Late Effects to the Heart
Friday, September 05, 2008

Late Effects to the Heart
by Kevin Oeffinger MD and Nancy Keene

Part I: Anthracyclines and the Heart

Anthracyclines, such as Adriamycin, are a group of chemotherapy medications used to treat a variety of childhood cancers. Use of anthracyclines has resulted in significantly increased rates of survival, but can also lead to a problem with the heart that may not show up until 10 - 15 years after treatment. Because some survivors are at higher risk for developing heart problems than others and because tests are available that can pick up the problem at an early stage, it is important for each childhood cancer survivor to find out his/her individual risk.

The Heart

The heart is a large muscle that is divided into four chambers and is designed to pump the blood around the body. The upper chambers or rooms are called atria and the lower chambers are called ventricles. The blood returning from the body enters the right atrium, is squeezed into the right ventricle, and then is pumped into the blood vessels in the lungs. It is here that the oxygen we breathe is transferred into many small blood vessels in the lungs. The blood, now rich with oxygen, returns to the left atrium and then is squeezed into the left ventricle, the largest and most powerful of the chambers. The left ventricle contracts to circulate the blood to the entire body.

The Problem

The cells of the heart muscle are called cardiomyocytes (cardio = heart, myo = muscle, cytes = cells). In ways that are not well understood, anthracyclines can cause damage to the cardiomyocytes of the left ventricle. Over time, this can lead to thinning of the outside wall or muscle of the left ventricle, resulting in a stiff, noncompliant (loss of normal resiliency) left ventricle. The medical term for this condition is cardiomyopathy (cardio = heart, myo = muscle, pathy = abnormal, weakened).

Generally, this is not a problem while at rest, but when the heart needs to work harder, such as during exercise or strenuous physical activity, the stiff left ventricle may not be capable of increased pumping action. If this happens, the blood that is being pumped through the left side of the heart (atrium and ventricle) does not get pumped out fast enough and some of it "backlogs" in the small blood vessels of the lungs. Remember that the oxygen in the lungs is transferred to these small blood vessels, and so when the vessels become engorged with the backlogged blood, the oxygen can not be transferred properly. Though this problem, called congestive heart failure, can be quite serious, there are medications that can help.

Who is at risk?

Over half of the survivors who received anthracyclines (Adriamycin - doxorubicin; Cerubidine - daunorubicin; Idamycin - idarubicin) will have some damage to the heart muscle that can be detected with sophisticated testing. The percentage of survivors with some damage who will experience progressive weakening of their heart muscle and develop congestive heart failure is not known. It is likely that most survivors who have mild changes in heart functioning will not have increasing damage and will never develop symptoms. Long-term studies following survivors for many years are needed to help us better understand the process and factors that may worsen heart function. From studies to date, we know that patients treated with moderate to high dosages of an anthracycline are at higher risk. Use of chest/mantle radiation along with an anthracycline further increases the risk. In addition, females and survivors treated at a younger age (before 5 years old) are generally more likely to have problems than males or survivors treated at an older age.

What are the symptoms of a heart problem from an anthracycline?

Possible symptoms of congestive heart failure include:

• increasing shortness of breath or difficulties in breathing with exercise
• shortness of breath when lying flat, especially at night
• chest pain (generally of a smothering type sensation)
• increasing fatigue
• poor appetite
• swelling of the ankles

These symptoms may be caused by a variety of other medical conditions, so it is very important to see a physician if you have any of these symptoms.

Is there anything that could worsen the weakened heart muscle or make me symptomatic?

Yes, the following things can potentially worsen a cardiomyopathy:

• Pregnancy - During pregnancy, the volume of blood is increased in a woman's body and can stress the heart. Thus, the first time a survivor may develop symptoms is during pregnancy or labor. It is very important that a pregnant survivor who has been treated with an anthracycline be evaluated by a doctor knowledgeable about this late effect.
• Alcohol -More than a beer or glass of wine a day can further weaken the heart muscle, so only drinking in moderation is important.
• Cocaine - Use of cocaine can cause a life-threatening rhythm disturbance of a heart that has been weakened by an anthracycline.
• Weight lifting - Isometric exercises, such as weight lifting, can cause an acute decompensation (significant worsening of heart function at the time of weight lifting). Heavy weight lifting can be dangerous if a survivor has some weakening of the heart muscle, and so other forms of exercise are recommended. Weight lifting with high repetition and low weights is probably not a problem.

So now that you have scared me with all of this information, what should I do?

It is not our intent to scare survivors with these facts and figures, but rather to educate the reader about potential long-term risks related to previous treatment. Many survivors have no heart damage. Many of those who do show damage have no progressive weakening of the heart muscle. However, it is very important to find out about your individual risk. In a past column, we discussed the value of each survivor obtaining a summary of his/her previous cancer treatment, including a list of chemotherapy medications. If you have a list, see if you received an anthracycline (Adriamycin - doxorubicin; Cerubidine - daunorubicin; Idamycin - idarubicin). If you didn't, this is not a problem you need to worry about. If you did (or if you are not sure), see your doctor and discuss your risk. Although recommendations vary, many institutions recommend periodic testing for survivors who had 175 mg/m2 or more of an anthracycline after the age of five. Those who received any anthracyclines before the age of five require life-long periodic testing.

If you are at risk, the most common test that is ordered to evaluate the heart for cardiomyopathy is an echocardiogram. This test is like an ultrasound of the heart and allows a cardiologist (heart specialist) to measure the thickness of the muscle of the left ventricle and to assess the pumping ability of the heart. The two primary measures used to assess the function of the left ventricle, the main pumping chamber of the heart, are the ejection fraction and the shortening fraction. The ejection fraction is a ratio, calculated by measuring the amount of blood that is pumped out with each beat and dividing it by the amount of blood that waits for the next cycle. Generally, a normal ejection fraction is considered to be above 60%. A decrease in the shortening fraction usually precedes a detectable decrease in the ejection fraction. The shortening fraction is also a ratio, determined by the diameter change of the left ventricle between the relaxation and the contraction phases divided by the diameter of the left ventricle in the relaxation phase. Above 30% is considered normal, with 26 to 30% representing a mild decrease in function.

If I have a problem with the heart muscle is there anything that can be done to help?

Yes. First, knowing that there is a problem allows your doctor to evaluate you more often and have a better idea of when and if the weakening of your heart muscle will become symptomatic and affect your life. This is especially important for female survivors who want to get pregnant. Second, there is a group of medications, called angiotensin converting enzyme (ACE) inhibitors, that have been very successful in helping patients with other types of cardiomyopathies. A current multi-institution study, funded by the National Institutes of Health, is evaluating one of the ACE inhibitors, enalapril, to see if it helps to improve the function of heart muscle that has been damaged by anthracyclines. Hopefully, this study and others to follow will provide some help for survivors with this late effect.

Part II: Radiation and the Heart

In our last column, we discussed the long-term effect anthracyclines (adriamycin, daunorubicin, idarubicin) can have on the heart. Several readers called asking about the recommendation for life-long follow up for those who received 175 mg/m2 after the age of five. This dosage refers to the total dose a survivor received during treatment. The summary of treatment that you should get from the treating institution should include total (also called cumulative dose) of every medication you received. So, if you received 175 mg/m2 of any combination of anthracyclines over the course of your treatment after the age of five (or any dose prior to the age of five) you should get periodic testing of your heart for the rest of your life. Lower dosages generally do not cause a problem. Nevertheless, because some survivors will have heart problems even with lower dosages, it is important for them to continue regular medical follow-up with a physician or a long-term follow-up program and discuss screening tests on an individual basis.

Like anthracyclines, high-dose radiation can cause several late effects to the heart. Use of radiation has made a tremendous difference in treating cancer and leading to significantly higher survival rates, but can also lead to problems many years after treatment. Because some survivors are at higher risk for heart problems than others and because tests are available that can pick up problems at an early stage, it is important for each survivor to find out his/her individual risk.

The Heart

As we discussed in Part I, the heart is a large muscle that is divided into four chambers and is designed to pump the blood around the body. The upper chambers or rooms are called atria and the lower chambers are called ventricles. The blood returning from the body enters the right atrium, is squeezed into the right ventricle, and then is pumped into the blood vessels in the lungs. It is here that the oxygen we breathe is transferred into many small blood vessels in the lungs. The blood, now rich with oxygen, returns to the left atrium and then is squeezed into the left ventricle, the largest and most powerful of the chambers. The left ventricle contracts to circulate the blood to the entire body.

The doors between the heart chambers are called valves (aortic, mitral, pulmonary, and tricuspid). One valve will open as blood flows into a chamber and then close as the chamber contracts and squeezes the blood into the next chamber. On the outside of the heart is a network of blood vessels (coronary arteries) that take oxygen and nutrients to the hard working heart muscle. This network starts as two vessels that then divide into several branches.

The Problem with Radiation

Most survivors who received radiation will not have a problem with their heart. But in some, the radiation can damage the heart in one of several ways, including damaging the heart muscle, the valves, or the coronary arteries. Each of these three problems is quite different, so let's discuss them one at a time.

Damage to the heart muscle is called cardiomyopathy. Remember from our last column that this term is used when the muscle does not work as well as it should. It generally affects the left ventricle (chamber) more than other parts of the heart, causing it to be stiff and less responsive to changes. Usually when someone is at rest the heart does not have to work hard. But when the heart needs to work harder, such as during pregnancy or strenuous physical activity, the stiff left ventricle may not be capable of increased pumping action. If this happens, the blood that is being pumped through the left side of the heart (atrium and ventricle) does not get pumped out fast enough and some of it "backlogs" in the small blood vessels of the lungs. The oxygen in the lungs is transferred to these small blood vessels, and so when the vessels become engorged with the backlogged blood, the oxygen can not be transferred properly. Though this problem, called congestive heart failure, can be quite serious, there are medications that can help.

Radiation can also damage the valves in the heart, especially the two valves on the left side of the heart (mitral and aortic). If a valve is damaged, it can lead to either being "leaky" so that blood flows backwards into the chamber it came from or it can be stiff and not open very well, slowing the flow of blood. This can lead to congestive heart failure and other problems with the heart.

A third problem that radiation can cause is premature coronary artery disease. The network of small blood vessels on the outside of the heart feed the heart muscle with oxygen and nutrition. The interiors of healthy blood vessels are smooth. Radiation can roughen the inside of blood vessels. These rough spots provide a site for fatty deposits (plaques) to develop in coronary arteries and other arteries and veins. Calcium deposits can harden the plaques resulting in atherosclerosis (hardening of the arteries).

Coronary artery disease (coronary = heart, artery = blood vessel, disease = what we don't want) is when one or more of the blood vessels or branches gets clogged with plaque. It is similar to a clogged pipe that does not allow much to flow by it. If this happens, the heart muscle cannot get enough oxygen and nutrition for all of its work. So when the heart needs to work harder and it cannot get enough oxygen or nutrition, it generally causes some chest pain (angina) which will last a few minutes until the oxygen gets gets through the partially clogged artery. If the blood vessel is fully blocked, the part of the muscle that was depending upon the oxygen from that vessel dies (a heart attack). If it is a small branching blood vessel going to a small amount of heart muscle, then the person has a small or minor heart attack. But if it is a larger vessel feeding a larger amount of heart muscle, the heart attack is serious and can be life-threatening.

Who is at risk?

Children or teens who received spinal radiation, chest radiation (Hodgkin's, non-Hodgkin's lymphoma), left flank (Wilms), or radiation directly to the heart are possibly at risk. Modern radiation techniques using lower total doses, hyperfractionation (smaller doses more often), and cardiac shielding are less likely to cause damage.

Whether the heart sustains injury after radiation treatment depends on several factors including:

• Total radiation dose
• Dose of radiation fractions
• Amount and areas of the heart treated
• Presence of tumor in or next to the heart
• Chemotherapy drugs used - the anthracyclines greatly increase the risk
• Age, weight, blood pressure, and family history.
• Smoking
• Cholesterol level

What are the symptoms of a heart problem from radiation?

The signs and symptoms for radiation-induced heart damage vary widely. Possible symptoms of congestive heart failure include:

• increasing shortness of breath or difficulties in breathing with exercise
• shortness of breath when lying flat, especially at night
• chest pain (generally a smothering type sensation)
• increasing fatigue
• poor appetite
• swelling of the ankles

Possible symptoms of coronary artery disease are:

• Uncomfortable pressure, fullness, squeezing or pain in the center of the chest that lasts a few minutes, or goes away and comes back
• Pain that spreads to the shoulders, neck or arms
• Chest discomfort with lightheadedness, fainting, sweating, nausea or shortness of breath

By the time you notice symptoms, secondary problems may have developed. Thus, it is important if you are at risk to have regular check-ups of your heart function.

Is there anything that I can do to stay healthy?

Very much so! The risk for each one of these three heart problems is increased by lifestyle choices. Smoking, lack of exercise, a poor diet, and alcohol (more than an occasional beer or glass of wine) can significantly add to damage done by the radiation. Cocaine is particularly dangerous because it can cause direct damage to the muscle or to the electrical system of the heart. Finally, uncontrolled high blood pressure or diabetes can add to the damage. Bottom line - take care of yourself and continue to get regular preventive medical care.

So now that you have scared me with all this information, what should I do?

It is not our intent to scare survivors with these facts and figures, but rather to educate the reader about potential long-term risks related to previous treatment. Many survivors have no heart damage. Many of those who do show damage have no progressive weakening of the heart muscle. However, it is very important to find out about your individual risk. In a past column, we discussed the value of each survivor obtaining a summary of his/her previous cancer treatment, including a list of chemotherapy medications. If you have a list, see if you received any radiation to the chest or heart. If you didn't, this is not a problem you need to worry about. If you did (or if you are not sure), see your doctor and discuss your risk and get any necessary testing.

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