
2 diabetes. It is scheduled to continue until 2017.
The omega-3 fatty acids for the prevention of post-
operative atrial fibrillation (OPERA) is a large, randomized-
controlled trial, which is expected to complete in late 2012.
It investigates the effects of omega-3 PUFAs on the major
public health challenge of atrial fibrillation.
The systematic analysis of the currently available literature
in this paper could not prove a significant benefit of a
general vitamin D or omega-3 FA supplementation for the
treatment and prevention of CVD, as the trial results are
still contradictory in many aspects. In addition, the adequate
dosage of these substances remains unclear.
Several studies indicate that n-3 PUFA consumption
improves vascular and cardiac hemodynamics, triglycerides,
and possibly endothelial function, autonomic control,
inflammation, thrombosis, and arrhythmia. Experimental
studies show relevant effects on membrane structure and
associated functions, ion channel properties, genetic reg-
ulation, and production of anti-inflammatory mediators.
Clinical trials evaluating a possible reduction in CVD by n-3
PUFA have shown different results. Nevertheless, as part of a
healthier dietary pattern including fruits, vegetables, whole
grains, nuts, vegetable oils, and dairy the consumption of
fish would be another reasonable contribution and should
Supplementation of vitamin D is common, regarding the
“traditional” roles of vitamin D with its positive effects on
bone mineral density, for the prevention and treatment of
osteoporosis. Furthermore, the individual risk of vitamin D
deficiency has to be taken into account. “Nontraditional”
roles of vitamin D seem to be malignancies like colorec-
tal cancer, diabetes mellitus, multiple sclerosis, impaired
immune response, and several effects on the cardiovascular
system. In which individuals a supplementation of vitamin
D is reasonable, and in which cases serum hydroxyvitamin D
level should be measured before is still unclear.
Randomized prospective clinical trials are needed to
determine whether vitamin D and omega-3 FA supplemen-
tation therapy could have any potential benefit in reducing
future CVD events and mortality risk, and if it should be
recommended as a routine therapy for primary or secondary
prevention of cardiovascular disease.
Conflict of Interests
All coauthorsstate that they do not have any possible conflict
 I. Mackay, I. Ford, F. Thies, S. Fielding, P. Bachoo, and J.
Brittenden, “Effect of Omega-3 fatty acid supplementation on
Cardiology Research and Practice9
markers of platelet and endothelial function in patients with
peripheral arterial disease,” Atherosclerosis, vol. 221, no. 514,
p. 520, 2012.
 GISSI-Prevenzione Investigators, “Dietary supplementation
with N-3 polyunsaturated fatty acids and vitamin E after
myocardial infarction: results of the GISSI-Prevenzione trial,”
The Lancet, vol. 354, no. 9177, pp. 447–455, 1999.
 S. Reddy Vanga, M. Good, P. A. Howard, and J. L. Vacek, “Role
of vitamin D in cardiovascular health,” American Journal of
Cardiology, vol. 106, no. 6, pp. 798–805, 2010.
 S. Pilz, A. Tomaschitz, E. Ritz, and T. R. Pieber, “Vitamin D
status and arterial hypertension: a systematic review,” Nature
Reviews, Cardiology, vol. 6, no. 10, pp. 621–630, 2009.
 J. N. Artaza, R. Mehrotra, and K. C. Norris, “Vitamin D and
the cardiovascular system,” Clinical Journal of the American
Society of Nephrology, vol. 4, no. 9, pp. 1515–1522, 2009.
 J. H. Lee, J. H. O’Keefe, D. Bell, D. D. Hensrud, and M.
F. Holick, “Vitamin D deficiency. An important, common,
and easily treatable cardiovascular risk factor?” Journal of the
American College of Cardiology, vol. 52, no. 24, pp. 1949–1956,
 A. Levin and Y. C. Li, “Vitamin D and its analogues: do they
protect against cardiovascular disease in patients with kidney
disease?” Kidney International, vol. 68, no. 5, pp. 1973–1981,
 J. R. Wu-Wong, M. Nakane, J. Ma, X. Ruan, and P. E. Kroeger,
“Effects of Vitamin D analogs on gene expression profiling in
human coronary artery smooth muscle cells,” Atherosclerosis,
vol. 186, no. 1, pp. 20–28, 2006.
 D. Mozaffarian and J. H. Y. Wu, “Omega-3 fatty acids
and cardiovascular disease. Effects on risk factors, molecular
pathways, and clinical events,” Journal of the American College
of Cardiology, vol. 58, no. 20, pp. 2047–2067, 2011.
 A. Leaf, J. X. Kang, Y. F. Xiao, and G. E. Billman, “Clinical
prevention of sudden cardiac death by n-3 polyunsaturated
fatty acids and mechanism of prevention of arrhythmias by n-
3 fish oils,” Circulation, vol. 107, no. 21, pp. 2646–2652, 2003.
 D. B. Jump, “N-3 polyunsaturated fatty acid regulation of
19, no. 3, pp. 242–247, 2008.
 Y. Adkins and D. S. Kelley, “Mechanisms underlying the
cardioprotective effects of omega-3 polyunsaturated fatty
acids,” Journal of Nutritional Biochemistry, vol. 21, no. 9, pp.
 D. Rees, E. A. Miles, T. Banerjee et al., “Dose-related effects of
eicosapentaenoic acid on innate immune function in healthy
humans: a comparison of young and older men,” American
Journal of Clinical Nutrition, vol. 83, no. 2, pp. 331–342, 2006.
 I. Vedin, T. Cederholm, Y. Freund-Levi et al., “Reduced
after oral supplementation of ω3 fatty acids: the OmegAD
study,” Journal of Lipid Research, vol. 51, no. 5, pp. 1179–1185,
 C. Arnold, A. Konkel, R. Fischer, and W. H. Schunck, “Cyto-
chrome p450-dependent metabolism of ω-6 and ω-3 long-
chain polyunsaturated fatty acids,” Pharmacological Reports,
vol. 62, no. 3, pp. 536–547, 2010.
S. Harris, “Effects of omega-3 fatty acids on resting heart rate,
heart rate recovery after exercise, and heart rate variability
in men with healed myocardial infarctions and depressed
ejection fractions,” American Journal of Cardiology, vol. 97, no.
8, pp. 1127–1130, 2006.
 B. Villa, L. Calabresi, G. Chiesa, P. Ris` e, C. Galli, and C. R.
Sirtori, “Omega-3 fatty acid ethyl esters increase heart rate
variability in patients with coronary disease,” Pharmacological
Research, vol. 45, no. 6, pp. 475–478, 2002.
 J. H. Christensen, P. Gustenhoff, E. Korup et al., “Effect of
fish oil on heart rate variability in survivors of myocardial
infarction: a double blind randomised controlled trial,”British
Medical Journal, vol. 312, no. 7032, pp. 677–678, 1996.
 J. H. Christensen and E. B. Schmidt, “n-3 fatty acids and the
risk of sudden cardiac death,” Lipids, vol. 36, supplement, pp.
 M. Yokoyama, H. Origasa, M. Matsuzaki et al., “Effects of
eicosapentaenoic acid on major coronary events in hyperc-
holesterolaemic patients (JELIS): a randomised open-label,
blinded endpoint analysis,” The Lancet, vol. 369, no. 9567, pp.
 T. J. Wang, M. G. Larson, D. Levy et al., “Temporal relations
of atrial fibrillation and congestive heart failure and their
joint influence on mortality: the Framingham heart study,”
Circulation, vol. 107, no. 23, pp. 2920–2925, 2003.
 M. C. Heidt, M. Vician, S. K. Stracke et al., “Beneficial
effects of intravenously administered N-3 fatty acids for the
prevention of atrial fibrillation after coronary artery bypass
surgery: a prospective randomized study,” The Thoracic and
Cardiovascular Surgeon, vol. 57, no. 5, pp. 276–280, 2009.
 S. Nodari, M. Triggiani, U. Campia et al., “N-3 polyun-
saturated fatty acids in the prevention of atrial fibrillation
recurrences after electrical cardioversion: a prospective, ran-
domized study,” Circulation, vol. 124, no. 10, pp. 1100–1106,
 B. Rauch, R. Schiele, S. Schneider et al., “OMEGA, a ran-
domized, placebo-controlled trial to test the effect of highly
purified omega-3 fatty acids on top of modern guideline-
adjusted therapy after myocardial infarction,” Circulation, vol.
122, no. 21, pp. 2152–2159, 2010.
 D. Kromhout, E. J. Giltay, and J. M. Geleijnse, “n-3 fatty acids
and cardiovascular events after myocardial infarction,” The
New England Journal of Medicine, vol. 363, no. 21, pp. 2015–
 GISSI-HF investigators, “Effect of rosuvastatin in patients
with chronic heart failure (the GISSI-HF trial): a randomised,
double-blind, placebo-controlled trial,” The Lancet, vol. 372,
no. 9645, pp. 1231–1239, 2008.
lower serum triglycerides?” Current Opinion in Lipidology, vol.
17, no. 4, pp. 387–393, 2006.
 J. M. Geleijnse, E. J. Giltay, D. E. Grobbee, A. R. T. Donders,
and F. J. Kok, “Blood pressure response to fish oil supplemen-
tation: metaregression analysis of randomized trials,” Journal
of Hypertension, vol. 20, no. 8, pp. 1493–1499, 2002.
 D. Mozaffarian, A. Geelen, I. A. Brouwer, J. M. Geleijnse, P.
L. Zock, and M. B. Katan, “Effect of fish oil on heart rate
in humans: a meta-analysis of randomized controlled trials,”
Circulation, vol. 112, no. 13, pp. 1945–1952, 2005.
 D. Kenny, D. C. Warltier, J. A. Pleuss, R. G. Hoffmann, T. L.
Goodfriend, and B. M. Egan, “Effect of omega-3 fatty acids on
the vascular response to angiotensin in normotensive men,”
American Journal of Cardiology, vol. 70, no. 15, pp. 1347–1352,
 P. Nestel, H. Shige, S. Pomeroy, M. Cehun, M. Abbey, and D.
Raederstorff, “The n-3 fatty acids eicosapentaenoic acid and
docosahexaenoic acid increase systemic arterial compliance in
humans,” American Journal of Clinical Nutrition, vol. 76, no. 2,
pp. 326–330, 2002.
10Cardiology Research and Practice
 C. Wang, M. Chung, A. Lichtenstein et al., “Effects of omega-
3 fatty acids on cardiovascular disease,” Evidence Report/
Technology Assessment (Summary), no. 94, pp. 1–8, 2004.
 S. D. Kristensen, A. M. Bach Iversen, and E. B. Schmidt, “n-3
polyunsaturated fatty acids and coronary thrombosis,” Lipids,
vol. 36, supplement, pp. S79–S82, 2001.
 V. Schiano, E. Laurenzano, G. Brevetti et al., “Omega-3
polyunsaturated fatty acid in peripheral arterial disease: effect
on lipid pattern, disease severity, inflammation profile, and
endothelial function,” Clinical Nutrition, vol. 27, no. 2, pp.
 G. E. Peoples, P. L. McLennan, P. R. C. Howe, and H. Groeller,
“Fish oil reduces heart rate and oxygen consumption during
exercise,” Journal of Cardiovascular Pharmacology, vol. 52, no.
6, pp. 540–547, 2008.
 S. Ghio, L. Scelsi, R. Latini et al., “Effects of n-3 polyun-
saturated fatty acids and of rosuvastatin on left ventricular
function in chronic heart failure: a substudy of GISSI-HF
trial,” European Journal of Heart Failure, vol. 12, no. 12, pp.
 S. Nodari, M. Triggiani, U. Campia et al., “Effects of n-3
polyunsaturated fatty acids on left ventricular function and
functional capacity in patients with dilated cardiomyopathy,”
Journal of the American College of Cardiology, vol. 57, no. 7, pp.
 J. Hartweg, R. Perera, V. Montori, S. Dinneen, H. A. Neil,
and A. Farmer, “Omega-3 polyunsaturated fatty acids (PUFA)
for type 2 diabetes mellitus,” Cochrane Database of Systematic
Reviews, no. 1, Article ID CD003205, 2008.
 M. James, S. Proudman, and L. Cleland, “Fish oil and
rheumatoid arthritis: past, present and future,” Proceedings of
the Nutrition Society, vol. 69, no. 3, pp. 316–323, 2010.
 H. Le´ on, M. C. Shibata, S. Sivakumaran, M. Dorgan, T.
and mortality: systematic review,” British Medical Journal, vol.
337, Article ID a2931, 2008.
 D. Weitz, H. Weintraub, E. Fisher, and A. Z. Schwartzbard,
“Fish oil for the treatment of cardiovascular disease,” Cardi-
ology in Review, vol. 18, no. 5, pp. 258–263, 2010.
 A. H. Lichtenstein, “Remarks on clinical data concerning
dietary supplements that affect antithrombotic therapy,”
Thrombosis Research, vol. 117, no. 1-2, pp. 71–73, 2005.
 W. S. Harris, “Expert opinion: omega-3 fatty acids and
bleeding-cause for concern?” American Journal of Cardiology,
vol. 99, no. 6, supplement 1, pp. S44–S46, 2007.
 A. H. Lichtenstein, L. J. Appel, M. Brands et al., “Diet and
from the American heart association nutrition committee,”
Circulation, vol. 114, no. 1, pp. 82–96, 2006.
 D. M. Lloyd-Jones, Y. Hong, D. Labarthe et al., “Defining and
disease reduction: the American heart association’s strategic
impact goal through 2020 and beyond,” Circulation, vol. 121,
no. 4, pp. 586–613, 2010.
 U.S. Department of Agriculture and U.S. Department of
2010, U.S. Government Printing Office, Washington, DC,
USA, 7th edition, 2010.
of Medicine, vol. 357, pp. 266–281, 2007.
 Y. C. Li, J. Kong, M. Wei, Z. F. Chen, S. Q. Liu, and L.
P. Cao, “1,25-Dihydroxyvitamin D3 is a negative endocrine
regulator of the renin-angiotensin system,” Journal of Clinical
Investigation, vol. 110, no. 2, pp. 229–238, 2002.
 R. Agarwal, M. Acharya, J. Tian et al., “Antiproteinuric
effect of oral paricalcitol in chronic kidney disease,” Kidney
International, vol. 68, no. 6, pp. 2823–2828, 2005.
 D. Duprez, M. de Buyzere, T. de Backer, and D. Clement,
“Relationship between vitamin D3 and the peripheral cir-
culation in moderate arterial primary hypertension,” Blood
Pressure, vol. 3, no. 6, pp. 389–393, 1994.
 E. Kristal-Boneh, P. Froom, G. Harari, and J. Ribak, “Associ-
ation of calcitriol and blood pressure in normotensive men,”
Hypertension, vol. 30, no. 5, pp. 1289–1294, 1997.
 R. Scragg, I. Holdaway, V. Singh, P. Metcalf, J. Baker, and E.
Dryson, “Serum 25-hydroxycholecalciferol concentration in
newly detected hypertension,” American Journal of Hyperten-
sion, vol. 8, no. 4, part 1, pp. 429–432, 1995.
 M. L. Melamed, P. Muntner, E. D. Michos et al., “Serum
25-hydroxyvitamin D levels and the prevalence of peripheral
arterial disease results from NHANES 2001 to 2004,” Arte-
 G. Targher, L. Bertolini, R. Padovani et al., “Serum 25-
hydroxyvitamin D3 concentrations and carotid artery intima-
media thickness among type 2 diabetic patients,” Clinical
Endocrinology, vol. 65, no. 5, pp. 593–597, 2006.
 E. Giovannucci, Y. Liu, B. W. Hollis, and E. B. Rimm, “25-
Hydroxyvitamin D and risk of myocardial infarction in men: a
prospective study,” Archives of Internal Medicine, vol. 168, no.
11, pp. 1174–1180, 2008.
 T. J. Wang, M. J. Pencina, S. L. Booth et al., “Vitamin D
deficiency and risk of cardiovascular disease,” Circulation, vol.
117, no. 4, pp. 503–511, 2008.
 E. Shane, D. Mancini, K. Aaronson et al., “Bone mass, vitamin
D deficiency, and hyperparathyroidism in congestive heart
failure,” American Journal of Medicine, vol. 103, no. 3, pp. 197–
 H. Bahrami, R. Kronmal, D. A. Bluemke et al., “Differences
in the incidence of congestive heart failure by ethnicity: the
multi-ethnic study of atherosclerosis,” Archives of Internal
Medicine, vol. 168, no. 19, pp. 2138–2145, 2008.
 S. S. Coughlin, L. Myers, and R. K. Michaels, “What explains
black-white differences in survival in idiopathic dilated car-
diomyopathy? The Washington, DC, dilated cardiomyopathy
study,” Journal of the National Medical Association, vol. 89, no.
4, pp. 277–282, 1997.
 V. Vaccarino, E. Gahbauer, S. V. Kasl, P. A. Charpentier,
D. Acampora, and H. M. Krumholz, “Differences between
African Americans and whites in the outcome of heart
failure: evidence for a greater functional decline in African
Americans,” American Heart Journal, vol. 143, no. 6, pp. 1058–
 M. E. Reusser, D. B. DiRienzo, G. D. Miller, and D. A.
McCarron, “Adequate nutrient intake can reduce cardiovascu-
lar disease risk in African Americans,” Journal of the National
Medical Association, vol. 95, no. 3, pp. 188–195, 2003.
 S. Pilz, H. Dobnig, G. Nijpels et al., “Vitamin D and mortality
in older men and women,” Clinical Endocrinology, vol. 71, no.
5, pp. 666–672, 2009.
 R. D. Semba, D. K. Houston, L. Ferrucci et al., “Low serum 25-
hydroxyvitamin D concentrations are associated with greater
all-cause mortality in older community-dwelling women,”
Nutrition Research, vol. 29, no. 8, pp. 525–530, 2009.
 P. Szulc, B. Claustrat, and P. D. Delmas, “Serum concentra-
tions of 17β-E2 and 25-hydroxycholecalciferol (25OHD) in
Cardiology Research and Practice11 Download full-text
relation to all-cause mortality in older men—the MINOS
study,” Clinical Endocrinology, vol. 71, no. 4, pp. 594–602,
 P. Autier and S. Gandini, “Vitamin D supplementation and
total mortality: a meta-analysis of randomized controlled
 H. A. Bischoff-Ferrari, E. Giovannucci, W. C. Willett, T.
Dietrich, and B. Dawson-Hughes, “Estimation of optimal
serum concentrations of 25-hydroxyvitamin D for multiple
health outcomes,” American Journal of Clinical Nutrition, vol.
84, no. 1, pp. 18–28, 2006.
 Food and Nutrition Board, Dietary supplement fact sheet:
vitamin D, http://ods.od.nih.gov/.
 J. E. Manson, S. S. Bassuk, I. M. Lee et al., “The VITamin D
and OmegA-3 TriaL (VITAL): rationale and design of a large
randomized controlled trial of vitamin D and marine omega-
3 fatty acid supplements for the primary prevention of cancer
and cardiovascular disease,” Contemporary Clinical Trials, vol.
33, no. 1, pp. 159–171, 2012.