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Clinical Nutrition for prevention and
treatment of cardiovascular disease
Sophie Tully
BSc MSc DIPPT
Diet and lifestyle issues are closely associated with a
myriad of cardiovascular disease risk factors,
including abnormal plasma lipids, hypertension,
insulin resistance, diabetes and obesity, suggesting
that diet-based approaches may be of benefit
Omega-3 fatty acids and cardiovascular health
1950’s
• Observational reports of relatively low incidence of coronary disease in the
Greenland Inuit (Ehrstrom 1951)
1970’s work by Bang & Dyerberg
• Consumption of a large amount of fish or marine mammals rich in omega-3
fatty acids (specifically EPA) contributes to the low incidence of
cardiovascular disease (CVD) among the Greenland Eskimos
• Blood cholesterol, triglycerides, low density and very low density
lipoprotein shown to be lower in the Greenland Inuit than in Danish
controls
• Blood polyunsaturated fatty acids were predominantly omega-3 in the Inuits
and omega-6 in the Danes, yet serum lipid patterns of Inuits living in
Denmark (migrants) were similar to that of Danes - suggesting a dietary link
Inuit Dane
Percent of total calories from fat 39% 42%
Percent of total fatty acids
Saturated 23% 53%
Monounsaturated 58% 34%
Polyunsaturated 19% 13%
Polyunsaturated : Saturated (P : S) ratio 0.84 0.24
Grams per day
Omega-3 fatty acids 14g 3g
Omega-6 fatty acids 5g 10g
Cholesterol 0.70g 0.42g
Based on daily energy intake of approximately 3,000 kcal.
Comparing fatty acid composition of fishing and
farming population (Japan)
Farming Fishing
Daily fish intake (g) 90 250
Of which EPA (g) 0.9 2.5
AA to EPA ratio 2.5 1.7
RBC 0mega-3 (%) 6.8 10.9
Average AA to EPA ratio
Inuit 0.14
Japanese 2.0
European 10.0
American 16.6
Hirai et al., 1980
Rose & Holub 2006
• 13 cohorts from 11 independent prospective studies comprising 222,364
participants (3032 CHD deaths) with an average of 11.8 years of follow-up
• Fish consumption inversely associated with fatal CHD
• Eating fish once per week might significantly reduce death from CHD by 15%
• A dose-response relation was evident between fish consumption and risk of CHD
mortality
• An increment of 20 g/d of fish intake could possibly lower CHD mortality rates by 7%
• The inverse association was more apparent among studies with a follow-up period
of 12 years or longer (He et al., 2004)
Accumulated Evidence on Fish Consumption and Coronary Heart Disease Mortality: A
Meta-Analysis of Cohort Studies
Applied nutrition for cardiovascular health
Physicians health study (Albert et al., 2002)
• Prospective, nested case-control analysis among apparently healthy men who
were followed for up to 17 years in the Physicians' Health Study
• The fatty-acid status of 94 men in whom sudden death occurred as the first
manifestation of cardiovascular disease and for 184 controls matched with
them for age and smoking status
• After adjustments, there was a 90% reduced risk of sudden death among men
with levels of EPA and DHA (total omega-3) in the highest quartile as compared
with the lowest quartile
3.58% 4.76% 5.63% 6.87%
100%
48%
81%
90%
90% reduced risk (RR)
RelativeRisk(RR)
EPA + DHA
Risk of sudden cardiac death and omega-3 blood levels
Source: Albert et al., 2002
• Should be interpreted with caution
• Fish intake may be a surrogate for some other healthy lifestyle factors
• Individuals with higher fish consumption tended to exercise more, smoke
less, and less likely to be overweight
• Studies in this meta-analysis were well designed and adjusted for major
dietary and non-dietary lifestyle variables
• Possibility observed inverse association between fish intake and CVD in
part explained by undefined healthy lifestyle factors can not be ruled out
Observational studies
Establishing a causal relationship: randomised, placebo-
controlled trials
Diet and Reinfarction Trial (the DART Study)
• 2,033 male patients with myocardial infarction
• 2-year intervention
• group consuming 2 servings per week of fish had a 29% reduced all-cause
mortality and 16% reduced risk of ischaemic heart events (Burr et al., 1989)
GISSI-Prevenzione Trial (Marchioli et al., 2002)
• 11,323 patients with recent MI - fish oil supplementation (1 g/d) significantly
reduced cardiac death by 32% and sudden death by 45% during 3.5 years of follow
up
The Japan eicosapentaenoic acid (EPA) Lipid Intervention Study (JELIS)
• 18,645 Japanese men and women with hypercholesterolaemia receiving statins,
• fish oil supplementation (EPA 1.8 g/d) significantly reduced major coronary events
by 19% during 4.6 years of follow-up
(Yokoyama et al., 2007)
Omega-3 recommendations
• American Heart Association recommends everyone eat two
servings (100 g/4 oz per serving) oily fish per week
• Those with coronary heart disease eat 1 g/d of EPA plus DHA from
oily fish or supplements
• The UK Food Standards Agency recommends servings of fish per
week (one white, one oily) to deliver 450mg omega-3/day
- Actual intake 244mg/day
- <50mg for non-fish/meat eaters
Using omega-3s as biomarkers of
cardiovascular health
The omega-3 index
• The omega-3 index = content of EPA and DHA in the cell membrane of RBCs,
expressed as a percentage of total fatty acids
• Reflects tissue fatty acid composition
• Correlates highly with the EPA+DHA content in plasma and whole blood, but is
better correlated to long-term fatty acid intake and thus a suitable biomarker
for the nutritional status
• RBC EPA+DHA also correlates to EPA and DHA content of cardiac muscle
• Half-life of EPA+DHA in RBCs is 4–6 times longer than in serum, with
concentrations returning to baseline 16 weeks after supplementation
(Harris & Von Schacky, 2004)
The omega-3 index: a dose response
Harris & Von Schacky, 2004
Omega-3index(%)
0.0g 0.5g 1.0g 2.0g
Omega-3 dose (12 weeks)
0 % 4% 8%
Omega-3 index - biomarker of cardiovascular health
Desirable
Optimal
Undesirable
Harris & Von Schacky, 2004
• EPA+DHA needed to achieve a target omega-3 index is poorly defined, as are
the determinants of the omega-3 index in response to a change in EPA+DHA
intake
• A randomised, placebo-controlled, double-blind, parallel-group study (n=115)
• One of 5 doses (0, 300, 600, 900, 1800 mg) of EPA+DHA was given daily as
placebo or fish oil supplements for 5 months
• Aim: to develop a predictive model of the omega-3 index in response to
EPA+DHA supplementation and identify factors that determine the response
Flock et al., 2013
RBC omega‐3 fatty acid content in response to fish oil
supplementation: A dose–response randomised controlled trial
• The omega-3 index after supplementation was largely determined by the dose of
EPA+DHA administered
• Baseline omega-3 index and percent DHA in RBCs also independently predicted
the change in omega-3 index
• Individuals with a low baseline omega-3 index status experienced greater rise in
omega-3
• The dose of EPA+DHA, adjusted per unit body weight (g/kg), also was a strong
predictor of change in omega-3 index
• Increasing the dose (g/kg/BW) resulted in greater omega-3 index response
Applied nutrition for cardiovascular health
• Variability was influenced by baseline omega-3 index, age, sex and physical
activity
• Lower baseline omega-3 index and older age each predicted greater
increases in omega-3 index
• Increased physical activity level was associated with a higher omega-3 index
• Female subjects had a non-significant increase in omega-3 compared to
males
• However, body weight was the greatest influencer
• Using the body‐weight‐adjusted values to increase the omega-3
index from 4.3% to 8% (change of 3.7% = 0.016mg/kg EPA+ DHA)
An individual weighing:
95 kg requires 1.5 g omega-3/day
75 kg requires 1.2 g omega-3/day
55 kg requires 0.9 g omega-3/day
• Igennus is the only independent manufacturer
of specialist Fatty Acid in the UK. Based in
Cambridge the medical innovation hub for the
UK:
- Seven Seas Merck Pharma Germany
- Minami Atrium Pharma Canada
- Biocare Elder Pharma India
- Eskimo 3 Bringwell Pharma Sweden
- Equizen Vifor Pharma Swiss
The AA to EPA ratio
• Historically, the human diet was high in omega-3 fatty acids, with a ratio of
omega-6 to omega-3 fatty acids of around 1-2:1
• During the last few decades, there has been a marked increase in consumption
of omega-6 and a decrease in consumption of omega-3 fatty acids
• Many modern food types are ‘new’ in regard to human evolution, rich in added
omega-6 and stripped of omega-3
The role of lipid mediators
• Pro-inflammatory lipid
arachidonic acid (AA)
• Anti-inflammatory/pro-resolving lipids
dihomo-gamma-linolenic acid (DGLA)
eicosapentaenoic acid (EPA)
docosahexaenoic acid (DHA)
• AA and EPA are the significant eicosanoid precursors
• AA to EPA ratio is a direct biomarker of inflammatory status
Anti-inflammatory
eicosanoids
Anti-inflammatory
eicosanoids
Anti-inflammatory
docosanoids
Inflammatory
eicosanoids
Series-3 prostaglandins
Series-3 thromboxanes
Series-5 leukotrienes
Hydroxy fatty acids
Series-1 prostaglandins
Series-1 thromboxanes
Series-2 prostaglandins
Series-2 thromboxanes
Series-4 leukotrienes
Hydroxy fatty acids
Resolvins
Protectins
DGLA
EPA
DHA
AA
Omega-6
Omega-3
The AA to EPA ratio is an indication of the balance between pro-
inflammatory and anti-inflammatory eicosanoids
High AA and low EPA levels will drive the inflammatory response and the
subsequent failure to resolve inflammation may increase susceptibility to
the development of chronic, low-grade, inflammation-based diseases
AA to EPA ratio - biomarker of inflammatory status
Ratio
1.5 - 3.0
3.1 – 6.9
7.0 – 14.9
>15.0
Inflammatory status
 low
 moderate
 elevated
 high
Resoleomics - the process of inflammation resolutionInflammatoryresponse
Initiation Resolution Termination
PGE2
LTB4
Eicosanoid switch Stop signal
Time
Pro-inflammatory reduced
Anti-inflammatory increased
Source: Bosma-den Boer et al., 2012
Inflammation is central to cardiovascular disease
• Pro-inflammatory markers are associated with cardiovascular disease risk
• IL-6, TNF- - most prominent - C-reactive protein (CRP)
• CRP has many advantages as a marker: it is stable, negligible circadian
variation and is easily measured
• Lowering CRP concentrations <2 mg/L [statin therapy] reduces the risk of
recurrent MI or death from cardiovascular causes (Ridker et al., 2005)
• Increased AA to EPA ratio in patients with pulmonary thrombo-embolism
compared to controls (Oshima et al., 2013)
• AA to EPA ratio higher in angina patients than controls, with a ratio of >33
observed in 42% of patients (due to significantly lower levels of EPA) (Kondo
et al., 1986)
• Imbalanced AA to EPA (but not AA to DHA ratio) significantly associated with
acute coronary syndrome (Nishiza et al., 2014)
AA to EPA ratio - biomarker of inflammatory status
Effect of omega-3 on CRP, IL-6 and TNF- : A Meta-Analysis
• Omega-3 supplementation significantly lowered markers in all subjects
(chronic non-autoimmune disease, chronic autoimmune disease and healthy)
Li et al., 2014
• Significant negative linear relationship between duration and effect size of
omega-3 supplementation on fasting blood levels of TNF- and IL-6 in subjects
with chronic non-autoimmune disease was observed, indicating that longer
duration of supplementation could lead to a greater lowering effect and this
relationship was greater for EPA than DHA
• AA to EPA ratio of >3.5 and a high CRP level of ≥1.0 mg/dL are at high risk for
cardiovascular disease; subjects with chronic systemic inflammation are likely
to receive more benefits from anti-atherosclerotic effects of omega-3
(Ninomiya et al., 2013)
EPA and DHA benefits shared or different?
• Two very comprehensive reviews outline the potential importance of the ‘EPA to
DHA ratio’ in the treatment of conditions
• Recent meta-analysis indicates EPA has to be in excess of DHA for the treatment
of conditions such as depression and ADHD (Martins 2009; Sublette et al., 2011)
• DHA is predominantly localised at the sn-2 position of the triglyceride, with
esterification of EPA at each site more random; re-esterification after absorption
often sees DHA concentrated, at the expense of EPA
• Either alone or in combination, EPA and DHA contribute differentially to reduced
inflammation, oxidative stress and platelet aggregation; enhanced cardiac and
arterial function seen with omega-3 intake
• Accumulation of DHA leads to ‘potential surplus’ and increased lipid
peroxidation
(Jacobson et al., 2012; Wei & Jacobson 2011)
The unique properties of EPA and DHA
• EPA is the major ‘physiologically active’ omega-3 fatty acid
• Prostaglandins
• Leukotrienes
• Thromboxanes
• AA to EPA ratio is a reliable biomarker of inflammatory status
• DHA is the major structural omega-3 fatty acid
• EPA to DHA ratio appears to be a significant influencer when considering anti-
inflammatory therapeutic outcomes (not all ‘fish oil’ offers therapeutic
outcomes)
• Pure EPA is a viable ‘standalone’ treatment for inflammatory
based conditions
• Anti-dysrhythmic
 Reduced sudden death
 Possible prevention of arterial fibrillation
 Possible protection against pathologic ventricular arrhythmias
 Improvement in heart rate variability
• Anti-atherogenic
 Reduction in non-HDL-C levels, TG, VLDL-C levels
 Reduction in chylomicrons (and VLDL and chylomicron remnants)
 Increase in HDL-C levels
 “Improvement” (increase) in LDL and HDL particle size
 Plaque stabilisation
• Anti-thrombotic
 Decreased platelet aggregation
 Improved blood flow
• Anti-inflammatory and endothelial protective effects
 Reduced endothelial adhesion molecules
 Decreased leukocyte adhesion receptor expression
 Reduction in pro-inflammatory eicosanoids
 Vasodilation
• Decreased systolic and diastolic blood pressure
EPA as a therapeutic tool
• Products containing a combination of EPA and DHA, including dietary
supplements, are more likely to raise LDL than EPA-only products, especially
for those not on statin therapy (Ballantyne et al., 2013)
• A systematic review of 22 RCTs of EPA and/or DHA reported increased LDL-C
in 71% of studies of DHA monotherapy (Jacobson et al., 2012; Wei &
Jacobson 2011)
• Patients who are switched from EPA/DHA containing products to pure ethyl-
EPA show substantial improvements in lipid profiles (Hilleman & Malesker
2014)
A new wave of pure EPA studies
JELIS study found
• 1.8g/day of ethyl-EPA in just under 20,000 hypercholesterolaemic
subjects randomised to EPA + statins or statins alone = 19% reduced
incidence of major CVD
• That increasing EPA and reducing AA to EPA ratio were both useful in
preventing coronary artery disease
Vascepa™ trials:
• ANCHOR & MARINE looked at role of EPA on inflammatory markers
associated with CVD and atherosclerosis in hypertriglyceridaemic
patients taking statins for cholesterol control
• Both studies randomised subjects to 12 weeks of taking 4 or 2g EPA or
placebo daily
• Results showed 4g EPA reduced TGs, non-HDL cholesterol and other
markers of atherosclerosis without increasing total LDL
• The ANCHOR study used predominantly (>70%) diabetic subjects - 4g
EPA daily significantly improved lipid profiles and lipid related markers
without negatively impacting glycaemic control
• Igennus is the only independent manufacturer
of specialist Fatty Acid in the UK. Based in
Cambridge the medical innovation hub for the
UK:
- Seven Seas Merck Pharma Germany
- Minami Atrium Pharma Canada
- Biocare Elder Pharma India
- Eskimo 3 Bringwell Pharma Sweden
- Equizen Vifor Pharma Swiss
Tani et al., 2013
• Hypertriglyceridaemia patients randomised to 2 x 900mg ethyl-EPA for 6
months
• significantly increased LDL particle size, reduced serum TGs and non-HDL
cholesterol vs no significant changes in controls
• LDL particle size at 6 months positively correlated with serum EPA and
negatively correlated with AA to EPA ratio
• 6 month AA to EPA ratio was found to be better than any other marker at
predicting LDL particle size
There’s more to come!
• The REDUCE-IT (Reduction of Cardiovascular Events with EPA - Intervention
Trial)
• Multinational, prospective, randomised, double-blind, placebo-controlled,
parallel-group study taking place at over 400 clinical sites in 11 countries to
evaluate the effectiveness and safety of ethyl-EPA capsules, as an adjunct
to optimised statin therapy, in reducing the incidence of first major
cardiovascular events in a patient population at high risk for such events
• Overall Vascepa™ has been hailed as safe, effective and a new alternative
with potential benefits over existing treatments
What next?
• Importance of EPA as stand-alone and co-therapy for CVD now well
established
• In 2012 the FDA approved a high purity ethyl-EPA product for use in
treating hypertriglyceridaemia
• Phase III placebo-controlled clinical trials using pure EPA further
support the benefits of ethyl-EPA in managing and treating CVD
Homocysteine and cardiovascular health
• Elevated levels of circulating total homocysteine levels are a well-documented
risk factor for the development of cardiovascular disease
(Wald et al., 2002 Aronow etal., 2000)
• A decrease in serum homocysteine of 3 mmol/L lowers the risk of myocardial
infarction and stroke by 15% and 24% respectively
• 5 mmol/L increase in levels increasing the risk of coronary heart disease events
by approximately 20% (Debreceni& Debreceni 2014)
• Levels of homocysteine in the blood are directly influenced by levels of the B-
complex vitamins (folic acid, vitamin B6 and vitamin B12), with low levels
directly contributing to elevated homocysteine. (Selhub et al., 1993)
• The role of homocysteine in the development of CVD is not fully understood
• Homocysteines’ involvement in endothelial cell dysfunction and apoptosis of
endothelial and smooth muscle cells of the vascular wall is well established
• Homocysteine also appears to play a role in a number of cellular
mechanisms contributing to the development of atherosclerosis
Homocysteine levels
Normal 5-15 μmol/L
Mild 15-30 μmol/L
Moderate 30-100 μmol/L
Severe ≥ 100 μmol/L
• Reduced vasodilation – due to its role in decreasing availability of nitric oxide
• Endothelial inflammation – via increased production of inflammatory cytokines and
vascular adhesion molecules
• Increased oxidative stress-induced cell damage – due to its role in the generation of
glutathione, a process highly sensitive to oxidative stress
• Impaired activity of glutathione peroxidase and heme oxygenase-1 – enzymes
implicated in the attenuation of homocysteine-induced endothelial dysfunction and
the development of atherosclerosis
• Endoplasmic reticulum (ER) stress, causing a subsequent increase in the expression
of apoptosis genes
• Persistent ER stress may also contribute to dysregulated lipid metabolism,
affecting both cholesterol and triglyceride synthesis and uptake, further
contributing to CVD risk
• Homocysteine also appears to add to increased blood coagulation and thus
the promotion of thrombosis
(Splaver et al., 2004)
Coenzyme Q10 (CoQ10) and cardiovascular health
• Coenzyme Q10 (CoQ10), essential for oxidative phosphorylation and ATP
production, is heavily involved in cardiac function – in particular, cardiac
muscle contraction and ATP-dependent membrane channels.
• The heart is particularly sensitive to endogenously low CoQ10 and
subsequent reduction in energy production capacity – considered to
contribute to the progression of heart failure.
• CoQ10’s role in cellular energy production and consistently low CoQ10
observed in CVD patients has led to the investigation of the mechanisms by
which CoQ10 plays a role in the prevention and treatment of cardiovascular
conditions.
• Calcium is vital for relaxation of the heart muscle, a process that requires ATP
• ATP is required for cross-bridging during muscle contraction - low levels of
CoQ10 may contribute to reduced cardiac contraction and relaxation due to
low energy supply
• CoQ10 in activated form ubiquinol, is a powerful antioxidant that also plays a
role in regenerating other antioxidants including vitamin E, vitamin C and
lipoic acid.
• Ability to quench free radicals helps maintain structural integrity and stability
of mitochondrial and cell membranes
• And reduce associated lipid peroxidation - LDL oxidation contributes to the
development of atherosclerosis
• CoQ10 may help prevent oxidation of nitric oxide - in turn improves
relaxation of the endothelium
• May prevent glucose-induced endothelial apoptosis and adhesion, further
reducing atherosclerosis risk in patients with metabolic syndrome
• CoQ10 positively influences the immune system by reducing oxidative and
nitrative stress, inflammatory markers such as IL-6 and TNF-alpha, thus
vascular wall inflammation
• CoQ10 shown to reduce: risk and mortality from congestive heart failure,
cardiomyopathy, angina, hypertension, ischaemic heart disease and
arrhythmias and enhance recovery post-cardiac surgery
(Kumar et al., 2009)
Acetyl-CoA
Cholesterol
HMG-CoA
Mevalonate
HMG-CoA reductase
inhibitors (statins)
Coenzyme Q10
(ubiquinone)
HMG-CoA reductase
HMG-CoA synthase
Igennus CVD Nutrition Protocol
Applied nutrition for cardiovascular health
Igennus CVD support protocol
Pharmepa Step 1: Restore
2 capsules = 1g pure ethyl EPA
Vitamin E for antioxidant protection
Designed to
• Increase cellular EPA levels quickly
• Restore a healthy AA:EPA ratio
• Reduce the production of pro-inflammatory products
• Increase the production of anti-inflammatory products
• Support cardiovascular health and cholesterol levels
Vegetarian alternative to fish oil
• Linseed? Algae? Hempseed?
• Echium seed oil (Echiomega) is a source of the
omega-3 fatty acids SDA (stearidonic acid) and
ALA. SDA is the precursor to EPA
• 25-30% of SDA converts to EPA, compared with
just 5-8% of ALA – the principal omega-3 in most
other plant-derived oils
• Echiomega, rich in SDA, is the superior choice of
omega-3 for vegetarians and vegans
• Walker CG1, Jebb SA, Calder PC. Stearidonic acid as a supplemental source of ω-3
polyunsaturated fatty acids to enhance status for improved human health. Nutrition.
2013 Feb;29(2):363-9. Epub 2012 Oct 24.
• Kuhnt K1, Fuhrmann C, Köhler M, Kiehntopf M, Jahreis G. Dietary Echium Oil Increases Long-
Chain n-3 PUFAs, Including Docosapentaenoic Acid, in Blood Fractions and Alters
Biochemical Markers for Cardiovascular Disease Independent of Age, Sex, and
Metabolic Syndrome. J Nutr. 2014 Feb 19.
• Forrest LM1, Lough CM, Chung S, Boudyguina EY, Gebre AK, Smith TL, Colvin PL, Parks JS. Echium
oil reduces plasma triglycerides by increasing intravascular lipolysis in apoB100-only
low density lipoprotein (LDL) receptor knockout mice. Nutrients. 2013 Jul 12;5(7):2629-45.
• Kavanagh K, Flynn DM, Jenkins KA, Wilson MD, Chilton FH: Stearidonic and gamma-linolenic
acids in echium oil improves glucose disposal in insulin resistant monkeys.
Prostaglandins, leukotrienes, and essential fatty acids 2013, 89:39-45.
• Igennus is the only independent manufacturer
of specialist Fatty Acid in the UK. Based in
Cambridge the medical innovation hub for the
UK:
- Seven Seas Merck Pharma Germany
- Minami Atrium Pharma Canada
- Biocare Elder Pharma India
- Eskimo 3 Bringwell Pharma Sweden
- Equizen Vifor Pharma Swiss
VESIsorb Ubiquinol-QH
Faster acting, stronger plasma concentration and longer lasting effects
 Unprecedented bioavailability
 Fully reduced ‘bioactive’ form
 Solubilised for maximum absorption
 Novel VESIsorb® delivery system mimics the natural transport system
of the intestine, providing significantly higher plasma concentrations†
than any other delivery system offering a comparable dose
 One capsule daily delivers a therapeutic dose (100 mg)
Enhances energy production Potent antioxidant Supports antioxidant turnover
Enhances cellular communication Cell cycle support Reduces statin-associated myopathy
Cardioprotective Neuroprotective Anti-inflammatory
• Igennus is the only independent manufacturer
of specialist Fatty Acid in the UK. Based in
Cambridge the medical innovation hub for the
UK:
- Seven Seas Merck Pharma Germany
- Minami Atrium Pharma Canada
- Biocare Elder Pharma India
- Eskimo 3 Bringwell Pharma Sweden
- Equizen Vifor Pharma Swiss
Homocysteine Control
Sustained Release
Homocysteine Control Sustained Release tablets contain a
synergistic blend of bioavailable vitamins B6, B12 and folic acid at
precise dosages for maintaining healthy homocysteine levels.
 Formulated at proven dosages for efficacy
 Highly bioavailable actives
 Easy-to-swallow tablets
 Suitable for vegetarians & vegans
 Sustained release tablets to maintain optimal blood
concentrations
 Split dosing overcomes bioavailability issues associated with
B12 supplementation
• Igennus is the only independent manufacturer
of specialist Fatty Acid in the UK. Based in
Cambridge the medical innovation hub for the
UK:
- Seven Seas Merck Pharma Germany
- Minami Atrium Pharma Canada
- Biocare Elder Pharma India
- Eskimo 3 Bringwell Pharma Sweden
- Equizen Vifor Pharma Swiss
www.igennus.com
01223 421434
info@igennus.com
Thanks to Dr. Nina Bailey
Sophie Tully
Nutrition education manager
sophiet@igennus.com
education@igennus.com
07908683174
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Applied nutrition for cardiovascular health

  • 1. Clinical Nutrition for prevention and treatment of cardiovascular disease Sophie Tully BSc MSc DIPPT
  • 2. Diet and lifestyle issues are closely associated with a myriad of cardiovascular disease risk factors, including abnormal plasma lipids, hypertension, insulin resistance, diabetes and obesity, suggesting that diet-based approaches may be of benefit
  • 3. Omega-3 fatty acids and cardiovascular health
  • 4. 1950’s • Observational reports of relatively low incidence of coronary disease in the Greenland Inuit (Ehrstrom 1951) 1970’s work by Bang & Dyerberg • Consumption of a large amount of fish or marine mammals rich in omega-3 fatty acids (specifically EPA) contributes to the low incidence of cardiovascular disease (CVD) among the Greenland Eskimos • Blood cholesterol, triglycerides, low density and very low density lipoprotein shown to be lower in the Greenland Inuit than in Danish controls • Blood polyunsaturated fatty acids were predominantly omega-3 in the Inuits and omega-6 in the Danes, yet serum lipid patterns of Inuits living in Denmark (migrants) were similar to that of Danes - suggesting a dietary link
  • 5. Inuit Dane Percent of total calories from fat 39% 42% Percent of total fatty acids Saturated 23% 53% Monounsaturated 58% 34% Polyunsaturated 19% 13% Polyunsaturated : Saturated (P : S) ratio 0.84 0.24 Grams per day Omega-3 fatty acids 14g 3g Omega-6 fatty acids 5g 10g Cholesterol 0.70g 0.42g Based on daily energy intake of approximately 3,000 kcal.
  • 6. Comparing fatty acid composition of fishing and farming population (Japan) Farming Fishing Daily fish intake (g) 90 250 Of which EPA (g) 0.9 2.5 AA to EPA ratio 2.5 1.7 RBC 0mega-3 (%) 6.8 10.9 Average AA to EPA ratio Inuit 0.14 Japanese 2.0 European 10.0 American 16.6 Hirai et al., 1980 Rose & Holub 2006
  • 7. • 13 cohorts from 11 independent prospective studies comprising 222,364 participants (3032 CHD deaths) with an average of 11.8 years of follow-up • Fish consumption inversely associated with fatal CHD • Eating fish once per week might significantly reduce death from CHD by 15% • A dose-response relation was evident between fish consumption and risk of CHD mortality • An increment of 20 g/d of fish intake could possibly lower CHD mortality rates by 7% • The inverse association was more apparent among studies with a follow-up period of 12 years or longer (He et al., 2004) Accumulated Evidence on Fish Consumption and Coronary Heart Disease Mortality: A Meta-Analysis of Cohort Studies
  • 9. Physicians health study (Albert et al., 2002) • Prospective, nested case-control analysis among apparently healthy men who were followed for up to 17 years in the Physicians' Health Study • The fatty-acid status of 94 men in whom sudden death occurred as the first manifestation of cardiovascular disease and for 184 controls matched with them for age and smoking status • After adjustments, there was a 90% reduced risk of sudden death among men with levels of EPA and DHA (total omega-3) in the highest quartile as compared with the lowest quartile
  • 10. 3.58% 4.76% 5.63% 6.87% 100% 48% 81% 90% 90% reduced risk (RR) RelativeRisk(RR) EPA + DHA Risk of sudden cardiac death and omega-3 blood levels Source: Albert et al., 2002
  • 11. • Should be interpreted with caution • Fish intake may be a surrogate for some other healthy lifestyle factors • Individuals with higher fish consumption tended to exercise more, smoke less, and less likely to be overweight • Studies in this meta-analysis were well designed and adjusted for major dietary and non-dietary lifestyle variables • Possibility observed inverse association between fish intake and CVD in part explained by undefined healthy lifestyle factors can not be ruled out Observational studies
  • 12. Establishing a causal relationship: randomised, placebo- controlled trials Diet and Reinfarction Trial (the DART Study) • 2,033 male patients with myocardial infarction • 2-year intervention • group consuming 2 servings per week of fish had a 29% reduced all-cause mortality and 16% reduced risk of ischaemic heart events (Burr et al., 1989) GISSI-Prevenzione Trial (Marchioli et al., 2002) • 11,323 patients with recent MI - fish oil supplementation (1 g/d) significantly reduced cardiac death by 32% and sudden death by 45% during 3.5 years of follow up The Japan eicosapentaenoic acid (EPA) Lipid Intervention Study (JELIS) • 18,645 Japanese men and women with hypercholesterolaemia receiving statins, • fish oil supplementation (EPA 1.8 g/d) significantly reduced major coronary events by 19% during 4.6 years of follow-up (Yokoyama et al., 2007)
  • 13. Omega-3 recommendations • American Heart Association recommends everyone eat two servings (100 g/4 oz per serving) oily fish per week • Those with coronary heart disease eat 1 g/d of EPA plus DHA from oily fish or supplements • The UK Food Standards Agency recommends servings of fish per week (one white, one oily) to deliver 450mg omega-3/day - Actual intake 244mg/day - <50mg for non-fish/meat eaters
  • 14. Using omega-3s as biomarkers of cardiovascular health
  • 15. The omega-3 index • The omega-3 index = content of EPA and DHA in the cell membrane of RBCs, expressed as a percentage of total fatty acids • Reflects tissue fatty acid composition • Correlates highly with the EPA+DHA content in plasma and whole blood, but is better correlated to long-term fatty acid intake and thus a suitable biomarker for the nutritional status • RBC EPA+DHA also correlates to EPA and DHA content of cardiac muscle • Half-life of EPA+DHA in RBCs is 4–6 times longer than in serum, with concentrations returning to baseline 16 weeks after supplementation (Harris & Von Schacky, 2004)
  • 16. The omega-3 index: a dose response Harris & Von Schacky, 2004 Omega-3index(%) 0.0g 0.5g 1.0g 2.0g Omega-3 dose (12 weeks)
  • 17. 0 % 4% 8% Omega-3 index - biomarker of cardiovascular health Desirable Optimal Undesirable Harris & Von Schacky, 2004
  • 18. • EPA+DHA needed to achieve a target omega-3 index is poorly defined, as are the determinants of the omega-3 index in response to a change in EPA+DHA intake • A randomised, placebo-controlled, double-blind, parallel-group study (n=115) • One of 5 doses (0, 300, 600, 900, 1800 mg) of EPA+DHA was given daily as placebo or fish oil supplements for 5 months • Aim: to develop a predictive model of the omega-3 index in response to EPA+DHA supplementation and identify factors that determine the response Flock et al., 2013 RBC omega‐3 fatty acid content in response to fish oil supplementation: A dose–response randomised controlled trial
  • 19. • The omega-3 index after supplementation was largely determined by the dose of EPA+DHA administered • Baseline omega-3 index and percent DHA in RBCs also independently predicted the change in omega-3 index • Individuals with a low baseline omega-3 index status experienced greater rise in omega-3 • The dose of EPA+DHA, adjusted per unit body weight (g/kg), also was a strong predictor of change in omega-3 index • Increasing the dose (g/kg/BW) resulted in greater omega-3 index response
  • 21. • Variability was influenced by baseline omega-3 index, age, sex and physical activity • Lower baseline omega-3 index and older age each predicted greater increases in omega-3 index • Increased physical activity level was associated with a higher omega-3 index • Female subjects had a non-significant increase in omega-3 compared to males • However, body weight was the greatest influencer
  • 22. • Using the body‐weight‐adjusted values to increase the omega-3 index from 4.3% to 8% (change of 3.7% = 0.016mg/kg EPA+ DHA) An individual weighing: 95 kg requires 1.5 g omega-3/day 75 kg requires 1.2 g omega-3/day 55 kg requires 0.9 g omega-3/day
  • 23. • Igennus is the only independent manufacturer of specialist Fatty Acid in the UK. Based in Cambridge the medical innovation hub for the UK: - Seven Seas Merck Pharma Germany - Minami Atrium Pharma Canada - Biocare Elder Pharma India - Eskimo 3 Bringwell Pharma Sweden - Equizen Vifor Pharma Swiss The AA to EPA ratio • Historically, the human diet was high in omega-3 fatty acids, with a ratio of omega-6 to omega-3 fatty acids of around 1-2:1 • During the last few decades, there has been a marked increase in consumption of omega-6 and a decrease in consumption of omega-3 fatty acids • Many modern food types are ‘new’ in regard to human evolution, rich in added omega-6 and stripped of omega-3
  • 24. The role of lipid mediators • Pro-inflammatory lipid arachidonic acid (AA) • Anti-inflammatory/pro-resolving lipids dihomo-gamma-linolenic acid (DGLA) eicosapentaenoic acid (EPA) docosahexaenoic acid (DHA) • AA and EPA are the significant eicosanoid precursors • AA to EPA ratio is a direct biomarker of inflammatory status
  • 25. Anti-inflammatory eicosanoids Anti-inflammatory eicosanoids Anti-inflammatory docosanoids Inflammatory eicosanoids Series-3 prostaglandins Series-3 thromboxanes Series-5 leukotrienes Hydroxy fatty acids Series-1 prostaglandins Series-1 thromboxanes Series-2 prostaglandins Series-2 thromboxanes Series-4 leukotrienes Hydroxy fatty acids Resolvins Protectins DGLA EPA DHA AA Omega-6 Omega-3
  • 26. The AA to EPA ratio is an indication of the balance between pro- inflammatory and anti-inflammatory eicosanoids High AA and low EPA levels will drive the inflammatory response and the subsequent failure to resolve inflammation may increase susceptibility to the development of chronic, low-grade, inflammation-based diseases AA to EPA ratio - biomarker of inflammatory status Ratio 1.5 - 3.0 3.1 – 6.9 7.0 – 14.9 >15.0 Inflammatory status  low  moderate  elevated  high
  • 27. Resoleomics - the process of inflammation resolutionInflammatoryresponse Initiation Resolution Termination PGE2 LTB4 Eicosanoid switch Stop signal Time Pro-inflammatory reduced Anti-inflammatory increased Source: Bosma-den Boer et al., 2012
  • 28. Inflammation is central to cardiovascular disease • Pro-inflammatory markers are associated with cardiovascular disease risk • IL-6, TNF- - most prominent - C-reactive protein (CRP) • CRP has many advantages as a marker: it is stable, negligible circadian variation and is easily measured • Lowering CRP concentrations <2 mg/L [statin therapy] reduces the risk of recurrent MI or death from cardiovascular causes (Ridker et al., 2005)
  • 29. • Increased AA to EPA ratio in patients with pulmonary thrombo-embolism compared to controls (Oshima et al., 2013) • AA to EPA ratio higher in angina patients than controls, with a ratio of >33 observed in 42% of patients (due to significantly lower levels of EPA) (Kondo et al., 1986) • Imbalanced AA to EPA (but not AA to DHA ratio) significantly associated with acute coronary syndrome (Nishiza et al., 2014) AA to EPA ratio - biomarker of inflammatory status
  • 30. Effect of omega-3 on CRP, IL-6 and TNF- : A Meta-Analysis • Omega-3 supplementation significantly lowered markers in all subjects (chronic non-autoimmune disease, chronic autoimmune disease and healthy) Li et al., 2014 • Significant negative linear relationship between duration and effect size of omega-3 supplementation on fasting blood levels of TNF- and IL-6 in subjects with chronic non-autoimmune disease was observed, indicating that longer duration of supplementation could lead to a greater lowering effect and this relationship was greater for EPA than DHA • AA to EPA ratio of >3.5 and a high CRP level of ≥1.0 mg/dL are at high risk for cardiovascular disease; subjects with chronic systemic inflammation are likely to receive more benefits from anti-atherosclerotic effects of omega-3 (Ninomiya et al., 2013)
  • 31. EPA and DHA benefits shared or different? • Two very comprehensive reviews outline the potential importance of the ‘EPA to DHA ratio’ in the treatment of conditions • Recent meta-analysis indicates EPA has to be in excess of DHA for the treatment of conditions such as depression and ADHD (Martins 2009; Sublette et al., 2011) • DHA is predominantly localised at the sn-2 position of the triglyceride, with esterification of EPA at each site more random; re-esterification after absorption often sees DHA concentrated, at the expense of EPA • Either alone or in combination, EPA and DHA contribute differentially to reduced inflammation, oxidative stress and platelet aggregation; enhanced cardiac and arterial function seen with omega-3 intake • Accumulation of DHA leads to ‘potential surplus’ and increased lipid peroxidation (Jacobson et al., 2012; Wei & Jacobson 2011)
  • 32. The unique properties of EPA and DHA • EPA is the major ‘physiologically active’ omega-3 fatty acid • Prostaglandins • Leukotrienes • Thromboxanes • AA to EPA ratio is a reliable biomarker of inflammatory status • DHA is the major structural omega-3 fatty acid • EPA to DHA ratio appears to be a significant influencer when considering anti- inflammatory therapeutic outcomes (not all ‘fish oil’ offers therapeutic outcomes) • Pure EPA is a viable ‘standalone’ treatment for inflammatory based conditions
  • 33. • Anti-dysrhythmic  Reduced sudden death  Possible prevention of arterial fibrillation  Possible protection against pathologic ventricular arrhythmias  Improvement in heart rate variability • Anti-atherogenic  Reduction in non-HDL-C levels, TG, VLDL-C levels  Reduction in chylomicrons (and VLDL and chylomicron remnants)  Increase in HDL-C levels  “Improvement” (increase) in LDL and HDL particle size  Plaque stabilisation • Anti-thrombotic  Decreased platelet aggregation  Improved blood flow • Anti-inflammatory and endothelial protective effects  Reduced endothelial adhesion molecules  Decreased leukocyte adhesion receptor expression  Reduction in pro-inflammatory eicosanoids  Vasodilation • Decreased systolic and diastolic blood pressure
  • 34. EPA as a therapeutic tool • Products containing a combination of EPA and DHA, including dietary supplements, are more likely to raise LDL than EPA-only products, especially for those not on statin therapy (Ballantyne et al., 2013) • A systematic review of 22 RCTs of EPA and/or DHA reported increased LDL-C in 71% of studies of DHA monotherapy (Jacobson et al., 2012; Wei & Jacobson 2011) • Patients who are switched from EPA/DHA containing products to pure ethyl- EPA show substantial improvements in lipid profiles (Hilleman & Malesker 2014)
  • 35. A new wave of pure EPA studies JELIS study found • 1.8g/day of ethyl-EPA in just under 20,000 hypercholesterolaemic subjects randomised to EPA + statins or statins alone = 19% reduced incidence of major CVD • That increasing EPA and reducing AA to EPA ratio were both useful in preventing coronary artery disease
  • 36. Vascepa™ trials: • ANCHOR & MARINE looked at role of EPA on inflammatory markers associated with CVD and atherosclerosis in hypertriglyceridaemic patients taking statins for cholesterol control • Both studies randomised subjects to 12 weeks of taking 4 or 2g EPA or placebo daily • Results showed 4g EPA reduced TGs, non-HDL cholesterol and other markers of atherosclerosis without increasing total LDL • The ANCHOR study used predominantly (>70%) diabetic subjects - 4g EPA daily significantly improved lipid profiles and lipid related markers without negatively impacting glycaemic control
  • 37. • Igennus is the only independent manufacturer of specialist Fatty Acid in the UK. Based in Cambridge the medical innovation hub for the UK: - Seven Seas Merck Pharma Germany - Minami Atrium Pharma Canada - Biocare Elder Pharma India - Eskimo 3 Bringwell Pharma Sweden - Equizen Vifor Pharma Swiss Tani et al., 2013 • Hypertriglyceridaemia patients randomised to 2 x 900mg ethyl-EPA for 6 months • significantly increased LDL particle size, reduced serum TGs and non-HDL cholesterol vs no significant changes in controls • LDL particle size at 6 months positively correlated with serum EPA and negatively correlated with AA to EPA ratio • 6 month AA to EPA ratio was found to be better than any other marker at predicting LDL particle size
  • 38. There’s more to come! • The REDUCE-IT (Reduction of Cardiovascular Events with EPA - Intervention Trial) • Multinational, prospective, randomised, double-blind, placebo-controlled, parallel-group study taking place at over 400 clinical sites in 11 countries to evaluate the effectiveness and safety of ethyl-EPA capsules, as an adjunct to optimised statin therapy, in reducing the incidence of first major cardiovascular events in a patient population at high risk for such events • Overall Vascepa™ has been hailed as safe, effective and a new alternative with potential benefits over existing treatments
  • 39. What next? • Importance of EPA as stand-alone and co-therapy for CVD now well established • In 2012 the FDA approved a high purity ethyl-EPA product for use in treating hypertriglyceridaemia • Phase III placebo-controlled clinical trials using pure EPA further support the benefits of ethyl-EPA in managing and treating CVD
  • 41. • Elevated levels of circulating total homocysteine levels are a well-documented risk factor for the development of cardiovascular disease (Wald et al., 2002 Aronow etal., 2000) • A decrease in serum homocysteine of 3 mmol/L lowers the risk of myocardial infarction and stroke by 15% and 24% respectively • 5 mmol/L increase in levels increasing the risk of coronary heart disease events by approximately 20% (Debreceni& Debreceni 2014) • Levels of homocysteine in the blood are directly influenced by levels of the B- complex vitamins (folic acid, vitamin B6 and vitamin B12), with low levels directly contributing to elevated homocysteine. (Selhub et al., 1993)
  • 42. • The role of homocysteine in the development of CVD is not fully understood • Homocysteines’ involvement in endothelial cell dysfunction and apoptosis of endothelial and smooth muscle cells of the vascular wall is well established • Homocysteine also appears to play a role in a number of cellular mechanisms contributing to the development of atherosclerosis Homocysteine levels Normal 5-15 μmol/L Mild 15-30 μmol/L Moderate 30-100 μmol/L Severe ≥ 100 μmol/L
  • 43. • Reduced vasodilation – due to its role in decreasing availability of nitric oxide • Endothelial inflammation – via increased production of inflammatory cytokines and vascular adhesion molecules • Increased oxidative stress-induced cell damage – due to its role in the generation of glutathione, a process highly sensitive to oxidative stress • Impaired activity of glutathione peroxidase and heme oxygenase-1 – enzymes implicated in the attenuation of homocysteine-induced endothelial dysfunction and the development of atherosclerosis • Endoplasmic reticulum (ER) stress, causing a subsequent increase in the expression of apoptosis genes
  • 44. • Persistent ER stress may also contribute to dysregulated lipid metabolism, affecting both cholesterol and triglyceride synthesis and uptake, further contributing to CVD risk • Homocysteine also appears to add to increased blood coagulation and thus the promotion of thrombosis (Splaver et al., 2004)
  • 45. Coenzyme Q10 (CoQ10) and cardiovascular health
  • 46. • Coenzyme Q10 (CoQ10), essential for oxidative phosphorylation and ATP production, is heavily involved in cardiac function – in particular, cardiac muscle contraction and ATP-dependent membrane channels. • The heart is particularly sensitive to endogenously low CoQ10 and subsequent reduction in energy production capacity – considered to contribute to the progression of heart failure. • CoQ10’s role in cellular energy production and consistently low CoQ10 observed in CVD patients has led to the investigation of the mechanisms by which CoQ10 plays a role in the prevention and treatment of cardiovascular conditions.
  • 47. • Calcium is vital for relaxation of the heart muscle, a process that requires ATP • ATP is required for cross-bridging during muscle contraction - low levels of CoQ10 may contribute to reduced cardiac contraction and relaxation due to low energy supply • CoQ10 in activated form ubiquinol, is a powerful antioxidant that also plays a role in regenerating other antioxidants including vitamin E, vitamin C and lipoic acid. • Ability to quench free radicals helps maintain structural integrity and stability of mitochondrial and cell membranes • And reduce associated lipid peroxidation - LDL oxidation contributes to the development of atherosclerosis
  • 48. • CoQ10 may help prevent oxidation of nitric oxide - in turn improves relaxation of the endothelium • May prevent glucose-induced endothelial apoptosis and adhesion, further reducing atherosclerosis risk in patients with metabolic syndrome • CoQ10 positively influences the immune system by reducing oxidative and nitrative stress, inflammatory markers such as IL-6 and TNF-alpha, thus vascular wall inflammation • CoQ10 shown to reduce: risk and mortality from congestive heart failure, cardiomyopathy, angina, hypertension, ischaemic heart disease and arrhythmias and enhance recovery post-cardiac surgery (Kumar et al., 2009)
  • 52. Igennus CVD support protocol Pharmepa Step 1: Restore 2 capsules = 1g pure ethyl EPA Vitamin E for antioxidant protection Designed to • Increase cellular EPA levels quickly • Restore a healthy AA:EPA ratio • Reduce the production of pro-inflammatory products • Increase the production of anti-inflammatory products • Support cardiovascular health and cholesterol levels
  • 53. Vegetarian alternative to fish oil • Linseed? Algae? Hempseed? • Echium seed oil (Echiomega) is a source of the omega-3 fatty acids SDA (stearidonic acid) and ALA. SDA is the precursor to EPA • 25-30% of SDA converts to EPA, compared with just 5-8% of ALA – the principal omega-3 in most other plant-derived oils • Echiomega, rich in SDA, is the superior choice of omega-3 for vegetarians and vegans
  • 54. • Walker CG1, Jebb SA, Calder PC. Stearidonic acid as a supplemental source of ω-3 polyunsaturated fatty acids to enhance status for improved human health. Nutrition. 2013 Feb;29(2):363-9. Epub 2012 Oct 24. • Kuhnt K1, Fuhrmann C, Köhler M, Kiehntopf M, Jahreis G. Dietary Echium Oil Increases Long- Chain n-3 PUFAs, Including Docosapentaenoic Acid, in Blood Fractions and Alters Biochemical Markers for Cardiovascular Disease Independent of Age, Sex, and Metabolic Syndrome. J Nutr. 2014 Feb 19. • Forrest LM1, Lough CM, Chung S, Boudyguina EY, Gebre AK, Smith TL, Colvin PL, Parks JS. Echium oil reduces plasma triglycerides by increasing intravascular lipolysis in apoB100-only low density lipoprotein (LDL) receptor knockout mice. Nutrients. 2013 Jul 12;5(7):2629-45. • Kavanagh K, Flynn DM, Jenkins KA, Wilson MD, Chilton FH: Stearidonic and gamma-linolenic acids in echium oil improves glucose disposal in insulin resistant monkeys. Prostaglandins, leukotrienes, and essential fatty acids 2013, 89:39-45.
  • 55. • Igennus is the only independent manufacturer of specialist Fatty Acid in the UK. Based in Cambridge the medical innovation hub for the UK: - Seven Seas Merck Pharma Germany - Minami Atrium Pharma Canada - Biocare Elder Pharma India - Eskimo 3 Bringwell Pharma Sweden - Equizen Vifor Pharma Swiss VESIsorb Ubiquinol-QH Faster acting, stronger plasma concentration and longer lasting effects  Unprecedented bioavailability  Fully reduced ‘bioactive’ form  Solubilised for maximum absorption  Novel VESIsorb® delivery system mimics the natural transport system of the intestine, providing significantly higher plasma concentrations† than any other delivery system offering a comparable dose  One capsule daily delivers a therapeutic dose (100 mg) Enhances energy production Potent antioxidant Supports antioxidant turnover Enhances cellular communication Cell cycle support Reduces statin-associated myopathy Cardioprotective Neuroprotective Anti-inflammatory
  • 56. • Igennus is the only independent manufacturer of specialist Fatty Acid in the UK. Based in Cambridge the medical innovation hub for the UK: - Seven Seas Merck Pharma Germany - Minami Atrium Pharma Canada - Biocare Elder Pharma India - Eskimo 3 Bringwell Pharma Sweden - Equizen Vifor Pharma Swiss Homocysteine Control Sustained Release Homocysteine Control Sustained Release tablets contain a synergistic blend of bioavailable vitamins B6, B12 and folic acid at precise dosages for maintaining healthy homocysteine levels.  Formulated at proven dosages for efficacy  Highly bioavailable actives  Easy-to-swallow tablets  Suitable for vegetarians & vegans  Sustained release tablets to maintain optimal blood concentrations  Split dosing overcomes bioavailability issues associated with B12 supplementation
  • 57. • Igennus is the only independent manufacturer of specialist Fatty Acid in the UK. Based in Cambridge the medical innovation hub for the UK: - Seven Seas Merck Pharma Germany - Minami Atrium Pharma Canada - Biocare Elder Pharma India - Eskimo 3 Bringwell Pharma Sweden - Equizen Vifor Pharma Swiss www.igennus.com 01223 421434 info@igennus.com Thanks to Dr. Nina Bailey Sophie Tully Nutrition education manager sophiet@igennus.com education@igennus.com 07908683174
  • 58. References Dyerberg J, Bang HO, Hjorne N: Fatty acid composition of the plasma lipids in Greenland Eskimos. The American journal of clinical nutrition 1975, 28:958-966. Galli C, Calder PC: Effects of fat and fatty acid intake on inflammatory and immune responses: a critical review. Annals of nutrition & metabolism 2009, 55:123-139. Calder PC: n-3 Fatty acids and cardiovascular disease: evidence explained and mechanisms explored. Clinical science 2004, 107:1-11. Albert CM, Campos H, Stampfer MJ, Ridker PM, Manson JE, Willett WC, Ma J: Blood levels of long-chain n-3 fatty acids and the risk of sudden death. The New England journal of medicine 2002, 346:1113-1118. Flock MR, Skulas-Ray AC, Harris WS, Etherton TD, Fleming JA, Kris-Etherton PM: Determinants of erythrocyte omega-3 fatty acid content in response to fish oil supplementation: a dose-response randomized controlled trial. Journal of the American Heart Association 2013, 2:e000513. Oshima Y, Niki K, Hiramoto Y, Morimoto S, Takami H, Izumi M: Serum eicosapentaenoic acid/arachidonic acid ratio is low in patients with pulmonary thromboembolism. Journal of nutritional science and vitaminology 2013, 59:474-477. Kondo T, Ogawa K, Satake T, Kitazawa M, Taki K, Sugiyama S, Ozawa T: Plasma-free eicosapentaenoic acid/arachidonic acid ratio: a possible new coronary risk factor. Clinical cardiology 1986, 9:413-416. Nishizaki Y, Shimada K, Tani S, Ogawa T, Ando J, Takahashi M, Yamamoto M, Shinozaki T, Miyauchi K, Nagao K, et al: Significance of imbalance in the ratio of serum n-3 to n-6 polyunsaturated fatty acids in patients with acute coronary syndrome. The American journal of cardiology 2014, 113:441-445. Ohnishi H, Saito Y: Eicosapentaenoic Acid (EPA) Reduces Cardiovascular Events: Relationship with the EPA/Arachidonic Acid Ratio. Journal of atherosclerosis and thrombosis 2013. Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, et al: Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007, 369:1090-1098. Tani S, Nagao K, Matsumoto M, Hirayama A: Highly Purified Eicosapentaenoic Acid May Increase Low-Density Lipoprotein Particle Size by Improving Triglyceride Metabolism in Patients With Hypertriglyceridemia. Circulation journal : official journal of the Japanese Circulation Society 2013. Caspar-Bauguil S, Fioroni A, Galinier A, Allenbach S, Pujol MC, Salvayre R, Cartier A, Lemieux I, Richard D, Biron S, et al: Pro-inflammatory phospholipid arachidonic acid/eicosapentaenoic acid ratio of dysmetabolic severely obese women. Obesity surgery 2012, 22:935-944.
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Editor's Notes

  1. 2008
  2. 2008
  3. 2008
  4. 2008
  5. Adenosine diphosphate induces platelet adhesiveness
  6. Figure 1. Pooled estimate of RR and 95% CI of CHD mortality rates for fish consumption 1/week vs &lt;1/month. Squares indicate adjusted RR in each study. Size of the square is proportional to the percent weight of each study in the meta-analysis; horizontal line represents 95% CI. Studies are ordered by year of publication. Pooled RR and 95% CI are indicated by the unshaded diamond.
  7. Figure 1. Pooled estimate of RR and 95% CI of CHD mortality rates for fish consumption 1/week vs &lt;1/month. Squares indicate adjusted RR in each study. Size of the square is proportional to the percent weight of each study in the meta-analysis; horizontal line represents 95% CI. Studies are ordered by year of publication. Pooled RR and 95% CI are indicated by the unshaded diamond.
  8. After all adjustment and adjusting for all other fatty acids (saturated, mono and n-6)
  9. Is support of epidemiological which only indicate association but randomised control trials can show causal relationship
  10. 2008
  11. Is support of epidemiological which only indicate association but randomised control trials can show causal relationship
  12. 3.2, 5.2, 6.9, (increases)
  13. 100,000 years ago
  14. Healthy individuals, chronic non-autoimmune disease, chronic autoimmune disease
  15. Check with sophie
  16. DHA increase LDL-C levels by 2.6% on average whereas EPA reduces LDL-C by 0.7%
  17. 2008
  18. 2008