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CARDIOVASCULAR DISEASE

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CARDIOVASCULAR DISEASE Powered By Docstoc
					Nutrition Medicine in CARDIOVASCULAR DISEASE
Dr. Melvyn A Sydney-Smith. KGSJ. Adjunct Professor (Nutrition Medicine) RMIT University. Melbourne.

Cardiovascular Disease ~ Prevalence in 200405
In 2004-2005: 18% (3.5 million) of Australians reported having a long-term cardiovascular condition.  hypertension ~ 11% (2.1 million)  heart, stroke or vascular conditions ~ 3.8% 28% reported angina, 20% another ischaemic heart disease, 12% a cerebrovascular disease, 35% oedema and heart failure and 27% reported an arterial disease capillaries The number of Australians with cardiovascular disease declined from 4.3% in 2001, to 3.8% in 2004-05

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Age-related prevalence of cardiovascular conditions ~ 2004-05

Age group (years)
Source ABS, National Health Survey: Summary of Results, Australia, 2004-05 cat. no 4364.0

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Reported prevalence of cardiovascular conditions, 2004-05

Source: ABS, National Aboriginal and Torres Strait Islander Health Survey, 2004-05, cat. no. 4715.0

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Cardiovascular Disease ~ mortality rate
Australian CVD mortality rates remain high ~ 110/1000 though lower than USA, New Zealand and the UK.
Australian Bureau Statistics. 2004

SELECTED CAUSES OF DEATH – 1970–72 AND 2002–04

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Cardiovascular Disease ~ mortality rates

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CARDIOVASCULAR DISEASE PATHOGENESIS

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Cardiovascular Disease ~ pathophysiology

 Atherothrombosis:  most common trigger factor of a CVD event  Atheromatous plaque erosion or rupture   Formation of a platelet-rich thrombus   Partial or complete vascular occlusion   Tissue ischaemia, damage and necrosis
Chapman MJ, Pharmacol Therapeut. 2007. 113(184-96)

 3 Major atherogenic mechanisms are: Dyslipidemia ~ Apo-lipoprotein balance Endothelial dysfunction Inflammation

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ATHEROMA PLAQUE DEVELOPMENT
 Key players in all stages of atherothrombosis are:
 Vascular endothelial cells
 Prostacyclin production ~ from PGH2 by prostacyclin synthase  Nitric Oxide synthesis ~ from Arginine by eNOS3

 Blood Platelets
 Atherogenesis ~  Plaque progression ~ inflammation  Thrombosis ~

 Leukocytes ~ monocytes & neutrophils & lymphocytes
 Inflammatory cascade ~ production of cytokines, free radicals

and proinflammatory eicosanoids

 Fibroblasts & myoblasts ~
 cellular proliferation and intercellular matrix changes

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Cardiovascular Disease ~ atherogenesis
 Pathophysiological mechanisms involved:

Endothelial dysfunction  Inflammation  Oxidative stress  Cholesterol accumulation  Cellular apoptosis  Extracellular matrix degeneration  Accelerated by major risk factors:  Dyslipidemia  Hypertension  Smoking  Insulin resistance  obesity
 Chapman MJ, Pharmacol Therapeut. 2007. 113(184-96)

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Cardiovascular Disease ~ atherogenesis
 Multiple mechanisms contribute synergistically to atheromatous plaque

development ~ cascading towards the disease phenotype
Chapman MJ, Pharmacol Therapeut. 2007. 113(184-96)

Endothelial Dysfunction

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CARDIOVASCULAR DISEASE ~ TREATMENT
 Primary ~ preventive

major disease reduction benefit occurs at this stage ~BUT~ only if therapy implemented  Secondary morbidity and mortality benefits from therapy is well below that of primary prevention

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CardioVascular Diease: TREATMENT
 Focus of primary and secondary preventive therapy is to:
 Reduce cholesterol levels ~
 Statins ~ PLUS ~ Mediterranean diet

 Reduce platelet activity
 Aspirin ~ PLUS ~ Omega-3-Essential fatty Acids

 Reduce Inflammation ~
 Statins + aspirin

 Improve Endothelial Dysfunction
 Statins

What about improving cardiac & vascular cell metabolism?

 Control blood pressure
 ACE inhibitors, ACE receptor inhibitors  chlorthiazides, calcium-channel blockers

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Cardiovascular Disease ~ Dyslipidemia is a major risk factor, related to CHD risk

 Cardiovascular Disease ~ Dyslipidemia  LDL cholesterol reduction reportedly decreases:
 CVD events ~ including myocardial infarction and stroke  CVD mortality ~ by about 30-40% Clinical Significance of Statin Pleiotropic Effects: Hypotheses Versus Evidence. Davidson MH. Circulation 2005;111;2280-2281

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Primary prevention ~ statin therapy
Baigent C, Keech A, et al. 2005. Lancet 366(9493).
"Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins."

 The meta-analysis reported: 12% proportional reduction in all-cause mortality per 1

mmol/L reduction in LDL cholesterol  RR 0.88, 95% CI 0.84-0.91; p<0.0001) 19% reduction in coronary mortality  RR 0.81, CI 0.76-0.85; p<0.0001), and  non-significant reductions in: non-coronary vascular mortality  RR 0.93, 0.83-1.03; p=0.2 non-vascular mortality  RR 0.95, 0.90-1.01; p=0.1

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Primary prevention ~ statin therapy
Thavendiranathan P. Bagai A, et al. 2006. Arch Intern Med. 166(21):2307.
Primary Prevention of Cardiovascular Diseases With Statin Therapy: A Meta-analysis of Randomized Controlled Trials. 7 trials: 42 848 patients, 90% no CVD history, Mean follow-up 4.3 yrs

Statin therapy reduced the RR of:
 major coronary events, by 29.2%  (95% CI, 16.7%-39.8%) (P<0.001)  major cerebro-vascular events, 14.4%  (95% CI, 2.8%-24.6%) (P=0.02)  revascularizations 33.8%  (95% CI, 19.6%-45.5%) (P<0.001)

Statin therapy produced non-significant reductions in:
 CHD mortality of 22.6%  (95% CI, 0.56-1.08) (P=0.13)  Overall mortality 8%  (95% CI, 0.84-1.01) (P=0.09)

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Secondary prevention~ statin therapy
Maycock A, Muhlestein CA et al. 2002. J Am Coll Cardiol 40(10): 1777.
“Statin therapy is associated with reduced mortality across all age groups of individuals with significant coronary disease, including very elderly patients.”

 Mortality was decreased among statin users vs

non-users in all age groups:
 >80 yrs: 29.5% non-users vs 8.5% users ~ HR 0.50, p =
0.036

 65-79 yrs: 18.7% non-users vs. 6.0% users ~HR 0.56,
p<0.001

 <65 yrs: 8.9% non-users vs. 3.1% users ~ HR 0.70, p =
0.097

NB: the Hazard Ratio for those <65 yrs age was actually NOT significant ~ contrary to the authors stated conclusions.

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CVD Therapy: omega-3-Fatty Acids
 Omega-3-EFAs 1000mg/day is also very effective  Gizzi Prevenzione Trial reported:  20% reduction in overall mortality  30% reduction in cardiovascular deaths ~and~  45% reduction in sudden death
Stone NJ. GISSI-Prevenzione Trial. Curr Cardiol Rep 2000; 2(5):445-451

 Omega-3-EFA therapy significantly prevents:  cardiac arrhythmia ~and~  Thrombotic disorders
Von Schacky C. The role of omega-3 fatty acids in cardiovascular disease. Curr Atheroscler Rep 2003; 5(2):139-145 Nambi V and Ballantyne CM. 2006). "Combination therapy with statins and omega-3 fatty acids. Am J Cardiol 2006:98: 341-381

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Dyslipidemia and Antilipidemic Therapy
Studer, M., M. Briel, et al. (2005). "Effect of Different Antilipidemic Agents and Diets on Mortality: A Systematic Review." Arch Intern Med. 165(7): 725-30.

 Compared with control groups, risk ratios for overall

mortality were:  0.77 for n-3 fatty acids (95% CI, 0.63-0.94)  0.87 for statins (95% CI, 0.81-0.94)  0.84 for resins (95% CI, 0.66-1.08)  0.96 for niacin (95% CI, 0.86-1.08)  0.97 for diet (95% CI, 0.91-1.04).  1.00 for fibrates (95% CI, 0.91-1.11)

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CVD ~ Omega-3-FAs & Statins
Nambi, V. and C. M. Ballantyne (2006). "Combination therapy with statins and omega-3 fatty acids. Am J Cardiol 2006:98: 341-381.

 statin monotherapy is commonly insufficient to reduce
 Non-HDL cholesterol to recommended goals  Triglyceride levels  Statin + omega-3FAs consistently shown to be:  effective, safe, and well-tolerated treatment  provide additional lipid improvement without requiring

additional laboratory tests  do not increase risk for adverse muscle or liver effects.  Patients with recent myocardial infarction may also benefit from this combination.

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Dyslipidemia: Statin & Niacin
Nicotinic acid is a more potent agent than fibrates for raising HDL-C, by up to 29% at recommended doses.  It also substantially reduces triglycerides and LDL-C, and  promotes a shift from small, dense LDL to larger, more buoyant LDL particles.  nicotinic acid with a statin will produce a greater reduction in cardiovascular risk in patients with diabetes and metabolic syndrome than statin monotherapy alone.  Nicotinic acid is safe for use in patients with diabetes, with no evidence of clinically relevant deterioration in glycaemic control at recommended doses (≤ 2g/day).
Chapman, M. J., G. Assmann, et al. (2004). "Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid a position paper developed by the European Consensus Panel on HDL-C." Current Medical Research and Opinion 20: 1253.

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Dyslipidemia: Statin & Niacin
 Simvastatin (mean daily dose 13 ± 6 mg) and nicotinic acid

(mean daily dose (2.4 ± 2.0 g) led to:  26% increase in HDL-C, 38% reduction in triglycerides and 42% reduction in LDL-C.  associated with a 90% fall in the frequency of major coronary events compared with placebo (p = 0.03) in patients with CHD,  significant angiographic regression of stenosis by 0.4% on average, compared with progression of 3.9% on placebo (p < 0.001).
Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92
Taylor, A. J., L. E. Sullenberger, et al. (2004). "Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: A Double-Blind, Placebo-Controlled Study of Extended-Release Niacin on Atherosclerosis Progression in Secondary Prevention Patients Treated With Statins." Circulation 110(23): 3512-7.

Secondary prevention Multiple Risk Factor Intervention
Multiple risk factor intervention trials show little overall benefit:
statins, hypertensive agents, lifestyle counselling, AHA diet “these interventions may have small effects on levels of the major risk factors but very limited, impact on reducing mortality and morbidity.”  the pooled odds ratios for total and CHD mortality were:  0.96 (95% CI 0.92 to 1.01) for total mortality and  0.96 (95% CI 0.89 to 1.04) for CHD mortality  Net changes in systolic and diastolic blood pressure, were (weighted mean differences) -3.6 mmHg (95% CI -3.9 to -3.3 mmHg), -2.8 mmHg (95% CI -2.9 to -2.6 mmHg) and and blood cholesterol -0.07 mMol/l (95% CI -0.8 to -0.06 mMol/l) respectively.

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Multiple risk factor interventions for primary prevention of coronary heart disease. Ebrahim S et al. Cochrane Database of Systematic Reviews: Reviews 2006 Issue 4

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Dyslipidemia: Red Yeast Rice ~ A Natural Statin
Journoud, M. and P. J. H. Jones (2004). "Red yeast rice: a new hypolipidemic drug.“ Life Sciences 74(22): 2675.

“Evidence shows that fermented red yeast rice: lowers cholesterol levels moderately compared to other statin drugs, ~but with~ the added advantage of causing less adverse effects. A review of the body of evidence surrounding the properties of red yeast rice underscores its potential as a new alternative to lipid level control.”

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Dyslipidemia: A Natural Statin
Zhao, S.-P., L. Liu, et al. (2003). "Effect of xuezhikang, a cholestin extract, on reflecting postprandial triglyceridemia after a high-fat meal in patients with coronary heart disease." Atherosclerosis. 168(2): 375.

 Xuezhikang (cholestin) significantly reduced:  fasting serum total cholesterol (TC) by 20%  low-density lipoprotein cholesterol (LDL-C) by 34%  Triglycerides (TG) by 32% and  ApoB by 27%) levels  Significantly (p<0.001) elevated  high-density lipoprotein cholesterol (HDL-C) by 18%  apoA-I levels by 13%

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CARDIOVASCULAR DISEASE

INFLAMMATION

CVD ~ Inflammation
Gerard C & Rollins BJ. 2001. Chemokines and disease. Nature Immunology 2:108-15 Moutsopoulos, N. M. and P. N. Madianos (2006). "Low-Grade Inflammation in Chronic Infectious Diseases: Paradigm of Periodontal Infections." Ann NY Acad Sci 1088(1): 251-64

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 Chronic inflammation is positively linked to CVD
 Elevated hs-CRP, proinflammatory cytokines {IL-6 and

TNF-alpha} and chemokines  Increased incidence of CVD in those with: Overt inflammatory conditions
 Autoimmune disease, renal disease, allergic disease, coeliac

disease, periodontal disease and inflammatory bowel disease

Fatty infiltration of liver
 Persistent elevated GGT is predictive of metabolic syndrome

insulin resistance  obesity
 Adipocyte production of cytokines and chemokines.

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CVD ~ Inflammation
Recommended treatment is Aspirin therapy:
 Downregulates platelet activation by selectively inhibiting

COX-1 activity   Reduces platelet TXA2 synthesis and decreases:  Thrombogenesis  Cytokine & chemokine release  Pro-Inflammatory eicosanoid production  Adverse effects of aspirin therapy are:  Increased intestinal mucosal permeability  Increased gastro-duodenal ulceration and bleeding  Increased risk of haemorrhagic stroke

CVD ~ Inflammation: aspirin therapy
Njaman W, Miyauchi K, et al. (2006). "Impact of Aspirin Treatment on Long-Term Outcome (Over 10Years) After Percutaneous Coronary Intervention." Int Heart J 47(1): 37-45

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 Aspirin therapy following PCI reportedly reduced:  all cause mortality (10% versus 16.4%; P = 0.01) and  cardiac death (3.7% versus 8.0%; P = 0.02) compared to other antiplatelet drugs.  The hazard ratio (HR) was  all cause mortality (HR, 0.49; 95%CI [0.29-0.80], P = 0.005) and  cardiac mortality (HR, 0.32; 95%CI [0.14-0.72], P = 0.006)
.

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CVD ~ Inflammation: aspirin therapy
Aspirin for the Primary Prevention of Cardiovascular Events in Women and Men: A Sex-Specific Metaanalysis of Randomized Controlled Trials. Berger JS, Roncaglioni MC et al. 2006 JAMA 295(3): 306-13.

 Among 51 342 women, aspirin therapy was associated with:
 12% reduction in CV events, OR 0.88; 95% CI, 0.79-0.99; P =0.03  17% reduction in stroke, OR 0.83; 95% CI, 0.70-0.97; P =0.02)  reflecting lower ischemic stroke (OR, 0.76; 95% CI, 0.63-0.93;

P=0.008)  No significant effect on MI or cardiovascular mortality.

 Among 44 114 men, aspirin therapy was associated with:
 14% reduction in CV events (OR, 0.86; 95% CI, 0.78-0.94; P =0.01)  32% reduction in MI (OR, 0.68; 95% CI, 0.54-0.86; P =0.001)  No significant effect on stroke or cardiovascular mortality

 Aspirin Rx increased risk of bleeding:
 In women (OR, 1.68; 95% CI, 1.13-2.52; P =.01) and  in men (OR, 1.72; 95% CI, 1.35-2.20; P<.001).

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CVD ~ Inflammation: combined therapy
Hippisley-Cox J. & Copland C. 2005. "Effect of combinations of drugs on all cause mortality in patients with ischaemic heart disease: nested case-control analysis." BMJ 330(7499):1059-63.

 Drug combinations apparently exhibit synergistic effects:  greatest reduction in all cause mortality were: statins, aspirin, and beta-blockers ~

83% reduction (77 - 88% CI) statins, aspirin, B-blockers, and ACE inhibitors ~ (75% reduction, 65% - 82% CI); statins, aspirin, and ACE inhibitors ~ (71% reduction, 59% - 79%)

What about Niacin and omega-3-EFAs?

Enter “THE POLYPILL”
Wald NJ and Law MR. 2003. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 326(7404): 1419.

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One statin drug (atorvastatin 10 mg/d or simvastatin 40 mg/d) Three antihypertensive drugs thiazide, beta blocker, ACE inhibitor (at half standard dose) Folic acid (0.8 mg/d) Aspirin (75 mg/d)
 Estimated to reduce CHD events by 88% and stroke by 80%
 30% people above age 55 would gain 11 years, event-free  8 – 15% would suffer medication adverse events

CVD ~ Inflammation: periodontal therapy
Moutsopoulos, N. M. and P. N. Madianos (2006). "Low-Grade Inflammation in Chronic Infectious Diseases: Paradigm of Periodontal Infections." Ann NY Acad Sci 1088(1): 251-64.

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 Periodontitis appears to be a primary risk factor for

cardiovascular disease  contributes to generation of a systemic inflammatory phenotype  Elevated systemic inflammation markers:
 C-reactive protein, interleukin 6, haptoglobin & fibrinogen

 These markers are higher in periodontal patients with

acute myocardial infarction (AMI) than in patients with AMI alone  Intervention trials indicate periodontal therapy:  improves endothelial function Reduces inflammatory markers

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CVD ~ Inflammation: periodontal therapy
Gebaraa EC, Pustiglioni AN et al. 2003. Propolis extract as an adjuvant to periodontal treatment. Oral Health Prev Dent..1(1):29-35.

 Post-scaling subgingival propolis irrigation was

more effective than conventional treatment ~ by both clinical and microbiological parameters
 Decreased anaerobic bacteria (p=0.007)  Increased sites with low level P. gingivalis (p=0.005)  Decreased sites with detectable yeasts (p=0.000)  No increase in coagulase positive Staphylococci and

Pseudomonas spp.  Increased sites with probing depth (PD) < or = 3 mm

English, H. K., A. R. Pack, et al. (2004). "The effects of manuka honey on plaque and gingivitis: a pilot study." J Int Acad Periodontol 6(2): 63-7.

CVD ~ Inflammation: periodontal therapy

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 Compared to the control group, manuka honey

significantly reduced:
 mean dental plaque scores (0.99 down to 0.65; p=0.001),  percentage of bleeding sites (48% down to 17%;

p=0.001),

 Conclusion: These results indicate potential

therapeutic role for manuka honey in the treatment of gingivitis and periodontal disease

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ENDOTHELIAL DYSFUNCTION
Probably the most important factor in the promotion of cardiovascular disease
Drexler, H. and B. Hornig (1999). "Endothelial Dysfunction in Human Disease.“ J Molec Cell Cardiol. 31: 51.

Napoli, C., W. C. Stanley, et al. (2007). Nutrition and cardiovascular disease: Putting a pathogenic framework into focus. Cardiovascular Research. 73(2): 253.

CVD ~ Endothelial Dysfunction

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 Critical elements include:
 Genotype ~
 multiple polymorphic genes interact adversely with environment  affecting lipid & glucose metabolism, cytokine & eicosanoid

synthesis & production

 Intrauterine & perinatal nutrition & growth  Dyslipidemia ~
 particularly LDL/HDL ratio & oxidised LDL

 Insulin Resistance and obesity  Diet
 Many have been chosen ~ but few are effective  Mediterranean diet most researched  Lyon Heart Study, GISSI Preventiozone, DASH

 Exercise ~ Sedentary lifestyle vs regular exercise  Smoking & environmental pollutants

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CVD ~ Genotypic disease
Multiple polymorphic genes interact adversely with environment
 affecting lipid & glucose metabolism, cytokine &

eicosanoid synthesis & production

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CVD ~ Genotypic disease
The human genome: is comprised of 46
chromosomes 22 autosomal pairs plus 2 sex chromosomes The 3 billion base pairs of DNA contain about 30,000 - 40,000 protein-coding genes. •a much smaller number than predicted – •only twice as many as in the worm or fly The coding regions are less than 5% of the genome •function of the remaining DNA is not clear •some chromosomes have a higher gene density than others.
Understanding Genetics: available from: http://www.geneticalliance.org/ksc_assets/pdfs/manual Accessed 12th July 2006.

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Gene Polymorphism
Single nucleotide polymorphisms ~
 Single base-pair DNA differences observed

between people  simplest and most common form of DNA polymorphism ~
 frequency about of 1/1,000 base pairs  In any individual, gene polymorphism is estimated

to affect about 10% of the genome  SNPs may cause disease if they affect expression

of an enzyme-coding gene
 About 1000 monogenic diseases due to SNPs have

been identified
Jimenez-Sanchez G et al. 2001. Nature. 409:853-55

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Gene Polymorphism

Each gene is composed of 2 alleles which may be:
 the same ~ homozygous ~ AA or aa

or  different ~ heterozygous ~ Aa However, there may be more than 2 allele variants {polymorphisms} ~ e.g: APO E2, APO E3, APO E4 Thus a person’s APO E genotype may be:

E2/E2, E2/E3, E2/E4 E3/E3, E3/E4, E4/E4 NB: 6 different genotypes

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Gene Polymorphism and Disease

Incidence of specific allele variants between populations often varies:
Thus the APO E4 gene ~

 Caucasian population


mean frequency 15% ~  North-South variance ~ 23% in Finland and 20% in Sweden down to 8% in Italy

 Non-Caucasian populations


About 30% in Africans (Nigeria)  35% in Papua New Guinea  5% in China

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Multi-Genetic Disease
Moreover, multiple polymorphisms interact to:  modify nutrient demand and metabolism  affect enzyme production and efficiency  alter epigenetic regulatory mechanisms  cytokines, hormones, sensor molecules and transcription factors  Ppars, MAP kinases, NF-Kappa-B  modulate expression of other genes  further alters metabolism and regulatory elements  change responses to environmental factors  nutrition, exercise, xenobiotics

Leads to development of disease phenotype
Hypertension, coronary heart disease, Type 2 diabetes

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Multigenic disease: arteriosclerosis

Multiple polymorphisms that regulate expression and activity of genes involved in blood lipid regulation are common:  Occur in 7 – 16% of population
 Apolipoproteins: Apo A-IV, Apo A, Apo B, Apo E  Lipoprotein lipase  Cholesterol ester transfer protein

Affect cholesterol binding and clearance  Promote hyperlipidaemia, arteriosclerotic disease and dementia  Alter responses to cholesterol reducing interventions
  Both dietary & pharmacological  Confound epidemiological & interventional research
Knoblauch H, Bauerfeind A et al. Hum Molec Genet, 2002; 11(12):1477–85.

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Other links have been identified ~  Peroxisome proliferator activated receptor
 Regulates genes coding for inflammatory mediators, lipogenesis and

glucose metabolism  Gene variants contribute to cholesterol metabolism, insulin resistance & obesity  Sterol regulatory element-binding protein 1c (SREBP-1c)  activates insulin-dependent increase in lipogenic gene expression  Carbohydrate Response element Binding Protein (ChREBP)  Glucose sensor that regulates glyco-lipid metabolism

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Carbohydrate Response-Element Binding Protein (ChREBP) ~ major gene-metabolic molecule
Transcription factor coded for by a polymorphic gene Upregulates genes that code for lipogenesis Downregulates genes that code for glucose and lipid oxidation Activated by dietary carbohydrate (glucose & sucrose) and insulin ChREBP activity inhibited/normalised by omega-3-EFA Uyeda et al, 2002

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Gene-Nutrients-Lifestyle

Genotype is NOT an immutable prescription for disease
Multiple dietary, nutritional & lifestyle factors strongly influence:  Nuclear & mitochondrial gene expression  Promoter & suppressor codon activity  Transcription factor production & activity  Modulatory epigenetic molecules Nutritional & lifestyle modification can counter a disease promoting genome
Kaput & Rodriguez, 2004

Endothelial Dysfunction: Foetal & Perinatal Nutrition
Atul Singhal. 2005. Endothelial dysfunction: role in obesity-related disorders and the early origins of CVD. Proceedings of the Nutrition Society (2005), 64, 15–22.

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 Intrauterine growth retardation impairs vascular function

programming.
 Vascular function is impaired in infants born small-for-gestational

age, but not in those of low birth weight due to prematurity
Singhal A et al. 2001. Preterm birth, vascular function and risk factors for atherosclerosis. Lancet 358, 1159–1160 Cheung YF et al. 2004. Relation of arterial stiffness with gestational age and birth weight. Archives of Disease in Childhood 89, 217–221  Vascular function is programmed in both preterm and full-term

infants and the effects appear to be independent of size at birth.

 Faster postnatal growth has a detrimental programming

effect on long-term vascular function.

Endothelial Dysfunction: Environmental Pollution
Bhatnagar, A. (2006). "Environmental Cardiology: Studying Mechanistic Links Between Pollution and Heart Disease." Circ Res 99(7): 692-705.

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 Many studies report that air pollution is associated with

increased cardiovascular mortality  significant relationships between particulate air pollution and ischemic heart disease, arrhythmias, and heart failure have been reported  Exposures to arsenic, lead, cadmium, pollutant gases, solvents, and pesticides are also linked to increased incidence of cardiovascular disease.  Urban diesel exhaust impairs vascular function and fibrinolysis
Mills NL, Tornqvist H., et al. 2005. Diesel Exhaust Inhalation Causes Vascular Dysfunction and Impaired Endogenous Fibrinolysis. Circulation 112(25): 3930-6.

However, The major influence on genomic an cardiovascular disease is probably the gross discrepancy between our human ancestral genome and the modern consumer-age diet

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The human genome evolved under harsh selection conditions over a period of 3.5 million years ~ The spontaneous mutation rate for nuclear DNA is estimated at about 0.5% per million years Over the past 10,000 years, the human genome is calculated to have changed only 0.05% from our paleolithic ancestors ~ The human genome is now struggling to cope with the vastly different diet and lifestyle of the modern era
Eaton SB. 2006. Proc Nutrit Soc. 65(1):1-6

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The modern Homo sapiens genome evolved in northeast Africa about 200,000 years ago ~ then migrated throughout the rest of the world The first migration occurred following hominid decimation about 70,000 years ago  hunter-gatherer societies of the Middle East, Asia and Australia

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Following the last Ice-Age 12,000 years ago, the birth of agriculture 10,000 years ago  Settled lifestyle and increased population density

~ increased demand for intensive farming & animal husbandry – which occurred about 8,000 years ago
~ greater starch-yielding grain crops ~ increased gluten content in grains ~ altered fat content in animals from supplemental feeding

~ Industrial revolution altered food supply even further
~ farming monoculture developed ~ increased dependence on grains ~ refined sugars became more accessible ~ increased fat and trans-fat intake ~ increased omega-6/omega-3 EFA ratio
Bradshaw Foundation. www.bradshawfoundation.com/stephenoppenheimer

Paleolithic diet: Protein ~ 30-40% Carbohydrates ~ 35% sugars ~ 2-3% Fats ~ 30-35% Saturated fats ~ 7.5% Trans-fat < 1% Omega-6/omega-3 ~ 2:1

Modern Diet 10-20% 60-70% 15% 30-35% 15-30% 5-10% of fats 10-20:1

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Before European contact, hunter-gatherer population diets approximated the Paleolithic Diet
~ Australian Aborigines ~ migrated 50,000 yrs ago and isolated until 1778 Diet based on wild game, seafood, nuts, seeds, yams & greens ~ Pacific Islands ~ Fiji 1500 BC, Samoa & Cook Islands 200 BC, Hawaii 600 AD, ~ New Zealand about 1250 AD Diet was based on seafood, poultry, pig + taro, cassava, various greens, tropical fruits, nuts, seeds and coconut

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Hunter-gatherer diets. Analysis of dietary intake of 229 Hunter-Gatherer populations around the world showed median animal food intakes of 66 – 75% and plant food intakes 26 – 35% of total energy.
Cordain L, Eaton SB et al. 2002. EJCN.56,Suppl 1:S42–S52.

Population Ache (Paraguay) 25S !Kung (Africa) 20S Aborigines (Arnhem Land) 12S

Animal food (%) 78 68 77

Plant food (%) 22 32 23

Anbarra (Australia) 12S
Hiwi (Venezuela) 6N Onge (Andaman Is) 12N

75
75 79

25
25 21

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Traditional diet improves chronic disease: In full-blood Aborigines with CHD, diabetes and hypertension, reversion for 7 weeks to a “traditional” diet resulted in: ~ mean wt loss of 8kg over 7 weeks ~ reduced blood pressure ~ reduced fasting insulin & glucose ~ improved glucose and insulin responses on GTT ~ reduced triglyceride and VLDL levels ~ reduction or cessation of medication

The traditional diet consisted of: ~ 64% protein, ~ 13% fat and ~ 23% low-GI/GL CHOs ~ 1200 Cal/person/day
K O'Dea. 1984. Diabetes, 33(6): 596-603.

61

Genes, Diet and Disease
Summary: The broad perspective of human metabolic and archeological data suggests that human genes are adapted to a nutrient intake that approximates that of the Paleolithic Diet Genomic research has identified multiple gene-regulated transcription binding proteins that are: a) responsive to dietary lipid and CHO intake and b) propel metabolism towards common disease phenotypes CHD, Hypertension, Insulin Resistance, Diabetes etc. Individual gene variants have also been identified that affect a) disease development and b) response to nutritional and pharmacological therapy

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DIET, Insulin Resistance & Obesity
Napoli, C., W. C. Stanley, et al. (2007). Nutrition and cardiovascular disease: Putting a pathogenic framework into focus. Cardiovascular Research. 73(2): 253.

 Improper diet and lack of exercise are the major

contributory factors in development of obesity  Obesity promotes atherogenesis via two related pathways:
 insulin resistance  hyperinsulinaemia and elevated blood glucose  endothelial dysfunction  Promotes low-grade chronic inflammation  elevated TNF-alpha and other cytokines

~ IL6, PAF and various chemokines

Endothelial Dysfunction: Obesity
Hotamisligil GS. 2006. Inflammation and metabolic disorders. NATURE. 444(14):860-67.

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 Metabolic and immune response pathways have been

evolutionarily conserved throughout the species
 Immune activity and metabolic regulation are highly integrated and

interdependent  This interface acts as a central homeostatic mechanism  Dysfunction promotes obesity and leads to a cluster of chronic metabolic disorders

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Atherogenesis ~ Endothelial Dysfunction: Diet
 Multiple dietary factors and nutrient balances reportedly

affect endothelial function, inflammation and blood lipids:
 Saturate fat vs unsaturated fat intake  Omega-6 vs omega-3 unsaturated fat intake

 Dietary carbohydrate load
 Carbohydrate vs fat intake  Dietary antioxidant and polyphenol intake  Dietary fibre intake  Dietary fat vs polyphenol vs carbohydrate intake Cordain, L., S. B. Eaton, et al. (2005). "Origins and evolution of the Western diet: health implications for the 21st century." Am J Clin Nutr. 81(2): 341-54. Giugliano, D., A. Ceriello, et al. (2006). "The Effects of Diet on Inflammation: Emphasis on the Metabolic Syndrome." J Am Coll Cardiol. 48(4): 677. Kopp, W. (2006). The atherogenic potential of dietary carbohydrate. Preventive Medicine. 42(5): 336.

The Assessment and Management of Cardiovascular Risk. Evidence-based Best Practice Guideline,
1) Enjoy three meals a day, selecting from dishes that encourage you to eat plant foods and fish, with little or no dairy fat, meat fat or deep fried foods 2) Choose fruits and/or vegetables at every meal and most snacks. 3) Select whole grains, whole grain breads, or high fibre breakfast cereals in place of white bread and low fibre varieties at most meals and snacks 4) Include fish, or dried peas, beans and soy products, or a small serving of lean meat or skinned poultry, at one or two meals each day 5) Choose low fat milk, low fat milk products, soy or legume products every day 6) Use small amounts of oil, margarine, nuts or seeds 7) Drink plenty of fluids each day, particularly water, and limit sugarsweetened drinks and alcohol 8) Use only small amounts of total fats and oils, sugar and salt when cooking and preparing meals, snacks, or drinks. Choose ready-prepared foods low in these ingredients 9) Mostly avoid or rarely include butter, deep-fried and fatty foods, and only occasionally choose sweet bakery products
New Zealand Guidelines Group, December 2003.

65

66

Atherogenesis ~ Endothelial Dysfunction: Diet
Parikh P, McDaniel MC et al. 2005. Diets and Cardiovascular Disease. J Am Coll Cardiol 2005;45:1379–87  Low-Fat diet  Low-Carbohydrate Diet  Difficult to achieve  Short-term weight loss  Promotes Insulin Resistance  Long-term effects on CVD unknown  No impact on mortality  Initiate decreased energy intake & weight loss  Very-Low-Fat Diet  Mediterranean Diet  May decrease cardiac events  Secondary prevention  Concern about applicability and  Prevention of sudden cardiac death sustainability  Healthy overall approach to dieting  Long-term sustainability  Low Glycemic Index Diet  DASH  Unproven effects on CVD  Decreased hypertension ~  Initiate reduced intake of by 5.5/3.3mm energy-dense CHOs and  Similar to Mediterranean Diet  initiate weight loss

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Low CHO Diet and Weight Loss
Length of Trial Low-CHO: baseline weight (kg) Low-CHO: diet weight change (%) Low-fat baseline weight (kg) Low-fat diet weight change (%) p value (between groups)

Foster et al. NEJM. 2003 12 mo 99 + 20 -4 + 7

Stern et al. Ann Int Med 2004 12 mo 130 + 23 -5 + 9

Brehm et al JCEM. 2003 6 mo 91 + 8 -9 + 1

Yancy et al. Ann Int Med, 2004 6 mo 97 + 19 -12 + 2

98 + 16
-3 + 6 0.26

132 + 27
-3 + 8 0.195

92 + 6
4+1 <0.001

98 + 15
-7 + 2 <0.001

Parikh P, McDaniel MC et al. Diets and Cardiovascular Disease. J Am Coll Cardiol 2005;45:1379–87

Low GI or GL diets inconclusive. Parikh P et al. J Am Coll Cardiol 2005;45:1379–87

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69

CHD Risk & DIET: Mediterranean Diet ~

70

Endothelial Dysfunction: Optimal Diet

What is the optimal diet?
 Maintain low-moderate Glycemic Index and Glycemic

Load ~  Optimise Antioxidant & fibre intake ~ fruit & vegetables  Increase Essential Fatty Acid intake & omega-3/omega-6 balance ~  Maintain protein intake ~ fish, nuts/seeds, lean meat, cheese, legumes & wholegrains  Reduce saturated fat & trans-fat intake ~  Reduce calorie intake ~ ? 20-30% reduction promotes antiaging effect

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Endothelial Dysfunction: Diet

72

Enter “THE POLYMEAL”

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SPECIFIC NUTRIENTS IN CARDIOVASCULAR DISEASE

Cardiovascular Disease ~
Endothelial Dysfunction, Nitric Oxide and Arginine
Wu G and Meininger CJ. 2000. Arginine Nutrition and Cardiovascular Function. J. Nutr. 130: 2626–2629, 2000

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 Nitric Oxide ~ is a major mediator in endothelial function:  Produced in vascular endothelial cells by NO-synthetase

from arginine  NO is a vital anti-atherogenic molecule that:
 Inhibits atherogenesis  Enhances vasodilator activity

 Reduced NO production:
 is a measure of impaired endothelial health and  directly facilitates development of atherosclerosis

 eNOS activity & NO production can be increased by:
 High antioxidant intake ~ particularly ascorbate  Arginine therapy  Statin therapy

Cardiovascular Disease ~
Arginine, NO and endothelial dysfunction

75

 Compelling evidence shows that Arginine:  reverses endothelial dysfunction associated with major cardiovascular risk factors: hypercholesterolemia, smoking, hypertension, diabetes, obesity/insulin resistance and aging  ameliorates many common cardiovascular disorders coronary and peripheral arterial disease, heart failure, and ischemia/reperfusion injury  Increasing dietary arginine & ascorbate intake increases endothelial NO production
Wu G and Meininger CJ. Arginine Nutrition and Cardiovascular Function. J. Nutr. 130: 2626–2629, 2000

Cardiovascular Disease ~
Arginine and endothelial dysfunction

76

77

CVD Therapy: Antioxidants ~ Vitamin C

Vitamin C:
 Epidemiological study reported development of CHD in

males correlated inversely with Vit C status
Nyyssonen K, Parviainen MT et al. Vitamin C deficiency and risk of myocardial infarction: BMJ 1997; 314(7081):634-638.

 Vit C was not useful in secondary prevention of CHD
MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: Lancet 2002; 360(9326):23-33

 Nurses Health Study showed significantly reduced CHD

event risk with ascorbate supplement use
Osganian SK, Stampfer MJ et al. Vitamin C and risk of coronary heart disease in women. J Am Coll Cardiol 2003; 42(2):246-252

78

CVD Therapy: Antioxidants ~ Vitamin E
 Vitamin E:  Regulates endothelial cell proliferation  Inhibits platelet adhesion & activation  Protects against oxidation ~ particularly LDL  BUT must be natural mixed tocopherols ~and~ high

dose > 400 ~ 800 IU/day  -tocopherol markedly reduces -tocopherol level  -tocopherol is the more effective endovascular protective agent  reduces LDL cholesterol  Neutralises peroxynitrite damage
Singh, I., A. H. Turner, et al. (2005). Effects of gamma-tocopherol supplementation on thrombotic risk factors and measures of oxidative stress. Asia Pacific J Clin Nutri.14: S48. Dietrich, M., M. G. Traber, et al. (2006). Does [Gamma]-tocopherol play a role in the primary prevention of heart disease and cancer? A review. JACN. 25(4): 292.

79

CVD Therapy: Antioxidants ~ Vitamin E
 Contemporary studies indicate Vit E therapy:  Has no impact on CVD occurrence or outcome ~OR~  May promote CCF occurrence and mortality
Lonn E, Bosch J, et al. (2005). "Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial." JAMA. 293(11): 1338.

 Most Vit E studies are heavily flawed:  No monitoring of oxidative stress and markers of vascular response,  No monitoring of vitamin E levels.  Short duration and suboptimal dosages of vitamin E,  Suppression of gamma-tocopherol by alpha-tocopherol,  Unbalanced Vitamin E supplementation  Inappropriate administration relative to meal ingestion,
Robinson, I., D. G. de Serna, et al. (2006). "Vitamin E in humans: an explanation of clinical trial failure. Endocrine Practice. 12(5): 576-82 .

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CVD Therapy: Antioxidants : Selenium

Useful antioxidants:
 Selenium: works synergistically with Vit E  protects cell membrane from oxidative damage  Selenium concentrations were inversely associated with

coronary heart disease risk in observational studies
Flores-Mateo, G., A. Navas-Acien, et al. (2006). Selenium and coronary heart disease: a meta-analysis. Am J Clin Nutr 84(4): 762-73.

 Women living in the community who have higher serum

selenium are at a lower risk of death HR: 0.71, 95% CI 0.56-0.90.
Ray AL, Semba RD, et al. 2006. Low serum selenium and total carotenoids predict mortality among older women living in the community: the women's health and aging studies. J Nutr 136(1): 172-6.

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CVD Therapy: Antioxidants ~ Flavonoids
 Bioflavonoids (quercetin & hesperidin) and polyphenols) :
 increase tissue antioxidant capacity  increase anti-inflammatory activity  decrease platelet activation ~and~  enhance vascular endothelial function  intake inversely associated with cardiovascular disease
Bucki R, Pastore JJ, et al. 2003. Flavonoid inhibition of platelet procoagulant activity and phosphoinositide synthesis. J Thromb Haemost 1(8): 1820-8. Geleijnse, J. M., L. J. Launer, et al. (2002). "Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam Study." Am J Clin Nutr 75(5): 880-6. Perez-Vizcaino, F., J. Duarte, et al. (2006). "Endothelial function and cardiovascular disease: effects of quercetin and wine polyphenols." Free Radic Res 40(10): 1054-65.

CVD Therapy: Antioxidants Cocoa & Chocolate
Engler, M. B. and M. M. Engler (2006). "The emerging role of flavonoid-rich cocoa and chocolate in cardiovascular health and disease." Nutr Rev 64(3): 109-18.

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 Cocoa and chocolate are rich sources of antioxidant

flavonoids with beneficial cardiovascular properties.
 Favorable physiological effects include:  antioxidant activity,  Vasodilation & blood pressure reduction,  reduced platelet activity  Increased anti-inflammatory activity

 Improved isulin sensitivity

 Increasing evidence, experimental & clinical, suggest an

important role for these high-flavanol-containing foods in heart and vascular protection.

83

CVD Treatment: Coenzyme Q10
Tran MT, Mitchell TM, et al. 2001. Role of coenzyme Q10 in chronic heart failure, angina, and hypertension. Pharmacotherapy 21(7): 797-806.

CoQ10 is an essential lipid-soluble element of the ElectronTransport Chain  Mitochondrial antioxidant & electron transfer molecule  Essential to mitochondrial oxidative activity ~and~  myocardial contractility  Improves outcomes in cardiomyopathy & CCF  Increases ejection fraction, stroke volume, cardiac output and exercise tolerance  Co-Q10 level is reduced by statin therapy
Sander S, Coleman CI, et al. 2006. The impact of coenzyme Q10 on systolic function in patients with chronic heart failure. J Card Fail 12(6): 464-72. Chew GT. and Watts GF. 2004. Coenzyme Q10 and diabetic endotheliopathy: oxidative stress and the 'recoupling hypothesis'. Quart J Med. 97(8): 537-48.

84

CVD Treatment: alpha-Lipoic acid
Jones W, Li X, et al. 2002. Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells. Free Radic Biol Med 33(1): 83-93

 Lipoic acid: sulphur-containing antioxidant  Essential to cell membrane integrity & function particularly electrical conductance  Stimulates glutathione synthesis  enhances endothelial antioxidant defence and function  recycles dehydroascorbic acid to ascorbate,  decreases ROS generated by redox cycling  generates nitric oxide  restores mitochondrial aldehyde dehydrogenase activity thereby improving nitrate tolerance
Wenzel P, Hink U, et al. 2007. Role of reduced lipoic acid in the redox regulation of mitochondrial aldehyde dehydrogenase (ALDH-2) activity. Implications for mitochondrial oxidative stress and nitrate tolerance. J Biol Chem 282(1):792-9.

CVD Treatment: alpha-Lipoic acid
Sethumadhavan, S. and P. Chinnakannu (2006). "L-carnitine and alpha-lipoic acid improve age-associated decline in mitochondrial respiratory chain activity of rat heart muscle." J Gerontol A Biol Sci Med Sci 61(7): 650-9.

85

 Progressive mitochondrial structural damage and

loss of integrity occurs with aging 
 impairs cellular energy genesis, reducing activity of:
TCA cycle enzymes and electron transport chain complexes

 Combined carnitine/lipoic acid treatment:  raises mitochondrial energy producing capacity  reverses age-related mitochondrial enzyme decline  protects mitochondria from aging

CVD Treatment: Garlic
Rahman K. and Lowe GM. 2006. Garlic and cardiovascular disease: a critical review. J Nutr 136(3 Suppl): 736S-40S.

86

 Epidemiologic studies show an inverse correlation between

garlic consumption and progression of cardiovascular disease.  Numerous in vitro studies report that garlic
        

inhibits enzymes involved in lipid synthesis, decreases platelet aggregation, prevents lipid peroxidation of oxidized erythrocytes and LDL, increases antioxidant status, inhibits angiotension-converting enzyme. reduces cholesterol, inhibits platelet aggregation, reduces blood pressure, increases antioxidant status.

 44% of clinical studies report positive effects from garlic:

87

CVD Treatment: Garlic
Borek C. 2006. Garlic reduces dementia and heart-disease risk. J Nutr 136(3 Suppl): 810S-2S.

 Aged Garlic Extract (AGE) reportedly:  scavenges oxidants,  increases superoxide dismutase, catalase, glutathione peroxidase, and glutathione levels,  inhibits lipid peroxidation and inflammatory prostaglandins.  reduces cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase effect is additive with statins in its action.

CVD Treatment: Garlic
Rahman K. and Lowe GM. 2006. Garlic and cardiovascular disease: a critical review. J Nutr 136(3 Suppl): 736S-40S.

88

 Over 50% of clinical trials report negative results,

possibly due to:
 usage of different garlic preparations,  unknown active constituents and their bioavalability,

 inadequate randomization,
 selection of inappropriate subjects,  short duration of trials.

CVD Therapy: Vitamins B6, Folate, B12 & Betaine These nutrients reduce serum homocysteine level
 Homocysteine > 12mm/L is an independent risk factor for

89

vascular disease ~ smoking & high lipids.
Graham IM, Daly LE et al. Plasma homocysteine as a risk factor for vascular disease.

JAMA 1997; 277(22):1775-1781.

 Elevated homocysteine impairs endothelial function  Endothelial dysfunction responds to folate therapy

independent of homocysteine level  ? By maintaining tetrahydrobiopterin activity  Vit B6 insufficiency impairs endothelial function
Moat SJ, Lang D et al. Folate, homocysteine, endothelial function and cardiovascular disease. J Nutr Biochem 2004; 15(2):64-79

90

CVD Therapy: Niacin
Elam MB, Humminghake DB et al. ADMIT study. JAMA. 2000. 284:1263-70

 Niacin therapy  Increased HDL cholesterol by 29%  Reduced triglycerides by about 25% ~and~  Reduced LDL cholesterol by about 9%  was safe for use in patients with diabetes  Use the Inositol Hexaniacinate form  Minimises risk of niacin reaction  With phosphatidylcholine, hexaniacinate can optimise bile-salt production & cholesterol excretion

Goldberg AC. 2004. A meta-analysis of randomized controlled studies on the effects of Extended-Release niacin in women. Am J Cardiol. 94(1):121.

91

Nutrient Therapy in Vascular Disease
 Mineral therapy:  Magnesium & Potassium:  improve myocardial metabolism ~and~ inhibits arrhythmia ~and~ lowers blood pressure  Calcium: essential for myocardial contraction ~and~ assists in regulating BP  Zinc: essential for mitochondrial function ~and~ DNA/RNA repair  Chromium: essential for Glucose Tolerance Factor activity  Vanadium: Stabilises blood sugar & reduces blood lipids

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Nutrient Therapy in Vascular Disease
 Cardiovascular disease arises as a result of the interaction

between multiple related causal factors  Good research into the role of many of these factors and the management thereof remains woefully inadequate  broad spectrum pharmacotherapy is NOT a good option ~ particularly for primary prevention  Good management should seek to remediate all causal factors identified in the patient, utilising an integrated regimen of: Diet Exercise Nutrient supplementation Targeted pharmacotherapy

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Nutrient Therapy in Vascular Disease
Effective management needs to be systematic ~ our protocol is to assess and optimise:
Digestion: Diet: Antioxidant capacity Essential Fatty Acid balance Bowel dysbiosis Specific therapy Neurotransmitter balance Hepatic detoxification Hormonal balance

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Thank you for your attention ~and~ Please feel free to speak to me during the breaks ~AND~

Don’t forget ~ enjoy your daily Polymeal
 Grilled salmon with onion & garlic  Served with sauce of: tomato paste, garlic, coriander  Salad: lettuce, purslane, celery, cucumber, tomato,

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capsicum, mushroom, avocado, tofu & almonds  Dressing: olive oil, garlic & vinegar  Green tea served before the meal  Dessert: blueberries, strawberries with chocolate sauce (made with soy-milk & dark chocolate)  After-dinner drinks: Cabernet sauvignon 1glass  Plus 1 Poly-nutrient pill


				
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