Heart failure
Highlights
Permanent Implantable Heart Approved
In 2006, the FDA approved the first permanent artificial heart. The AbiCor is intended for patients who are not eligible for heart transplants and who are only expected to survive about a month without medical treatment. Patients who received the AbiCor have survived, on average, about 5 months.
Statin Drug Approved for Heart Failure
In 2006, the FDA approved the cholesterol drug atorvastatin (Lipitor) to reduce the risks of hospitalization for heart failure in patients with heart disease.
Drug Research
The investigational drug tolvaptan improved symptoms in patients hospitalized with severe heart failure and fluid build-up in the lungs, according to several 2007 Journal of the American Medical Association (JAMA) studies. However, the drug did not reduce the risks of re-hospitalization and death.
Preserved Versus Reduced Ejection Fraction
Heart failure with preserved left-ventricular ejection fraction (LVEF) is becoming more common, suggests several 2006 studies published in JAMA and the New England Journal of Medicine. Unfortunately, this type of heart failure is less well studied than reduced LVEF. Experts are urging that more studies be conducted to determine better treatment options for preserved LVEF. Both types of heart failure have high mortality rates.
Systolic Blood Pressure Predictor of Mortality
Patients who are admitted to the hospital with heart failure and low systolic blood pressure have a poorer chance of survival than patients admitted with high blood pressure, indicates a 2006 JAMA study.
Diet and Lifestyle Factors
- Daily consumption of whole-grain breakfast cereals may reduce the risk for heart failure, suggests research presented at a 2007 American Heart Association conference on heart disease prevention.
- A drink or two a day is associated with lower risk of heart failure, indicates a 2006 Journal of the American College of Cardiology study. However, heavy alcohol consumption can increase the risk for heart failure.
Introduction
To understand what occurs in heart failure, it is useful to be familiar with the anatomy of the heart and how it works. The heart is composed of two independent pumping systems, one on the right side, and the other on the left. Each has two chambers, an atrium and a ventricle. The ventricles are the major pumps in the heart.
The Right Side of the Heart. The right system receives blood from the veins of the whole body. This is "used" blood, which is poor in oxygen and rich in carbon dioxide.
- The right atrium is the first chamber that receives blood.
- The chamber expands as its muscles relax to fill with blood that has returned from the body.
- The blood enters a second muscular chamber called the right ventricle.
- The right ventricle is one of the heart's two major pumps. Its function is to pump the blood into the lungs.
- The lungs restore oxygen to the blood and exchange it with carbon dioxide, which is exhaled.
The Left Side of the Heart. The left system receives blood from the lungs. This blood is now oxygen rich.
- The oxygen-rich blood returns through veins coming from the lungs (pulmonary veins) to the heart.
- It is received from the lungs in the left atrium, the first chamber on the left side.
- Here, it moves to the left ventricle, a powerful muscular chamber that pumps the blood back out to the body.
- The left ventricle is the strongest of the heart's pumps. Its thicker muscles need to perform contractions powerful enough to force the blood to all parts of the body.
- This strong contraction produces systolic blood pressure (the first and higher number in blood pressure measurement). The lower number ( diastolic blood pressure) is measured when the left ventricle relaxes to refill with blood between beats.
- Blood leaves the heart through the ascending aorta, the major artery that feeds blood to the entire body.
The Valves. Valves are muscular flaps that open and close so blood will flow in the right direction. There are four valves in the heart:
- The tricuspid regulates blood flow between the right atrium and the right ventricle.
- The pulmonary valve opens to allow blood to flow from the right ventricle to the lungs.
- The mitral valve regulates blood flow between the left atrium and the left ventricle.
- The aortic valve allows blood to flow from the left ventricle to the ascending aorta.
Click the icon to see an image of the internal structures of the heart.
The Heart's Electrical System. The heartbeats are triggered and regulated by the conducting system, a network of specialized muscle cells that form an independent electrical system in the heart muscles. These cells are connected by channels that pass chemically caused electrical impulses.
Click the icon to see an image of the conduction system of the heart.
Description of Heart Failure
Heart failure is not a disease. It is a condition or process in which the heart is unable to pump enough blood to meet the needs of the body's tissues. The heart doesn't "fail" in the sense of ceasing to beat (as occurs during a heart attack). Rather, it weakens, usually over the course of months or years, so that it is unable to pump out all the blood that enters its chambers. As a result, fluids tend to build up in the lungs and tissues, causing congestion. This condition used to be called "congestive heart failure," but the name was officially changed to heart failure in 2005.
Ways the Heart Can Fail. Heart failure can occur in several ways:
- The muscles of the heart pumps (ventricles) become thin and weakened. They stretch (dilate) to the extent that they cannot pump the blood with enough force to reach all the body's tissues.
- The heart muscles stiffen or thicken. Here, they lose elasticity and cannot relax. Insufficient blood enters the chamber, so not enough blood is pumped out into the body to serve its needs.
- Sometimes the valves of the heart are abnormal. (Valves open or close to control the flow of blood entering or leaving the heart). They may narrow, such as in aortic stenosis, causing a back up of blood, or they may close improperly so that blood leaks back into the heart. The mitral valve (which regulates blood flow between the two chambers on the left side of the heart) often becomes leaky in severe heart failure -- a condition called mitral regurgitation.
Click the icon to see an image of the valves of the heart.
- The very mechanisms that the body uses to compensate for inefficient heart pumping can, over time, change the architecture of the heart (called remodeling) and finally lead to irreversible problems.
The specific effects of heart failure on the body depend on whether it occurs on the left or right side. Over time, however, in either form of heart failure, the organs in the body do not receive enough oxygen and nutrients, and the body's wastes are removed slowly. Eventually, vital systems break down.
Failure on the Left Side (Left-Ventricular Heart Failure). Failure on the left side of the heart is more common than failure on the right side. The failure can be a result of abnormal systolic (contraction) or diastolic (relaxation) action:
- Systolic. Systolic heart failure is a pumping problem. In systolic failure, the heart muscles weaken and cannot pump enough blood throughout the body. The left ventricle is usually stretched (dilated). Fluid backs up and accumulates in the lungs (pulmonary edema). Systolic heart failure typically occurs in men between the ages of 50 - 70 years who have had a heart attack.
- Diastolic. Diastolic heart failure is a filling problem. When the left ventricle muscle becomes stiff and cannot relax properly between heartbeats, the heart cannot fill fully with blood. When this happens, fluid entering the heart backs up. This causes the veins in the body and tissues surrounding the heart to swell and become congested. Patients with diastolic failure are typically women, overweight, and elderly, and have high blood pressure and diabetes.
Failure on the Right Side (Right-Ventricular Heart Failure). Failure on the right side of the heart is most often a result of failure on the left. Because the right ventricle receives blood from the veins, failure here causes the blood to back up. As a result, the veins in the body and tissues surrounding the heart to swell. This causes swelling in the feet, ankles, legs, and abdomen.
Ejection Fraction. To help determine the severity of left-sided heart failure, doctors use an ejection fraction (EF) calculation, also called a left-ventricular ejection fraction (LVEF). This is the percentage of the blood pumped out from the left ventricle during each heartbeat. An ejection fraction of 50 - 75% is considered normal. Patients with left-ventricular heart failure are classified as either having a preserved ejection fraction (greater than 50%) or a reduced ejection fraction (less than 50%).
In general, systolic heart failure has been thought to be associated with a reduced ejection fraction, whereas diastolic heart failure was associated with a preserved (normal) ejection fraction. However, several 2006 studies indicated that diastolic heart failure can occur regardless of the ejection fraction, although it is more common in patients with a preserved ejection fraction. Mortality rates among patients with reduced LVEF and preserved LVEF are similar.
Although reduced LVEF heart failure is better studied, and its treatment goals more clearly defined, several important 2006 studies suggest that preserved LVEF heart failure is becoming increasingly common. The studies, published in the Journal of the American Medical Association and the New England Journal of Medicine, indicated that patients with preserved LVEF heart failure are more likely to be female and older, and have a history of high blood pressure and atrial fibrillation (a disturbance in heart rhythm). Experts are now urging that more studies focus on patients with preserved LVEF so that better treatment options can be established.
Causes
Heart failure has many causes and can evolve in different ways.
- It can be a direct, last-stage result of heart damage from one or more of several heart or circulation diseases.
- It can occur over time as the heart tries to compensate for abnormalities caused by these conditions, a condition called remodeling.
In all cases, the weaker pumping action of the heart means that less blood is sent to the kidneys. The kidneys respond by retaining water and salt. This in turn increases edema (fluid buildup) in the body, which causes widespread damage.
High Blood Pressure
Uncontrolled high blood pressure (hypertension) is also a major cause of heart failure even in the absence of a heart attack. In fact, about 75% of cases of heart failure start with hypertension. It generally develops as follows:
- The heart muscles thicken to make up for increased blood pressure.
- The force of the heart muscle contractions weaken over time, and the muscles have difficulty relaxing. This prevents the normal filling of the heart with blood.
[For more information, see In-Depth Report #14: High blood pressure.]
Coronary Artery Disease
Coronary artery disease is the end result of a complex process called atherosclerosis (commonly called "hardening of the arteries"). It is the most common cause of heart attack and involves the build-up of unhealthy cholesterol in the arteries, with inflammation and injury in the cells of the blood vessels. The arteries narrow and become brittle. Heart failure in such cases most often results from a pumping defect in the left side of the heart. [For detailed information, see In-Depth Report #3: Coronary artery disease and angina and In-Depth Report #23: Cholesterol.]
Click the icon to see an image of atherosclerosis.
Damage after a Heart Attack
People now often survive heart attacks, but eventually many develop heart failure from the physical damage done to the heart muscles by the attack. Ironically, heart attack recovery is probably one of the major factors in the dramatic increase in heart failure cases over the past decade. On an encouraging note, however, new therapies that are reducing the severity of heart attacks may help stabilize heart failure rates. [For more information, see In-Depth Report #12: Heart attack.]
Valvular Heart Disease
The valves of the heart control the flow of blood leaving and entering the heart. Abnormalities can cause blood to back up or leak back into the heart.
Click the icon to see an image of the heart valves.
In the past, rheumatic fever, which scars the heart valves and prevents them from closing, was a major cause of death from heart failure. Fortunately, antibiotics have relegated this disease to a minor cause of heart failure. Birth defects may also cause abnormal valvular development. Although more children born with heart defects are now living to adulthood, they still face a higher than average risk for heart failure as they age.
Cardiomyopathy
Cardiomyopathy is disease that damages the heart muscles and leads to heart failure. There are several different types. Injury to the heart muscles may cause the heart muscles to thin out (dilate) or become too thick (become hypertrophic). In either case, the heart doesn't pump correctly.
Dilated Cardiomyopathy. Dilated cardiomyopathy involves an enlarged heart ventricle. The muscles thin out, reducing the pumping action, usually on the left side. Although this condition is associated with genetic factors, the direct cause often is not known. (This is called idiopathic dilated cardiomyopathy.) Research strongly indicates that viruses, such as Coxsackie virus, or other infections may be at the base of this condition. Experts think that an autoimmune response occurs in which infection-fighting antibodies attack a person's own proteins in the heart, mistaking them for foreign substances.
Click the icon to see an image of dilated cardiomyopathy.
Hypertrophic Cardiomyopathy. In hypertrophic cardiomyopathy, the heart muscles become thick and contract with difficulty. Some research indicates that this occurs because of a genetic defect that causes a loss of power in heart muscle cells and, subsequently, lower pumping strength. To compensate for this power loss, the heart muscle cells grow. This condition, rare in the general population, is often the cause of sudden death in young athletes.
Click the icon to see an image of hypertrophic cardiomyopathy.
Corrective Mechanisms, Remodeling, and the Failing Heart
High blood pressure, heart attacks, or other initial processes that impair the pumping actions of the heart trigger a number of hormonal and neurochemical mechanisms to correct imbalances in pressure and blood flow. Unfortunately, while these corrective responses help in the short term, they increase the work of the heart. The mechanisms are now viewed as major contributors to the end stages of heart failure. Some are described briefly in the following sections.
Remodeling. The heart responds to high blood pressure and overload by enlarging in order to increase blood input. This leads to structural damage called remodeling:
- In order to accommodate the increased blood input, the heart muscle cells elongate. The muscular walls of the heart that they form become thinner and inefficient.
- The muscle cells undergo other changes that result in calcium loss. Calcium is a mineral that is crucial for healthy heart contractions.
- The thinner heart muscles and the impaired heart contractions further weaken the heart's pump.
- Mitral valve regurgitation is a possible outcome of remodeling. The mitral valve regulates blood flow between the two chambers on the left side of the heart. In response to remodeling, the structural changes in the heart may distort the mitral valve so that the blood leaks backward into the left atrium of the heart instead of flowing out into the body's circulation.
- These changes are generally irreversible, although heart pacemakers and certain drugs, including beta-blockers and ACE inhibitors, may reverse some of the remodeling in some patients.
Activation of the Sympathetic Nervous System. The sympathetic nervous system consists of the nerve cells that automatically govern and regulate the beating heart.
- This nervous system responds to the failing heart pump by signaling the release of stress hormones, in particular a powerful one called norepinephrine.
- These hormones flood the heart, causing it to beat even faster.
- These rapid heart beats, although intended to accommodate the weakened pumping actions, only accelerate the damage.
The Renin-Angiotensin-Aldosterone System (RAAS). The renin-angiotensin-aldosterone system (RAAS) is a group of hormones that are responsible for the opening and narrowing of blood vessels and retention of fluids. They also affect cell development in the heart.
- The RAAS hormones are called into action by the failing heart.
- They respond to the lower blood volume of the weakened heart by constricting the blood vessels and retaining fluids and sodium.
- The heart then works harder to pump blood through these narrowed vessels. Blood pressure, then, is forced to increase, which creates a vicious cycle.
Immune System Response. The immune system may also compound the damage. In response to injury in the heart muscle cells or in other parts of the body that occurs as the heart fails, the immune system releases factors intended to protect these areas.
In excess, however, they can cause inflammation and damage.
- The most important of these factors are called cytokines. Active cytokines include tumor necrosis factor (TNF) and possibly interleukins 1 and 6.
- High levels of these cytokines have been observed in patients with the most severe classes of heart failure.
- They may play an important role in the process leading to remodeling. High levels of these cytokines may actually trigger muscle cell growth and enlargement of the heart.
Other Players. Other molecules or compounds have been identified that might play a positive or negative role in the process of the failing heart.
- Natriuretic peptides are a family of compounds released to counterbalance the effects of RAAS. Atrial natriuretic peptide (ANP) is a specific member of this family that opens blood vessels and counteracts the sodium-retaining properties of aldosterone (one of the RAAS hormones). It is of particular interest to researchers looking for new treatments.
- Endothelin is a powerful protein involved in blood vessel constriction, cell proliferation and build-up, and other negative effects on the heart.
- Nitric oxide is important for blood vessel dilation and elasticity.
Symptoms
Many symptoms of heart failure result from the congestion that develops as fluid backs up into the lungs and leaks into the tissues. Other symptoms result from inadequate delivery of oxygen-rich blood to the body's tissues. Since heart failure can progress rapidly, it is essential to consult a doctor immediately if any of the following symptoms are detected.
Symptoms of Left-Side Heart Failure
Fatigue and shortness of breath (dyspnea) are the first symptoms. They are caused by fluid in the lungs. Patients typically report that they feel out of breath after mild exertion. It is unlike the breathlessness of angina, which feels like a heavy weight pressing on the chest.
- Fluid retention. Patients may complain of leg or abdominal swelling.
- Wheezing or cough. Patients may have asthma-like wheezing or a dry hacking cough that occurs a few hours after lying down, but then stops after the patient sits up.
- Central sleep apnea. This disorder results when the brain fails to signal the muscles to breathe during sleep. It occurs in up to half of people with heart failure. Sleep apnea causes disordered breathing at night. If heart failure progresses, the apnea may be so acute that a person, unable to breathe, may awaken from sleep in panic.
- Loss of muscle mass. Over time, patients may lose muscle weight due to low cardiac output.
Ultimately, fluid in the lungs may build up. This is called pulmonary edema. When this happens, symptoms become more severe.
- In addition to shortness of breath, patients sometimes have a cough that produces a pinkish froth.
- Patients may experience a bubbling sensation in the lungs and feel as if they are drowning.
- Typically, the skin is clammy and pale, sometimes nearly blue. This is a life-threatening situation, and the patient must go immediately to an emergency room.
Symptoms of Right-Side Heart Failure
- Fatigue. As with left-side heart failure, an early symptom of right-side (right-ventricular) failure is extreme tiredness.
- Fluid accumulation. This first occurs in the feet, then the ankles and legs, and finally in the abdomen. The liver may also be enlarged.
- Weight gain. Although appetites are often depressed, patients with heart failure gain weight because they retain salt and water.
- Loss of muscle mass.
Risk Factors
Nearly 5 million Americans currently suffer from heart failure. About 550,000 new cases of heart failure are now diagnosed each year. In 1970 there were only 250,000 new cases, so the annual numbers have risen dramatically. Such numbers represent an increasingly older population. Although there has been a dramatic increase over the last several decades in the number of people who suffer from heart failure, survival rates have been improving greatly.
Coronary artery disease and high blood pressure are the main causes of heart failure. Other diseases that damage or weaken the heart muscle or heart valves can also cause heart failure. Heart failure is most common in people over age 65, African-Americans, and women.
Advancing Age
Heart failure is the most common reason for hospitalization in the elderly, and as the population ages, the incidence of heart failure is rising dramatically. According to one report, it occurs at a rate of about 10 in 1,000 people after age 65. The positive implication is, however, that people are living longer with heart failure.
Gender
Men are at higher risk for heart failure than women, although the difference narrows with age. Women also have a better survival rate than men do when heart failure is caused by valvular heart disease, high blood pressure, or alcohol abuse. (Some studies indicate that this is because men may be more susceptible to the process of heart muscle-cell remodeling, a damaging effect of hypertension.)
The survival rates of women and men are more similar, however, when heart failure evolves from coronary artery disease or heart attack. Women are much more likely to develop heart failure after a heart attack than men. In such cases, some evidence suggests that the reasons for this may include less aggressive approach to treatment for the initial heart conditions.
Ethnicity
African-Americans are at higher risk for heart failure than Caucasians, and studies have reported that they tend to do much worse. In a 2003 study, however, in which Caucasians and African-Americans had comparable treatment, African-Americans actually had lower 1-year mortality rates (with slightly higher rates of rehospitalizations). Some evidence suggests that African-Americans are more often likely than Caucasians to develop diastolic heart failure (a failure of the heart muscle to relax normally), which is often a precursor to systolic heart failure (impaired ability to pump blood). Caucasians tend to develop systolic heart failure first.
Family History and Genetics
According to a 2006 New England Journal of Medicine study, people whose parents had heart failure have a greatly increased risk of developing heart failure, particularly left-ventricular systolic heart failure. Earlier studies have suggested that a family history of early heart failure caused by cardiomyopathies (diseases that damage the heart muscle) may also predispose people to the disease. Researchers are looking for changes in specific genes that might regulate systems involved in heart failure and so increase susceptibility in certain populations.
Chronic Alcohol Abuse
Chronic alcohol abuse can damage the heart muscles, can cause hypertension, and may prove to be one cause of idiopathic dilated cardiomyopathy. Moderate alcohol consumption, on the other hand (generally defined as 2 drinks a day for men and 1 drink for women), may protect against heart failure. Non-drinkers, though, are not advised to begin drinking.
Medical Conditions that Increase the Risk for Heart Failure
- Coronary artery disease. More than 60% of heart failure cases may be due to coronary artery disease and its risk factors (smoking, sedentary living, obesity).
- Heart attack. The injured heart after an attack is at high risk for failure. The improved survival rates from heart attack over the past decades have actually been responsible for the dramatic increase in heart failure rates.
- High blood pressure. Hypertension is a significant risk factor and is present in 75% of patients with heart failure.
- Diabetes. People with diabetes are at high risk for heart failure, particularly if they also have coronary artery disease. Even blood sugar abnormalities that precede diabetes increase the risk.
- Obesity. Obesity is associated with both hypertension and type 2 diabetes, conditions that place people at risk for heart failure. Evidence strongly suggests that obesity itself is a major risk factor for heart failure, particularly in women. In a major 2002 study, about 14% of heart failure cases in women and 11% in men could be attributed to obesity. Both overweight and obese women had a significantly higher than normal risk for heart failure. Only obesity led to a significant risk in men.
- Valvular heart disease. Specific valvular conditions that are common in patients with heart failure include aortic stenosis and mitral regurgitation.
- Severe emphysema. Chronic obstructive pulmonary disease is a major risk factor for right-side heart failure.
- Cardiomyopathies due to various causes, including birth defects, HIV infection, and other infections.
- In rare cases, heart failure can occur in women around the time of childbirth, a condition called peripartum cardiomyopathy.
Click the icon to see an image of peripartum cardiomyopathy.
- An overactive thyroid (hyperthyroidism) or underactive thyroid (hypothyroidism) can have severe effects on the heart and increase the risk for heart failure.
- Amyloidosis. A starchy protein (amyloid) that builds up in tissues and organs can lead to heart failure.
- Surviving childhood cancers. Survivors face a risk for developing heart failure in later years, particularly those treated with chemotherapies such as doxorubicin. Newer cancer advances may reduce this risk.
- Acute myocarditis. This rare viral infection involves the heart muscle and can produce temporary but potentially life-threatening heart failure.
Medications Associated with Heart Failure
Long-term use of anabolic steroids (male hormones used to build muscle mass) increases the risk for heart failure. The drug itraconazole (Sporanox), used to treat skin, nail, or other fungal infections, has been linked to heart failure. In 2006, the FDA warned that the cancer drug imatinib (Gleevec) has been associated with heart failure cases. Most patients who took imatinib and developed heart failure had a history of diabetes, high blood pressure, or heart disease.
Complications
At least 20% of hospitalizations in older adults are due to heart failure. For people over age 65, it is the number one cause of death, with nearly 290,000 people dying from this disease each year. Nevertheless, although heart failure produces very high mortality rates, treatment advances in hypertension, heart surgeries, and heart pacemakers are improving survival rates.
Life-Threatening Complications of Heart Failure
The most serious and life-threatening complications of heart failure are:
- Arrhythmias (irregular beatings of the heart)
- Acute pulmonary edema (fluid in the lungs)
Conditions Associated with Left-Side Heart Failure
Left-side heart failure tends to be more severe than right-side heart failure, particularly when it is associated with the following conditions:
- Coronary artery disease
- HIV infection
- Amyloidosis (a metabolic disorder than can lead to organ failure)
- Chemotherapy that uses the drug doxorubicin
The outlook is better in patients with left-side heart failure associated with:
- Idiopathic cardiomyopathy (the cause is unknown)
- Heart failure due to childbirth
Other Conditions Associated with Heart Failure Severity
Weight Issues. If patients with heart failure are overweight to begin with, their condition tends to be more severe. Once heart failure develops, however, an important indicator of a worsening condition is the occurrence of cardiac cachexia, which is unintentional rapid weight loss (a loss of at least 7.5% of normal weight within 6 months).
Impaired Kidney Function. Heart failure weakens the heart’s ability to pump blood. This can affect other parts of the body including the kidneys (which in turn can lead to fluid build-up). Decreased kidney function is common in patients with heart failure, both as a complication of heart failure and as a complication of other diseases associated with heart failure (such as diabetes). Studies suggest that in patients with heart failure, impaired kidney function increases the risks for heart complications including hospitalization and death.
Congestion (Fluid Buildup). In left-sided heart failure, fluid builds up first in the lungs. Later, as right-sided heart failure develops, fluid builds up in the legs, feet, and abdomen. According to one study, patients with severe symptoms who had congestion (fluid buildup) had poorer survival rates than those without fluid build up. Two-year survival rates were 87% in those who were congestion-free compared to 41 - 67% in patients with various signs of congestion (such as swelling, difficulty breathing when lying down, and weight gain from fluid buildup). Fluid buildup is treated with lifestyle measures, such as reducing salt in the diet, as well as drugs, such as diuretics. Sometimes, for hospitalized patients, an ultrafiltration device is used to remove excess water and salt from the body (see Surgery and Devices).
Atrial Fibrillation. This abnormal rhythm is a rapid quivering beat in the upper chambers of the heart. It is a major cause of stroke and very dangerous in people with heart failure.
Left Bundle Branch Block. Left bundle-branch block is an abnormality in electrical conduction in the heart. It develops in about 30% of patients with heart failure and is a major risk factor for serious adverse heart events.
Systolic Blood Pressure. An important 2006 study indicated that patients who arrive at the hospital with heart failure and low systolic blood pressure have a poorer prognosis than those who arrive with high systolic blood pressure. Researchers think that high systolic blood pressure may be a signal for unique clinical characteristics.
Sleep Apnea. With this disorder, a person stops breathing during the night, perhaps hundreds of times, usually for periods of 10 seconds or longer. It is a very strong risk factor for heart failure, and patients with apnea have a higher mortality rate than those who do not.
Depression. The presence of depression indicates a poorer outlook for the heart. Studies indicate that depression may have adverse biologic effects on the immune and nervous systems, blood clotting, blood pressure, blood vessels, and heart rhythms.
Seasonal and Daily Patterns. Studies have shown that more emergency room visits and higher mortality rates occur during winter months and on Mondays in patients with heart failure. One factor in this higher risk may be sudden and strenuous exertion, particularly snow-shoveling, which is associated with a risk for heart attack in people with heart problems.
Diagnosis
Doctors can often make a preliminary diagnosis of heart failure by medical history and careful physical examination.
The medical history risks for heart failure include:
- High blood pressure
- Diabetes
- Poor cholesterol levels
- Heart or peripheral vascular disease
- Sleep apnea
- Thyroid problems
- Obesity
- Lifestyle factors (smoking, alcohol use)
The following physical signs, along with medical history, strongly suggest heart failure:
- Enlarged heart
- Irregular heart sounds
- Abnormal sounds in the lungs
- Swelling or tenderness of the liver
- Fluid retention in legs and abdomen
- Elevation of pressure in the veins of the neck
Laboratory Tests
Both blood and urine tests are used to check for problems with the liver and kidneys and to detect signs of diabetes. Lab tests can measure:
- Cholesterol and lipid levels
- Blood sugar (glucose)
- Red blood cell count (to rule out anemia)
- Blood sugar levels
- Thyroid function
Urine tests can be used to assess the presence of a protein called albumin. Albumin in the urine is usually a sign of kidney disease, but even tiny amounts (microalbumin) signal an increased risk for heart failure in people with and without diabetes.
Exercise Stress Test
The exercise stress test measures heart rate, blood pressure, and oxygen consumption while a patient is performing physically, usually walking on a treadmill. It is an important diagnostic component in determining heart failure symptoms. Doctors also use exercise tests to gauge long-term outlook and the effects of particular treatments.
Electrocardiogram
An electrocardiogram (ECG) cannot diagnose heart failure, but it can indicate underlying heart problems. It is sometimes called an EKG. The test is simple and painless to perform. It may be used to diagnose:
- Enlargement of the heart muscle, which may help to determine long-term outlook
- The presence of coronary artery disease
- Abnormal cardiac rhythms. A rhythm pattern called a prolonged QT interval, for example, might predict people with heart failure who are at risk for severe complications and would need more aggressive therapies.
The major benefit of an ECG is that it can help determine which patients do not need an echocardiogram, a more accurate (but more expensive) diagnostic test.
Echocardiography
The best diagnostic test for heart failure is echocardiography. Echocardiography is a noninvasive, entirely safe test that uses ultrasound to image the heart as it is beating. Cardiac ultrasounds provide the following information:
- Accurate indications of valve function
- The amount of blood flow through the heart's chambers
- The location of the failure and where it has occurred
Doctors use information from the echocardiogram for calculating the ejection fraction (how much blood is pumped out during each heartbeat), which is important for determining the severity of heart failure.
Imaging Tests
Radionuclide Ventriculography. Radionuclide ventriculography is an imaging technique that uses a tiny amount of radioactive material (called a trace element). The substance is injected into a patient. As it passes through the bloodstream it is picked up on x-rays. This is a very important imaging technique for patients with heart failure. It is very sensitive in revealing heart enlargement or evidence of fluid accumulation around the heart and lungs. It is typically used in concert with angiography.
Magnetic Resonance Imaging. Magnetic resonance imaging (MRI) scans that use contrast dyes to improve resolution are proving helpful for identifying patients with irreversible heart damage. Damage appears as very bright areas on the scan.
Angiography
Doctors may recommend angiography if they suspect that blockage of the arteries is contributing to heart failure. This procedure is invasive.
- A thin tube called a catheter is inserted into one of the large arteries in the arm or leg.
- It is gently guided through the artery until it reaches the heart.
- The catheter measures internal blood pressure at various locations, giving the doctor a comprehensive picture of the extent and nature of the heart failure.
- Dye is then injected through the tube into the heart.
- X-rays called angiograms are taken as the dye moves through the heart and arteries.
- These images help locate problems in the heart's pumping action or blockage in the arteries.
Major complications of angiography are rare (about 0.1%) but can occur. They include stroke, heart attacks, and kidney damage. The more experienced the medical center in this procedure, the lower the risk.
Click the icon to see an image of cardiac catheterization.
Tests for Markers
Researchers are looking for biologic factors (called biomarkers) that will confirm a diagnosis or suggest a better or worse prognosis. Many are under investigation.
Tumor Necrosis Factor. Elevated levels of tumor necrosis factor (TNF) may be a very strong and accurate predictor of a poor outlook. This immune substance is known to be a potent substance in the inflammatory process.
Natriuretic Peptides. Natriuretic peptides are substances that help regulate salt and water balance in the body. Levels of these peptides increase as heart failure symptoms worsen. Blood tests for brain natriuretic peptide (BNP) are now used to help diagnose heart failure. There are two types of BNP tests: The enzyme-linked immunosorbent assay (ELISA) and the radioimmunosorbent assay (RIA). Research from 2006 suggested that the ELISA test may be more accurate, but it is also more expensive.
BNP testing can be very helpful in correctly diagnosing heart failure in patients who come to the emergency room complaining of shortness of breath (dyspnea). A 2006 study indicated that this test can also help predict which patients with dyspnea are at greatest risk of dying within a year from heart failure.
Brain Metabolites. High levels of a compound called N-acetylaspartate, generated as a byproduct of chemical processes in the brain, may indicate a poor outlook.
Treatment
Guidelines for evaluating the severity of heart failure and determining treatments use a staging system that is similar to the one used for major cancers:
- Stage A: Patients are at high risk for heart failure, but there is no evidence of structural damage to the heart. Risk factors include high blood pressure, heart diseases, diabetes, obesity, metabolic syndrome, and previous use of medications that damage the heart (such as some chemotherapy).
- Stage B: Patients have a structural heart abnormality but no symptoms of heart failure. Abnormalities include left ventricular hypertrophy and low ejection fraction, asymptomatic valvular heart disease, and a previous heart attack.
- Stage C: Patients have a structural abnormality and current or previous symptoms of heart failure, including shortness of breath, fatigue, and difficulty exercising.
- Stage D: Patients have end-stage symptoms that do not respond to standard treatments.
Treatment for Stage A Heart Failure
According to expert guidelines, the first step in managing heart failure is to treat the primary conditions causing or complicating heart failure. These include:
- Coronary artery disease. Treatment includes a healthy diet, exercise, smoking cessation, medications, and, possibly, bypass or angioplasty. [For more information, see In-Depth Report #3: Coronary artery disease and angina.]
- Cholesterol and lipid problems. Treatments include lifestyle management and medications, especially statins. [For more information, see In-Depth Report #23: Cholesterol.]
- High blood pressure. A normal systolic blood pressure is considered below 120 mm Hg, and a normal diastolic blood pressure is below 80 mm Hg. Patients with diabetes or chronic kidney disease should maintain blood pressure readings of 130/80 or less, while other patients with high blood pressure should aim for readings no higher than 140/90. Effective reduction of blood pressure reduces the risk of heart failure by 30 - 50%. [For more information, see In-Depth Report #14: High blood pressure.]
- Diabetes. Treating diabetes is extremely important for reducing the risk for heart disease. ACE inhibitors are especially beneficial, particularly for people with diabetes. Recent research suggests that metformin, a drug used to treat diabetes, may also help prevent heart failure. [For information on treatments, see In-Depth Report #60: Diabetes - type 2 and In-Depth Report #9: Diabetes - type 1.]
- Valvular abnormalities such as aortic stenosis and mitral regurgitation. Surgery may be required.
- Abnormal health rhythms (arrhythmias). Ventricular assisted devices, notably biventricular pacers (BVPs), are proving to be important in preventing hospitalizations for patients with these conditions.
- Anemia. Giving erythropoietin (EPO) and iron injections to patients with heart failure and underlying anemia not only reverses the anemia, but may markedly improve heart symptoms as well. [For more information, see In-Depth Report #57: Anemia.]
- Thyroid function. Various medications are used to treat overactive thyroid (hyperthyroidism) or underactive thyroid (hypothyroidism). [For more information, see In-Depth Report #38: Hypothyroidism.]
- Sleep apnea. Continuous positive airway pressure (CPAP) is an effective treatment for sleep apnea. CPAP may help reduce systolic blood pressure and improve left ventricular systolic function. [For more information, see In-Depth Report#65: Sleep apnea.]
Click the icon to see an image of CPAP treatment.
Treatment for Stage B
Treatments for patients with Stage B risk for heart failure include all of the treatments recommended in Stage A. In addition, the following types of drugs and devices may be recommended for some patients. These include:
- Angiotensin-converting enzyme (ACE) inhibitors for patients with a recent or past history of heart attack. Also for patients who have not had a heart attack if they have a low left ventricular ejection fraction (LVEF) and no heart failure symptoms. A reduced LVEF indicates that the heart’s left ventricle is not pumping blood efficiently.
- Beta blockers for patients with a recent or past history of heart attack. Also for patients who have not had a heart attack but who do have reduced LVEF without heart failure symptoms.
- Angiotensin-receptor blockers (ARBs) for patients who have had a heart attack or have low LVEF, but who cannot take ACE inhibitors.
- Implantable defibrillators for patients who have weakened heart pumps (ischemic cardiomyopathy), who had a heart attack more than 40 days prior, and who have low LVEF.
Treatment for Stage C
Treat conditions as recommended in Stage A plus:
- Restrict dietary salt. Lowering salt in the diet can help diuretics work better.
- ACE inhibitors, beta blockers, and diuretics are recommended for most patients.
- ARBs are recommended for patients who cannot tolerate ACE inhibitors.
- Aldosterone inhibitors or digitalis may be used for some patients.
- A hydralazine and nitrate combination (BiDil) may be used for African-American patients who are taking an ACE inhibitor and beta blocker and who still have heart failure symptoms.
- Avoid drugs that can worsen heart failure symptoms. These include nonsteroidal anti-inflammatory drugs (NSAIDs), most calcium channel blockers, and most drugs used to treat irregular heart rhythms (arrhythmia).
- Exercise training for appropriate patients.
- Biventricular pacemakers and implantable defibrillators for some patients.
Treatment for Stage D
Treatment includes appropriate measures used for Stages A, B, and C plus:
- Heart transplantation referral for appropriate patients.
- Left-ventricular assist devices (LVADs) as permanent therapy for patients who are not candidates for heart transplants. LVADs are surgically implanted to help pump blood through the body.
- Hospice and end-of-life care information for patients and families.
Medications
Many different medications are used in the treatment of heart failure. They include:
- Angiotensin-converting enzyme (ACE) inhibitors
- Angiotensin-receptor blockers (ARBs)
- Beta blockers
- Diuretics
- Aldosterone blockers
- Digitalis
- Hydralazine and nitrates
- Statins
- Nesiritide (Natrecor)
- Aspirin
ACE Inhibitors
Angiotensin-converting enzyme (ACE) inhibitors are among the most important drugs for treating patients with heart failure. ACE inhibitors open blood vessels and decrease the workload of the heart. They are used to treat high blood pressure but can also help improve heart and lung muscle function. Major studies suggest that ACE inhibitors may reduce the risk of death, heart attack, and hospital admissions by 28% in patients with existing heart failure.
ACE inhibitors are particularly important for patients with diabetes. A large study reported that patients with diabetes who took these drugs had fewer heart attacks and lower overall mortality rates than patients who took other types of high blood pressure medications. ACE inhibitors may also help slow progression of kidney disease, in addition to controlling blood pressure.
Doctors sometimes avoid giving aspirin to patients who are taking ACE inhibitors due to concerns that this drug combination can cause kidney problems. A 2005 study of patients with both coronary artery disease and heart failure indicated that an aspirin and ACE inhibitor combination is not harmful, and that aspirin can significantly reduce mortality risk for these patients.
Choosing an ACE inhibitor. ACE inhibitors treat Stage A high-risk conditions such as high blood pressure, heart disease, and diabetic nerve disorders (neuropathy). They also treat Stage B patients who have had a heart attack or who have left ventricular systolic disorder, and Stage C patients with heart failure. Specific brands and stages include:
- Benazepril (Lotrel) -- (Stage A)
- Captopril (Capoten) -- (Stages A, B, C)
- Enalapril (Vasotec) -- (Stages A, B, C)
- Fosinopril (Monopril) -- (Stages A, C)
- Lisinopril (Prinivil, Zestril) -- (Stages A, B, C)
- Moexipril (Univasc) -- (Stage A)
- Perindopril (Aceon) -- (Stage A)
- Quinapril (Accupril) -- (Stages A, C)
- Ramipril (Altace) -- (Stages A, B, C)
- Trandolapril (Mavik) -- (Stages A, B, C)
Side Effects of ACE Inhibitors:
- Low blood pressure is the main side effect of ACE inhibitors. This can be severe in some patients, especially at the start of therapy.
- Irritating cough is a common side effect, which some people find intolerable. Although all ACE inhibitors can have this side effect, sometimes switching to another brand will reduce this symptom.
- Although ACE inhibitors can protect against kidney disease, they also increase potassium retention in the kidneys. This increases the risk for cardiac arrest if potassium levels become too high. Because of this action, they are not generally given with potassium-sparing diuretics or potassium supplements.
- A rare but severe side effect is granulocytopenia, which is an extreme reduction in infection-fighting white blood cells.
- In very rare cases, patients suffer a sudden and severe allergic reaction called angioedema that causes swelling in the eyes and mouth and may close off the throat.
Patients who have difficulty tolerating ACE inhibitor side effects are usually switched to an angiotensin-receptor blocker (ARB).
Angiotensin-Receptor Blockers (ARBs)
ARBs, also known as angiotensin II receptor antagonists, are similar to ACE inhibitors in their ability to open blood vessels and lower blood pressure. They may have fewer or less-severe side effects than ACE inhibitors, especially coughing, and are sometimes prescribed as an alternative to ACE inhibitors. Some patients with heart failure take an ACE inhibitor along with an ARB.
Brands and Indications. ARBs are used to treat Stage A high-risk conditions such as high blood pressure and diabetic nerve disorders (neuropathy). They are also used to treat Stage B patients who have had a heart attack or who have left ventricular systolic disorder, and Stage C patients with heart failure. Specific brands, and the stage of heart failure they are used for, are listed below.
- Candesartan (Atacand) -- (Stages A, C)
- Eprosartan (Teveten) -- (Stage A)
- Irbesartan (Avapro) -- (Stage A)
- Losartan (Cozaar) -- (Stages A, B)
- Olmesartan (Benicar) -- (Stage A)
- Telmisartan (Micardis) -- (Stage A)
- Valsartan (Diovan) -- (Stages A, B, C)
Common Side Effects
- Low blood pressure
- Dizziness and lightheadedness
- Raised potassium levels
- Drowsiness
Beta Blockers
Beta blockers are almost always used in combination with other drugs, such as ACE inhibitors and diuretics. They help slow heart rate and lower blood pressure. Research presented at the 2006 American College of Cardiology meeting indicated that beta-blockers are an important treatment for most patients with left ventricular heart failure. Data from the study found that the beta blocker carvedilol (Coreg) significantly lowered the risk of death or rehospitalization within 3 - 6 months after hospital discharge.
Beta blockers can help patients with heart failure by:
- Treating high blood pressure, angina, arrhythmias, and preventing heart attack in high-risk patients.
- Preventing left ventricular remodeling in patients with enlarged heart chambers and weakened heart muscles (dilated cardiomyopathy), and in those who have suffered a first heart attack.
- Blocking inflammatory immune factors called cytokines, including tumor necrosis factor (TNF). TNF may play a key role in the process leading to heart failure.
- Preventing norepinephrine (adrenaline) from binding to heart cells. Elevated levels of norepinephrine, a stress hormone, can overstimulate the failing heart and are associated with severe heart failure.
Brands and Indications. Beta blockers treat Stage A high blood pressure. They are also treat Stage B patients (both those who have had a heart attack and those who have not had a heart attack but who have heart damage). Recent guidelines identify three drugs best for treating Stage C patients with heart failure. Specific brands and stages include:
- Acebutolol (Sectral) -- (Stage A)
- Atenolol (Tenormin) -- (Stages A, B)
- Betaxolol (Kerlone) -- (Stage A)
- Bisoprolol (Zebeta) -- (Stages A, C)
- Cartelol (Cartrol) -- (Stage A)
- Carvedilol (Coreg) -- (Stages A, B, C)
- Labetalol (Trandate) -- (Stage A)
- Metoprolol succinate (Toprol XL) -- (Stages A, C)
- Metoprolol tartrate (Lopressor) -- (Stages A, B)
- Nadolol (Corgard) -- (Stage A)
- Penbutolol (Levatol) -- (Stage A)
- Pindolol (Visken) -- (Stage A)
- Propranolol (Inderal) -- (Stages A, B)
- Timolol (Blocadren, Timolide) -- (Stages A, B)
Beta Blocker Concerns
- Do not abruptly stop taking these drugs. The sudden withdrawal of beta blockers can rapidly increase heart rate and blood pressure. Your doctor may want you to slowly decrease the dose before stopping completely.
- Beta blockers are categorized as non-selective or selective. Non-selective beta blockers such as carvedilol and propranolol can narrow bronchial airways. Patients with asthma, emphysema, or chronic bronchitis should not use these beta blockers.
- Beta blockers can lower HDL (“good”) cholesterol.
- These drugs can hide warning signs of low blood sugar (hypoglycemia) in patients with diabetes.
- Beta blockers are usually used in combination with ACE inhibitors, but the two drugs are not started at the same time. Research presented at the 2005 European Society of Cardiology meeting indicates that either a beta blocker or an ACE inhibitor can be prescribed at first, and the other drug added on later.
Common Side Effects
- Fatigue and lethargy
- Vivid dreams and nightmares
- Depression
- Memory loss
- Dizziness and lightheadedness
- Reduced ability to exercise
- Coldness in extremities (legs, toes, arms, hands)
Check with your doctor about any side effects. Do not stop taking these drugs on your own.
Diuretics
Diuretics cause the kidneys to rid the body of excess salt and water. Fluid retention is a major symptom of heart failure. Aggressive use of diuretics can help eliminate excess body fluids, while reducing hospitalizations and improving exercise capacity. These drugs are also important to help prevent heart failure in patients with high blood pressure. In addition, certain diuretics, notably spironolactone (Aldactone), block aldosterone, a hormone involved in heart failure. This drug class is beneficial for patients in late stages of heart failure (Stages C and D).
Diuretic Types and Brands. Diuretics come in many brands and are generally inexpensive. Some need to be taken once a day, some twice a day. Treatment is usually started at a low dose and gradually increased. Diuretics are virtually always used in combination with other drugs, especially ACE inhibitors and beta blockers. There are three main types of diuretics:
- Potassium-sparing diuretics. These include amiloride (Midamor), spironolactone (Aldactone), and triamterene (Dyrenium).
- Thiazide diuretics. These include chlorothiazide (Diuril), chlorthalidone (Hygroton), indapamide (Lozol), hydrochlorothiazide (Esidrix, HydroDiuril), and metolazone (Mykrox, Zaroxolyn).
- Loop diuretics. Because loop diuretics act faster than other diuretics it is important to avoid dehydration and potassium loss. Loop diuretics include bumentanide (Bumex), furosemide (Lasix), and torsemide (Demadex).
Problems with Diuretics. Loop and thiazide diuretics deplete the body's supply of potassium, which, if left untreated, increases the risk for arrhythmias. Arrhythmias are heart rhythm disturbances that can, in rare instances, lead to cardiac arrest. In such cases, doctors will prescribe lower doses of the current diuretic, recommend potassium supplements, or use potassium-sparing diuretics either alone or in combination with a thiazide. Potassium-sparing drugs have their own risks, which include dangerously high levels of potassium in people with existing elevated levels of potassium or in those with damaged kidneys. However, all diuretics are generally more beneficial than harmful.
Common Side Effects
- Fatigue
- Depression and irritability
- Urinary incontinence
- Reduced sexual drive
Aldosterone Blockers
Aldosterone is a hormone that is critical in controlling the body's balance of salt and water. Excessive levels may play important roles in hypertension and heart failure. Drugs that block aldosterone are prescribed for some patients with Stage C heart failure.
- Spironolactone (Aldactone, Spirinol) is both a potassium-sparing diuretic and an aldosterone blocker. A major study of patients with heart failure found that spironolactone reduced death rate by 30%. Like all medications for heart failure, it must be used with care; elevated potassium levels are a potential risk of therapy.
- Eplerenone (Inspra), a newer aldosterone blocker, has been specifically approved for treatment of heart failure. It is prescribed for patients who have heart failure following a heart attack. Its actions are similar to potassium-sparing diuretics and, like these drugs, it poses some risk for high potassium levels.
Digitalis
Digitalis is derived from the foxglove plant. It has been used to treat heart disease since the 1700s. Digoxin (Lanoxin) is the most commonly prescribed digitalis preparation. Digoxin decreases heart size and reduces certain heart rhythm disturbances (arrhythmias).
Unfortunately, digitalis does not reduce mortality rates, although it does reduce hospitalizations and worsening of heart failure. Controversy has been ongoing for more than 100 years over whether the benefits of digitalis outweigh its risks and adverse effects.
Digitalis may be useful for patients with left-ventricular systolic dysfunction who do not respond to other drugs (diuretics, ACE inhibitors). It is also used for patients who have atrial fibrillation.
Digitalis does not appear to help patients with left-ventricular diastolic heart failure. It may be harmful in patients with right-ventricular heart failure and those who stop taking digoxin after using it in combination with ACE inhibitors.
Side Effects and Problems. While digitalis is generally a safe drug, it can have toxic side effects due to overdose or other accompanying conditions. The most serious side effects are arrhythmias (abnormal heart rhythms that can be life-threatening). Early signs of toxicity may be irregular heartbeat, nausea and vomiting, stomach pain, fatigue, visual disturbances (such as yellow vision, seeing halos around lights, flickering or flashing of lights), and emotional and mental disturbances.
Many factors increase the chance for side effects.
- Advanced age
- Low blood potassium levels (which may be caused by diuretics)
- Hypothyroidism
- Anemia
- Valvular heart disease
- Impaired kidney function
Digitalis also interacts with many other drugs, including quinidine, amiodarone, verapamil, flecainide, amiloride, and propafenone.
A blood test that monitors drug levels in patients taking the drug can limit the rate of toxicity to about 2%. For most patients with mild-to-moderate heart failure, low-dose digoxin may be as effective as higher doses. If side effects are mild, patients should still consider continuing with digitalis if they experience other benefits.
Hydralazine and Nitrates
Hydralazine and nitrates are two older drugs that help relax arteries and veins, thereby reducing the heart's workload and allowing more blood to reach the tissues. In 2005, the FDA approved BiDil, a drug that combines isosorbide dinitrate and hydralazine. BiDil is approved to specifically treat heart failure in African-Americans. African-Americans have a particularly high risk for heart failure. BiDil is the first drug approved for a specific racial group. The Food and Drug Administration (FDA) based its approval on a landmark 2004 study published in the New England Journal of Medicine, which showed that African-Americans who took the drug were 43% more likely to survive heart failure than patients who took placebo. Some experts suggest that BiDil could also benefit other racial groups.
Statins
Statins are important drugs used to lower cholesterol and to prevent heart disease leading to heart failure. These drugs include lovastatin (Mevacor), pravastatin (Pravachol), simvastatin (Zocor), fluvastatin (Lescol), atorvastatin (Lipitor), and rosuvastatin (Crestor). In 2007, the FDA approved atorvastatin to reduce the risks for hospitalization for heart failure in patients with heart disease.
In a 2006 Journal of the American Medical Association study, patients with heart failure who began taking a statin drug had a 24% lower relative risk of death and a 21% lower relative risk of hospitalization for heart failure than patient who did not take a statin. Statins appeared to help these patients regardless of whether or not they had co-existing coronary heart disease.
Aspirin
Aspirin is a type of non-steroid anti-inflammatory (NSAID). A 2005 study in the Journal of the American College of Cardiology indicated that aspirin is important for preventing heart failure death in patients with heart disease, and can safely be used with ACE inhibitors. However, some research has suggested that NSAIDs may increase the risk of heart failure for patients with a history of heart disease, especially when used in combination with ACE inhibitors or diuretics. Patients with heart disease should ask their doctor which NSAIDs are right for them.
Nesiritide (Natrecor)
Nesiritide treats patients who have arrived at a hospital with decompensated heart failure. Decompensated heart failure is a life-threatening condition in which the heart fails over the course of minutes or a few days, often as the result of a heart attack or sudden and severe heart valve problems. However, nesiritide may cause serious kidney damage.
In 2005, the FDA released recommendations from an expert panel concerning the appropriate and inappropriate use of nesiritide. The panel emphasized that nesiritide should be used to treat only patients with decompensated heart failure who have shortness of breath (dyspnea) and trouble breathing. The drug should not be a replacement for diuretics.
Despite these warnings, some doctors have prescribed nesiritide “off-label” to treat patients with severe heart failure outside of a hospital setting. Research presented at the 2007 American College of Cardiology annual conference criticized this practice by demonstrating that nesiritide plus standard treatment does not reduce the risk of heart- or kidney-related death or hospitalization. In addition, the research suggested some concerns about nesiritide’s overall safety.
Other Drugs
Tolvaptan. Tolvaptan is an investigational drug that is being studied in combination with standard therapy for treatment of heart failure. It is especially being investigated for acute decompensated heart failure, a type of heart failure categorized by fluid build-up in the lungs (pulmonary edema) for which there are few available treatments. In patients hospitalized with heart failure, tolvaptan plus standard drugs improved breathing problems (dyspnea) and reduced fluid accumulation (edema) and body weight, according to two studies published in 2007 in the Journal of the American Medical Association. However, the drug did not appear to reduce the risk of re-hospitalization or death.
Levosimendan. Levosimendan is an experimental inotropic drug that is being investigated as a treatment for severely ill patients with heart failure. It belongs to a new class of drugs called calcium sensitizers that may help improve heart contractions and blood flow. Clinical trials suggest that levosimendan may improve survival in patients hospitalized for heart failure. The drug also appears to reduce levels of BNP (brain natriuretic peptide), a chemical marker for heart failure severity.
Prograf. Tacrolimus (Prograf) was approved in 2006 to help prevent organ rejection in patients who have received a heart transplant. The drug suppresses the immune system. Patients who receive this drug are at increased risk of developing lymphoma (a cancer of the immune system).
Surgery and Devices
Revascularization Surgery
Revascularization surgery helps to restore blood flow to the heart. It can treat blocked arteries in patients with coronary artery disease and may help selected patients with heart failure. Surgery types include coronary artery bypass graft (CABG) and percutaneous coronary intervention (PCI). CABG is a traditional type of open heart surgery. PCI, also called angioplasty, uses a catheter to inflate a balloon inside the artery. A metal stent may also be inserted during a PCI procedure. [For more information, see In-Depth Report#03: Coronary artery disease.]
A 2006 study suggested that early treatment with revascularization surgery may be particularly important for patients with systolic heart failure, a condition that occurs when the heart does not pump out enough blood. This condition has a very high death rate. Researchers found that CABG or PCI surgery halved the risk of dying compared to standard drug therapy. Patients in the study first underwent a positron emission tomography (PET) test to determine if they would be good candidates for surgery.
Click the icon to see an illustrated series detailing coronary artery balloon angioplasty.
Click the icon to see an illustrated series detailing heart bypass surgery.
Mitral Valve Surgery
In appropriate patients, mitral valve surgery may significantly reduce the severity of heart failure. In a study of 92 patients with late-stage heart failure and faulty valves, reconstruction of the heart's mitral valve drastically improved heart function.
An experimental mesh "heart sock" is being investigated as an adjunct to mitral valve repair surgery. Research presented at the 2004 American Heart Association Scientific Sessions suggested that the device reduced the progression of heart failure and halved the need for transplant surgery. The "sock" helps realign the shape of the heart and improve heart function. To date, it has been tested in patients with dilated cardiomyopathy.
Ventricular Remodeling and Restoration
Ventricular Remodeling. Ventricular remodeling (also called partial left ventriculectomy or the Batista procedure, after its inventor) may allow some patients with dilated cardiomyopathy to avoid a heart transplant.
The procedure involves the following:
- The surgeon first performs ventriculectomy, which is the removal of a section of healthy heart muscle weighing about 3 ounces.
- The surgeon then reshapes the heart to a more normal size and form.
- Any faulty heart valves are repaired.
Ventricular remodeling is still relatively new, and mortality rates are very high. Studies on long-term improvement are mixed. More research is needed to target the patients who would most benefit.
Heart Transplantation
Patients who suffer from severe heart failure and whose symptoms do not improve with drug therapy or mechanical assistance may be candidates for heart transplantation. Some 3,600 people are awaiting a transplant, although only about 2,000 operations are performed each year.
The most important factor for heart transplant eligibility is overall health. Chronological age is less important. Most heart transplant candidates are between the ages of 50 – 64 years. About 72% of transplant patients are male, and 70% are white.
While the risks of this procedure are high, the 1-year survival rate is about 86% for men and 84% for women. The 3-year survival rate is 78% for men and 75% for women. Five years after a heart transplant, about 71% of men and 67% of women remain alive. In general, the highest risk factors for death 3 or more years after a transplant operation are coronary artery disease and the adverse effects (infection and certain cancers) of immunosuppressive drugs used in the procedure. The rejection rates in older people appear to be similar to those of younger patients.
Implantable Artificial Heart
In 2004, the FDA approved a temporary artificial heart (Syncardia) intended to keep patients alive in the hospital while they waited for a heart transplant. In 2006, the FDA approved the first permanent implantable artificial heart (AbiCor). The AbiCor is available only for patients who are not eligible for a heart transplant and who are not expected to live more than a month without medical treatment. The device requires a large chest cavity, which means that most women will not be eligible for it. Of the 14 men who have received the AbiCor, the average survival was less than 5 months after surgery. Only one patient was discharged from the hospital. The device’s manufacturer is working on a new model that it hopes will extend survival by as long as 5 years.
Devices to Control Heart Pumping
A growing array of heart devices and machines are changing the face of heart failure treatment. They have gained widespread acceptance for use as a bridge to transplant in patients who are on medications but still have severe symptoms and are awaiting a donor heart. Increasingly, though, doctors are exploring the possibility that such devices may be satisfactory treatments themselves, forestalling the need for a transplant altogether in some patients.
Ventricular Assist Devices (VADs). Ventricular assist devices are machines that help improve pumping actions. Several models with slightly different features are in use or under investigation. Some include the following:
- Left ventricular assist device (LVAD) are used for patients whose heartbeat has slowed dangerously (a condition called bradycardia) to help take over the pumping action of the failing heart. Studies suggest that in some people the use of an LVAD may allow some of the damaged heart muscle to heal, perhaps even helping some patients avoid heart transplants. These devices are also being studied in combination with drug therapy to help recover heart function and improve patients’ chances for survival. Until recently, these machines required remaining in the hospital. Smaller battery-powered LVAD units, however, are allowing many patients to leave the hospital and are proving to be effective bridges to heart transplants in adults. The HeartMate, for example, a portable LVAD about the size of a portable CD player (2 in. by 4 in.), is implanted in the upper abdomen. The implanted device plugs into an external power base, which is used when the patient is at rest to recharge the battery and provide continuous power.
- Fully implanted miniature artificial pumps that assist the heart (not replace it) are also being tested. The DeBakey ventricular assist device (VAD) for example, is a tiny heart pump that weighs less than 4 ounces. It has been approved in Europe and is being tested in the United States. The Jarvik 2000 heart pump is also showing promise.
- The intra-aortic balloon pump (IABP) is helpful for maintaining heart function in people with left-side failure waiting for transplants and in those who develop a sudden and severe deterioration of heart function. The IABP is an implanted thin balloon that is usually inserted into the artery in the leg and threaded up to the aorta leading from the heart. Its pumping action is generated by inflating and deflating the balloon at certain rates. Usually, it is used only for short periods, but some studies indicate that patients may be able to use it safely for somewhat longer periods (an average duration of 23 days in one study).
There are risks involved with many of these devices, including bleeding, blood clots, and right-side heart failure. Infections are a particular hazard.
Devices to Control Heart Rhythm
Pacers (Pacemakers). Pacers, or pacemakers, help regulate the heart’s beating action, especially when the heart beats too slowly. Biventricular pacers (BVPs) are a special type of pacemaker used for patients with heart failure. Because BVPs help the heart’s left and right chambers beat together, this treatment is called cardiac resynchronization therapy (CST). BVPs may particularly help heart failure patients who have left bundle branch block, a condition in which the electrical impulses in the heart do not follow their normal pattern. In general, BVPs are recommended for patients with moderate-to-severe heart failure. A small 2006 study suggested that a defibrillator may be better suited for patients with moderate heart failure, while indicating a BVP might be best for patients with severe heart failure.
Implantable Cardioverter-Defibrillators. Devices called implantable cardioverter-defibrillators (ICDs), which are sometimes combined with pacemakers, work well for preventing arrhythmias (abnormal heart rhythms) in heart failure patients. Studies have also found them effective in preventing sudden death from severe rhythm disturbances in patients with weakened hearts from previous arrhythmias and in patients with genetic hypertrophic cardiomyopathy. Patients who have an ICD should avoid taking fish oil supplements. A 2005 Journal of the American Medical Association study found that omega-3 fatty acid supplements may increase the risk of rapid heart beat (ventricular tachycardia) or irregular heart rhythm (ventricular fibrillation) in some of these patients.
ICDs have many benefits, and recent expert guidelines recommend that they be used in more patients with heart failure. However, in June 2005, certain ICD models and biventricular pacemaker-defibrillators were recalled by the manufacturer because of a circuitry flaw that prevents the devices from delivering therapeutic electrical shocks when needed. The problem may result in patient death. Although the FDA did not make any specific recommendations, the agency encourages patients who may have such a device to ask their doctor if they should have it removed or replaced.
In April 2006, two studies published in the Journal of the American Medical Association evaluated data concerning the safety and reliability of implantable pacemakers and defibrillators. The studies found that from 1990 – 2002, pacemakers became increasingly reliable. From 1998 – 2002, ICDs had a significantly higher rate of malfunction than pacemakers, although the reliability of ICDs appeared to improve from 2003 – 2004.
In October 2006, the U.S. Heart Rhythm Society issued recommendations for doctors, manufacturers, and the FDA to help improve communication concerning performance and recalls of ICDs and pacemakers. Experts stress that the chance of an ICD or pacemaker saving a person’s life far outweigh the possible risks of these devices failing.
Devices to Remove Fluids
Ultrafiltration devices are used in hospitals to pump excess water and salt from the body. Catheters are inserted into several of the patient’s veins. The catheters are connected to a blood filter device. Blood is withdrawn through one of the catheters and filtered in the device to remove excess fluid. The filtered blood is then returned to the patient through another catheter. A 2006 study reported that ultrafiltration devices may work better than diuretic drugs for patients with acute decompensated heart failure (ADHF). ADHF is heart failure that has rapidly deteriorated so that patients require immediate hospitalization.
Lifestyle Changes
Between 30 - 47% of patients who require hospitalization for heart failure are back in the hospital within 6 months. Many people return because of lifestyle factors such as poor diet, failure to comply with medications, and social isolation.
Home Support and Rehabilitation Programs
In one study, elderly people who had no emotional support at home had triple the risk of a heart attack after hospitalization for heart failure than those who did have such support. (Women had eight times the risk.) In another study, the greatest risk factor for death and readmission to the hospital after a first hospitalization was being single, regardless of the health of the patient at discharge. A third study confirmed that a strong marriage predicted long-term survival. Evidence continues to mount that programs that offer intensive follow-up to ensure that the patient complies with lifestyle changes and medication regimens at home are reducing rehospitalization rates and improving survival. Patients without available rehabilitation programs should seek support from local and national heart associations and groups.
Monitoring Weight Changes
Patients should weigh themselves each morning and keep a record. Any changes are important:
- A sudden increase in weight of more than 2 - 3 pounds may indicate fluid accumulation and should prompt an immediate call to the doctor.
- Rapid wasting weight loss over a few months is a very serious sign and may indicate the need for surgical intervention.
Dietary Factors
Whole Grains. Evidence suggests that daily consumption of whole grain foods may help prevent heart failure. In research presented at a 2007 American Heart Association conference, people who ate whole-grain breakfast cereals seven or more times a week had a 28% lower risk of developing heart failure than those who never ate these cereals.
Mediterranean Diet. Evidence suggests that the Mediterranean diet helps protect the heart and may even reduce the risk for heart failure after a first heart attack. The diet emphasizes whole grains, fish, olive oil, garlic, and moderate daily intake of wine. There are several variations to the Mediterranean diet but general recommendations include:
- Limit red meats.
- Limit dairy products.
- Eat moderate amounts of fish and poultry. Fish is the diet’s main protein source. Some studies suggest that fish is the primary heart-protective ingredient in this diet. However, patients who have an implantable defibrillator should not take fish oil supplements. A 2005 study suggested that these supplements may worsen heart rhythm problems in some patients.
- Eat plenty of fresh fruits and vegetables, nuts, legumes, beans, and whole grains.
- Daily glass or two of wine. Light-to-moderate alcohol use may reduce the risk for heart failure, (but heavy alcohol consumption is a risk factor).
- Plenty of fresh fruits and vegetables, as well as nuts, legumes, beans, and whole grains.
DASH Diet. The Dietary Approaches to Stop Hypertension (DASH) diet is an important lifestyle step in managing blood pressure. It may also be useful for many patients with heart failure. This diet is not only rich in important nutrients and fiber but also includes foods that contain two and a half times the amounts of electrolytes, potassium, calcium, and magnesium found in the average American diet.
Potassium-rich foods, which are important for patients with heart failure, include bananas, oranges, prunes, cantaloupes, carrots, spinach, celery, alfalfa, mushrooms, lima beans, potatoes, avocados, and broccoli. However, patients who take potassium-sparing diuretics or ACE inhibitors, and those with kidney dysfunction, may have to restrict their potassium intake.
The DASH diet is rich in whole grains and fresh fruits and vegetables. It stresses avoiding saturated fats, as any healthy diet does, although it includes calcium-rich dairy products that are non- or low-fat. When choosing fats, the diet recommends monounsaturated oils such as olive or canola oil.
Salt Restriction. People with high blood pressure are generally urged to restrict salt, although certain people may be more susceptible to its effects. For example, a high intake of salt may be an independent risk factor for the development of heart failure in people who are overweight. All patients with heart failure should limit their salt intake, and in severe cases, very stringent salt restriction may be necessary. Patients should not add salt to their cooking and their meals. They should also avoid foods high in sodium. These salty foods include ham, bacon, hot dogs, lunch meats, prepared snack foods, dry cereal, cheese, canned soups, soy sauce, and condiments. Some patients may need to reduce their water intake as well. People with high cholesterol levels or diabetes require additional dietary precautions.
[For more information, see In-Depth Report #43: Heart-healthy diet.]
Exercise
People with heart failure used to be discouraged from exercising. Now, experts think that exercise, when performed under medical supervision, is extremely important for many patients with stable conditions. Studies have reported that patients with stable conditions who engage in regular moderate exercise (three times a week) experience a better quality of life and lower mortality rates than those who do not exercise.
The following guidelines are critical:
- Experts warn that exercise is not appropriate for all patients with heart failure. If you have heart failure, always consult your doctor before starting an exercise program.
- People who are approved for, but not used to, exercise should start with 5 - 15 minutes of easy exercise with frequent breaks. Although the goal is to build up to 30 - 45 minutes of walking, swimming, or low-impact aerobic exercises three to five times every week, even shorter times spent exercising are useful.
Studies report benefits from specific exercises:
- Progressive strength training may be particularly useful for patients with heart failure since it strengthens muscles, which commonly deteriorate in this disorder. Strength training typically uses light weights, weight machines, or even the body's weight (leg raises or sit-ups, for example). Even performing daily handgrip exercises can improve blood flow through the arteries.
- Patients who exercise regularly using supervised treadmill and stationary-bicycle exercises can increase their exercise capacity by 14 - 36%. In one study, patients as old as 91 years increased their oxygen consumption significantly after 6 months of supervised treadmill and stationary bicycle exercises. Exercising the legs may help correct problems in heart muscles. In one study, patients who did leg extension exercises for 8 weeks had higher levels of an enzyme involved in forming new blood vessels. Exercise has also been associated with reduced inflammation in blood vessels.
- Dancing may be a fun and beneficial alternative to standard aerobic exercise, according to research presented at the 2006 annual meeting of the American Heart Association. In a study of patients with stable chronic heart failure, dancing helped improve cardiopulmonary fitness, arterial elasticity, and quality of life. Patients in the study danced fast and slow waltzes for 21 minutes, three times a week.
Bed Rest
Bed rest may be required in cases of severe heart failure. To reduce congestion in the lungs, the patient's upper body should be elevated. For most patients, resting in an armchair is better than lying in bed. Relaxing and contracting leg muscles is important to prevent clots. As the patient improves, a doctor will progressively recommend more activity.
Warm Baths and Saunas
Experts have traditionally recommended that people with heart failure avoid warm baths, which can increase the heart rate. Some studies now report that carefully controlled bathing for short periods may not be harmful and may actually be beneficial, reducing irregular heart beats and increasing cardiac output and ejection fraction. Warm water may behave like a vasodilating drug, opening up the vessels gently and improving circulation. In clinical trials, patients sat in warm water or a dry sauna for 10 minutes, with their bodies tilted at a 45 degree angle.
Warning Note: Prolonged periods in hot or even warm conditions can be dangerous. Any patient with heart failure should consult their doctor first, not bathe unaccompanied, and be sure that the temperature does not go above 106° Fahrenheit for water bathing or 140° Fahrenheit for dry saunas.
Stress Reduction
Stress reduction techniques, such as meditation and relaxation response methods, may have direct physical benefits for lowering stress hormones. These hormones include cortisol, which suppresses the immune system, and norepinephrine (also known as adrenaline), the chemical messenger associated with heart dysfunction.
Alternative Remedies
Patients with heart failure may resort to alternative remedies. Such remedies are often ineffective and may have severe or toxic effects. Of particular note for patients with heart failure is an interaction between St. John's wort (an herbal medicine used for depression) and digoxin (a heart drug). St. John's wort can significantly interfere with this drug.
Arginine. Some evidence suggests that arginine (also called L-arginine) may have some benefit. This amino acid appears to reduce endothelin, a protein that causes blood vessel constriction and is found in high amounts in patients with heart failure. It can have adverse effects, however, including gastrointestinal problems. It can also lower blood pressure and change levels of certain chemicals and electrolytes in the body. It may increase the risk for bleeding. Some people have an allergic reaction to it, which in same cases may be severe. It may worsen asthma.
Coenzyme Q10 and Vitamin E. Small studies have suggested that coenzyme Q10 (CoQ10) may help patients with heart failure, particularly when combined with vitamin E. CoQ10 is a vitamin-like substance found in organ meats and soybean oil. More recent studies, however, have found that CoQ10 and vitamin E do not help the heart or prevent heart disease. According to a 2005 Journal of the American Medical Association study, vitamin E supplements can actually increase the risk of heart failure, especially for patients with diabetes or vascular diseases.
Crataegus Extract. An herbal remedy, Crataegus Extract WS1442, which is made from the leaves of the Crataegus tree, may have antioxidant properties that can help patients with heart failure. In a study presented at the 2007 American College of Cardiology annual meeting, over 2,000 patients with severe heart failure were randomized to receive either Crataegus Extract or placebo (plus standard drug treatment) for 2 years. The researchers noted a 20% reduction in heart-related deaths among patients who received the extract, and suggested that the herb extended patients’ lives by 4 months during the first 18 months of the study.
Other Vitamins and Supplements. A wide variety of other vitamins (thiamin, B6, and C), minerals (calcium, magnesium, zinc, manganese, copper, selenium), nutritional supplements (carnitine, creatine), and herbal remedies (hawthorn) have been proposed as treatments for heart failure. None have been adequately tested. There is no evidence that a particular vitamin or supplement can cure heart failure. In any case, vitamins are best consumed through the food sources contained in a healthy diet.
Herbs and SupplementsGenerally, manufacturers of herbal remedies and dietary supplements do not need FDA approval to sell their products. Just like a drug, herbs and supplements can affect the body's chemistry, and therefore have the potential to produce side effects that may be harmful. There have been several reported cases of serious and even lethal side effects from herbal products. Always check with your doctor before using any herbal remedies or dietary supplements. |
Resources
- www.nhlbi.nih.gov -- National Heart, Lung, and Blood Institute
- www.americanheart.org -- American Heart Association
- www.acc.org -- American College of Cardiology
- www.hfsa.org -- Heart Failure Society of America
- www.heartfailure.org -- Heart Failure Online
- www.unos.org -- United Network for Organ Sharing
- www.organdonor.org -- National Transplant Society
- www.organdonor.gov -- US government organ donor site
References
Ahmed A, Rich MW, Fleg JL, Zile MR, Young JB, Kitzman DW, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation. 2006 Aug 1;114(5):397-403.
Battaglia M, Pewsner D, Juni P, Egger M, Bucher HC, Bachmann LM. Accuracy of B-type natriuretic peptide tests to exclude congestive heart failure: systematic review of test accuracy studies. Arch Intern Med. 2006 May 22;166(10):1073-80.
Bhatia RS, Tu JV, Lee DS, Austin PC, Fang J, Haouzi A, et al. Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med. 2006 Jul 20;355(3):260-9.
Birks EJ, Tansley PD, Hardy J, George RS, Bowles CT, Burke M, et al. Left ventricular assist device and drug therapy for the reversal of heart failure. N Engl J Med. 2006 Nov 2;355(18):1873-84.
Bryson CL, Mukamal KJ, Mittleman MA, Fried LP, Hirsch CH, Kitzman DW, et al. The association of alcohol consumption and incident heart failure: the Cardiovascular Health Study. J Am Coll Cardiol. 2006 Jul 18;48(2):305-11.
Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nkomo VT, et al. Systolic and diastolic heart failure in the community. JAMA. 2006 Nov 8;296(18):2209-16.
Carlson MD, Wilkoff BL, Maisel WH, Carlson MD, Ellenbogen KA, Saxon LA, et al. Recommendations from the Heart Rhythm Society Task Force on Device Performance Policies and Guidelines Endorsed by the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) and the International Coalition of Pacing and Electrophysiology Organizations (COPE). Heart Rhythm. 2006 Oct;3(10):1250-73.
Davis BR, Piller LB, Cutler JA, Furberg C, Dunn K, Franklin S, et al. Role of diuretics in the prevention of heart failure: the Antihypertensive andLipid-Lowering Treatment to Prevent Heart Attack Trial. Circulation. 2006 May 9;113(18):2201-10. Epub 2006 May 1.
Gheorghiade M, Abraham WT, Albert NM, Greenberg BH, O'Connor CM, She L, et al. Systolic blood pressure at admission, clinical characteristics, and outcomes inpatients hospitalized with acute heart failure. JAMA. 2006 Nov 8;296(18):2217-26.
Gheorghiade M, Konstam MA, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heartfFailure: the EVEREST clinical status trials. JAMA. 2007 Mar 25; [Epub ahead of print]
Go AS, Lee WY, Yang J, Lo JC, Gurwitz JH. Statin therapy and risks for death and hospitalization in chronic heart failure. JAMA. 2006 Nov 1;296(17):2105-11.
Hildebrandt P. Systolic and nonsystolic heart failure: equally serious threats. JAMA. 2006 Nov 8;296(18):2259-60.
Konstam MA, Gheorghiade M, Burnett JC Jr, Grinfeld L, Maggioni AP, Swedberg K, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: the EVEREST Outcome Trial. JAMA. 2007 Mar 25; [Epub ahead of print]
Lee DS, Pencina MJ, Benjamin EJ, Wang TJ, Levy D, O'Donnell CJ, et al. Association of parental heart failure with risk of heart failure in offspring. N Engl J Med. 2006 Jul 13;355(2):138-47.Maisel WH. Pacemaker and ICD generator reliability: meta-analysis of device registries. JAMA. 2006 Apr 26;295(16):1929-34.
Maisel WH, Moynahan M, Zuckerman BD, Gross TP, Tovar OH, Tillman DB, et al. Pacemaker and ICD generator malfunctions: analysis of Food and Drug Administration annual reports. JAMA. 2006 Apr 26;295(16):1901-6.
Mueller C, Laule-Kilian K, Schindler C, Klima T, Frana B, Rodriguez D, et al. Cost-effectiveness of B-type natriuretic peptide testing in patients with acute dyspnea. Arch Intern Med. 2006 May 22;166(10):1081-7.
Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006 Jul 20;355(3):251-9.
Reviewed By: Harvey Simon, M.D., Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital
