"Perspectives: Journal of the Council on Nutrition of the American Chiropractic AssociationVol. 28, No.3 July 2005"
CVD, Statin Drugs and Heart Failure
James P. Seim, DC, DACBN
Dipolomate American Clinical Board of Nutrition
Member Minnesota Chiropractic Association
Member American Chiropractic Association'
Clinical Board of Nutrition
Address Correspondence to : James P. Seim, DC, DACBN
20010 75th Ave. No.
Corcoran MN 55340
E-mail: [email protected]
Cardiovascular Disease is projected to be the leading cause of death world wide in the next two decades. Currently, half of those suffering from the disease have no known risk factors. The National Institutes of Health National Education Program Guidelines now include up to 36 million Americans as candidates for statin therapy. Current treatment parameters of life style intervention and reduction of cholesterol through the use of statin drugs corresponds to an explosion in the number of cases of CHF. There are many safe alternatives to the statin drugs. Research continues to provide us with new opportunities for product development. We must remember the quote attributed to Hippocrates "First, do no harm".
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Over the last century cardiovascular disease (CVD) was the leading cause of death in the United States every year except 1918.1 The rest of the industrialized and developing nations fair better than this. However, it is projected the other industrialize and developing nations will catch up and that by the year 2020, CVD will be the leading cause of death world wide, accounting for over 35% of all deaths. This will be nearly double the rate of death from cancer. The statistic for 2002 are the most recent available and have been published by the American Heart Association.1
2005 MORTALITY STATISTICS
"CVD accounted for 38.0 percent of all deaths or 1 in every 2.6 deaths in the US 2002... CVD claims as many lives each year as the next 5 leading causes combined, including cancer, chronic respiratory disease. accidents, diabetes mellitus, and influenza and pneumonia cardiovascular disease. The estimated direct and indirect cost of CVD in 2005 is 393.5 billion."1
RISK FACTORS FOR CVD
The American Heart Association lists the following risk factors for CVD in alphabetical order:
High Blood Cholesterol and Other Lipids
High Blood Pressure
Overweight and Obesity
However, it should be noted that "over one half of all patients with CVD have no known risk factors for CVD."2
HISTORY OF CHOLESTEROL HYPOTHESIS
"Cholesterol is the most decorated molecule in history, having contributed to 13 Nobel prizes."3 It is generally accepted that Dr. Nikolai Anichkov the Russian physiologist was the first to induce atherosclerosis by feeding rabbits in a diet laden with cholesterol and is therefore, credited for originating the cholesterol hypothesis. It is quite clear that the focus of preventative cardiology for the last half century has been life style modification and cholesterol reduction.
FUNDAMENTALS OF CHOLESTEROL
The following is a brief review of cholesterol which comes from Lehninger Principles of Biochemistry Third Edition. The authors write on page 799 "Cholesterol is doubtless the most publicized lipid because of the strong correlation between high levels of cholesterol in the blood and the incidence of human cardiovascular disease. Less well advertised is cholesterol's crucial role in the structure of many membranes and as a precursor of steroid hormones and bile acids. Cholesterol is an essential molecule in many animals, including humans, but is not required in the mammalian diet because all cells can synthesize it from simple precursors… Cholesterol is made from Acetyl-CoA in four stages."4 The authors continue on page 804 " Much of the cholesterol synthesis in vertebrates take place in the liver. A small fraction of the cholesterol made there is incorporated into the membranes of hepatocytes, but most of it is exported in one of three forms: biliary cholesterol, bile acids, or cholesteryl esters… Cholesterol and cholesteryl esters, like triacylglycerols and phospholipids are essentially insoluble in water. However, these lipids must be moved form the tissue of origin to the tissues in which they will be stored or consumed. They are carried in the blood plasma from one tissue to another as plasma lipoproteins."6 There are four major categories of lipoproteins: Chylomicrons, VLDL, LDL and HDL. The general population is well aware of the LDL and HDL, although it has been my experience there is confusion as to which is the good and which is the bad cholesterol. A memory peg that has been helpful is to call the LDL lethal or bad cholesterol and HDL healthy or good cholesterol.
LDL cholesterol is subject to lipid peroxidation and there are LDL receptors in the vessel walls that "belong to a scavenger class of lipoprotein receptors and mediate the uptake of oxidized LDL into macrophages."5 "This mechanism contributes to the removal of modified lipoproteins in the sub endothelial layer where they can mediate an inflammatory reaction. Because the scavenger receptors are not down regulated by cellular cholesterol, lipid-laden macrophages can rapidly become foam cells and adhere to the subendothelial matrix and initiate a cascade of events leading to fatty streaks."6
Exactly what is meant by good cholesterol (HDL)? "HDL originates in the liver and small intestine as small, protein rich particles that contain relatively little cholesterol and no cholesteryl esters. It also has on its surface an enzyme lecithin-cholesterol acyl transferase (LCAT). The LCAT on the surface of nascent (newly forming) HDL particle converts the cholesterol phosphatidylcholine of Chylomicrons and VLDL remnants to cholesteryl esters which begin to form a core, transforming the disk-shaped nascent HDL to a mature spherical HDL particle. This cholesterol rich lipoprotein returns to the liver (and steroidogenic tissues)5 where the cholesterol is unloaded: some of this cholesterol is converted to bile salts… Depleted HDL can also pick up cholesterol stored in extrahepatic tissue and carry it to the liver, in reverse cholesterol transport pathway."6 So it appears as if the HDL literally is a sanitary engineer that goes throughout the body searching for LDL and VLDL and returning it to the liver for recycling or removal from the body. "Most epidemiological studies have shown an inverse relationship between plasma levels of HDL-C and the presence of coronary artery disease." 5, 9
So far there has not been established an upper limit for HDL cholesterol. The AHA update states: "The higher a person's HDL cholesterol level the better." Less than 40 mg/dL of HDL in adults is low and a risk factor for heart disease and stroke." They further report "Men and women who have low HDL and high total cholesterol have the highest risk of heart attack. However, "men with HDL levels of 37 mg/dL or lower and women whose level are 47 mg/dL are at a high risk regardless of the total cholesterol level." (emphasis added) "Conversely, those with high levels of total cholesterol have a lower risk of heart attack when they also have higher levels of HDL."1 The figures that they suggest for optimal HDL cholesterol levels are 53 mg/dL or greater in men and 67 mg/dL or greater in women. Low total cholesterol and low HDL are risk factors while high total cholesterol and high HDL are not risk factors. "HDL-increasing interventions are expected to constitute an important therapeutic option for CVD prevention in the next decade." 9
In the late 1980's a classification of drugs was introduced known as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG CoA reductase inhibitors), commonly referred to as statin drugs. These drugs are produced from fungal metabolites and block one of the 4 steps in the conversion of Acetyl CoA to Cholesterol. They have been widely used and successful for the treatment of hypercholesterolemia.8 However, simply lowering cholesterol has not yielded the dramatic results in reducing the number of coronary events we would anticipate. While it is clearly beneficial for some of the patients, nearly 70 percent of coronary events have not been prevented in statin trails.9 "Indeed, the course of cardiovascular disease remains unchanged in the majority of patients who receive the optimal therapy in the most successful clinical trials."2 These drugs while reasonably well tolerated are not benign they have been associated with various adverse effects, "most commonly involving muscle tissues and ranging from myalgia to muscle breakdown and myoglobinuria. In the case of cerviastatin sodium (Baycol), the adverse effects were so common and severe that the drug was withdrawn from the market."10 Another unintended consequence is that they block the formation of ubiquinone (Co Q-10). Ubiquinone was originally named because it was a quinone that was found ubiquitously throughout living organisms. In humans it is concentrated in human heart liver and kidneys. Co-Q10 is not only a vital component of the mitochondrial respiratory chain but also a membrane stabilizer and excellent oxygen radical scavenger.10
"Key points to know about Co Q-10:
It is needed for energy production.
It is an essential antioxidant.
It will regenerate other antioxidants.
It stimulates cell growth and inhibits cell death.
Decreased biosynthesis may caused deficiency."
I believe it is essential that any person who is taking statin medications be on supplemental Co Q10 of at least 150 to 300 mg per day to replete the supplies depleted by the statins.
NEW EPIDEMICS IN CARDIOVASULAR DISEASE
Since the statin drugs have been introduced there has been an explosion in the number of cases of heart failure (CHF). "By 1997 the number of deaths from that condition had doubled in 14 years."2 The (REACH) study in 2002 concluded: "…we have confirmed a chronic disease epidemic of heart failure manifested primarily by an increase in prevalence over the past decade…10 Confirmation of a Heart Failure Epidemic: Findings From the Resource Utilization Among Congestive Heart Failure ( REACH) Study. They suggest that aging is the most important factor in the increase of CHF. I am of the opinion that it is not a coincidence that the increased use of statin drugs corresponds directly to the rise of heart failure.
Are there treatment alternatives to the statin drugs? Clearly there are safe and well researched alternatives. Nicotinic acid was first reported in 1955 by Altshul, Hoffer, and Stephen as having a hypercholesterolemic effect.11 They found " that nicotinic acid reduces both cholesterol and triglyceride (TG) in plasma. Plasma cholesterol fell an average of 22% and total TG was reduced by 52%. To our knowledge, no other single agent has such potential for lowering both cholesterol and TG."14 Niacin has also been shown to be a safe and effective way to increase HDL Cholesterol.9 Compared to statins, it is very safe but it is prudent to check liver enzymes after 6 weeks of therapy.12
Plant Sterols from fruit and vegetable sources are another agent that has been shown to be effective at lowering LDL cholesterol without the undesired effects of statin therapy. The mechanism of action is that of blocking the absorption of dietary cholesterol not interfering with its synthesis.13,14 Policosanols are bi-products of the sugar cane stalk have been one of the few good things to come from Cuba in recent years. Clinical trials have shown that doses from 5-20 mg daily have the effect of raising the HDL cholesterol from 8-15% which tends to be even greater than those reported with statins. The LDL decrease was generally between 20 -25 percent.15,16 Pantethine but not Pantothenic acid or pantetheine greatly reduces TG with an average effect of between 20-35% at a dose of 600-900 mg/d. This dose will also lower LDL by 10-15%. Larger doses should be avoided due to GI complications.15 Currently, clinical trials are underway at the University of Minnesota under the direction of Joel J. Pins, PhD, MS, MPH, LN for a combination of niacin, pantethine, phytosterols and policosanol under name CardioauxinTM. Preliminary reports are very encouraging and final results should be available this spring. The publication date is uncertain. Anyone whishing to obtain the results may contact this author and I will provide them when available.
Coronary vascular disease is projected to be the leading cause of death world wide in the next two decades. Currently, half of those suffering from the disease have no known risk factors. Current treatment parameters of life style intervention and reduction of cholesterol through the use of statin drugs corresponds to an explosion in the number of cases of CHF. I believe this is due to the law of unintended consequences. There are many safe alternatives to the statin drugs. Research continues to provide us with new opportunities for product development. We must remember the quote attributed to Hippocrates "First, do no harm."
I. American I-Heart Association, Heart Disease and Stroke Statistics - 2005 update
2. Braunwald. M.D. Shattuck Lecture - Cardiovascular medicine at the turn of the millennium: Triumphs. Concerns and Opportunities. New England Journal of Medicine:37: 19: 1360-9
3. J. Genst Lipoprotein disorders and cardiovascular risk. J. Inherit. Metab. Dis 26 (2003) 267-287
4. Lehninger Principles of Biochemistry Third Edition. David L. Nelson. Michael M. Cox Worth Publishers
5. Emi et al. The journal of Biological Chemistry Vol. 268, N03, Issue of January 25 pp. 2120-2125, 1993
6. Ross, Ph.D. Russell Atherosclerosis - An Inflammatory Disease N Eng .I of Med 340:2: 2120-25
7. Birjmohun et al. Efficacy and Safery of High-DensityLipoprotein Cholesterol-Increasing Compounds
8. Rundek et al. Arch Neurol. 2004:61:889-892 Atorvastatin Decrease the Coenzyme Q to Level in the Blood of Patients at Risk for Cardiovascular Disease and Stroke
9. Crane FL Biochemical functions of coenzyme Q 10.1 AM Coll Nutr'. 200 I: 20:591-598
10. McCullough, et al. Confirmations of a Heart Failure Epidemic: Findings From the Resource Utilization Among Congestive Heart Failure (REACH) Study Journal of the American College of Cardiology Vol. 39, Nol,2002
II. Grundy et al. Influence of nicotinic acid on metabolismof cholesterol and triglycerides in man. J. Lipid Res.1981. 22: 24-36.
12. Pins, Joel .I. PhD, MS, MPH,LN Concepts in Nutritional medicine and Clinical Applications by Lifestage. On Campus Seminar Northwestern Health Sciences University Nov 20-21, 2004
13. Vanstone et al. Unesterified plantsterols and stanols lower LDL-cholesterol concentrations equivalently in hypercholesterolemic persons. Am .I Clin Nutr 2002;76: 1272-8
14. Beno-':t Lamarche et al. Combined effccts of a dietary portfolio of plant sterols, vegetable protein, viscous fibre and almonds on LDL particle size British Journal of Nutrition (2004), 92, 657-663
15. McCarty, Mark F. An ezetimibe-policosanol combination has the potential to be an OTC agent that could dramatically lower LDL cholesterol without side effects. Medical Hypotheses. (2005) 64, 636-645
16. Varady, Krista A. et al. Role of Policosanols in the prevention and treatment of Cardiovascular Disease. Nutrition Reviews Vol. 61. No II 26