Natural Methods To Control Cholesterol

Approximately 25 million people take statin drugs to reduce their cholesterol, yet heart disease remains the number one killer of Americans.^1-3

While statins lower LDL cholesterol and C-reactive protein, and modestly elevate protective HDL cholesterol,^4,5 they may increase the risk of heart failure in certain people.^6,7

Researchers have now discovered two compounds that work together to safely lower dangerous LDL cholesterol—while simultaneously boosting protective HDL.

An extract from the leaves of artichoke has been shown to raise protective HDL levels without the side effects of statins.⁸

In addition, a derivative of vitamin B5, called pantethine, safely lowers LDL while maintaining CoQ10 at protective levels—resulting in an 11% reduction in major coronary heart disease events.⁹

Together, these two nutrients offer protection against two causes of vascular disease.

Statins Do Only Half The Job

Statin drugs potently lower cholesterol when used properly, but produce a number of side effects that too often cause people to discontinue using them.

Statins have been associated with muscle weakness and pain (myalgia), muscle breakdown (rhabdomyolysis), kidney disease, and negative effects on the digestive and central nervous systems.^10,11 Even more disturbing, statins also raise the risk of developing diabetes by 9 to 13%^12-15 (a risk that is up to 48% higher in postmenopausal women).¹⁶

Clearly, statins are not the panacea that pharmaceutical companies have led physicians and the public to believe. One drawback is that they don’t elevate HDL enough to confer meaningful removal of excess cholesterol buildup on the arterial wall via reverse cholesterol transport.

How Cholesterol Balance Dictates Your Health Risks

Lowering LDL is one piece of the puzzle for preventing heart disease. Another component is to raise HDL levels, which removes cholesterol from blood vessel walls and protects it from oxidation.^17,18 Numerous epidemiological, animal, and human studies demonstrate the value of achieving and maintaining high HDL levels.^19-30

In one impressive human study, each 5 mg/dL increase in HDL led to a reduction of up to 29% in the risk of cardiovascular disease; other studies show that the risk of having a heart attack or dying goes down 3% for each 1% increase in HDL.^29,30

Statin drugs have a major problem: They reduce the production of coenzyme Q10, which is necessary for releasing energy from foods that heart cells need to function. This negative effect may paradoxically raise heart failure risk in certain populations.^6,7

What aging humans need is a balanced approach to reducing cardiovascular disease—one that safely lowers LDL while simultaneously raising HDL levels. Researchers have found two nutrients that can do just that.

Pantethine , a derivative of vitamin B5, safely lowers LDL without negatively impacting CoQ10 levels, while artichoke leaf extract can raise HDL levels without harmful side effects.

Let’s look at artichoke leaf extract first.

Ranges Of LDL Levels And Impact On Risk^9,60

LDL Level (mg/dL)	Associated Risk Category
Less than 100*	Optimal (minimal risk)
100-129	Near optimal (low risk)
130-159	Borderline high
160-189	High
190 and above	Very high

* While less than 100 mg/dL is the published upper limit of optimal, Life Extension^®feels that the ideal limit should be less than 80 mg/dL. Those with pre-existing/high-risk cardiovascular disease should strive for less than 70 mg/dL,^61,62 but should have hormone levels checked to make sure they are not being suppressed (many vital hormones are built on a “scaffold” of cholesterol molecules).^63,64

Artichoke Leaf Extract

Artichokes are members of the thistle family. The edible portion of the plant is actually a giant flower bud, but the leaves that cover it are rich in flavonoid molecules that have been shown to help lower LDL cholesterol levels and raise protective HDL levels.

Chief among these is cynaropicrin,³¹ along with luteolin, cynaroside, and chlorogenic acid.^32,33 These molecules protect the cholesterol in LDL particles from the dangerous oxidation that leads to atherosclerosis.^32,34 Artichoke extracts are also able to inhibit the synthesis of new cholesterol molecules by nearly 60%, which might help to lower total blood cholesterol levels. ³⁵

In addition, artichoke leaf extract promotes the fecal excretion of bile acids, which are detergent-like molecules that carry cholesterol out of the body. This action has been shown to lower total and non-HDL cholesterol levels in a preclinical study by 15 and 30%, respectively.³⁶

These complementary mechanisms likely all contribute to the observed reduction in cardiovascular risk factors seen in human studies of supplementation with artichoke leaf extract.

Modest Reductions In Total Cholesterol And LDL

Human studies of supplementation with artichoke leaf extract show a reduction in cardiovascular risk factors, including reduced LDL and total cholesterol levels and improved endothelial function.

When researchers gave patients with high cholesterol (more than 280 mg/dL) 1,800 mg per day of dry artichoke leaf extract for six weeks, they saw tremendous results. Patients using the artichoke leaf extract experienced an 18.5% reduction in total cholesterol, while the placebo patients only saw an 8.6% reduction.³⁷ Importantly, LDL fell 23% in supplemented patients but by only 6% in controls, while the ratio of LDL to HDL decreased 20% in supplemented patients and only 7% in controls.

Another study demonstrated the ability of artichoke supplementation to improve the function of the endothelium, the thin layer of cells lining arteries. Since endothelial dysfunction is a first step in atherosclerosis, improving endothelial function is especially important in helping prevent heart disease.³⁸ The study showed that patients with moderate hyperlipidemia who supplemented with artichoke experienced a 36.4% improvement in endothelial function compared with controls and also had favorable decreases in blood markers of endothelial dysfunction, demonstrating the ability of artichoke to directly improve vascular health.

And in a study published in Phytomedicine, adults with mild to moderate cholesterol elevations who took 1,280 mg per day of a standardized artichoke leaf extract for 12 weeks reduced total cholesterol by an average of 4.2% from baseline, while in control subjects that figure increased by an average of 1.9% during the study.³⁹

What you need to know

Safely Control Cholesterol

• Americans continue to die at unacceptable rates from cardiovascular disease, partially driven by persistent elevations in LDL (“bad”) cholesterol and insufficient protection by HDL (“good”) cholesterol.
• Statins lower LDL cholesterol and some raise HDL cholesterol, but they produce side effects that may cause many people to stop taking the drugs, leaving them unprotected.
• Two natural ingredients are now available that can lower LDL cholesterol without reducing CoQ10 levels and increase beneficial HDL cholesterol.
• Pantethine, a derivative of vitamin B5, reliably lowers LDL cholesterol and the LDL carrier protein apoB, without statin-like side effects, and without lowering protective CoQ10 levels.
• Artichoke leaf extract raises protective HDL levels and levels of the HDL carrier protein, apoA.
• Dual-acting protection against America’s leading killer, cardiovascular disease, is now within reach of all Americans, without a prescription and through a natural product.

Artichoke Leaf Extract Increases HDL Cholesterol

The unique benefit from artichoke leaf extract comes from its ability to raise protective HDL cholesterol levels without adverse side effects.

Compelling evidence that artichoke leaf extract can raise protective HDL cholesterol levels has now arrived in a human study demonstrating a never-before-seen improvement in this vital risk-reducing factor.

The study examined 92 overweight subjects with an average body mass index of 25.4 who had mild elevations of total cholesterol. The subjects received either 250 mg twice daily (total 500 mg per day) of a triple standardized artichoke leaf extract or a placebo.⁸ After eight weeks, mean HDL cholesterol rose by 8 mg/dL in supplemented patients, but only by 0.2 mg/dL in controls. In those who received artichoke leaf extract, this represents a 10% increase in mean HDL cholesterol from baseline measurements.

In addition to a beneficial rise in good cholesterol, mean total cholesterol levels fell in supplemented patients by 15 mg/dL, but by only 5 mg/dL in controls. Significant differences were also shown in the total cholesterol/HDL ratio and in the LDL/HDL ratio in supplemented patients, compared with controls.⁸

Importantly, there were no adverse effects noted in this study.⁸

In a follow-up study, the same researchers found that when patients with mild cholesterol elevations took a daily 200 mg dose of artichoke leaf extract, their total cholesterol fell by nearly 10% after only 30 days.⁴⁰ Excitingly, this study also demonstrated a 19% increase in levels of protective apoA (the HDL cholesterol-carrying protein) and a similar 19% rise in the ratio of apoA to apoB (the LDL-associated protein).

The “Magic Bullet” Behind Increased HDL Cholesterol

It’s clear that artichoke leaf extract can favorably impact HDL cholesterol levels, but how? Scientists are still uncovering those answers, but so far we know that artichoke extract has a number of potential mechanisms that could have a positive impact on HDL cholesterol.

Studies in humans demonstrate that supplementation with artichoke leaf extract raises levels of the protective apoA carrier molecule that supports the HDL particle,⁴¹ which contributes to observed increases in beneficial HDL levels.⁴⁰ A pilot study has shown a significant 19% increase in apoA after 30 days of supplementation in a human population; in addition, the ratio of apoA to apoB rose by 19%.⁴⁰

Another leading hypothesis behind artichoke leaf extract’s ability to raise HDL levels has to do with its high content of chlorogenic acid, known to raise HDL-cholesterol by enhancing PON1, the powerful enzyme that forms part of the HDL particle.^8,42 Increased PON1 correlates strongly with HDL cholesterol.⁴³

Pantethine Safely Lowers LDL Cholesterol

 

A long-standing concern with statins is that they reduce the production of essential coenzyme Q10, which may ultimately raise some cardiovascular risks in certain populations.^6,7

Pantethine, a derivative of vitamin B5, reliably lowers LDL cholesterol without reducing CoQ10 levels.

Studies indicate that pantethine helps reduce cholesterol levels by dual mechanisms—reducing the rate of new cholesterol production and speeding the breakdown of existing cholesterol.⁹ Both lab and clinical studies show that these mechanisms lead to real-world reductions in dangerous cholesterol levels.

Laboratory studies have shown that adding pantethine to liver cells in culture significantly reduces the production of fatty acids while increasing fat-burning activity.⁴⁴ As far back as 1984, a study on live rabbits fed a high-cholesterol diet found that pantethine supplementation reduced plasma total cholesterol levels by 64.7% compared with control animals.⁴⁵ Supplemented animals also demonstrated an increase in the beneficial HDL/total cholesterol ratio, a more than 18% reduction in the area of aortic plaque formation, and a reduction in the severity of lesions in the aorta and in the coronary arteries.

After that study was published, a variety of small studies during the late 1980s and early 1990s began exploring pantethine for human use—and all demonstrated pantethine’s ability to reduce total and LDL cholesterol, as well as its ability to reduce the ratio of total cholesterol to HDL. ^46-50

But it is the dramatic findings of two recent studies that have experts re-energized about pantethine in reducing risk factors for cardiovascular disease.

The first study involved people in basically good health, but whose lipid profiles placed them in a low-to-moderate risk of cardiovascular disease. ⁵¹ Because of their low risk, these patients were not candidates for statin therapy, making them ideal for a prevention study of this kind.

For four weeks, all subjects were started on a therapeutic lifestyle-change diet, with the main focus being a reduction in saturated fat. After that, they were randomly assigned to receive 600 mg per day of pantethine or a placebo for the next eight weeks, and then 900 mg per day for an additional eight weeks. At the end of the study, placebo recipients had no significant changes in total or LDL cholesterol or levels of apoB (the LDL-associated protein). Pantethine-supplemented subjects, however, had modest reductions in total cholesterol of 6 mg/dL (3% from baseline), in LDL of 4 mg/dL (4% from baseline), and in apoB of 4 mg/dL (5% from baseline).⁵¹

A study of similar design in 2014 found better results.⁹ After just four weeks, the researchers noted significant differences between the supplemented and placebo groups. And after 16 weeks, the patients supplementing with pantethine experienced reductions from baseline in total cholesterol of 6%, in LDL of 11%, and non-HDL cholesterol of 8%. Interestingly, an increase in the dose of pantethine from 600 to 900 mg per day during weeks 8 through 16 did not produce additional changes in LDL. An additional critical finding in this study was an 8% reduction in apoB from baseline in the supplemented group—a significant reduction since apoB is the core protein in the deadly LDL cholesterol particle.

Given that for each 1% reduction in LDL cholesterol levels there is a correlating 1% reduction in the risk of coronary artery events, these pantethine-induced changes bode extremely well for those at risk for cardiovascular diseases. In this study, the 11% reduction in LDL cholesterol translates into a highly meaningful 11% decrease in the risk of a heart attack or other coronary artery disorder.⁹

An additional important factor in the context of safety here is that levels of CoQ10 did not fall (indeed, they rose slightly) with supplementation. This is in direct contradistinction to statins, which produce dangerous lowering of CoQ10, potentially impairing energy metabolism in heart and skeletal muscles.

New And Improved Vitamin B5

Pantethine is a derivative of vitamin B5 (pantothenic acid).^9,65 It lowers cholesterol—particularly the risk-producing LDL form—by enhancing cellular utilization of fats and sugars and by reducing the production of new cholesterol molecules.⁹ Pantethine essentially functions as a more metabolically active form of vitamin B5. Its benefits are especially seen in how it relates to an essential enzyme cofactor called Coenzyme A (CoA).

Vitamin B5 is the precursor molecule to CoA. Unlike vitamin B5, however, pantethine participates directly in reactions requiring CoA, without the need to undergo additional enzymatic conversion that is required of B5 itself.⁶⁶

Once pantethine has been efficiently converted into CoA, CoA participates in more than 70 crucial enzymatic reactions in the body—particularly those involving the breakdown of food molecules and release of the energy in their chemical bonds to do useful work in the cell.⁶⁶ This is important because every single fat and sugar molecule you eat must eventually combine with a CoA molecule to enter the cycle of reactions that will release its chemical energy.

Research shows that supplementation with pantethine significantly raises the content and activity of CoA in the liver, much more efficiently than does vitamin B5 itself.⁶⁷

Summary

Virtually every American is at significant risk for cardiovascular diseases as they age. Factors behind this risk include elevations in LDL and insufficient protective HDL.

Mainstream medicine and Big Pharma have succeeded in getting more than 25 million Americans to use statin drugs that lower LDL cholesterol at the expense of side effects so pronounced that over 20% stop using statins,⁵² leaving them vulnerable to LDL-induced arterial disease.

A new combination of ingredients includes pantethine, shown to safely lower LDL without statin-like side effects, and a novel artichoke leaf extract, capable of raising HDL levels. This combination is likely to provide dual-acting benefits.

Those with moderately elevated LDL and/or insufficient HDL may be able to eliminate statin drugs through use of the natural compounds described in this article.

For people with stubbornly high LDL that may require statin drug therapy, the advantage of adding these natural compounds is that it may enable the dose of the statin drug to be reduced to a level where side effects are minimized or eliminated.

A fact that physicians have yet to grasp is that lower-dose statins in most patients can provide equivalent protective benefits as high doses promoted by profit-hungry pharmaceutical companies. This was shown in a study with the popular statin drug atorvastatin (Lipitor^®), whereby fewer patients taking lower doses died from any cause compared to higher doses.⁵³

Statin drugs are demonized by advocates of natural approaches, and the horrific side effects inflicted by high-dose statins justify these concerns, especially for those who do not adequately supplement with CoQ10.

An objective strategy when taking into account the high rates of disability and death caused by arterial disease is to try lifestyle and natural approaches to reduce LDL below 100 mg/dL and increase HDL as high above 50 mg/dL as possible. If these safe methods fail, then use the absolute lowest dose of a statin drug to achieve LDL/HDL blood readings in the safe ranges.

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

References

1. Pencina MJ, Navar-Boggan AM, D’Agostino RB, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014;370:1422–31.
2. Institute of Medicine (US) Committee on a National Surveillance System for Cardiovascular and Select Chronic Diseases. A Nationwide Framework for Surveillance of Cardiovascular and Chronic Lung Diseases. Washington (DC): National Academies Press (US); 2011.
3. Available at: http://www.heart.org/idc/groups/ahamah-public/@wcm/@sop/@smd/documents/downloadable/ucm_470704.pdf. Accessed February 2, 2015.
4. Yamashita S, Tsubakio-Yamamoto K, Ohama T, Nakagawa-Toyama Y, Nishida M. Molecular mechanisms of HDL-cholesterol elevation by statins and its effects on HDL functions. J Atheroscler Thromb. 2010 May;17(5):436-51.
5. Barter PJ, Brandrup-Wognsen G, Palmer MK, Nicholls SJ. Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER Database. J Lipid Res. 2010 Jun;51(6):1546-53.
6. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Coenzyme Q10 deficiency in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is related to fatigue, autonomic and neurocognitive symptoms and is another risk factor explaining the early mortality in ME/CFS due to cardiovascular disorder. Neuro Endocrinol Lett. 2009;30(4):470-6.
7. Molyneux SL, Florkowski CM, George PM, et al. Coenzyme Q10: an independent predictor of mortality in chronic heart failure. J Am Coll Cardiol. 2008 Oct 28;52(18):1435-41.
8. Rondanelli M, Giacosa A, Opizzi A, et al. Beneficial effects of artichoke leaf extract supplementation on increasing HDL-cholesterol in subjects with primary mild hypercholesterolaemia: a double-blind, randomized, placebo-controlled trial. Int J Food Sci Nutr. 2013 Feb;64(1):7-15.
9. Evans M, Rumberger JA, Azumano I, Napolitano JJ, Citrolo D, Kamiya T. Pantethine, a derivative of vitamin B5, favorably alters total, LDL and non-HDL cholesterol in low to moderate cardiovascular risk subjects eligible for statin therapy: a triple-blinded placebo and diet-controlled investigation. Vasc Health Risk Manag. 2014;10:89-100.
10. Kostapanos MS, Milionis HJ, Elisaf MS. Rosuvastatin-associated adverse effects and drug-drug interactions in the clinical setting of dyslipidemia. Am J Cardiovasc Drugs. 2010;10(1):11-28.
11. Hodel C. Myopathy and rhabdomyolysis with lipid-lowering drugs. Toxicol Lett. 2002 Mar 10;128(1-3):159-68.
12. Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009 Oct;32(10):1924-9.
13. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010 Feb 27;375(9716):735-42.
14. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. Jama. 2011 Jun 22;305(24):2556-64.
15. Waters DD, Ho JE, DeMicco DA, et al. Predictors of new-onset diabetes in patients treated with atorvastatin: results from 3 large randomized clinical trials. J Am Coll Cardiol. 2011 Apr 5;57(14):1535-45.
16. Culver AL, Ockene IS, Balasubramanian R, et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women’s Health Initiative. Arch Intern Med. 2012 Jan 23;172(2):144-52.
17. Barter P. HDL-C: role as a risk modifier. Atheroscler Suppl. 2011 Nov;12(3):267-70.
18. Barter, P. The role of HDL-cholesterol in preventing atherosclerotic disease. Eur Heart J Supp. 2005;7(suppl F):F4-F8.
19. Parolini C, Marchesi M, Chiesa G. HDL therapy for the treatment of cardiovascular diseases. Curr Vasc Pharmacol. 2009 Oct;7(4):550-6.
20. Andersson LO. Pharmacology of apolipoprotein A-I. Curr Opin Lipidol. 1997 Aug;8(4):225-8.
21. Berliner JA, Navab M, Fogelman AM, et al. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation. 1995 May 1;91(9):2488-96.
22. Eriksson M, Carlson LA, Miettinen TA, Angelin B. Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I. Potential reverse cholesterol transport in humans. Circulation. 1999 Aug 10;100(6):594-8.
23. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977 May;62(5):707-14.
24. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998 Jul 23;339(4):229-34.
25. Kawashiri MA, Maugeais C, Rader DJ. High-density lipoprotein metabolism: molecular targets for new therapies for atherosclerosis. Curr Atheroscler Rep. 2000 Sep;2(5):363-72.
26. Mooradian AD. Cardiovascular disease in type 2 diabetes mellitus: current management guidelines. Arch Intern Med. 2003 Jan 13;163(1):33-40.
27. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med. 1999 Aug 5;341(6):410-8.
28. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). Bmj. 1998 Mar 14;316(7134):823-8.
29. 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.
30. Goldenberg I, Benderly M, Sidi R, et al. Relation of clinical benefit of raising high-density lipoprotein cholesterol to serum levels of low-density lipoprotein cholesterol in patients with coronary heart disease (from the Bezafibrate Infarction Prevention Trial). Am J Cardiol. 2009 Jan 1;103(1):41-5.
31. Ramos PA, Guerra AR, Guerreiro O, et al. Lipophilic extracts of Cynara cardunculus L. var. altilis (DC): a source of valuable bioactive terpenic compounds. J Agric Food Chem. 2013 Sep 4;61(35):8420-9.
32. Brown JE, Rice-Evans CA. Luteolin-rich artichoke extract protects low density lipoprotein from oxidation in vitro. Free Radic Res. 1998 Sep;29(3):247-55.
33. Fritsche J, Beindorff CM, Dachtler M, Zhang H, Lammers JG. Isolation, characterization and determination of minor artichoke (Cynara scolymus L.) leaf extract compounds. Eur Food Res Technol. 2002;215:149-57.
34. Jiménez-Escrig A, Dragsted LO, Daneshvar B, Pulido R, Saura-Calixto F. In vitro antioxidant activities of edible artichoke (Cynara scolymus L.) and effect on biomarkers of antioxidants in rats. J Agric Food Chem. 2003 Aug 27;51(18):5540-5.
35. Gebhardt R. Inhibition of cholesterol biosynthesis in HepG2 cells by artichoke extracts is reinforced by glucosidase pretreatment. Phytother Res. 2002 Jun;16(4):368-72.
36. Qiang Z, Lee SO, Ye Z, Wu X, Hendrich S. Artichoke extract lowered plasma cholesterol and increased fecal bile acids in Golden Syrian hamsters. Phytother Res. 2012 Jul;26(7):1048-52.
37. Englisch W, Beckers C, Unkauf M, Ruepp M, Zinserling V. Efficacy of Artichoke dry extract in patients with hyperlipoproteinemia. Arzneimittelforschung. 2000 Mar;50(3):260-5.
38. Lupattelli G, Marchesi S, Lombardini R, et al. Artichoke juice improves endothelial function in hyperlipemia. Life Sci. 2004 Dec 31;76(7):775-82.
39. Bundy R, Walker AF, Middleton RW, Wallis C, Simpson HC. Artichoke leaf extract (Cynara scolymus) reduces plasma cholesterol in otherwise healthy hypercholesterolemic adults: a randomized, double blind placebo controlled trial. Phytomedicine. 2008 Sep;15(9):668-75.
40. Rondanelli M, Riva A, Sala P, Giacosa A. Pilot study on the efficacy of 200 mg daily dose of PYCRINIL on glyco-lipidic parameters in adult subjects with mild hypercholesterolemia: University of Pavia, Department of Public Health, Experimental and Forensic Medicine, Section of Human Nutrition, Azienda di Servizi alla Persona, Pavia, Italy; 2014.
41. Matsuyama A, Sakai N, Hiraoka H, Hirano K, Yamashita S. Cell surface-expressed moesin-like HDL/apoA-I binding protein promotes cholesterol efflux from human macrophages. J Lipid Res. 2006 Jan;47(1):78-86.
42. Gouedard C, Barouki R, Morel Y. Dietary polyphenols increase paraoxonase 1 gene expression by an aryl hydrocarbon receptor-dependent mechanism. Mol Cell Biol. 2004 Jun;24(12):5209-22.
43. van der Gaag MS, van Tol A, Scheek LM, et al. Daily moderate alcohol consumption increases serum paraoxonase activity; a diet-controlled, randomised intervention study in middle-aged men. Atherosclerosis. 1999 Dec;147(2):405-10.
44. Hsu JC, Tanaka K, Inayama I, Ohtani S. Effects of pantethine on lipogenesis and CO2 production in the isolated hepatocytes of the chick (Gallus domesticus). Comp Biochem Physiol Comp Physiol. 1992 Jul;102(3):569-72.
45. Carrara P, Matturri L, Galbussera M, Lovati MR, Franceschini G, Sirtori CR. Pantethine reduces plasma cholesterol and the severity of arterial lesions in experimental hypercholesterolemic rabbits. Atherosclerosis. 1984 Dec;53(3):255-64.
46. Prisco D, Rogasi PG, Matucci M, et al. Effect of oral treatment with pantethine on platelet and plasma phospholipids in IIa hyperlipoproteinemia. Angiology. 1987 Mar;38(3):241-7.
47. Gaddi A, Descovich GC, Noseda G, et al. Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia. Atherosclerosis. 1984 Jan;50(1):73-83.
48. Bertolini S, Donati C, Elicio N, et al. Lipoprotein changes induced by pantethine in hyperlipoproteinemic patients: adults and children. Int J Clin Pharmacol Ther Toxicol. 1986 Nov;24(11):630-7.
49. Arsenio L, Bodria P, Magnati G, Strata A, Trovato R. Effectiveness of long-term treatment with pantethine in patients with dyslipidemia. Clin Ther. 1986;8(5):537-45.
50. Coronel F, Tornero F, Torrente J, et al. Treatment of hyperlipemia in diabetic patients on dialysis with a physiological substance. Am J Nephrol. 1991;11(1):32-6.
51. Rumberger JA, Napolitano J, Azumano I, Kamiya T, Evans M. Pantethine, a derivative of vitamin B(5) used as a nutritional supplement, favorably alters low-density lipoprotein cholesterol metabolism in low- to moderate-cardiovascular risk North American subjects: a triple-blinded placebo and diet-controlled investigation. Nutr Res. 2011 Aug;31(8):608-15.
52. Ellis JJ, Erickson SR, Stevenson JG, Bernstein SJ, Stiles RA, Fendrick AM. Suboptimal statin adherence and discontinuation in primary and secondary prevention populations. J Gen Intern Med. 2004 Jun;19(6):638-45.
53. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005 Apr 4;352(14):142535.
54. Kellner-Weibel G, Luke SJ, Rothblat GH. Cytotoxic cellular cholesterol is selectively removed by apoA-I via ABCA1. Atherosclerosis. 2003 Dec;171(2):235-43.
55. Bachorik PS, Lovejoy KL, Carroll MD, Johnson CL (1997) Apolipoprotein B and AI distribution in the United States, 1988–1991: results of the National Health and Nutrition Examination Survey III (NHANES III). Clin Chem. 1997 Dec;43(12):2364-78.
56. Mackness MI, Durrington PN, Mackness B. The role of paraoxonase 1 activity in cardiovascular disease: potential for therapeutic intervention. Am J Cardiovasc Drugs. 2004;4(4):211-7.
57. Cagnin A, Leon A, Vianello D, et al. LDL density and oxidation are modulated by PON1 promoter genotype in patients with Alzheimer’s disease. J Alzheimers Dis. 2013;34(2):377-85.
58. Nus M, Frances F, Librelotto J, Canales A, et al. Arylesterase activity and antioxidant status depend on PON1-Q192R and PON1-L55M polymorphisms in subjects with increased risk of cardiovascular disease consuming walnut-enriched meat. J Nutr. 2007 Jul;137(7):1783-8.
59. Elshourbagy NA, Meyers HV, Abdel-Meguid SS. Cholesterol: the good, the bad, and the ugly - therapeutic targets for the treatment of dyslipidemia. Med Princ Pract. 2014;23(2):99-111.
60. Walker AE, Eskurza I, Pierce GL, Gates PE, Seals DR. Modulation of vascular endothelial function by low-density lipoprotein cholesterol with aging: influence of habitual exercise. Am J Hypertens. 2009 Mar;22(3):250-6.
61. Available at: https://www.lifeextension.com/magazine/2010/9/no-cure-for-heart-disease/page-01. Accessed February 12, 2015.
62. Available at: https://www.lifeextension.com/magazine/2011/6/the-fda-most-heinous-drug-approval. Accessed February 12, 2015.
63. Nussey S, Whitehead S. Endocrinology: An Integrated Approach. Oxford: BIOS Scientific Publishers; 2001. Chapter 1: Principles of Endocrinology.
64. Ballantyne CM, Pitt B, Loscalzo J, Cain VA, Raichlen JS. Alteration of relation of atherogenic lipoprotein cholesterol to apolipoprotein B by intensive statin therapy in patients with acute coronary syndrome (from the Limiting UNdertreatment of lipids in ACS With Rosuvastatin [LUNAR] Trial). Am J Cardiol. 2013 Feb 15;111(4):506-9.
65. Horvath Z, Vecsei L. Current medical aspects of pantethine. Ideggyogy Sz. 2009 Jul 30;62(7-8):220-9.
66. Kelly GS. Pantethine: A Review of its Biochemistry and Therapeutic Applicaitons. Alt Med Rev. 1997;2(5):365-76.
67. Branca D, Scutari G, Siliprandi N. Pantethine and pantothenate effect on the CoA content of rat liver. Int J Vitam Nutr Res. 1984;54(2-3):211-6.