Understanding Risk Factors for Heart Disease
Part I: Lipids and C-Reactive ProteinAugust 2009
By Dr. William Davis
Triglycerides and Very low-density lipoproteins (VLDL)
After LDL cholesterol and HDL cholesterol, very low-density lipoproteins (VLDL) are a third class of blood particles that contain cholesterol. On a standard cholesterol panel, VLDL cholesterol is estimated by measuring triglycerides (since triglycerides ¸ 5 yields VLDL cholesterol levels.)
VLDL particles are formed in the liver by combining cholesterol, triglycerides, and the protein, apoprotein B, in addition to other “ingredients.” VLDL production is very sensitive to the availability of triglycerides, and any increase in triglyceride availability also increases VLDL production in the liver. This is a very common situation with excess carbohydrates in the diet, diabetes, metabolic syndrome and insulin resistance.
After release from the liver, VLDL particles encounter enzymes that transform them into LDL particles. Increased VLDL can therefore lead to increased LDL. In addition, when triglycerides and VLDL particles are plentiful, they also interact directly with LDL particles, which cause the excess triglycerides to be deposited in LDL particles. This triggers a chain of events that leads to the most undesirable small LDL particles (discussed in Part II). Excess triglycerides and VLDL also interact with HDL particles, which also causes a reduction in HDL, as well as a shift in HDL to the less beneficial smaller varieties of HDL particles.14
Both triglycerides and VLDL can be effectively managed with:
Nutritional strategies can be enormously effective for reduction of triglycerides and VLDL. In past, low-fat diets were used to reduce triglycerides but proved miserable failures that eventually made triglycerides worse. Instead, reduction in carbohydrates, especially refined carbohydrates, can reduce triglycerides and VLDL.15 Low-glycemic index foods like proteins and healthy oils; exercise; weight loss, when appropriate; and adequate sleep can all contribute to reducing triglycerides and VLDL. One unique strategy we have used with enormous success is to eliminate all wheat products (refined and whole grain), along with elimination of any food made with cornstarch, as well as other high-glycemic index foods (e.g., fruit drinks, candies, snacks, etc.). This has yielded drops in triglycerides of hundreds of milligrams.
It is important to minimize exposure to fructose, particularly processed foods made with high fructose corn syrup, since this common sweetener boosts triglycerides significantly, as well as possibly increasing risk for diabetes and increasing appetite.16
National guidelines (ATP-III) recommend that triglycerides be kept at 150 mg/dl or lower. However, in our experience in reversal of heart disease, we aim for triglyceride levels of 60 mg/dl or lower. At this triglyceride level, VLDL is also minimized.
C-reactive protein (CRP)
While inflammation can serve a protective function at the site of an injury, it has another face: a silent process that erodes health and lies at the source of multiple conditions, including diabetes, cancer, and heart disease.17
CRP is a blood protein produced by the liver whenever any inflammatory process is active in the body, whether or not you’re aware of it. Obvious sources of inflammation, like pneumonia and knee arthritis, will raise CRP to high levels. Although its exact function in the body is unknown, the blood concentration of CRP does seem to parallel the degree of inflammation.
CRP is therefore a commonly available blood test that can serve as a gauge of inflammation. While very high C-reactive protein levels >10 mg/l nearly always represent inflammation outside of the heart and do not necessarily indicate increased coronary risk, lower levels (<10 mg/l) can be used to gauge low-grade inflammation that stimulates coronary plaque activity. Levels >3 mg/dl increase risk for heart attack three-fold, even when LDL cholesterol is low.17 When elevated CRP occurs in the company of other risks for heart disease (increased LDL, small LDL, etc.), there is as much as a 6 to 7-fold greater risk of heart attack.19
“We have to think of heart disease as an inflammatory disease, just as we think of rheumatoid arthritis as an inflammatory disease.”
Paul Ridker, MD
Why another blood test?
Though cholesterol and the values from the standard lipid panel are helpful, they all too often fail to reliably predict future heart attack. As inflammation that lurks beneath the surface is proving to be a potent cause of heart disease, increased CRP has also proved to improve the predictive power of lipids, perhaps yielding a clearer glimpse into the future.
Predictably, drug manufacturers have tried to persuade us that the only effective way to reduce CRP is with statin drugs, which reduce CRP from 20–50%.20 This is simply not true: there are many ways to reduce CRP as well as, or even more effectively, than the statin drugs.
Here are approaches to consider that reduce CRP and thereby help remove inflammation as a contributor to your risk for heart disease:
Nutritional supplements that reduce inflammation:
Besides statin drugs, other medications that reduce inflammation and CRP include aspirin, which reduces CRP modestly, usually no more than 15%; glitazones (Actos™ and Avandia™) for diabetes or insulin resistance; anti-hypertensive drugs in the ACE inhibitor or angiotensin-receptor blocker categories (lisinopril, enalapril, valsartan, irbesartan, etc.); anti-hypertensive agents in the beta-blocker category (metoprolol, atenolol, etc.).26 One fascinating agent that has shown promise in preliminary studies is the antibiotic, doxycycline. At low doses (too low to treat infections except gingivitis), doxycycline suppresses an important class of inflammatory enzymes called matrix metalloproteinases. It also lowers CRP dramatically. Preliminary studies from England suggest that doxycycline, 20 mg twice per day for 6 months, shuts down the inflammation that drives heart attack and abdominal aneurysm expansion.26
Dr. William Davis is an author and cardiologist practicing in Milwaukee, Wisconsin. He is author of the book, Track your Plaque: The only heart disease prevention program that shows you how to use the new heart scans to detect, track, and control coronary plaque. He can be contacted through www.trackyourplaque.com.
1. Nissen SE, Nicholls SJ, Sipahi I et al for the ASTEROID Investigators. Effect of Very High-Intensity Statin Therapy on Regression of Coronary Atherosclerosis: The ASTEROID Trial. JAMA. 2006;295:1556-65.
2. Kannel WB, Castelli WP, Gordon T. Cholesterol in the prediction of atherosclerotic disease. New perspectives based on the Framingham Study. Ann Intern Med 1979 Jan;90(1):85-91.
3. Kannel WB. Range of serum cholesterol values in the population developing coronary artery disease. Am J Cardiol 1995 Sep 28;76(9):69C-77C.
4. ATP III. Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection. JAMA. 2001;285(19):2486-2497.
5. Selwyn AP. Antiatherosclerotic effects of statins: LDL versus non-LDL effects. Curr Atheroscler Rep 2007 Oct;9(4):281-85.
6. Cromwell WC, Otvos JM. Low-density lipoprotein particle number and risk for cardiovascular disease. Curr Atheroscler Rep 2004 Sep;6(5):381-87.
7. Maron DJ, Lu GP, Cai NS et al. Cholesterol-lowering effect of a theaflavin-enriched green tea extract: a randomized controlled trial. Arch Intern Med 2003 Jun 23;163(12):1448-1453.
8. Baba S, Natsume M, Yasuda A et al. Plasma LDL and HDL cholesterol and oxidized LDL concentrations are altered in normo- and hypercholesterolemic humans after intake of different levels of cocoa powder. J Nutr 2007 Jun;137(6):1436-1441.
9. Prospective Studies Collaboration; Lewington S, Whitlock G, Clarke R et al. Blood cholesterol and vascular mortality by age, sex and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet 2007 Dec 1;370(9602):1829-39.
10. Miettinen T, Kesaniemi YA. Cholesterol absorption: reugulation of cholesterol synthesis and elimination and within-population variations of serum cholesterol levels. Am J Clin Nutr 1989:49:629-35.
11. Robins SJ, Collins D, Wittes JT et al. Relation of gemfibrozil treatment and lipid levels with major coronary events. JAMA 2001;285:1585-91.
12. Boden WE. High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the Veterans Affairs High--Density Lipoprotein Intervention Trial. Am J Cardiol 2000 Dec 21;86(12A):19L-22L.
13. Matthan NR, Giovanni A, Schaefer EJ et al. Impact of simvastatin, niacin, and/or antioxidants on cholesterol metabolism in CAD patients with low HDL. J Lipid Res 2003 Apr;44(4):800-6.
14. Siri P, Krauss RM. Influence of dietary carbohydrate and fat on LDL and HDL particle distributions. Curr Atheroscler Rep 2005 Nov;7(6):455-59.
15. Jeppesen J, Chen YD, Zhou MY, Wang T, Reaven GM. Effect of variations in oral fat and carbohydrate load on postprandial lipemia. Am J Clin Nutr 1995 Dec;62(6):1201-5.
16. 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.
17. Aggarwal BB, Shishoda S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: how hot is the link? Biochem Pharmacol 2006 Nov 30;72(11):1605-21.
18. Tsimikas S, Willerson JT, Ridker PM. C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J Am Coll Cardiol 2006 Apr 18;47(8 Suppl):C19–31.
19. St-Pierre AC, Bergeron J, Pirro M et al. Effect of plasma C-reactive protein levels in modulating the risk of coronary heart disease associated with small, dense, low-density lipoproteins in men (The Quebec Cardiovascular Study). Am J Cardiol 2003 Mar 1;91(5):555–58.
20. Deveraj S, Rogers J, Jialal I. Statins and biomarkers of inflammation. Curr Atheroscler Rep 2007 Jan;9(1):33–41.
21. Timms PM, Mannan N, Hitman GN et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? QJM 2002 Dec;95(12):787-96.
22. Kuvin JT, Dave DM, Sliney KA et al. Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. Am J Cardiol 2006 Sep 15;98(6):743–745.
23. Vayalil PK, Mittal A, Katiyar SK. Proanthocyanidins from grape seeds inhibit expression of matrix metalloproteinases in human prostate carcinoma cells, which is associated with the inhibition of activation of MAPK and NF kappa B. Carcinogenesis. 2004 Jun;25(6):987–995.
24. Kaszkin M, Beck K, Eberhardt W, Pfeilschifter J. Unravelling green tea’s mechanisms of action: more than meets the eye. Mol Pharmacol 2004;65:15–17.
25. Oak MH, El Bedoui J, Anglard P, Schini-Kerth VB. Red wine polyphenolic compounds strongly inhibit pro-matrix metalloproteinase-2 expression and its activation in response to thrombin via direct inhibition of membrane type 1-matrix metalloproteinase in vascular smooth muscle cells. Circulation. 2004 Sep 28;110(13):1861–1867.
26. Prasad K. C-reactive protein (CRP)-lowering agents. Cardiovasc Drug Rev 2006 Spring;24(1):33–50.
27. Brown DL, Desai KK, Vakili BA, Nouneh C, Lee HM, Golub LM. Clinical and biochemical results of the metalloproteinase inhibition with subantimicrobial doses of doxycycline to prevent acute coronary syndromes (MIDAS) pilot trial. Arterioscler Thromb Vasc Biol. 2004 Apr;24(4):733–738.
28. Selvin E, Paynter NP, Erlinger TP. The effect of weight loss on C-reactive protein: a systematic review. Arch Intern Med 2007 Jan 8;167(1):31–39.
29. Fredrikson GN, Hedblad B, Nilsson JA, Alm R, Berglund G, Nilsson J. Association between diet, lifestyle, metabolic cardiovascular risk factors, and plasma C-reactive protein levels. Metabolism 2004;53:1436-1142.