Life Extension Magazine®

Woman pointing to platter of fruit full of fructose that can elevate uric acid production

The 2014 Cardiovascular Disease Prevention Symposium

At the world’s largest conference on cardiovascular disease prevention organized by Dr. Michael Ozner, scientists presented compelling studies for reducing heart disease risks. Topics included gluten sensitivity, fructose’s link to diabetes, coronary artery calcification, preventing blood vessel aging, chelation therapy, processed meat risks, and cardiac medications.

Scientifically reviewed by Dr. Gary Gonzalez, MD, in October 2024. Written by: Ben Best, BS, Pharmacy.

Agatston
Dr. Ozner

For years, Michael Ozner, MD, has been organizing the world’s largest cardiology conference devoted to the prevention of cardiovascular disease.

Dr. Ozner serves as medical director for the Cardiovascular Prevention Institute of South Florida and is a member of Life Extension’s Scientific Advisory Board.

On February 6, 2014, Dr. Ozner gave opening remarks at his 12th Annual Cardiovascular Disease Prevention International Symposium in Miami Beach, Florida. This article provides an overview of the various presentations made at this conference dedicated to preventing the most prevalent disease striking Americans.

South Beach Diet Gluten Solution

Agatston
Agatston

Arthur Agatston, MD, (Associate Professor of Medicine, University of Miami School of Medicine) is best known as the originator of the South Beach Diet for which he has written many best-selling books. The subject of his presentation (and the subject of his latest book) was gluten.

Gluten is a protein found in wheat and a few other grains. Gluten readily forms cross-links with itself and with other proteins. This crosslinking property makes bread chewy (viscous and elastic), but it also makes gluten difficult to digest. In people with celiac disease, gluten greatly damages intestinal villi, leading to diarrhea, abdominal pain, weight loss, fatigue, and anemia. Although up to 1% of the population has celiac disease, most of the victims are unaware they are afflicted.1-3

Much more common than celiac disease, according to Dr. Agatston, is gluten sensitivity, which can cause headaches, foggy mind, chronic fatigue, sinus problems, and constipation or diarrhea (among other problems).1 Although there is a definitive diagnostic test for celiac disease, gluten sensitivity can only be established by removing gluten from the diet and seeing if the symptoms go away. Celiac disease cannot be cured, symptoms can improve and intestinal healing can occur if celiac patients completely remove gluten from their diet.4 Removing gluten from one’s diet is not such an easy task, because gluten and wheat are added to so many products, particularly to achieve thickening. Dr. Agatston mentioned such unsuspected products as tomato sauce, yogurt, and toothpaste. Although wheat is not a GMO (Genetically Modified Organism), centuries of selective breeding and hybridization have increased the gluten content of wheat for the purpose of strengthening dough,2 which has led to an increase in celiac disease and gluten sensitivity.5

Dangers Of Fructose

Lustig
Lustig

Robert Lustig, MD, (Professor of Clinical Pediatrics, University of California, San Francisco) believes that sugar consumption, fructose consumption in particular, is more of a cause of type II diabetes than obesity. He said that sugar consumption in the US increased by a factor of 10 between 1820 and 1900, and doubled between 1900 and the year 2000.

Table sugar (sucrose) is composed of equal parts of the two simple sugars glucose and fructose.6 Fructose has often been recommended to diabetics because unlike glucose, fructose consumption does not stimulate insulin secretion as much as glucose (fructose has a lower glycemic index).7,8

But a study of overweight human subjects showed that a high-fructose diet promotes insulin resistance, visceral obesity, and elevated serum triglycerides (fats in the bloodstream), an effect not seen when glucose was substituted for fructose in the same diet.9

Insulin resistance is generally thought about as reduced ability of insulin to cause muscle to absorb glucose. But to Dr. Lustig, insulin resistance in the liver is more crucial. Unlike glucose, fructose is rapidly removed from the blood stream by the liver, which protects the rest of the body from the damaging effects of fructose. But the liver itself becomes damaged by fructose, and by the fats (triglycerides) that fructose causes the liver to manufacture.10,11 The resultant fatty liver is more causative of type II diabetes and insulin resistance than visceral fat,12,13 although the consequences are not so bad when fructose consumption is moderate.14

Fructose elevates uric acid production, which has damaging effects on the kidney and cardiovascular system.15,16 Most soda drinks are currently sweetened with high fructose corn syrup,17 partly because fructose is sweeter and more soluble than glucose.18 Increased consumption of those soda beverages has been linked to weight gain and might play a role in the growing incidence of obesity.19 Even fruit juice, which can be high in fructose, has been linked to type II diabetes.20 Dr. Lustig lamented the promotion of orange juice by pediatricians. Apple juice, which has more than twice the fructose as orange juice, is the juice most often given to children under age 5.21 Fruit juice is a poor substitute for fruit or milk, especially in light of the fact that half of children between the ages of 1 and 5 do not get enough calcium.21

Smoking And Psychological Factors In Cardiovascular Disease

Sotile
Sotile

Wayne Sotile, PhD, (Clinical Assistant Professor, Tulane University) discussed efforts to reduce or stop cigarette smoking. A long-term study of British doctors showed that smokers died about 10 years younger than non-smokers.22 A study of smokers who suffered a heart attack showed that 80% attempted to quit smoking after the heart attack, but after one year only about half were still not smoking.23

Dr. Sotile described tactics for reducing smoking, such as only smoking if a smoker rated the desire to smoke as being greater than 7 on a scale from 1 to 10. He said that simply encouraging smokers to keep a count of the cigarettes they smoked reduced cigarette consumption by half. But he also cited a study of heavy smokers which showed that a 50% reduction of cigarette consumption did not significantly reduce the risk of premature death.24 Complete cessation of smoking will provide definite health benefits—life and health are extended in proportion to how early in life a smoker completely stopped smoking.22 Dr. Sotile said that for those who are unable or unwilling to quit smoking, electronic cigarettes have considerably fewer toxicants and carcinogens than tobacco cigarettes.25

In a separate lecture, Dr. Sotile discussed psychological factors leading to cardiovascular disease. Studies of certain “type-A” behavior factors (competition and exaggerated commitment to work) have not shown convincing results that the personality type leads to increased risk of coronary artery disease, whereas hostility (a major attribute of the type A personality) has been associated with increased risk.26 Confounding this analysis, however, is the fact that hostile people more often have unhealthy lifestyles.26 Work stress is particularly toxic when there is high demand, but low decision latitude.26 Dr. Sotile thinks that the number of stresses is less important for cardiovascular risk than the number of uplifts (gratitude, interest, hope, pride, amusement, and love).

Women’s Issues In Cardiovascular Disease

Hayes
Hayes

Sharonne Hayes, MD, (Professor of Medicine and Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota) is concerned with both women’s issues and psychological issues associated with cardiovascular disease.

For example, certain metabolic changes during pregnancy can resemble diabetes, and may accelerate the development of diabetes after pregnancy.27 In a study involving subjects who lost their significant other, women were three times more likely to experience death of a spouse after age 65 than a man.28 The risk of a heart attack in the first 24 hours after the death of a spouse was increased more than 20 times, and it decreased subsequently.28 Women are more likely to die of stroke than coronary artery disease, whereas the opposite is the case for men.29 Women with a history of depression are two to three times more likely to have calcification of their coronary arteries than women without a history of depression.30 Patients with coronary heart disease are much more likely to have impaired endothelial function, and are much more likely to die if they are depressed.31 A study showed that anxiety is a stronger predictor of coronary artery disease than depression.32 Exercise reduces death rates in depressed heart patients.33,34 Another study cited showed that pet ownership is associated with lower blood pressure, reduced incidence of cardiovascular disease risk factors, and increased survival in individuals with existing cardiovascular disease.35

Dr. Hayes reported on a Mayo Clinic survey of the hierarchy of female concerns. What is most important to women is their children, followed by their home, their career, their pet, their spouse, and lastly, themselves. Dr. Hayes suggested that the low priority women give to their own needs can manifest in not taking time to look after their health, such as by exercising. As another example, she reported that 79% of women said they would call 911 if someone else was experiencing symptoms of a heart attack, but only 53% would call 911 if they were the one experiencing heart attack symptoms.29

Removing The Cause Of Atherosclerotic Inflammation

Tabas
Tabas

Ira Tabas, MD, PhD, (Professor of Medicine and Anatomy and Cell Biology, Columbia University, New York, New York) summarized his argument by saying that the first step in stopping inflammation caused by a splinter in the finger is to remove the splinter. Inflammation in atherosclerosis involves the inability to effectively clear dead immune cells with accumulated oxidized non-HDL cholesterol from blood vessel walls.36,37 Preventing the entry and retention of oxidized non-HDL cholesterol in blood vessel walls would help prevent atherosclerosis.38,39

Calcium In Coronary Arteries

Nasir
Nasir

Khurram Nasir, MD, (Research Director, Center for Prevention and Wellness, Miami, Florida) is concerned that half of the serious coronary artery disease incidents (including death) occur in individuals who displayed no previous symptoms.40 As a predictor of coronary artery disease, he has found imaging of calcium in the coronary artery to be superior to assessments of coronary artery wall thickness41 or blood levels of the inflammatory agent C-reactive Protein (CRP).42

In a study of about 44,000 patients, about half of the participants had coronary artery calcium detectable by electron beam tomography. The patients having the highest coronary artery calcium were about seven times more likely to die during a mean 5.6-year period.43 Dr. Nasir believes that because scanning for coronary artery calcium is easy and inexpensive, it should be as routine as mammograms. Some people avoid the coronary calcium score diagnostic test because of the radiation exposure.

Small Cholesterol Particles Are The Worst

Richman
Richman

Michael Richman, MD, (Cardiothoracic/Vascular Surgeon, Center for Cholesterol Management, Los Angeles, California) did not agree with Dr. Nasir that routine screening for coronary artery calcium justifies the radiation exposure. He said calcified atherosclerotic plaques do not rupture, and that in his surgical experience, ruptured plaques are soft. He cited a study showing that coronary vessel blockage frequently occurs without calcification.44

Dr. Richman noted that many small cholesterol particles are a better indicator of cardiovascular risk than the total amount of cholesterol.45 Small cholesterol particles are more easily oxidized,46,47 and small particles enter blood vessel walls more easily than large cholesterol particles.48 Dr. Richman’s preferred phrase for helping people to remember the importance of the number of small particles as opposed to total amount of cholesterol is “The number of cars that cause a traffic jam is not related to the number of people in the cars.”

Prevention Of Blood Vessel Aging

Valentin Fuster, MD, (Professor, Mount Sinai School of Medicine, New York, New York) asked if aging can be prevented—in particular, aging of blood vessels. The extensive shortening of telomeres that cap the ends of chromosomes causes cells to stop dividing (become senescent). In white blood cells, telomeres shorten about 6 to 9% per decade.49 Senescence of the cells that line blood vessels (endothelial cells) causes them to more readily bind to cells (monocytes) that contribute to atherosclerosis.49 Age-related decline in the supply of stem cells is observed in blood vessels which might ultimately lead to age-related atherosclerosis.49 In addition, aging leads to an increasing deposition of calcium in blood vessels and is associated with a reduction in bone mineral density.50 Blood vessel calcification causes kidney disease.50,5l It is a misconception that rupture of atherosclerotic plaques is usually a fatal event. Plaques frequently rupture in the absence of clinical symptoms.52 What can be fatal is repeated ruptures leading to increasing risk for blood vessel occlusion and eventually to clots that block the blood vessels completely.52

Chelation Therapy For Cardiovascular Disease

Chelation Therapy For Cardiovascular Disease  

Gervasio Lamas, MD, (Chairman of Medicine, Mount Sinai Medical Center, Miami Beach, Florida) reported on his clinical trial showing a reduction in cardiovascular disease in patients receiving intravenous chelation therapy with disodium EDTA (ethylene diamine tetraacetic acid).53

Chelation is a controversial intravenous therapy that removes metal ions such as calcium, lead, zinc, cadmium, arsenic, iron, and more from the blood stream.53,54 Some of these metals are toxic, whereas others are essential for health and survival. The claim that chelation could remove calcium from atherosclerotic plaques makes no sense insofar as EDTA is water soluble and cannot cross cell membranes,55 but removal of toxic metals could be beneficial for other reasons. Chelation therapy must be done slowly, because when done too rapidly blood calcium levels can become so low as to cause death.56

Dr. Lamas’ study was criticized because the chelation therapy infusion mixture needed to be made locally (shortly before administration), because so many of the testing centers practiced alternative medicine (including chelation therapy), and because so many more patients in the placebo group than in the chelation group withdrew from the study, leading to suspicion that many patients had discovered that they were being given a placebo.57

A follow-up analysis of the chelation clinical trial by Dr. Lamas’ team showed considerably greater benefit for heart attack patients in the trial who were diabetic compared to those who were not diabetic.58 It is plausible that chelation therapy could be particularly beneficial for diabetics due to the fact that it most likely inhibits the formation of advanced glycation end-products (AGEs), which are responsible for many of the health problems associated with diabetes.59 At the conference, Dr. Lamas suggested that his study was not being given the credibility it deserved because of a bias of his critics against chelation therapy. But both of his publications of his study concluded that the results do not justify routine use of chelation therapy, and that further research is required.53,58

Fish And Mercury Toxicity In Cardiovascular Disease

Mozaffarian
Mozaffarian

Dariush Mozaffarian, MD, (Associate Professor of Medicine and Epidemiology, Harvard Medical School, Boston, Massachusetts) has researched the benefits and hazards of consuming fish. The main omega-3 fatty acids in fish oil are DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), and DPA (docasapentaenoic acid).60 Omega-3 fatty acids provide multiple health benefits as they are incorporated into cell membranes, modulating the function of enzymes, receptors, and ion-channels embedded in the cell membranes.61,62 The omega-3 fatty acids also modify gene expression to reduce inflammation and improve lipid metabolism.61

DHA is incorporated into the membranes of heart muscle cells five to 10 times more than EPA (DPA is also incorporated more than EPA),63 which could also be relevant in explaining why DHA was associated with a lower risk of certain arrhythmias.61 But EPA and DPA are much more effective than DHA in reducing inflammatory protein (C-reactive protein) and the clotting factor fibrinogen.61 And DPA most strongly reduced death from stroke.64

The toxic metal mercury in fish is a concern, especially for pregnant women, but mercury intake can be reduced by eating small, short-lived species rather than larger, predatory, long-lived species (such as swordfish).65 Fish oil from supplements rather than from fish reduces mercury ingestion because mercury is tightly bound to the protein in the meat.66 Dr. Mozaffarian reports the cardiovascular benefits of fish consumption outweigh the risks,63,67 but he did not elaborate on the toxic effects of fish mercury on the nervous system, immune function, reproduction, or cancer.68

Benefits Of Chocolate (Cocoa)

In a separate lecture, Dr. Mozaffarian discussed the cardiovascular benefits of chocolate (cocoa). Cocoa, which is rich in flavonoids, has been shown to significantly reduce blood pressure, insulin resistance, endothelial dysfunction, and fats in the bloodstream.69 A study of subjects fed dark chocolate (containing cocoa) or white chocolate (no cocoa) for 18 weeks showed a small, but significant reduction in blood pressure for the dark chocolate group, but not for the white chocolate group.70 An analysis of several studies showed that the highest levels of chocolate consumption were associated with a 37% reduction in cardiovascular disease, and a 29% reduction in stroke compared with the lowest levels of consumption.71 Despite the sugar and fat content of chocolate, reduced insulin resistance and reduced serum insulin levels were associated with chocolate consumption.72 The flavanol epicatechin is believed to be the main source of benefit.72

Hazards Of Processed Meat And Red Meat

Castro-Romero
Castro-Romero

Natalie Castro-Romero, RD, (Chief Dietitian, Baptist Health South Florida, Miami, Florida) cited one study that showed slightly increased death rates for both cancer and cardiovascular disease resulting from the consumption of both processed meat and red meat.73 However, another study showed that consumption of processed meat, but not red meat, is associated with a higher incidence of coronary heart disease (42% higher), and diabetes (19% higher).74 Processed meat does not contain more saturated fat, cholesterol, or iron than red meat, but processed meat does contain more sodium and nitrate preservative.74

Subclinical Thyroid Disease And Cardiovascular Disease

Subclinical Thyroid Disease And Cardiovascular Disease 

Irwin Klein, MD, (Professor of Medicine, New York School of Medicine, New York City, New York) spoke of the impact of subclinical hypothyroidism and subclinical hyperthyroidism on cardiovascular disease. These conditions are called subclinical because they are detected in blood tests, but don’t necessarily manifest the clinical symptoms of hypothyroidism or hyperthyroidism.

High levels of thyroid hormone affect the cardiovascular system by increasing heart rate, lowering vascular resistance, and increasing blood volume, whereas low levels of thyroid hormone have the opposite effect.75 There is controversy about whether patients with subclinical thyroid disease should be treated. But there is more certainty about certain classes of patients. Treatment is recommended for elderly patients having subclinical hyperthyroidism because of the risk of atrial fibrillation (irregular heartbeats in the upper chambers of the heart).76 Treatment is also recommended for pregnant women because of the risk to the mother and/or fetus.76-78

As people age, there is an increasing incidence of subclinical hypothyroidism. But in the elderly (older than 85 years), subclinical hypothyroidism is protective against cardiovascular disease, whereas for the young and middle-aged, subclinical hypothyroidism increases the risk of cardiovascular disease.79 The risk of treating subclinical hypothyroidism is that thyroid hormone dosage and blood levels must be frequently monitored. Overdosing occurs in about 20% of patients, leading to atrial fibrillation, cardiac dysfunction, and reduced bone mineral density.80

Medications To Control Blood Cholesterol

Toth
Toth

Peter Toth, MD, PhD, (Professor of Clinical Medicine, Michigan State University, East Lansing, Michigan) said that blood levels of non-HDL cholesterol are a better indicator of cardiovascular disease risk than is LDL cholesterol.81

Conventional wisdom holds that LDL cholesterol is bad and HDL cholesterol is good in terms of heart disease risk. But this simple description overlooks other forms of cholesterol, such as VLDL (very low density lipoprotein).82 Only HDL cholesterol reduces cardiovascular disease risk, whereas the other forms of cholesterol are all harmful―with VLDL being more harmful than LDL.81 Combining a statin (which lowers synthesis of non-HDL cholesterols) with an agent that lowers absorption of cholesterol from the intestine (ezetimibe) results in greater reductions of non-HDL cholesterols, and greater increase in HDL cholesterol than statin alone.83 Although niacin can raise HDL cholesterol, addition of niacin to statin therapy showed no additional benefit.84

Medications Against Cardiovascular Death From Type II Diabetes

Ginsberg
Ginsberg

Henry Ginsberg, MD, (Professor of Medicine, Columbia University Medical Center, New York City, New York) said that the vast majority of people with type II diabetes are obese,85 but that the vast majority of obese people do not have type II diabetes.86 He also supported the view that insulin resistance cannot be separated from type II diabetes or metabolic syndrome.87,88

A 40-year-old patient newly diagnosed with type II diabetes has a life expectancy that is eight years less than that of the general population, largely due to early death from cardiovascular disease.87 Administration of the drug pioglitazone (Actos® ) to type II diabetes patients significantly reduces all-cause mortality, non-fatal heart attacks, and strokes.89 Pioglitazone is a PPAR-ˠ ( peroxizome proliferator-activated receptor-gamma) activator which reduces various inflammatory markers.89 He cited a study showing that for patients at risk of developing diabetes due to high blood glucose, the blood glucose-lowering drug metformin reduced the incidence of diabetes by 31%, whereas lifestyle intervention (weight loss and physical activity) reduced the incidence by 58%.90

Nonalcoholic Fatty Liver Disease (NAFLD) affects up to 20 to 30% of the general population, and up to three-quarters of those have insulin resistance or metabolic syndrome.91 For type II diabetes patients who lost 8% of their body weight over a 12-month period, there was a significant reduction of NAFLD.91

Concluding Remarks

Although the above report only includes approximately half the speakers at the Cardiovascular Disease Prevention International Symposium, I believe it provides a good coverage of the flavor and highlights of the presentations. It was inspiring to be with so many medical professionals seeking to prevent disease, rather than to simply treat disease.

If you have any questions on the scientific content of this article, please call a Life Extension Wellness Specialist at 1-866-864-3027.

References

  1. Sapone A, Bai JC, Ciacci C, et al. Spectrum of gluten-related disorders: consensus on new nomenclature and classification. BMC Med. 2012 Feb 7;10:13.
  2. Shewry PR. Wheat. J Exp Bot. 2009;60(6):1537-53.
  3. Rubio-Tapia A, Ludvigsson JF, Brantner TL, Murray JA, Everhart JE. The prevalence of celiac disease in the United States. Am J Gastroenterol. 2012 Oct;107(10):1538-44; quiz 1537, 1545.
  4. Celiac disease-sprue. 2012. A.D.A.M. Medical Encyclopedia. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/pmh0001280. Accessed April 9, 2014.
  5. van den Broeck HC, de Jong HC, Salentijn EM, et al. Presence of celiac disease epitopes in modern and old hexaploid wheat varieties: wheat breeding may have contributed to increased prevalence of celiac disease. Theor Appl Genet. 2010 Nov;121(8):1527-39.
  6. Ackroff K, Sclafani A. Rats’ preferences for high fructose corn syrup vs. sucrose and sugar mixtures. Physiol Behav. 2011 Mar 28;102(5):548-52.
  7. Bantle JP. Is fructose the optimal low glycemic index sweetener? Nestle Nutr Workshop Ser Clin Perform Programme. 2006;11:83-91; discussion 92-5.
  8. Hung CT. Effects of high-fructose (90%) corn syrup on plasma glucose, insulin, and C-peptide in non-insulin-dependent diabetes mellitus and normal subjects. Taiwan Yi Xue Hui Za Zhi. 1989 Sep;88(9):883-5.
  9. Stanhope KL, Schwarz JM, Keim NL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest. 2009 May;119(5):1322-34.
  10. Lee O, Bruce WR, Dong Q, Bruce J, Mehta R, O’Brien PJ. Fructose and carbonyl metabolites as endogenous toxins. Chem Biol Interact. 2009 Mar 16;178(1-3):332-9.
  11. Bremer AA, Mietus-Snyder M, Lustig RH. Toward a unifying hypothesis of metabolic syndrome. Pediatrics. 2012 Mar;129(3):557-70.
  12. Brown MS, Goldstein JL. Selective versus total insulin resistance: a pathogenic paradox. Cell Metab. 2008 Feb;7(2):95-6.
  13. Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, Okunade A, Klein S. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A. 2009 Sep 8;106(36):15430-5.
  14. Rizkalla SW. Health implications of fructose consumption: A review of recent data. Nutr Metab (Lond). 2010 Nov 4;7:82.
  15. Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang DH, Gersch MS, Benner S, Sánchez-Lozada LG. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr. 2007 Oct;86(4):899-906.
  16. Perez-Pozo SE, Schold J, Nakagawa T, Sánchez-Lozada LG, Johnson RJ, Lillo JL. Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int J Obes (Lond). 2010 Mar;34(3):454-61.
  17. Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr. 2004 Apr;79(4):537-43.
  18. Hallfrisch J. Metabolic effects of dietary fructose. FASEB J. 1990 Jun;4(9):2652-60.
  19. Mozaffarian D, Hao T, Rimm EB, Willett WC, Hu FB. Changes in diet and lifestyle and long-term weight gain in women and men. N Engl J Med. 2011 Jun 23;364(25):2392-404.
  20. Bazzano LA, Li TY, Joshipura KJ, Hu FB. Intake of fruit, vegetables, and fruit juices and risk of diabetes in women. Diabetes Care. 2008 Jul;31(7):1311-7.
  21. Dennison BA. Fruit juice consumption by infants and children: a review. J Am Coll Nutr. 1996 Oct;15(5 Suppl):4S-11S.
  22. Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ. 2004 Jun 26;328(7455):1519.
  23. Choi YJ, Park JS, Kim U, et al. Changes in smoking behavior and adherence to preventive guidelines among smokers after a heart attack. J Geriatr Cardiol. 2013 Jun;10(2):146-50.
  24. Tverdal A, Bjartveit K. Health consequences of reduced daily cigarette consumption. Tob Control. 2006 Dec;15(6):472-80.
  25. Goniewicz ML, Knysak J, Gawron M, et al. Levels of selected carcinogens and toxicants in vapour from electronic cigarettes. Tob Control. 2014 Mar;23(2):133-9.
  26. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation. 1999 Apr 27;99(16):2192-217.
  27. Sattar N, Greer IA. Pregnancy complications and maternal cardiovascular risk: opportunities for intervention and screening? BMJ. 2002 Jul 20;325(7356):157-60.
  28. Mostofsky E, Maclure M, Sherwood JB, Tofler GH, Muller JE, Mittleman MA. Risk of acute myocardial infarction after the death of a significant person in one’s life: the Determinants of Myocardial Infarction Onset Study. Circulation. 2012 Jan 24;125(3):491-6.
  29. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women― 2011 update: a guideline from the American Heart Sssociation. Circulation. 2011 Mar 22;123(11):1243-62.
  30. Agatisa PK, Matthews KA, Bromberger JT, Edmundowicz D, Chang YF, Sutton-Tyrrell K. Coronary and aortic calcification in women with a history of major depression. Arch Intern Med. 2005 Jun 13;165(11):1229-36.
  31. Sherwood A, Hinderliter AL, Watkins LL, Waugh RA, Blumenthal JA. Impaired endothelial function in coronary heart disease patients with depressive symptomatology. J Am Coll Cardiol. 2005 Aug 16;46(4):656-9.
  32. Dimsdale JE. What does heart disease have to do with anxiety? J Am Coll Cardiol. 2010 Jun 29;56(1):47-8.
  33. Milani RV, Lavie CJ, Mehra MR, Ventura HO. Impact of exercise training and depression on survival in heart failure due to coronary heart disease. Am J Cardiol. 2011 Jan;107(1):64-8.
  34. Janszky I, Ahnve S, Lundberg I, Hemmingsson T. Early-onset depression, anxiety, and risk of subsequent coronary heart disease: 37-year follow-up of 49,321 young Swedish men. J Am Coll Cardiol. 2010 Jun 29;56(1):31-7.
  35. Levine GN, Allen K, Braun LT, et al. Pet ownership and cardiovascular risk: a scientific statement from the American Heart Association. Circulation. 2013 Jun 11;127(23):2353-63.
  36. Tabas I. Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis: the importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol. 2005 Nov;25(11):2255-64.
  37. Tabas I. Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol. 2010 Jan;10(1):36-46.
  38. Tabas I, Williams KJ, Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation. 2007 Oct 16;116(16):1832-44.
  39. Moore KJ, Tabas I. Macrophages in the pathogenesis of atherosclerosis. Cell. 2011 Apr 29;145(3):341-55.
  40. Nasir K, Blaha MJ. Short and lifetime cardiovascular risk estimates: same wine, different bottles. Do we have the COURAGE to abandon risk scores? J Nucl Cardiol. 2014 Feb;21(1):46-9.
  41. Malik S, Budoff MJ, Katz R, et al. Impact of subclinical atherosclerosis on cardiovascular disease events in individuals with metabolic syndrome and diabetes: the multi-ethnic study of atherosclerosis. Diabetes Care. 2011 Oct;34(10):2285-90.
  42. Blaha MJ, Budoff MJ, DeFilippis AP, et al. Associations between C-reactive protein, coronary artery calcium, and cardiovascular events: implications for the JUPITER population from MESA, a population-based cohort study. Lancet. 2011 Aug 20;378(9792):684-92.
  43. Blaha M, Budoff MJ, Shaw LJ, et al. Absence of coronary artery calcification and all-cause mortality. JACC Cardiovasc Imaging. 2009 Jun;2(6):692-700.
  44. Gottlieb I, Miller JM, Arbab-Zadeh A, et al. The absence of coronary calcification does not exclude obstructive coronary artery disease or the need for revascularization in patients referred for conventional coronary angiography. J Am Coll Cardiol. 2010 Feb 16;55(7):627-34.
  45. Castelli WP. Lipids, risk factors and ischaemic heart disease. Atherosclerosis. 1996 Jul;124 Suppl:S1-9.
  46. Wakatsuki A, Ikenoue N, Okatani Y, Fukaya T. Estrogen-induced small low density lipoprotein particles may be atherogenic in postmenopausal women. J Am Coll Cardiol . 2001 Feb;37(2):425-30.
  47. Lautamäki R, Nuutila P, Airaksinen KE, et al. The effect of PPARgamma-agonism on LDL subclass profile in patients with type II diabetes and coronary artery disease. Rev Diabet Stud . 2006 Spring;3(1):31-8.
  48. Koba S, Yokota Y, Hirano T, et al. Small LDL-cholesterol is superior to LDL-cholesterol for determining severe coronary atherosclerosis. J Atheroscler Thromb. 2008 Oct;15(5):250-60.
  49. Kovacic JC, Moreno P, Hachinski V, Nabel EG, Fuster V. Cellular senescence, vascular disease, and aging: Part 1 of a 2-part review. Circulation. 2011 Apr 19;123(15):1650-60.
  50. Kovacic JC, Moreno P, Nabel EG, Hachinski V, Fuster V. Cellular senescence, vascular disease, and aging: part 2 of a 2-part review: clinical vascular disease in the elderly. Circulation. 2011 May 3;123(17):1900-10.
  51. Safar ME, London GM, Plante GE. Arterial stiffness and kidney function. Hypertension. 2004 Feb;43(2):163-8.
  52. Arbab-Zadeh A, Nakano M, Virmani R, Fuster V. Acute coronary events. Circulation. 2012 Mar 6;125(9):1147-56.
  53. Lamas GA, Goertz C, Boineau R, et al. Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial. JAMA. 2013 Mar 27;309(12):1241-50.
  54. Flora SJ, Pachauri V. Chelation in metal intoxication. Int J Environ Res Public Health. 2010 Jul;7(7):2745-88.
  55. Lewin MR. Chelation therapy for cardiovascular disease. Review and commentary. Tex Heart Inst J. 1997;24(2):81-9.
  56. Atwood KC, Woeckner E, Baratz RS, Sampson WI. Why the NIH Trial to Assess Chelation Therapy (TACT) should be abandoned. Medscape J Med. 2008 May 13;10(5):115.
  57. Nissen SE. Concerns about reliability in the Trial to Assess Chelation Therapy (TACT). JAMA. 2013 Mar 27;309(12):1293-4.
  58. Escolar E, Lamas GA, Mark DB, et al. The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT). Circ Cardiovasc Qual Outcomes. 2014 Jan;7(1):15-24.
  59. Nagai R, Murray DB, Metz TO, Baynes JW. Chelation: a fundamental mechanism of action of AGE inhibitors, AGE breakers, and other inhibitors of diabetes complications. Diabetes. 2012 Mar;61(3):549-59.
  60. Sinclair AJ, Murphy KJ, Li D. Marine lipids: overview “news insights and lipid composition of Lyprinol.” Allerg Immunol (Paris). 2000 Sep;32(7):261-71.
  61. Mozaffarian D, Wu JH. (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr. 2012 Mar;142(3):614S-625S.
  62. Siddiqui RA, Harvey KA, Zaloga GP. Modulation of enzymatic activities by n-3 polyunsaturated fatty acids to support cardiovascular health. J Nutr Biochem . 2008 Jul;19(7):417-37.
  63. Miller E, Kaur G, Larsen A, Loh SP, Linderborg K, Weisinger HS, Turchini GM, Cameron-Smith D, Sinclair AJ. A short-term n-3 DPA supplementation study in humans. Eur J Nutr. 2013 Apr;52(3):895-904.
  64. Mozaffarian D, Lemaitre RN, King IB, et al. Plasma phospholipid long-chain omega-3 fatty acids and total and cause-specific mortality in older adults: a cohort study. Ann Intern Med. 2013 Apr 2;158(7):515-25.
  65. Mozaffarian D, Rimm EB. Fish intake, contaminants, and human health: evaluating the risks and the benefits. JAMA. 2006 Oct 18;296(15):1885-99.
  66. Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011 Nov 8;58(20):2047-67.
  67. Mozaffarian D, Shi P, Morris JS, Spiegelman D, Grandjean P, Siscovick DS, Willett WC, Rimm EB. Mercury exposure and risk of cardiovascular disease in two U.S. cohorts. N Engl J Med. 2011 Mar 24;364(12):1116-25.
  68. Hong YS, Kim YM, Lee KE. Methylmercury exposure and health effects. J Prev Med Public Health. 2012 Nov;45(6):353-63.
  69. Shrime MG, Bauer SR, McDonald AC, Chowdhury NH, Coltart CE, Ding EL. Flavonoid-rich cocoa consumption affects multiple cardiovascular risk factors in a meta-analysis of short-term studies. J Nutr. 2011 Nov;141(11):1982-8.
  70. Taubert D, Roesen R, Lehmann C, Jung N, Schömig E. Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide: a randomized controlled trial. JAMA. 2007 Jul 4;298(1):49-60.
  71. Buitrago-Lopez A, Sanderson J, Johnson L, et al. Chocolate consumption and cardiometabolic disorders: systematic review and meta-analysis. BMJ. 2011 Aug 26;343:d4488.
  72. Hooper L, Kay C, Abdelhamid A, et al. Effects of chocolate, cocoa, and flavan-3-ols on cardiovascular health: a systematic review and meta-analysis of randomized trials. Am J Clin Nutr. 2012 Mar;95(3):740-51.
  73. Sinha R, Cross AJ, Graubard BI, Leitzmann MF, Schatzkin A. Meat intake and mortality: a prospective study of over half a million people. Arch Intern Med. 2009 Mar 23;169(6):562-71.
  74. Micha R, Wallace SK, Mozaffarian D. Red and processed meat consumption and risk of incident coronary heart disease, stroke, and diabetes mellitus: a systematic review and meta-analysis. Circulation. 2010 Jun 1;121(21):2271-83.
  75. Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001 Feb 15;344(7):501-9.
  76. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004 Jan 14;291(2):228-38.
  77. Liu D, Teng W, Shan Z, et al. The effect of maternal subclinical hypothyroidism during pregnancy on brain development in rat offspring. Thyroid . 2010 Aug;20(8):909-15.
  78. Gallego G, Goodall S, Eastman CJ. Iodine deficiency in Australia: is iodine supplementation for pregnant and lactating women warranted? Med J Aust. 2010 Apr 19;192(8):461-3
  79. Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev. 2008 Feb;29(1):76-131.
  80. Rodondi N, Aujesky D, Vittinghoff E, Cornuz J, Bauer DC. Subclinical hypothyroidism and the risk of coronary heart disease: a meta-analysis. Am J Med. 2006 Jul;119(7):541-51.
  81. Liu J, Sempos CT, Donahue RP, Dorn J, Trevisan M, Grundy SM. Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease. Am J Cardiol. 2006 Nov 15;98(10):1363-8.
  82. Mackey RH, Kuller LH, Sutton-Tyrrell K, Evans RW, Holubkov R, Matthews KA. Lipoprotein subclasses and coronary artery calcium in postmenopausal women from the healthy women study. Am J Cardiol . 2002 Oct 17;90(8A):71i-76i.
  83. Morrone D, Weintraub WS, Toth PP, Hanson ME, Lowe RS, Lin J, Shah AK, Tershakovec AM. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis. 2012 Aug;223(2):251-61.
  84. AIM-HIGH Investigators, Boden WE, Probstfield JL, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011 Dec 15;365(24):2255-67.
  85. Hauner H. Managing type II diabetes mellitus in patients with obesity. Treat Endocrinol. 2004;3(4):223-32.
  86. Boden G. Effects of free fatty acids (FFA) on glucose metabolism: significance for insulin resistance and type II diabetes. Exp Clin Endocrinol Diabetes. 2003 May;111(3):121-4.
  87. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988 Dec;37(12):1595-607.
  88. Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care. 2002 Jul;25(7):1177-84.
  89. Erland Erdmann , John Dormandy, Robert Wilcox, et al. Secondary prevention of macrovascular events in patients with type II diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomized controlled trial. Lancet. 2005 Oct 8;366(9493):1279-89.
  90. Knowler WC , Barrett-Connor E, Fowler SE, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type II diabetes with lifestyle intervention or metformin. N Engl J Med. 2002 Feb 7;346(6):393-403.
  91. Lazo M, Solga SF, Horska A, et al. Fatty Liver Subgroup of the Look AHEAD Research Group. Effect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type II diabetes. Diabetes Care. 2010 Oct;33(10):2156-63.