Cardiotoxicity is the most serious of a long list of potential chemotherapy side effects. Around five percent of all chemotherapy patients develop heart failure, while up to 20 percent experience a decrease in heart function. Certain chemotherapy drugs can cause a range of heart-related problems, from arrhythmias (irregular heartbeats) and pericarditis (inflammation of the pericardium, a sack that surrounds the heart) to cardiomyopathy (heart muscle disease), stroke, and heart failure.
What is the link between chemotherapy and heart muscle disease?
Tumor cells behave unconventionally — growing, dividing, and avoiding programed cell death, even when our organism sends them the exact opposite signals. They can trick our immune system into thinking that they’re a part of normal, healthy tissue and even use it to help them spread throughout the body. To kill such invasive and resilient cells, we have to turn to drastic methods like radiation and chemotherapy. In the last 20 years, the survival rates among cancer patients has improved immensely. However, this comes with a price in the form of serious, life-threatening side effects.
Cardiotoxic drugs can affect the heart in two ways. While type II of cardiotoxicity can be reversed, type I cardiotoxicity is more serious and leads to permanent damage to the heart muscle.
The mechanism through which cardiotoxic drugs cause cardiomyopathy and other heart problems is still poorly understood for both types of cardiotoxicity. One of the proven effects is the formation of reactive oxygen species (ROS). ROS are highly-unstable oxygen-containing molecules that react with whatever comes their way — like DNA, cell organelles, or important proteins.
Heart tissue is more susceptible to this type of damage because it has fewer enzymes that would normally protect the tissue from ROS, and some chemotherapy agents, like doxorubicin, block the activity of some of these enzymes. In turn, that leads to damage and possibly to the death of the heart muscle cells.
Another way in which these medications damage the heart is through the involvement of cytokines. Cytokines are small molecules that cells of the immune system use to communicate with one another. For example, some cells can produce cytokines to inform the other cells that there’s an inflammation and they need to come to the site of the battle. These types of cytokines are called inflammatory cytokines. While they are important when there’s an actual threat to the tissue, their constant presence in the cardiac tissue damages the heart cells. It can lead to a type of cardiomyopathy called dilated cardiomyopathy, in which the walls of the heart muscle become stretched and the heart can’t pump blood as efficiently.
Which chemotherapy drugs are cardiotoxic?
Not all of the drugs that are used in chemotherapy are toxic to the heart. The cardiotoxic effect has been well established for two types of drugs: anthracyclines and more recently trastuzumab. Several other chemotherapy drugs are thought to have cardiotoxic effects, but they still require more research.
Anthracyclines are a class of drugs that is associated with type I of cardiotoxicity. This group includes agents like doxorubicin (Adriamycin, Rubex), daunorubicin (Cerubidine), epirubicin (Ellence) and idarubicin (Idamycin). These medications are used to treat several types of cancer, including:
- Leukemia (a group of blood cells cancer)
- Lymphoma (cancer of the lymphatic system, part of the immune system)
- Breast cancer
- Stomach cancer
- Uterine cancer
- Prostate cancer
- Ovarian cancer
- Bladder cancer
- Lung cancer
The most important information that you should have about anthracyclines is:
- They are associated with type I of cardiotoxicity, which means the damage is permanent.
- They can lead to dilated cardiomyopathy in adults and restrictive cardiomyopathy in children.
- While some patients develop cardiomyopathy during or shortly after treatment, in others it can cause late-onset cardiomyopathy years or even decades after. Being aware that you’re at risk of developing cardiomyopathy and having regular check-ups is important, since cardiomyopathy can often go without symptoms until the disease has progressed and the damage is substantial.
- Their toxicity depends on the dose (in the majority of cases). That goes both for individual doses and the cumulative dose (the sum up of all received doses). The administration schedule has also been shown to impact the level of toxicity.
- Factors that put you at greater risk of developing anthracyclines-induced cardiomyopathy are being female, young or advanced age, previous heart conditions or hypertension (high blood pressure).
2. Trastuzumab (Herceptin)
Trastuzumab is a monoclonal antibody used to treat breast cancer. Antibodies or immunoglobulins are proteins that specifically recognize and bind to pathogens like bacteria and viruses. This allows the immune cells to see the pathogens and fight them. You can think of antibody binding as putting a target on one cell, which acts as a signal for the immune cells to kill it.
Monoclonal antibodies are considered to be the future of medicine and they are currently being researched as a trearment for many diseases, from cancer to Alzheimer’s. Monoclonal means that they recognize one specific structure, like for example the molecules on the cell membranes. Essentially, this allows us to choose which cells will be recognized and fought against since different types of cells usually have some distinctive molecules on their surface. In that way, trastuzumab recognizes a protein called HER2 that is only present on the surface of breast cancer cells and signals the cells called natural killers (NK) to kill the cancer cells.
What are the signs of chemotherapy-induced cardiomyopathy (CIC)?
How the CIC presents depends greatly on the drug that caused it.
For example, symptoms of CIC caused by trastuzumab usually appear within three months of the first dose, and responds well to therapy. On the other hand, CIC caused by anthracyclines can go without symptoms for a very long time. Not having symptoms might not seem like a bad thing at first, especially in diseases like cardiomyopathy where there's a great impact on the quality of life. However, symptoms tell us that something is wrong and allow us to treat it. In anthracycline-induced cardiomyopathy, the disease progresses and leads to the irreversible death of the heart muscle cells. In many cases, when the symptoms present, the damage has already been done.
In the asymptomatic stage, tests can show the following changes:
- Mild changes in blood pressure
- Arrhythmias (irregular heartbeats)
- Abnormal levels of cardiac biomarkers like troponin I (these biomarkers signal that there's been some damage in the heart muscle)
- Decreased function of the left ventricle (the heart’s main pumping chamber)
In the symptomatic stages, patients can present with more serious symptoms including:
- Myocarditis (inflammation of the heart muscle)
- Pericarditis (inflammation of the pericardium, a sack that holds the heart)
- Thrombosis (formation of blood clots in the vessels)
- Congestive heart failure