UNDERSTANDING ATHEROSCLEROSIS: THE NEW RISK FACTORS June 10, 2008 Mordechai Litman, M.D.

UNDERSTANDING ATHEROSCLEROSIS:

THE “NEW” RISK FACTORS

June 10, 2008Mordechai Litman, M.D.

TRADITIONAL RISK FACTORS

Cholesterol-high LDL

-low HDL High Triglycerides High Blood Pressure Smoking Obesity

ENHANCE Trial2008

• Comparison of Simvistatin to Simvistatin plus Ezetimibe(different cholesterol-lowering drug)

• Simvistatin lowered LDL cholesterol on average from 320 to 188

• Combination drug lowered LDL to average of 134

• But the significantly lower cholesterol had no further improvement in slowing carotid artery narrowing

• Brought into question how significant is cholesterol level in itself in atherosclerosis

RISKS OF LOW CHOLESTEROL

• Levels below 180 associated with increased risk of suicidal behaviour, depression, cancer, car accidents, hemorrhagic stroke

• Cholesterol part of normal cell membrane function, cell receptors, and hormone production

“NEW RISK FACTORS”

• CRP—indicator of inflammation• Homocysteine• Lp(a)—lipoprotein (a)• Ferritin• Oxidative Stress—uncontrolled free radical damage• Fibrinogen—tendency to form clots• Transfats• Insulin ResistanceIn general, these risk factors damage endothelium (lining of

arteries) and promote inflammation

“OLD THEORY”

High cholesterol causes plaque by building up on wall of arteries—therefore, focus was on lowering cholesterol as much as possible

BUT…. 1) In 10 year study period on island of Crete,

there were no recorded heart attacks despite high cholesterols

2) French study showed reduced risk of second heart attack or cardiac-related death in those following the “Mediterranean Diet” compared to those on a low fat “cardiac” diet, despite similar cholesterol levels in both groups

“NEW” THEORY

Atherosclerosis is the result of damage to the endothelium (inner lining of arteries) and inflammation causing progressive damage

This then allows cholesterol (especially “oxidized” LDL) to enter the artery wall-causing more damage and reaction from the immune system-builds plaque

Creates cycle of inflammation and plaque Progressively narrows the artery and it becomes

stiffer, interfering with blood to vital organs

STABLE and UNSTABLE PLAQUE

Stable--strong “seal” or cap forms over the plaque—still interferes with blood flow, but less likely to cause sudden heart attacks

Unstable—continuing inflammation starts to break down cap—plaque can rupture—cause clot to form and completely block artery—resulting in heart attack or stroke

PREVENTING PLAQUE FORMATION and INSTABILITY

Stop active process of atherosclerosis: Reduce damage to endothelium Reduce inflammation Reduce tendency to clot

CRP—C-Reactive Protein

Mediator of inflammation-normally rises transiently to help fight infection

Constant high levels reflect inappropriate inflammation

Abdominal fat can lead to increased levels of CRP (one of the ways that obesity increases risk)

High CRP statistically related to increased risk of heart attack and stroke

HOMOCYSTEINE

Amino acid (metabolite of important amino acid methionine)

Usually metabolized further to useful substances Can build up if not processed properly High homocysteine associated with increased

atherosclerosis (and many other chronic diseases)

Causes damage in the arterial wall and oxidizes (damages) cholesterol and proteins

LIPOPROTEIN (a)—Lp(a)

Functions normally in role of basic repair of damage in arterial wall

When in excess (usually in response to inflammation or insufficient amounts of Vitamin C), it becomes a more powerful promoter of plaque than LDL

In medical studies, there is a connection between high Lp(a) and poor outcomes of angioplasty or by-pass surgery

FERRITIN

Measurement of iron levels in the body Too much iron can oxidize LDL, making it

more likely to form plaque Can damage endothelial cells Can promote inflammationFinnish Study—men aged 42-60 yrs with

ferritin levels above 200 had 2x risk of heart attack. If combined with high LDL, then there was 5x risk.

OXIDATIVE STRESS Free radical (positively-charged) atoms Can damage DNA, proteins, mitochondria (cell’s main

energy producers) Can oxidize LDL, increasing plaque-forming tendency Major factor in “aging process” in general Free radicals produced as product of normal metabolism

or taken into the body as toxins eg. smoking Also generated by high refined sugar intake, heavy

metals (eg lead, mercury), stress, radiation Controlled by antioxidants—both those produced in the

body or taken in food or supplements If insufficient antioxidants to control free radicals, then

resulting damage known as oxidative stress

FIBRINOGEN

Factor in blood clotting--needed in normal process to stop bleeding

Too much can promote abnormal blood clots High levels are a risk for heart attack, stroke,

sudden death, and re-stenosis after angioplasty Smoking raises fibrinogen Low estrogen in women and low testosterone in

both sexes raises fibrinogen

TRANSFATTY ACIDS

Artificially hydrogenated fatty acids—made in order to prolong shelf life

Can also occur when heating many oils at high temperatures

Associated with-increased free radical damage to cell membranes

-increased inflammation -raised Lp(a) -promotion of LDL oxidation -lowered HDL

INSULIN RESISTANCE Combination of both high insulin and high blood sugar The cells do not respond as well to insulin—more than

normal amounts needed to get response Both high insulin and high glucose can cause damage Glycation—glucose binds to and damages healthy

proteins Increase tendency of blood to clot Increase tendency of blood vessels to constrict Increase blood pressure Probably result of prolonged high intake of refined

sugars and starches requiring need for high output of insulin to deal with it

MANAGING THE RISKS

Diet--low in refined carbohydrates, hydrogenated fats, toxins

--high in fruits/vegetables with high antioxidant and high anti-inflammatory nutrients

Appropriate supplements Physical activityNo smokingManage stress

SUPPLEMENTS

Vitamins, minerals, and food extracts can modify many risk factors

Usually need to be used in combinations—generally more effective than individual supplements

Some studies had negative results because they either used low doses, less effective forms of vitamins, or high doses of isolated vitamins without their needed “partners”

SUPPLEMENTS

Some related research:1) Vit C or E alone decreased 3 year carotid

artery disease progression by 5%. But together, progression is slowed by 45%

2) Vit C, E, A, beta-carotine together improved post-MI recovery and decreased death rate by 1/3 in the first month following heart attack

3) Combinations of anti-oxidants protect against arrhythmia and heart attack in bypass surgery patients

OMEGA-3 FATTY ACIDS (FISH OIL)

Decreases Lp(a)Decreases triglyceridesDecreases blood pressureDecreases inflammation in artery wallDecreases clot formationMay help counteract arrhythmiasLarge Italian study showed that supplementation

with 850 mg of EPA/DHA reduced the risk of sudden cardiac death and all causes of death by 30% over a 1 year period

MAGNESIUM

Deficiency now common due to lower levels in many foods than in the past

Magnesium necessary for many biochemical processes in the body

Helps:Stabilize plaqueDecrease arrhythmiasDilate coronary arteries—decrease anginaLower blood pressure Improve energy production in heart muscle

MAGNESIUM--Studies

• AmJCard 2003: study from Israel, U.S.,Austria. Magnesium improved exercise tolerance and quality of life in heart patients

• Honolulu Heart Program: 7000 patients followed for over 30 years. Those with low magnesium intake had almost 2x risk of heart attack compared to those with high intake

• CurrOpinLipidol 2008: “Role of dietary magnesium in cardiovascular disease, prevention, insulin sensitivity and diabetes”

-lowers inflammation -decreases oxidative stress -decreases endothelial dysfunction -reduces platelet aggregation (helps prevent clots)

MAGNESIUM-Studies

• IntJCardiol 2008: “Magnesium orotate in severe congestive heart failure”

Double-blind trial of patients receiving “optimal” cardiovascular medication with either magnesium or a placebo.

Only 52% of medication-only group alive after 1 year.

76% of magnesium group alive after 1 year.Conclusion in study: adding magnesium improved

survival and lessened symptoms.

VITAMIN C

For people with atherosclerosis, Vit C can decrease heart attacks and deaths by 40-60%

Decreases the need for repeat angioplasty by 57%

Improves endothelial functionLowers CRPDecreases harmful effects of Lp(a) and

HomocysteineAn analysis of 9 major studies showed that those

who take more than 700 mg of Vit C per day had 30% less CVD mortality compared to non-users

VITAMIN C--Study

2002 Italian study: followed 1000 patients for over 10 years—1/2 received 1000 mg Vit C per day

-those with mild atherosclerosis at beginning showed significant progression of disease in 13% without Vit C supplement compared to 3% with Vit C

-those with moderate plaque at beginning showed deterioration in 38% without Vit C and 8% with Vit C

-those with more severe plaque at beginning showed deterioration in 66% without Vit C and 21% with added Vit C

NIACIN-Vitamin B3 Lowers LDL Lowers triglycerides Lowers Lp(a) Raises HDL Improves almost all of the lipid disorders associated with

atherosclerosis Many studies done over many years have shown that

niacin reduces progression of atherosclerosis and mortality from heart disease

Main problem in past with niacin use was the “niacin flush”—mainly when first starting niacin at high doses.

--can avoid it with use of new “no-flush niacin”, but may need higher to get same results

B VITAMINS & HOMOCYSTEINE

The enzymes needed to metabolize Homocysteine require sufficient amounts of vitamins B6, B12, Folic acid—or the homocysteine levels can rise to dangerous levels

JAMA 2002-study of patients after angioplasty -1/2 of group was given added B6, B12, Folic acid and ½

given placebo -in group given B vitamins, 19% showed re-narrowing of

arteries after 6 months -in placebo group, 38% showed re-narrowing

Some studies indicated that those already with severe disease, treatment of homocysteine may not be very effective or it may need even greater lowering of the levels than was accomplished in those studies

VITAMIN E Complex of 8 different molecules (most commercial supplements

contain only 1 component) Conclusions of some medical studies: 1) decreased by 50% the 2 year heart attack rate in newly diagnosed

CVD patients 2) decreased disease progression following by-pass surgery 3) decreased by an additional 50% the incidents of strokes when

added to ASA as preventionThere have been recent controversies from some “negative” studies.

There are problems with results if only testing 1 of 8 components rather than a normal physiological blend. Also problems when not combining with other antioxidants that normally work as a “team” with Vit E

VITAMIN K2

Vitamin K needed to make clotting factors Newer research looking into the effects on bone

density and health of blood vessels Helps to reduce calcium in plaque (which is

related to the severity of atherosclerosis) and increases calcium in bone eg. puts calcium where it is needed and removes it from where it is harmful

( caution when using it along with Coumadin, a “blood thinner”—need to monitor closely)

VITAMIN D

Low levels are associated with increased cardiovascular disease, high blood pressure, stroke (and many other diseases)

Deficiency is now common—even taking the old RDA’s was insufficient to maintain normal blood levels—recommended intakes are continually increasing—old concerns about toxicity have been shown to have been greatly exaggerated when using Vit D3(natural vit D)

Can now follow by measuring blood levels

CO-ENZYME Q10 (CoQ10) Produced in all cells in the body Powerful antioxidant Involved in energy production in cells Highest levels normally in heart muscle—uses the highest amount

of energy Protects endothelium from free-radical damage ( especially when

combined with other antioxidants ) Can help lower blood pressure Heart failure correlated to low CoQ10 levels Studies show significant benefit for heart failure and improving

results of by-pass surgery(CoQ10 levels are significantly lowered by statin use—same enzyme

involved in cholesterol production also used in CoQ10 production)

POMEGRANATE JUICE

Research study in: ClinNutr 2004Title: Pomegranate juice consumption for 3 years by

patients with carotid artery stenosis reduces common carotid intima thickness, blood pressure and LDL oxidation

Patients with severe carotid artery stenosis (narrowing) treated with drugs (statins and blood pressure drugs) or the same drugs plus pomegranate juice.

Results-drugs only group showed 9% increase in intima thickness (worsening) after 1 year

-pomegranate plus drugs showed a 35% decrease (improvement) in thickness and a 44% increase in carotid blood flow after 1 year

HORMONES AND THE HEART--TESTOSTERONE

• Higher physiological levels associated with lower cardiovascular disease

• Decreases clotting tendency• Decreases fibrinogen• Decreases Lp(a)• Decreases triglycerides• Decreases blood pressure• Decreases abdominal fat• Increases HDL• Improves blood sugar controlUsed in Europe for many years in management of heart

disease (if levels low on testing)

HORMONES AND THE HEART--ESTROGEN

• Inhibits vasoconstriction• Lowers fibrinogen• Decreases LDL, increases HDL• Improves insulin sensitivity• Lowers Lp(a)Meta-analysis of HRT and Heart Disease RiskJGenIntMed 2007Results: 32% reduction in coronary heart disease

events (eg heart attack) for women who start treatment in their 50’s (soon after menopause)