The objective of the previous lessons as well as this chapter is to motivate you to live longer and have a better quality of life. We as a nation, spend a great portion of our resources in a partially successful attempt to correct cardiovascular problems that could have been avoided. We spent 1.4 trillion dollars In a year on health care, half of which was dedicated to cardiovascular events. We urge you to take action to prevent cardiovascular disease.

PREVENTION IS THE NAME OF THE GAME!

Imagine the expense:

A 50-year-old person suffering of angina pectoris (chest pains) that undergoes diagnostic testing probably will need an electrocardiogram, stress testing, and a coronary angiogram. The bill up to this point will exceed $25,000, dollars. The next step will probably be an angioplasty and or stent placement (dilatation of a narrow artery or implanting a semi-rigid tube inside of the artery to keep it open). The bill will go up to $100,000 dollars. Imagine if coronary bypass is indicated (attachment of a piece of vein or artery to bypass the area of blockage), the bill will exceed $150,000. We have over 750,000 bypass surgeries in the USA in the year 2000. Over 2500 patients received the last step in “heart repairs” which is a transplant. There are over 4,000 patients on a waiting list for available heart donors (according a 2003 Mayo Clinic report). The approximate cost for a heart transplant is at least $750,000 dollars! The magnitude of the problem is mind blowing. Despite of all these efforts over 1 million of people die prematurely of cardiovascular disease. Try to add up all the resources spent in the attempt to patch up these problems.

Now, lets go back to the same person suffering from angina, play back his life like you do in a video, try to visualize him or her as far back as the late teens. If a life style change had taken place earlier, the arteriosclerotic cardiovascular disease process would not have started. Chances are that no arteriosclerotic changes would be present at all!  By life style change we mean simply “recognition and elimination of risk factors”. How can we expect people to change their life style? The answer is: Through good information. Information is disseminated through the education of children, parents, teachers and the omnipotent “media”.

We made our commitment to provide accurate and accessible information to you. However, it is up to each individual to reach the final goal of TOTAL LIFE STYLE CHANGE (TLC).

Risk Factors Revisited:

From what you have read so far, it is clear that the concept of Total Life Style Change requires the modification or suppression of risk factors. The knowledge regarding the subject of risk factors is continuously evolving. Sometimes in a few days new knowledge is developed or previous concepts are modified, but the basic information remains solid. We continue to focus on the foundation of risk factor knowledge and expand our focus as new discoveries are made.

We dealt in previous lessons with eleven risk factors. The current thinking is to divide risk factors in two categories with some additional factors added in the second.

Major Risk Factors: (4)
     - Smoking
     - Hyperlipidemia (high cholesterol and other lipids)
     - Diabetes
     - Arterial Hypertension (High blood pressure)
Emerging Risk Factors: (7)
     - Sedentary Life
     - Poor diet
     - Overweight, obesity and metabolic syndrome
     - Inflammation
     - Homocysteine levels
     - Emotional Factors (depression, anxiety, hostility)
     - Heredity (Genetic factors)

More recent additions to Emerging Risk Factors:

Clotting abnormalities: New markers are high fibrinogen levels, Von Willebrand factor antigen, plasminogen activator inhibitor-1 or PAI-1 and platelet related factors.

New inflammation markers: In addition to C-Reactive Protein, lipoprotein-associated phospholipase A2 or Lp-PLA2, myeloperoxidase, Interleukines, serum Amyloid A, white cell count (WBC) and others.

Lipid fractions and their ratio: very low-density lipoproteins (VLDL), apolipotroteins A1 and B, oxidized LDL, non-HDL cholesterol.

Hormone and enzyme factors: Elevated insulin levels and insulin resistance, angiotensin-converting enzyme genotype, apoE genotype and others.

Overwhelming evidence supports the role of the major risk factors in cardiovascular disease.  A recent analysis of 14 international clinical trials conducted in the previous decade involving over 122,000 patients reveals that 80% to 90% of patients with cardiovascular disease have at least one or more of the four major risk factors. Historically, the Framingham Heart Study, which began in 1948, was the first study involving non-institutional men and women. About 5200 people from the town of Framingham, Massachusetts’s ages 30 to 62 were studied and followed closely for over 50 years.

Let us deal with each of major risk factors and point out the mechanism by which they do their damage.

Smoking:

1) Tobacco contains nicotine. This compound constricts the arteries impairing the blood supply to the heart muscle as well as the brain and the lower extremities, contributing to the symptoms of angina (chest pain), transitory ischemic attacks to the brain (TIA) and pains in the calves on walking (intermittent claudication). Nicotine opposes the normal function of the endothelium of the arteries (lining) impairing the production nitrous – oxide. Nitrous oxide is necessary for the arteries to dilate (open).
2) Tobacco contains a number of highly irritant tars, which induce chronic irritation of the bronchial tubes leading to the development of chronic bronchitis, emphysema, and chronic cor- pulmonale. The symptoms of cough and shortness of breath are earmarks of this condition. Some changes take place over the years in the bronchial mucosa (also lips and mouth) leading to cancer. Some of these elements affect the arteries as well by inducing inflammatory reaction, which has been determined to be very important in the development of arteriosclerosis.
3) The inhalation of cigarettes and cigar smoke impairs the proper absorption of oxygen by the hemoglobin of the red cells, so there is lower oxygen content in the blood of smokers when compared to normal people. In addition, carbon monoxide is combined with hemoglobin. The compound is called carboxihemoglobin which is very stable, so hemoglobin is unable to take up oxygen. The levels of carboxyhemoglobin are high in the blood of smokers.
4) Tobacco contains a number of oncogenic substances (cancer producing) which increase the incidence of other forms of cancer outside the respiratory system, such as in the ovaries, breasts, colon.
5) Smoking is a strongly addictive disease because of nicotine. Serious withdrawal symptoms may occur in some instances resembling” Delirium Tremens” as seen in alcoholics.
6) Tobacco smoke stains teeth, fingers and coats objects with a fine gummy layer. This problem has been reported as important even in sensitive electronic instruments. As a pilot Dr. Paredes did not allow any smoking pilot to operate his airplane if he was a smoker because the navigation instruments could be affected and malfunction. 

Hyperlipidemia or elevated levels of lipids:

The relationship between high levels of cholesterol and arteriosclerosis has been established for over 75 years. See lesson two.

What is Cholesterol?

Cholesterol is a fatty, waxy substance present in foods, blood and in all the tissues (body cells). It is essential for life and is part of brain matter, cell membranes, the insulating sheath of all nerves, white cells, sex hormones and bile salts. The majority of cholesterol is produced in the liver (endogenous cholesterol), approximately 1,000 milligrams per day while another 350 milligrams are ingested daily in the average diet. As you can see the liver is responsible for over  2/3 of the total cholesterol measured in the blood. The liver creates cholesterol using a complicated chemical process which requires an enzyme called HMG-Coenzyme A reductase. The drugs called “statins” inhibit this enzyme. Their use lowers cholesterol levels effectively.

Why is the content of cholesterol in the diet important? Because the cholesterol already present in the blood is increased by the dietary cholesterol . Cholesterol is deposited in the lining of the arteries building “plaques” that narrow or block them. This is arteriosclerosis or atherosclerosis, also known as hardening of the arteries. It can be compared to clogging of your kitchen pipes when pouring chicken fat down the sink. A total blockage in a coronary artery produces a heart attack. A blockage in a brain artery produces a stroke. A blockage in an artery of the legs can lead to gangrene. The American Heart Association recommends an oral intake of no more than250 milligrams of cholesterol daily. However, if the cholesterol levels in the blood are elevated over 200 milligrams %, it is extremely important to restrict the cholesterol consumption. The average American cholesterol level is 220 mg%.

How many kinds of cholesterol are there? Which is bad and which is good? The definition of good, bad and very bad cholesterol depends on the transporter or carrier of cholesterol. The carriers are proteins referred as “apoproteins”. Cholesterol is a fat that does not dissolve in water or in the blood. Cholesterol joins the protein molecules forming “lipoproteins”. Depending on the proportion of protein versus fat of this compound we have low density, bad cholesterol or LDL, high density, good cholesterol or HDL and very low-density lipoproteins. very bad cholesterol or VLDL. The protein content should be greater than the lipid content. The low density and very low density cholesterol tends to deposit more easily in the lining of the arteries, while the high density remains in the blood longer, flushing away the low density cholesterol already deposited in the lining of the arteries. Imagine: HDL  is like Draino,  cleaning blocked greasy pipes in your kitchen.  

Diabetes:

We have discussed preliminary information on diabetes in lesson five. We stated that diabetes, when present, multiplies by 2 to 4 times the incidence of events (heart attack and strokes). Diabetes “amplifies” the development and progression of cardiovascular disease and it is closely associated with the presence of overweight and obesity.

The mechanisms by which diabetes enhances arteriosclerosis:

Hyperglycemia (elevated levels of blood sugar)

Insulin Resistance and hyperinsulinemia (elevated levels of insulin)

Multifactors that accompany diabetes, such as dyslipidemias (abnormal content of lipids), arterial hypertension (elevated blood pressure), small artery disease particularly in the retina (eyes) and kidneys.

Hyperglycemia or elevated blood sugar is a risk factor in itself. It damages the lining of the arteries. There are multiple studies that showed a direct correlation between the development of arteriosclerotic cardiovascular disease and high levels of blood sugar. This has been seen in type I Diabetes (juvenile) when the sugar level is well controlled throughout the day by multiple insulin injections. In this case the incidence of cardiovascular complications is reduced up to 76% (Dr. David Natham, Harvard University communication to the 63rd American Diabetes Association 2003).

In type II Diabetes (adult onset) it has been found that high blood sugar level prevents improvement of the coronary flow in patients that suffer heart attacks and undergo reperfusion procedures (Dr. Hiroshi Ito, Osaka, Japan June 2003). The explanation is that more white cells are trapped in the coronary capillaries (smallest branches of the coronary arteries) and micro-thrombus (small clots, formed by platelets sticking together)) plug these tiny tubes. Recently, in a large European study on diabetic patients, Dr. J. Chiasson found that “controlling “the high blood sugar level that follows meals by administering acarbose at meal time, the medication delays the digestion and absorption of sugar and reduces the incidence of their cardiovascular complications by up to 49% (published in JAMA 2003; 290: 486-494).

Hyperinsulinemia (elevated level of insulin) is due to insulin resistance (inability of the body to utilize insulin). Elevated levels of insulin are present in the early stages of type II Diabetes, but later in life, the production of insulin eventually declines due to fatigue of the pancreas and at this point patients will require insulin administration.  

Individuals with elevated blood sugar have elevated levels of free fatty acids. High levels of blood sugar and free fatty acids attack the beta cells of the pancreas reducing their ability to produce insulin normally. The combination of high blood sugar and free fatty acids cause small blood vessels and retinal damage seen in diabetics, leading to blindness, renal arterial hypertension and renal failure.

Arterial Hypertension or High Blood Pressure:

High blood pressure occurs when the arteries undergo a constrictive effect caused by certain substances normally produced by the body. These substances are counteracted by vasodilators. If the equilibrium between the two elements is upset and the constrictive effect predominates, hypertension takes place. These substances are part of the renin-angiotensin-aldosterone-system, which responds to sympathetic stimulation through catecholamines. Sodium is an important element at the cellular level in mediating the overall phenomenon of vasoconstriction.

The Framingham study revealed that arterial hypertension more than doubles the incidence of events (heart attacks and strokes). The proportion rises with age.

There are over 50 million people with high blood pressure in the USA. Only one third are being adequately treated. The majority of hypertensive patients have primary or essential hypertension which is possibly genetic in origin. Secondary arterial hypertension is less common and it is due to kidney problems, certain tumors (pheochromocytoma) and endocrine disorders (glandular).

The blood pressure is measured in millimeters of mercury (mmHg). The top number is the systolic pressure and the bottom number is the diastolic pressure.

Blood pressure values: According to the USA Joint Conference on Arterial Hypertension, 2003, blood pressure levels are as follows:

     - Normal -- 120/80
     - Pre-hypertension -- 135/85
     - High Normal -- 139/86
     - Grade one hypertension -- 140-159/90-99
     - Grade two hypertension -- 160-179/100-110
     - Grade three hypertension -- 180 or more/110 or more

High blood pressure is more frequent in males than in females. It affects Afro-Americans more than whites and Hispanics and its incidence increases with age. At age 65 over 50% of people have arterial hypertension. High pulse pressure (top number minus the bottom number) has a worse prognosis as manifested by higher number of events (heart attacks and strokes). High systolic pressure alone increases the incidence of strokes. By reducing 2 mm of systolic pressure, mortality is reduced by 7% and stroke incidence by 10%.

Why is arterial hypertension such an important risk factor?
The mechanic effect of high blood pressure affects the arteries, modifying their structure. It damages their lining and changes the elasticity of their walls. The walls of the arteries become rigid and fragile. At times, an aneurysm is formed which ruptures inducing hemorrhagic strokes in the brain or a major artery such as the aorta. The damage to the lining of the arteries accelerates the arteriosclerotic process facilitating the accumulation of cholesterol plaques and events (heart attacks and “thrombotic” strokes).

Anti-hypertensive therapy:

Diet: Salt and calorie restriction. The Nurses Health Study recently published a report stating that mega-doses of folic acid may prevent the development of arterial hypertension in females(94,000 women were studied achieving a reduction of 46% in the incidence of arterial hypertension by taking 1000 micrograms of folate, 2004)

Diuretics are the first line of anti-hypertensive drugs. They increase urination, lower the blood volume and increase sodium content in the urine,  they are effective and less expensive. The most commonly used diuretics are hydrochlorothiazide (Hydrodiuril), furosemide (Lasix), metolazone (Zaroxylin). They tend to waste potassium (K) so this element should be replaced by potassium containing foods: Oranges, tomato juice, bananas or tablets of potassium supplements (KCl).

Aldosterone blockers (Spironolactones). They neutralize aldosterone  which is a compound secreted in excess in patients with arterial hypertension. They are usually given in combination with diuretics such as in Aldactazyde. A newer compound is eplerenone (Inspra) is an effective aldosterone blocker; it is  used in cases de arterial hypertension resistant to conventional therapy. This drug has been very beneficial in patients with congestive heart failure as well.

 Agents interfering with the Renin-Angiotensin axis

Ace -Inhibitors type I block the conversion of  angiotensin I into angiotensin II (angiotensin I derives from angiotensinogen, produced by the liver + renin, produced by the kidneys). Examples of ACE-I inhibitors are ramipril (Altace), lisinopril (Prinivil), captopril (Capoten). These drugs may induce coughing spells in 5 + % of people, specially in women.

Ace Inhibitors type II or angiotensin receptors blockers ( ARB’s) prevent the receptor’s response to angiotensin II already formed, allowing the vasodilator factors to predominate over the constricting factors. This results in a lower blood pressure.
Examples of Ace-II blockers: valsartan (Diovan), candesartan (Atacand), losartan (Cozaar). They do not cause coughing spells.

Renin Inhibitors block the action of renin. Aliskerin , produced by Novartis is the first available successful renin inhibitor; it was proposed during the 2006 European Congress of Cardiology. This drug In doses of 150, 300 and 600 mgs daily is very  effective to reduce the blood pressure smoothly. Its  therapeutic effect is enhanced if combined with a diuretic (HCTZ).

Beta-blockers protect the cardiovascular system from the effect of the sympathetic system stimulation through beta receptors to catecholamines (adrenalin or epinephrine by-products). Examples of most commonly used beta-blockers are: propanolol (Inderal), metaprolol (Toprol, Lopressor), nadolol (Corgard). They may induced slow pulse, depression, tiredness, impotence, Reynaud phenomenon in the fingers. Recent reports place beta-blockers as number 3 or 4 in the therapy of arterial hypertension.

Calcium-blockers block calcium channels induces relaxation of the arteries (vasodilatation).
The most commonly used calcium-channel blockers are: diltiazem (Cardizem), verapamil (Verelan, Calan, Isoptin), amiodipine (Norvasc). These compounds are particularly effective in Afro-americans. Afro-Americans do not respond well to Ace inhibitors and beta blockers.

Alpha-Blockers counteract the vasoconstriction effect of the sympathetic system stimulation through alpha- receptors.
Examples: prazocin (Minipres), doxazosin (Cardura), terazosin (Hytrin). They also help urinary retention in prostate patients.

Central Vasodilators act through the Central Nervous System (Brain). Examples: clonidine (Catapres) tablets or patches, guanfacine (Tenex), minoxidil (Loniten)

Direct Vasodilators act directly on the arterial walls. Examples: hydralazine (Apresoline). pentoxifyline (Trental) which acts primarily modifying the red cells  improving perfusion through the capillaries. 

Emerging Risk Factors (7):

Sedentary Life Style and Physical Fitness have been reviewed in lesson seven. Poor diet, Overweight, Obesity and Syndrome X have been reviewed in lessons three, four, five and six. Emotional Factors have been reviewed in lesson eight. Genetic factors were reviewed in lesson nine.

We are going to deal with the remaining two factors:
     - Inflammation,
     - Homocysteine levels

Inflammation:

The inflammatory changes in the lining of the arteries induce accumulation of cholesterol and plaque formation. Inflammation may be produced by viruses (flu virus), bacteria (Chlamydia, helicobacter) and certain oxidants. Some infectious agents may act even at remote locations without being present in the arteries. Anti-oxidants reduce this effect. Anti-viral drugs as well as antibiotics may be indicated.

The inflammatory process starts with white cells, macrophages, T-cells  and platelets that accumulate in the affected area. The macrophages secrete matrix metalloproteinases (MMPs) leading to tissue breakdown. The T-cells secrete cytokines and tumor necrosis factor (TNF) leading to plaque instability and rupture. This creates a snowball effect trapping low density and “oxidized” lipids (cholesterol) building a plaque, which blocks the arteries. Inflammatory cells replace normal cells that are part of the lining. Elastic fibers are transformed and the wall of the arteries becomes more rigid. Statins have proven to stem the inflammatory process independently from their action reducing cholesterol levels.

What are the markers of inflammation?
Common signs of infection may or may not be present (fever, elevated white count, elevated sedimentation rate etc). There are, however, other important “bio-markers ”for an inflammatory process:

• Elevated high sensitive C-reactive protein normally should be under 2.5 mg%. If it reaches 3 mg. it indicates a high risk for events (heart attacks and strokes).
• Another marker has been disclosed after a trial study called ARIC (Atherosclerosis Risk in Communities). The lipoprotein-associated phospholipase A2 (Lp-PLA2). which is related to a platelet activator oxidizer of fatty acids transforming LDL cholesterol particles; these particles infiltrate the arterial walls to form plaques. Dr. Christie Ballantyne made this important contribution from Baylor University, Texas and presented it at the meeting of the American College of Cardiology in Chicago, April of 2003. The study involved 12,819 men and women with normal or low LDL cholesterol of which 609 developed coronary events (heart attacks) in a period of 6-8 years. More than half of the affected people had elevated levels of Lp-PLA2 despite their relatively low levels of LDL. The normal levels of Lp-PLA2 should be under 300 micrograms/L.
• The Myeloperoxidase, abundant in  leukocytes, when elevated indicates a high risk of myocardial infarction. This substance disables HDL, thus enhancing the oxidation and deposition of LDL.in the arteries.
• Another marker that has become fashionable is the calcium score Electron- bean computed- tomography, (EBCT). It indicates the degree of calcification in the coronary arteries. The calcium score is a significant predictor of events (heart attacks, strokes and coronary deaths).  Recently a double test, called Hybrid PET/CT by special cameras gives in addition to anatomic information, perfusion or flow  in certain areas de of the heart..   A low EBCT score is under 100. Scores over 150 indicate high risk for events. The presence of a high level sensitive C-reactive protein with a high EBCT score predicts a six fold increment in risk for events, even if LDL (Low density lipoprotein) is normal or below normal.
• A blood test to determine the presence of a combination of amino-acids may signal the likelihood to suffer a stroke or heart attack in the near future. This amino-acid compound, called  NT-proBNP may indicate a eight-fold risk  towards these events, as reported in Chicago in January, 2007.

What should be done if the markers for inflammation are high?
If there is an obvious infection, this should be treated promptly. There are a number of underlying low -grade “silent” processes such as gum inflammation, sinusitis, and dental caries and abscess, chronic respiratory infections that should be detected and treated.

If there are not clear cut signs of infection, but the biomarkers of inflammation are high, statins are indicated even if the lipid levels are normal or below normal.

Homocysteine Levels:

Epidemiological evidence suggests that the homocysteine level is an independent risk factor for cardiovascular disease. It is a recognized predictor of death in patients with coronary and cerebral vascular disease. High levels of homocysteine causes damage to the lining of the arteries (endothelium) and promote lipid oxidation. Oxidized lipids inflame the lining of the arteries and accumulate to form plaques. High levels of homocysteine affect the veins as well, promoting inflammation and clotting in the leg veins (deep vein throb phlebitis), which can cause pulmonary embolism (clots in the lungs). Reisberg et al.reported in the The New England Journal of Medicine, that there is evidence for a relationship between high levels of homocysteine and the development of Alzheimer’s disease. It has been reported that high homocysteine levels may promote bone fractures.

Levels of homocysteine are reduced by folic acid, vitamin B6 and vitamin B12. Lately, a pill containing all three vitamins in one is available (Foltx). Latest reports demonstrate however, that it is not necessary to take folic acid supplements routinely if the levels of homocysteine are normal (2006).

More recent reports indicated that the role of homocysteine has been overplayed in the past ; at present there is not justification for the average person to take additional folic acid routinely.

Revised August 26th, 2007