Doxorubicin cardiotoxicity varies from 4 to 36% depending on the dose; epirubicin and idarubicin have a lower incidence of CHF.

Free radical formation is generally accepted as the main mechanism; apoptosis also plays a prominent role in the myocardial cell loss that has been demonstrated in such cases. Risk factors for AC are high, single intravenous dose; time of drug infusion <30 min; history of previous irradiation; use of other concomitant agents such as cyclophosphamide, trastuzumab, and paclitaxel; female gender; and young or old age.

There is an acute effect with a transient decline in myocardial contractility after infusion and a chronic progressive effect presenting as dilated cardiomyopathy is typically manifested as clinical heart failure or subclinical decline in myocardial function, and may present early, within 1 year of the termination of chemotherapy, or late-delayed, becoming evident beyond 1 year post-treatment. The chronic cardiomyopathy is related to myocardial necrosis and vacuolization, caused by the suppression of the synthesis of DNA, RNA, proteins, and transcription factors. Reduced protein expression results in disruption of sarcomeric proteins and myofilaments. Anthracycline also alters the adenylyl cyclase activity and calcium homeostasis disrupting the dynamic regulation of cardiac function [11–13].

This is a monoclonal antibody that binds to the extracellular domain of HER2 (human epidermal growth factor receptor 2), inhibiting signal transduction. The HER2 gene is overexpressed in 15–20% of breast cancer cases, with overproduction of HER2.

The treatment with this type of therapy results in higher rates of cardiac dysfunction if combined with a high dose of anthracyclines (>300 mg/m²).

The cardiotoxicity is related to the role of HER2 in cardiomyocyte survival and development [14, 15]: the cellular level overexpression of HER2 and/or neuregulin (NRG)-mediated activation of the HER2/HER4 signaling pathway protect against oxidative stress and prevent apoptosis. High serum levels of HER2 have been detected in individuals with chronic HF [16, 17] and clinical trials have shown that administration of recombinant human NRG-1 improves cardiac function in chronic HF and is well tolerated [18]. Thus, although cardiac stress leads to increased HER2 expression and HER2/HER4 activation by NRG, for example, during anthracycline therapy with pressure overload, inhibition of HER2 by trastuzumab induces ventricular dysfunction, developing dilated cardiomyopathy. The concomitant use of trastuzumab and anthracyclines increases ROS levels, and creates an oxidative stress that causes overexpression of angiotensin II, which inhibits the action of NRG and its binding to HER, blocking anti-apoptotic pathways. Moreover, the Ang II, through activation of NADPH oxidase, produces superoxide anion radicals (potent ROS; Fig. 19.1).

The incidence of cardiotoxicity was evaluated in several studies and the highest incidence was registered in association with anthracycline (>20%) [19, 20].

Tyrosine kinase inhibitors (TKIs) are small-molecule targeted therapeutics that are directed against specific molecules and signaling pathways [21]. The drugs in this class are similar; they differ in their specific targets or combination of targets and thus result in a variety of toxicities.

For example, CHF caused by sunitinib may be related to mitochondrial damage in cardiomyocytes or activation of apoptosis and interference in cellular metabolism. CHF related to the use of lapatinib may be a result of HER2 inhibition [22].

In addition to evaluating LV structure, echocardiography provides information on both systolic function and diastolic function; also, recent techniques have become available to measure myocardial deformation, including LV strain, strain rate, or twist and torsion that may provide a new understanding regarding the early stages of the pathophysiology of cardiac dysfunction upon receipt of cancer treatment [32, 33]. Moreover, echocardiography provides additional information about valvular function and pericardial fluid/physiology that might occur after cancer treatment.

The m-mode, Doppler, and 2D and 3D information is useful, not only for diagnosing a cardiac injury, but also often to predict the cardiotoxicity. For example, some studies have shown that LV diastolic properties, such as a decrease in the E/A ratio, or prolongation of IVRT, or the deceleration time of early diastolic filling, can predict doxorubicin-induced LV systolic dysfunction [34]. Some authors demonstrated that a reduction of more than 10% of global and regional longitudinal and radial strain in the first weeks of treatment with anthracycline and trastuzumab predicts the later development of a reduction of LVEF 6 months after the initiation of these therapies [32, 35] with a sensitivity of 78% and specificity of 79%, and a negative predictive value of 93%.

Other studies try to determine the prognostic utility of other echocardiographic measures, such as the twist and torsion of the LV in those treated for cancer, and this may be the expression of myo-filament disorganization and cardiomyocyte necrosis.

Cardiovascular magnetic resonance (CMR) imaging gives information about cardiac and vascular anatomy, tissue characteristics (presence of fibrosis, inflammation, injury, etc.), left and right ventricular systolic or diastolic function, blood flow, and myocardial perfusion or metabolism for the purposes of understanding the etiology of LV systolic or diastolic dysfunction. For this reason, the American College of Cardiology/American Heart Association recognize CMR imaging as a method of identifying CV dysfunction after treatment for cancer and have incorporated it across research studies to define the pathophysiology of cancer treatment-related CV toxicity. By CMR imaging the presence and severity of morphological and functional abnormalities of the LV or RV myocardium can be identified and understood, determining the underlying etiology (e.g., ischemic versus non-ischemic disease) of LV or RV dysfunction, and identifying prognostic factors related to patient outcomes. CMR offers more accurate assessment of function and morphology than most available imaging modalities, providing reliable volumetric data with high diagnostic image quality in nearly all patients. Table 19.3 displays quantitative and qualitative parameters, each of which can be used as diagnostic markers or descriptors in patients with suspected heart failure [36].

Cardiovascular CT may be useful for evaluating the pericardium of patients who received radiation or surgical treatments; to identify abnormal thickening and calcification of the pericardium; and to measure coronary artery calcium or directly visualize the coronary arteries. There are currently insufficient data to recommend the routine use of coronary CT angiography or calcium scoring in patients who underwent high-dose radiation therapy. In addition, the presence of coronary artery calcification before treatment for cancer has not been shown to predict future CV risk upon receipt of chemotherapy, tyrosine kinase inhibitors, or radiation therapy.

Today, equilibrium radionuclide angiography (ERNA) is used to measure LV function through determination of the LV ejection fraction (LVEF). LV diastolic function is often assessed using radioisotope-based techniques. Count–time curves, the peak filling rate (PFR), the PFR normalized to stroke volume, and time-to-peak filling rate are detected with planar equilibrium radionuclide ventriculography (ERNV). For example, a reduction in these ERNV measures of LV diastolic function correlates with the simultaneous decreases in LVEF, suggesting an impairment of systolic and diastolic function during anthracycline therapy [37, 38]

Early identification of patients at risk for cardiotoxicity represents a primary goal for cardiologists and oncologists; we know the usefulness of LVEF monitoring in patients who have undergone chemotherapy, but it is not specific and sensitive enough to predict damage, because it permits the identification of cardiac damage only after the onset of cardiac dysfunction. An alternative diagnostic strategy is the use of troponin and cardiac peptides in the early detection of cardiotoxicity in clinical practice. Measurement of EF may underestimate actual cardiac damage, because patients may experience subtle changes in cardiac function not detected on imaging studies. Serum cardiac biomarkers, such as N-terminal prohormone brain natriuretic peptide and/or troponin, may also play a role in the detection of cardiac damage, but further investigation is needed to classify their predictive value.

The mechanisms responsible for troponin release after chemotherapy are still being defined. Results of many studies support the non-ischemic etiology of the serum troponin increase after chemotherapy [39]. Furthermore, the persistence of cTnI elevation, observed in some studies, 1 month or more after the end of chemotherapy, suggests the occurrence of a release pattern different from ischemic injury [40]. In acute coronary syndromes, indeed, troponin typically returns to baseline within 10 days and is associated with, not followed by, ventricular dysfunction [41].

Troponin determination detects the presence of cardiotoxicity very early, before impairment of cardiac function, and can be revealed by any other diagnostic technique. Immediately after the last dose of chemotherapy, determination of troponin allows for the discrimination of patients at a high risk for cardiotoxicity from patients at low risk; among patients with positive troponin values, persistence of the increase 1 month after the last administration of chemotherapy is related to an 85% probability of major cardiac events within the first year of follow-up [39, 42, 43], whereas a persistently negative troponin test result can identify, with a predictive negative value of 99%, patients with the lowest risk for cardiotoxicity (Fig. 19.2).

Although the role of Tn is clear, for the cardiac natriuretic peptides (CNPs), such as B-type natriuretic peptide (BNP) and the amino-terminal fragment of its precursor (NT-proBNP), it is not the same thing. They represent efficient markers of ventricular dysfunction as they are rapidly produced and secreted by the heart in response to ventricular wall distention. There are no definitive results regarding the role of CNPs in assessing cardiotoxicity in clinical practice.