Cancer and Heart Disease

Introduction

At the intersection of oncology and cardiology, the field of cardio-oncology is growing primarily with the aim of recognizing, monitoring, and treating cardiovascular complications resulting from cancer-related treatments. With advances in cardiac imaging technologies, we now have a much better understanding of the cardiac effects of cancer and cancer therapies; and are refining therapies in the subspecialty of heart failure (HF).

Although a number of different measures are recognized as capable of evaluating systolic function, the left ventricular ejection fraction (LVEF) continues to be the most widely utilized. In the clinical setting and in multiple research protocols, cardiotoxicity has been defined as a decline of LVEF ≥5% to final ejection fraction (EF) <55% with symptoms of congestive HF, or an asymptomatic decline of LVEF ≥10% to a final EF <55%. As controversial and arbitrary as this definition might be considered, special attention is given to LVEF quantification in cardio-oncology oriented practices.

Quantification of Systolic Function in Cardio-oncology

In clinical practice, the most commonly accepted definition of cardiac toxicity comes from the independent Cardiac Review and Evaluation Committee’s (CREC) retrospective review of patients enrolled onto a variety of trastuzumab clinical trials. Echocardiography is the most used test for sequential measurement of LVEF in the assessment of potential cardiotoxicity from chemotherapy or immune therapy in patients with malignancies. In most oncology practices, the LVEF is followed closely, and the EF value is given significant clinical importance.

In practice, given the use of singular numbers for any particular cardiotoxicity definition used, it has been common for echocardiography clinicians in this field to report single numbers and avoid range EF reporting. It is understandable that it would be confusing for our oncology colleagues who make critical clinical decisions based on a 5% or 10% EF change, or a drop to under 50% or 55%, when, for example, the value reported from one study to the next is 55%–60% followed by 50%–55%.

The decisions that oncologists are faced with include the possibility of cessation of further anticancer therapy, which could have significant clinical consequences. We also need to understand the history of single digit measure from the historic perspective in oncology. In this field, cardiac imaging was established in the late 70s and early 80s when a number of publications supported the different available modalities, and over a short period, measurement of LVEF by nuclear methods (multiple-gated acquisition scan [MUGA]) became the established practice and was considered the gold standard for left ventricular function assessment during chemotherapy. LVEF by radionuclide imaging proved to be sensitive, specific, and reproducible and was reported as a single measure. Clearly, measurement of LVEF as a sole indicator of cardiotoxicity has significant limitations. These include image quality, the technical realities of the measurement that may include the single beat selection, operator experience, and volume drawing styles. In addition, the EF—the relative volume ejected in systole—can be load dependent.

It is important that our EF measurements are accurate with the lowest variability possible. The most commonly used LVEF methods in routine practice are the two-dimensional (2D) methods. Among the 2D options, the most commonly used method for volume calculations is the biplane method of disks summation (modified Simpson’s rule). This is the recommended 2D echocardiographic method according to consensus and current published left ventricular quantification guidelines. The literature is clear that among the 2D methods, using biplane volumes with the use of microbubble enhancement offers the best results in terms of intra- and interobserver variability; and contrast agents are recommended when there is a need to improve endocardial border delineation, particularly when two or more contiguous LV endocardial segments are poorly visualized in apical views. It is important to remember that microbubble-enhanced images provide larger volumes than unenhanced images. Volumes obtained in this fashion are closer to those obtained with cardiac magnetic resonance (CMR).

Three-dimensional echocardiography (3DE) has been shown to be more accurate than 2D for both ventricular volume and EF measurements when compared with CMR imaging, and therefore it is an attractive modality in this field and should be used when available. ^, This method, while not routinely available in most centers, has been shown to offer the lowest temporal variability for EF and ventricular volumes on the basis of multiple echocardiograms performed over 1 year in women with breast cancer receiving chemotherapy.

Cardiac Mechanics in Cardio-oncology

Earlier detection of cardiotoxicity allows for a time advantage in risk stratification. New techniques are aimed at detecting cardiotoxicity before the onset of a measurable decrease in LVEF or symptoms. These methods include echocardiographic assessment for strain using speckle-tracking imaging, as well as testing for elevations in cardiac biomarkers, including troponin. Speckle tracking takes full advantage of a new capacity for image acquisition at higher frame rates. Several reports regarding cancer populations receiving cardiotoxic agents and the use of this particular technology in the realm of cancer therapeutics–related cardiac dysfunction have been very exciting, particularly regarding the use of longitudinal deformation measures and the global longitudinal strain (GLS) value.

It was first reported in 2009 that changes in tissue deformation, assessed by myocardial strain and strain rate, were able to identify left ventricular dysfunction earlier than LVEF in women undergoing treatment with trastuzumab for breast cancer. Following this, two reports resulted in comparable findings. ^, A multicenter collaboration reported on the use of troponin and longitudinal strain measures to predict the development of cardiotoxicity in patients treated with anthracyclines and trastuzumab. Patients who demonstrated decreases in longitudinal strain measures or elevations in hypersensitive troponin had a ninefold increase in risk for cardiotoxicity at 6 months compared with those with no changes in either of these markers. Furthermore, diastolic function parameters and LVEF alone did not help predict cardiotoxicity.

In a review including over 30 studies, it was reported that although the best GLS value to predict cardiotoxicity is not clear, an early relative change between 10% and 15% appears to have the best specificity. Similar studies, however, have found a stronger correlation with ventricular-arterial coupling and circumferential strain than longitudinal measures. A consensus statement on the evaluation of adult patients during and after cancer therapy published by the American Society of Echocardiography and the European Association of Cardiovascular Imaging also reports that a relative percentage reduction in GLS of >15% is very likely to be abnormal, whereas a change of <8% appears to be of no clinical significance.

Cardiac Dysfunction and the Heart Failure Spectrum

Cancer therapy–related cardiac dysfunction (CTRCD) is one of the most feared and undesirable side effects of chemotherapy despite occurring only in a small minority of cases.

Despite widespread screening recommendations, a clear universal definition of cardiotoxicity is lacking in the current literature. While there are different definitions of CTRCD presented by clinical trials and guideline statements, there is no universal consensus at this time. The first publication defining mild cardiotoxicity as a decline in EF by >10% and moderate cardiotoxicity as EF decline by >15% to a value less than 45% was by Alexander and colleagues in 1979. In 1987 a large clinical trial defined CTRCD as a decline in EF by >10% to a final value <50%. Both of these studies used MUGA scans as the method of screening and only included patients who had been treated with anthracycline. In 2002, after review of the trastuzumab trials, the CREC defined CTRCD as asymptomatic decline of LVEF ≥10% to a final EF <55%. Over a decade later (in 2014), the American Society of Echocardiography and European Association of Cardiovascular Imaging (ASE/EACI) chose a cutoff value of <53%.

Controversy still persists regarding the definitions of cardiac toxicity, the true incidence, detection, monitoring, and treatment of the late effects in survivors of cancer of all ages. There are multiple explanations for the lack of consensus regarding clinical guidelines in CTRCD. Most importantly, there is a lack of large-scale randomized clinical trial data to support any evidence-proven, effective long-term treatment and/or surveillance strategies. Furthermore, there has been minimal success at showing the cost-effectiveness of aggressive cardiac surveillance and treatment to providers.

In this chapter, discussion of CTRCD will be limited to the proper management of the cardiac effects of anthracycline therapy in cancer survivors. The antitumor actions include inhibition of topoisomerase II, an enzyme that regulates the uncoiling of DNA strands and in doing so induces breaks in DNA and ultimately cell death. Anthracycline therapy results in the formation of toxic reactive oxygen species (ROS) and interferes with macromolecule synthesis with a subsequent increase in cardiac oxidative stress-associated apoptosis. In addition, a relationship between topoisomerase IIβ activity in the heart and cardiac toxicity was reported, potentially opening a new avenue for future therapies.

Clinical presentations of toxicity can include arrhythmias, heart block, HF, pericarditis-myocarditis syndrome, and cardiac ischemia. Late toxicity is almost universally limited to myocardial systolic dysfunction. There are several known clinical risk factors associated with toxicity such as pre-existing cardiovascular disease (CVD), hypertension, the use of other cardiotoxic nonanthracycline agents (trastuzumab, taxanes), and exposure to mediastinal radiotherapy. It is also important to recognize that children are at particular risk for development of anthracycline-induced cardiomyopathy, but there is also increased incidence of systolic dysfunction with age, particularly in the elderly population. Although there is an accepted direct relationship between cardiotoxicity and cumulative anthracycline dose, cardiotoxicity has been reported in patients who have received doses under 100 mg/m² of doxorubicin, and there are patients who have received doses >550 mg/m ² and never developed cardiotoxicity.

Biomarkers have been an exciting area of investigation in this arena, and there is increasing evidence that using a biomarker or a panel of them could significantly contribute to the clinical monitoring and surveillance of these patients in the future. The traditional tests have been troponin T/I, B-type natriuretic peptide (BNP), or N-terminal pro-BNP (NT-proBNP). However, new markers in the mRNA category such as miR-208b, miR-34a, and miR-150 have been recently reported, particularly for breast cancer patients receiving anthracyclines and/or trastuzumab.

There is no specific therapy for systolic dysfunction in CTRCD. If a reduction in LVEF is detected, patients should be treated in accordance with established guidelines for the management of HF. Drug antiremodeling therapy should include agents approved with appropriate indications such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), and beta blockers as tolerated. There are no quality or long-term outcome data to guide treatment of CTRCD.

It is critical to consider alternate causes of LV dysfunction beyond chemotherapy, particularly in patients who present after low levels of anthracycline exposure or nonanthracycline regimens. It is always clinically mandatory to consider common causes such as coronary disease, hypertension, infiltrative conditions, and alcohol excess depending on the individual clinical picture.

Among patients who are still candidates for active cancer therapy, a multidisciplinary discussion, including the cardiologists and oncology providers, is usually beneficial. The risks and benefits of further chemotherapy should be carefully considered in planning subsequent treatments. It should be noted that there is some evidence that LVEF by echocardiography could be used to improve patient selection for enrollment in clinical trial–based regimens. One study suggests that it is safe to treat patients with LVEF between 35% and 50%. However, in general, it is recommended to avoid further exposure to regimens containing known toxic agents in the presence of ongoing LV dysfunction. See Figs. 6.1 and 6.2 .