CoQ10 Proven Benefits In Heart Failure Patients

This ten year study conclusively showed that CoQ10 supplementation significantly improves survival for even the most severe heart failurepatients while radically reducing incidences of hospitalization.1

Life Extension Magazine April 2014

REPORT

CoQ10 Proven Benefits In Heart Failure Patients

By Bradley Tompkins

  

The European Journal of Heart Failure has published data from one of the most robust studies to date on coenzyme Q10.

This ten year study conclusively showed that CoQ10 supplementation significantly improves survival for even the most severe heart failure patients while radically reducing incidences of hospitalization.1

This new study shows that CoQ10 supplementation can restore deficient CoQ10 levels in patients with moderate-to-severe heart failure, extend lifespan, and improve quality of life.1

The compelling results from this 10-year-long study found that patients who took 100 mg of CoQ10 three times daily were…

• Significantly less likely to die from heart failure,
• Less than half as likely to die from any cause at all, and
• Half as likely to have a major adverse cardiac event during the study period, compared with control subjects.1

After only three months of supplementation, the researchers detected a trend towards reduced levels of a blood marker of heart failure severity that is released from over-worked heart muscle cells.1,2 At two years, significantly more treated patients had improved measurements of heart function than did placebo recipients.1

This impressive study demonstrates how CoQ10 offers important heart health benefits and how essential it is to cardiac patients. Ideally, the practice of cardiology will soon include CoQ10 as part of their protocol to improve the lives of those living with heart failure.

NEW YORK HEART ASSOCIATION FUNCTIONAL CLASSES OF HEART FAILURE65

Class	Functional Capacity: How a patient with cardiac disease feels during physical activity
I	Patients with cardiac disease but resulting in no limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, difficulty breathing, or anginal pain.
II	Patients with cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, difficulty breathing, or anginal pain.
III	Patients with cardiac disease resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes fatigue, palpitation, difficulty breathing, or anginal pain.
IV	Patients with cardiac disease resulting in inability to carry on any physical activity without discomfort. Symptoms of heart failure or the anginal syndrome may be present even at rest. If any physical activity is undertaken, discomfort increases.

Cardiac Bioenergetics

Most people have heard of heart failure, but few understand what it really is.

Contrary to what most people might think, heart failure does not mean that the heart stops beating. Rather, heart failure occurs whenever the heart is unable to pump enough blood to sustain normal function in other organs.3

Your heart is one of the hardest-working organs in your body; it literally never takes a rest. Beat after beat, hour after hour, day after day, for your entire life, your heart contracts and relaxes a little more than once per second, providing the blood flow that every other organ in your body relies on.

That much effort requires a steady supply of energy. And to perform at optimal function—literally without missing a beat—your heart needs to be able to derive that energy from its fuel (primarily fatty acids and glucose) efficiently and with little waste.4-6

In order to support this task, your mitochondria pump out a steady supply of energy derived from food. This is called bioenergetics.7 But your mitochondria don’t work alone. Just as a clean-burning automobile engine is more fuel-efficient and lasts longer than an out-of-tune one, the mitochondria need help maintaining top-level efficiency and performance.

CoQ10 is essential for the heart to maintain sufficient energy management.1,8 But when CoQ10 levels decline, tissues burn fuel inefficiently, eventually producing oxidative damage and ultimately losing their function. When the heart muscle loses its fuel efficiency, heart failure may occur.4,9

Research has shown that CoQ10 levels are lower in patients with heart failure and the lower the levels, the more severe the failure.8,10,11 In fact, heart failure patients with lower CoQ10 levels have up to a two-fold risk of dying compared to those with higher levels.12

WHAT YOU NEED TO KNOW

CoQ10 Benefits: Heart Failure Patients

• Loss of efficient energy management, or bioenergetics, is a root cause of heart failure and many other conditions associated with aging.
• Many patients with heart failure are deficient in CoQ10, a nutrient that optimizes bioenergetics in the heart muscle’s mitochondria.
• A dramatic new study shows that CoQ10 supplementation can restore deficient CoQ10 levels, extending life span and improving quality of life, even in patients with the most severe classes of heart failure.
• CoQ10 supplementation is finding a role in the management of other cardiovascular disease processes, including endothelial dysfunction, hypertension, heart attack, and the ischemia-reperfusion injury that accompanies heart attacks and strokes.
• Aging changes your basic biochemistry; you can restore optimal bioenergetics with CoQ10 supplementation.

CoQ10’s Heart-Healthy Track Record

Over the past 30 years, mounting evidence has been establishing CoQ10 as one of the most vital nutrients necessary for heart health.

CoQ10 has been known to benefit cardiac bioenergetics since the 1970s.13-15 In 1985, a small study found that patients with the most severe levels of heart failure experienced significant improvements in cardiac function and clinical state during CoQ10 treatment.6

Since then, other small studies showed similar improvement in clinical status and heart function testing, typically using doses of 100 to 200 mg/day.9,16 Roughly 75% of patients taking CoQ10 experienced improvements in cyanosis (bluish skin), liver enlargement, lung examinations, difficulty breathing, palpitations, sweating, heart arrhythmias, insomnia, vertigo, and nighttime urination.10,17

Several of the studies demonstrated an improvement in cardiac functional status, as determined by the New York Heart Association, reducing patients’ class levels of heart failure by an average of 0.5 compared with placebo.11,18,19 This means that heart failure patients could move from a strict Class II with limitations on physical activity to a class I-II with fewer or even no limitations resulting in substantial improvements in quality of life.

Other studies over the past 15 years or so showed small but significant improvements in objective measures of heart function, such as ejection fraction (the proportion of blood pumped out of the heart with each beat), stroke volume (volume of blood pumped with each beat), and cardiac output (total amount of blood pumped per minute).14,20

But it wasn’t until mid-2013 that results were published from the first comprehensive, double-blind, multi-center study demonstrating the dramatic, life-saving impact of CoQ10 supplementation in patients withchronic heart failure.

ARE YOU TAKING THE RIGHT COQ10?

Most biochemical compounds exist in more than one form. CoQ10 is no exception. A common form of the substance is called ubiquinone, and, while it has demonstrated biological activity, it is much less bioavailable than ubiquinol.42 Ubiquinolis the so-called “reduced” form of CoQ10. In chemical terms, that means it carries an extra electron. This is important because that electron is what allows CoQ10 to help neutralize, or “reduce,” dangerous reactive oxygen and nitrogen species. Therefore, your CoQ10 supplement should ideally contain the ubiquinol form of CoQ10.

Landmark Study Shows CoQ10 Saves Lives Of Heart Failure Victims!

This new study showed that even in patients with the most severe classes of heart failure, CoQ10 supplementation can restore deficient CoQ10 levels, extending life span and improving quality of life.

The study, begun in 2003, included only the most severely affected patients (those in the New York Heart Association class III or IV).1 In addition to their regular medication, study subjects were randomly assigned to receive either 100 mg of CoQ10 or placebo 3 times daily. Each patient was followed up with a wide variety of outcomes measures for two years.

After only three months of supplementation, the researchers detected a trend towards reduced levels of proBNP, a marker of heart failure severity that is released from over-worked heart muscle cells.1,2 At two years,significantly more treated patients had improved their heart failure class than did placebo recipients.

But the study’s main endpoint measurement was the most dramatic indicator of success. Only 14% of patients in the supplemented group had a major adverse cardiac event (defined as unplanned hospitalization for worsening heart failure, death from a cardiovascular cause, urgent heart transplantation, or artificial mechanical heart support), while 25% of those in the placebo group had a major cardiac event.1 In statistical terms, that produced a “hazard ratio” of 2.0—meaning the untreated patients had twice the risk of a major cardiac event!

Compared with control patients, those taking CoQ10 experienced significantly fewer cardiovascular deaths and hospitalizations for worsening heart failure. The difference in death rate from all causes between the CoQ10 and placebo groups was striking. Subjects on placebo had twice the rate of death compared to those taking CoQ10.1 And, unlike most drug studies, there were significantly fewer adverse events in the supplemented group than in the placebo group.

This study was the first ever to show that CoQ10 supplementation in advanced heart failure improves survival, while slashing hospitalization rates.

It highlights the importance of regular supplementation with this cardiac “fuel additive” for anyone with heart failure or its risk factors, such as endothelial dysfunction, hypertension, and a history of a heart attack. Studies have shown that CoQ10 improves each of these risk factors for heart failure. Let’s look at each in turn.
WHAT CAUSES HEART FAILURE?

Heart failure affects around 5.7 million Americans, and causes or contributes to more than 335,000 deaths each year. Half of those with heart failure die within 5 years of their diagnosis.3

There are many primary causes of heart failure.9,43 The most common include coronary artery disease and high blood pressure but can also include heart attacks, obesity, and diabetes, all of which place excessive demands on the heart muscle, making it work harder and harder just to produce enough blood flow to sustain life at rest. That extra demand for energy uses up CoQ10, resulting in a loss of fuel efficiency precisely when the heart needs every bit of energy it can generate.9

Eventually, the heart muscle simply tires out, becoming enlarged and flabby, squeezing more weakly with each contraction, and pumping smaller and smaller amounts of blood out to the body.

Symptoms of heart failure reflect the diminished blood flow to all of the organs in the body, especially the lungs, kidneys, and liver. Such symptoms commonly include shortness of breath even with normal daily activities, difficulty breathing when lying down, and swelling in the lower extremities or lower back. These symptoms are usually accompanied by substantial weight gain (“water weight”), and generalized fatigue and weakness.44

Eventually, symptoms worsen, requiring frequent hospitalization with increased risk of life-threatening heart arrhythmias and pulmonary edema.44 Even with the best conventional treatment, some people with heart failure, particularly those who in spite of conventional treatment fail to show evidence of clinical improvement, may die within two years.6

CoQ10 Improves Endothelial Function

Chronic oxidative stress is one of the main factors reducing the functioning of the endothelium, the thin layer of cells lining arteries that controls blood flow and pressure.21 Endothelial dysfunction is a major precursor to hypertension, coronary heart disease, and strokes. Since CoQ10 is a unique antioxidant, it makes sense that it would have beneficial effects on endothelial function.

That has proven to be the case. In patients with known coronary artery disease, who are at high risk for heart attack, and who need every bit of functioning endothelium, supplementation with 300 mg of CoQ10 a day significantly improved their natural endothelial antioxidant levels, improved their arterial relaxation, and improved their oxygen utilization.22

Similar improvements were seen in patients with New York Heart Association grade II to III heart failure, who experienced a 9% improvement in oxygen utilization and a 38% improvement in endothelial function when they used the same dose of CoQ10, with no side effects.23

CoQ10 has subsequently shown value in improving endothelial dysfunction caused by diabetes and by high LDL-cholesterol, two major contributors to cardiovascular disease.24,25 In addition, it reduces blood vessel stiffness, a consequence of endothelial dysfunction.26,27

COQ10 SHOWS PROMISE IN CANCER PREVENTION

Low levels of CoQ10 have been correlated with increased cancer risk in some populations.45 This is due in part to the fact that cancer cells are enormous users of energy, perturbing the bioenergetics of surrounding tissue and bathing host cells in free radicals and other destructive byproducts.

Though research is still in its early stages, CoQ10 supplementation is showing real promise in counteracting these effects to slow—and in some cases reverse—cancer’s progression. Here is a synopsis of scientific progress:

• CoQ10 along with vitamin B6 boosted the function of cancer-fighting immune cells.46
• CoQ10 alone or in combination with B vitamins enhanced the efficacy of the anti-breast cancer drug tamoxifen in animal studies, and decreased plasma markers of metastasis and new blood vessel growth in human breast cancer patients.47-50
• CoQ10 suppressed development of pre-cancerous lesions in animal models of colon cancer.51,52
• CoQ10 increased median actual survival by more than 40% in patients with a variety of end-stage cancers.53

It seems all but inevitable that further studies will highlight greater benefits in humans, especially at the level of prevention rather than treatment, an area in which mainstream medicine is sadly lacking.

CoQ10 Lowers Blood Pressure

Oxidative stress and endothelial dysfunction are major causes of elevated blood pressure, which affects about 67 million US adults.28,29 CoQ10 supplementation is showing promise in reducing blood pressure in hypertensive patients, without producing dangerous abrupt drops in pressure.

A multitude of studies have shown that doses of CoQ10 as low as 60 mg twice daily can lower blood pressure by up to 17.8 points systolic (top number) and 7 points diastolic (bottom number).30-32 None of these studies reported significant side effects, and CoQ10 is now recommended by some researchers for use in addition to standard drug treatment for hypertension, especially in elderly patients.33

COQ10 PROTECTS YOUR BRAIN

Your brain receives the largest proportion of total blood flow from your heart; as a result, it has some of the most volatile fluctuations in bioenergetic demands.54 Because of this, CoQ10 is of tremendous importance in maintaining brain health and preventing neuronal damage.

Unfortunately, studies have clearly shown a loss of CoQ10 functioning in the aging brain—with severe deficiencies in those with neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases, and following strokes.55,56

Fortunately, laboratory studies have shown that supplementing with CoQ10 has multiple brain-protective effects, especially in aging animals. Take a look:

• CoQ10 has been shown to decelerate the aging process in a strain of mice with abnormally accelerated aging.57
• When aging, stroke-prone mice were supplemented long-term with CoQ10, they had smaller volumes of damaged brain, and larger volumes of healthy, functioning brain.58
• In culture dishes, CoQ10 kept brain stem cells alive following periods of oxygen deprivation (as seen in strokes), setting the stage for possible recovery through new cell development.59
• In a mouse model of Alzheimer’s disease, CoQ10 decreased the amount of destructive amyloid beta plaque in brain tissue, while improving the animals’ behaviors.60
• In aging mice at risk for Parkinson’s disease, supplementation reduced the loss of dopamine-producing neurons and raised brain dopamine levels (dopamine is the neurotransmitter that is diminished in human Parkinson’s).61

Preliminary human studies show good results as well—especially in patients with early and mild Parkinson’s disease. CoQ10 at 360 mg/day produced moderate reduction in symptom scores, while1,200 mg/day appeared to slow functional decline in those with early disease.62,63 Studies have shown that up to 3,000 mg/day is well tolerated, with 2,400 mg/day being the highest dose used in studies involving Parkinson’s patients.64

The superior absorption of the ubiquinol form of CoQ10 would allow lower doses to be used. Those with congestive heart failure or neurological conditions should ideally strive for a coenzyme Q10 blood level of over 3.5 micrograms per milliliter (mcg/mL).66

CoQ10 Reduces Heart Attack Damage

CoQ10 is especially valuable in reducing the damage caused by a heart attack. Never is your heart in greater need of efficient bioenergetics than during and immediately after a heart attack. CoQ10 is sharply diminished in heart attack victims. In fact, low CoQ10 levels are associated with an increased risk of dying in post-cardiac arrest patients.34

The main damage in survivors of a heart attack doesn’t come from the loss of blood flow itself (ischemia), but rather from the restoration of oxygen-rich blood to tissues that have lacked oxygen for the critical minutes before circulation is restored (reperfusion).35

CoQ10 reduces the impact of ischemia-reperfusion injury by optimizing the heart muscle’s bioenergetics and providing antioxidant support during this crucial period.36 Supplementation reduces markers of extreme oxidative stress and poor mitochondrial function, while reducing the rates of post-reperfusion arrhythmias and improving heart musclefunctioning.37,38

Studies show that CoQ10 at doses of 100 to 120 mg/day reduced total arrhythmias and other cardiac events, increased left ventricular (main pumping chamber) function, and reduced the death rate from repeat heart attacks.39,40

CoQ10 is powerful enough that it has been given intravenously during bypass grafting procedures, where it improved left ventricular functioning 6 to 10 hours after the operation, compared with control patients, and reduced blood markers of heart muscle damage.37 Similar beneficial effects have now been shown in patients who take 150 to 180 mg of CoQ10 per day for 7 to 10 days prior to elective bypass surgery.41

Summary

Your mitochondria pump out a steady supply of energy derived from the food you supply them with. Like any finely-tuned machine, however, they need help maintaining top-level efficiency and performance.

CoQ10 is the main molecule your body requires to keep mitochondrial energy production, orbioenergetics, running smoothly. Declining CoQ10 levels cause tissues to burn fuel inefficiently, eventually producing oxidative damage and ultimately losing their function.

CoQ10 deficiency and the resulting bioenergetic collapse is the underlying cause of heart failure, one of the largest causes of death and disability in Americans today. Studies show that CoQ10 supplementation at 300 mg/day not only restores normal CoQ10 levels, but prevents progression of heart failure and in fact can reverse that progression and extend survival and improve quality of life.

Similar beneficial effects have now been shown in patients with endothelial dysfunction, hypertension, and coronary artery disease, the precursors of heart attacks and ultimately heart failure.

Since we all require efficient and uninterrupted energy supplies, we all need to be thinking about optimizing our bioenergetic status with CoQ10 supplementation.

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

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63. Shults CW, Oakes D, Kieburtz K, et al. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol. 2002 Oct;59(10):1541-50.
64. Shults CW, Flint Beal M, Song D, Fontaine D. Pilot trial of high dosages of coenzyme Q10 in patients with Parkinson’s disease. Exp Neurol. 2004 Aug;188(2):491-4.
65. Available at: http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes-of-Heart-Failure_UCM_306328_Article.jsp. Accessed June 4, 2013.
66. Langsjoen PH, Langsjoen AM. Overview of the use of CoQ10 in cardiovascular disease. Biofactors. 1999;9(2-4):273-84.

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CoQ10 shows protective effect in heart attack study

This issue of Life Extension Updatereports the outcome of experimental research which found a protective role for CoQ10 against damage caused by heart attack.

Tuesday, June 23, 2015. An article published online on March 20, 2015 in the International Journal of Physiology, Pathophysiology and Pharmacology reveals a benefit for pretreatment with coenzyme Q10 (CoQ10) in rats in which myocardial infarction (MI, or heart attack) was experimentally induced. The study involved groups of rats that underwent sham surgery, no surgery, experimental MI alone, or experimental MI that followed a week of treatment with resveratrol, CoQ10 or both compounds. Infarct area, hemodynamic factors, inflammation and markers of oxidative stress were assessed 24 hours following the surgery. Among animals that received CoQ10 alone or in combination with resveratrol, left ventricular infarct area was significantly reduced and left ventricular hemodynamic parameters were normalized. Serum brain natriuretic peptide, which can be elevated in heart failure, and markers of inflammation, including tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6), were also lower among animals pretreated with CoQ10. While thiobarbituric acid reactive substances (a byproduct of lipid peroxidation) were lower in CoQ10-treated animals, indicating decreased oxidative stress, the endogenous antioxidants superoxide dismutase (SOD) and glutathione peroxidase were found to have increased. "The mechanism of the cardioprotective action of CoQ10 involved blocking exaggerated oxidative stress and inflammation post MI, resulting in normalized/optimized hemodynamics and reduced infarct area of the left ventricle," write Mahmoud Alkhateeb of King Khalid University and colleagues. "The mechanism of the cardioprotective action of CoQ10 involved blocking exaggerated oxidative stress and inflammation post MI, resulting in normalized/optimized hemodynamics and reduced infarct area of the left ventri-cle," write authors Samy M. Eleawa and colleagues. "DNA damage to the heart following MI was likely also reduced with CoQ10, as supported by reduced Bax and p53 gene expression in the left ventricle." "We propose that CoQ10 is an effective antioxidant/anti-inflammatory agent to combat against acute cardiac changes induced by MI and can be an attractive therapeutic option in patients undergoing cardiac changes post MI," they conclude.

What's Hot CoQ10 may reduce Afib in heart failure patients An article appearing ahead of print on April 27, 2015 in the Journal of Investigative Medicine reports the outcome of a randomized trial of patients being treated for heart failure which found a benefit for coenzyme Q10 (CoQ10) in reducing atrial fibrillation, a common cardiac arrhythmia that occurs in up to 27% of heart failure patients. The trial included 128 men and women treated for heart failure with ACE inhibitors, beta-blockers, statins and/or other drugs. Sixty-two subjects received 30 milligrams CoQ10 daily for one year. Twenty-four hour ambulatory electrocardiogram monitoring, echocardiography, and blood measurement of inflammatory markers and malondialdehyde (MDA, a marker of oxidative stress) were performed upon enrollment and at six and twelve months. At the end of the trial, three participants who received CoQ10 and 12 members of the control group had experienced atrial fibrillation episodes. Malondialdehyde levels were reduced at 12 months in the CoQ10 group while remaining unchanged among untreated patients. "There is an increasing body of evidence linking inflammation and oxidative stress to a broad spectrum of cardiovascular conditions, such as heart failure, coronary artery disease, and hypertension," write Quingyan Zhao, MD, PhD, and colleagues. "In addition, there are emerging data to support the association between inflammation and atrial fibrillation. This has created exciting potential opportunities to target inflammatory and oxidative stress processes for the prevention of atrial fibrillation and heart failure." "The present study suggests that CoQ10 as adjuvant treatment attenuates the incidence of atrial fibrillation," they conclude. "The mechanisms of the effect perhaps have relation with the reduced levels of MDA."

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Life Extension: Health Concerns - Atherosclerosis and Cardiovascular Disease

Atherosclerosis and cardiovascular disease take a huge toll on our society. More than 81 million Americans suffer from some form of cardiovascular disease, making it the leading cause of death in the country. 

Health Concerns
Atherosclerosis and cardiovascular disease take a huge toll on our society. More than 81 million Americans suffer from some form of cardiovascular disease, making it the leading cause of death in the country. As of 2006, cardiovascular disease was responsible for at least one in every 2.9 deaths in the United States (American Heart Association: Heart Disease and Stroke Statistics 2010).

Despite the fact that cardiovascular disease is the single most deadly disease in the United States, most individuals, including most mainstream physicians, have a flawed fundamental understanding of the disease. The fact is, long before any symptoms are clinically evident, vascular disease begins as a malfunction of specialized cells that line our arteries. These cells, called endothelial cells, are the key to atherosclerosis and underlying endothelial dysfunction is the central feature of this dreaded disease.

Not every person who suffers from atherosclerosis presents with the risk factors commonly associated with the condition, such as elevated cholesterol, but every single person with atherosclerosis has endothelial dysfunction. Aging humans are faced with an onslaught of atherogenic risk factors that, over time, contribute to endothelial dysfunction and the development of atherosclerosis.

Maturing individuals must address all of the underlying factors that contribute to endothelial dysfunction if they are striving to protect themselves from the ravages of vascular disease. Regrettably, mainstream medicine has failed to identify and correct all of the cardiovascular disease risk factors. This means that people wishing to stave off atherosclerosis must take matters into their own hands to ensure that all underlying causes are effectively neutralized.

In the antiquated view of mainstream medicine, blood vessels have been thought of as stiff pipes that gradually become clogged with excess cholesterol circulating in the bloodstream. The solution that physicians recommend most often is cholesterol-lowering drugs, which target only a very small number of the numerous factors that contribute to cardiovascular disease.

Conventional medicine’s preferred method of reestablishing blood flow in clogged vessels is through surgery (coronary artery bypass graft surgery) or by insertion of catheters bearing tiny balloons that crush the plaque deposits against the arterial walls (angioplasty), followed by the implantation of tiny mesh tubes (stents) to keep the blood vessels open. However, the grafts used to reestablish blood flow often develop plaque deposits themselves. The same was true for balloon angioplasty; in their early years, up to half of all angioplasty procedures “failed” when the arteries gradually closed again. Even today, with the use of improved stents, the failure rate is considerable and many people have to undergo repeat angioplasty or even surgery.

Mainstream Medicine Overlooks Proven Alternative to Coronary Stents and Bypass Surgery: Enhanced External Counterpulsation (EECP) Stable coronary artery disease and angina can cause disabling symptoms including shortness of breath, pressure or discomfort in the chest, exercise intolerance, and fatigue. A safe, effective, non-invasive therapy for the symptoms of coronary artery disease and angina is now available. Enhanced external counterpulsation (EECP) alleviates cardiac symptoms by enhancing coronary collateral circulation—alternate pathways by which blood can reach the heart muscle. The procedure is performed in a series of outpatient treatments, in which inflatable cuffs wrapped around the legs inflate and deflate in rhythm with the patient’s heartbeat. More than 100 published studies show that EECP can effectively relieve symptoms of heart failure, increase exercise tolerance, reduce reliance on medication, and improve quality of life. Benefits of treatment can last up to five years. This novel therapy simulates the circulatory benefits of exercise, allowing patients to overcome symptoms and resume a healthy, active lifestyle. To learn more about EECP, please review the article titled “Doctors Ignore Proven Alternative to Coronary Stents and Bypass Surgery” in the June 2008 issue of Life Extension Magazine.

Endothelial Dysfunction: The Underlying Cause of All Vascular Diseases

The cause and progression of vascular disease is intimately related to the health of the inner arterial wall. Blood vessels are composed of three layers. The outer layer is mostly connective tissue and provides structure to the layers beneath. The middle layer is smooth muscle; it contracts and dilates to control blood flow and maintain blood pressure. The inner lining consists of a thin layer of endothelial cells (the endothelium), which provides a smooth, protective surface. Endothelial cells prevent toxic, blood-borne substances from penetrating the smooth muscle of the blood vessel.

However, as we age, a barrage of atherogenic factors, if left unchecked, damages the delicate endothelial cells. This damage leads to endothelial dysfunction and ultimately allows lipids and toxins to penetrate the endothelial layer and enter the smooth muscle cells. This results in the initiation of an oxidative and inflammatory cascade that culminates in the development of plaque deposits. Subsequently, these plaques begin to calcify and, over time, become prone to rupture. If a plaque deposit ruptures, the result is oftentimes a deadly blood clot.

If people do not take steps to correct the endothelial dysfunction occurring in their aging bodies, the consequence will be a worsening of the epidemic of arterial disease that currently kills 35% of Americans and 30% of all people worldwide (American Heart Association: Heart Disease and Stroke Statistics 2010). Sadly, mainstream medicine continuously fails patients by prescribing drugs that address only a very small number of risk factors that contribute to the pathogenesis of vascular disease.

Numerous factors that directly contribute to endothelial dysfunction have been identified and aging individuals can easily assess their risk for vascular disease through blood testing. The results of these blood tests can then be used to develop targeted intervention strategies to modify levels of risk factors that do not fall within an optimal range. Atherogenic factors that all aging individuals must be aware of include:

• Elevated LDL cholesterol. LDL is dangerous because it can penetrate the endothelial wall and contribute to the creation foam cells, which form the core of a plaque deposit. Oxidized LDL cholesterol (LDL that has been exposed to free radicals) within the endothelium also triggers an inflammatory process that accelerates vascular disease. Life Extension recommends keeping LDL cholesterol levels below 80 mg/dL.
• Low HDL cholesterol. HDL protects against vascular disease by transporting cholesterol from the blood vessel wall back to the liver for disposal through a process known as reverse cholesterol transport. If HDL levels are low, then reverse cholesterol transport becomes inefficient, allowing for increased accumulation of cholesterol in the vessel wall. HDL levels of at least 50-60 mg/dL are recommended for optimal vascular protection.
• Elevated triglycerides. Triglycerides interact with LDL cholesterol to form a particularly dangerous sub-type of LDL known as small-dense LDL. Small-dense LDL particles penetrate the endothelial layer and contribute to plaque formation much more efficiently than larger, more buoyant LDL particles. Life Extension recommends keeping fasting triglycerides below 80 mg/dL to limit the formation of small-dense LDL particles.
• Oxidized LDL. The oxidation of LDL results in severe vascular damage. Thousands of studies now reveal how oxidized LDL contributes to the entire atherogenic process from start to finish. Commercial blood tests are not yet available at affordable prices to measure oxidized LDL. Aging individuals should assume their endogenous antioxidant levels (superoxide dismutase, catalase, and glutathione) are being depleted and that the oxidation of their LDL is progressively worsening (Matsuura, 2008). Many of the nutrient suggestions in this protocol afford considerable protection against LDL oxidation.
• Hypertension. High blood pressure is known to aggravate endothelial dysfunction and leading researchers have identified the endothelium as an “end organ” for damage caused by high blood pressure. Life Extension suggests a target optimal blood pressure of 115/75 mmHg (or lower).
• Elevated C-reactive protein. Inflammation is central to the endothelial dysfunction that underlies vascular disease. An effective way to measure inflammation is through a high-sensitivity C-reactive protein (CRP) blood test. Studies have shown that higher levels of CRP are associated with increased risk of stroke, heart attack, and peripheral vascular disease (Rifai N 2001; Rifai N et al 2001). Stroke patients with the highest CRP levels are two to three times more likely to die or experience a new vascular event within a year than are patients with the lowest levels (Di Napoli M et al 2001).
• Elevated Lp-PLA2. Like CRP, Lp-PLA2 is a marker of inflammation. However, Lp-PLA2 is a much more specific measure of vascular inflammation than CRP. Lp-PLA2 is an enzyme secreted by inflamed vascular plaque, thus the quantity of it in circulation correlates with the amount of inflamed plaque in the blood vessels. Levels of Lp-PLA2 above 200 ng/mL are indicative of heightened levels of vascular plaque buildup.
• Elevated omega-6:omega-3 ratio. High levels of pro-inflammatory omega-6 fatty acids relative to anti-inflammatory omega-3 fatty acids create an environment that fosters inflammation and contributes to vascular disease. It has been shown that lowering the omega-6:omega-3 ratio significantly decreases atherosclerotic lesion size and reduces numerous measures of inflammation (Wan, 2010). Life Extension recommends maintaining a blood omega-6:omega-3 ratio of less than 4:1.
• Elevated glucose. High circulating levels of blood glucose (and insulin) cause microvascular damage that accelerates the atherogenic process, partly by contributing to endothelial dysfunction (Beckman JA et al 2002). It has been shown that a fasting blood glucose level of greater than 85 mg/dL significantly increases risk of cardiovascular related mortality (Bjørnholt, 1999). Life Extension suggests keeping fasting blood glucose levels below 86 mg/dL.
• Excess insulin. As we age, we lose our ability to utilize insulin to effectively drive blood glucose into energy-producing cells. As glucose levels rise in the blood, the pancreas compensates by producing more insulin. As “insulin resistance” worsens, even more insulin is secreted in attempt to restore glucose control. Excess insulin is associated with a significantly greater risk of heart disease (Bonora, 2007). Life Extension suggests keeping fasting insulin below 5 mcIU/mL.
• Elevated homocysteine. High homocysteine levels damage endothelial cells and contribute to the initial pathogenesis vascular disease (Riba R et al 2004). Homocysteine levels are associated with risk of heart disease (Haynes WG 2002; Guilland JC et al 2003). To keep homocysteine-induced endothelial damage to a minimum, levels of homocysteine should be kept below 7-8 µmol/L.
• Elevated fibrinogen. When a blood clot forms, fibrinogen is converted to fibrin, which forms the structural matrix of a blood clot (Koenig W 1999). Fibrinogen also facilitates platelet adherence to endothelial cells (Massberg S et al 1999). People with high levels of fibrinogen are more than twice as likely to die of a heart attack or stroke as people with normal fibrinogen levels (Wilhelmsen L et al 1984; Packard CJ et al 2000). In a review which included data for over 154,000 patients, every 100 mg/dL increase in fibrinogen levels was associated with a significantly increased risk of developing coronary heart disease, stroke, and with vascular related mortality. In one study, those patients with the lowest one-third fibrinogen levels (mean 236 mg/dL) were much less likely to suffer a stroke, develop cardiovascular disease, or die of other vascular related causes when compared to those with the highest one-third fibrinogen levels (mean 374 mg/dL) (Danesh, 2005). This risk goes up even more in the presence of hypertension (Bots ML et al 2002). Fibrinogen levels should be kept between 295 to 369 mg/dl.
• Insufficient vitamin D. Vitamin D protects against vascular disease via several different mechanisms, including reducing chronic inflammatory reactions that contribute to the pathology of the disease. It has been shown that low vitamin D levels are associated with increased cardiovascular mortality (Dobnig, 2008). Life Extension suggests maintaining a 25-hydroxy vitamin D blood level of 50 – 80 ng/mL.
• Insufficient vitamin K. Vitamin K is essential for regulating proteins in the body that direct calcium to the bones and keep it out of the arterial wall. Low vitamin K status predisposes aging humans to vascular calcification (Adams, 2005; Beulens, 2009; Schurgers, 2007), chronic inflammation (Morishita, 2008), and sharply higher heart attack risks (Geleijnse, 2004). Vitamin K blood tests assess levels of vitamin K to maintain healthy coagulation, but at this time are not used to identify optimal levels to reduce heart attack risk. However, there is a substantial amount of evidence that suggests that supplementation with vitamin K (as K1, MK-4 and MK-7) easily corrects the vitamin K deficits that are so common among Americans today (Nouso, 2005; Lin, 2005; Braam, 2004; Berkner, 2004; Gunther, 2004).
• Low testosterone and excess estrogen (in men). Numerous studies link low testosterone (and excess estradiol) with increased heart attack and stroke risk (Wranicz, 2005; Abbott, 2007; Tivesten, 2006; Dunajska, 2004). Testosterone is intimately involved in the reverse cholesterol transportprocess, which removes cholesterol from the arterial wall by HDL. Excess estrogen is linked with higher C-reactive protein and a greater propensity for abnormal blood clots to form in arteries, causing a sudden heart attack or stroke (Stork, 2008; Zegura, 2006). Men should keep their free testosterone in a range of 20 – 25 pg/mL and their estradiol levels between 20 – 30 pg/mL (Jankowska, 2009).
• Insufficient CoQ10. Supplemental CoQ10 alters the pathology of vascular diseases and has the potential for prevention of vascular disease through the inhibition of LDL cholesterol oxidation and by the maintenance of optimal cellular and mitochondrial function throughout the ravages of time and internal and external stresses. The attainment of higher blood levels of CoQ10 (> 3.5 micrograms/mL) with the use of higher doses of CoQ10 appears to enhance both the magnitude and rate of clinical improvement (Langsjoen, 1999).
• Nitric oxide deficit. Nitric oxide is an important messenger molecule required for healthy cardiovascular function. Nitric oxide enables blood vessels to expand and contract with youthful elasticity and is vital to maintaining the structural integrity of the endothelium, thus protecting against vascular disease. Even when all other risk factors are controlled for, the age-related decline in endothelial nitric oxide too often causes accelerated vascular disease unless corrective measures are taken. Commercial blood tests are not yet available at affordable prices to assess nitric oxide status. Aging individuals should assume they are developing a nitric oxide deficit in their inner arterial wall (the endothelium) and follow simple steps outlined in this protocol to protect themselves (Yavuz, 2004; Cai, 2000; Nitenberg, 2006).

The VAP™ Test: Measuring the Atherogenic Potential of Blood Lipids The Vertical Auto-Profile (VAP™) assesses subclasses of lipids that are known or emerging risk factors for cardiovascular disease, such as LDL particle size and lipoprotein(a) (Kulkarni, 1995). This enables cardiologists and nutritionists to help high-risk patients to identify these new risk factors for cardiovascular disease that are based on the amounts and sizes of cholesterol and other fat molecules that circulate in the blood. Comprehensive tests such as the VAP™ can provide the highly specialized information that doctors and patients need to make informed decisions about diet, lifestyle, supplements, and medication changes. One of the chief advantages of the VAP™ method over other techniques of measuring lipid profiles is that it can determine not only the types of cholesterol particles (HDL, LDL, VLDL, etc), but also their individual size and density(Ensign, 2006; Kulkarni, 1997). That’s vital because people who produce small, dense LDL particles, for example, are known to be at increased risk of heart disease (Kulkarni, 1997). The VAP™ test also measures lipoprotein(a), a particularly dangerous lipoprotein that can lead to heart attacks and strokes. Knowledge of particle size and density is critical for determining the next steps in management of people who may have achieved their “target” lipid values, but who still have high-risk lipid particle types (Brook, 2005). In essence, the VAP™ provides a “higher-resolution” picture of what’s really going on in a person’s lipid profile, allowing them to customize their management regimen. It can even help detect early risk factors in people who have apparently “normal” lipid profiles on older kinds of tests—according to Dr. Kulkarni, one of the experts who helped to develop the test, “because VAP™ measures so many different parameters of the lipid profile, it can identify patients at high risk for coronary heart disease who cannot be identified using the standard lipid profile” (Kulkarni, 2006). The VAP™ can be used to monitor the results of specific treatments, such as statin therapy (Miller, 2006), to assure that goals are being met. When the VAP uncovers hidden risk factors, additional approaches using diet, lifestyle, supplements, and certain drugs are advised.

Targeting Vascular Disease Risk Factors with Nutritional Therapeutics

Scientific studies have revealed that several nutrients effectively protect against endothelial dysfunction caused by the atherogenic factors identified above. Unlike mainstream medicine’s approach to treating atherosclerosis, which involves addressing only very few proven cardiac risk factors, a comprehensive nutritional regimen can be designed to target all of the risk factors that contribute to atherosclerosis. Omega-3 fatty acids. Studies have shown that omega-3 fatty acids combat the development and progression of vascular disease via multiple mechanisms including, lowering triglycerides, lowering blood pressure, improving endothelial function and raising HDL levels (Robinson, 2006). A team of researchers examined the correlation between tissue omega-3 fatty acid levels and measures of circulating Lp-PLA2, a marker of inflammatory arterial plaque, in over 300 patients. They found a strong, independent and inverse association between tissue omega-3 levels and circulating Lp-PLA2. The researchers went on to conclude that intake of omega-3 fatty acids might reduce Lp-PLA2 levels and reduce the risk of vascular disease (Schmidt, 2008). In another study involving 563 elderly men, 2.4 grams per day of omega-3 fatty acid supplementation was found to improve arterial elasticity (Hjerkinn, 2006). In 16 patients with peripherial artery disease who were already being treated with conventional methods, the addition of 2 grams daily of omega-3 fatty acids was shown to significantly improve endothelial function, as measured by brachial artery flow-mediated dilation (from 6.7% to 10.0%) and plasma soluble thrombomodulin (from 33.0 ng/mL to 17.0 ng/mL) (Schiano, 2008). Similarly, another study found that when omega-3 fatty acids were combined with rosuvastatin, the combination improved endothelial dependent vasodilation (-1.42% to 11.36%) while rosuvastatin alone failed to improve endothelial function (Mindrescu, 2008). Propionyl L-carnitine (PLC). PLC has received attention for its ability to directly improve endothelial function. PLC passes across the mitochondrial membrane to supply L-carnitine directly to the mitochondria, the energy-producing organelles of cells. Carnitines are essential for mitochondrial fatty acid transport and energy production, which is important because endothelial cells and heart muscle cells burn fatty acids for 70 percent of their energy. By contrast, most other cells generate 70 percent of their energy from glucose and only 30 percent from fatty acids (Kaiser KP, 1987). In human studies, PLC produced significant improvement in maximum walking distance with claudication (sclerotic peripheral vascular disease) and had no major side effects (Wiseman LR et al 1998). Another study found that PLC significantly reduced homocysteine levels when administered intravenously to hemodialysis patients (Signorelli, 2006). Animal studies suggest PLC may help prevent or decrease the severity of vascular disease. In rabbits fed a high-cholesterol diet, which normally induces endothelial dysfunction and subsequent atherosclerosis, supplementation with PLC resulted in reduced plaque thickness, markedly lower triglyceride levels and reduced proliferation of foam cells (Spagnoli, 1995). PLC also improves endothelial function by increasing nitric oxide production in animals with normal blood pressure and in animal models of hypertension. Nitric oxide is important because it helps keep arteries open. The increased nitric oxide production induced by PLC is related to its antioxidant properties; PLC reduces reactive oxygen species and increases nitric oxide production in the endothelium in the presence of the antioxidative enzymes superoxide dismutase and catalase (Bueno R et al 2005). L-arginine. This amino acid has attracted attention for its ability to improve endothelial function. L-arginine serves as the precursor of nitric oxide in the endothelium (Cockcraft JR 2005). To find out whether L-arginine improved arterial function in people with peripheral arterial disease, as well as determine an optimal oral dose, a group of researchers from the University of California, San Francisco, looked at L-arginine’s ability to improve walking distance and walking speed among people with peripheral arterial disease. The research group found in a pilot study of 80 patients that 3 g L-arginine daily improved both walking speed and distance (Oka RK et al 2005). Another study looked at the effects of oral L-arginine in patients with stable coronary artery disease. The team found that L-arginine therapy of 10 g daily improved brachial artery dilation, a measure of endothelial function (Yin WH et al 2005). CoQ10. CoQ10 is critically important for vascular health, as it is directly involved in the production of ATP, the “energy currency” of the human body. Because the heart is a muscle that never rests, it needs a substantial amount of CoQ10. CoQ10 levels in heart tissue decline disproportionately with age. At age 20, the heart has a higher CoQ10 level than other major organs. At age 80 this is no longer true, with heart levels cut by more than half (Kalen, 1989). CoQ10 pioneer Karl Folkers (1985), in agreement with other Japanese studies, found lower CoQ10 levels in patients with more severe heart disease and showed that CoQ10 supplements significantly raised blood and heart tissue levels of CoQ10 in these patients. In addition to its involvement in energy production, CoQ10 is also a potent antioxidant. CoQ10 is the first line of defense against LDL oxidation; oxidized LDL is a major contributor to endothelial dysfunction (Thomas, 1995). CoQ10, in combination with vitamins C, E and selenium, was shown in a randomized controlled trial to significantly improve arterial elasticity in patients with multiple cardiovascular risk factors. The authors found that the antioxidant-induced increases in arterial elasticity were associated with improved glucose and lipid metabolism, as well as decreased blood pressure (Shargorodsky, 2010). In an animal study, CoQ10 supplementation was shown to improve endothelial function, as measured by thoracic aorta nitric oxide availability and blood pressure (Graham, 2009). Pomegranate. For HDL to perform its vital functions, an enzyme called paraoxonase-1 (PON-1) is attached to its surface. PON-1 serves to protect HDL from oxidation, which impairs its ability to protect arteries. As humans age, PON-1 levels markedly decline, thereby reducing the ability of HDL to protect against heart attack and stroke. This phenomenon helps explain the onset of accelerated atherosclerosis; where within a period of only a few years, an aging person’s healthy arteries rapidly occlude with plaque. In addition to its ability to protect HDL against oxidation, PON-1 has also been shown to hydrolyze (break apart) homocysteine thiolactones, which are responsible for damage to blood vessels. So PON-1, on its own, is a blood vessel protector (Jakubowski, 2001). Lipid peroxidation is a free radical reaction that severely damages cell membranes and is implicated in a host of degenerative diseases. PON-1 blocks destructive lipid peroxidation reactions, making it a crucialenzyme for aging humans to maintain (Rozenberg, 2003; Leus, 2000; Sapian-Paczkowska, 2010; Ikeda, 2007). Research indicates that pomegranate and its extracts can significantly elevate levels of PON-1 activity in the body. Pomegranate does this through a number of distinct biomolecular pathways that include combating inflammation and LDL adhesion and favorably modulating gene expression. Pomegranate extracts reduce oxidation and inflammation largely through their effect on PON-1 activity, intervening at each step in the development of atherosclerosis (Aviram, 2000). Researchers studied the effects of pomegranate on human subjects who consumed pomegranate juice for 2 weeks. The team found dramatic reductions in LDL “clumping” and retention in vessels, accompanied by a 20% increase in PON-1 activity (van Himbergen, 2006). In atherosclerosis-prone mice supplemented with pomegranate, a 90% reduction in oxidation of LDL cholesterol was seen. Supplemented mice also developed atherosclerotic lesions 44% smaller than controls, an effect attributed to reduction in the number of inflammatory foam cells (van Himbergen, 2006). Lipoic acid. This naturally occurring antioxidant serves as a coenzyme in energy metabolism of fats, carbohydrates, and proteins. It can regenerate thioredoxin (an antioxidant protein), vitamin C, and glutathione, which in turn can recycle vitamin E. Lipoic acid also helps manage proper serum glucose levels in diabetic patients (Packer, 2001). In animal studies, it has been shown to reduce endothelial dysfunction (Lee WJ et al 2005a). Human studies have found that lipoic acid improves endothelial function among people with metabolic syndrome (Sola, 2005). Lipoic acid works best in combination with antioxidants including vitamin E, coenzyme Q10, carnitine, and selenomethionine (Mosca, 2002). Garlic. Aged garlic extract has been studied for its ability to reduce inflammation and the damaging effects of cholesterol in the endothelium (Orekhov,1995). In one study of 15 men with coronary artery disease who were also being treated with statin drugs and low-dose aspirin, two weeks of supplementation with aged garlic extract significantly improved blood flow by improving endothelial function (Williams, 2005). Finally, high-dose garlic was studied in 152 individuals with clinically observable atherosclerotic plaque buildup. Over 48 months, the study participants experienced significantly less increase in plaque deposits than a control group, and a regression of plaque was seen in some participants, leading researchers to conclude that garlic had a “not only preventative but possibly also a curative role in arteriosclerosis therapy” (Koscielny,1999). Ginkgo biloba. Several studies have shown that ginkgo favorable alters endothelial function and reduces levels of oxidized LDL (Kudolo GB et al 2003; Ou, 2009; Pierre, 2008). Ginkgo has also been shown to protect against the formation of foam cells (Tsai, 2010). In a study involving eight patients who had recently undergone aortocoronary bypass surgery, supplementation with ginkgo biloba extract, 120 mg twice daily, was shown to reduce atherosclerotic plaque formation by 11.9% and reduce nanoplaque size by 24.4%. Furthermore, ginkgo increased levels of endogenous antioxidant enzymes and reduce levels of the dangerous oxidized-LDL (Rodriguez, 2007). In an animal model, researchers found that ginkgo was effective in reducing high homocysteine-induced intimal thickening, indicating a reversal in the atherosclerotic process (Liu, 2008). Resveratrol. Experiments have shown that the benefits of resveratrol include improvements in the health of the endothelial tissue lining blood vessels (Balestrieri, 2007; Ungvari, 2007; Wang, 2007; Ballard, 2007). One mechanism by which it does this is to facilitate the generation of endothelial progenitor stem cells, thereby providing the endothelium with fresh new cells. Resveratrol benefits the circulatory system by eliciting a decrease in the oxidation of low-density lipoprotein (LDL); by fostering decreases in platelet aggregation; and by promoting relaxation of small blood vessels called arterioles (Nissen, 2006; Taylor, 2002; Crouse, 2007; Cloarec, 2007). Collectively, these mechanisms benefit the overall health of the cardiovascular system by decreasing factors that contribute to the development of atherosclerosis, and by decreasing the likelihood of undesirable clotting, which, in turn, decreases the risk of stroke (Opie, 2007). Furthermore, data indicate that resveratrol decreases the incidence of dangerous heart arrhythmias (Chen, 2007). Quercetin. The so-called French paradox is the phenomenon of low rates of heart disease in a country known for its high intake of fatty foods. Recent research suggests that one of the reasons French people are protected from heart disease is a high intake of quercetin, a potent antioxidant and polyphenol found in red wine (Kuhlman, 2005) and certain vegetables. Numerous studies have examined quercetin and found it to be both a powerful antioxidant and a stimulator of nitric oxide, which inhibits endothelial proliferation, a hallmark of atherosclerosis (Kuhlman, 2005). In spontaneously hypertensive rats, quercetin, along with other bioflavonoids, preserved endothelial function by increasing nitric oxide and reducing blood pressure (Machha, 2005). A porcine study showed that quercetin has potent antioxidative properties and protects endothelial cells against induced dysfunction (Reiterer, 2004). Quercetin and resveratrol may work particularly well together. Green tea extract. Green tea extracts, which are rich in natural antioxidants and antiplatelet agents, are routinely used in Asia to lower blood pressure and reduce elevated cholesterol. In studies of smokers, 600 mL green tea (not extract) was shown to decrease markers of inflammation and decrease oxidized cholesterol, both of which are intimately involved in the development of atherosclerosis (Lee W et al 2005b). A Japanese study of 203 patients found that the more green tea patients drink, the less likely they are to suffer from coronary artery disease (Sano J et al 2004). This study supported an earlier study that found that greater green tea consumption was related to a reduced presence of coronary artery disease in Japanese men (Sasazuki S et al 2000). Vitamin C (ascorbic acid). Vitamin C inhibits damage caused by oxidative stress. In cigarette smokers, daily supplementation with 500 mg vitamin C significantly decreased the appearance of oxidative stress markers (Dietrich M et al 2002). Another study showed that supplementation with 500 mg vitamin C and 400 IU vitamin E daily reduced the development of accelerated coronary arteriosclerosis following cardiac transplantation (Fang JC et al 2002). Vitamin C’s benefits seem especially profound in people who suffer from both diabetes and coronary artery disease. One study demonstrated that, in this group, vitamin C significantly improved vasodilation (Antoniades C et al 2004). Vitamin K. Vitamin K is steadily gaining attention for its ability to reduce vascular calcification and help prevent vascular disease (Jie KSG et al 1996). Evidence for the ability of vitamin K to prevent calcification can also be found in an animal study in which researchers administered the anticoagulant warfarin to rats. Warfarin is known to deplete vitamin K. At the end of the study, all the animals had extensive calcification, suggesting they had lost the protective effect of vitamin K (Howe AM 2000). A large study of more than 4,800 subjects followed for 7-10 years in the Netherlands demonstrated that people in the highest one-third of vitamin K2 intake had a 57% reduction in risk of dying from vascular disease, compared to those with the lowest intake. Furthermore, their risk of having severe aortic calcification plummeted by 52%—a clear demonstration of the vitamin’s protective effects (Geleijnse, 2004). Another study by the same group showed that higher vitamin K2 intake was associated with a 20% decreased risk of coronary artery calcification (Beulens, 2009). Vitamin E. Vitamin E is often studied in conjunction with vitamin C for its potent antioxidant powers. It has been shown to decrease lipid peroxidation and inhibit smooth muscle cell proliferation, platelet aggregation, monocyte adhesion, oxidized LDL uptake, and cytokine production—all of which occur during sclerotic vascular disease (Munteanu A et al 2004; Harris A et al 2002). In cultured arterial endothelial cells, vitamin E increased the production of prostacyclin, a potent vasodilator and inhibitor of platelet aggregation (Wu D et al 2004). Most vitamin E supplements come in the form of alpha tocopherol, but it is also important to supplement with around 200 mg of gamma tocopherol to gain vitamin E’s comprehensive benefits. Several studies show that patients with advanced cardiovascular disease exhibit normal plasma levels of alpha tocopherol but have substantially lower levels of gamma tocopherol (Ohrvall, 1996; Kontush, 1999; Ohrvall, 1994). In a seven-year follow-up study of more than 334,000 postmenopausal women with no previous heart disease, greater intake of dietary vitamin E—consisting predominantly of gamma tocopherol—was strongly associated with a lower risk of death from cardiovascular disease. The data did not appear to demonstrate a similarly protective role for supplemental alpha tocopherol (Kushi, 1996). Numerous animal studies likewise suggest that gamma tocopherol may provide powerful protection for the heart. In laboratory rats, supplementation with gamma tocopherol reduced platelet aggregation and clot formation even more effectively than alpha tocopherol (Saldeen, 1999). In addition, gamma tocopherol at physiological doses was more effective than alpha tocopherol in enhancing the activity of superoxide dismutase (SOD), an antioxidant enzyme that may help reduce the risk of cardiac events (Li, 1999). Niacin. Niacin reduces VLDL particles. Less VLDL leads to less small-dense LDL (prone to oxidation and atherogenesis) and higher HDL (Carlson, 2005). Niacin also improves endothelial function and nitric oxide synthase activity. Niacin’s benefits are not limited to its influence on blood markers of vascular disease risk. It also reduces heart attack risk dramatically. The Coronary Drug Project was the first to establish that niacin is a powerful agent in lowering heart attack risk. When more than 1,000 heart attack survivors were given 3000 mg of (immediate-release/crystalline) niacin daily for six years, the incidence of recurrent non-fatal heart attacks was reduced by 27%, and the number of strokes was reduced by 26% (Canner, 1986). The Remarkable Lifesaving Benefits of Aspirin Oftentimes, the benefits of aspirin are overlooked in light of the numerous nutritional ingredients that convey cardio-protective effects. This is unfortunate because maturing individuals can utilize aspirin, along with these nutritional ingredients, to significantly enhance their defense against cardiovascular disease. Studies indicate that aspirin may protect against heart disease in part by improving endothelial function. In a study involving 41 patients with hypertension and high cholesterol, 100 mg of aspirin daily was shown to lower both systolic and diastolic blood pressure and to increase flow-mediated dilation, a maker of endothelial function (Magen, 2005). The heart depends on its coronary arteries for the oxygen supply that fuels this most vital of organs. Coronary heart disease occurs when normal blood flow through the arteries that feed the heart is slowed or interrupted by factors such as blood clots or plaque. Preventing clots is another way that aspirin helps prevent heart attacks. By irreversibly blocking production of clot-promoting compounds known as thromboxanes, aspirin prevents platelets in the blood from latching on to each other and forming a clot. A platelet has a life span of 10 days, and aspirin irreversibly impairs the platelet’s clotting ability. Aspirin helps blood flow more smoothly past any plaque that is narrowing an artery, and if a plaque ruptures, aspirin will reduce the likelihood of a clot clinging to it (Steinhubl, 2005). Aspirin can also help prevent heart disease through its anti-inflammatory action. Inflammation participates in many disease processes in the body, including plaque accumulation in the arteries (Libby, 2002). The growth of plaque can obstruct blood flow through the arteries. If a plaque ruptures due to inflammation, it can trigger a heart attack. A 2003 meta-analysis examined aspirin’s effects on primary heart-attack prevention (that is, the prevention of first heart attacks). In more than 55,000 men and women, aspirin use was associated with a 32% reduction in the risk of having a first heart attack, and with a 15% reduction in the risk of all major vascular events (Eidelman, 2003). A study presented at the 2005 meeting of the American Heart Association reported on the lifesaving benefits of aspirin therapy. This study examined nearly 9,000 women with stable heart disease, ranging in age from 50 to 79. During more than six years of follow-up, women taking aspirin were 25% less likely to die from heart disease and 17% less likely to die from any cause. Some women took 81 mg of aspirin daily, while others took 325 mg. The study authors stated that the two doses appeared to be similarly effective, but that higher doses of aspirin are associated with a greater risk of certain side effects, such as stomach bleeding (American Heart Association). A meta-analysis published in 2006 examined the effects of aspirin therapy in preventing cardiovascular events in women and men. Examining data from more than 50,000 women, investigators determined that aspirin therapy was associated with a significant 12% reduction in cardiovascular events in women. Among more than 44,000 men, aspirin therapy produced a significant 14% reduction in all cardiovascular events and an even more impressive 32% reduction in heart attacks (Berger, 2006). According to the US Preventive Services Task Force, aspirin’s proven benefits are reason enough for people to start using it if they have at least a 6% chance of developing coronary heart disease in the next 10 years. By contrast, the American Heart Association recommends aspirin for people whose 10-year risk of developing coronary heart disease is 10% or higher, as long they have no medical contraindications for taking the drug. A doctor can help you calculate your cardiovascular risk based on factors such as tobacco use, cholesterol, and blood pressure. You can also assess your cardiovascular risk by using online risk factor calculators available at the American Heart Association website. Life Extension strongly recommends that people who have already had a heart attack (or other episode of heart disease) discuss aspirin therapy with their doctor as part of a strategy to prevent future problems. Life Extension also suggests that people with no previous history of cardiovascular disease—but who are nevertheless at high risk for heart disease—strongly consider aspirin therapy in consultation with their personal physician. The recommended dose for preventing heart-related problems is 81-325 mg daily. Speak with your doctor about your personal needs before beginning aspirin therapy. Hormones and Cardiovascular Health Testosterone and estrogen balance (men). Recent studies suggest that testosterone-replacement may improve the symptoms of vascular disease. A placebo-controlled crossover study in men with ischemic heart disease and low testosterone levels reported that exercise time and the time to development of ischemic changes on a treadmill test were both increased with testosterone-replacement therapy (Malkin, 2004). It has been shown that men with lower levels of testosterone have poorer endothelial function. In a study of 187 males, researchers found that those men in the highest quartile of testosterone levels had 1.7 fold greater flow mediated dilation, a marker of endothelial function (Akishita, 2007). In another study, researchers examined the correlation between testosterone levels and mortality in over 900 men with coronary heart disease. The team found that the mortality rate in patients with testosterone deficiency was 21%, while only 12% of subjects with normal testosterone levels died. The authors of the study concluded that “in patients with coronary disease testosterone deficiency is common and impacts significantly negatively on survival” (Malkin, 2010). Researchers analyzed 30-day survival data for 126 men who had suffered a heart attack. All of the men who did not survive were found to have low total testosterone levels (<= 300 ng/dL). The team went on to conclude that “a low level of testosterone was independently related to total short-term [post-heart attack] mortality (Militaru, 2010). Testosterone levels are also inversely associated with the development of coronary artery disease. In a study of men 45 years of age or younger, researchers found that subjects with diagnosed coronary artery disease had significantly lower levels of free testosterone than did healthy, age-matched controls. The researchers went on to caution that, based on their findings, “a low level of free testosterone may be related to the development of premature coronary artery disease” (Turhan, 2007). Italian researchers compared plasma testosterone levels of 119 elderly men with isolated systolic hypertension to those of 106 nonhypertensive elderly men. All the study participants were 60 to 79 years old, non-obese, nondiabetic, and nonsmokers. The hypertensive men were found to have 14% lower levels of testosterone compared to the nonhypertensive men. In both the hypertensive and nonhypertensive men, low testosterone levels correlated with higher blood pressure values (Fogari, 2003). In a study of over 11,000 men, followed for up to 10 years, baseline testosterone concentrations were inversely associated with cardiovascular and all-cause mortality. Men with total testosterone levels of 481 ng/dL or greater at baseline were significantly less likely to die of cardiovascular disease or any cause during the follow-up period compared to men with testosterone levels below 481 ng/dL. The correlation held even after adjustment for various other confounding factors. The authors of this study declared that “low testosterone may be a predictive marker for those at high risk of cardiovascular disease” (Khaw, 2007). A study published in the Journal of the American Medical Association (JAMA) measured blood estradiol (a dominant estrogen) in 501 men with chronic heart failure. Compared to men in the balanced estrogen quintile, men in the lowest estradiol quintile were 317% more likely to die during a 3-year follow-up, while men in the highest estradiol quintile were 133% more likely to die (Jankowska, 2009). The men in the balanced quintile—with the fewest deaths—had serum estradiol levels between 21.80 and 30.11 pg/mL. This is very similar to the optimal range that Life Extension has long recommended for aging men. The men in the highest quintile who suffered 133% increased death rates had serum estradiol levels of 37.40 pg/mL or above. The lowest estradiol group that suffered a 317% increased death rate had serum estradiol levels under 12.90 pg/mL. For more information on optimizing male hormone levels in order to prevent not only vascular disease, but many other age-related diseases as well, please review the chapter on Male Hormone Restoration Therapy. Testosterone Protects Women Too Testosterone is often thought to be beneficial only for men. However, a study of nearly 3,000 women reveals that maintaining optimal testosterone levels is important for females as well. After assessing testosterone levels at baseline, researchers found that, over a 4.5 year follow-up period, those women with the lowest levels of testosterone were more likely to experience a cardiovascular event and to die of any cause than women with the highest testosterone. The authors concluded “low baseline testosterone in women is associated with increased all-cause mortality and incident cardiovascular events independent of traditional risk factors” (Sievers, 2010). DHEA (men and women). DHEA is a precursor to sex hormones such as testosterone and estrogen. Levels of steroid hormones, including DHEA, decline with the age-associated onset of a variety of medical conditions, including chronic inflammation, hypertension, and atherosclerosis. Higher levels of DHEA in humans are associated with lower levels of inflammatory biomarkers (Sondergaard HP et al 2004). A study showed that men with high levels of DHEA tended to have greater protection against aortic atherosclerosis progression (Hak AE et al 2002). Similarly, another study of 419 Japanese individuals found that those with the highest circulating levels of DHEA-sulfate (form of DHEA commonly measured on blood tests) were much less likely to have carotid atherosclerosis (Yoshida, 2010). Animal studies show a protective role for DHEA in preventing atherosclerosis. Providing DHEA to human vascular endothelial cells in culture increases nitric oxide synthesis, which boosts blood flow (Simoncini T et al 2003). Progesterone (women). Several studies have determined that non-bioidentical progestin promotes the formation of atherosclerosis (Register, 1998; Levine, 1996). The story is quite different for bioidenticalprogesterone, where multiple animal studies have shown that bioidentical progesterone inhibits the process of atherosclerosis (Morey, 1997; Houser, 2000). To illustrate, scientists fed postmenopausal monkeys a diet which is known to cause atherosclerosis for 30 months. The scientists then divided the monkeys into groups that received estrogen alone, estrogen plus non-bioidentical progestin, or a control group that did not receive hormones. The control group developed substantial atherosclerotic plaque. The administration of estrogen resulted in a 72% decrease in atherosclerotic plaque, compared to the control group. Treatment with non-bioidentical progestin yielded disturbing results. The group that received estrogen combined with non-bioidentical progestin had a similar amount of atherosclerotic plaque as the control group, meaning that non-bioidentical progestin completely reversed estrogen’s inhibitory effects on the formation of atherosclerosis (Adams, 1997). In contrast, when the same investigators administered bioidentical progesterone along with estrogen, no such inhibition of estrogen’s cardiovascular benefit was seen (Adams, 1990). In a trial published in the Journal of the American College of Cardiology, researchers studied postmenopausal women with a history of heart attack or coronary artery disease. The women were given estrogen in combination with either bioidentical progesterone or non-bioidentical progestin. After 10 days of treatment the women underwent exercise treadmill tests. Compared to the non-bioidentical progestin group, the amount of time it took to produce myocardial ischemia (reduced blood flow to the heart) on the exercise treadmill was substantially improved in the bioidentical progesterone group (Rosano, 2000). Estriol (women). Growing evidence suggests that estriol may offer benefits to the cardiovascular system. For instance, Japanese scientists found that a group of menopausal women given estriol for 12 months had a significant decrease in both systolic and diastolic blood pressure (Takahashi, 2000). Another study compared the use of estriol for 10 months in 20 postmenopausal and 29 elderly women. Some of the elderly women had decreases in total cholesterol and triglycerides and an increase in beneficial HDL (Nishibe, 1996). To examine the effects of estriol on atherosclerosis, researchers conducted an experiment in which female rabbits were fed a high cholesterol diet with or without supplemental estriol. The rabbits had their ovaries removed surgically to mimic menopause. Remarkably, the group receiving estriol had 75% lessatherosclerosis than the group fed the high cholesterol diet alone (without estriol) (Kano, 2002). Phytoestrogens (women). Following menopause, circulating levels of estrogen are depleted. Phytoestrogens are plant hormones with estrogenic activity. In postmenopausal women, phytoestrogens appear to have estrogen-like benefits such as protection against osteoporosis (Atkinson C et al 2004; Crisafulli A et al 2004a) and possibly hot flashes (Crisafulli A et al 2004b). Phytoestrogens have also been shown to improve vascular function, which tends to decline with age. In one study genistein, a phytoestrogen, provided in a daily 54 mg supplement for one year, significantly improved endothelium-dependent vasodilation in postmenopausal women. Moreover, its benefits were as substantial as those observed in women receiving an estrogen-progestin regimen (Squadrito F et al 2003). For more information on optimizing female hormone levels in order to prevent not only cardiovascular disease, but other age-related diseases as well, please review the chapter on Female Hormone Restoration Therapy. Summary Atherosclerosis is a serious threat to the health of a staggering number of individuals across the globe. Its progression has been linked to increased risk of heart attack, stroke, atrial fibrillation and dementia, among other potentially fatal conditions. Since it may begin as early as childhood and aging has been identified as the greatest risk factor for its development, it is vital to combat this disease as early—and as aggressively—as possible. Unfortunately, if aging individuals leave the health of their arteries in the hands of mainstream medicine, they cannot expect conventional approaches to address all the risk factors that lead to atherosclerosis and cardiovascular disease. Comprehensive blood testing helps aging individuals identify and target their specific risk factors, allowing for the development of a personalized, targeted treatment regimen that can be used to preserve and improve cardiovascular health. In contrast to the methods of mainstream medicine, which address only very few heart disease risk factors, Life Extension has identified numerous scientifically validated ways by which aging individuals can improve the function of their endothelial cells and greatly reduce their risk of developing deadly atherosclerotic plaque buildup in their blood vessels. Life Extension Suggestions Any program aimed at reducing the risk of vascular disease begins with comprehensive blood testing. This step is vital to designing a program that targets an individual’s specific risk factors. Healthy adults should have their blood tested at least once a year. People who have vascular disease or a family history of vascular disease should have their blood tested twice a year to monitor their progress. The following table summarizes optimal ranges for various blood levels: Blood Test Conventional Medicine’s Reference Range Life Extension’s Optimal Range Fibrinogen Up to 460 mg/dL 295 to 369 mg/dL C-reactive protein Up to 4.9 mg/L Less than 0.55 mg/L (men) Less than 1.0 mg/L (women) Homocysteine Up to 15 µmol/L Less than 7–8 µmol/L Chemistry Panel & Complete Blood Count (CBC) · Cholesterol Less than 200 mg/dL 160 – 180 mg/dL · LDL Less than 100 mg/dL Less than 80 mg/dL · HDL Greater than 40 mg/dL Greater than 50-60 mg/dL · Triglycerides Up to 199 mg/dL Less than 80 mg/dL · Fasting Glucose 65 – 99 mg/dL Less than 86 mg/dL Fasting Insulin Up to 24.9 µIU/mL Less than 5 µIU/mL Testosterone (Free with Total) (men) · Free 6.8 to 21.5 pg/mL 20 – 25 pg/mL (LabCorp testing method) · Total 280 to 800 ng/dL 700 to 900 ng/dL Omega-6:Omega-3 ratio None established Less than 4:1 Lp-PLA2 Less than 200 ng/mL Less than 200 ng/mL CoQ10 0.37 to 2.20 µg/mL At least 3.0 µg/mL (preferably higher) Vitamin D, 25-Hydroxy 30 – 100 ng/mL 50 – 80 ng/mL The following nutrients have been shown to improve and preserve endothelial function: Folate (as methyltetrahydrofolate): 1000 mcg daily Fish oil: 3000 – 6000 mg daily Vitamin B12 (as methylcobalamin): 1000 – 2000 mcg daily Propionyl-L-carnitine: 1000 – 2000 mg daily Standardized pomegranate extract: 500 – 1500 mg daily Trans-resveratrol: 250 – 500 mg daily Coenzyme Q10 (as ubiquinol): 200 – 400 mg daily L-arginine: 6000 – 12 000 mg daily (in 3 divided doses) R-lipoic acid: 150 – 300 mg daily Aged garlic extract: 1200 mg daily Ginkgo biloba extract: 120 mg daily Green Tea; standardized extract: 725 mg daily Quercetin: 500 – 1000 mg daily (water-soluble quercetin) Vitamin C: 1000 – 3000 mg daily Vitamin E: 400 IU daily (with 200 mg gamma tocopherol) Vitamin K: 2200 mcg daily; providing K1, MK-4 and MK-7 Vitamin B6 (as pyridoxal 5’-phosphate): 100 – 300 mg daily Niacin: 1000 – 3000 mg daily Aspirin: 81 – 325 mg daily Superoxide Dismutase/Gliadin Complex (SOD Enzyme Activity = 500 IU): 500 mg daily In addition, bioidentical hormone therapy may be recommended, depending on blood testing results. For more information on comprehensive blood testing, please call 1-800-544-4440. ​​ Disclaimer and Safety Information This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein. The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.

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