have been identified as "public health enemy no. 1" by the
World Health Organization.
Cardiovascular diseases kill more people than any other
The search for reliable preventive methods should be
sudden death requires a better understanding
of the transition from plaque to arrhythmias.
Weekly overview on new findings and reviews.
Is the ratio
of serum eicosapentaenoic acid (EPA) to
arachidonic acid (AA) associated with the risk of
Are benefits of omega-3 fatty on
cardiovascular parameters related to the level of C-reactive
protein (CRP)? When CRP binds to phosphocholine
expressed on the surface of dying or dead cells and
some bacteria, the complement system is activated
and the phagocytosis by macrophages
is enhanced. CRP is, therefore, involved in the
clearance of apoptotic and necrotic cells. Since the
highly unsaturated omega-3 fatty acids (HUFA) EPA
and DHA have anti-inflammatory effects, the question
arises whether links exist between CRP and
cardiovascular benefits of omega-3 HUFA. Ninomiya
et al.examined the association between the
ratio of serum EPA to arachidonic acid (EPA/AA) or
docosahexaenoic acid (DHA)/AA and the development of
cardiovascular disease. 3103 Japanese individuals
aged ≥40 years were followed up for 5.1 years.
Incidence rates of cardiovascular disease increased
with lower serum EPA/AA ratios in persons with
high-sensitivity C-reactive protein (HS-CRP) of ≥1.0
mg/L, whereas no clear association was observed in
those with HS-CRP of <1.0 mg/L. Risk of
cardiovascular disease increased by 1.52 times per
0.20 decrement in serum EPA/AA ratio in subjects
with HS-CRP of ≥1.0 mg/L. A lower serum EPA/AA ratio
was associated with an increased risk of coronary
heart disease. It was intriguing that there was no
evidence of an association with stroke. The
influence of serum EPA/AA ratio on cardiovascular
risk increased with elevating HS-CRP levels.
However, no such association was observed for DHA/AA
et al.concluded that their
findings suggest that a lower serum
EPA/AA ratio is associated with a
greater risk of cardiovascular disease,
especially coronary heart disease in
subjects with higher HS-CRP levels.
doi:10.1016/j.atherosclerosis.2013.09.023. Epub 2013 Oct
Association between ratio of serum eicosapentaenoic acid
to arachidonic acid and risk of cardiovascular disease:
The Hisayama Study.
Ninomiya T, Nagata M, Hata J, Hirakawa Y, Ozawa M,
Yoshida D, Ohara T, Kishimoto H, Mukai N, Fukuhara M,
Kitazono T, Kiyohara Y.
Department of Medicine and Clinical Science, Graduate
School of Medical Sciences, Kyushu University, Fukuoka,
Japan; Department of Environmental Medicine, Graduate
School of Medical Sciences, Kyushu University, Fukuoka,
Japan. Electronic address:
OBJECTIVE: We examined the association between the ratio
of serum eicosapentaenoic acid to arachidonic acid
(EPA/AA) or the docosahexaenoic acid
(DHA)/AA and the development of cardiovascular disease
in a general Japanese population.
METHODS: A total of 3103 community-dwelling Japanese
individuals aged ≥40 years were followed up for an
average of 5.1 years. Serum EPA/AA ratios were
categorized into quartiles. The risk estimates were
computed using a Cox proportional hazards model.
RESULTS: During the follow-up period, 127 subjects
experienced cardiovascular events. Age- and sex-adjusted
incidence rates of cardiovascular disease increased
with lower serum EPA/AA ratios in individuals with
high-sensitivity C-reactive protein (HS-CRP) of ≥1.0
mg/L (p for trend = 0.006), whereas no clear association
was observed in those with HS-CRP of <1.0 mg/L (p for
trend = 0.27). The multivariable-adjusted risk of
cardiovascular disease increased significantly, by
1.52 times (95% confidence interval 1.12-2.04) per 0.20
decrement in serum EPA/AA ratio in subjects with HS-CRP
of ≥1.0 mg/L. A lower serum EPA/AA ratio was
significantly associated with an increased risk of
coronary heart disease, but there was no evidence of an
association with stroke. The magnitude of the
influence of the serum EPA/AA ratio on the
cardiovascular risk increased significantly with
elevating HS-CRP levels taken as a continuous variable
heterogeneity = 0.007). However, no such association was
observed for DHA/AA ratio.
CONCLUSION: Our findings suggest that a lower serum
EPA/AA ratio is associated with a greater risk of
cardiovascular disease, especially coronary heart
among subjects with higher HS-CRP levels in the general
Is a low ratio of eicosapentaenoic acid and
arachidonic acid (EPA/AA) ratio associated with
higher vulnerability of plaques to rupture?
identification of risks associated with sudden cardiac death
remains a major challenge. In previous studies (e.g. Risk
stratification by the “EPA+DHA level” and the “EPA/AA ratio") we
addressed the question whether parameters can be established
which not only describe an increased risk of an enhanced
electrical instability of the heart but also of inflammatory
events underlying plaque rupture. Also in view of the JELIS
trial and the pioneering studies of Calder et
al. on plaque stabilization by EPA, it is of great
interest to assess links between the ratio of EPA and
arachidonic acid (EPA/AA) and the vulnerability of coronary
plaques. In the study of Hasegawa
et al., patients with stable angina pectoris undergoing
percutaneous coronary intervention were examined. Optical
coherence tomography (OCT) image acquisition was performed
before the procedure in the culprit lesions. The patients were
divided into two groups, i.e. a low-EPA/AA group (EPA/AA
<0.36) and a high-EPA/AA group (EPA/AA ≥0.36). In the
low-EPA/AA group, the following parameters had a significantly
greater frequency: thin-cap fibroatheroma (TCFA) (35.4 vs 6.9
%), macrophage infiltration (48.3 vs 13.8 %) and microvessels
(44.8 vs 10.3 %). The low-EPA/AA group had wider maximum lipid
arc (114.0 ± 94.8° vs 56.4 ± 66.0°), longer lipid length (4.8
± 4.5 vs 1.6 ± 2.6 mm), and thinner fibrous cap (69.3 ± 28.3
vs 113.3 ± 46.6 μm) compared with the high-EPA/AA group. The
EPA/AA ratio was positively correlated with fibrous cap
thickness. In a multivariate model, an EPA/AA ratio <0.36
was associated with the presence of thin-cap fibroatheroma. Hasegawa
et al. concluded that a lower EPA/AA ratio was
associated with higher vulnerability of coronary plaques to
In ongoing studies we examine in patients with left
ventricular (LV) dysfunction consequences of
reduced levels of highly unsaturated fatty acids including
EPA, DHA and arachidonic (HUFA
deficiency) for plaque vulnerability (Rupp et al.,
2013 Sep 5. [Epub ahead of print]
Serum n-3 to n-6 polyunsaturated fatty acids ratio
correlates with coronary plaque vulnerability: an optical
coherence tomography study.
Hasegawa T, Otsuka K, Iguchi T, Matsumoto K, Ehara S, Nakata
S, Nishimura S, Kataoka T, Shimada K, Yoshiyama M.
Department of Cardiovascular Medicine, Graduate School of
Medicine, Osaka City University, 1-4-3 Asahi-machi,
Abeno-ku, Osaka, 545-8585, Japan, firstname.lastname@example.org.
Residual cardiovascular risk in
intensive statin therapy: is inflammation as assessed by
C-reactive protein (CRP) involved?
CRP is a general marker
for infection and inflammation. Although statins
have been shown to reduce levels of CRP,
it remains unclear whether CRP is a bystander or active
trial involving apparently healthy persons without
hyperlipidemia but with elevated high-sensitivity
C-reactive protein levels, rosuvastatin reduced not
only LDL cholesterol and CRP levels but also the
incidence of major cardiovascular events. For the SATURN
trial, it was reported by Puri
et al. that a non-increasing CRP level was
independently associated with greater regression of the
atheroma volume. While the change in CRP did not
associate with major adverse cardiovascular events
(MACE: death, myocardial infarction, stroke, coronary
revascularization and hospitalization for unstable
angina), the on-treatment CRP associated significantly
with MACE. Thus, despite
aggressive statin therapy, inflammation
may be an important driver of residual cardiovascular
risk in patients with coronary artery disease.
2013 Sep 16. [Epub ahead of print]
C-Reactive Protein, but not Low-Density Lipoprotein
Cholesterol Levels, Associate with Coronary Atheroma
Regression and Cardiovascular Events Following Maximally
Intensive Statin Therapy.
Puri R, Nissen SE, Libby P, Shao M, Ballantyne CM, Barter
PJ, Chapman MJ, Erbel R, Raichlen JS, Uno K, Kataoka Y,
Cleveland Clinic, Cleveland, OH.
omega-3 polyunsaturated fatty acids
associated with inflammatory biomarkers
in patients with peripheral artery
of peripheral artery disease (PAD) is a powerful
and independent predictor of cardiac and cerebral
ischemic events, whereby the cardiovascular risk
is linked to the underlying atherosclerotic
disease. Increased levels of inflammatory markers
in PAD are associated with
the development of PAD, cardiovascular
comorbidity, and risk of future cardiac and
cerebral ischemic events.
is in this context an important finding by Grenon et
al. that in patients with PAD, the sum of EPA and
DHA in red blood cells (omega-3 index) was
negatively associated with CRP (38% increase in CRP
for one standard deviation decrease in the omega-3
index). There was also an independent association
with IL-6. It was concluded that further studies
should be conducted in patients with PAD who have a
high inflammatory burden. It was suggested to
determine if manipulation of omega-3 index via
dietary changes or fish oil supplementation could
improve inflammation and symptoms in these patients.
should be noted in this respect that
progression of heart failure is
associated with reduced levels of highly
unsaturated fatty acids (HUFA) including
EPA and DHA (HUFA deficiency). Work
is in progress to determine consequences
for the inflammatory state and
atherosclerosis. In case of an
administration of omega-3 fatty acids, it
will be examined to what extent the
presence of oxidized
products of EPA and DHA in certain
dietary fish oils have adverse
consequences particularly for
Surg. 2013 Jul 2. pii: S0741-5214(13)00965-8.
doi:10.1016/j.jvs.2013.05.024. [Epub ahead of print]
Association between n-3 polyunsaturated fatty acid content
of red blood cells and inflammatory biomarkers in patients
with peripheral artery disease.
Grenon SM, Conte MS, Nosova E, Alley H, Chong K, Harris
WS, Vittinghoff E, Owens
Department of Surgery, University of California, San
Francisco, San Francisco, Calif; Department of Surgery,
Veterans Affairs Medical Center, San Francisco,
Calif. Electronic address: email@example.com.
Lipoprotein-associated phospholipase A2 (Lp-PLA2)
and highly unsaturated fatty acids (HUFA):
phospholipase A2 (Lp-PLA2) travels in the blood mainly
together with low-density lipoprotein (LDL). It is an
enzyme produced also by plaque inflammatory cells and is
involved in the development of atherosclerosis. Lp-PLA2
levels were positively correlated with increased risk
of coronary heart disease and stroke.
the study of Steffen et al., important links between
Lp-PLA2 and polyunsaturated fatty acids have been
identified. Persons with the highest quintiles of plasma
EPA and DHA exhibited lower Lp-PLA2 mass and activity.
It is noteworthy that lower Lp-PLA2 was also associated
with higher levels of n-6 arachidonic acid. EPA,
DHA and arachidonic acids are highly usaturated
fatty acids (HUFA) that have been found to be
reduced during progression of dilative heart failure
J Nutr. 2013 Apr 3:1-8.
n-3 and n-6 Fatty acids are independently associated
with lipoprotein-associated phospholipase A2 in the
Multi-Ethnic Study of Atherosclerosis.
Steffen BT, Steffen LM, Liang S, Tracy R, Jenny NS,
Department of Laboratory Medicine and Pathology,
University of Minnesota, 420 Delaware Street, SE,
Mayo Mail Code 609, Minneapolis, MN 55455-0392, USA.
Residual risk of statin-treated patients: an
important target for the omega-3 fatty acid EPA?
It remains a great
challenge to identify interventions that reduce the
markedly increased risk of statin-treated patients with
dyslipidemia, often referred to "residual risk". In view
of the increasing evidence that omega-3 fatty acids
interfere by various mechanisms with plaque instability
or even atherosclerosis progression, the study of Urabe
et al. deserves particular attention: In statin-treated
patients, the low-EPA group showed higher incidences of
3-vessel plaque involvement (62% vs. 43%), noncalcified
plaques (NCPs) (74% vs. 52%), extensive NCPs (≥2
segments) (56% vs. 34%), and high-risk plaques. Low EPA
levels were an independent factor for these coronary
plaque findings. The DHA levels were apparently not
associated with these findings. It was concluded that
low serum EPA level is associated with the presence and
extent of NCPs and high-risk plaques detected by
coronary CTA in patients undergoing lipid-lowering
therapy with statins.
J. 2013 Jul 18. [Epub ahead of print]
Association Between Serum Levels of n-3 Polyunsaturated
Fatty Acids and Coronary Plaque Detected by Coronary
Computed Tomography Angiography in Patients Receiving
Urabe Y, Yamamoto H, Kitagawa T, Utsunomiya H, Tsushima
H, Tatsugami F, Awai K, Kihara Y.
Department of Cardiovascular Medicine, Hiroshima
University Graduate School of Biomedical and Health
Do omega-3 fatty acids reduce the risk of sudden cardiac
death in dialysis patients?
cardiac death accounts for the majority of deaths in
dialysis patients, whereby the frequency of
cardiac arrest increases with time on dialysis. Also in uremic patients,
coronary disease is a major risk for sudden death.
It is, therefore, an important observation by Friedman
et al. that the serum omega-3 fatty acid
docosapentaenoic acid was inversely associated with the
odds of sudden death during year one of hemodialysis. By
contrast, the level of saturated fatty acids had a
Nephrol. 2013 Jun 25;38(1):12-18. [Epub ahead of print]
Fatty Acids and Other Risk Factors for Sudden Cardiac
Death in Patients Starting Hemodialysis.
AN, Yu Z, Denski C, Tamez H, Wenger J, Thadhani R, Li
Y, Watkins B.
Department of Medicine, Division of Nephrology,
Indiana University School of Medicine, Indianapolis,
Are reduced omega-3 fatty acids associated with
progression of coronary atherosclerosis?
Omega-3 fatty acids (EPA and DHA) have various
favourable effects on markers associated with
atherosclerosis. Although some of the underlying mechanisms
remain unresolved, a decrease in the ratio of omega-3 to
omega-6 fatty acids was found to be linked with progression
of atherosclerosis in coronary artery disease patients.
Furthermore, the change in the fibrous component volume of
plaques was inversely correlated with the change in
EPA+DHA/arachidonic acid ratio.
Am J Cardiol. 2013;111:6-11.
Effects of serum n-3 to n-6 polyunsaturated fatty acids ratios on coronary atherosclerosis in statin-treated patients with coronary artery disease.
Nozue T, Yamamoto S, Tohyama S, Fukui K, Umezawa S, Onishi Y, Kunishima T, Sato A, Nozato T, Miyake S, Takeyama Y, Morino Y, Yamauchi T, Muramatsu T, Hibi K,
Terashima M, Michishita I.
Division of Cardiology, Department of Internal Medicine, Yokohama Sakae Kyosai Hospital, Yokohama, Japan. firstname.lastname@example.org
mast cells in plaques predict cardiovascular events?
What contributes to plaque vulnerability?
Microvessels at the base of a plaque can promote plaque
hemorrhage and favor plaque rupture. It is shown by Willems
et al. that microvessel
density in atherosclerotic lesions of the carotid artery
are associated with mast cells which are highly prevalent
and associated with future cardiovascular events.
Heart J. 2013 Jun 11. [Epub ahead of print]
Mast cells in human carotid atherosclerotic plaques are
associated with intraplaque microvessel density and the
occurrence of future cardiovascular events.
Willems S, Vink A, Bot I, Quax PH, de Borst GJ, de Vries
JP, van de Weg SM, Moll FL, Kuiper J, Kovanen PT, de
Kleijn DP, Hoefer IE, Pasterkamp G.
Experimental Cardiology Laboratory (room G02.523),
University Medical Centre Utrecht, Heidelberglaan 100,
3584 CX, Utrecht, the Netherlands.
MCP-1 reduced by omega-3 fatty acids?
In a focused view, the accumulation of macrophages in the
wall of arteries is associated with the development of
"soft" or vulnerable plaques. Acute rupture of the plaque
results in blood clotting and myocardial infarction. A key
role has the monocyte-chemoattractant protein (MCP)-1 on
endothelial cells which triggers the infiltration
and activation of macrophages. In the study of Spencer
et al. it is shown that in nondiabetic insulin-resistant
persons omega-3-acid ethyl esters (4 g
daily) decrease MCP-1 in adipose tissue macrophages, whereby
the greatest response was observed in those with the most
macrophages. Furthermore, omega-3 fatty acids suppressed the
upregulation of adipocyte MCP-1 that occurred when
adipocytes were cocultured with macrophages:
Omega-3 fatty acids reduce adipose tissue macrophages in
human subjects with insulin resistance.
Spencer M, Finlin BS, Unal R, Zhu B, Morris AJ, Shipp LR,
Lee J, Walton RG, Adu A, Erfani R, Campbell M, McGehee RE
Jr, Peterson CA, Kern PA.
Department of Medicine, Division of Endocrinology, and
Barnstable Brown Diabetes and Obesity Center, University
of Kentucky, Lexington, Kentucky.
Smoking and plaque rupture?
Cigarette smoking is known to increase the risk of plaque
rupture resulting in myocardial infarction and sudden death as
the worst outcome. While the body has mechanisms to stop
bleeding in case of acute injury, the vital balance between
thrombus formation and fibrinolysis can be disturbed. An
imbalance favoring blood coagulation exists in smokers.
Various mechanisms involving endothelial cells, platelets,
coagulation factors and fibrinogen contribute to this
pathological pro-thrombotic state. This is why public smoking
bans were associated with reduced thrombotic cardiovascular
events. The pathophysiological rationale is provided in the
overview by Barua and Ambrose:
Thromb Vasc Biol. 2013 May 16. [Epub ahead of print]
Mechanisms of Coronary Thrombosis in Cigarette Smoke
Barua RS, Ambrose JA.
Department of Medicine, Division of Cardiology, University
of Kansas School of Medicine, KS
and Division of Cardiology, Kansas City Veterans Affairs
Medical Center, MO (R.S.B.).
Prediction of high risk of plaque rupture?
Plaque rupture is a devastating event leading to myocardial
infarction and greatly increased risk of sudden death. How can
we identify patients predisposed to plaque rupture? Clearly,
risk markers are required beyond parameters associated with
stable coronary artery disease. Eapen et al. show that an
aggregate score comprising 3 biomarkers involving
inflammation, cellular stress and fibrin degradation provides
a sensitive and independent predictor of future risk of death
and myocardial infarction:
J Am Coll
Cardiol. 2013 May 8. pii: S0735-1097(13)01796-8. doi:
Aggregate Risk Score Based on Markers of Inflammation, Cell
Stress, and Coagulation is an Independent Predictor of
Adverse Cardiovascular Outcomes.
Eapen DJ, Manocha P, Patel RS, Hammadah M, Veledar E, Wassel
C, Nanjundappa RA, Sikora S, Malayter D, Wilson PW, Sperling
L, Quyyumi AA, Epstein SE.
Emory University School of Medicine, Department of Medicine,
Division of Cardiology. Atlanta, GA.
Stem cells - involved in plaque rupture?
It remains greatly unresolved whether reinfarction in patients
post myocardial infarction is simply a consequence of a
prevailing plaque instability or whether factors derived from
the MI promote plaque instability and, therefore, increase the
risk of reinfarction. In the review of Baruch et al. novel
therapeutic approaches are summarized which target the risk of
reinfarction. In particular, he points out that immune
modulation to target the production and release of
hematopoietic stem cells, their differentiation to
inflammatory monocytes and their ingress into plaque represent
new therapeutic approaches:
Atheroscler Rep. 2013 Jun;15(6):327. doi:
Anti-inflammatory strategies for plaque stabilization
after acute coronary syndromes. Baruch A, van Bruggen N,
Kim JB, Lehrer-Graiwer JE.
Genentech Research and Early Development, 1 DNA Way MS
453a, South San Francisco, CA, 94080, USA.
From stable to unstable plaque?
In the seminal paper by Sakakura et al., the transition from a
stable to an unstable plaque is described. We know from
ancient mummies that stable plaques are not simply a
consequence of our industrial lifestyle. What is crucial is
the destabilization of the plaque leading to rupture and
Lung Circ. 2013 Mar 28. pii: S1443-9506(13)00071-1. doi: 10.1016/j.hlc.2013.03.001. [Epub
ahead of print]
Pathophysiology of Atherosclerosis Plaque Progression.
Sakakura K, Nakano M, Otsuka F, Ladich E, Kolodgie FD,
CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg,
MD 20878, USA.