applied nutrition for cardiovascular health

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 DanePercent 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 0.24Grams per day Omega-3 fatty acids 14g 3gOmega-6 fatty acids 5g 10gCholesterol 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 ratioInuit 0.14Japanese 2.0European 10.0American 16.6

Hirai et al., 1980Rose & 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

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)

Rela

tive

Risk

(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

Om

ega-

3 in

dex

(%)

0.0g 0.5g 1.0g 2.0g

Omega-3 dose (12 weeks)

0 % 4% 8%

Omega-3 index - biomarker of cardiovascular health

Desirable

OptimalUndesirable

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

• 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/day75 kg requires 1.2 g omega-3/day55 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 lipidarachidonic acid (AA)

• Anti-inflammatory/pro-resolving lipidsdihomo-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

Inflammatoryeicosanoids

Series-3 prostaglandinsSeries-3 thromboxanesSeries-5 leukotrienesHydroxy fatty acids

Series-1 prostaglandinsSeries-1 thromboxanes

Series-2 prostaglandinsSeries-2 thromboxanesSeries-4 leukotrienesHydroxy 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

Ratio1.5 - 3.03.1 – 6.9

7.0 – 14.9>15.0

Inflammatory status low moderate elevated high

Resoleomics - the process of inflammation resolution In

flam

mat

ory

resp

onse

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- a - 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: 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-a 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



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

Igennus CVD support protocol

Pharmepa Step 1: Restore2 capsules = 1g pure ethyl EPAVitamin 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.



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Homocysteine ControlSustained 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

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www.igennus.com01223 421434

[email protected]

Thanks to Dr. Nina Bailey

Sophie TullyNutrition education manager

[email protected]@igennus.com

07908683174

http://www.igennus.com/

mailto:[email protected]



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