If cherries are good, grapes are even better for a CHF patient.

Grapes activate genes that reduce high blood pressure related heart failure

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• May 7, 2013
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It has been known that grapes are able to reduce heart failure associated with chronic high blood pressure. A US study appearing in the "Journal of Nutritional Biochemistry" has now shown how this effect is achieved: The grapes activate a number of genes that improve the levels of glutathione, the most abundant cellular antioxidant in the heart.

The scientists from the University of Michigan hypertensive, fed heart failure-prone rats a grape-enriched diet for 18 weeks. The results reproduced earlier findings that grape consumption reduced the occurrence of heart muscle enlargement and fibrosis, and improved the diastolic function of the heart. Furthermore, the mechanism of action was uncovered. Grape intake "turned on" antioxidant defense pathways, increasing the activity of related genes that boost production of glutathione.

In the next phase, which will continue into 2014, E. Mitchell Seymour, the head of the study, aims to further define the mechanisms of grape action, and also look at the impact of whole grape intake compared to individual grape phytonutrients on hypertension-associated heart failure. His hypothesis is that whole grapes will be superior to any individual grape component. "The whole fruit contains hundreds of individual components, which we suspect likely work together to provide a synergistic beneficial effect," reasons Seymour.

Seymore, EM. Diet-relevant phytochemical intake affects the cardiac AhR and nrf2 transcriptome and reduces heart failure in hypertensive rats, The Journal of Nutritional Biochemistry - 25 March 2013 (10.1016/j.jnutbio.2013.01.008)

Life IS a bowel of Cherries especially with someone with Gout.

 

www.medscape.com

 

Do Cherries Really Work in Gout?

Jonathan Kay, MD

May 03, 2013

Hello. I am Jonathan Kay, Professor of Medicine and Director of Clinical Research in the Division of Rheumatology at the University of Massachusetts Medical School and UMass Memorial Medical Center, both in Worcester, Massachusetts.

In the 1931 musical Scandals, Ethel Merman sang a song that began, "Life is just a bowl of cherries." It turns out that gout might also be just a bowl of cherries. Gout is a very prevalent condition, affecting more than 8 million individuals in the United States, and is a very common reason for patients to present to the rheumatologist.

Recently, many patients have come in saying that they take cherry extract or eat cherries to prevent an attack of gout. Is there any scientific basis for this?

In December 2012, Zhang and colleagues^[1] from Boston University Medical Center published a very interesting paper inArthritis and Rheumatism. In this case/control study, patients with gout were enrolled in an Internet-based registry. Investigators picked a 2-day period just before an attack of gout and compared that period with the 2 preceding days and the 2 subsequent days as control periods unrelated to an attack of gout.

The investigators validated the diagnosis of gout in more than 550 patients by looking at medical records authorized by the patients for review, and found that this group of patients had more than 1250 attacks of gout. The investigators looked at various self-reported dietary items, including cherries and other unrelated foods. They found that the intake of cherries before an attack of gout reduced the likelihood of experiencing an acute attack of gout by one third compared with the intake of unrelated foods.

This interesting finding suggests that there may be some basis to the ingestion of cherry extract or cherries to reduce attacks of gout. What might be the scientific basis for this? Cherry extract blocks the tubular reabsorption of urate and increases urate excretion in the urine. Cherry juice may also block xanthine oxidase and reduce the production of uric acid.

Cherry extract has a synergistic effect with allopurinol. Moreover, cherries contain anthocyanins, which are somewhat anti-inflammatory. Thus, there may actually be a reason why patients are making the right decision by ingesting cherries. Future controlled clinical trials of cherry extract should help to confirm or disprove this very interesting epidemiologic observation.

Thank you very much for your attention, and I look forward to seeing you on Medscape.

References

1. Zhang Y, Neogi T, Chen C, Chaisson C, Hunter DJ, Choi HK. Cherry consumption and decreased risk of recurrent gout attacks. Arthritis Rheum. 2012;64:4004-4011. Abstract

 

Medscape Rheumatology © 2013  WebMD, LLC

Cite this article: Do Cherries Really Work in Gout? Medscape. May 03, 2013.

Cholesterol and Statins: Part II

Cholesterol & Statins:  Part II

by Yusuf M. Saleeby, MD

to be published in American Fitness magazine (Mar/April 2013 issue)

In the last issue (Cholesteron & Statins : Part I, American Fitness Jan/Feb 2013), the discussion centered on cholesterol, that necessary but often maligned molecule.  The previous article made one realize that this steroid compound is a double edged sword as it relates to health concerns.  While essential for the life of human cells, high serum levels of total cholesterol and in particular elevated non-HDL-cholesterol, designated bad cholesterol, end up being harmful to our cardiovascular system.

Plenteous research, time and money have been devoted to the study of this low density lipoprotein substance that carries cholesterol (LDL-C) out of the liver to cells.  It was discovered that too much would ‘’clog up’’ arteries back in the 1970s.  This was the driving force for aggressive development of medications to combat the formation and lower the level of LDL-C in circulation.¹

As previously mentioned in Part I, dietary restriction of cholesterol is of limited value.  When we limit our oral intake of dietary cholesterol, our body produces cholesterol in the liver to compensate for a predetermined genetic set point.  Thus a cholesterol restrictive diet alone is usually not enough to reduce markedly elevated levels of the ‘’bad cholesterol.’’ ²   Dietary restrictions alongside weight loss and exercise are a more effective approach.  Lipid lowering medications like the class of statin drugs have a more potent affect.

History:

Statins or HMG-CoA reductase inhibitors are a class of drug that inhibits an enzyme which plays a central role in manufacturing cholesterol in the liver.  The term ‘’statin’’ is derived by the last few letters of some of the original drugs developed, lovostatin and simvastatin being examples.  Historically, the Japanese biochemist Dr. Akira Endo isolated the first statin drug (mevastatin), but it showed toxicities and never made it to market.  Not long afterwards in the early 1970’s researchers from Merck pharmaceuticals following up on published research and developed the first marketable statin (lovostatin) which was extracted similar to Dr. Endo’s from the fungus (Aspergillus terreus).^1,3   Incidentally, there are naturally occurring statins, namely those found in the oyster mushroom (Pleurotus ostreatus) and the extracts from fermented red yeast rice fungi (Monascus purpureus).⁴    This latter extract is used commercially as a natural alternative to reduce cholesterol.

Merck capitalized on the statin drugs Zocor® and Mevacor®, which earned the company over $1-Billion each by 1995.  Dr. Endo was also the beneficiary of the 2006 Japan Prize and Lasker-DeBakey Clinical Research Award in 2008 for his achievements in the field of lipid chemistry.  Today there are a number of statins in the marketplace, as both stand alone drugs and in combination with other lipid lowering agents.  Names the public would recognize include Lipitor® (atorvastatin), Lescol® (fluvastatin), Mevacor® (lovastatin), Pravachol® (pravastatin), Crestor® (rosuvastatin) and Zocor® (simvastatin).  All are lab synthesized drugs except for lovastatin and pravastatin which are derived directly from naturally occurring yeast and bacterium. 

Statin Drugs (HMG-coA reductase inhibitors)

Numerous medical trials show the statins as having a major affect on lowering LDL-C, and thus bringing the total cholesterol in serum down.   Statins can, with varying degree raise HDL-C levels.  When compared to diet alone, statins are proven more effective in lowering LDL-C.  However, this is not accomplished without some undesirable side effects.  The drugs mostly affect the liver hepatocytes and muscle cells.  The toxicity of natural occurring statins in mushrooms is unobtrusive, but some serious muscle damage can occur with pharmaceuticals.  One such incident occurred when Baycol® (cerivastatin) came to market some years ago.  It was so toxic that the Federal Drug Administration (FDA) had to remove it from pharmacies in 2001.⁵

Recent changes to the National Institute of Health (NIH) guidelines for testing individuals now suggest that children between the ages of 9 to 11 have lipid screening performed.  Most statins are approved for use in children 10-years and older, but use should be judicious.  Statins are classified as Category X in pregnancy which means they are contraindicated in expectant women because of high risk of birth defects.⁶ 

Statin drugs produce muscle pain in approximately 30-percent of individuals who take them.  Other side effects include liver damage, digestive problems, rash, cataracts, an increase in blood glucose and type-2 diabetes (T2DM) risk, and neurological conditions as a rise in amyotrophic lateral sclerosis (ALS) incidence.  Those that are at higher risks are females, those taking other cholesterol medications, people with small body frames and with underlying kidney or liver disease and/or diabetes.  Being over the age of 65-years also increases risk for untoward effects for statin users.  There are reports of a fifty-percent increase in risk of developing age-related cataracts with those using statin drugs compared with non-users.^5,6,7

To combat detrimental side effects, sometimes a prescriber will switching from one statin to another, or reduce the dose, or change the dosing schedule to every other day.  If a person is taking a statin they should avoid grapefruit and grapefruit juice as this can potentiate the drug’s harmful effects.  The cardiac rhythm drug amiodarone (Cardarone®) has an interaction with simvastatin.  Lopid® another lipid lowering agents concomitant use with statins is ill advised.  Some HIV drugs (protease inhibitors) interact with lovastatin in a negative way.  There are even interactions with antibiotics and antifungal drugs.  The immunosuppressant drug cyclosporine (Sandimmune®) can increase risk for rhabdomyolysis (muscle breakdown) as well.^5,7   With statin use monitoring of liver function tests (transaminases) and muscle biomarkers creatine kinase (CPK) and aldolase are indicated routinely along with monitoring the effects of the drug to meet goal (serum LDL-C and ApoB levels).  Yet other measures to reduce untoward effects of statin drugs have been to add coenzyme Q10, correct Vitamin D and thyroid deficiencies, or switch to a non-statin regimen.  There is a theoretical risk that lowering cholesterol drastically can affect production and levels of beneficial steroid hormones.  More study in this area is needed to confirm or dispel fears.

Since the mapping of the human genome, genetic tests have been developed to help predict coronary risk and the effectiveness of statin therapy.  The blood test analyzing the KIF6 genotype (offered by Berkeley Heart Labs) may aid doctors in directing lipid therapy as polymorphisms in this gene identify those at higher risk for coronary heart disease.  Once identified, those individuals can reduce their risk with statin therapy.  The SLCO1B1 genotype test, help clinicians predict who may be at greater risk for muscle damage while on lipid lowering therapy.  Carriers of the SLCO1B1 gene are more likely to have problems with statin induced myopathy then those who do not carry that gene.^8,9

With the drug market eventually becoming saturated with statin medications and coming under fire with a plethora of side effects, researchers began looking elsewhere.  Focus was centered on manipulation of beneficial lipoproteins, namely HDL-C.  It was reasonable to think that raising HDL-C would scavenge the bad cholesterol away to be recycled and thus not be around to form foam cells.  Research had already proven that reduction in native LDL-C and foam cells, which lead to arterial plaque formation, would lessen the risk for heart disease.  A genetic malady, albeit rare gave promise that developing pro-HDL-C drugs may be a superior alternative to statin therapy.  Tangier Disease afflicts a very small number of people worldwide, but with extremely low levels of HDL-C there is a tendency for more advanced cardiovascular disease in younger victims.^10-13   Initial trials of HDL-C raising drugs were a disappointment to those proponents of raising HDL, but research continues in this direction.¹⁴ 

In all fairness to statin drugs, there have been reports of other benefits such as improving endothelial function, reducing inflammatory C-Reactive Protein, coronary plaque stability and reduction in thrombus formation (clots).  Additionally, for reasons not quite clear there was a reduction in cancer risk while study subjects were on statin drugs.^15,16

According to an October 2012 JAMA report on trends in lipids in the United States between 1988 and 2010, total cholesterol and LDL-C numbers experienced a reduction.  Unfortunately during the same time frame triglycerides (TG) went up while HDL-C remained unchanged.  This is all apparently the result of aggressive statin use with Americans having dyslipidemia.¹⁷

Pharmaceutical Alternatives to Statin Therapy

Ezetimibe a drug known in the US market as Zetia® is an alternative for those who cannot tolerate statin therapy.  Ezetimibe can lower cholesterol by interrupting intestinal re-absorption of cholesterol.  However, studies have reported continued use can thicken the arterial walls.  So it is recommended as a drug of last resort by some.  Ezetimibe is also used in conjunction with statins in some dual agent drugs such as Vytorin®.  Dual therapy is a means of using two agents at lower individual doses to achieve a particular lipid level goal and limit side effects.^18,19

Fibric Acid derivatives such as gemfibrozil (Lopid®) and fenofibrate (TriCor®) are other alternatives to statin therapy.  While not as effective in lowering LDL-C as stains, they do raise HDL-C and lower Triglycerides (TG).  Fibric Acid drugs are known to improving insulin resistance as an added benefit.  However, in combination with statins they can increase risk for liver and muscle injury.^20,21

Vitamin B3 (nicotinic acid) in high doses is commonly used to raise HDL-C.  This naturally occurring substance while relatively safe in high doses does come with the undesirable side effect of flushing.  Flushing can be thwarted by a delayed release delivery system (Niaspan®) by prescription and by premedication with low dose aspirin.²²

Questran® and WelChol® are in a class of drug called bile acid resins.  Bile acid resins are used to lower LDL-C and total Cholesterol by sequestration and expulsion in feces.  They are effective and are another pharmaceutical alternative with limited systemic effects used in statin-intolerant patients.²²

Cholesteryl ester transfer protein (CETP) inhibitors came on the scene recently.  They were touted as the new wonder drug for cholesterol management, or so it was thought.  This class of medication is used to raise HDL-C.^12,13   However, initial attempts by Roche pharmaceuticals were halted in phase III trials due to failure of the agent (torcetrapid) to perform safely.¹⁴  Nonetheless, the Academy for the Advancement of HDL Science is optimistic about future developments and new drugs in the pipeline.¹⁵

Natural Alternatives to Statin Therapy

Fish oil is a clinically proven agent in lowering cholesterol and triglycerides.  The omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are well researched as being effective for dyslipidemia.  Krill oil is a newer arrival into the forum; it has been peddled as being better than fish oil by proponents.  Having a lower DHA and EPA content than fish oil and costing 5 to 10-times as much, it may not be a preferred choice.  Only a few high concentrated Krill or Krill/Fish oil combinations give you the necessary concentrations of DHA/EPA to lower lipids and provide cardiac risk reduction.²³   Fish oil has the FDA nod of approval for lowering cholesterol and triglycerides (TG) and even comes as the FDA approved prescriptive Lovaza®.  While Lovaza® is rather expensive; those seeking pharmaceutical grade fish oil have many less expensive choices that are equally effective and safe.  Caution should be taken when using fish oil with other blood thinning medications prior to elective surgery or with those with seafood allergies.

Besides fish oil there are several herbal and dietary supplements that can lower cholesterol and heart disease risk.  Garlic in some studies reported a reduction of total cholesterol by a few points.  Caution however, must be taken when taken in conjunction with blood thinners such as Coumadin® as bleeding risks may increase.²⁴   Oat bran and barley have been studied and demonstrate that with regular ingestion a person can lower cholesterol and cardiac risk.²⁵  

The resin Guggulipid derived from the mukul myrrh tree, illustrates a reduction of LDL-C and total cholesterol in clinical studies performed in India.  Demonstrating Guggulipid to be an important natural lipid lowering agent will require more scientific examination.  As mentioned earlier the extract of fermented red yeast rice is a naturally occurring statin.  While showing lower risk of toxicity, there is a linear correlation with lower effectiveness due to its reduced potency.  The product of the waxy coating of sugar cane and beet skins known as policosanol was shown in several clinical trials to lower LDL-C when taken orally in standard doses.^24,26,27

Extracts of fenugreek, artichoke, yarrow, and holy basil may also help lower cholesterol, but again clinical trials will have to prove this to the medical community.  The use of ginger, turmeric, and rosemary in cholesterol lowering preparations are common as there may be some benefit.  Consumption of dietary fiber, soy based foods, and plant sterols (aka phytosterols, compounds similar to cholesterol) can reduce LDL-C.  Phytosterols interfere with the re-absorption of cholesterol and can be found in commercial bread spreads like Benecol®, Promise®, and Smart Balance®.^26,27   With the advent of ‘’Medical Foods” there are patented combination therapies, sanctioned by the FDA for prescriptive use, that have shown promise in scientific studies.  Metagenic’s UltraMeal360® is an example of such a prescriptive medical food.²⁸   Another medical food is Hypertensa® designed for those with metabolic syndrome by Physician Therapeutics; and more of these safer alternatives are on the horizon.²⁹

Whether you put your chips on lowering LDL-C or raising HDL-C one important fact remains; both courses of action will reduce cardiovascular risk, but when you add weight loss and exercise then risk of heart disease really drops.  According to Mayo Clinic reports, weight loss of between 5 and 10 lbs can lower LDL-C levels.  For every six pounds of weight loss you can increase HDL-C by 1mg/dL in serum levels.  Physical activity, as in sustained exercise, lasting 30 minutes or more at least five times a week can yield a five-percent increase in HDL-C.  Smoke cessation is also a big player; quit smoking and you can increase your HDL-C by ten-percent and in a year reduce your heart disease risk by fifty-percent.^26,27,30,31

Controlling cholesterol is a complicated process for physicians and patients alike.  Wrought with drug tolerance, unproven alternatives, and cost issues, it is a daunting task to manage dyslipidemia.  Along with ever changing practice guidelines for serum cholesterol levels offered up every couple of years by national medical societies and institutions, therapeutic recommendations will likely remain in flux for the unforeseeable future.

References:

1.      Endo A., The discovery and development of HMG-CoA reductase inhibitors, J. Lipid Res. 1992;33 (11): 1569–82. 

2.      Ahmed SM, Clasen ME, Donnelly JE. Management of dyslipidemia in adults. Am Fam Physician, 1998;1;57(9):2192-2204, 2207-8.

3.      Simons, John. "The $10 billion pill", Fortune magazine, January 20, 2003.

4.      Liu J, Zhang J, Shi Y, Grimsgaard S, Alraek T, Fønnebø V, Chinese red yeast rice (Monascus purpureus) for primary hyperlipidemia: a meta-analysis of randomized controlled trials". Chin Med 2006;1: 4.

5.      Golomb BA, Evans MA., Statin Adverse Effects: A Review of the Literature and Evidence for a Mitochondrial Mechanism. Am J Cardiovasc Drugs 2008;8(6): 373–418. 

6.      Prescriber’s Letter, January 2012 (vol. 19, no. 1) and June 2012 (vol. 19, no. 6) section on Statins and Dyslipidemia.

7.      Statin Side Effects, Retrieved from http://www.mayoclinic.com/health/statin-side-effects/MY00205 (Accessed 12/3/2012)

8.      SLCO1B1 Genotype testing, Retrieved from http://www.bhlinc.com/clinicians/test-descriptions/SLCO1B1-Genotype-Test (Accessed 12/3/2012)

9.      KIF6 Genotype testing, Retrieved from http://www.bhlinc.com/clinicians/test-descriptions/KIF6, (Accessed 12/3/2012)

10.  Grover SA, et al., Evaluating the incremental benefits of raising high-density lipoprotein cholesterol levels during lipid therapy after adjustment for the reductions in other blood lipid levels. Arch. Internal Med. 2009;169:1775.

11.  Singh IM, et al., High-density lipoprotein as a therapeutic target: A systematic review. JAMA. 2007;298:786.

12.  High Cholesterol: Cholesterol-lowering medication, Retrieved from http://www.webmd.com/cholesterol-management/guide/cholesterol-lowering-medication, (Accessed 12/3/2012)

13.  HDL Cholesterol: How to boost your ‘good’ cholesterol, Retrieved from http://www.mayoclinic.com/health/hdl-cholesterol, (Accessed 12/3/2012)

14.  "Roche provides update on Phase III study of dalcetrapib." Roche press release, May 7, 2012.

15.  Academy for the Advancement of HDL Science, Retrieved from http://lipid.org (Accessed 12/3/2012)

16.  Ridker PM, Danielson E, Fonseca FAH et al., Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. NEJM 2008;359 (21): 2195–207.

17.  Mitka M., Cholesterol drug controversy continues. JAMA 2008;299 (19): 2266.

18.  Carroll, MD., et al, Trends in Lipids and Lipoproteins in US Adults, 1988-2010., JAMA, 2012;308(15):1545-1554.

19.  Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci, 2005;102(23):8132-7.

20.  Jun M, Foote C, Lv J, et al., Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010;375 (9729): 1875–1884.

21.  Steiner G., Atherosclerosis in type 2 diabetes: a role for fibrate therapy?. Diab Vasc Dis Res, 2007;4 (4): 368–74.

22.  Alternative Treatments for High Cholesterol, Retrieved from http://www.webmd.com/cholesterol-management/guide/high_cholesterol_alternative-therapies, (Accessed 12/3/2012)

23.  Krill Oil: A substitute for Fish oil? Prescriber’s Letter August 2010, Retrieved from http://prescribersletter.therapeuticresearch.com (Accessed 12/3/2012)

24.  Cholesterol-lowering supplements: Lower your numbers without prescription medication, Retrieved from

http://www.mayoclinic.com/health/cholesterol-lowering-supplements/CL00013 (Accessed 12/3/2012)

25.  Jenkins, D. [Oats bran and Barley on Cholesterol] American Journal of Clinical Nutrition, 2005; vol 81:pp 380-87.

26.  Alternative Cholesterol Treatments, Retrieved from http://naturaldatabase.therapeuticresearch.com (Accessed 12/3/2012)

27.  Alternative Cholesterol Treatments, Retrieved from Cleveland Clinic Department of Nutrition and Cleveland Clinic Heart Center web sites (Accessed 12/3/2012)

28.  Metagenics UltraMeal360®, Retrieved from http://www.metagenics.com/products/health-conditions/hypercholesterolemia, (Accessed 11/16/2012)

29.  Hypertensa® Package Insert, Retrieved from http://tmedpharma.com/docs/monographs-5-22/Hypertensa_Product_Monograph_for_website_5-22-08.pdf (Accessed 11/16/2012)

30.  Smith SC Jr, Benjamin EJ, Bonow RO, et al., AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation endorsed by the World Heart Federation and the Preventive Cardiovascular Nurses Association. J Am Coll Cardiol. 2011;58(23):2432-2446.

31.  Greenland P, Alpert JS, Beller GA, et al., 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2010;122(25):e584-e636.

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Yusuf (JP) Saleeby, MD is medical director of WellnessOne and WellnessFirst which offer extensive and advanced cardiovascular and stroke biomarker and genetic analysis, including lipid subtypes, Lp(a), CRP, HDL₂ and HDL₃, LDL_1-4, ApoB, NT-proBNP, Lp-PLA2, and the 4q25, 9p21, ApoE, KIF6 and SLCO1B1-Genotype tests.  He is a regular contributor to American Fitness and serves on the medical advisory board.  He can be reached for comment at ymsaleeby@gmail.com.

Cholesterol and Statins: Part I

Cholesterol & Statins (Part I)

by Yusuf M. Saleeby, MD

to be published in American Fitness magazine (Jan/Feb 2013)

Today when one hears the word “cholesterol” it conjures up thoughts of “something bad”.  Whether we hear about a cholesterol level over 200 from a neighbor, or one of many TV shows preaching the avoidance of cholesterol rich foods, cholesterol always seems to drum up connotations of bad, evil or unhealthy.  This two part series will dispel the myths and urban legends about cholesterol and expand the reader’s knowledge of this rather important steroid compound.  Part II of this series will encompass the atherogenic (plaque forming properties of oxidized native LDL-Cholesterol) and what measures can be taken to minimize the risk of stroke and heart attack specifically focusing on a class of medication call statin drugs.

Although Cholesterol as a solid fatty substance was first isolated a half-century before, recognition was given to the scientist who named it in the early 1800’s.  A French chemist named Michel Eugène Chevreul, while studying bile acids and animal fats, christened this new compound.  He derived the name we use today from two Greek words Chole (of the bile) and stereos (solid) adding the –ol usually used to denote an alcohol component [(3β)-cholest-5-en-3-ol is the chemist’s nomenclature for cholesterol] (Olson, 1998).

Cholesterol is essential to mammalian cells as a major component in cell membranes.  This steroid molecule allows for membrane permeability and the flexibility and fluidity integral to our cells.  Additionally, cholesterol is the substrate or building block of other essential biologic end-products, namely the steroid hormones (testosterone, progesterone, estrogens and DHEA to name a few), the bile acids that help with digestion, and as a precursor substrate to the important vitamin/hormone vitamin D (Hanukogul, 1992). 

Essential to life and proper bodily functions as we know it cholesterol is a double edged sword and has in fact a dark side.  Too much either by dietary intake or endogenous production can cause damage to arteries and lead to cardiovascular disease.  Cardiovascular events such as acute myocardial infarction (heart attack) and cerebral vascular accident (stroke) are the consequence in part to the narrowing of blood carrying vessels to the heart and brain respectively.  This narrowing occurs in great part to the formation of plaques rich in cholesterol that line the lumen of arterial vessels.  After a period of time, growth and maturation these plaques “clog” those vessels.

Breaking down cholesterol into further sub-components sometimes adds to the confusion of the part cholesterol plays in health.  For example there are two major subcomponents of total serum cholesterol called low-density lipoprotein (LDL-C) and high-density lipoprotein (HDL-C).  One is often referred to as the “bad cholesterol.”  Because LDL-C is responsible for building up on artery walls when there is too much in circulation it is referred to as bad.  Produced in the liver and transported to cells, LDL is rather harmless until levels in the serum get too high or the native-LDL is oxidized by free-radicals and becomes atherosclerogenic (that which forms plaques) (Rosenson, 2010).  On the other hand HDL-C is called the “good cholesterol” in part because the smaller subcomponents are themselves protective and also because it’s main function is to transports cholesterol away from the cells and back to the liver for recycling or disposal.  The higher levels you have of HDL-C in your serum, the lower your chances for cardiovascular disease and its sequelae (Brunzell, 2008; Durrington, 2003).  A caveat recently realized is that lowering LDL-C is not the end-all-be-all of lipid management.  It turns out there are other players in plaque forming dyslipidemia such as triglycerides (TG), apolipoprotein B (apoB), and others that may be as important (or more so) in controlling cardiovascular disease (Miller, 2009; Sierra-Johnson, 2009; Handrean, 2011).  Apolipoproteins are proteins that bind lipids (including cholesterol) making the non-water-soluble lipids easier for transport through the water-based blood and lymphatic systems (Saito, 2004).

The Good, Bad and Ugly of cholesterol. 

Firstly let us discuss the body’s requirements and utilization of cholesterol, that we will call the “good”; then we can discuss how some types of cholesterol can hurt our cardiovascular system, that discussion we will call the “bad.”  And finally, we will reserve the discussion of controlling elevated levels of cholesterol with statin drugs (HMG-coA-reductase inhibitors) and by other means as the “ugly” aspect of our two part series.  Ugly you may ask?  Well there is much controversy and debate on how to lower, what to lower and how far or aggressive we need to get in lowering cholesterol.  There are schools of thought about lowering LDL and others on raising HDL.  Then there are the lipoproteins and triglycerides and their role in this game.

From its formation, cholesterol is made predominately in the liver.  A complex 37-stage enzymatic process has to occur to derive cholesterol from the base substrate substances of acetyl coenzyme A.  An important enzyme called 3-hydroxy-3-methylglutaryl CoA reductase (or HMG-CoA reductase) is critical for the formation of cholesterol in the liver.  This concept is important for our discussion on statin drug therapy.  Statin drugs are effective at lowering cholesterol as they inhibit this crucial enzyme. 

Production of cholesterol is in full force at night while we sleep.  Our bodies produce up to 1000 mg of cholesterol per day on average, while the typical 70 Kg (~150lb) person contains about 35 grams of cholesterol by weight.  Our diet, even the standard American high-fat diet, provides us with only between 200 and 300 mg of cholesterol per day.  So our bodies make more cholesterol than what we can possibly take in orally.  This becomes an important fact in how we can effectively treat elevated cholesterol, and in a way reveals the true etiology of dyslipidemia.  It shows the importance of genetics versus environment.  [Hint:  Dietary restriction of high cholesterol foods is a poor way of controlling dyslipidemia.] can be used in a side bar 

Cholesterol is recycled, first excreted by the liver, making a round trip to our cells and back via LDL-C and HDL-C, and then reabsorbed back into the liver to be excreted as bile acid.  This bile is stored in the gallbladder until needed to help digest ingested foods that contain fats and oils.  Approximately 50% of the excreted bile acids are then reabsorbed in the small intestines and returned into circulation.  These facts are again important when we consider how to manager elevated LDL-C.  The use of drugs that inhibit bile acid reabsorption can in theory work, as can phytosteroils from some plants that mimic bile acids.  Phytosteroils are preferentially secreted back into the gut, thus interfering with normal recirculating of bile acids.

Cholesterol is responsible for the absorption of critically important nutrients via the digestive system as the component of bile acids in bile.  The body’s requirements for vitamins A, D, E and K (all fat soluble) are linked to how well they are absorbed in our intestines when solubilized by bile.  Additionally, fats necessary for good health and energy production also require bile for intestinal absorption.  Cholesterol as a metabolic building block is necessary for the synthesis of vitamin D, and our steroid hormones (sex hormones) as well as those of the adrenal gland such as cortisol and aldosterone (Hanukogul, 1992).

So why all the fear about high levels of cholesterol?

Well it goes back to research showing a strong link between elevated total cholesterol and LDL-C specifically and heart disease.  While not the only major risk factor for coronary artery disease, it remains one of intense focus and scrutiny.  Researchers and drug companies hustled into the arena of determining how to control LDL and how best to drive the numbers down in the masses to relieve our industrialized society of the burden of sudden death by heart attack.  Reduce LDL and total cholesterol and the thinking was increased longevity and a better quality of life.

To put things into perspective if too much LDL is abound and not being utilized by the cells in a productive way, they eventually become oxidized as the lazy loiterers they are and start doing bad things to our artery wall lining.  The process is assisted by macrophages (part of our body’s immune system) which takes up this oxidized-LDL and becomes engorged forming what we refer to as “foam cells”.  These foam cells are trapped in the walls of blood vessels and when they mature over time, become atherosclerotic plaques (Weingärtner, 2010; Tymoczko, 2002).  They form on arterial walls of our carotid artery, our larger vessels and even the smaller coronary artery vessels. There may be other factors as to why they develop here versus there and it has been theorized that micro-trauma, inflammation or even infectious organisms may play a role.  Non-the-less, as these plaques get larger, they narrow the lumen of the arteries and thus set up a situation for bottlenecking of blood corpuscles passing through.  Add a few clotted platelets and presto, you have a recipe for disaster, a clotted artery unable to provide critical oxygenated blood to distal tissues (myocardium in the case of a heart attack and brain tissue in the case of a thrombotic stroke).  Without the oxygenated blood servicing our cells there is injury and eventual death of those cells which lead to one clutching their chest in pain or loosing neurological function.

To the rescue comes HDL-C, remember this is the good cholesterol.  This high density cholesterol and its lipoproteins are given credit for removing excess cholesterol from peripheral tissues and transporting them back to the liver.  This process known as reverse cholesterol transport is one of the chief functions of this beneficial type of cholesterol thus lowering risk for coronary disease (Gordon, 1989).  So what would do our bodies better, lowering LDL-C or raising HDL-C?  That argument continues.

Why the big focus on total cholesterol and LDL-Cholesterol? 

To answer that question one has to consider a few landmark studies in lipids related to plaques in the aorta.  The famous pathologist Dr. Rudolf Virchow noted back in 1856 lipid like plaques on arteries, this was followed by a celebrated study by the Russian scientist Dr. Nikolai Anitschkow in 1913, who fed rabbits high cholesterol diets (Virchow,1856, Steinberg, 2004).  Since then these high-lipid diet studies have been repeated in almost every animal model know.  LDL-cholesterol and it’s link to atherogenesis was what won Drs. Joseph Goldstein and Michael Brown a Nobel prize in medicine in 1985 for their appreciation of the LCL-C and heart disease connection (Goldstein,1973).  From that point, there was an explosion of research showing elevated cholesterol either by overconsumption of bad dietary fats or by poor genes.  Either way there was a link to heart disease (Steinberg, 2004-2006). 

In 1984 one of the first large scale double-blinded interventional trials called the Coronary Primary Prevention Trial (LRC-CPPT) demonstrated that a decrease in serum cholesterol, by a sequestrant drug called cholestyramine, significantly reduced heart attacks (JAMA, 1984).  From there pharmaceutical companies started their marathon race toward producing some of the most prescribed therapeutics in history that reduces cholesterol.  That will all be discussed in Part II of this series.  Despite the fact that there are other risk factors for heart disease and heart attack/stroke, the focus currently remains fervently on LDL-C and the development of statin drugs for lowering cholesterol. 

Other risk factors may actually be of greater importance to the health of the heart and brain, notably among them are family history/genetics, gender, race, obesity, diabetes, tobacco abuse, hypertension, hypertriglyceridemia, elevated homocysteine, inflammation, chronic kidney disease, sedentary lifestyle, Lp(a), fibrinogen, and elevate Lipoprotein B (Watts, 2011).  Of these it is currently though that the top three risk factors for heart disease and stroke are diabetes mellitus (DM), hypertension (HTN) and tobacco smoking and not LCL-C elevation.  In a 2002 cross-sectional analysis of the Copenhagen City Heart Study lipid disorder as a cardiac risk factor was ranked fifth and sixth overall in importance given one’s gender (Schnohr, 2002).

References:

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Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, Witztum. "Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation". Diabetes Care 2008, 31 (4): 811–22.

Durrington P., "Dyslipidaemia". Lancet 2003, 362 (9385): 717–31.

Miller M, “Dyslipidemia and cardiovascular risk: the importance of early prevention”, QJM (2009) 102 (9): 657-667.

Sierra-Johnson J et. al.,”Concentration of apolipoprotein B is comparable with the apolipoprotein B/apolipoprotein A-I ratio and better than routine clinical lipid measurements in predicting coronary heart disease mortality: findings from a multi-ethnic US population”, Eur Heart J , 2009, 30 (6): 710-717.

Handrean, S., et. al., “Apolipoprotein B100 is a better treatment target than calculated LDL and non-HDL cholesterol in statin-treated patients”, Ann Clin Biochem November 2011 vol. 48 no. 6566-6571.

Saito H, Lund-Katz S, Phillips MC. "Contributions of domain structure and lipid interaction to the functionality of exchangeable human apolipoproteins". Prog. Lipid Res. 2004, 43 (4): 350–80.

Weingärtner O, et. al. (2010). Federici, Massimo. ed. "The relationships of markers of cholesterol homeostasis with carotid intima-media thickness".

Tymoczko, John L.; et, al., (2002). Biochemistry. San Francisco: W.H. Freeman. pp. 726–727.

Gordon DJ, et. al., "High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies". Circulation 1989, 79 (1): 8–15.

Virchow, Rudolf (1856). "Gesammelte Abhandlungen zur wissenschaftlichen Medizin". Germany: Staatsdruckerei Frankfurt. Phlogose und Thrombose im Gefäßsystem. (German)

Steinberg D., “Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: part I”. J Lipid Res. 2004 Sep;45(9):1583-1593.

Steinberg D.,  "Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy, part V: the discovery of the statins and the end of the controversy". J. Lipid Res. 2006, 47 (7): 1339–51.

Goldstein JL, Brown MS, "Familial Hypercholesterolemia: Identification of a Defect in the Regulation of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Activity Associated with Overproduction of Cholesterol". Proc. Natl. Acad. Sci. USA, 1973, 70 (10): 2804–2808.

The Lipid Research Clinics Coronary Primary Prevention Trial Results: I. Reduction in Incidence of Coronary Heart Disease. JAMA. 1984;251(3):351-364.

Watts, G., “Republished review: Triglycerides and atherogenic dyslipidaemia: extending treatment beyond statins in the high-risk cardiovascular patient”, Postgrad Med J 2011;87:776-782.

Schnohr, et. al., “Coronary heart disease risk factors ranked by importance for the individual and community: a 21 year follow-up of 12 000 men and women from The Copenhagen City Heart Study”, European Heart Journal (2002) 23, 620–626.

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Yusuf (JP) Saleeby, MD is medical director of WellnessOne and WellnessFirst which offer extensive and advanced cardiovascular and stroke biomarker and genetic analysis, including lipid subtypes, Lp(a), HDL₂ and HDL₃, LDL_1-4, ApoB, NT-proBNP, and  the 4q25, 9p21, ApoE & KIF6 genotypes, and other evaluations.  He is a regular contributor to American Fitness and is on the medical advisory board.  He can be reached for comment at ymsaleeby@gmail.com.