Coronary Artery Disease and Angina

Description

Alternative Names

Introduction

The heart is the human body's hardest working organ. Throughout life it continuously pumps blood enriched with oxygen and vital nutrients through a network of arteries to all parts of the body's tissues.

The external structures of the heart include the ventricles, atria, arteries and veins. Arteries carry blood away from the heart while veins carry blood into the heart. The vessels colored blue indicate the transport of blood with relatively low content of oxygen and high content of carbon dioxide. The vessels colored red indicate the transport of blood with relatively high content of oxygen and low content of carbon dioxide.

Click the icon to see an image of the anterior heart arteries.

Click the icon to see an animation about coronary artery disease.

The Process of Atherosclerosis

Coronary artery disease is the end result of a complex process called atherosclerosis (commonly called "hardening of the arteries"). This causes blockage of arteries (ischemia) and prevents oxygen-rich blood from reaching the heart. There are many steps in the process leading to atherosclerosis and some are not fully understood.

Click the icon to see an image of atherosclerosis.

Increasingly, however, researchers are studying the interactions between cholesterol and processes known as oxidation and the inflammatory response.

Cholesterol and Lipoproteins. The story begins with cholesterol and sphere-shaped bodies called lipoproteins that transport cholesterol.

• Cholesterol is a white, powdery nutrient that is found in all animal cells and in animal-based foods. It is critical for many functions, but under certain conditions cholesterol can have harmful effects.
• The lipoproteins that transport cholesterol are referred to by their size. The most commonly known are low-density lipoproteins (LDL) and high density lipoproteins (HDL). LDL is often referred to as the "bad" cholesterol and HDL as the "good" cholesterol.

Click the icon to see an image of cholesterol inside an artery.

Oxidation. The damaging process called oxidation is an important trigger in the atherosclerosis story.

• Oxidation is a chemical process in the body caused by the release of unstable particles known as oxygen-free radicals. It is one of the normal processes in the body, but under certain conditions (such as exposure to cigarette smoke or other environment stresses) these free radicals are over-produced.
• In excess amounts, they can be very dangerous, including causing damaging inflammation and even affecting genetic material in cells.
• In heart disease, free radicals are released in artery linings and oxidize low-density lipoproteins (LDL). The oxidized LDL is the basis for cholesterol build-up on the artery walls and damage leading to heart disease.

Inflammatory Response. For the arteries to harden there must be a persistent reaction in the body that causes on-going harm. Researchers now believe that this reaction is an immune process known as the inflammatory response. The following is one theory about how the inflammatory response contributes to heart disease:

• The injuries to the arteries during oxidation signal the immune system to release white blood cells (particularly those called neutrophils and macrophages) at the site. These factors initiate the inflammatory response.
• Macrophages literally "eat" foreign debris, in this case oxidized LDL cholesterol.
• The process converts LDL cholesterol into foamy material that attaches to the smooth muscle cells of the arteries. The cholesterol becomes mushy and accumulates on artery walls.
• Over time the cholesterol dries and forms a hard plaque, which causes further injury to the walls of the arteries.
• In response to this additional harm, the immune system releases other factors called cytokines. These are powerful inflammatory molecules that attract more white blood cells and perpetuate the whole cycle, causing persistent injury to the arteries.

Click the icon to see an image of atherosclerosis.

Evidence is growing that the inflammatory response may be present not just in local plaques in single arteries but that it occurs throughout the arteries leading to the heart.

Blockage in the Arteries. Eventually these calcified (hardened) arteries become narrower (a condition known as stenosis).

• As this narrowing and hardening process continues, blood flow slows and prevents sufficient oxygen-rich blood from reaching the heart.
• Such oxygen deprivation in vital cells is called ischemia. When it affects the coronary arteries, it causes injury to the tissues of the heart.
• Injured inner vessel walls also fail to produce enough nitric oxide, a substance critical for maintaining blood vessel elasticity. (Of note: nitric oxide has complex effects and, in fact, may have effects that increase inflammation in the arteries.)
• These narrow and inelastic arteries not only slow down blood flow but they also become vulnerable to injury and tears.

Click the icon to see an image of coronary artery blockage

The End Result: Heart Attack. Heart attack can occur as a result of one or two effects of atherosclerosis:

(1) If the artery becomes completely blocked and ischemia becomes so extensive that oxygen-bearing tissues around the heart die.

(2) If the plaque itself develops fissures or tears. Blood platelets adhere to the site to seal off the plaque and a blood clot (thrombus) forms. A heart attack can then occur if the formed blood clot completely blocks the passage of oxygen-rich blood to the heart.

Click the icon to see an image of the developmental process of atherosclerosis.

Angina

Angina is the primary symptom of coronary artery disease and, in severe cases, of a heart attack. It is typically experienced as chest pain and occurs when the heart muscle doesn't get as much blood (hence as much oxygen) as it needs for a given level of work (ischemia).

Click the icon to see an image about angina.

Angina is usually referred to as one of two states:

• Stable Angina (which is predictable).
• UnstableAngina (which is less predictable and a sign of a more serious situation).

Angina itself is not a disease. Much evidence exists, in fact, that onset of angina less than 48 hours before a heart attack may be protective, possibly by conditioning the heart to resist the damage resulting from the attack. Angina may be experienced in different ways and can be mild, moderate, or severe.

Click the icon to see an image of angina.

Specific factors are typically considered in determining whether symptoms indicate angina:

• Quality of the pain. It is typically described by patients with one or more adjectives similar to the following: squeezing, heavy, suffocating, or griplike. It is rarely described as stabbing or burning. Changing one's position or breathing in and out does not affect the pain. Note: the intensity of the pain does not always relate to the severity of the medical problem. Some people may feel a crushing pain from mild ischemia, while others might experience only mild discomfort from severe ischemia. In some cases, the patient experiences shortness of breath, fatigue, or palpitations instead of pain. In others, the ischemia is entirely asymptomatic ("silent ischemia").
• Duration. A typical angina attack lasts minutes. If it is more fleeting or lasts for hours, it is probably not angina.
• Location. Pain is usually in the chest under the breast bone. It often radiates to the neck, jaw, or left shoulder and arm. Less commonly, patients report symptoms that radiate to the right arm or back.
• Triggers of Angina. Angina is usually triggered by physical exertion, emotional stress, or exposure to cold.
• Factor that Relieve Angina. Angina is usually relieved by rest or by sublingual nitroglycerine.

Stable Angina. Stable angina is predictable chest pain. Although less serious than unstable angina, it can be extremely painful. It is usually relieved by rest and responds well to medical treatment (typically nitroglycerin). Any event that increases oxygen demand can cause an angina attack. Some typical triggers include the following:

• Exercise.
• Cold weather.
• Emotional tension.
• Large meals.

Angina attacks can occur at any time during the day, but a high proportion seems to take place between the hours of 6:00 AM and noon.

Unstable Angina and Acute Coronary Syndrome. Unstable angina is a much more serious situation and is often an intermediate stage between stable angina and a heart attack, in which an artery leading to the heart (a coronary artery) becomes completely blocked. A patient is usually diagnosed with unstable angina under one or more of the following conditions:

• Pain awakens a patient or occurs during rest.
• A patient who has never experienced angina has severe or moderate pain during mild exertion (walking two level blocks or climbing one flight of stairs).
• Stable angina has progressed in severity and frequency within a two-month period, and medications are less effective in relieving its pain.

Unstable angina is now usually discussed as part of a condition called acute coronary syndrome (ACS). ACS also includes people with a condition called NSTEMI (non ST-segment elevation myocardial infarction)---also referred to as non-Q wave heart attack. With NSTEMI, the blood tests suggest a developing heart attack. These conditions are less severe than heart attacks but may develop into full-blown attacks without aggressive treatment. [For additional information on this syndrome see Report #12 Heart Attack and Acute Coronary Syndrome.]

Prinzmetal's Angina. A third type of angina, called variant or Prinzmetal's angina, is caused by a spasm of a coronary artery. It almost always occurs when the patient is at rest. About two-thirds of people with it have severe atherosclerosis in at least one major blood vessel. Irregular heartbeats are common, but the pain is generally relieved immediately with standard treatment.

Click the icon to see an image of a coronary artery spasm.

Silent Ischemia. Some people with severe coronary artery disease do not experience angina pain, a condition known as silent ischemia, which some experts attribute to abnormal processing of heart pain by the brain. This is a dangerous condition because patients have no warning signs of heart disease. Some studies suggest that people with silent ischemia experience higher complication and mortality rates than those with angina pain. (Angina pain may actually protect the heart by conditioning it before a heart attack.)

Syndrome X. Syndrome X is a condition that occurs when patients have atypical angina chest pain, their electrocardiograms are abnormal during a stress test, but they have no signs of blocked arteries. It is more likely to occur in women. Although it unclear what causes this condition, sensitive imaging tests are suggesting that Syndrome X may also be caused by ischemia, as is angina.

Prognosis

Coronary artery disease is the leading killer in America of both men and women, responsible for nearly 530,000 deaths in 1999. On the positive side, the heart attack mortality rates have declined by over 24% between 1988 and 1999. (Because of the aging population, however, the absolute numbers of deaths fell by only about 6.8%). At this time, half of men and 63% of women who died of heart disease did not have angina or other warning symptoms prior to their fatal attacks. Although at this time no tests can reliably predict whether a heart attack will occur, experts estimate that up to 30% of fatal attacks and many follow-up surgeries could be avoided with healthy lifestyle changes and adherence to medical treatments. Two-thirds of patients who have suffered a heart attack, however, do not take the necessary steps to prevent another.

Determining the Degree of Severity

The following syndromes suggest different degrees of severity among patients with heart disease.

Stable Angina. This condition can usually be managed with lifestyle measures and medications, such as low-dose aspirin. The more severe the angina, however, the greater the chance for progressing to a more serious condition.

Acute Coronary Syndromes. This includes severe and sudden heart conditions that require aggressive treatment but have not developed into a full-blown heart attack.

Angina is a specific type of pain in the chest caused by inadequate blood flow through the blood vessels (coronary vessels) of the heart muscle (myocardium).

• Unstable angina is potentially serious and chest pain is persistent, but blood tests do not show markers for heart attack.
• With NSTEMI, the blood tests suggest a developing heart attack, but most likely, injury in the arteries is less serious than with a full-blown heart attack.

Most discussions of the treatment of unstable angina now refer to acute coronary syndrome. Physicians use the presence of a number of factors to help predict which ACS patients are most at risk for developing a heart attack. First, patients are categorized by whether they have a history of heart disease or risk factors for heart disease (such as diabetes, high blood pressure, peripheral artery disease), or other complicating conditions (e.g., lung disease, heart failure). The physician also gauges the severity of the angina. Some major studies further suggest that following factors further pose a high danger to patients:

• Age 65 years or older.
• Evidence of severe heart tissue injury.
• Being lighter weight.
• Having a history of severe chronic angina.
• Having abnormal lung sounds called rales (a bubbling or crackling sound) on examination.
• ST-segment deviation.
• Having either very slow or very fast heat beats.
• Having very low blood pressure.

Heart Attack. The full-blown heart attack occurs with severe damage to the heart, which blocks oxygen.

Click the icon to see an image about heart attack symptoms.

Click the icon to see an image about heart attack symptoms.

Risk Factors

About 12.6 million Americans currently have heart disease and 1.1 million people are expected to have a serious heart event each year. An estimated 25% of all Americans have one or more risk factors for heart disease. Most risk factors for heart disease are related to lifestyle and environmental factors.

Heart disease may be prevented by recommended healthy diet, regular exercise and to stop smoking if you are a smoker. Follow your health care provider's recommendations for treatment and prevention of heart disease.

Over the past decades, heart disease rates declined in both men and women as they quit smoking and improved dietary habits. This rate, however, has stabilized in recent years, most likely because of the dramatic increase in obesity in the US and other industrialized nations. There have also been minimal changes in other risk factors, including smoking, sedentary behavior, and blood pressure control. Some risk factors cannot be changed, including age, gender, and genetics. Nevertheless, their effects can still be modified with healthy lifestyle changes.

Nonmodifiable Risk Factors

Age. About 85% of people who die from heart disease are over the age of 65.

Gender. Coronary artery disease and heart attacks are much more common in middle-aged men. Women have, on average, ten to fifteen more years of heart-disease free life than do men, but as women age, they catch up to men. Women, in fact, are more likely to have angina than men. The American Heart Association reported in 2002 that four million women had angina compared to 2.4 million men. Younger women with heart disease often do not have the same symptoms as their male counterparts do and may be less likely to be diagnosed correctly. They are also more likely than men are to die after a heart attack. Evidence suggests that this is because women tend to be older and sicker than men at the time of a first attack. A 2002 study indicated, however, that with early aggressive treatment women with acute coronary syndrome do as well or better than men with the same condition and treatments.

Genetic Factors. Genetics are involved in increasing the likelihood of developing important risk factors (e.g., diabetes and high blood pressure). For example, one genetic variant called apolipoprotein E4 (ApoE4) affects cholesterol levels, particularly those associated with heart disease.

Ethnicity. Of all major ethnic groups, African American women face the highest risk for death from heart disease, and their rate of heart attacks is increasing. (Mortality rates in men do not differ much by race.) Native American men have a lower risk for heart disease than Caucasian men, and Hispanics have the lowest risk for heart disease of all major American population groups.

African Americans face a number of biologic and social dangers to their hearts:

• They have a higher prevalence of diabetes and hypertension than do Caucasians.
• They tend to have poorer diets, higher stress levels, and lack of access to health care.
• All African Americans risk discrimination in obtaining optimal treatments, but women may be at particular risk for unequal treatment. In one study in which female actors portrayed heart patients, African American women were 60% less likely to receive aggressive (and expensive) diagnostic tests than African American men or any Caucasians, even though they presented with similar symptoms.
• While African Americans comprise 13% of the US population, African Americans have comprised only 2% to 9% of subjects in most of the major research trials, and so knowledge about their specific risks is limited.
• Some African Americans with coronary artery disease appear to have a genetic trait that increases the danger of triglycerides, which may be particularly hazardous in women.
  

Click the icon to see an image about ethnicity and heart disease risks.

Cholesterol and Other Lipids

Cholesterol. Cholesterol is a white, powdery substance that is found in all animal cells and in animal-based foods (not in plants). In spite of its bad press, cholesterol is an essential nutrient necessary for many functions. When cholesterol levels rise in the blood, they can have dangerous consequences, depending on the type of cholesterol, particularly low-density lipoprotein (LDL) cholesterol.

For example, according to a 2000 study, men with cholesterol levels over 240 mg/dl have a risk that is 2.15 to 3.63 times higher than those whose cholesterol is below 200. A number of studies have now demonstrated that reducing LDL and total cholesterol levels and boosting HDL levels have improved survival and prevented heart attacks. Only 40% of people with high cholesterol levels actually die of heart disease, however, and experts cannot yet define which people are most at risk from high cholesterol levels.

Click the icon to see an image about serum cholesterol.

Triglycerides. Triglycerides are made up of fatty acid molecules and are the basic chemicals in animal and plant fats. Evidence now suggests that these molecules may be major trouble-makers for the heart. Triglycerides appear to interact with HDL cholesterol in such a way that HDL levels fall as triglyceride levels rise. Low HDL is known to be harmful to the heart. The harmful imbalance of high triglycerides with low HDL levels is also associated with obesity (particularly around the abdomen), insulin resistance, and diabetes. Some evidence further suggests that high triglycerides pose other dangers, regardless of cholesterol levels. Triglycerides, for example, may be responsible for blood clots that form and block the arteries. High triglyceride levels are also associated with the inflammatory response--the harmful effect of an overactive immune system that can cause considerable damage to cells and tissues, including the arteries.

Other Lipids. Elevated levels of other fatty molecules (lipids) are also now thought to be important indicators of heart disease risk. Studies are finding an elevated risk for angina and first heart attacks in people with elevated levels of lipoprotein(a), or lp(a). This lipoprotein falls somewhere in density between HDL and LDL and may have some properties that increase the risk for blood clots. Some experts suggest, however, that high levels of lp(a) may merely be markers of late-stage atherosclerosis, not a cause.

[For more information, see the Reports #23, Cholesteroland #43, Heart Healthy Diet.]

High Blood Pressure

High blood pressure, or hypertension, has long been a proven cause of coronary artery disease. People in normal health should aim for 139/89 mm Hg or less. Patients with certain health problems should aim lower (e.g., blood pressure in patients with kidney insufficiency, heart failure, or diabetes should be equal to or lower than 130/80 mm Hg).

Click the icon to see an image about hypertension.

Obesity and Metabolic Syndrome

American obesity is at epidemic levels in all age groups. The effect of obesity on cholesterol levels is complex. Although obesity does not appear to be strongly associated with overall cholesterol levels, among obese individuals triglyceride levels are usually high while HDL (beneficial cholesterol) levels tend to be low, both risk factors for heart disease. Obesity, in any case, has other effects (hypertension, increase in inflammation) that pose major risks to the heart.

Click the icon to see an image of childhood obesity.

Obesity is particularly hazardous when it is one of the components of the metabolic syndrome. This syndrome is diagnosed when three of the following are present: abdominal obesity, low HDL cholesterol, high triglyceride levels, high blood pressure, and insulin resistance. Metabolic syndrome is a pre-diabetic condition that is significantly associated with heart disease and higher mortality rates from all causes. A 2002 study estimated that 24% of the population now has this condition.

Obesity is highly linked with type 2 diabetes, in any case. And diabetes itself poses a significant risk for high cholesterol levels and heart disease.

[For more information, see the Report #53, Weight Control and Diet.]

Sedentary Lifestyle and Exercise

People who are sedentary are almost twice as likely to suffer heart attacks as are people who exercise regularly. Exercise has a number of effects that benefit the heart and circulation, including improving cholesterol and lipid levels, reducing inflammation in the arteries, assisting weight loss programs, and helping to keep blood vessels flexible and open. Studies continue to show that physical activity and avoiding high-fat foods are the two most successful means of reaching and maintaining heart healthy levels of fitness and weight.

Experts have been attempting to define how much exercises is needed to produce heart benefits.

Click the icon to see an image about exercise.

Click the icon to see an image about hypertension and lifestyle changes.

Some studies suggest that for the greatest heart protection, it is not the duration of a single exercise session that counts but the total daily amount of energy expended. Therefore, the best way to exercise may be in multiple short bouts of intense exercise, which can be particularly helpful for older people.

Important warning note: Sudden strenuous exercise (such as snow shoveling and mowing lawns) puts such people at risk for angina and heart attack. Activities that involve raising the arms above the head may also be risky. Patients with angina should never exercise shortly after eating. People with risk factors for heart disease should seek medical clearance and a detailed exercise prescription. And all people, including healthy individuals, should listen carefully to their bodies for signs of distress as they exercise. [Seethe Report #29, Exercise.]

Diabetes and Insulin Resistance

Heart disease and stroke are the leading causes of death in people with diabetes. People with diabetes are at risk for the following heart-risk conditions, and the more of these conditions they have, the worse the outlook:

• High blood pressure (hypertension). Up to 75% of cardiovascular problems in people with diabetes may be due to hypertension.
• Very unhealthy cholesterol and lipid balances (high triglyceride levels and lower high density lipoprotein).
• Blood clotting problems.
• Impaired nerve function (neuropathy), which can also damage the heart. In fact, some experts estimate that the mortality rates from neuropathy-related heart conditions ranges from 15% to 53%.

Diabetics with heart disease may have a higher risk for silent ischemia, a condition in which people have blocked arteries but do not experience the angina, the chest pain that signals heart disease [For more information, see the Reports #9, Diabetes: Type I or #60, Diabetes: Type II.]

Peripheral Artery Disease

Peripheral artery disease (PAD) occurs when atherosclerosis affects the extremities, particularly the feet and legs. In fact, the major risk factors for heart disease and stroke are also the most important risk factors for PAD. (The combination of such conditions with PAD also produces more severe forms of heart or circulatory disease.) Although signs of heart disease are detected in only 20% to 40% of patients with PAD after an initial diagnosis, studies suggest that when intense heart-diagnostics tests are performed, such as angiography or thallium stress tests, co-existing heart disease is detected in up to 90% of all PAD patients. [For more information see Report #102 Peripheral Artery Disease.]

Smoking

Smokers in their thirties and forties have a heart-attack rate that is five times higher than their nonsmoking peers. Cigarette smoking may be directly responsible for at least 20% of all deaths from heart disease, or about 120,000 deaths annually. Smoking cigars may increase the risk of early death from heart disease, although evidence is much stronger for cigarette smoking. Although heavy cigarette smokers are at greatest risk, a 2002 study suggested that people who smoke as few as three standard brand cigarettes a day are at higher risk for blood vessel abnormalities that endanger the heart. Regular exposure to passive smoke is now estimated to increase the risk of heart disease in the nonsmoker by between 25% and 91%, causing more than 30,000 deaths each year [For more information, see the Report #41 Smoking.]

Eating Habits

Eating habits can be protective or dangerous to the heart. Although the best diet is not clear for each individual, avoiding saturated fats and trans-fatty acids is recommended for everyone.

Stress and Psychologic Factors

Stress. The effects of mental stress on heart disease are controversial. Stress can certainly influence the activity of the heart when it activates the sympathetic nervous system (the automatic part of the nervous system that affects many organs, including the heart). This effect may support the association between acute stress and a higher risk for serious cardiac events, such as heart rhythm abnormalities and heart attacks, in people with heart disease. Nevertheless, not all studies report strong evidence that stress has any effect on the heart, particularly in people without any history of heart disease. [Seethe Report #31, Stress.]

Depression. Depression increases the severity of heart attack and may even impair a patient's response to medication for heart disease. Although people with heart disease may certainly become depressed, this does not explain entirely the link between the two problems. The data are now suggesting that depression itself may be a true risk factor for heart disease as well as its increased severity. A number of studies have suggested that depression has biologic effects on the heart, including blood clotting and heart rate. A study in 2001, for example, reported an association between depression and a greater risk for death from heart problems even in people without a history of heart disease. A 2002 study reported a higher risk for heart failure in women--although not in men--with depression. The more severe the depression, the more dangerous to the health, although even mild depression, including feelings of hopelessness, experienced over many years, may harm the heart, even in people with no early signs of heart disease. [Seethe Report #8, Depression.]

Alcohol

Benefits of Moderate Drinking.A number of studies have found heart protection from moderate intake alcohol (defined as one or two glasses a day). The benefits reported have been higher HDL levels, blood clot prevention, and anti-inflammatory properties. Although red wine is most often cited for healthful properties, any type of alcoholic beverage appears to have similar benefit.

Adverse Effects of Heavy Drinking on the Heart. It should be strongly noted that heavy drinking harms the heart. And, in fact, cardiovascular disease is the leading cause of death in alcoholics. Evidence suggests that people who consume more than three drinks a day have abnormal blood clotting factors. Heavy alcohol consumption can raise blood pressure and, particularly binge drinking, may also increase the risk for hemorrhagic stroke (caused by bleeding in the brain). Large doses of alcohol can trigger irregular heartbeats, which can be dangerous in people with existing heart disease.

Note: Alcohol increases the risk for breast cancer in women. Pregnant women and people who can't drink moderately should not drink at all.

Emerging or Possible Risk Factors for Heart Disease

Homocysteine and Vitamin B Deficiencies. Deficiencies in the B vitamins folate (known also as folic acid) and B12 have been associated with a higher risk for heart disease in some (but not all) studies. Such deficiencies produce elevated blood levels of homocysteine, an amino acid that has been associated with a higher risk for heart disease, stroke, and heart failure. Some studies in 2002, suggest that any risk posed by homocysteine or benefits from folic acid for heart disease are at most modest. One study, however, reported lower failure rates after angioplasty in patients who took folic acid and vitamins B12 and B6. And a major 2002 study suggested that lowering homocysteine levels with folic acid would reduce the risk for heart disease by 16% and stroke by 24%. More evidence is needed to determine whether homocysteine plays a causal role in cardiovascular disease and whether the B vitamins are protective. Folate improves blood flow through the arteries, which may be important for the heart, regardless of its effect on homocysteine.

Click the icon to see the benefits of vitamin B.

Click the icon to see the food sources of vitamin B.

C-Reactive Protein. C-reactive protein is a product of the inflammatory process and evidence increasingly supports the idea that high levels strongly predict future heart disease. Some studies suggest, in fact, that measuring this protein may be as useful for determining future risk for heart disease as measuring LDL cholesterol levels. It is not known if the protein plays any causal role or whether it is simply a marker for other factors in the disease process. More evidence is needed to determine the benefits of measuring C-reactive protein before it gains acceptance as a routine screening tool.

C. pneumoniae and Other Infectious Agents. Some microorganisms and viruses have been under suspicion for triggering the inflammation and damage in the arteries that contributes to heart disease. The strongest evidence to date supports a possible role from Chlamydia (C.) pneumoniae (a non-bacterial organism that causes mild pneumonia in young adults). C. pneumoniae has been detected in plaques in the arteries of patients with heart disease. In some studies, evidence of previous infection has been associated with a higher risk for heart events.

Other studies also suggest that cytomegalovirus (CMV), a common virus, may have similar effects. Many people, however, have been infected with these organisms and no clear association has been found with any of these infections.(H. pylori, the bacteria that causes peptic ulcers, has also been studied for heart effects, but evidence is very weak on any link.)

Periodontal Disease. A number of studies now strongly supports an association between periodontal disease and cardiovascular disorders. According to a 2003 major analysis, periodontal (gum) disease is associated with a 20% higher risk for ischemic stroke and heart disease. (The added risk may be even higher in adults under 65.) Recent evidence is pointing to the inflammatory response as the common element.

Click the icon to see an image of gum disease.

Anemia. Anemia has adverse effects on the heart and increases the severity of cardiac conditions, including heart failure and heart attacks. And, in fact, blood transfusions after a heart attack improve survival rates in elderly patients who are anemic. A 2002 study further suggested that anemia might even be a risk factor for heart disease itself.

Iron Overload. An inherited disease called hemochromatosis, in which the intestinal tract absorbs too much iron from food, has been associated with atherosclerosis and heart attack. About 10% of Caucasians carry the gene. There is no strong evidence that excess iron levels in people without hemochromatosis can contribute to heart disease.

Sleep Apnea. Obstructive sleep apnea is a condition in which tissues in the upper throat collapse at intervals during sleep, thereby blocking the passage of air. It has been strongly associated with high blood pressure and obesity, but is also associated with heart disease and heart attacks, regardless of these risk factors. Some evidence suggests that obstructive apneas cause an increase in stiffness and inflammation in the arteries.

Conditions Associated with Heart Disease

Some inborn or natural conditions are not risk factors themselves but have been associated with a higher incidence of heart disease or its consequences:

Factors Before Birth and In Infancy. Low weight at birth and in the womb has been associated with later heart disease in a few studies. Some suggest, however, that this may just reflect poor nutrition in the mother, which appears to affect life-long risk. A 2000 British study reinforced the idea that pre-birth or other early events have little significant effect on heart disease risk in later life.

Seasonal Differences. More deaths from heart disease occur in December and January and fewest in the summertime. Although lower temperatures and snow shoveling may play a role in some cases, more winter deaths have been reported even in warm regions. Holiday stress or fewer daylight hours have been suggested as other reasons for these higher winter rates.

Physical Characteristics. Male pattern baldness, hair in the ear canals, and creased earlobes are associated with a higher risk for heart disease in white males. (Interestingly, in African American men, of these factors, only creased earlobes were associated with a higher risk in one study.)

Click the icon to see an image of an ear lobe crease.

Air Pollution. A 2000 study suggested that air pollution is linked to a higher risk of death from heart disease as well as lung disease and all other causes.

Diagnosis

There are many tests are available to diagnose possible heart disease. The choice of which (and how many) tests to perform depends on factors such as the patient's risk factors, history of heart problems, and current symptoms. Usually the tests begin with the simplest and may progress to more complicated ones. Specific tests depend on the patient's particular condition and the physician's assessment.

Routine Tests to Determine Risk for Heart Disease

Physicians routinely check for high blood pressure and unhealthy cholesterol levels in all older adults. Specific tests are also important in people who may have risk factors or symptoms of diabetes. Other tests being investigated for indications of risk include blood tests for homocysteine, the protein albumin, and blood clotting factors, especially fibrinogen.

Electrocardiograms (ECGs)

An electrocardiogram (ECG) measures and records the electrical activity of the heart.

The electrocardiogram (ECG, EKG) is used extensively in the diagnosis of heart disease, from congenital heart disease in infants to myocardial infarction and myocarditis in adults. Several different types of electrocardiogram exist.

Between 25% and 50% of people who suffer from angina or have silent ischemia, however, have normal ECG readings. The waves measured by the ECG correspond to the contraction and relaxation pattern of the different parts of the heart. Specific waves seen on an ECG are named with letters as follows:

• The P wave is associated with the contractions of the atria (the two chambers in the heart that receive blood from outside).
• QRS. The QRS is a series of waves associated with ventricular contractions. (The ventricles are two major pumping chambers in the heart.)
• T and U. These waves follow the ventricular contractions.

The most important wave patterns in diagnosing and determining treatment for heart disease and heart attack are called ST elevations and Q waves.

• A depressed or horizontal ST wave suggests some blockage and the presence of a heart disease, even if there is no angina present. (This finding, however, is not very accurate, particularly in women, and can occur without heart problems).
• ST elevations and Q waves are the most important wave patterns in diagnosing and determining treatment for a heart attack. They suggest that an artery to the heart is blocked and that the full thickness of the heart muscle is damaged. (ST segment elevations do not always mean the patient has a heart attack. Also some heart attack patients do not have elevated ST segments. Other factors are important in making a diagnosis.)

Exercise Stress Test

The primary value of exercise stress tests is not to detect coronary artery disease in people without symptoms but to help determine the severity and predict the outcome of an existing heart condition. It is considered for the following people:

• Patients with possible or probable angina and low or intermediate risk for adverse heart events.
• Selected adults who do not have symptoms of heart disease but are at moderate risk to high risk for developing heart disease (a 10% to 20% chance within ten years). In fact, heart blockage without angina (silent ischemia) may suggest a more severe condition, at least in men.

Basic Procedure. A stress test (exercise tolerance test) monitors the patient's heart rhythms, blood pressure, and clinical status. It can tell how well the heart handles work and if parts of the heart have decreased blood supply. A typical stress test involves the following:

• The patient walks on a treadmill or rides a stationary bicycle. Exercise continues until the heart is beating at least 85% of its maximum rate, until symptoms of heart trouble occur (e.g., changes in blood pressure, heart rhythm abnormalities, angina, fatigue) or the patient simply wants to stop.
• For patients who cannot exercise, the physician may administer dobutamine or arbutamine, which are agents that simulate the stress of exercise.
• An ECG is used to monitor heart rhythms during a stress test. (An echocardiogram or more advanced imaging technique may also be used to visualize the actions of the heart and blood flow.)

More than 25% of patients stop exercising before they reach their own maximum limits because of fear of a heart event. Patients should be reassured that the activities performed in the test under the guidance of a professional are safe.

Interpreting Results. To accurately assess heart problems, experts look at a number of findings derived from the ECG and other tools during exercise. They include the following:

• Exercise capacity. This is a gauge of a person's capacity to reach achieve certain metabolic rates.
• Heart rate and ST waves. On ECGs, physicians specifically look for abnormalities in part of the wave tracing called an ST segment. A certain type of ST segment depression suggests the presence of heart disease, but this finding is not very sensitive, particularly in women. Drugs and other medical conditions can also effect the ST segment. Using a measurement that adjusts the ST segment to heart rate is improving accuracy.
• Dukes Treadmill Score. This is an important score using the number of minutes a patient can exercise and other factors that are present in patients with exercise-limiting angina.
• Heart rate recovery.
• Chronotropic index. This is the percentage of the heart-rate reserve that is used during the exercise. A result of 80% or less suggests a significant risk for serious heart problems in most patients.
• Changes in systolic blood pressure.

Using these and other factors, physicians can determine risk fairly accurately, particularly for men of any age with chronic stable angina. The test has limitations, however, and some are significant. For example, a 2002 study indicated that in patients with suspected unstable angina the chances for a future adverse heart event remain high even if the exercise test shows low risk. In addition, for many reasons, the test is less accurate in women, and an echocardiogram may be a more accurate procedure for them. About 10% of patients, particularly younger people, will have false positive test results. In such cases, test results indicate abnormalities when there are no heart problems.

Echocardiograms

An echocardiogram is a noninvasive test that uses ultrasound images of the heart. This test is more expensive than an ECG, but it can be very valuable, particularly when used with a stress test, to detect the location and extent of heart muscle damage. It appears to be more accurate for women than ECG stress tests, but at this time it is not routinely recommended as a replacement for most women.

Computed Tomography

Computed tomography (CT) scans used alone or with ECG may be used to detect calcium deposits on the arterial walls, strong indicators of current and future coronary artery disease. In fact, the absence of calcification in the arteries suggests virtually no risk at all for heart disease. (It should be noted that the presence of calcium does not always signify significant narrowing in the arteries.)

Click the icon to see an image of a CT scan.

Advanced CT techniques are improving accuracy:

• Electron Beam Computed Tomography. Electron beam computed tomography (EBCT) (formerly called ultrafast computed tomography (CT) scans) is a CT technique that scans the heart so quickly that the motion of the heart appears frozen. This procedure identifies calcification and stratifies cardiac risk accurately in 80% to 92% of cases.
• Helical Multislice Computed Tomography. Another CT technique called helical multislice computed tomography (MSCT) angiography is able take pictures of the entire heart in one millimeter slices in the time it takes for a patient to hold one breath. It is highly accurate but exposes the patients to a higher radiation levels than EBCT.

Some expert groups recommend CT scans in selected patients who have an intermediate risk (i.e., a 10% to 20% chance of heart disease within 10 years). In fact, one study suggested that in this group, EBCT would be a better first choice than exercise stress testing. In general, the use of these expensive imaging tests are probably not very useful in people at low- or high risk. (In people with high risk the additional information from these tests would not add much value.) More research is needed to determine the benefits of CT scanning in specific individuals.

Radionuclide Imaging

Radionuclide procedures use imaging techniques and computer analyses to plot and detect the passage of radioactive tracers through the region of the heart. Such tracing elements are typically given intravenously. Radionuclide imaging is useful for the following situations:

• To diagnose or determine the severity of unstable angina when less expensive diagnostic approaches are unavailable or unreliable.
• To determine the severity of chronic coronary artery disease.
• To assess the success of surgeries for coronary artery disease.
• To diagnose a heart attack.

Various imaging techniques may be used with radionuclide procedures, including the following:

• Planar scintigraphy. This uses a special overhead camera and is the oldest scanning technique.
• Single-photon emission computed tomography (SPECT) uses a camera that rotates around the patient and takes pictures of "slices" of the heart. It is more accurate than planar imagine in precisely locating problems in the arteries.
• Positron-emission tomographic (PET) scanners employ multiple rings that surround the patients, which detect and record atomic particles (photons) that are emitted by the tracer elements (such as radioactive oxygen, nitrogen, or carbon). It is more expensive and less widely available than SPECT.

Myocardial Perfusion (Blood Flow) Imaging Test (also called the Thallium Stress Test). This radionuclide test is typically used with an exercise stress test to determine blood flow to the heart muscles. It is a reliable measure of severe heart events. It may be prove to be useful in determining the need for angiography if CT scans have detected calcification in the arteries. About a minute before the patient is ready to stop exercising, the physician administers a radioactive tracer (e.g., thallium 201 or, more often now, sestamibi) into the intravenous line. Immediately afterward the patient lies down and heart scans are performed, usually with a planar scintigraphy or with SPECT. If the scan detects damage, more images are taken three or four hours later. Damage due to a prior heart attack will persist when the heart scan is repeated. Injury caused by angina, however, will have resolved by that time.

Radionuclide Angiography. This is a technique for visualizing the chambers and major blood vessels of the heart. It uses an injected radioactive tracer and can be performed during exercise, at rest, or with use of stress-inducing drugs.

Click the icon to see an internal view of the heart.

It is an excellent test for assessing the heart's pumping action both at rest and during exercise and for determining the severity of coronary artery disease. It is an alternative to echocardiograms in certain situations.

Other Investigative Noninvasive Imaging Techniques

Magnetic Resonance Angiography (MRA). MRA is a very promising noninvasive imaging technique that can provide three-dimensional images of the major arteries to the heart and identify disease with high accuracy. Experts believe this approach will eventually be a good alternative to angiography.

Click the icon to see an image of a MRI.

Angiography

Angiography is an invasive test. It is used for patients who show strong evidence for severe obstruction on stress and other tests and for patients with acute coronary syndrome.

• A narrow tube is inserted into an artery, usually in the leg or arm, and then threaded up through the body to the coronary arteries.
• A dye is injected into the tube and an x-ray records the flow of dye through the arteries.

Click the icon to see an image of dye in the coronary artery.

• This process provides a map of the coronary circulation, revealing any blocked areas.

Major complications include stroke, heart attacks, and kidney damage. These risks are very low (about 0.1%), however, if the procedure is done in an experienced medical center (one that performs at least 300 of these operations every year). Allergic reactions can also occur. The procedure is expensive, and between 10% to 30% of patients who have this procedure have normal results.

Biologic Markers

When heart cells become damaged, they release different enzymes and other molecules into the blood stream. Elevated levels of such markers of heart damage in the blood or urine may help predict a heart attack in patients with severe chest pain and help determine treatment. Some of these factors currently measured include the following:

• Troponins. The proteins cardiac troponin T and I are released when the heart muscle is damaged. Both are proving to be among the best diagnostic indications of heart attacks. They are proving to identify many individuals with ACS, such as older women with serious other conditions, who might otherwise be misdiagnosed.
• Creatine kinase myocardial band (CK-MB). CK-MB has been a standard marker but the MB fraction is not as accurate as troponin levels, since elevated levels can appear in people without heart injury.
• Myoglobin. Myoglobin is a protein found in heart muscles. It is released early in the injured heart and it may be useful in combination with CK-MB and the troponins.

Managing Heart Disease

The approach for managing any degree of coronary artery disease involves lifestyle changes. Depending on severity and individual conditions, patients may need one or more medications, surgery, or both.

Heart disease may be prevented by recommended healthy diet, regular exercise and to stop smoking if you are a smoker. Follow your health care provider's recommendations for treatment and prevention of heart disease.

Experts have come up with a mnemonic device (ABCDE) for remembering ten factors that are fundamental for management of stable angina and coronary artery disease:

A. Aspirin and anti-angina drugs.

B. Blood pressure and beta-blockers.

C. Cholesterol-lowering agents (typically statins) and cigarettes (stopping).

D. Diet and diabetes control.

E. Exercise and education.

Unstable angina is now usually classified with non-Q myocardial infarction as acute coronary syndrome (ACS) in professional discussions of treatments. ACS usually requires more aggressive treatments, including surgery. [ACS is more fully discussed in Well-Connected Report #12 Heart Attack and Acute Coronary Syndrome.]

Click the icon to see an image about angina.

Important Medications and The Polypill

The most important medications for individuals at high risk for heart disease are aspirin, beta-blockers, and cholesterol-lowering agents (especially statins). A disturbing 2003 study reported that such medications were underused in women who needed them, including women with the greatest risks for heart attack. (Other medications are also necessary for people with specific risk factors, such as high blood pressure and diabetes.)

The Polypill. An intriguing study in 2003 suggested that taking a single daily pill containing a number of heart- and circulatory protective agents could largely prevent heart attacks and stroke in nearly everyone over 55. It would contain the following:

• A statin (such as Lipitor or Zocor). Statins inhibit the liver enzyme hMG-CoA reductase, which is used in the manufacturing of cholesterol. They are the most effective drugs for the treatment of high cholesterol and, according to a 2003 major analysis over 200 studies, they reduce risk for heart events by 60% and stroke by 17%.
• Three blood pressure lowering agents in low doses (e.g., a thiazide diuretic, a beta blocker, and an ACE inhibitor). An important study in 2003 suggested that this approach to lowering blood pressure may reduce the risk of stroke by 63% and heart disease by half. Using low doses of single agents also reduces the risk for side effects.
• Aspirin (low-dose).
• Folic acid. Folic acid lowers homocysteine levels, an amino acid believed to increase the risk for heart disease and stroke.

The experts in the study believed this combination would reduce ischemic heart events by 88% and stroke by 80%. Only 1% and 2% of the population would have to withdraw because of side effects. More research on this is certainly warranted.

Anti-Clotting Medications

Anti-clotting agents that inhibit or break up blood clots are used at every stage of heart disease. They are generally either anti-platelet agents or anticoagulants. Investigators are also studying combinations of anti-clotting agents, which may be useful in patients with severe heart disease. All anti-clotting therapies carry the risk of bleeding, which can lead to dangerous situations, including stroke.

A thrombus is a blood clot that forms in a vessel and remains there. An embolism is a clot that travels from the site where it formed to another location in the body. Thrombi or emboli can lodge in a blood vessel and block the flow of blood in that location depriving tissues of normal blood flow and oxygen. This can result in damage, destruction (infarction), or even death of the tissues (necrosis) in that area.

Anti-platelet Drugs. These agents prevent formation of blood platelets. Platelets are very small disc-shaped blood cells that are important for blood-clotting .

• Aspirin. Aspirin is an antiplatelet agent. It is the most common anti-clotting drug. Nearly anyone with existing heart disease or at risk for it is advised to take a low-dose aspirin every day.
• Glycoprotein IIb/IIIa Inhibitors. These potent blood-thinning agents include abciximab (ReoPro, Centocor), eptifibatide (Integrilin), tirofiban (Aggrastat), and lamifiban. They are administered intravenously in the hospital and are being used after surgery angioplasty and stent placement. Other benefits are not yet clear.
• Thienopyrindines. Clopidogrel (Plavix) and ticlopidine (Ticlid) are potent oral platelet inhibitors.

Click the icon to see an image about blood.

Anticoagulants. Anticoagulants help thin blood and include the following:

• Heparin. Standard, or unfractionated, heparin; Low-molecular weight heparin (LMWH), which include Enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep).
• Warfarin (Coumadin).
• Direct thrombin inhibitors. They include argatroban (Novastan), danaproid (Orgaran), and lepirudin (Refludan).

Anti-Platelet Drugs

Aspirin. Aspirin is known as a nonsteroidal anti-inflammatory agent (NSAID). It inhibits blood platelets, which are major clotting factors, from sticking together to form a blood clot. A daily low-dose aspirin (75 to 160 mg) is usually the first choice for preventing heart disease in high-risk individuals. It is proving to prevent heart attacks and death in people with existing heart disease and a history of heart attack. Aspirin alone has been reported to reduce risk of death from heart attack by 25% to 50%, at least in men. (Whether it has significant heart benefits for women is less clear.) It also reduces the risk for stroke.

Click the icon to see an image about stomach ulcers.

Side effects for anyone from prolonged use of aspirin may include gastrointestinal ulcers and bleeding. (There may be a slight increased risk for bleeding-related strokes, which are very uncommon, however. Furthermore, this risk may be outweighed by protection against the more common stroke, which is caused by artery blockage.)

Of great concern is research suggesting certain interactions that might reduce the benefits of aspirin or other heart protective drugs. One 2000 report suggested that taking ibuprofen (Advil) right before taking an aspirin may inhibit aspirin's benefits on the heart. Both are drugs known as NSAIDs. Some studies suggest that both these NSAIDs along with others, such as naproxen (Aleve), interfere with diuretics and ACE inhibitors. Recent use of NSAIDs, in fact, has been associated with a higher risk of hospitalization in heart failure patients, especially those taking diuretics or ACE inhibitors. An encouraging 2003 analysis, however, reported that ACE inhibitors still significantly reduced risks for adverse heart events, including hospitalizations for heart failure, regardless of whether or not the patients were also taking aspirin.

Clopidogrel and Other Thienopyrindines. Clopidogrel (Plavix, Iscover) is an oral platelet inhibitor called a thienopyrindine. When taken with aspirin, this agent is proving to significantly reduce the risk for heart attack and stroke in patients with acute coronary artery syndrome (unstable angina or early signs of heart attack). Clopidogrel is also recommended for patients who are undergoing angioplasty. If possible, however, it should be delayed for at least five days in patients undergoing bypass surgery because of a significant bleeding risk.

Click the icon to see an image of the developmental process of atherosclerosis.

Ticlopidine (Ticlid) is another effective thienopyrindine, but has largely been replaced by clopidogrel because of dangerous blood disorders, particularly thrombocytopenia.

Glycoprotein IIb/IIIa Inhibitors. Glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors are potent drugs that thin blood by blocking platelets (clotting factors in the blood). They are administered intravenously and include abciximab (ReoPro, Centocor), eptifibatide (Integrilin), tirofiban (Aggrastat), and lamifiban. GPIIb/IIIa inhibitors are used for acute coronary syndrome (ACS), not for management of day-to-day angina. Studies on their benefits have been mixed, depending on how they are used. Evidence suggest their use in the following situations:

• These agents are very beneficial when used with angioplasty and coronary stent placement in patients with acute coronary artery syndromes (ACS). They may be most effective in such cases if administered during angioplasty, rather than beforehand.

Click the icon to see an image about atherosclerosis.

• Early use of these drugs in the emergency room appears to benefit selected patients with high-risk ACS (such as those who have high levels of troponins--markers of heart damage).

As in heparin there is a risk for thrombocytopenia, a drastic reduction in platelets that can cause severe bleeding. Certain patients at highest risk for this complication are thin, elderly, nonwhite, and have more than one heart risk factor.

Note: Oral GPIIb/IIIa inhibitors (called super-aspirins) have been under investigation but many were withdrawn after reports of significantly high mortality rates.

Anticoagulants

Anticoagulants are drugs that prevent or delay blood coagulation and the formation of blood clots. Heparin has been the standard anticoagulant, but a number of agents are now available that are proving to be better choices in many cases.

Standard (Unfractionated) Heparin. The heparin referred to as unfractionated heparin has been the standard for year, used alone or in combination with aspirin for managing unstable angina. It is no longer the recommended first choice, however, for this patient group. It must be intravenously administered and monitored with frequent blood tests. The major complication is thrombocytopenia (a severe drop in platelets). This condition is extremely serious and can become life-threatening, particularly with bleeding in various body tissues. Alternatives include low-molecular weight heparin and direct thrombin inhibitors.

Low-Molecular Weight Heparin. Enoxaparin (Lovenox), dalteparin (Fragmin), tinzaparin (Innohep) are drugs known as low-molecular weight heparins (LMWHs). Many physicians now recommend these agents over standard heparin for patients with unstable angina (unless bypass surgery is being planned). They have similar rates of survival, recurring angina, and bleeding as standard heparin. However, they appear to pose lower risks for heart attack, repeat angioplasties, and thrombocytopenia. They require injections but do not require the ongoing monitoring that standard heparin does. Patients may even be able to self-administer LMWHs as people with diabetes do insulin.

Warfarin. Warfarin (Coumadin) is an oral anticoagulant. It prevents clots by inhibiting vitamin K. Warfarin is used with aspirin after a heart attack to prevent another one and to prevent blood clots in patients with atrial fibrillation. Warfarin is also proving to be more effective than aspirin for preventing heart attacks in patients with acute coronary syndromes. There is even some evidence that it might prevent disease progression itself in the arteries of the heart. Warfarin therapy must be monitored with frequent blood tests. In one study, bleeding occurred in 1% of patients taking aspirin or warfarin alone and in 2% taking a combination.

Direct Thrombin Inhibitors (DTIs). Direct thrombin inhibitors are a more recent group of anti-coagulants. The first DTI hirudin, a natural substance derived from the saliva of leeches. New forms include argatroban (Novastan), bivalirudin (Angiomax), danaproid (Orgaran), lepirudin (Refludan), desirudin (Revasc), inogatran, and efegatran. Ximelagatran (Exanta) is a new oral DTI that may prove to be specifically effective. Many of these agents used along with warfarin are proving to be good options for patients who develop thrombocytopenia with heparin use. DTIs may prove to be superior to standard heparin for patients with acute coronary syndrome.

Other Medications

Nitrates have been used in the treatment of angina for over a hundred years. These drugs release nitric oxide, thereby relaxing the smooth muscles in blood vessels.

Many nitrate preparations are available; the most commonly used are nitroglycerin, isosorbide dinitrate, and isosorbide mononitrate. Nitrates can be absorbed from the gastrointestinal tract (oral tablet), skin (ointment or patch), and from under the tongue (sublingual tablet or spray).

Rapid Acting Nitrates. Rapid-acting nitrates are used to treat acute attacks. Nitroglycerin is the most widely used agent for this purpose. It can be administered under the tongue (sublingually or as a spray) or pocketed between the upper lip and gum (buccally) and can relieve angina within minutes. The procedure for taking nitroglycerin during an attack is as follows:

• At the onset of an angina attack, the patient administers one sublingual or buccal tablet or one metered dose of the spray.
• If the pain is not relieved within five minutes the patient takes a second dose; a third can be taken after another five minutes if symptoms persist.
• If pain continues after a total of three doses in 15 minutes, the patient should go to the nearest emergency room at once.

Nitroglycerin is very volatile so its potency can be easily lost. A patient should take the follow precautions:

• Keep no more than 100 tablets on hand stored in their original container.
• When first opened, the cotton filler should be discarded, and the cap screwed on tightly immediately after each use.
• A supply should always be kept close at hand in case of an attack, with the rest kept in a cool dry place.

Intermediate to Long-Term Nitrates. Sublingual tablets of isosorbide dinitrate have a somewhat slower onset of action than nitroglycerin and are useful for preventing exercise angina. Ointments, patches, and oral tablets are used for longer-term prevention of angina attacks:

• Transdermal patches are applied in the morning to any hair- or injury-free area on the chest, back, stomach, thigh, or upper arm. Hands should be washed after each patch or ointment application and sites of application should be rotated to avoid skin irritation.
• Nitroglycerin ointment is applied by measuring out an even amount on an applicator paper and then placing, not rubbing or massaging, it on the chest, stomach, or thigh. Any ointment that remains from the previous application should be removed.

Long-acting forms may lose their effectiveness over time, so physicians generally schedule nitrate-free breaks to prevent tolerance. Some concern exists that nitrate-free periods might increase the risk for angina and adverse heart events. One large study, however, found no increased danger when patients used a nitroglycerine patch with scheduled breaks. The use of drugs known as ACE inhibitors, normally used for high blood pressure, may help prevent tolerance to nitrates. (Some studies suggest that vitamin C or E might also help.)

Side Effects. Nitrates have many side effects, some of which can be serious.

Common side effects of nitrates include headaches, dizziness, nausea and vomiting, blurred vision, fast heartbeat, sweating, and flushing on the face and neck. Low blood pressure and dizziness can be relieved by lying down with the legs elevated. Note: These effects can be significantly worsened by alcohol, beta-blockers, calcium channel blockers, sildenafil (Viagra), and certain antidepressants. Your doctor may prescribe medicines to lessen these side effects. Contact your doctor if these side effects are persistent or severe.

Serious side effects requiring immediate medical help include fever, joint or chest pain, sore throat, skin rash (especially on the face), unusual bleeding or bruising, weight gain, and swelling of the ankles.

Withdrawal. Withdrawal from nitrates should be gradual. Abrupt termination may cause angina attacks.

Beta-Blockers

Beta-blockers are useful for preventing angina attacks and reducing high blood pressure. They reduce the oxygen demand of the heart by slowing the heart rate and lowering blood pressure. They are now well known for reducing deaths from heart disease and from heart surgeries, including angiography and coronary bypass. Beta-blockers are the drugs of choice for older patients with stable angina and may also be beneficial for people with silent ischemia. They can be used effectively in combination with nitrates or calcium channel blockers. Of great concern is a 2003 study reporting their underuse in women, including those at very high risk for heart attack.

Of note: Beta-blockers are less useful for the treatment of Prinzmetal's angina. Also, in patients with high blood pressure, other drugs, notably diuretics, are associated with higher survival rates.

Specific Beta-blockers. Beta-blockers include propranolol (Inderal), labetalol (Normodyne, Trandate), acebutolol (Sectral), atenolol (Tenormin), metoprolol (Toprol-XL, Lopressor), and bisoprolol (Zebeta). Carvedilol (Coreg), a newer agent known as a nonselective beta-blocker, appears to be as safe as the older beta-blockers and may prove to have additional advantages. A nasal spray form of propranolol appears to be very beneficial in helping to reduce exercise-induced angina attacks.

Side Effects. In spite of the significant benefits of these agent, they are greatly underused, possibly because of reports of distressing side effects that include the following:

• Some beta-blockers lower HDL cholesterol (the beneficial cholesterol) by about 10%. The effect is most marked in smokers.
• Fatigue and lethargy are the most common neurologic side effects. Some people experience vivid dreams and nightmares, depression, and memory loss.
• Dizziness and lightheadedness, especially when getting up from a lying down position.
• Exercise capacity may be reduced.
• Sexual dysfunction has been reported but actual studies report only a slight increased risk.
• Other side effects may include cold extremities, asthma, decreased heart function, and gastrointestinal problems (e.g., heartburn, gas, diarrhea, or constipation). Although depression has been reported, it does not appear to occur at any higher rates than in the general population.

If side effects occur, the patient should call a physician, but it is extremely important not to stop the drug abruptly. Angina, heart attack, and even sudden death have occurred in patients who discontinued treatment without gradual withdrawal.

Calcium Channel Blockers (CCBs)

Calcium channel blockers reduce heart rate and slightly dilate the blood vessels of the heart, thereby decreasing oxygen demand and increasing oxygen supply. They also reduce blood pressure. CCBs vary chemically, however, and although some are helpful, others may even be dangerous for certain patients with angina.

Click the icon to see an image of the anterior heart arteries.

• Long-acting nifedipine (Adalat, Procardia) and nisoldipine (Sular) and newer CCBs, such as amlodipine (Norvasc) and nicardipine (Cardene), may be beneficial for some patients with angina. They can be considered alone for patients who cannot tolerate beta-blockers, but may provide the best results when used in combination with a beta-blocker. Studies suggest that they reduce the need for repeat angioplasties. There effects on other outcomes, including mortality rates and heart attack, are less clear.
• Short-acting CCBs, including short-acting forms of verapamil, diltiazem, nifedipine, and nicardipine are helpful for many patients with Prinzmetal's angina. It should noted, however, that short-acting forms of certain CCBs, such as nifedipine and nisoldipine, have been associated with severe and even dangerous side effects, including an increase in heart attacks and sudden death in some patients with unstable angina. They also increase the risk for adverse effects in patients with stable angina. Short-acting CCBs are, therefore, not used for stable or unstable angina.

There is no strong evidence that any calcium channel blockers improve survival rates. Overdose can cause dangerously low blood pressure and slow heart beats. Patients with heart failure have a higher risk for death with these agents and should not take them. No one taking any calcium channel blocker should withdraw abruptly because such action could dangerously increase the risk of high blood pressure. Note: Grapefruit and Seville, or sour, oranges (often used in marmalade), boosts the effects of CCBs, sometimes to toxic levels. (Regular oranges do not appear to pose any hazard.)

Angiotensin Converting Enzyme (ACE) Inhibitors

Angiotensin converting enzyme (ACE) inhibitors are important heart protective drugs, particularly for people with diabetes. They reduce the production of angiotensin, a chemical that causes arteries to constrict, and so are commonly used to lower blood pressure. Evidence now further suggests that they have additional protective effects, however, and that they reduce risk for heart attack, stroke, complications of diabetes, and death in patients at high risk for heart disease. (Unlike beta-blockers and nitrates, however, calcium channel blockers have no specific effects on angina.)

ACE inhibitors include captopril (Capoten), ramipril (Altace), enalapril (Vasotec), quinapril (Accupril), benazepril (Lotensin), perindopril (Aceon), and lisinopril (Prinivil, Zestril).Most studies have been conducted using ramipril, but other agents are also promising.

Some research has also suggested that ACE inhibitors improved heart and lung muscle function, which should be very helpful for patients with existing heart failure. (A 2002 study also indicated that these agents may help preserve general muscle strength in older individuals.)

Side Effects. Side effects of ACE inhibitors are uncommon but may include an irritating cough, excessive drops in blood pressure, and allergic reactions. Of great concern is research suggesting that aspirin interfere with ACE inhibitors (and other so-called NSAIDs) increases the risk for heart failure in patients taking ACE inhibitors. An encouraging 2003 analysis, however, reported that ACE inhibitors still significantly reduced risks for adverse heart events, including hospitalizations for heart failure, regardless of whether the patients also took aspirin or not.

Statins and Other Cholesterol and Lipid-Lowering Agents

In 2002, The National Cholesterol Education Program's Adult Treatment Panel issued its latest recommendations. The results of these guidelines would increase the number of Americans taking LDL-lowering agents from 15 million to 36 million, with significant increases occurring in people under 45 and over 65 years old and among men in all age groups. A number of agents are available for lowering cholesterol and other dangerous fat molecules (lipids).

Click the icon to see an image of cholesterol.

They include the following:

• Statins are now the standard agents for most people who require LDL-lowering therapy. Bile-acid binding resins or niacin may be considered. (Another LDL-lowering agent, probucol, is usually limited to people with genetic disorders that cause severely high cholesterol levels.) If LDL-goals are not achieved, combinations of a statin with a bile-acid resin such ezetimibe (Zetia) or niacin should be considered.
• Fibrates or niacin are beneficial for people who need to lower triglycerides and increase HDL.

[For more detailed information on other cholesterol-lowering agents and cholesterol in general see the Well-Connected Report, Cholesterol, Other Lipids, and Lipoproteins.]

Statins. Statins inhibit the liver enzyme HMG-CoA reductase, which is used in the manufacturing of cholesterol. They are the most effective drugs for the treatment of high cholesterol, and, according to a 2003 major analysis over 200 studies, they reduce risk for heart events by 60% and stroke by 17%.

Two studies in 2002 and 2003, however, muddied these positive findings. In one, lowering moderately-high LDL cholesterol levels with a statin did not improve survival rates among high-risk patients. Some experts believe that statin treatment was not aggressive enough in this study. In the other 2003 study, however, cholesterol levels--whether high or low--had no effect on mortality rates among heart attack survivors over 65. More research is needed on these findings.

Still, most experts estimate a 25% or more reduction in mortality rates when patients take statins after a heart attack. They may even become important agents for many people at risk for heart disease who have normal cholesterol levels or below. In fact, the benefits of statins may go beyond simply improving cholesterol levels.

Statins include lovastatin (Mevacor), simvastatin (Zocor), and pravastatin (Pravachol). These are the most studied statins and have proven effectiveness and good safety record. Newer synthetic statins including fluvastatin (Lescol), atorvastatin (Lipitor), and rosuvastatin (Crestor) are proving to be very beneficial.

In many studies, the side effects reported by statin users were nearly the same as those taking placebo (inactive agents). Those reported include gastrointestinal discomfort, headaches, skin rashes, muscle aches, sexual dysfunction, drowsiness, dizziness, nausea, constipation, and peripheral neuropathy (numbness or tingling in the hands and feet).

The primary safety concern with statins has involved an uncommon condition called myopathy, which can cause muscle damage and in some cases, muscle and joint pain. Severe cases of myopathy warrant discontinuation. Patients should tell their physicians about any unusual muscle discomfort or weakness and if their urine becomes brown-colored.

Statins also can effect the liver, particularly at higher doses, so periodic liver function tests should be administered.

Infection-Fighting Agents

Influenza Vaccinations (Flu Shots). Evidence now suggests influenza vaccinations help protect against adverse heart events (including after heart surgeries), stroke, and death from all causes in the elderly. Still, studies suggest that only two thirds of this group are vaccinated, mostly because of unwarranted fears of ineffectiveness or adverse effects.

Antibiotics. The antibiotics prescribed for Chlamydia pneumoniae are being investigated for prevention of heart attacks in patients with heart disease and evidence of infection. Studies in 2001 and 2002 are suggesting they may have effects on blood vessels that may benefit people with coronary heart disease and evidence of infection.

Experimental Agents

Gene Therapy and Angiogenesis.Proteins known as growth factors are being investigated for their ability to grow new blood vessels for supplying oxygen to the heart. After promising small trials, two large studies of genetically engineered forms of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF [GenerX]) failed to detect any benefits. Studies on therapies that actually genetically encode these proteins are underway.

Testosterone Supplements. Some trials using testosterone supplements or patches have reported improved exercise-induced blood flow in the coronary arteries and improvement in angina in some cases. Supplements of this male hormone, however, may increase the risk for prostate cancer. Experts suggest that testosterone be used only in older men with significant deficiencies in testosterone.

Selective Estrogen-Receptor Modulators (SERMs). Selective estrogen-receptor modulators (SERMs), including raloxifene (Evista), have been designed to produce the benefits of estrogen without its risks. They are thought to act like estrogen in some tissues but behave like estrogen blockers (antiestrogens) in others. Raloxifene may have some heart benefits, although it poses a risk for deep vein blood clots, which may have long-term implications on heart problems. A major study is underway to determine its effects on the heart.

Surgery

To date, surgery is usually recommended for patients who have the following conditions:

• Unstable angina that does not respond promptly to medical treatment.
• Severe recurrent episodes of angina that last more than 20 minutes.
• Severe coronary artery disease (e.g., severe angina, multi-artery involvement, evidence of ischemia), particularly if abnormalities are evident in the left ventricle of the heart, the main pumping chamber.

Atherosclerosis is a disease of the arteries in which fatty material is deposited in the vessel wall, resulting in narrowing and eventual impairment of blood flow. Severely restricted blood flow in the arteries to the heart muscle leads to symptoms such as chest pain. Atherosclerosis shows no symptoms until a complication occurs.

Researchers have been investigating whether surgery offers any advantages if used as early treatment for mild angina. A major analysis in 2003 reported that the use of angioplasty in patients with mild heart blockage did not reduce the risk for heart attack or death over the long term.

Choosing Either Angioplasty or Bypass

There are two effective surgical procedures now available for heart patients:

• Coronary artery bypass grafting (commonly called bypass or CABG).

Click the icon to see an image about bypass grafting.

• Percutaneous transluminal coronary angioplasty (commonly called angioplasty or PTCA), usually with coronary artery stent placement.

Click the icon to see an image about bypass grafting.

Each of these procedures is described below.

Studies have generally reported similar survival rates with either procedure. There are some differences, however, and decision often depends on individual conditions. (Patients considering surgery should discuss all options and risks with their physician.) No surgical procedure cures coronary artery disease, and patients must continue to rigorously maintain a healthy lifestyle and continue any necessary medications.

Considerations for Choosing Angioplasty with Stent Placement. Angioplasty has the following advantages for most patients:

• Angioplasty is less invasive than bypass. (Although a minimally invasive variation of bypass surgery may over time reduce this distinction.)
• Angioplasty is initially less expensive. (Although the postoperative need for more medications and the high risk for repeat procedures to reopen the artery may reduce the long-term difference in cost between the two procedures.)
• Angioplasty is an important and life-saving emergency procedure for many patients with heart attacks. (The use of bypass after a heart attack has much higher mortality rates than when it is used electively and its use is controversial in heart attack patients.)

It has the following disadvantages:

• The blood vessels close up (restenosis) in a large minority of patients and require additional procedures. (New blood thinning agents, coronary stent coatings, and radiation treatments may help to significantly reduce restenosis rates.)
• It is not as appropriate as bypass for many patients with angina (e.g., people with diabetes, elderly patients, or those with multi-vessel blockage). Increasingly, however, angioplasty is proving to be safe and as effective as bypass even in many of high-risk patients (other than people with diabetes). Even if the physician recommends bypass, patients should discuss the risks and benefits of angioplasty if they would prefer it.

Considerations for Choosing Bypass. Bypass is usually the appropriate procedure in patients with the high-risk conditions, such as the following:

• Multi-vessel blockage. (In one report comparing surgery to angioplasty in patients with two or three blocked vessels, the mortality rate one year after bypass of 0.8% and after angioplasty was 2.5%. About 80% in the study were men.)
• Diabetes. (Bypass produces significantly higher survival rates in these patients and some experts believe angioplasty should rarely, if ever, be used in this population.)
• Being elderly.
• Certain structural features, such as a left main artery narrowed by 50% or more or a very long diseased portion of the artery.

Considerations for Women. Studies have reported higher mortality rates in women than in men after any heart surgery. Some experts theorize that on average women may be older and sicker when they have a heart operation. A 2002 study, however, suggested that when women with acute coronary syndromes are given the same aggressive and early treatment as men are, their survival rates are equal or even better.

Other Procedures

In addition to angioplasty and bypass procedures, a number of other procedures are available or under investigation for coronary artery disease. They include the following:

• Atherectomy.
• Myocardial Laser Revascularization.
• Enhanced External Counterpulsation (EECP).

Coronary Artery Bypass Graft Surgery

Coronary artery bypass graft surgery (CABG) is a good alternative to angioplasty for many patients, but it is very invasive. It involves the following processes:

Click the icon to see an animation about CABG.

• The chest is opened and the blood is rerouted through a lung-heart machine.
• The heart is stopped during the procedure.
• Large blood vessels supply the grafts, which are used to reroute the blood. The blood vessel grafts are transplanted in front of and beyond the blocked arteries, so the blood flows through the new vessels around the blockage.
• The standard grafts now use arteries taken from the chest wall. Studies are reporting that with such grafts arteries remain open in 90% of cases after 15 years.
• In general, patients with triple bypass procedures stay in the hospital for five days. Those with one-vessel bypass may be able to go home in three days.

Click the icon to see an illustrated series detailing a heart bypass surgery.

Complications

In spite of the invasive nature of this procedure, in general, elective bypass procedures produce better long-term survival rates than angioplasty, particularly in patients with diabetes and multi-vessel blockage. Overall mortality rates after this procedures ranges from 1% to slightly over 2%. The risk for stroke or heart attack after a bypass operation range from 1.3% to 5%. A 2002 study suggested that giving patients beta-blocker drugs before surgery may reduce complication rate and improve survival rates. Finding a surgeon who performs at least 100 of the procedures a year helps reduce the risk for complications.

Blood clots may form in the new graft, closing it up or narrowing the treated vessel over time. Therapy with aspirin and other anti-clotting drugs help keep the graft open and working properly. For long-term prevention of closure as well as slowing progression of atherosclerosis, aggressive use of cholesterol-lowering drugs may be more beneficial than the standard anti-clotting drugs.

Of some concern are studies reporting a decline in mental function five years after bypass surgery. It is not known, however, if patients with bypass procedures tend to have other higher risk factors for mental decline (being older or sicker than those who choose angioplasty). Long-term studies are underway. Some experts attribute problems leading to brain injuries to the pump used in these procedures. Some early studies suggest that newer procedures that allow the heart to keep beating will reduce the risk, but a 2002 study found no difference.

Minimally Invasive Bypass

Minimally invasive bypass (also called buttonhole or keyhole bypass) surgeries are exciting advances in basic bypass surgery that are currently being tested with good success for patients with disease in single vessels. They are even being investigated for multiple vessels.

• One variation of minimally invasive bypass uses a four-inch incision, and the surgeon works on the front of the heart while it is beating slowly. To date, there have been no differences in cardiac events or later mental complications between this so-called off-pump procedure and the standard bypass procedure.
• In another variation, the heart is stopped, and the patient is put on a machine that reroutes the blood through a device that keeps it oxygenated. Fiberoptic scopes and instruments are passed through a number of finger-sized incisions and the surgeon works on all sides of the heart guided by a video image from a tiny camera inserted through a four-inch incision.
• Some advanced heart centers now employ robotic systems, which allow the surgeon to perform extremely delicate maneuvers on tiny vessels through pencil-size incisions. They are not yet used for the whole bypass process.

Eventually minimally invasive bypass procedures may prove to be less expensive, require a shorter hospital stay, and have fewer complications than conventional coronary artery bypass surgery--or even angioplasty. To date, however, they are experimental and are performed only in a few medical centers for select candidates. Long term-success rates are unknown.

Angioplasty and Stents

Percutaneous transluminal coronary angioplasty (PTCA), usually simply called angioplasty, involves opening the blocked artery.

Click the icon to see an animation about percutaneous transluminal coronary angioplasty.

• The surgeon threads a narrow catheter (a tube) containing a fiber optic camera directly to the blocked vessel.
• The physician opens the blocked vessel using balloon angioplasty, in which the surgeon passes a tiny deflated balloon through the catheter to the vessel.

Click the icon to see an animation about percutaneous transluminal coronary angioplasty.

• The balloon is inflated to compress the plaque against the walls of the artery, flattening it out so that blood can once again flow through the blood vessel freely.
• In order to keep the artery open afterwards, surgeons now most often employ a device called a coronary stent, which is an expandable metal mesh tube that is implanted during angioplasty at the site of the blockage. (A stent may be used as the initial opening device, in some cases, instead of balloon angioplasty. It is not yet clear if this approach is significantly more beneficial than PTCA plus optional stenting.)

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• Once in place, the stent pushes against the wall of the artery to keep it open.

Complications occur in about 10% of patients (about 80% within the first day). In one report of 53 European and Canadian medical centers, the mortality rate from all causes four years after PTCA was 4.1% Outcomes are better in hospital settings with experienced teams and backup.

Click the icon to see an illustrated series detailing coronary artery balloon angioplasty surgery.

The most important long-term complication is reclosure (restenosis), which can lead to heart attack if not treated with a repeat procedure. Stenting and other advances have helped significantly in preventing reclosure and reducing heart attack rates. Nevertheless, a repeat procedure is still needed to restore the opening in 10% to 15% of procedures that use stents. Radiation therapies and stents coated with immunosuppr