Nutrition Medicine in CARDIOVASCULAR DISEASE

1. Nutrition Medicine in CARDIOVASCULARDISEASE Dr. Melvyn A Sydney-Smith. KGSJ. Adjunct Professor (Nutrition Medicine) RMIT University. Melbourne.

2. 2 Cardiovascular Disease ~ Prevalence in 2004-05 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

3. 3 Age-related prevalence of cardiovascular conditions ~ 2004-05

4. 4 Reported prevalence of cardiovascular conditions, 2004-05

5. 5 Cardiovascular Disease ~ mortality rate

6. 6 SELECTED CAUSES OF DEATH � 1970�72 AND 2002�04

7. 7 Cardiovascular Disease ~ mortality rates

8. 8 CARDIOVASCULAR DISEASE PATHOGENESIS

9. 9 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

10. 10 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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12. 12 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)

13. 13 Cardiovascular Disease ~ atherogenesis Multiple mechanisms contribute synergistically to atheromatous plaque development ~ cascading towards the disease phenotype Chapman MJ, Pharmacol Therapeut. 2007. 113(184-96)

14. 14 CARDIOVASCULAR DISEASE ~ TREATMENT Primary ~ preventivemajor disease reduction benefit occurs at this stage ~BUT~ only if therapy implemented Secondarymorbidity and mortality benefits from therapy is well below that of primary prevention

15. 15 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 Control blood pressure ACE inhibitors, ACE receptor inhibitors chlorthiazides, calcium-channel blockers

16. 16 Cardiovascular Disease ~ Dyslipidemia is a major risk factor, related to CHD risk

17. 17 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

18. 18 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

19. 19 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)

20. 20 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.

21. 21 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

22. 22 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)

23. 23 CVD ~ Omega-3-FAs & StatinsNambi, 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.

24. 24 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.

25. 25 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.

26. 26 Secondary preventionMultiple 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. Multiple risk factor interventions for primary prevention of coronary heart disease. Ebrahim S et al. Cochrane Database of Systematic Reviews: Reviews 2006 Issue 4

27. 27 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 potentialas a new alternative to lipid level control.�

28. 28 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%

29. 29 CARDIOVASCULAR DISEASE INFLAMMATION

30. 30 CVD ~ InflammationGerard C & Rollins BJ. 2001. Chemokines and disease. Nature Immunology 2:108-15Moutsopoulos, 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 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.

31. 31 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

32. 32 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 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) .

33. 33 CVD ~ Inflammation: aspirin therapy Aspirin for the Primary Prevention of Cardiovascular Events in Women and Men: A Sex-Specific Meta-analysis 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).

34. 34 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%)

35. 35 Enter �THE POLYPILL� Wald NJ and Law MR. 2003. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 326(7404): 1419. 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

36. 36 CVD ~ Inflammation: periodontal therapyMoutsopoulos, 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. 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

37. 37 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

38. 38 CVD ~ Inflammation: periodontal therapy 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. 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

39. 39 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.

40. 40 CVD ~ Endothelial Dysfunction Napoli, C., W. C. Stanley, et al. (2007). Nutrition and cardiovascular disease: Putting a pathogenic framework into focus. Cardiovascular Research. 73(2): 253. 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

41. 41 CVD ~ Genotypic disease Multiple polymorphic genes interact adversely with environment affecting lipid & glucose metabolism, cytokine & eicosanoid synthesis & production

42. 42 CVD ~ Genotypic disease

43. 43 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

44. 44 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

45. 45 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

46. 46 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

47. 47 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.

48. 48 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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50. 50 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

51. 51 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. 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.

52. 52 Endothelial Dysfunction: Environmental Pollution  Bhatnagar, A. (2006). "Environmental Cardiology: Studying Mechanistic Links Between Pollution and Heart Disease." Circ Res 99(7): 692-705. 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 andImpaired Endogenous Fibrinolysis. Circulation 112(25): 3930-6.

53. 53 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

54. 54 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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56. 56 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

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58. 58 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

59. 59 Hunter-gatherer diets. Analysis of dietary intake of 229 Hunter-Gatherer populations around the world showed median animal food intakes of66 � 75% and plant food intakes 26 � 35% of total energy.Cordain L, Eaton SB et al. 2002. EJCN.56,Suppl 1:S42�S52.

60. 60 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

61. 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 disease development and response to nutritional and pharmacological therapy

62. 62 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

63. 63 Endothelial Dysfunction: Obesity Hotamisligil GS. 2006. Inflammation and metabolic disorders. NATURE. 444(14):860-67. 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

64. 64 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.

65. 65 The Assessment and Management of Cardiovascular Risk. Evidence-based Best Practice Guideline, New Zealand Guidelines Group, December 2003. 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 sugar-sweetened 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

66. 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 Difficult to achieve Promotes Insulin Resistance No impact on mortality Very-Low-Fat Diet May decrease cardiac events Concern about applicability and sustainability Low Glycemic Index Diet Unproven effects on CVD Initiate reduced intake of energy-dense CHOs and initiate weight loss Low-Carbohydrate Diet Short-term weight loss Long-term effects on CVD unknown Initiate decreased energy intake & weight loss Mediterranean Diet Secondary prevention Prevention of sudden cardiac death Healthy overall approach to dieting Long-term sustainability DASH Decreased hypertension ~ by 5.5/3.3mm Similar to Mediterranean Diet

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68. 68 Low GI or GL diets inconclusive. Parikh P et al. J Am Coll Cardiol 2005;45:1379�87

69. 69 CHD Risk & DIET: Mediterranean Diet ~

70. 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

71. 71 Endothelial Dysfunction: Diet

72. 72 Enter �THE POLYMEAL�

73. 73 SPECIFIC NUTRIENTS IN CARDIOVASCULAR DISEASE

74. 74 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 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

75. 75 Cardiovascular Disease ~ Arginine, NO and endothelial dysfunction 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

76. 76 Cardiovascular Disease ~ Arginine and endothelial dysfunction

77. 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. 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. 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 .

80. 80 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.

81. 81 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 activityand 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.

82. 82 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. 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. 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 Electron-Transport 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. 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 stressand nitrate tolerance. J Biol Chem 282(1):792-9.

85. 85 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. 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

86. 86 CVD Treatment: Garlic  Rahman K. and Lowe GM. 2006. Garlic and cardiovascular disease: a critical review. J Nutr 136(3 Suppl): 736S-40S. 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. 44% of clinical studies report positive effects from garlic: reduces cholesterol, inhibits platelet aggregation, reduces blood pressure, increases antioxidant status.

87. 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.

88. 88 CVD Treatment: Garlic  Rahman K. and Lowe GM. 2006. Garlic and cardiovascular disease: a critical review. J Nutr 136(3 Suppl): 736S-40S. 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.

89. 89 CVD Therapy: Vitamins B6, Folate, B12 & Betaine These nutrients reduce serum homocysteine level Homocysteine > 12mm/L is an independent risk factor for 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. 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. 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

92. 92 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

93. 93 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

94. 94  Thank you for your attention ~and~ Please feel free to speak to me during the breaks ~AND~

95. 95 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, 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