Is the ratio of serum eicosapentaenoic acid (EPA) to arachidonic acid (AA) associated with the risk of cardiovascular disease?
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 ratio. Ninomiya 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.

Atherosclerosis. 2013 Dec;231(2):261-7. doi:10.1016/j.atherosclerosis.2013.09.023. Epub 2013 Oct 5.
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: nino@intmed2.med.kyushu-u.ac.jp.

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 (p for
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 disease,
among subjects with higher HS-CRP levels in the general Japanese population.



Is a low ratio of eicosapentaenoic acid and arachidonic acid (EPA/AA) ratio associated with higher vulnerability of plaques to rupture?
The 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 rupture.

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., unpublished).
 
Heart Vessels. 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, takao0321@aol.com.


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 participant. In the JUPITER 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. 

Circulation. 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, Nicholls SJ.
Cleveland Clinic, Cleveland, OH.


Are omega-3 polyunsaturated fatty acids associated with inflammatory biomarkers in patients with peripheral artery disease?
The presence 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.
 
It 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.

 It 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 atherosclerosis.

J Vasc 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
CD.
Department of Surgery, University of California, San Francisco, San Francisco, Calif; Department of Surgery, Veterans Affairs Medical Center, San Francisco,
Calif. Electronic address: marlene.grenon@ucsfmedctr.org.


Lipoprotein-associated phospholipase A2 (Lp-PLA2) and highly unsaturated fatty acids (HUFA): inversely correlated?
Lipoprotein-associated 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. In 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 (HUFA deficiency).

Br 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, Tsai MY.
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.

Circ 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 Statin Therapy.
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 Sciences.


Do omega-3 fatty acids reduce the risk of sudden cardiac death in dialysis patients?
Sudden 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 direct association:

Am J 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.
Friedman 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, Ind., USA.


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. nozue2493@yahoo.co.jp

Do 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. 

Eur 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:

Diabetes. 2013;62:1709-17
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:
Arterioscler Thromb Vasc Biol. 2013 May 16. [Epub ahead of print]
Mechanisms of Coronary Thrombosis in Cigarette Smoke Exposure.
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: 10.1016/j.jacc.2013.03.072.
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:
Curr Atheroscler Rep. 2013 Jun;15(6):327. doi: 10.1007/s11883-013-0327-7.
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 infarction:
Heart 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, Virmani R.
CVPath Institute, Inc., 19 Firstfield Road, Gaithersburg, MD 20878, USA.


22.12.2013 (HR)