“Looking” Inside Your Blood Vessels

 

Part One of this article examines the many influences affecting the numerical value that represents your own unique blood LDL-cholesterol level.   This, added to uncertainty about the accuracy of cholesterol lab tests, reveals the need for additional ways to quantify the health of your blood vessels.  In other words, how do you react to a disappointing LDL-cholesterol level test result?

What is really needed here is to get to the “heart” of the problem.  Why do we monitor lipid levels in our bodies in the first place?  The answer is that they correspond with the risk of atherosclerotic cardiovascular disease (the build-up of harmful particles inside blood vessels that narrow the vessels and lead to heart attacks and strokes).  Indeed, elevated LDL-cholesterol is now considered a cause of cardiovascular disease (1).   But the truth may be that high LDL-cholesterol is only part of the story.  What if LDL-cholesterol is also a marker of the consumption of other artery-damaging food that also play a part in this process?

 

The Evolution of Atherosclerosis

Our bodies are able to manufacture all the cholesterol they need for good health and are fairly efficient at balancing the amount of cholesterol they produce with the amount ingested in the diet.  Plants do not contain cholesterol, but animal-sourced foods (meats including red meat, poultry, fish and processed meat, eggs and dairy products) do.  Unfortunately, a diet high in animal-sourced foods will overwhelm the body’s regulation of cholesterol.  Moreover, foods derived from animals are also high in saturated fat, which is known to increase the production of cholesterol by the body (2); and animal protein, which has an impressive collection of evidence regarding its tendency to raise cholesterol blood levels (3).  Eminent researcher, Dr. T. Colin Campbell, is now proposing that the actual instigators of artery injury may be hidden within the complex progression that occurs in arteries as they become damaged.  Cholesterol is always present in the “plaques” accumulating in blood vessel walls during atherosclerosis, however the PROCESS of plaque formation may be more important than the COMPONENTS of which it is made (4).  Is there a way for us to understand what is taking place inside our own blood vessels?

An explosion of recent research is beginning to sort out the events occurring during the development of atherosclerosis. It all begins with LDL-cholesterol particles becoming oxidized.  This means that they have undergone a chemical reaction that involves removing electrons from molecules, resulting in the destabilization of those molecules and increasing their reactivity in the surrounding tissues.  This can cause the breakdown of connections between atoms within important cell components such as the cell membrane, essential nutrients like proteins and DNA. Oxidation of fats such as cholesterol occurs during their processing and cooking.  It can also be generated through natural processes such as digestion.  For example, in the environment of a warm stomach filled with gastric fluid whose purpose is to break down food components, oxidation can increase by eight-fold (5,6).

Inside the blood vessels, oxidized LDL-cholesterol deposits itself into the thin lining of the artery walls.  The ensuing inflammatory environment induces the accumulation of other fats, cell waste products, dead cells, calcium and fibrin (a clotting material) into the developing plaques.  The consequence is further creation of free radicals and surges in inflammation (7,8,9,10,11).

All this inflammatory activity in the artery wall is irritating and summons a type of white blood cells called macrophages to the site as a first line of defense against arterial plaque.  Macrophages focus on removing oxidized cholesterol particles from the arterial wall, partly by passing them on to HDL-cholesterol, the “good cholesterol”, one of whose functions is escorting cholesterol out of the body.  In the process, HDL-cholesterol can also become oxidized and consequently dysfunctional, not only losing its beneficial effects, but becoming part of the inflammatory disease developing in the arteries (42).  If the incoming cholesterol overwhelms the amount that is being removed from the body, the macrophages become heavily laden with oxidized lipids and transform into inflammatory “foam cells” that add to the materials making up an atherosclerotic plaque (12,13,14,15).

Along with its oxidizing effects, high quantities of protein in the diet provide excessive amounts of amino acids (the building blocks of protein).  This causes the activation of another protein present in the macrophages called mTOR.  Recent investigations in mice discovered that stimulated mTOR signals macrophages to grow rather than continue their removal of cholesterol from a blood vessel wall.  The abnormal growth hastens macrophage death.  Research is revealing that rodents fed a high fat, high protein diet develop approximately 30% more plaque in their arteries than those on a high fat, low protein diet.  In addition, the plaque building up under these conditions is thin and unstable and able to break off the arterial wall easily, increasing the risk of blockages and cardiovascular events such as heart attacks and strokes.  This research pinpoints two specific amino acids that seem to be the main players in the death of plaque-fighting macrophages.  One is leucine, an amino acid particularly high in red meat.  The other is arginine that is found in highest concentration in animal foods such as meats, eggs and dairy products but also exists in low quantities in nuts, seeds and legumes (13).

In addition to animal proteins, cholesterol and saturated fats, foods derived from animals contain other inflammatory components such as; (16,17,18,19)

• Heme iron
• Arachidonic acid, an omega-6 fatty acid
• POPs (persistent organic pollutants) that are present in much higher quantities in meat than in plant-sourced foods
• PAHs (polycyclic aromatic hydrocarbons) and HCAs (heterocyclic amines) formed by high temperature methods used in cooking muscle meat
• AGEs (advanced glycation end-products) that occur naturally in foods, especially meats, eggs and dairy products, but are increased by cooking with dry heat (barbecuing, grilling, roasting, baking, frying, sautéing, broiling, searing and toasting).
• Infectious agents such as Bovine Leukemia Virus in cattle
• Neu5Gc (N-glycolylneuraminic acid – a non-human sialic acid) from red meat which can become incorporated into the tissues of its human consumers where it is recognized as foreign by the immune system
• Carnitine and choline that are transformed into TMA (trimethylamine) by certain bacterial species in the microbiome.  The liver then oxidizes the TMA into TMAO (trimethylamine-N-oxide).  TMAO is associated with accelerated atherosclerosis development.

All of these elements generate free radicals which augment the tissue damage caused by oxidation, further accelerating inflammation throughout the body.

 

Averting Atherosclerosis

Presence of plant-sourced foods in the stomach at the same time as animal-sourced foods reduces the extent of oxidation and the subsequent production of free radicals during digestion (6).  But why stop there?  Eating a diet consisting of as many plants as possible, especially one composed solely of plant-sourced foods, will have the happy result of both limiting the amount of damaging inflammatory components of animal-sourced foods ingested from the diet as well as boosting the intake of the antioxidant-containing foods that are important in combatting inflammation.

A 2019 study of over 12,000 adults showed that those eating the most plants had 16% lower risk of cardiovascular disease, 31 to 32% lower mortality from cardiovascular disease, and 25% lower risk of early death from any cause compared to those eating the lowest amount of plant-sourced foods (20).

Research from 2018 illustrated that a vegan diet (no meat, poultry, eggs, dairy, or fish) reduces inflammation more than the diet recommended by the American Heart Association for heart disease prevention (fewer servings of non-fish animal protein, more servings of fish, and only low- or no-fat dairy).  In this trial, blood levels of high-sensitivity C-reactive protein (hsCRP), a marker for inflammation, were 32% lower in the vegan group compared to the American Heart Association diet group (21).

Many studies have reported that polyphenols, a type of phytonutrient found only in plants, have anti-atherosclerotic properties and can prevent cholesterol accumulation in macrophages.  They also act as antioxidants to suppress oxidation and can regulate cholesterol removal from the body (12).  Foods richest in polyphenols are herbs (saffron, celery seed, peppermint, verbena, Mexican oregano); cocoa powder and dark chocolate; and dark-coloured berries (black elderberries, chokeberries, blueberries and black currants).  Other good polyphenol sources include green and black tea, citrus fruits, nuts, legumes (especially soybeans and their products, miso and tempeh) and dark-coloured vegetables (red cabbage, red onions, red radishes, eggplant and spinach) (22).

Additionally, simply reducing animal protein intake impedes mTOR activity.  Furthermore, many plants contain specific inhibitors of mTOR.  These include cruciferous vegetables such as broccoli and Brussels sprouts; green tea; grapes; soybeans (including edamame, soy milk, tofu, miso and tempeh); turmeric; onions; cucumbers; strawberries; blueberries; and mangoes (23,24).

Eating more plants offers many avenues towards the lowering of inflammation and the lessening of the risk of atherosclerosis.

 

“Taking a Look” Inside Our Blood Vessels

Customarily, cholesterol levels are used as markers of the health of a cardiovascular system.  “Markers” are an objective measure that captures what is happening in a cell or an organism at a given moment that can serve as an early warning system regarding health (25).   But cholesterol levels may be a very blunt indicator of the development of cardiovascular disease.  Fortunately, there are alternative methods for virtually examining the inside of arteries that can augment the information needed to make an informed evaluation regarding artery health.  The following are some of these other approaches.

 

Blood and Urine Tests

CRP (C-reactive protein) and hs-CRP (high-sensitivity C-reactive protein) tests

These are simple blood tests.  C-reactive protein increases when there is inflammation in the body.  The most useful form of this test is the hs-CRP test.  It is more sensitive than the standard test and can specifically evaluate the risk of developing coronary heart disease (atherosclerosis) (26).

A trial from 2008 discovered that people with high inflammation levels as measured by the hs-CRP test had considerably increased risk of a major cardiovascular event and death, even if their lipid levels were not elevated (27).  These outcomes were supported in 2017 by the CANTOS Trial which showed that targeting inflammation without changing cholesterol levels can significantly lower the risk of cardiovascular events (28).

An hs-CRP test may give rise to false positives because it can detect inflammation occurring anywhere in the body.  To confirm an hs-CRP test result, it can be helpful to also perform another test, such as one or more of the following.

 

MPO (Myeloperoxidase) Test

This is a blood test that measures levels of MPO, an enzyme that oxidizes LDL-cholesterol.  MPO is released from white blood cells in an inflamed artery wall and is a specific marker of blood vessel inflammation and plaque development.  Individuals with elevated MPO levels have more than twice the risk of death due to cardiovascular causes (29,30).

 

Oxidized LDL Test

This blood test detects the presence of oxidized LDL-cholesterol in the blood and can be used in the diagnosis and treatment of lipid disorders and atherosclerosis (29).

 

Urine Albumin/Creatinine Ratio Test

This test measures the amount of a protein called albumin present in the urine. Increased albumin indicates damage and thickening of arterial walls and increased risk of cardiovascular disease (31)

  

Medical Imaging of Arteries

Ultrasound of the carotid arteries that run through the neck is a safe and painless procedure that uses sound waves to examine the flow of blood through the area.  The results expose any narrowing of the arteries and an estimate of the amount of plaque buildup present (32).

 

Carotid Intima-Media Thickness test (CIMT) is an upgrade of the standard carotid ultrasound, providing precise, digital measurements regarding the thickness of the inner wall of the carotid artery.  This test is not available in all areas (33).

 

Coronary Artery Calcium Scoring (CACS) is a CT scan of the coronary arteries (the blood vessels that supply the heart).  It measures the amount of calcium in the walls of the coronary arteries, a sign of atherosclerosis (34)

 

Coronary Angiogram is another method used to examine the coronary arteries that surround the heart but is a much more invasive procedure (35).

 

Ankle-Brachial Index

Narrowing of blood vessels may also be revealed by comparing the blood pressure in the arms to that of the ankles.  Significant differences in these two pressures can suggest peripheral artery disease (narrowing of arteries in the extremities, usually the legs).  Because artery disease found in any part of the body increases the probability of artery disease in another area, this test can also be used as an indicator of atherosclerosis (35).

 

Living to Preserve Healthy Arteries

Does this sound like you?

• You eat a healthy diet consisting of almost exclusively whole plants.
• You make sure you eat a wide variety of vegetables, including legumes and dark leafy greens as well as fruits, whole grains, nuts and seeds.
• You obtain your fat from whole foods but consume those foods at a low level so that your daily

calories from fat make up less than 20% of your total calories.

• You are sparing with the use of oils, including olive oil and coconut oil.
• You are frugal in your use of salt.
• If you choose to eat some animal-sourced foods, you limit them to a few times a year.
• You save sugary foods only for very special occasions.
• You exercise regularly on five days a week.
• You maintain a sleep schedule that supports a moderate amount (6 to 8 hours) of nightly sleep.
• Your blood pressure is normal.
• Your BMI is in the healthy range.
• You do not smoke.

Still, your cholesterol has not decreased as much as you would like.

 

Next Steps

You’ll be happy to know that there are ways to constructively move forward from this point.  Note that It is important to include your health care team in any possible treatment decisions so be sure to discuss your cholesterol concerns with your physician or other health professional.

 

Canadian Dyslipidemia Guidelines

Deciding whether or not to treat high LDL-cholesterol and how to treat it is a highly personalized one.  It usually begins with a risk assessment which includes such aspects as your age, gender, cholesterol levels, blood pressure and whether or not you are a smoker or suffer from diabetes.  From this, your 10-year cardiovascular disease risk score is calculated, assessing your personal risk for cardiovascular disease as high, intermediate or low.  The Canadian Cardiovascular Society’s Dyslipidemia Guidelines provide a course of action for each of these risk levels.  The lower your risk, the less intensive are the therapies, if any, that are required.  These guidelines take into account lifestyle habits.  The more healthful habits you have adopted or plan to adopt, the lower the need for more aggressive treatments such as medications (36).

 

2019 ESC/EAS Guidelines on Management of Dyslipidaemias

The dyslipidemia guidelines in Europe were revamped in 2019 and it is interesting to look at their recommendations for diet and lifestyle.  They note continuing new evidence supporting the use of diet and lifestyle as a prevention strategy for high blood lipids and indeed, their new guidelines place healthy life choices as the very first preventative step for people at any risk of cardiovascular disease, from low risk all the way up to very high risk (37).

The ESC/EAS guidelines point out that altering only four dietary habits can result in a 30 to 35% decrease in LDL-cholesterol level, an effect that is almost comparable to that achieved using medication.

• Reducing saturated fat by 10% provides an approximate 10% decrease in LDL
• Increasing daily dietary fiber by 15 to 20 gm delivers an 8% decrease in LDL
• Reducing weight by 5 kg offers a 5% decrease in LDL
• Eating foods rich in phytosterols that provide at least 2 gm of phytosterols daily give a 10% decrease in LDL.
• Note that plant sterols and stanols are substances that occur naturally in small amounts of many grains, vegetables, fruits, legumes, nuts and seeds and are capable of lowering the absorption of cholesterol from the diet.

The potentially huge impact of these four healthy eating behaviours is further enhanced when they are adopted by young adults (37).

The 2019 version of the European dyslipidemia guidelines recommend cardiovascular imaging, including ultrasound of the carotid (neck) or femoral (groin) arteries and CAC scoring as approved methods for accurate assessment of cardiovascular risk (37,38).

 

Summing up

Keep in mind that atherosclerosis CAN be reversed by adopting healthy lifestyle habits.  Dr. Dean Ornish showed this definitively in 1990 in his patients who were eating completely plant-based with no added fat.  These patients also adopted other healthy routines such as walking daily, managing stress and recruiting social support to help them along (39).  In 2010, the Ornish Lifestyle program was recognized by Medicare in the US for reimbursement as a therapy for coronary artery disease (40).  Dr. Ornish’s research was substantiated by Dr. Caldwell B. Esselstyn Jr. in 2017 with his plant-eating patients also showing significant shrinking and reversal of heart blockages (41).

Armed with your risk assessment, your cholesterol test results, scores from other tests that you have pursued, your family history, and your present lifestyle habits along with any further changes you plan to make, you and your healthcare professional should have the understanding needed to decide on the next steps to take to improve the health of your blood vessels and ensure your future cardiovascular health.

If you discover during this process that your arteries are free of plaque, you will have the information you need to simply keep on with the healthy habits you have already adopted.

If your arteries show signs of artery damage, it is time to give thought to methods for shrinking this plaque.  Depending on how much blockage is present in your blood vessels, you might choose to intensify and expand your diet and lifestyle improvements, or to try a low dose of a medication such as a statin.

Whatever the outcome, your decision for achieving the best cardiovascular health possible will be an informed one that is based on a sound understanding of what is taking place inside your blood vessels.

 

SOURCES:

 1  Ference, B.A., Ginsberg, H.N., Graham, I. et al.  Low-density lipoproteins cause atherosclerotic cardiovascular disease. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel.  Eur Heart J April 4, 2017.

2  https://www.heart.org/en/health-topics/cholesterol/prevention-and-treatment-of-high-cholesterol-hyperlipidemia/the-skinny-on-fats

3  Wang, D.D., Li, Y., Chiuve, S.E., Stampfer, M.J., Manson, J.E., Rimm, E.B., Willett, W.C., Hu, F.B.   Association of specific dietary fats with total and cause-specific mortality. JAMA Intern Med. 2016 Aug 1; 176(8): 1134-1145. Doi: 10.1001/jamainternmed.2016.2417.

4  https://nutritionstudies.org/fallacious-faulty-foolish-discussion-about-saturated-fat/

5 Korzeniowska, M., Króliczewska, B., Kopeć, W.   Effect of Dietary Selenium on Protein and Lipid Oxidation and the Antioxidative Potential of Selected Chicken Culinary Parts during Frozen Storage.  J Chem. 2018; Article ID 3492456: Doi.org/10.1155/2018/3492456.

6  Kanner, J., Lapidot, T. The stomach as a bioreactor: Dietary lipid peroxidation in the gastric fluid and the effects of plant-derived antioxidants. Free Radic. Biol. Med. 2001 31(11):1388 – 1395.

7  https://www.nhlbi.nih.gov/health-topics/atherosclerosis

8  https://www.mayoclinic.org/diseases-conditions/arteriosclerosis-atherosclerosis/symptoms-causes/syc-20350569

9  Rognoni, A., Cavallino, C., Veia, A., Bacchini, S., Rosso, R. et al.  Pathophysiology of Atherosclerotic Plaque Development. Cardiovascular & Hematological Agents in Medicinal Chemistry. 2015; 13: 10-13.

10  Kattoor, A.J., Pothineni, N.V.K., Palagiri, D., Mehta, J.L.  Oxidative Stress in Atherosclerosis.  Curr Atheroscler Rep. 2017 Sep 18; 19(11): 42. Doi: 10.1007/s11883-017-0678-6.

11  Williams, M.J., Sutherland, W.H., McCormick, M.P., de Jong, S.A., Walker, R.J., Wilkins, G.T. Impaired endothelial function following a meal rich in used cooking fat. J. Am. Coll. Cardiol. 1999 33(4):1050 – 1055.

12  Fumiaki, I.  Polyphenols Can Potentially Prevent Atherosclerosis and Cardiovascular Disease by Modulating Macrophage Cholesterol Metabolism.  Curr Mol Pharmacol. 2020 Mar 20; Doi: 10.2174/1874467213666200320153410. Published on-line ahead of print.

13  Zhang, X., Sergin, I., Evans, T.D., Jeong, S.-J., Rodriguez-Velez, A., Kapoor, D., et al.  High-protein diets increase cardiovascular risk by activating macrophage mTOR to suppress mitophagy.  Nature Metabolism. 2020; 2: 110–125.

14 Yu, X.-H., Fu, Y.-C., Zhang, D.-W., Yin, K., Tang, C.K.  Foam cells in atherosclerosis.  Clin Chim Acta. 2013 Sep 23; 424:245-252. Doi: 10.1016/j.cca.2013.06.006.

15 Chistiakov, D.A., Melnichenko, A.A., Myasoedova, V.A., Grechko, A.V., Orekhov, A.N.  Mechanisms of foam cell formation in atherosclerosis.   J Mol Med (Berl). 2017 Nov; 95(11): 1153-1165. Doi:10.1007/s00109-017-1575-8.

16  Alisson-Silva, F., Kawanishi, K., Varki, A.  Human risk of diseases associated with red meat intake: Analysis of current theories and proposed role for metabolic incorporation of a non-human sialic acid.  Mol Aspects Med. 2016 Oct; 51: 16-30. Doi: 10.1016/j.mam.2016.07.002.

17  Seah, J.Y.H., Gay, G.M.W., Su, J., et al.  Consumption of Red Meat, but Not Cooking Oils High in Polyunsaturated Fat, Is Associated with Higher Arachidonic Acid Status in Singapore Chinese Adults.  Nutrients. 2017 Jan 31 ;9(2):101. Doi: 10.3390/nu9020101.

18  Pham, T., Gregg, C.J., Karp, F., Chow, R., Padler-Karavani, V., Cao, H., Chen, X., Witztum, J.L., Varki, N.M., Varki, A. Evidence for a novel human-specific xeno-auto-antibody response against vascular endothelium. Blood. 2009 Dec 10; 114(25):5225-5235.

19  Uribarri, J., Woodruff, S., Goodman, S., Cai, W., et al.  Advanced Glycation End Products in Foods and a Practical Guide to Their Reduction in the Diet.  J Am Diet Assoc. 2010 Jun; 110(6): 911–916.  Doi:10.1016/j.jada.2010.03.018.

20 Kim, H., Caulfield, L.E., Garcia‐Larsen, V., Steffen, L.M., Coresh, J., Rebholz, C.M.  Plant‐Based Diets Are Associated With a Lower Risk of Incident Cardiovascular Disease, Cardiovascular Disease Mortality, and All‐Cause Mortality in a General Population of Middle‐Aged Adults.   J Am Heart Ass. Aug 2019; 8 (16): Doi.org/10.1161/JAHA.119.012865.

21  Shah, B., Newman, J.D., Woolf, K., Ganguzza, L., Guo, Y., Allen, N.  Anti-inflammatory effects of a vegan diet versus the American Heart Association–recommended diet in coronary artery disease trial. J Am Heart Assoc. 2018 Dec;7(23):  Doi: 10.1161/JAHA.118.011367.

22  Mrduljas, N., Kresic, G., Bilušić, T. Polyphenols: Food Sources and Health Benefits.  2017.  10.5772/intechopen.68862.

23  Lamb, R.F. Amino acid sensing mechanisms: an Achilles heel in cancer?   FEBS J. 2012 Aug; 279(15): 2624-2631. Doi: 10.1111/j.1742-4658.2012.08659.x. Epub 2012 Jul 3.

24  Jung, C.H., Kim, H., Ahn, J., Jeon, T.-I., Lee, D.-H., Ha, T.-Y. Fisetin regulates obesity by targeting mTORC1 signaling.  J Nutr Biochem. 2013 Aug; 24(8): 1547-1554. Doi: 10.1016/j.jnutbio.2013.01.003.

25  https://www.niehs.nih.gov/health/topics/science/biomarkers/index.cfm

26  https://www.mayoclinic.org/tests-procedures/c-reactive-protein-test/about/pac-20385228

27  Ridker, P.M., Danielson, E., Fonseca, F.A.H., Genest, J., Gotto, Jr., A.M., Kastelein, J.J.P. et al.   Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein.  N Engl J Med 2008; 359:2195-2207.  DOI: 10.1056/NEJMoa0807646.

28 Baylis, R.A., Gomez, D., Mallat, Z., Pasterkamp, G., Owens, G.K.  The CANTOS Trial: One Important Step for Clinical Cardiology but a Giant Leap for Vascular Biology.   Arteriosclerosis, Thrombosis, and Vascular Biology.  Sept. 28 2017; 37(11): e174-3177.

29  https://www.dynacare.ca/specialpages/secondarynav/find-a-test/nat/oxidized%C2%A0low-density%C2%A0lipoprotein.aspx?sr=ONT&st=OXIDIZED%C2%A0LOW-DENSITY%C2%A0LIPOPROTEIN

30  Heslop, C.L. et al. Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography. J AM Coli Cardiol. 2010; 55: 1102-1109.

31  Marcovecchio, M.L., Chiesa, S.T., Armitage, J., et al. Renal and cardiovascular risk according to tertiles of urinary albumin-to-creatinine ratio: The adolescent type 1 diabetes cardio-renal intervention trial (AdDIT).  Diabetes Care. Sept. 2018; 41(9): 1963-1969.  Doi.org/10.2337/dc18-1125.

32  https://www.mayoclinic.org/tests-procedures/carotid-ultrasound/about/pac-20393399

33  https://www.healthline.com/health/heart-disease/cimt-test

34  https://www.nhlbi.nih.gov/health-topics/coronary-calcium-scan

35  https://stanfordhealthcare.org/medical-conditions/blood-heart-circulation/atherosclerosis/diagnosis.html

36 https://www.ccs.ca/images/Guidelines/PocketGuides_EN/Lipids_Gui_2016_EN.pdf

37  https://www.eas-society.org/page/dyslipidemia_guide_2019

38  Laclaustra, M., Casasnovas, J.A., Fernández-Ortiz, A., et al. Femoral and carotid subclinical atherosclerosis association with risk factors and coronary calcium: the AWHS study. J Am Coll Cardiol. 2016; 67: 1263-1274.

39  Ornish, D., Scherwitz, L.W., Billings, J.H., et al.  Intensive Lifestyle Changes for Reversal of Coronary Heart Disease.  JAMA. 1998; 280(23): 2001-2007. Doi:10.1001/jama.280.23.2001.

40  https://www.cms.gov/medicare-coverage-database/details/ncd-details.aspx?NCDId=341

41  Esselstyn, C.B.  A plant-based diet and coronary artery disease: a mandate for effective therapy.  J Geriatr Cardiol. 2017 May; 14(5): 317–320.  Doi: 10.11909/j.issn.1671-5411.2017.05.004.

42  Ito, F., Ito, T.  Perspective: High-Density Lipoprotein (HDL) Triglyceride and Oxidized HDL: New Lipid Biomarkers of Lipoprotein-Related Atherosclerotic Cardiovascular Disease.  Antioxidants 2020; 9(5): 362; https://doi.org/10.3390/antiox9050362.