Chemotherapy-induced cardiotoxicity remains a significant and unresolved issue in treating adult and pediatric cancer patients. Current approaches to surveillance are often inadequate to detect myocardial disease, which can delay medical therapy and lead to symptomatic heart failure. Evaluation includes the consideration of patients' symptoms and serologic biomarkers such as troponins and B-type natriuretic peptide, together with noninvasive imaging in the form of echocardiography or multiple-gated acquisition scanning. Three-dimensional echocardiography has been validated as the ultrasonic technique with the best accuracy for the calculation of left ventricular (LV) ejection fraction.1,2 In comparison with cardiovascular magnetic resonance, the current gold standard, it can be considered our tool of choice for the initial evaluation and follow-up of the chemotherapy patient—given its advantages in cost and availability. When 3-dimensional echocardiography is unavailable or the quality of the images is poor, ultrasonic contrast imaging can be useful for the optimal definition of endocardial borders and for the identification of the true cardiac apex, thereby strengthening the ability of the interpreter to accurately calculate cavity volumes and ejection fraction.
Conventional echocardiography detects changes in cardiac function, but it is usually late in doing so. Diastolic function has been investigated to see whether relaxation measurements can predict the development of cardiotoxicity. However, so far, diastolic measures have proved more complex than systolic to obtain and interpret. Diastole is described with multiple echocardiographic measures that can prove difficult to reproduce. Until now, multiple diastolic measurements have had varying levels of success in identifying early cardiac toxicity. This is well illustrated in a study of patients who had been exposed to anthracyclines in childhood for the treatment of leukemia.3 More advanced echocardiographic techniques, including myocardial strain imaging, might provide earlier detection of myocardial dysfunction and offer an additional noninvasive measure to follow these patients longitudinally. Strain echocardiography with speckle-tracking imaging is a technique that analyzes motion by tracking acoustic reflections within an ultrasonic window. The image is processed with algorithms that track defined regions of interest, with digital loops obtained at high frame rates.4,5 The technology has been used to characterize the function of ventricular tissue and, it is hoped, to detect tissue-level or mechanical changes that can occur earlier than observed wall-motion defects. This already has been demonstrated in animal models.6 Recent reports also suggest that the use of strain imaging, in addition to traditional echocardiographic techniques, can offer significant prognostic information in the adult population.7
These findings have established the basis for an ongoing collaboration between MD Anderson Cancer Center and Texas Children's Hospital to determine the feasibility and clinical usefulness of strain analysis in our echocardiographic surveillance of pediatric cardiotoxicity. The use of these novel imaging techniques is advantageous because they do not require a blood specimen, which can be challenging to obtain from pediatric patients. Strain echocardiography and other noninvasive techniques can supplement biomarkers in monitoring actively treated patients and long-term pediatric cancer survivors. Furthermore, this approach might enable earlier detection of cardiotoxicity, referral to a cardiologist, and treatment of cardiomyopathy or heart failure.
Cardiovascular magnetic resonance can be used to characterize myocardial tissue and to evaluate LV performance. Given the association of anthracycline administration with cardiovascular events, several recent investigations have used magnetic resonance imaging of the heart and vascular system to identify potential mechanisms (and early evidence) of cardiovascular injury in patients treated for cancer. Using an animal model, Lightfoot and colleagues8 discovered a new MRI myocardial tissue characterization technique for identifying early evidence of myocellular injury after exposure to doxorubicin. Importantly, this evidence was associated with intracellular vacuolation and preceded substantive clinical deterioration in LV performance. Future studies are needed in human subjects to determine whether noninvasive magnetic resonance techniques that characterize myocardial tissue can find early evidence of myocellular injury before the development of a severely reduced LV ejection fraction or the onset of congestive heart failure. To answer questions concerning vascular injury (primarily myocardial infarction and stroke), Chaosuwannakit and colleagues9 recently performed a case-control study that evaluated aortic stiffness in cancer survivors and in members of a control group. Relatively early upon the receipt of anthracycline chemotherapy, aortas became stiff in the cancer patients, relative to the aortas of the healthy individuals. Given the marked association of aortic stiffness with LV hypertrophy and with future cardiovascular events, further studies should be performed to determine whether vascular stiffening upon receipt of anthracyclines has these associations.
In conclusion, the rise of cardiovascular morbidity and death in cancer survivors threatens to offset some of the substantive reductions in cancer-related morbidity and death that have been achieved with recently developed chemotherapeutic agents. New studies, such as these with innovative cardiovascular magnetic resonance techniques, might well find early evidence of myocellular or vascular injury and thereby enable early treatment to reduce the cardiovascular morbidity and death associated with cancer survivors.