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 .

A female with breast cancer treated with Herceptin has a GLS value of −19.6% at baseline. GLS , Global longitudinal strain.

The same patient with a GLS of −14.6, 3 months later. This preceded a 14% decrease in LVEF that was noted in her 6-month follow-up echocardiogram. GLS , Global longitudinal strain; LVEF , left ventricular ejection fraction.

Considerations in Radiation-Induced Heart Disease

Radiation-induced cardiac changes include a spectrum of pericardial disease, valvular disease, coronary/microvascular disease or dysfunction, and restrictive cardiomyopathy. Most commonly, these are pathologic processes that are late manifestations, becoming clinically significant years after radiation. Pericardial thickening appears as increased echogenicity of the pericardium on 2D echocardiography or M-mode imaging. Correct distinction between normal to thickened pericardium is challenging. Characteristic echocardiographic findings of constrictive pericarditis include a thickened pericardium, prominent respiratory phasic diastolic motion of the interventricular septum, restrictive diastolic filling pattern, and significant inspiratory variation of the mitral E-wave velocity (>25%). Other secondary findings include inferior vena cava dilatation and expiratory diastolic flow reversal in the hepatic veins. Typically, tissue Doppler interrogation of the medial mitral annulus reveals a normal or increased velocity that can be higher than the lateral annulus velocity. Another important consideration is effusive-constrictive pericarditis. This clinical syndrome is characterized by concurrent pericardial effusion and pericardial constriction, with constrictive hemodynamics that persists after the drainage of the pericardial effusion. In effusive-constrictive pericarditis, the visceral layer of the pericardium, rather than the parietal layer, constricts the heart. This is a rare condition; however, effective recognition is important because pericardiectomy is sometimes indicated for management.

In the particular case of valvular disease, manifestations of radiation-induced heart disease (RIHD) include fibrosis and patchy calcification of structures, such as the aortic root, annulus, leaflets, the aorto-mitral intervalvular fibrosa, mitral annulus, and the base and mid-portions of the mitral valve leaflets usually sparing the tips and commissures (a key difference from rheumatic heart disease). Grading the severity of valvular disease should be based on published guidelines. Valve regurgitation is more commonly encountered than stenosis. Stenotic lesions more commonly involve the aortic valve. Reported incidence of clinically significant valve disease is 1% at 10 years, 5% at 15 years, and 6% at 20 years after radiation exposure. Incidence of valve disease increases significantly after >20 years following chest radiation (mild aortic regurgitation [AR] up to 45%, moderate AR up to 15%, aortic stenosis up to 16%, mild mitral regurgitation up to 48%, mild pulmonary regurgitation up to 12%). ^,

Cardiac Tumors

Cardiac tumors are rare, and are generally categorized as primary or secondary. Primary cardiac tumors are the rarest, with an autopsy incidence of 0.002%–0.3%. ^, Primary cardiac tumors include both benign and malignant neoplasms that originate from cardiac tissue. Secondary or metastatic cardiac tumors are around 30 times more common than primary malignancy, with a reported autopsy incidence of 1.7%–14%.

Other possible categories of tumors could include those from the lower body that reach the cardiac cavities by extension through the inferior vena cava, and tumors that extend from the mediastinal space directly invading the pericardial layers. The infradiaphragmatic tumors can occur with almost any cell type, but the large majority of these have been attributed to renal cell carcinoma (RCC) where as much as 10% of patients will have tumor extension into the inferior vena cava. In patients with RCC, involvement of the right atrium (RA) is encountered in up to 5% of cases, and pulmonary artery tumor emboli is rarely observed. Other sources for this route of invasion include uterine malignancies and hepatocellular carcinoma. ^, Tumors with direct extension in the mediastinal space again can occur with almost any cell type. Thymoma compromises 20%–25% of all mediastinal tumors and is the most commonly described anterior mediastinal tumor ; however, most case reports of direct mediastinal invasion are not from thymic origin. ^,

The clinical manifestation of cardiac tumor is variable and not unlikely to be found on routine surveillance echocardiogram examination or other chest imaging modality. In terms of clinical presentation, tumors cause signs and symptoms, depending on location, size, and etiology. Presence of a growing mass inside a contractile and moving cavity can eventually cause hemodynamic compromise of blood flow in the affected or receiving chamber and even disrupt valve coaptation. In this setting, syndromes of congestive failure can be present. This can be further accelerated in the case of myocardial involvement and secondary limitations to contractility. See Table 6.1 .

Careful evaluation of segmental ventricular dysfunction is pertinent, as direct occlusive pressure or extension of the tumor into the lumen of the coronary arteries (including the possible embolization of tumor fragments) has also been described. ^, Repolarization changes in patients with cardiac metastases are believed to occur by myocardial ischemia caused by the tumor’s direct myocardial injury and invasion, as this presentation has been found in subjects without obstructive coronary lesion on angiography.

Due to its noninvasive nature, availability, relative portability, and affordability (when compared with other modalities), echocardiography is the most widely used diagnostic modality for the evaluation of cardiac tumors. As indicated earlier, this technology has advanced to include mechanical function analysis, which may increase our sensitivity to recognize subtler wall motion defects.

A great complement to transthoracic echocardiogram (TTE) is the use of transesophageal echocardiography, which provides a significant upgrade in spatial resolution and overall image clarity compared to transthoracic imaging. This technique has also demonstrated impressive and rapidly improving quality of three-dimensional images. The use of echo contrast has also added a significant degree of confidence and accuracy to transthoracic echo; and is also frequently used for mass characterization. See Fig. 6.3 .

A young woman with sarcoma. On echocardiogram, we see a mass at the base of the right ventricle. The mass is easily visible in the echo-contrast enhanced image (A), which the unenhanced image at the same angle fails to demonstrate clearly (B).

However, when it comes to more detailed characterization of a malignant lesion infiltrating the myocardium, CMR and cardiac computerized tomography (CCT) can give a more complete view of the mediastinum, extra cardiac structures, and the possible attachments of a mass outside of the cardiac cavities. This is considered critical information for the surgeon when planning resection. These modalities also have well-known advantages when it comes to tissue characterization. They do not suffer from the acoustic “window” limitations that often make transthoracic echocardiographic examination technically difficult, particularly in obese patients, subjects with history of previous chest surgery, and those with chronic lung disease.

Cardiac interventional procedures described in the diagnosis of cardiac tumors, both primary and secondary, include endomyocardial biopsy and pericardiocentesis. The latter has been frequently used to confirm malignant cells within the fluid or as a palliative tool for patients with increased intrapericardial pressures secondary to progressive disease. Echocardiography (TEE) is often helpful for imaging guidance during these procedures.

Acute Coronary Syndromes

Rudolf Virchow postulated that three features predispose to thrombus formation, namely abnormalities in vessel wall, blood constituent, and blood flow. Although originally Virchow was referring to venous thrombosis, the concept also relates to arterial thrombosis. A number of patients with cancer show abnormalities in each component of Virchow’s triad leading to a prothrombotic or hypercoagulable state. Exposure to radiation and various chemotherapy agents predisposes to the development of cardiovascular disease. Radiation damages the endothelium, predisposing to vascular disease and ischemic heart disease in a relatively younger patient population. ^, Of all chemotherapeutic agents, 5-flurouracil (and its analogue capecitabine) is particularly known to cause ischemic heart disease. ^, In addition to 5-fluorouracil, other medications, such as paclitaxel, docetaxel, bevacizumab, erlotinib, and sorafenib, are also implicated in the development of ischemic heart disease.

In patients with cancer, in addition to underlying coronary atherosclerosis, there are multiple other etiologies and predisposing factors for cardiovascular abnormalities, including cardiac metastasis/coronary compression, tumor-related coagulation disorder (especially in patients with leukemia), coronary embolization from tumor or endocarditis, radiation, and chemotherapy, for example, 5-fluorouracil. In terms of incidence and overall prognosis, there are limited reports available in the literature. However, a recent report from a national US database with more than 6 million patients showed a prevalence of acute myocardial infarction (AMI) of 9% in patients with cancer in the decade after 2004. A very recent analysis on a large AMI population revealed that patients with active cancer have a 50% increased risk of major in-hospital adverse cardiac events than those without cancer. In a 2017 study of more than 48,000 patients admitted with ST segment elevation myocardial infarctions, those with cancer had a significantly higher in-hospital and 1-year mortality than those without. In summary, we have few observational, mainly retrospective studies comparing the clinical outcomes of patients with and without cancer and acute coronary syndromes. These analyses consistently report that patients with cancer are at higher risk of both in-hospital and long-term morbidity and mortality than those without.

Acute Pericarditis

Acute pericarditis is acute inflammation of the pericardium resulting in a clinical syndrome consisting of pleuritic/positional chest pain, electrocardiogram changes, and a pericardial frictional rub. A pericardial effusion may or may not develop. ^, Malignancy is a common cause of pericardial disease in cancer, and in one study of 100 consecutive patients hospitalized with acute pericarditis, malignancy was found in 7% of the patients, with lung carcinoma being the commonest primary tumor.

Acute pericarditis presents with retrosternal chest pain, which is typically worse on inspiration and in supine position and improves with sitting and on leaning forward. In some cases, it may radiate to the shoulder due to irritation of the phrenic nerve. On physical examination, the classic finding is a pericardial friction rub. The rub is best heard in end expiration with the patient leaning forward. It is a high-pitched scratchy sound that can have one, two, or all three components. A pericardial friction rub is present in approximately 34% of cases.

Clinical criteria for diagnosis of acute pericarditis include typical chest pain, presence of audible pericardial friction rub, widespread ST-segment elevation on the electrocardiograms, and new or worsening pericardial effusion. ^, A diagnosis of acute pericarditis is made if at least two of the four criteria are present. ^,

Evidence of pericardial inflammation gained through the use of imaging techniques such as computerized tomographic scan or cardiac magnetic resonance, elevation of inflammatory markers, for example, C-reactive protein, white cell count, and erythrocyte sedimentation rate are additional supporting findings. A 12-lead electrocardiogram is the most useful diagnostic test. The classic electrocardiogram finding is concave ST elevation and PR-segment depression in all leads, except AvR, which shows PR-segment elevation, and ST depression. The electrocardiogram changes evolve in stages. In stage 1 the electrocardiogram shows ST-segment elevation and PR-segment depression. In stage 2 the normalization of PR and ST segments occurs. In stage 3 there are widespread T wave inversions and in stage 4 normalization of these T waves occurs.

A chest x-ray is recommended in all patients with pericardial disease. It is usually normal but may show other concomitant pathology such as pneumonia or enlarged cardiac silhouette in patients with associated pericardial effusion. Echocardiography is usually obtained to exclude a large pericardial effusion and tamponade. Small pericardial effusion is present in about 60% of the cases and is responsive to medical therapy. Computed tomography scan and CMR imaging can be used when the first level of investigations are not sufficient for diagnostic purposes or when there are complications related to pericarditis. ^,

Pericardial Effusion and Cardiac Tamponade

Generally, the pericardial space contains <50 mL of fluid. Accumulation of larger amounts of fluid is usually due to the disease process in the pericardium, which may or may not be related to cancer or a systemic disease. It may range from minimal to moderate and large, with symptoms and signs not only related to the size of effusion but also to the rapidity of fluid collection. In the general population, malignancy is the commonest cause of large pericardial effusion.

The clinical symptoms and signs of pericardial effusion depend on the size, cause, and rate of accumulation of the pericardial fluid. A large but slowly growing effusion, for example, in a patient with malignancy, may lead to fewer symptoms and less-acute presentation, whereas a rapidly accumulating smaller pericardial fluid, for example, a complication of a radiofrequency ablation or cardiac biopsy, may cause acute tamponade. Common symptoms of pericardial effusion include dyspnea on exertion with orthopnea, palpations, chest pain, or tightness. Other nonspecific symptoms include weakness, fatigue, and anorexia. The classic clinical findings in tamponade consist of low blood pressure, distended neck veins, and muffled heart sounds, which is known as Beck’s triad. Claude S. Beck described this in 1935 as two cardiac compression triads: acute cardiac compression (low arterial pressure, high venous pressure, quiet heart) and chronic cardiac compression (ascites, high venous pressure, quiet heart).

A 2D echocardiogram is the most common noninvasive test utilized for the diagnosis of pericardial effusion. It not only provides information on the size but also on the features of increased intrapericardial pressure. As for the general population, in patients with cancer the effusion is categorized into small (≤1 cm), moderate (1–2 cm), and large ( > 2 cm). Signs of hemodynamic compromise and tamponade include the presence of right atrial and right ventricular collapse/compression, respiratory variation in tricuspid and mitral valve inflow velocities, and usually associated with inferior vena cava plethora. See Fig. 6.4 .

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