Late Effects: Heart
Chemotherapy (specifically, the anthracyclines) and radiation can affect the heart years after treatment. The following two articles appeared in the Fall and Winter 2000 CCCF (Candlelighters Childhood Cancer Foundation) Newsletters and are reproduced here with the permission of CCCF.
After reading these articles, you may still have a lot of questions about late effects to the heart. I know that I did, largely because I knew very little about how the heart works, what the different heart diseases are, and how doctors diagnose and treat the various heart problems. First, here is a summary of the treatment and the late effect, from the above articles. Click on the "late effect" link in the table to learn more about the condition.
|Anthracyclines||anthracycline-induced cardiomyopathy||thinning of the left ventricle|
|Radiation||radiation-induced cardiomyopathy||usually stiffening of the left ventricle|
|Radiation||damages the valves||valve damage|
|Radiation||premature coronary artery disease||scarring of the arteries|
Are you at risk? If you did not have anthracyclines or radiation, no. Anthracyclines include Adriamycin (or doxorubicin); Cerubidine (or daunorubicin); Idamycin (or idarubicin). These are common to many leukemia and lymphoma protocols as well as some solid tumor protocols, especially those for Wilm's tumor.
- Giesler G, Lenihan D, Tong A, et al. Withdrawal of ACE inhibitors and beta-blockers in cancer patients with congestive heart failure leads to severe cardiovascular adverse events. J Card Fail. 2003;9(5 suppl):S77. Abstract 281.
- Lenihan D, Woods ML, Vooletich MT, et al. Herceptin (trastuzumab)-associated cardiomyopathy: Sequential stress and response to ACE inhibitors and carvedilol therapy. J Card Fail. 2003;9(5 suppl):S102. Abstract 383.
Anthracyclines can damage the left ventricle, causing thinning of the outside wall of the left ventricle. This is a form of cardiomyopathy, or damage to the heart muscle. It can lead to congestive heart failure, or CHF.
What is the left ventricle, anyway? I searched the web looking for ready-explanations and found quite a few. Start with the link below for a diagram of the heart:
From the diagram (and the discussion that accompanies it) we learn that the left ventricle is one of four chambers of the heart. The left ventricle, or "chamber," receives (via the left atrium) blood which was oxygenated in the lungs and then it squeezes to pump the blood to the body. The right ventricle receives (via the right atrium) blood from the body which needs oxygen and it squeezes (pumps) it to the lungs. The left ventricle is a stronger pumper than is the right ventricle.
(Because I am never satisfied with just one explanation of anything, below are three more good descriptions of how the heart works.)
According to the article by Oeffinger and Keene, if a person who has anthracycline-induced heart damage (cardiomyopathy) is at rest, anthracycline-induced cardiomyopathy does not cause a problem. However, strenuous physical activity can pose a problem. During exercise, the heart may not be able to pump fast enough to keep up with the exercise. If the blood is not pumped out of the heart through the left ventricle, it "backlogs" in the small blood vessels of the lungs. The lungs cannot transfer oxygen to blood in clogged vessels. This problem is called congestive heart failure (CHF).
There is more than one type of cardiomyopathy. I learned from the information in the web sites linked to below , a book from the library, and applicable MedLine abstracts that anthracyclines can cause "dilated cardiomyopathy." In anthracycline-induced cardiomyopathy, the left ventricle wall is thinned and it has reduced contractility (cannot contract to push the blood out as well) and increased afterload (more blood left in the heart after each beat since it can't contract as well) compared to a normal heart.
(Although I found a journal article that stated that it also can cause restrictive cardiomyopathy: "Children may manifest impairment of left ventricular contractility and increased afterload due to thinning of left ventricular walls." Grenier et al, bibliography.)
Here are some more links on cardiomyopathy and congestive heart failure. Note that these sites are not specific for anthracycline-induced cardiomyopathy.
The likelihood of developing CHF depends on the total dose of anthracyclines. "Although recommendations vary, many institutions recommend periodic testing [see below] 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."
Overt heart failure occurs in 2% to 7% of patients treated with anthracyclines and the incidence of cardiac function abnormalities increases with the time. (This is a consensus from journal articles in the bibliography.) There is a lot of controversy on the percentages of kids affected. In addition, female gender appears to affect early and late cardiotoxicity in both adults and children, although this risk factor has been described predominantly in the survivors of childhood cancer. (Grenier et al, Bibliography.)
Symptoms of CHF are listed below. These symptoms can be confused with many other medical conditions. But if you are a survivor of treatment for childhood cancer and had anthracyclines, then you should consider that these symptoms might indicate CHF.
- 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
- dry cough
- (This list is from the Oeffinger/Keene article with the addition of "dry cough" -- in general the above lists correlates well with CHF symptoms listed on the following sites.)
- Jon's Place - symptoms
- Heart Disease/Cardiology on About.com - symptoms
- The Cleveland Clinic Heart Center
If you are experiencing the above symptoms, you should see a cardiologist who specializes in CHF. Even better, you should see a cardiologist who is familiar with anthracycline-induced cardiomyopathy. Some or all of the tests described in the next section. The results of the tests listed in following section will indicate if there is damage to the heart. In the general population (meaning, all those people who never were treated for cancer as a child), CHF is usually not diagnosed until the symptoms become severe. Survivors have the advantage that they know they might have experienced heart damage.
Note: Severe CHF is most common in the first year after treatment. Asymptomatic (and symptomatic) cardiomyopathy is experienced by a disputed percentage of survivors 1-15 years after treatment. Different researchers use different diagnostic tests and sample different populations of survivors. If you are interested in details, peruse the bibliography.
If you are at risk for anthracycline-induced CHF, you should have periodic testing throughout your life. Currently, the echocardiogram is the most common test performed. In some cases, a MUGA might be ordered. (Editor's note: at the time of this writing, I do not know the testing schedule that the COG recommends for at-risk survivors. Many kids have a baseline echo before treatment starts, a mid-treatment echo, and one at the end of treatment. Anthracycline-induced damage might take years to show up - or it might never show up. Survivors are advised to ask their oncologists, consult late effects clinics, or check the medical literature as to current recommendations for follow-up echos.)
Tests include: echocaridiogram, cardiopulmonary stress test, stress echocardiography, and Holter monitor. More on these on the ped-onc cardio tests page:
If damage to the heart is detected by one or more of the above tests, it's extremely important to see a cardiologist with knowledge of chemo-induced heart failure. Remember: cardiomyopathy may be present even if the patient is asymptomatic. Medications are available that have an impact on recovery (see below) and the management of these medications takes a cutting-edge doctor experienced in this particular form of heart failure.
The current state-of-the-art treatment for CHF are the ACE inhibitors: Enapril, Capopril, Lininopril, and Quinapril. ACE stands for "angiotensin-converting enzyme inibitor." ACE inhibitors block the conversion of angiotensin I to angiotensin II. This has the effect of increasing the cardiac ouput by reducing blood pressure and of helping the body excrete salt and water. Beyond that, these drugs may improve long-term prognosis in heart failure, preventing further damage to the heart, although the mechanism of this beneficial effect is not yet known. (Reference: Essential Cardiology.)
Some survivors of childhood cancer who have been treated with anthracyclines took part in a COG clinical trial studying ACE inhibitors. The contact for this study is also the author of many articles in the bibliography: (this could be a good doctor to contact)
- Steve Lipshultz
Primary Study Coordinator for A9480
Steven Lipshultz, M.D.
University of Rochester Medical Center
- (Another author of several articles is:)
- Laurel Steinherz
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Some other medications sometimes prescribed to CHF patients are: diuretics, vasodilators, digoxin, anticoagulants, and beta-blockers. I'm going to send you to Jon's Place because he has good, patient-to-patient descriptions of these drugs and what a patient might expect if he/she takes them.
General Advice for At-risk Survivors
The online listserve, Ped-Onc Survivors, is a discussion group for parents of survivors of childhood cancer. Many of us have heard either from our doctors or the literature that our kids that have been treated with anthracyclines should avoid certain activities. It's difficult for us to hold our kids back, especially when they seem very healthy and have a lot of physical endurance, and when they have had echocardiograms at the end of treatment which indicate that they do not have heart damage. We need to be aware that everything is not yet known about anthracycline-induced heart damage. The damage might not be detectable until years after treatment; survivors can be asymptomatic and still have heart damage. So, just what should these young survivors NOT do, in case they do have damage?
"Do we know the recommendations for cardiology tests for our kids at regular intervals post-treatment? (Guess I should open the survivors' book next to me, eh?) Okay here it is, pp. 324-5. Echos every 2-5 years. Other tests suggested (and listed), but it's somewhat controversial and up to the individual doctor." NK book
First, back to the Oeffinger/Keene article. The authors state that certain activities can potentially worsen a cardiomyopathy [direct quotes]:
- 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.
Of the above, weight lifting is the most applicable to most of the kids in our discussion group (so far, at least!). Many of us do not understand exactly what it is our kids should not do in weight lifting. I'm including the discussions here: REMEMBER! this is not medical advice.
- Anthracycline-induced heart damage bibliography, on this site.
Radiation Damage: General
Radiation causes not one type but several types of damage to the heart. A search of PubMed turned up only a handful of articles including several types of heart problems.
From the article by Nancy Keene/Oeffinger on radiation damage to the heart:
"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, family history, smoking cholesterol."
Radiation damage to the heart can show up years after treatment. It is very helpful to know how much radiation you had and where that radiation was directed. Even then, the damage and can be hard to diagnose, largely because it is so rare. Your best bet is to consult a doctor who is experienced in treating radiation-induced damage.
For more information, begin with the technical reading listed on this ped-onc site for radiation-induced heart damage:
Note: Linda Z points out one more heart problem related to treatment, ant that is the potential for developing sudden and life threatening arrhythmias because of scarring to the clump of nerves that are responsible for monitoring the rhythm of the heart.
Radiation can affect the left ventricle, causing a type of cardiomyopathy designated restrictive cardiomyopathy (as opposed to the dilated cardiomyopathy caused by anthracyclines). In restrictive cardiomyopathy, the left ventricle is stiff and less responsive to changes. The damaged ventricle is less efficient at filling with blood and pumping it out, and some blood backlogs in the small blood vessels of the lungs. This leads (like dilated cardiomyopathy) to congestive heart failure (CHF).
In the general population, restrictive cardiomyopathy is a lot less common than dilated cardiomyopathy. There are causes for it other than radiation damage, but it is still hard to find as much information about this less-common form of heart disease. The link below takes you to a site that ir pretty good:
You might notice one or more of the following symptoms (pretty much the same as for symptoms of anthracycline-induced heart damage):
- shortness of breath when you exercise
- shortness of breath when lying flat, especially at night
- chest pain (generally a smothering type sensation)
- poor appetite, nausea or upset stomach
- swelling of the ankles (edema)
Restrictive cardiomyopathy is diagnosed by pretty much the same tests used to diagnose dilated cardiomyopathy. Other tests might include: MRI, CT, chest X-ray, electrocardiogram. These tests are described on the Heart Center Online site.
- ped-onc site diagnostic tests for dilated cardiomyopathy
- Heart Center Online site tests for restrictive cardiomyopathy
In restrictive cardiomyopathy, normal ejection fractions are seen. "This is because the ventricle is stiffened and that makes it difficult for the heart to relax enough to allow blood to fill the ventricle. So the ejection fraction ma be normal or near to normal; systolic function is preserved while diastolic function is disturbed. This is not the usual form of heart failure and thus since this is unexpected it is harder to diagnosis." (Linda Z)
Some of the PubMed articles mention that restrictive pericarditis (and other pericardium disorders) can be caused by radiation. "Radiation causes scarring of the pericardium, the thin membranous sac that surrounds the heart. This can be both an acute problem happening within weeks or months of radiation or a slow chronic process that may evolve over years. But when the sac becomes scarred what you see is a pericardial effusion which can be quite painful (the pain is very distinct" and potentially life threatening." (Linda Z)
Restrictive pericarditis leads to almost identical symptoms as restrictive cardiomyopathy. The two conditions can be differientiated by biopsy; pericarditis can be treated with surgery.
"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." (Oeffinger/Keene article.)
In the general (non-cancer survivor) population, valvular heart damage affects a lot more people than does the cardiomyopathies, and hence the Internet and public libraries have a lot of information on this subject. It can be caused by hardening of the arteries, birth defects, heart attacks, infections, etc. Rheumatic fever can cause valve disease, and at one time was the major cause of this defect. However, I couldn't find any source that mentioned radiation as a cause of valvular heart disease. The following sites are all good references:
- The Cleveland Center Heart Clinic (very good descriptions and pictures)
- Texas Heart Institute
- The Merck Manual Home Edition
Often people with some valve disease will not have symptoms. When the disease progresses to a certain point, the following might be noted:
- shortness of breath
- chest pain
- unusual tiring
- dizziness or fainting
- heart palpitations
- swelling in hands, feet, abdomen.
Tests for this condition include echocardiography, doppler echocardiography, MUGA, angiogram, and MRI. (See the links above in the anthracycline and radiation-induced cardiomyopathy sections.)
Valvular heart disease is treated by management with medications and lifestyle adjustments; surgery to repair or even replace valves is possible.
Radiation can cause is premature coronary artery disease. Radiation can roughen the inside of normally-smooth blood vessels that feed the heart muscle. "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)." (Oeffinger/Keene article.)
Many of us are familiar with hardening of the arteries, known technically as coronary artery disease, or CAD. This is the most common form of heart disease, especially in the elderly. In CAD, the blood vessels get clogged and the heart cannot get enough oxygen and nutrition. This can lead to chest pain, or angina, and to a heart attack if the vessel is fully blocked.
Since it is so common, many sites and books are devoted to CAD.
- Mayo Clinic on Coronary Artery Disease (excellent)
- Heartpoint - an overview and also a good description of the coronary arteries
- NIH/National Heart, Lung, and Blood Institute, their pamphlet available online
- Merck Manual Home Edition on Arteriolosclerosis
- Heart Center Online
The symptoms can include any of the following, or the disease may be asymptomatic.
- chest pain (angina)
- shortness of breath, especially after stress or exercise
- nausea or upset stomach
- severe sweating
Tests are much the same as for the above conditions, especially including: different types of echocardiograms, interview, electrocardiogram, exercise stress testing, and blood tests.
Treatments for CAD are available, with lifestyle changes being a major factor of treatment. Blood-pressure and cholesterol play a factor in CAD and are controlled by diet and medications. (Please refer to the above sites.)
I wrote this section with the help of the linked web sites, the Keene/Oeffinger articles, journal abstracts, and several books from the public library (listed below). And, many many thanks to Linda Zame, who had a lot of input on this page.
- Essential Cardiology by AD Timmis, AW Nathan, and ID Sullivan, 3rd ed. Blackwell Science Ltd, MA USA, 1997.
- Exercise and Heart Failure, GJ Balady and IL Pina, editors. American Heart Association, Futura Publishing Company, Inc, NY. 1997.
- Measurements in Cardiology, P Sutton, editor. The Parthenon Publishing Group, NY. 1998.
- The New Living Heart by ME DeBakey and AM Gotto, Jr. Adams Media Corporation, MA USA. 1997.
These pages are intended for informational purposes only and are not intended to render medical advice. The information provided on Ped Onc Resource Center should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you suspect your child has a health problem, you should consult your health care provider.