Expert Consensus for Multimodality Imaging Evaluation of Adult Patients during and after Cancer Therapy: A Report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging

      Keywords

      Abbreviations:

      ASE (American Society of Echocardiography), BNP (Brain-type natriuretic peptide), CAD (Coronary artery disease), CMR (Cardiac magnetic resonance), CTRCD (Cancer therapeutics–related cardiac dysfunction), DTI (Doppler tissue imaging), EACVI (European Association of Cardiovascular Imaging), EAE (European Association of Echocardiography), GLS (Global longitudinal strain), HF (Heart failure), LGE (Late gadolinium enhancement), LV (Left ventricular), LVEF (Left ventricular ejection fraction), MUGA (Multigated blood pool imaging), NT-proBNP (N-terminal pro–B-type natriuretic peptide), RV (Right ventricular), STE (Speckle-tracking echocardiography), 3D (Three-dimensional), 3DE (Three-dimensional echocardiography), TnI (Troponin I), 2D (Two-dimensional), 2DE (Two-dimensional echocardiography), VEGF (Vascular endothelial growth factor)

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      I. Cancer Therapeutics–Related Cardiac Dysfunction

      Definition, Classification, and Mechanisms of Toxicity

      Cardiac dysfunction resulting from exposure to cancer therapeutics was first recognized in the 1960s, with the widespread introduction of anthracyclines into the oncologic therapeutic armamentarium.
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      Daunomycin, an antitumor antibiotic, in the treatment of neoplastic disease. Clinical evaluation with special reference to childhood leukemia.
      Heart failure (HF) associated with anthracyclines was then recognized as an important side effect. As a result, physicians learned to limit their doses to avoid cardiac dysfunction.
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      • Dainiak N.
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      Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography.
      Several strategies have been used over the past decades to detect it. Two of them evolved over time to be very useful: endomyocardial biopsies and monitoring of left ventricular (LV) ejection fraction (LVEF) by cardiac imaging. Examination of endomyocardial biopsies proved to be the most sensitive and specific parameter for the identification of anthracycline-induced LV dysfunction and became the gold standard in the 1970s. However, the interest in endomyocardial biopsy has diminished over time because of the reduction in the cumulative dosages used to treat malignancies, the invasive nature of the procedure, and the remarkable progress made in noninvasive cardiac imaging. The noninvasive evaluation of LVEF has gained importance, and notwithstanding the limitations of the techniques used for its calculation, has emerged as the most widely used strategy for monitoring the changes in cardiac function, both during and after the administration of potentially cardiotoxic cancer treatment.
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      Echocardiographic evaluation of adriamycin cardiotoxicity in children.
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      A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin.
      The timing of LV dysfunction can vary among agents. In the case of anthracyclines, the damage occurs immediately after the exposure
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      ; for others, the time frame between drug administration and detectable cardiac dysfunction appears to be more variable. Nevertheless, the heart has significant cardiac reserve, and the expression of damage in the form of alterations in systolic or diastolic parameters may not be overt until a substantial amount of cardiac reserve has been exhausted. Thus, cardiac damage may not become apparent until years or even decades after receiving the cardiotoxic treatment. This is particularly applicable to adult survivors of childhood cancers.
      Not all cancer treatments affect the heart in the same way. Therefore these agents cannot be viewed as a single class of drugs.

      Definition of Cancer Therapeutics–Related Cardiac Dysfunction (CTRCD)

      Different definitions of CTRCD have been used historically.
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      Cancer therapy-induced cardiac toxicity in early breast cancer: addressing the unresolved issues.
      It is the consensus of this committee to define CTRCD as a decrease in the LVEF of >10 percentage points, to a value <53% (normal reference value for two-dimensional (2D) echocardiography (2DE) (see Section II). This decrease should be confirmed by repeated cardiac imaging. The repeat study should be performed 2 to 3 weeks after the baseline diagnostic study showing the initial decrease in LVEF. LVEF decrease may be further categorized as symptomatic or asymptomatic, or with regard to reversibility:
      • Reversible: to within 5 percentage points of baseline
      • Partially reversible: improved by ≥10 percentage points from the nadir but remaining >5 percentage points below baseline
      • Irreversible: improved by <10 percentage points from the nadir and remaining >5 percentage points below baseline
      • Indeterminate: patient not available for re-evaluation
      In this expert consensus document, a classification of CTRCD on the basis of the mechanisms of toxicity of the agents is used (Table 1).
      Table 1Characteristics of type I and II CTRCD
      Type IType II
      Characteristic agentDoxorubicinTrastuzumab
      Clinical course and typical response to antiremodeling therapy (β-blockers, ACE inhibitors)May stabilize, but underlying damage appears to be permanent and irreversible; recurrence in months or years may be related to sequential cardiac stressHigh likelihood of recovery (to or near baseline cardiac status) in 2–4 months after interruption (reversible)
      Dose effectsCumulative, dose relatedNot dose related
      Effect of rechallengeHigh probability of recurrent dysfunction that is progressive; may result in intractable heart failure or deathIncreasing evidence for the relative safety of rechallenge (additional data needed)
      UltrastructureVacuoles; myofibrillar disarray and dropout; necrosis (changes resolve over time)No apparent ultra structural abnormalities (though not thoroughly studied)
      ACE, Angiotensin-converting enzyme.

      Classification by Mechanism of Toxicity

      Type I CTRCD

      Doxorubicin is believed to cause dose-dependent cardiac dysfunction through the generation of reactive oxygen species. Recently, investigators using an animal model proposed that doxorubicin-induced CTRCD is mediated by topoisomerase-IIβ in cardiomyocytes through the formation of ternary complexes (topoisomerase-IIβ–anthracycline–deoxyribonucleic acid). These complexes induce deoxyribonucleic acid double-strand breaks and transcriptome changes responsible for defective mitochondrial biogenesis, and reactive oxygen species formation.
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      • et al.
      Identification of the molecular basis of doxorubicin-induced cardiotoxicity.
      The damage caused by the anthracyclines occurs in a cumulative dose–dependent fashion. The expression of damage is related to preexisting disease, the state of cardiac reserve at the time of administration, coexisting damage, and individual variability (including genetic variability). Electron microscopy of myocardial biopsies shows varying degrees of myocyte damage: vacuolar swelling progressing to myofibrillar disarray and ultimately cell death.
      • Friedman M.A.
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      Doxorubicin cardiotoxicity. Serial endomyocardial biopsies and systolic time intervals.
      Once myocytes undergo cell death, they have minimal potential for replacement via regeneration. In this regard, cardiac damage at the cellular level may be deemed irreversible, although cardiac function may be preserved and compensation optimized through antiremodeling pharmacologic therapy, and/or less frequently, mechanical intervention. Agents that are associated with type I CTRCD include all of the anthracyclines (doxorubicin, epirubicin, and idarubicin) as well as mitoxantrone. These agents are now considered to have increased potential for long-term cardiac dysfunction, increased morbidity, and mortality.
      • Ewer M.S.
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      Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity.
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      Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy.

      Type II CTRCD

      A number of agents do not directly cause cell damage in a cumulative dose–dependent fashion. There is considerable evidence for this: first, the typical anthracycline-induced cell damage by electron microscopy is not seen with these agents, and second, in many instances, these agents have been continued for decades, without the progressive cardiac dysfunction that would be expected with type I agents. Finally, functional recovery of myocardial function is frequently (albeit not invariably) seen after their interruption, assuming a type I agent was not given before or at the time of therapy.
      • Ewer M.S.
      • Lippman S.M.
      Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity.
      This document uses trastuzumab as the classical example of type II CTRCD and presents evidence and consensus recommendations for cardiac evaluation of patients receiving this targeted therapy, primarily indicated for HER2-positive breast cancer (summarized in Section V of this document). The role of cardiac assessment and imaging in patients receiving this regimen is further complicated by the fact that type I (doxorubicin) and type II agents (trastuzumab), are often given sequentially or concurrently. Such sequential or concurrent use may increase cell death indirectly by compromising the environment of marginally compensated cells, contributing to the concern that type II agents can still result in cell death at the time of administration. We recognize that in the setting of a variety of predisposing factors, varying cumulative dosages of recognized cardiotoxic agents, and use of other agents that are known to increase oxidative stress and compromise myocyte stability, the algorithm proposed in this document cannot be based on strong clinical data.
      Since the approval of trastuzumab, numerous agents have entered the therapeutic armamentarium, including the small-molecule tyrosine kinase inhibitors. It is difficult to make broad generalizations about these agents, because they often have different kinase targets. However, it appears that the most problematic are the agents that target vascular endothelial growth factor (VEGF) and VEGF receptors. These agents typically are associated with severe systemic arterial hypertension and ischemic events. The development of CTRCD in these patients may be related to transient impairment of the contractile elements within the cell or to the increased afterload on a compromised ventricle. The most concerning of this group are the nonselective agents, including sunitinib and sorafenib, because these drugs can target up to 50 different kinases, in addition to the intended target.
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      Cancer genetics and the cardiotoxicity of the therapeutics.
      Because those “off-target” kinases play important roles in the heart and vasculature, the risk for toxicity is increased. As a result of the unspecific nature and predictability of myocardial damage, it is difficult to provide general recommendations regarding how to monitor patients receiving these agents. A number of attempts have been made to unify approaches to manage these patients, all stopping short of proposing guidelines; one attempt focused on arterial hypertension
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      and the other on CTRCD.
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      Careful management of comorbidities was urged in these documents.

       Key Points

      • Highly effective chemotherapeutic agents may cause CTRCD.
      • CTRCD has been classified as follows:
        • 1.
          Type I CTRCD is characterized by anthracyclines. It is dose dependent, leads to cell apoptosis, and is therefore irreversible at the cell level. Early detection and prompt treatment may prevent LV remodeling and the progression to the HF syndrome.
        • 2.
          Type II CTRCD is characterized by trastuzumab. It is not dose dependent, does not lead to apoptosis by itself, and is often reversible.

      II. Echocardiographic Evaluation of Cardiac Structure and Function in Cancer Patients

      Echocardiography is the cornerstone in the cardiac imaging evaluation of patients in preparation for, during, and after cancer therapy, because of its wide availability, easy repeatability, versatility, lack of radiation exposure, and safety in patients with concomitant renal disease. In addition to the evaluation of LV and right ventricular (RV) dimensions, systolic and diastolic function at rest and during stress, echocardiography also allows a comprehensive evaluation of cardiac valves, the aorta, and the pericardium.
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      Table 2 summarizes the recommended cardio-oncology-echocardiogram protocol.
      Table 2Recommended cardio-oncology echocardiogram protocol
      Standard transthoracic echocardiography
      • In accordance with ASE/EAE guidelines and IAC-Echo
      2D strain imaging acquisition
      • Apical three-, four-, and two-chamber views
        • Acquire ≥3 cardiac cycles
      • Images obtained simultaneously maintaining the same 2D frame rate and imaging depth
        • Frame rate between 40 and 90 frames/sec or ≥40% of HR
      • Aortic VTI (aortic ejection time)
      2D strain imaging analysis
      • Quantify segmental and global strain (GLS)
      • Display the segmental strain curves from apical views in a quad format
      • Display the global strain in a bull’s-eye plot
      2D strain imaging pitfalls
      • Ectopy
      • Breathing translation
      3D imaging acquisition
      • Apical four-chamber full volume to assess LV volumes and LVEF calculation
      • Single and multiple beats optimizing spatial and temporal resolution
      Reporting
      • Timing of echocardiography with respect to the IV infusion (number of days before or after)
      • Vital signs (BP, HR)
      • 3D LVEF/2D biplane Simpson’s method
      • GLS (echocardiography machine, software, and version used)
      • In the absence of GLS, measurement of medial and lateral s′ and MAPSE
      • RV: TAPSE, s′, FAC
      BP, Blood pressure; FAC, fractional area change; HR, heart rate; IAC-Echo, Intersocietal Accreditation Commission Echocardiography; MAPSE, mitral annular plane systolic excursion; TAPSE, tricuspid annular plane systolic excursion; RV, right ventricle; VTI, velocity-time integral.

      LV Systolic Function

      Exposure to potentially cardiotoxic chemotherapeutic agents is a well-recognized indication for baseline and longitudinal evaluation of LV function.
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      The most commonly used parameter for monitoring LV function with echocardiography is LVEF. Accurate calculation of LVEF should be done with the best method available in a given echocardiography lab. Consistency with regard to the method used to determine LVEF should be maintained whenever possible during treatment and surveillance after treatment. Importantly, the digital images obtained to calculate LVEF on follow-up echocardiography should be visually compared with the previous ones to minimize reader variability. As previously reported,
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      imaging at baseline has been particularly helpful in patients with a history or clinical findings suggestive of LV systolic dysfunction (known cardiac ischemic or nonischemic insult) and those at high risk for cardiac events on the basis of traditional risk factors (age, gender, hypertension, hyperlipidemia, and family history of premature coronary artery disease [CAD]). Other imaging modalities, such as multigated blood pool imaging (MUGA) and cardiac magnetic resonance (CMR) imaging, have been used in the evaluation of LVEF. CMR is considered the reference standard for the calculation of LV volumes and LVEF. However, echocardiography is suitable for serial evaluation of LV structure and function. The incorporation of modern techniques such as myocardial contrast echocardiography, three-dimensional (3D) echocardiography (3DE), Doppler tissue imaging (DTI), and speckle-tracking echocardiography (STE), offer a prudent compromise between cost-effectiveness and clinical predictive value (discussed in detail in Sections II and III of this document). According to joint recommendations from the American Society of Echocardiography (ASE), and the European Association of Echocardiography (EAE), the method of choice for LV volumes quantitation and LVEF calculation is the modified biplane Simpson’s technique (method of disks) by 2DE (Figures 1a and 1b).
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      Historically, fractional shortening using linear measurements from M-mode echocardiography or 2DE was used as a surrogate of LVEF in the evaluation of oncologic (especially pediatric) patients. However, this approach should be discouraged, as it takes into consideration only two LV walls (the anterior septum and inferolateral wall) for the calculation of LVEF. The common occurrence of CAD in patients with cancer, along with the observation that CTRCD due to some chemotherapeutic agents may be regional, and not necessarily global, makes necessary a calculation of LVEF using a volumetric assessment.
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      The recommendations for chamber quantification from the ASE and EAE established LVEF ≥ 55% as a normal reference range.
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      New data extracted from six databases, including Asklepios, FLEMENGHO, CARDIA5 and CARDIA25, Padua 3D Echo Normal, and the Normal Reference Ranges for Echocardiography (NORRE) study, indicate that the normal LVEF using the biplane method of disks is 63 ± 5%. LVEF in the range of 53% to 73% should be classified as normal.
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      A revision of the current guideline incorporating these new data is being completed as of this writing. Changes in LVEF indicative of LV damage can be more appropriately identified when comparisons are made between baseline and follow-up studies. In addition, the calculation of LVEF should be combined with assessment of the wall motion score index.
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      Resting wall motion score index based on a 16-segment model of the left ventricle has been demonstrated to be a more sensitive marker of anthracycline-induced CTRCD than relying on the LVEF alone.
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      Figure thumbnail gr1
      Figure 1Calculation of LVEF using the biplane Simpson’s method. (A) Apical two-chamber view obtained at end-diastole. (B) Apical two-chamber view obtained at end-systole.
      Several studies have been published on cardiac monitoring to assess CTRCD, particularly with anthracyclines, the most frequent implicated agents.
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      There has been controversy as to the definition of CTRCD by using changes in resting LVEF, occurring during or after chemotherapy. The use of different LVEF cutoffs and methods of measurement (Teichholz, Simpson’s biplane, or area-length method) have compromised the ability to compare results from different studies and collect evidence-based data.
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      Although monitoring guidelines have been proposed for several potentially cardiotoxic treatments,
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      limited data are available to formulate evidence-based screening and follow-up recommendations for CTRCD.
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      Although LVEF is a robust predictor of cardiac outcomes in the general population, it has low sensitivity for the detection of small changes in LV function. LVEF calculated by conventional 2DE often fails to detect small changes in LV contractility because of several factors. These factors include LV geometric assumptions, inadequate visualization of the true LV apex, lack of consideration of subtle regional wall motion abnormalities, and inherent variability of the measurement.
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      It is also important to bear in mind the load dependency of this measurement. Changes in loading conditions are frequent during chemotherapy and may affect the LVEF value (volume expansion due to the intravenous administration of chemotherapy or volume contraction due to vomiting or diarrhea).
      Otterstad et al.
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      reported in 1997 that 2DE is capable of recognizing differences in sequential measurements of LVEF of 8.9%. In a more recent study of cancer patients undergoing chemotherapy but free of HF symptoms, the upper limit of the 95% confidence interval for longitudinal variability of 2D LVEF measurement was 9.8% (range, 9.0%–10.8%). In this study, Thavendiranathan et al.
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      followed the ASE recommendations for the biplane calculation of LVEF (using apical four- and two-chamber views), in contrast to the apical four- and three-chamber views used by Otterstad et al., and adjusted for intraobserver variability in their calculation of interobserver variability. They concluded that 2DE appears to be reliable in the detection of differences close to 10% in LVEF. Because this is the same magnitude of change used to adjudicate CTRCD, the sensitivity of 2DE has been questioned. Accordingly, strategies using newer echocardiographic technology, such as STE-derived strain imaging for the early detection of subclinical LV systolic dysfunction, have been actively investigated (see Section III). When this technology is not available, the quantitation of LV longitudinal function by simple ultrasound tools such as mitral annular plane systolic excursion by M-mode echocardiography, and/or the peak systolic velocity (s′) of the mitral annulus by pulsed-wave DTI, could be useful adjunct information to LVEF in the evaluation of LV systolic function.
      • Ewer M.S.
      • Ewer S.M.
      Long-term cardiac safety of dose-dense anthracycline therapy cannot be predicted from early ejection fraction data.
      • Karakurt C.
      • Kocak G.
      • Ozgen U.
      Evaluation of the left ventricular function with tissue tracking and tissue Doppler echocardiography in pediatric malignancy survivors after anthracycline therapy.
      • Ganame J.
      • Claus P.
      • Eyskens B.
      • Uyttebroeck A.
      • Renard M.
      • D’hooge J.
      • et al.
      Acute cardiac functional and morphological changes after Anthracycline infusions in children.
      • Tassan-Mangina S.
      • Codorean D.
      • Metivier M.
      • Costa B.
      • Himberlin C.
      • Jouannaud C.
      • et al.
      Tissue Doppler imaging and conventional echocardiography after anthracycline treatment in adults: early and late alterations of left ventricular function during a prospective study.
      • Kapusta L.
      • Thijssen J.M.
      • Groot-Loonen J.
      • Antonius T.
      • Mulder J.
      • Daniels O.
      Tissue Doppler imaging in detection of myocardial dysfunction in survivors of childhood cancer treated with anthracyclines.
      Mitral annular plane systolic excursion is less dependent on image quality. Although there are no cutoff values that allow the prediction of CTRCD, a progressive decline should raise concern for subclinical LV dysfunction.

       Key Points

      • Echocardiography is the method of choice for the evaluation of patients before, during, and after cancer therapy. Accurate calculation of LVEF should be done with the best method available in the echocardiography laboratory (ideally 3DE).
      • When using 2DE, the modified biplane Simpson’s technique is the method of choice.
      • LVEF should be combined with the calculation of wall motion score index.
      • In the absence of global longitudinal strain (GLS) by STE, quantification of LV longitudinal function using mitral annular displacement by M-mode echocardiography and/or peak systolic velocity (s′) of the mitral annulus by pulsed-wave DTI is recommended.
      • LVEF assessed by 2DE often fails to detect small changes in LV contractility.

      LV Diastolic Function

      A comprehensive assessment of LV diastolic function should be performed, including grading of diastolic function, and providing an estimate of LV filling pressure (by using the E/e′ ratio) according to the joint ASE and EAE recommendations on LV diastolic function.
      • Nagueh S.F.
      • Appleton C.P.
      • Gillebert T.C.
      • Marino P.N.
      • Oh J.K.
      • Smiseth O.A.
      • et al.
      Recommendations for the evaluation of left ventricular diastolic function by echocardiography.
      Use of the E/e′ ratio remains questionable in the oncologic setting, as E and e′ velocities fluctuation in these patients could be the consequence of changes in loading conditions as a result of side effects associated with the chemotherapy (nausea, vomiting, and diarrhea) more than the result of a real change in LV diastolic performance. Diastolic parameters have not yet demonstrated value in predicting subsequent CTRCD (please see full discussion in Section III.A).

       Key Point

      • Although diastolic parameters have not been found to be prognostic of CTRCD, a conventional assessment of LV diastolic function, including grading of diastolic function and noninvasive estimation of LV filling pressures, should be added to the assessment of LV systolic function, per ASE and EAE recommendations for the evaluation of LV diastolic function with echocardiography.

      RV Function

      RV abnormalities may occur in oncologic patients for a number of reasons: preexisting RV dysfunction, neoplastic involvement (primary or metastatic), or as a result of the cardiotoxic effects of chemotherapy. It may be implied that the right ventricle is affected by chemotherapy, as early studies of CTRCD often included RV biopsies.
      • Mason J.W.
      • Bristow M.R.
      • Billingham M.E.
      • Daniels J.R.
      Invasive and non invasive methods of assessing Adriamycin cardiotoxic effects in man: superiority of histiopathologic assessment using endomyocardial biopsy.
      However, the frequency of RV involvement or its prognostic value has not been adequately studied. There is only one study reporting subclinical decrease in RV systolic and diastolic echocardiographic indices, although mostly in the normal range in 37 patients in a relatively short time interval after onset of chemotherapy with anthracyclines.
      • Tanindi A.
      • Demirci U.
      • Tacoy G.
      • Buyukberber S.
      • Alsancak Y.
      • Coskun U.
      • et al.
      Assessment of right ventricular functions during cancer chemotherapy.
      Evaluation of the right ventricle should include qualitative and quantitative assessments of chamber size (at least RV basal diameter) and right atrial size (area), as well as quantitative assessment of RV longitudinal M-mode-derived tricuspid annular plane systolic excursion (Figure 2a) and pulsed DTI–derived systolic peak velocity of the tricuspid annulus (s′) (Figure 2b) and RV radial function (fractional area shortening).
      • Rudski L.G.
      • Lai W.W.
      • Afilalo J.
      • Hua L.
      • Handschumacher M.D.
      • Chandrasekaran K.
      • et al.
      Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography.
      Figure thumbnail gr2
      Figure 2(A) Tricuspid annular plane systolic excursion (TAPSE) obtained from an apical chamber view in patient receiving anthracycline based therapy. The TAPSE is normal, measuring 2.26 cm (abnormal <1.6 cm). (B) Pulse Doppler peak systolic velocity at the tricuspid valve annulus in a patient 6 months after completion of trastuzumab-based therapy. The measurement is normal at 18 cm/sec (abnormal <10 cm/sec).
      It is recommended when technically possible to provide an estimate of RV systolic pressure. This is particularly important in patients treated with dasatinib, a tyrosine kinase inhibitor, as pulmonary arterial hypertension may be a specific complication.
      • Montani D.
      • Bergot E.
      • Gunther S.
      • Savale L.
      • Bergeron A.
      • Bourdin A.
      • et al.
      Pulmonary arterial hypertension in patients treated by dasatinib.

       Key Point

      • Although the prognostic value of RV dysfunction has not been demonstrated in patients undergoing chemotherapy, a quantitative assessment of RV chamber and function should be performed because of possible RV involvement.

      Valvular Heart Disease

      Chemotherapeutic agents do not appear to directly affect cardiac valves. However, valvular heart disease may manifest in oncologic patients for a number of reasons, including preexisting valve lesions,
      • Bansal R.C.
      Infective endocarditis.
      • Roberts W.C.
      The congenitally bicuspid aortic valve. A study of 85 autopsy cases.
      • Freed L.A.
      • Levy D.
      • Levine R.A.
      • Larson M.G.
      • Evans J.C.
      • Fuller D.L.
      • et al.
      Prevalence and clinical outcome of mitral-valve prolapse.
      concomitant radiation therapy,
      • Lancellotti P.
      • Nkomo V.T.
      • Badano L.P.
      • Bergler J.
      • Bogaert J.
      • Davin L.
      • et al.
      Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
      severe infection as a complication of chemotherapy, or CTRCD.
      Primary or secondary cardiac tumors may rarely affect valve function by their local effects. In patients with advanced malignant tumors, nonbacterial thrombotic, or marantic endocarditis (Figures 3a and 3b) may occur.
      • Edoute Y.
      • Haim N.
      • Rinkevich D.
      • Brenner B.
      • Reisner S.A.
      Cardiac valvular vegetations in cancer patients: a prospective echocardiographic study of 200 patients.
      • Eiken P.W.
      • Edwards W.D.
      • Tazelaar H.D.
      • McBane R.D.
      • Zehr K.J.
      Surgical pathology of nonbacterial thrombotic endocarditis in 30 patients, 1985-2000.
      This is more common with left-sided valves. Valve lesions may vary in size from microscopic to large bulky lesions, leading to impaired valve coaptation and regurgitation, which is occasionally severe. Significant valve stenosis is infrequent. However, it is thromboembolism from these lesions that is most consequential to the patient rather than hemodynamic impact.
      Figure thumbnail gr3
      Figures 3Transesophageal apical four-chamber and 3D reconstruction in an 86-year-old woman with marantic endocarditis, in the setting of metastatic pancreatic cancer. Please note the diffuse involvement of the edge of the anterior and posterior leaflets.
      Valve disease may occur because of concomitant or previous radiation therapy.
      • Hamza A.
      • Tunick P.A.
      • Kronzon I.
      Echocardiographic manifestations of complications of radiation therapy.
      • Heidenreich P.A.
      • Kapoor J.R.
      Radiation induced heart disease: systemic disorders in heart disease.
      • Heidenreich P.A.
      • Hancock S.L.
      • Lee B.K.
      • Mariscal C.S.
      • Schnittger I.
      Asymptomatic cardiac disease following mediastinal irradiation.
      The effect of radiotherapy on the valvular apparatus was described thoroughly in the recent joint ASE and European Association of Cardiovascular Imaging (EACVI) recommendations,
      • Lancellotti P.
      • Nkomo V.T.
      • Badano L.P.
      • Bergler J.
      • Bogaert J.
      • Davin L.
      • et al.
      Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
      and cardiac imaging evaluation of patients undergoing radiotherapy should be performed according to that document.
      Chemotherapy may lead to pancytopenia and result in bacteremia and sepsis, which in turn may lead to increased risk for endocarditis, with vegetations and valve regurgitation. This is more likely in those with predisposing valve lesions (i.e., mitral valve prolapse
      • Bansal R.C.
      Infective endocarditis.
      and bicuspid aortic valve) or with indwelling central venous catheters placed for vascular access.
      • Tomlinson D.
      • Mermel L.A.
      • Ethier M.C.
      • Matlow A.
      • Gillmeister B.
      • Sung L.
      Defining bloodstream infections related to central venous catheters in patients with cancer: a systematic review.
      Valve disease may occur as a consequence of CTRCD. This usually manifests as mitral regurgitation caused by annular dilation or apical tethering in the setting of LV dysfunction and secondary LV remodeling. Secondary tricuspid regurgitation may also occur because of RV dysfunction or pulmonary arterial hypertension in the setting of CTRCD. Both secondary mitral and tricuspid regurgitation occur late in the course of CTRCD, after significant ventricular dysfunction and geometric remodeling have occurred.
      Echocardiography is the technique of choice for the evaluation of valvular heart disease in patients with cancer. Assessment of the severity of valvular stenosis or regurgitation should be performed on the basis of the current ASE and EAE recommendations.
      • Baumgartner H.
      • Hung J.
      • Bermejo J.
      • Chambers J.B.
      • Evangelista A.
      • Griffin B.P.
      • et al.
      Echocardiographic assessment of valve stenosis: EAE/ASE recommendations for clinical practice.
      • Lancellotti P.
      • Tribouilloy C.
      • Hagendorff A.
      • Popescu B.A.
      • Edvardsen T.
      • Pierard L.A.
      • et al.
      Recommendations for the echocardiographic assessment of native valvular regurgitation: an executive summary from the European Association of Cardiovascular Imaging.
      • Cosyns B.
      • Garbi M.
      • Separovic J.
      • Pasquet A.
      • Lancellotti P.
      Education Committee of the European Association of Cardiovascular Imaging Association (EACVI). Update of the Echocardiography Core Syllabus of the European Association of Cardiovascular Imaging (EACVI).
      • Zoghbi W.A.
      • Enriquez-Sarano M.
      • Foster E.
      • Grayburn P.A.
      • Kraft C.D.
      • Levine R.A.
      • et al.
      Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography.
      Although a complete transthoracic echocardiographic Doppler evaluation is often sufficient to evaluate the valve pathology and the hemodynamic consequences of valve dysfunction, transesophageal echocardiography may be of incremental value in the setting of suspected endocarditis.
      • Mugge A.
      • Daniel W.G.
      • Frank G.
      • Lichtlen P.R.
      Echocardiography in infective endocarditis: reassessment of prognostic implications of vegetation size determined by the transthoracic and the transesophageal approach.
      Both computed tomographic scanning and CMR are not typically required in the routine evaluation of valve disease in oncologic patients, but may have a role in assessing tumor infiltration of valvular structures or when radiation-induced constriction or restrictive cardiomyopathy is suspected.
      • Klein A.L.
      • Abbara S.
      • Agler D.A.
      • Appleton C.P.
      • Asher C.R.
      • Hoit B.
      • et al.
      American society of echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with pericardial disease: endorsed by the society for cardiovascular magnetic resonance and society of cardiovascular computed tomography.
      CMR may be valuable in following ventricular volumes and function in patients with significant valve regurgitation.
      Patients with significant baseline or changing valvular findings during chemotherapy require more frequent serial echocardiographic examinations. The indications for follow-up and interventions for specific valve lesions should be based on guidelines published by the American Heart Association and American College of Cardiology, and the European Society of Cardiology,
      • Bonow R.O.
      • Carabello B.A.
      • Chatterjee K.
      • de Leon Jr., A.C.
      • Faxon D.P.
      • Freed M.D.
      • et al.
      2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.
      • Vahanian A.
      • Alfieri O.
      • Andreotti F.
      • Antunes M.J.
      • et al.
      Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC)European Association for Cardio-Thoracic Surgery (EACTS)
      Guidelines on the management of valvular heart disease (version 2012).
      though follow-up should be adjusted to the clinical situation and individual prognosis of each patient.

       Key Points

      • Cardiac valves should be carefully evaluated in patients undergoing chemotherapy.
      • Patients with baseline or changing valvular findings during chemotherapy should undergo careful reevaluation of valve structure and function on serial echocardiography during and after the course of their treatment.

      Pericardial Disease

      Pericardial disease in oncologic patients is relatively common. It may be secondary to cardiac metastasis, or may be a consequence of radiotherapy
      • Morton D.L.
      • Glancy D.L.
      • Joseph W.L.
      • Adkins P.C.
      Management of patients with radiation-induced pericarditis with effusion: a note on the development of aortic regurgitation in two of them.
      • Gaya A.M.
      • Ashford R.F.
      Cardiac complications of radiation therapy.
      and/or chemotherapy.
      • Krupicka J.
      • Markova J.
      • Pohlreich D.
      • Kozak T.
      • Linkova H.
      • Diehl V.
      • et al.
      Echocardiographic evaluation of acute cardiotoxicity in the treatment of Hodgkin disease according to the German Hodgkin’s Lymphoma Study Group.
      Pericardial disease induced by chemotherapy usually manifests as pericarditis, with or without associated myocarditis. The pericarditis may be associated with pericardial effusion with varying degrees of hemodynamic impairment.
      Several chemotherapy agents are associated with pericardial disease. Anthracyclines,
      • Krupicka J.
      • Markova J.
      • Pohlreich D.
      • Kozak T.
      • Linkova H.
      • Diehl V.
      • et al.
      Echocardiographic evaluation of acute cardiotoxicity in the treatment of Hodgkin disease according to the German Hodgkin’s Lymphoma Study Group.
      • Tohda S.
      • Kobayashi H.
      • Suzuki T.
      • Koyama T.
      • Kamiyama T.
      • Nakamura Y.
      • et al.
      Acute pericarditis caused by daunorubicin in acute myelocytic leukemia.
      • Casey D.J.
      • Kim A.Y.
      • Olszewski A.J.
      Progressive pericardial effusion during chemotherapy for advanced Hodgkin lymphoma.
      • Dazzi H.
      • Kaufmann K.
      • Follath F.
      Anthracycline-induced acute cardiotoxicity in adults treated for leukaemia. Analysis of the clinico-pathological aspects of documented acute anthracycline-induced cardiotoxicity in patients treated for acute leukaemia at the University Hospital of Zurich, Switzerland, between 1990 and 1996.
      cyclophosphamide,
      • Katayama M.
      • Imai Y.
      • Hashimoto H.
      • Kurata M.
      • Nagai K.
      • Tamita K.
      • et al.
      Fulminant fatal cardiotoxicity following cyclophosphamide therapy.
      • Santos G.W.
      • Sensenbrenner L.L.
      • Burke P.J.
      • Colvin M.
      • Owens Jr., A.H.
      • Bias W.B.
      • et al.
      Marrow transplanation in man following cyclophosphamide.
      • Gottdiener J.S.
      • Appelbaum F.R.
      • Ferrans V.J.
      • Deisseroth A.
      • Ziegler J.
      Cardiotoxicity associated with high-dose cyclophosphamide therapy.
      • Goldberg M.A.
      • Antin J.H.
      • Guinan E.C.
      • Rappeport J.M.
      Cyclophosphamide cardiotoxicity: an analysis of dosing as a risk factor.
      • Yamamoto R.
      • Kanda Y.
      • Matsuyama T.
      • Oshima K.
      • Nannya Y.
      • Suguro M.
      • et al.
      Myopericarditis caused by cyclophosphamide used to mobilize peripheral blood stem cells in a myeloma patient with renal failure.
      • Braverman A.C.
      • Antin J.H.
      • Plappert M.T.
      • Cook E.F.
      • Lee R.T.
      Cyclophosphamide cardiotoxicity in bone marrow transplantation: a prospective evaluation of new dosing regimens.
      and cytarabine
      • Gahler A.
      • Hitz F.
      • Hess U.
      • Cerny T.
      Acute pericarditis and pleural effusion complicating cytarabine chemotherapy.
      • Reykdal S.
      • Sham R.
      • Kouides P.
      Cytarabine-induced pericarditis: a case report and review of the literature of the cardio-pulmonary complications of cytarabine therapy.
      • Yamada T.
      • Tsurumi H.
      • Hara T.
      • Sawada M.
      • Oyama M.
      • Moriwaki H.
      Cytarabine-induced pericarditis.
      • Hermans C.
      • Straetmans N.
      • Michaux J.L.
      • Ferrant A.
      Pericarditis induced by high-dose cytosine arabinoside chemotherapy.
      • Vaickus L.
      • Letendre L.
      Pericarditis induced by high-dose cytarabine therapy.
      are associated with acute or subacute development of pericarditis and pericardial effusion, which may or not be accompanied by myocarditis. Imatinib mesylate
      • Barton J.C.
      • Jones S.C.
      • Lamberth W.C.
      • Reymann M.T.
      • Scott V.C.
      Cardiac tamponade associated with imatinib mesylate therapy of chronic myelogenous leukemia.
      • Breccia M.
      • D’Elia G.M.
      • D’Andrea M.
      • Latagliata R.
      • Alimena G.
      Pleural-pericardic effusion as uncommon complication in CML patients treated with Imatinib.
      and dasatinib,
      • Breccia M.
      • Alimena G.
      Pleural/pericardic effusions during dasatinib treatment: incidence, management and risk factors associated to their development.
      • Krauth M.T.
      • Herndlhofer S.
      • Schmook M.T.
      • Mitterbauer-Hohendanner G.
      • Schlogl E.
      • Valent P.
      Extensive pleural and pericardial effusion in chronic myeloid leukemia during treatment with dasatinib at 100 mg or 50 mg daily.
      both tyrosine-kinase inhibitors, are associated with the development of pleural and pericardial effusions, which may progress to cardiac tamponade. Interferon-α,
      • Rauw J.
      • Ahmed S.
      • Petrella T.
      Pericardial effusion and tamponade following interferon alpha treatment for locally advanced melanoma.
      • Cervera Miguel J.I.
      • Vallalta M.
      • Iranzo E.
      • Navarro Ibanez V.
      Pericardial effusion associated with interferon therapy.
      • Velasco J.
      • Orinuela I.
      • Sanjuan A.Z.
      • Ortiz de Zarate Z.
      Pericardial effusion associated to interferon in an immunocompetent patient.
      • Wisniewski B.
      • Denis J.
      • Fischer D.
      • Labayle D.
      Pericarditis secondary to interferon alpha in chronic hepatitis C.
      • Popescu C.
      • Arama V.
      • Gliga S.
      Acute pericarditis due to pegylated interferon alpha therapy for chronic HCV hepatitis - case report.
      used in the treatment of melanoma, can cause pericarditis and pericardial effusion. Retinoic acid syndrome occurs in approximately 26% of patients treated with this drug and is characterized by fever, arterial hypotension, acute renal failure, and pleural and pericardial effusions.
      • Tallman M.S.
      • Andersen J.W.
      • Schiffer C.A.
      • Appelbaum F.R.
      • Feusner J.H.
      • Ogden A.
      • et al.
      All-trans-retinoic acid in acute promyelocytic leukemia.
      • Frankel S.R.
      • Eardley A.
      • Lauwers G.
      • Weiss M.
      • Warrell Jr., R.P.
      The “retinoic acid syndrome” in acute promyelocytic leukemia.
      The occurrence of pericardial and endomyocardial fibrosis years after administration of busulfan has also been described.
      • Terpstra W.
      • de Maat C.E.
      Pericardial fibrosis following busulfan treatment.
      Other agents associated with pericardial disease are methotrexate,
      • Forbat L.N.
      • Hancock B.W.
      • Gershlick A.H.
      Methotrexate-induced pericarditis and pericardial effusion; first reported case.
      • Savoia F.
      • Gaddoni G.
      • Casadio C.
      • Patrizi A.
      • Spadola G.
      • Bassi P.
      • et al.
      A case of aseptic pleuropericarditis in a patient with chronic plaque psoriasis under methotrexate therapy.
      • Mohyuddin T.
      • Elyan M.
      • Kushner I.
      Pericarditis: a rare complication of methotrexate therapy.
      • Palungwachira P.
      • Palungwachira P.
      • Laohathai P.
      Methotrexate induced pericarditis and pericardial effusion in psoriatic patient.
      arsenic trioxide,
      • Huang S.Y.
      • Chang C.S.
      • Tang J.L.
      • Tien H.F.
      • Kuo T.L.
      • Huang S.F.
      • et al.
      Acute and chronic arsenic poisoning associated with treatment of acute promyelocytic leukaemia.
      • Ueda K.
      • Nagai S.
      • Miyashita S.I.
      • Kaise T.
      • Ichikawa M.
      • Kumano K.
      • et al.
      Arsenic-induced pericardial and pleural effusion without acute promyelocytic leukemia differentiation syndrome.
      and, less frequently, 5-fluorouracil
      • Calik A.N.
      • Celiker E.
      • Velibey Y.
      • Cagdas M.
      • Guzelburc O.
      Initial dose effect of 5-fluorouracil: rapidly improving severe, acute toxic myopericarditis.
      and docetaxel.
      • Vincenzi B.
      • Santini D.
      • Frezza A.M.
      • Rocci L.
      • Tonini G.
      Docetaxel induced pericardial effusion.
      Transthoracic echocardiography is the method of choice for the initial evaluation of patients with suspected pericardial disease. In most cases, it allows not only diagnosis but also guidance of pericardiocentesis. The echocardiographic findings in patients with pericarditis can be entirely normal or show evidence of a pericardial effusion. The pericardial effusion should be quantified and graded according to recognized methods, to allow comparison in subsequent evaluations (Figure 4).
      • Maisch B.
      • Seferovic P.M.
      • Ristic A.D.
      • Erbel R.
      • Rienmuller R.
      • Adler Y.
      • et al.
      Guidelines on the diagnosis and management of pericardial diseases executive summary; The Task force on the diagnosis and management of pericardial diseases of the European society of cardiology.
      Evaluation of cardiac tamponade (particularly frequent in the case of malignant effusions) should be performed according to published guidelines.
      • Klein A.L.
      • Abbara S.
      • Agler D.A.
      • Appleton C.P.
      • Asher C.R.
      • Hoit B.
      • et al.
      American society of echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with pericardial disease: endorsed by the society for cardiovascular magnetic resonance and society of cardiovascular computed tomography.
      • Appleton C.P.
      • Hatle L.K.
      • Popp R.L.
      Cardiac tamponade and pericardial effusion: respiratory variation in transvalvular flow velocities studied by Doppler echocardiography.
      • Pepi M.
      • Muratori M.
      Echocardiography in the diagnosis and management of pericardial disease.
      • Wann S.
      • Passen E.
      Echocardiography in pericardial disease.
      Figure thumbnail gr4
      Figure 4Parasternal long-axis view of a patient with metastatic lung cancer. Echo-lucent spaces are seen anterior (pericardial effusion [PEff]) and posterior to the descending aorta (pleural effusion [Plr-Eff]). Echo-lucent space is also seen anterior to the free wall of the right ventricle (pericardial effusion). Findings are consistent with a circumferential pericardial effusion.
      When pericardial thickening is evident, especially if there are clinical signs of RV failure and low cardiac output in the presence of normal ventricular dimension and function, evaluation of constrictive physiology should be made. Constrictive pericarditis is more often associated with radiation-induced cardiotoxicity,
      • Lancellotti P.
      • Nkomo V.T.
      • Badano L.P.
      • Bergler J.
      • Bogaert J.
      • Davin L.
      • et al.
      Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
      • Applefeld M.M.
      • Cole J.F.
      • Pollock S.H.
      • Sutton F.J.
      • Slawson R.G.
      • Singleton R.T.
      • et al.
      The late appearance of chronic pericardial disease in patients treated by radiotherapy for Hodgkin’s disease.
      • Kane G.C.
      • Edie R.N.
      • Mannion J.D.
      Delayed appearance of effusive-constrictive pericarditis after radiation for Hodgkin lymphoma.
      but there are reports of occurrence after high-dose chemotherapy administration.
      • Tulleken J.E.
      • Kooiman C.G.
      • van der Werf T.S.
      • Zijlstra J.G.
      • de Vries E.G.
      Constrictive pericarditis after high-dose chemotherapy.
      Echocardiographic signs of constriction should be explored according to published guidelines.
      • Klein A.L.
      • Abbara S.
      • Agler D.A.
      • Appleton C.P.
      • Asher C.R.
      • Hoit B.
      • et al.
      American society of echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with pericardial disease: endorsed by the society for cardiovascular magnetic resonance and society of cardiovascular computed tomography.
      • Maisch B.
      • Seferovic P.M.
      • Ristic A.D.
      • Erbel R.
      • Rienmuller R.
      • Adler Y.
      • et al.
      Guidelines on the diagnosis and management of pericardial diseases executive summary; The Task force on the diagnosis and management of pericardial diseases of the European society of cardiology.
      • Oki T.
      • Tabata T.
      • Yamada H.
      • Abe M.
      • Onose Y.
      • Wakatsuki T.
      • et al.
      Right and left ventricular wall motion velocities as diagnostic indicators of constrictive pericarditis.
      • Sengupta P.P.
      • Mohan J.C.
      • Mehta V.
      • Arora R.
      • Pandian N.G.
      • Khandheria B.K.
      Accuracy and pitfalls of early diastolic motion of the mitral annulus for diagnosing constrictive pericarditis by tissue Doppler imaging.
      • Sohn D.W.
      • Kim Y.J.
      • Kim H.S.
      • Kim K.B.
      • Park Y.B.
      • Choi Y.S.
      Unique features of early diastolic mitral annulus velocity in constrictive pericarditis.
      Differentiating constrictive pericarditis from restrictive cardiomyopathy in oncologic patients may be a challenge because the two conditions can overlap.
      • Klein A.L.
      • Abbara S.
      • Agler D.A.
      • Appleton C.P.
      • Asher C.R.
      • Hoit B.
      • et al.
      American society of echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with pericardial disease: endorsed by the society for cardiovascular magnetic resonance and society of cardiovascular computed tomography.
      In some instances, the use of other imaging modalities, such as computed tomography or CMR, can be a useful complement to the echocardiographic evaluation. They should especially be considered in the evaluation of primary tumors of the heart, with or without compromise of the pericardium, or when the diagnosis of constrictive pericarditis remains uncertain after a careful echocardiographic evaluation.
      • Klein A.L.
      • Abbara S.
      • Agler D.A.
      • Appleton C.P.
      • Asher C.R.
      • Hoit B.
      • et al.
      American society of echocardiography clinical recommendations for multimodality cardiovascular imaging of patients with pericardial disease: endorsed by the society for cardiovascular magnetic resonance and society of cardiovascular computed tomography.
      CMR is particularly useful in determining the presence of late gadolinium enhancement (LGE) for the identification of patients with transient constriction, who will benefit from aggressive anti-inflammatory regimens rather than pericardiectomy.

       Key Points

      • Pericardial disease in oncologic patients can be associated with cardiac metastasis or be a consequence of chemotherapy and/or radiotherapy.
      • Pericardial effusion should be quantified and graded according to standard methods.
      • Echocardiographic and Doppler signs of cardiac tamponade should be investigated, particularly in patients with malignant effusions.
      • CMR should be considered in evaluation of primary tumors of the heart with or without compromise of the pericardium or when the diagnosis of constrictive pericarditis remains uncertain after a careful echocardiographic evaluation.

      3DE

      Although 3DE is more accurate than 2DE for the measurement of LV volumes
      • Badano L.P.
      • Boccalini F.
      • Muraru D.
      • Bianco L.D.
      • Peluso D.
      • Bellu R.
      • et al.
      Current clinical applications of transthoracic three-dimensional echocardiography.
      in normally shaped ventricles, the accuracy of 2D LVEF calculation should be conceptually similar to that of 3DE because the extent of volume underestimation by 2DE should be similar in both diastole and systole. However, improved accuracy of 3DE (sensitivity, 53%; false-negative rate, 47%) over 2DE (25% and 75%, respectively) in detecting LVEF < 50% on CMR has been observed in survivors of childhood cancer.
      • Armstrong G.T.
      • Plana J.C.
      • Zhang N.
      • Srivastava D.
      • Green D.M.
      • Ness K.K.
      • et al.
      Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic resonance imaging.
      This result may be explained by the fact that 3DE volume measurements are not conditioned by errors induced by geometric assumptions of LV shape, foreshortening of views, or uncontrolled orientation of apical two-chamber and four-chamber views that commonly affect the accuracy of 2DE (Figure 5).
      Figure thumbnail gr5
      Figure 5Semiautomated calculation of LVEF using real-time 3DE in a patient with trastuzumab-induced CTRCD. The LVEF is abnormal at 44% (normal >53%).
      Moreover, serial evaluation of patients at risk for CTRCD requires that the imaging technique should be repeatable and provide consistent results when quantitative analysis is performed on images acquired at different time points and also when images are acquired and/or analyzed by different observers. To address this issue, a recent study
      • Thavendiranathan P.
      • Grant A.D.
      • Negishi T.
      • Plana J.C.
      • Popovic Z.B.
      • Marwick T.H.
      Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy.
      compared different echocardiographic techniques (2D biplane Simpson’s method, 2D triplane, and 3DE with and without contrast) for the serial evaluation of LVEF in patients with cancer undergoing chemotherapy with stable LV function, to identify the technique with the lowest test-retest variability over 1 year of follow-up. Among 56 patients, noncontrast 3DE showed significantly lower temporal variability than all other techniques. Noncontrast 3D echocardiographic measurement of LVEF provided the desired level of longitudinal reproducibility of 5.6% (95% confidence interval, 5.0%–6.2%), whereas 2D echocardiographic techniques showed higher temporal variability (9.8%). Noncontrast 3DE also had the best intra- and interobserver and test-retest variability. Low test-retest variability is as important as the actual LVEF measurement and warrants careful adherence to optimal lab techniques aimed at minimizing it. The superiority of 3DE over 2DE may be explained by the fact that the former is less affected by acquisition differences from one scan to the next, as often seen with the latter,
      • Jenkins C.
      • Moir S.
      • Chan J.
      • Rakhit D.
      • Haluska B.
      • Marwick T.H.
      Left ventricular volume measurement with echocardiography: a comparison of left ventricular opacification, three-dimensional echocardiography, or both with magnetic resonance imaging.
      • King D.L.
      • Harrison M.R.
      • King Jr., D.L.
      • Gopal A.S.
      • Kwan O.L.
      • DeMaria A.N.
      Ultrasound beam orientation during standard two-dimensional imaging: assessment by three-dimensional echocardiography.
      and by use of an automated or semiautomated method for identifying endocardium, compared with manual tracing of endocardial contour required by 2DE. The improved reproducibility of semiautomated versus manual contouring has been previously reported both with 2DE and 3DE.
      • Cannesson M.
      • Tanabe M.
      • Suffoletto M.S.
      • McNamara D.M.
      • Madan S.
      • Lacomis J.M.
      • et al.
      A novel two-dimensional echocardiographic image analysis system using artificial intelligence-learned pattern recognition for rapid automated ejection fraction.
      • Muraru D.
      • Badano L.P.
      • Piccoli G.
      • Gianfagna P.
      • Del Mestre L.
      • Ermacora D.
      • et al.
      Validation of a novel automated border-detection algorithm for rapid and accurate quantitation of left ventricular volumes based on three-dimensional echocardiography.
      Three-dimensional echocardiography appears to be the technique of choice for monitoring the cardiac effects of chemotherapy.
      • Mor-Avi V.
      • Lang R.M.
      Is echocardiography reliable for monitoring the adverse cardiac effects of chemotherapy?.
      However, it is important to realize that this technology has several limitations as well. It is not widely available because of cost, and it relies heavily on high-quality images and operator expertise to achieve the superior performance mentioned above. A recent study by Tsang et al.
      • Tsang W.
      • Kenny C.
      • Adhya S.
      • Kapetanakis S.
      • Weinert L.
      • Lang R.M.
      • et al.
      Interinstitutional measurements of left ventricular volumes, speckle-tracking strain, and dyssynchrony using three-dimensional echocardiography.
      demonstrated that a quality improvement session dedicated to formally standardize the analytic approach of the readers in the echocardiography laboratory can eliminate the systematic bias and improve the agreement among readers in the measurement of LV volumes. It is recommended to include in the echocardiographic report the calculation of LVEF by the biplane Simpson’s method, allowing comparison with previous studies if this method was used. Where available, serial 3D echocardiographic calculation of LVEF should be encouraged for monitoring CTRCD. It is to be expected that during the years to come, less expensive, more automated, and user-friendly 3DE machines that rely less on operator expertise could allow a wider application of this technique.

       Key Points

      • Three-dimensional echocardiography is the preferred technique for monitoring LV function and detecting CTRCD in patients with cancer. Advantages include better accuracy in detecting LVEF below the lower limit of normal, better reproducibility, and lower temporal variability compared with 2DE in patients with cancer treated with chemotherapy.
      • Costs, availability, high reliance on image quality, and need for training of operators currently limit the wide application of 3DE in the oncologic setting.

      Contrast Echocardiography

      Underestimation of volumes may occur when the endocardium is not adequately visualized.
      • Yu E.H.
      • Sloggett C.E.
      • Iwanochko R.M.
      • Rakowski H.
      • Siu S.C.
      Feasibility and accuracy of left ventricular volumes and ejection fraction determination by fundamental, tissue harmonic, and intravenous contrast imaging in difficult-to-image patients.
      Endocardial border dropout can frequently occur in patients undergoing chemotherapy (in particular patients with breast cancer after mastectomy and chest irradiation). According to the ASE consensus statement on the clinical applications of ultrasonic contrast agents in echocardiography and EAE recommendations
      • Mulvagh S.L.
      • Rakowski H.
      • Vannan M.A.
      • Abdelmoneim S.S.
      • Becher H.
      • Bierig S.M.
      • et al.
      American Society of Echocardiography Consensus Statement on the Clinical Applications of Ultrasonic Contrast Agents in Echocardiography.
      • Senior R.
      • Becher H.
      • Monaghan M.
      • Agati L.
      • Zamorano J.
      • Vanoverschelde J.L.
      • et al.
      Contrast echocardiography: evidence-based recommendations by European Association of Echocardiography.
      on myocardial contrast echocardiography, a contrast agent should be used when two contiguous LV segments from any apical view are not seen on noncontrast images (Figure 6).
      Figure thumbnail gr6
      Figure 6End-diastolic endocardial tracing obtained from the apical four-chamber view after the administration of contrast for the calculation of LVEF using the method of disks in a patient with inadequate 2D echocardiographic images.
      There is limited literature to support the use of contrast for 3D assessment of LV volumes in patients with cancer.
      • Jenkins C.
      • Moir S.
      • Chan J.
      • Rakhit D.
      • Haluska B.
      • Marwick T.H.
      Left ventricular volume measurement with echocardiography: a comparison of left ventricular opacification, three-dimensional echocardiography, or both with magnetic resonance imaging.
      A recent study performed in patients with cancer undergoing chemotherapy did not demonstrate any advantage of using contrast-enhanced 3DE for the measurement of LV volumes and LVEF (lower reproducibility and higher temporal variability were noted compared with 3DE alone).
      • Thavendiranathan P.
      • Grant A.D.
      • Negishi T.
      • Plana J.C.
      • Popovic Z.B.
      • Marwick T.H.
      Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy.
      There are two potential explanations for the findings. First, blooming and attenuation artifacts may hinder the delineation of structures such as the mitral valve, with the resultant variability in contouring of the left ventricle. Second, most of the patients studied had adequate acoustic windows with harmonic imaging and therefore did not meet traditional criteria for contrast administration.

       Key Points

      • The use of myocardial contrast agents could be potentially useful in chemotherapy patients when endocardial dropout occurs.
      • According to current recommendations, contrast should be used when two contiguous LV segments are not well visualized on noncontrast apical images.
      • Contrast agents are not recommended in conjunction with 3DE in the longitudinal follow-up of patients with cancer.

      Stress Echocardiography

      Stress echocardiography, an established technique for the detection and prognostication of stable CAD as recommended by guidelines, may be useful in the evaluation of patients with intermediate or high pretest probability for CAD (uninterpretable electrocardiogram or unable to exercise),
      • Douglas P.S.
      • Carr J.J.
      • Cerqueira M.D.
      • Cummings J.E.
      • Gerber T.C.
      • Mukherjee D.
      • et al.
      Developing an action plan for patient radiation safety in adult cardiovascular medicine: proceedings from the Duke University Clinical Research Institute/American College of Cardiology Foundation/American Heart Association Think Tank held on February 28, 2011.
      who are undergoing regimens that may be associated with ischemia (fluorouracil, bevacizumab, sorafenib, and sunitinib).
      • Yeh E.T.H.
      • Bickford C.L.
      Cardiovascular Complications of Cancer Therapy: Incidence, Pathogenesis, Diagnosis, and Management.
      In addition, there are two specific areas in which stress echocardiography may be useful: (1) the evaluation of subclinical LV dysfunction and (2) the evaluation of contractile reserve in patients with CTRCD.
      Although both exercise
      • Bountioukos M.
      • Doorduijn J.K.
      • Roelandt J.R.
      • Vourvouri E.C.
      • Bax J.J.
      • Schinkel A.F.
      • et al.
      Repetitive dobutamine stress echocardiography for the prediction of anthracycline cardiotoxicity.
      and dobutamine stress echocardiography
      • Bountioukos M.
      • Doorduijn J.K.
      • Roelandt J.R.
      • Vourvouri E.C.
      • Bax J.J.
      • Schinkel A.F.
      • et al.
      Repetitive dobutamine stress echocardiography for the prediction of anthracycline cardiotoxicity.
      • Pepi M.
      • Muratori M.
      Echocardiography in the diagnosis and management of pericardial disease.
      • Jarfelt M.
      • Kujacic V.
      • Holmgren D.
      • Bjarnason R.
      • Lannering B.
      Exercise echocardiography reveals subclinical cardiac dysfunction in young adult survivors of childhood acute lymphoblastic leukemia.
      • De Wolf D.
      • Suys B.
      • Maurus R.
      • Benoit Y.
      • Verhaaren H.
      • Matthijs D.
      • et al.
      Dobutamine stress echocardiography in the evaluation of late anthracycline cardiotoxicity in childhood cancer survivors.
      • De Wolf D.
      • Suys B.
      • Verhaaren H.
      • Matthys D.
      • Taeymans Y.
      Low-dose dobutamine stress echocardiography in children and young adults.
      • Cottin Y.
      • L’huillier I.
      • Casasnovas O.
      • Geoffroy C.
      • Caillot D.
      • Zeller M.
      • et al.
      Dobutamine stress echocardiography identifies anthracycline cardiotoxicity.
      • Lanzarini L.
      • Bossi G.
      • Laudisa M.L.
      • Klersy C.
      • Arico M.
      Lack of clinically significant cardiac dysfunction during intermediate dobutamine doses in long-term childhood cancer survivors exposed to anthracyclines.
      • Elbl L.
      • Hrstkova H.
      • Chaloupka V.
      • Novotny J.
      • Michalek J.
      The evaluation of left ventricular function in childhood cancer survivors by pharmacological stress echocardiography.
      • Hamada H.
      • Ohkubo T.
      • Maeda M.
      • Ogawa S.
      Evaluation of cardiac reserved function by high-dose dobutamine-stress echocardiography in asymptomatic anthracycline-treated survivors of childhood cancer.
      • Civelli M.
      • Cardinale D.
      • Martinoni A.
      • Lamantia G.
      • Colombo N.
      • Colombo A.
      • et al.
      Early reduction in left ventricular contractile reserve detected by dobutamine stress echo predicts high-dose chemotherapy-induced cardiac toxicity.
      have been applied to patients with cancer for the identification of anthracycline-induced CTRCD, the results of these studies appear to be inconclusive and contradictory. One of these studies prospectively assessed LV contractile reserve by low-dose dobutamine stress echocardiography in 49 women with breast cancer before each chemotherapy cycle and 1, 4, and 7 months after stopping the treatment. A 5-unit fall in LV contractile reserve was found to be predictive of subsequent LVEF reduction <50%.
      • Civelli M.
      • Cardinale D.
      • Martinoni A.
      • Lamantia G.
      • Colombo N.
      • Colombo A.
      • et al.
      Early reduction in left ventricular contractile reserve detected by dobutamine stress echo predicts high-dose chemotherapy-induced cardiac toxicity.
      Dobutamine could potentially allow the earlier identification of disease by recognizing a compromise in cardiac reserve.
      In case of the development of CTRCD, the transient recovery of LV function during stress echo may also predict a better outcome.
      • Grosu A.
      • Bombardini T.
      • Senni M.
      • Duino V.
      • Gori M.
      • Picano E.
      End-systolic pressure/volume relationship during dobutamine stress echo: a prognostically useful non-invasive index of left ventricular contractility.

       Key Points

      • Stress echocardiography may be helpful in the evaluation of patients with intermediate or high pretest probability for CAD (uninterpretable electrocardiogram or unable to exercise) who will receive regimens that may cause ischemia (fluorouracil, bevacizumab, sorafenib, and sunitinib).
      • Stress echocardiography may be of help in the determination of contractile reserve of patients with evidence of CTRCD.

      Other

      In the presence of implanted ports, tunneled catheters, or peripherally inserted central lines, it is recommended to report the location of the tip with respect to the superior vena cava–right atrium junction, as well as the presence of thrombus or vegetations.

      III. Detection of Subclinical LV Dysfunction

      Detection of Subclinical LV Dysfunction Using Imaging

      LVEF as a Tool to Detect Subclinical LV Dysfunction

      Although the decrease in LVEF during treatment has been associated with symptomatic HF,
      • Mitani I.
      • Jain D.
      • Joska T.M.
      • Burtness B.
      • Zaret B.L.
      Doxorubicin cardiotoxicity: prevention of congestive heart failure with serial cardiac function monitoring with equilibrium radionuclide angiocardiography in the current era.
      • Jensen B.V.
      • Skovsgaard T.
      • Nielsen S.L.
      Functional monitoring of anthracycline cardiotoxicity: a prospective, blinded, long-term observational study of outcome in 120 patients.
      • Steinherz L.J.
      • Steinherz P.G.
      • Tan C.T.
      • Heller G.
      • Murphy M.L.
      Cardiac toxicity 4 to 20 years after completing anthracycline therapy.
      the ability of serial LVEF assessment during and after treatment to identify CTRCD and prevent subsequent HF remains controversial.
      • Alexander J.
      • Dainiak N.
      • Berger H.J.
      • Goldman L.
      • Johnstone D.
      • Reduto L.
      • et al.
      Serial assessment of doxorubicin cardiotoxicity with quantitative radionuclide angiocardiography.
      • Ewer M.S.
      • Ali M.K.
      • Mackay B.
      • Wallace S.
      • Valdivieso M.
      • Legha S.S.
      • et al.
      A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving Adriamycin.
      • Swain S.M.
      • Whaley F.S.
      • Ewer M.S.
      Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials.
      Recently, the value of baseline LVEF and LVEF measured after anthracyclines in the prediction of subsequent HF was underlined in a large study of women with breast cancer treated with anthracyclines, with or without trastuzumab. In this study, a reduced LVEF (including LVEFs of 50%–54%) at baseline or after anthracyclines was associated with higher rates of cardiac events on follow-up,
      • Tan-Chiu E.
      • Yothers G.
      • Romond E.
      • Geyer Jr., C.E.
      • Ewer M.
      • Keefe D.
      • et al.
      Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31.
      although the percentage of patients with LVEFs < 55% after anthracyclines in the study was quite low (10%–12%). Unfortunately, detecting a decreased LVEF after anthracyclines may be too late for treatment,
      • Cardinale D.
      • Colombo A.
      • Lamantia G.
      • Colombo N.
      • Civelli M.
      • De Giacomi G.
      • et al.
      Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy.
      suggesting that more sensitive parameters of LV dysfunction would be helpful.

      Diastolic Dysfunction: Early Signs and Prognostic Value

      In a small prospective study, a prolongation in the isovolumic relaxation time preceded and predicted a drop in LVEF of >10%, occurring up to 3 months later.
      • Stoddard M.F.
      • Seeger J.
      • Liddell N.E.
      • Hadley T.J.
      • Sullivan D.M.
      • Kupersmith J.
      Prolongation of isovolumetric relaxation time as assessed by Doppler echocardiography predicts doxorubicin-induced systolic dysfunction in humans.
      Larger studies, however, although confirming early changes of LV diastolic parameters after treatment, have not reproduced its predictive value.
      • Dorup I.
      • Levitt G.
      • Sullivan I.
      • Sorensen K.
      Prospective longitudinal assessment of late anthracycline cardiotoxicity after childhood cancer: the role of diastolic function.
      Significant increases in the myocardial performance index occur early after anthracycline administration and were reported in two studies to predict later decreases in LVEF.
      • Eidem B.W.
      • Sapp B.G.
      • Suarez C.R.
      • Cetta F.
      Usefulness of the myocardial performance index for early detection of anthracycline-induced cardiotoxicity in children.
      • Ishii M.
      • Tsutsumi T.
      • Himeno W.
      • Eto G.
      • Furui J.
      • Hashino K.
      • et al.
      Sequential evaluation of left ventricular myocardial performance in children after anthracycline therapy.
      The prognostic value of myocardial performance index could not be replicated in subsequent studies.
      • Rohde L.E.
      • Baldi A.
      • Weber C.
      • Geib G.
      • Mazzotti N.G.
      • Fiorentini M.
      • et al.
      Tei index in adult patients submitted to adriamycin chemotherapy: failure to predict early systolic dysfunction. Diagnosis of adriamycin cardiotoxicity.
      Two studies have reported LV diastolic abnormalities late after anthracycline administration; these abnormalities were associated with wall motion abnormalities despite a preserved LVEF.
      • Pellicori P.
      • Calicchia A.
      • Lococo F.
      • Cimino G.
      • Torromeo C.
      Subclinical anthracycline cardiotoxicity in patients with acute promyelocytic leukemia in long-term remission after the AIDA protocol.
      Another study reported that a reduced transmitral E/A ratio was associated with a reduction in longitudinal strain by STE in patients with normal LVEFs late after treatment.
      • Ho E.
      • Brown A.
      • Barrett P.
      • Morgan R.B.
      • King G.
      • Kennedy M.J.
      • et al.
      Subclinical anthracycline- and trastuzumab-induced cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study.
      It is unclear, however, if these findings have any clinical significance.
      As a result, it can be concluded that the use of Doppler-derived diastolic indices is not useful in the early detection of CTRCD because of their inability to predict subsequent HF (Table 3).
      Table 3Clinical studies assessing diastolic function indices in cancer treatment demonstrating predictive value of subsequent cardiotoxicity
      StudyPopulationTreatmentTiming of echocardiographyFindingsDecrease in LVEFPredictive value/correlations
      Stoddard et al. (1992)
      • Stoddard M.F.
      • Seeger J.
      • Liddell N.E.
      • Hadley T.J.
      • Sullivan D.M.
      • Kupersmith J.
      Prolongation of isovolumetric relaxation time as assessed by Doppler echocardiography predicts doxorubicin-induced systolic dysfunction in humans.
      26 adults; mean age, 48 yDoxorubicin > 200 mg/m2Baseline, 3 wk, and 3 mo after treatmentProlonged IVRT and deceleration time at 3 wk9/26 (35%)Prolongation of IVRT > 37% predicted a drop in LVEF > 10% (78% sensitivity, 88% specificity)
      Dorup et al. (2004)
      • Dorup I.
      • Levitt G.
      • Sullivan I.
      • Sorensen K.
      Prospective longitudinal assessment of late anthracycline cardiotoxicity after childhood cancer: the role of diastolic function.
      88 ALL, 66 Wilms’ tumor, age not reportedALL: daunorubicin 90, 180, or 270 mg/m2; Wilms’ tumor: doxorubicin 303 mg/m2∼1.5 and 6.5 y after treatmentReduced E wave and reduced E/A ratio, prolonged IVRT and E deceleration timeNot reported13% of those with reduced E wave at 1.5 y had reduced fractional shortening at FU
      Tassan-Mangina et al. (2006)
      • Tassan-Mangina S.
      • Codorean D.
      • Metivier M.
      • Costa B.
      • Himberlin C.
      • Jouannaud C.
      • et al.
      Tissue Doppler imaging and conventional echocardiography after anthracycline treatment in adults: early and late alterations of left ventricular function during a prospective study.
      16; mean age, 38 yDoxorubicin 211 mg/m2Before chemotherapy, 1–3 mo and 3.5 y after treatmentReduced mitral E wave and DTI E velocity at early FU; more pronounced changes at late FU4/16 (25%)All those with decreased LVEFs had a short IVRT at early FU
      ALL, Acute lymphoblastic leukemia; FU, follow-up; IVRT, isovolumic relaxation time.

      Detection of Subclinical LV Dysfunction Using DTI Velocities

      Several investigators have demonstrated an early reduction in e′ velocity of the mitral annulus in patients receiving anthracyclines (Figures 7c and 7d),
      • Tassan-Mangina S.
      • Codorean D.
      • Metivier M.
      • Costa B.
      • Himberlin C.
      • Jouannaud C.
      • et al.
      Tissue Doppler imaging and conventional echocardiography after anthracycline treatment in adults: early and late alterations of left ventricular function during a prospective study.
      • Ho E.
      • Brown A.
      • Barrett P.
      • Morgan R.B.
      • King G.
      • Kennedy M.J.
      • et al.
      Subclinical anthracycline- and trastuzumab-induced cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study.
      • Nagy A.C.
      • Tolnay E.
      • Nagykalnai T.
      • Forster T.
      Cardiotoxicity of anthracycline in young breast cancer female patients: the possibility of detection of early cardiotoxicity by TDI.
      • Nagy A.C.
      • Cserep Z.
      • Tolnay E.
      • Nagykalnai T.
      • Forster T.
      Early diagnosis of chemotherapy-induced cardiomyopathy: a prospective tissue Doppler imaging study.
      which remained reduced during treatment
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Cohen V.
      • et al.
      Early detection and prediction of cardiotoxicity in chemotherapy-treated patients.
      and several years thereafter.
      • Ho E.
      • Brown A.
      • Barrett P.
      • Morgan R.B.
      • King G.
      • Kennedy M.J.
      • et al.
      Subclinical anthracycline- and trastuzumab-induced cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study.
      The reductions in e′ velocity appear heterogeneous,
      • Ho E.
      • Brown A.
      • Barrett P.
      • Morgan R.B.
      • King G.
      • Kennedy M.J.
      • et al.
      Subclinical anthracycline- and trastuzumab-induced cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study.
      • Nagy A.C.
      • Tolnay E.
      • Nagykalnai T.
      • Forster T.
      Cardiotoxicity of anthracycline in young breast cancer female patients: the possibility of detection of early cardiotoxicity by TDI.
      • Ganame J.
      • Claus P.
      • Uyttebroeck A.
      • Renard M.
      • D’hooge J.
      • Bijnens B.
      • et al.
      Myocardial dysfunction late after low-dose anthracycline treatment in asymptomatic pediatric patients.
      suggesting differences in regional wall stress, apoptosis, or fibrosis.
      Figure thumbnail gr7
      Figure 7Reductions in pulsed DTI e′ velocities in the setting of anthracycline-induced CTRCD. (A,B) Septal and lateral e′ velocities were 8 and 15 cm/sec, respectively, before the initiation of therapy. (C,D) Septal and lateral velocities decreased to 4 and 5 cm/sec, respectively, during anthracycline therapy.
      In a study by Negishi et al.,
      • Negishi K.
      • Negishi T.
      • Hare J.L.
      • Haluska B.A.
      • Plana J.C.
      • Marwick T.H.
      Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity.
      a 10% reduction in e′ velocity was observed in patients who developed CTRCD. Nevertheless, the reduction was not statistically significant (P = .09) or predictive of subsequent reduction in LVEF (P = 0.14).
      A reduction in DTI-derived systolic velocity (s′) was reported in animal models of doxorubicin-induced cardiac injury
      • Neilan T.G.
      • Jassal D.S.
      • Perez-Sanz T.M.
      • Raher M.J.
      • Pradhan A.D.
      • Buys E.S.
      • et al.
      Tissue Doppler imaging predicts left ventricular dysfunction and mortality in a murine model of cardiac injury.
      and in the chronic follow-up of patients treated with anthracyclines.
      • Ho E.
      • Brown A.
      • Barrett P.
      • Morgan R.B.
      • King G.
      • Kennedy M.J.
      • et al.
      Subclinical anthracycline- and trastuzumab-induced cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study.
      A marked early decrease in s′, and its value as a potential predictor of changes of LV systolic function after chemotherapy, was reported in a study of 42 patients with breast cancer treated with trastuzumab in the adjuvant setting.
      • Fallah-Rad N.
      • Walker J.R.
      • Wassef A.
      • Lytwyn M.
      • Bohonis S.
      • Fang T.
      • et al.
      The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy.
      It is to be noted, however, that the rate of symptomatic HF in this study was of 24% at 6 months of treatment, an unusually high rate in chemotherapy-treated populations. Whether these results can be generalized to patients with a lower incidence of HF is unknown.

       Key Point

      • A decreased LVEF at baseline or after anthracyclines is associated with higher rates of cardiac events on follow-up.
      • Although it has been suggested that alterations in LV diastolic function (as evaluated by Doppler indices of mitral inflow and e′ by pulsed DTI) precede alterations in systolic function, the evidence does not support the role of these indices for the prediction of later CTRCD.

      Early Detection of LV Dysfunction Using Strain and Strain Rate

      A recent systematic review shows that as of 2014, 21 peer-reviewed studies have reported the sensitivity of measuring deformation indices (strain, strain rate, and twist) in the detection of subclinical LV dysfunction in patients treated for cancer (Table 4 summarizes these studies).
      • Thavendiranathan P.
      • Poulin F.
      • Lim K.D.
      • Plana J.C.
      • Woo A.
      • Marwick T.H.
      Use of Myocardial Strain Imaging by Echocardiography for the Early Detection of Cardiotoxicity in Patients During and After Cancer Chemotherapy: A Systematic Review.
      The studies evaluated patients treated with anthracyclines alone, or in association with other therapies, either during treatment or late after completion of the therapy (survivor studies).
      Table 4Clinical studies using STE-derived deformation indices during or early after cancer treatment
      Reproduced with permission from the Journal of the American College of Cardiology.
      StudyEchocardiographic methodCancer typenAge, yrsFemale, %TreatmentEchocardiography timingPre-echoPost-echoCardiotoxicity Rate (%)Thresholds for Toxicity PredictionVendor, Reproducibility
      Mornos et al. (2013)
      • Mornos C.
      • Petrescu L.
      Early detection of anthracycline-mediated cardiotoxicity: the value of considering both global longitudinal left ventricular strain and twist.
      STEBreast lymphoma, ALL, AML, osteosarcoma74 & 37 controls51 ±1158AnthracyclinesPre, post, and 6, 12, 24 and 52 weeksGLS -21.2 ± 2.5% GRS 47.8 ± 5.3%GLS -19.0 ± 2.4% GRS 41.1 ± 5.4% (6 weeks)13ΔGLS 2.8% (13.1% relative), sensitivity 79% and specificity 73% at 6 weeks for toxicity at 24 -52 weeksGE, intraobserver ICC for GLS 0.95, interobserver 0.91
      Negishi et al. (2013)
      • Negishi K.
      • Negishi T.
      • Hare J.L.
      • Haluska B.A.
      • Plana J.C.
      • Marwick T.H.
      Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity.
      STEBreast8150 ± 11100Trastuzumab, doxorubicin 46% RT 62%Pre-trastuzumab, and 6 and 12 months laterGLS -20.7 ± 2.6% GLSR -1.17 ± 0.24/s GLSR-E 1.36 ± 0.28/sGLS -18.3 ± 2.1% GLSR -1.00 ± 0.15/s GLSR-E 1.20 ± 0.28/s (at 6 months in patients who later had toxicity)30GLS change ≥11% between pre-treatment and 6 months, sensitivity 65%, spec 95% or absolute GLS >-20.5 at 6 months, sensitivity 96%, spec 66% for toxicity at 12 monthsGE, intraobserver ICC (95% CI) for GLS 0.85 (0.54%-0.96%), GSLR 0.91 (0.70-0.98/s), GLSR-E 0.90 (0.66-0.97/s), Interobserver 0.71 (0.23%-0.92%), 0.85 (0.28-0.97/s), 0.87 (0.56-0.97/s)
      Baratta et al. (2013)
      • Baratta S.
      • Damiano M.
      • Marchese M.
      • Trucco J.
      • Rizzo M.
      • Bernok F.
      • et al.
      Serum Markers, Conventional Doppler Echocardiography and Two-dimensional Systolic Strain in the Diagnosis of Chemotherapy-Induced Myocardial Toxicity.
      STEBreast3647 ± 1658Doxorubicin 58% trastuzumab 22%Pre- and 2,3,4, and 6 months after start of therapyGLS -20.3 ± 2.7% GRS 53.1 ± 4%GLS -18.9 ± 2.5% (3 months) GRS 50 ± 3.9% (4 months)19.4GLS fall ≥ 15% at 3 months, sensitivity 86%, spec 86%. GRS fall ≥ 10% at 4 months, sensitivity 86% spec 69%GE, mean (SD) absolute difference inter/intraobserver GLS 0.6 (1.4%)/0.2 (1/1%), GRS 3.4 (7.1%)/3.2 (6.6%)
      Sawaya et al. (2012)
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Tan T.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      STEBreast8150 ± 10100Doxorubicin, epirubicin, trastuzumab, RT 60%Pre-anthracycline and at 3, 6, 9, 12, and 15 monthsGLS -21 ± 2% GRS 53 ± 15% GCS -18 ± 4%GLS -19 ± 2% GRS 50 ± 17% GCS -16 ± 4% at 3 months32Absolute GLS < -19% at 3 months, sensitivity 74%, spec 73% for subsequent toxicityGE, same variability as in previous study (153)
      Sawaya et al. (2011)
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Cohen V.
      • et al.
      Early detection and prediction of cardiotoxicity in chemotherapy-treated patients.
      STEBreast4349 ± 10100Doxorubicin, epirubicin, trastuzumab, RT 11.6%Pre-anthracycline and at 3 and 6 monthsGLS -20.5 ± 2.2% GCS 18 ± 4%GLS -19.3 ± 2.4% GCS 15 ± 4%21GLS fall > 10% at 3 months, sensitivity 78%, spec 79% for toxicity at 6 monthsGE, intraobserver as absolute mean error (SD) GLS -0.14 (1.1%), interobserver 0.5 (1.5%)
      Fallah-Rad et al. (2011)
      • Fallah-Rad N.
      • Walker J.R.
      • Wassef A.
      • Lytwyn M.
      • Bohonis S.
      • Fang T.
      • et al.
      The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy.
      STEBreast4247 ± 9100Epirubicin, doxorubicin, trastuzumab, RT 98%Pre-anthracycline, Pre-trastuzumab and at 3, 6, 9, and 12 monthsGLS -19.8 ± 1.8% GLS 41.4 ± 15.2%GLS -16.4 ± 1.1% GRS 34.5 ± 15.2% (3 months into trastuzumab)24Absolute GLS fall of 2.0%, sensitivity 79%, spec 82%. Absolute GRS fall of 0.8%, sensitivity 86%, spec 81% for subsequent toxicityGE, intraobserver as ICC (COV) GLS 0.94 (3.5%), GRS 0.91 (3.2%). Interobserver 0.90 (5.2%), 0.82 (5.4%)
      Hare et al. (2009)
      • Hare J.L.
      • Brown J.K.
      • Leano R.
      • Jenkins C.
      • Woodward N.
      • Marwick T.H.
      Use of myocardial deformation imaging to detect preclinical myocardial dysfunction before conventional measures in patients undergoing breast cancer treatment with trastuzumab.
      TDI and STEBreast3551 ± 8100Doxorubicin, epirubicin, trastuzumab, RT 77%Pre- and/or post-anthracycline and at 3-month intervalsSTE GLSR -1.30 ± 0.21/s STE RSR 2.02 ± 0.61/sSTE GLSR -1.24 ± 0.18/s (by 3 months) STE RSR 1.75 ± 0.41/s (by 6-9 months)14A >1 SD drop in GLSR (toxicity at mean follow-up of 22 ± 6 months)GE, intra/interobserver as ICC for 2D GLS 0.94/0.91, GLSR 0.94/0.91, GRS 0.86/0.50, GRSR 0.83/0.65
      Mavinkurve-Groothuis et al. (2013)
      • Mavinkurve-Groothuis A.M.
      • Marcus K.A.
      • Pourier M.
      • Loonen J.
      • Feuth T.
      • Hoogerbrugge P.M.
      • et al.
      Myocardial 2D strain echocardiography and cardiac biomarkers in children during and shortly after anthracycline therapy for acute lymphoblastic leukaemia (ALL): a prospective study.
      STEALL60, 60 controls6 (2.2-15.4)38Anthracycline, RT 100%Pre-anthracycline, 10 weeks, and 12 monthsGLS -18.2 ± 3.1% GLSR -1.44 ± 0.3/s GRS 66.8 ± 1% GCS -19.4 ± 4.3GLS -16.7 ± 5.2% GLSR -1.20 ± 0.4/s GRS 55.2 ± 16% GCS -16.9 ± 3.1% (by 12 months)0Strain values were not predictive of decrease in LV fractional shorteningGE, no data
      AC, Adriamycin; ALL, acute lymphoblastic leukemia; AML, acute myoblastic leukemia; CHF, congestive heart failure; CREC, Cardiac Review and Evaluation Committee; FEC, 5-fluorouracil, epirubicin, and cyclophosphamide; 4CH, four-chamber; FS, fractional shortening; GCS, global circumferential strain; GLSR, global longitudinal strain rate; GLSR-E, global longitudinal early diastolic strain rate; GRS, global radial strain; GRSR, global radial strain rate; LS, longitudinal strain; LSR, longitudinal strain rate; NPV, negative predictive value; PPV, positive predictive value; RSR, radial strain rate; SAX, short-axis; 2CH, two-chamber.
      The decrease in myocardial systolic function induced by anthracyclines appears to be extremely rapid, as early as 2 hours after the first anthracycline dose.
      • Ganame J.
      • Claus P.
      • Eyskens B.
      • Uyttebroeck A.
      • Renard M.
      • D’hooge J.
      • et al.
      Acute cardiac functional and morphological changes after Anthracycline infusions in children.
      As in most of the other studies, the decrease in deformation indices preceded the decrease in LVEF and persisted during the subsequent cancer treatment. Early decreases in radial and longitudinal strain and strain rate were noted using DTI
      • Jurcut R.
      • Wildiers H.
      • Ganame J.
      • D’hooge J.
      • De Backer J.
      • Denys H.
      • et al.
      Strain rate imaging detects early cardiac effects of pegylated liposomal Doxorubicin as adjuvant therapy in elderly patients with breast cancer.
      and STE
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Cohen V.
      • et al.
      Early detection and prediction of cardiotoxicity in chemotherapy-treated patients.
      • Fallah-Rad N.
      • Walker J.R.
      • Wassef A.
      • Lytwyn M.
      • Bohonis S.
      • Fang T.
      • et al.
      The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy.
      • Poterucha J.T.
      • Kutty S.
      • Lindquist R.K.
      • Li L.
      • Eidem B.W.
      Changes in left ventricular longitudinal strain with anthracycline chemotherapy in adolescents precede subsequent decreased left ventricular ejection fraction.
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Tan T.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      • Stoodley P.W.
      • Richards D.A.
      • Hui R.
      • Boyd A.
      • Harnett P.R.
      • Meikle S.R.
      • et al.
      Two-dimensional myocardial strain imaging detects changes in left ventricular systolic function immediately after anthracycline chemotherapy.
      and have been confirmed in patients treated with anthracyclines (in some studies in association with taxanes and trastuzumab), with or without later decreases in LVEF. In one small study, radial indices decreased earlier than longitudinal indices after three cycles of anthracyclines.
      • Jurcut R.
      • Wildiers H.
      • Ganame J.
      • D’hooge J.
      • De Backer J.
      • Denys H.
      • et al.
      Strain rate imaging detects early cardiac effects of pegylated liposomal Doxorubicin as adjuvant therapy in elderly patients with breast cancer.
      Decreases in global
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Tan T.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      and regional
      • Stoodley P.W.
      • Richards D.A.
      • Hui R.
      • Boyd A.
      • Harnett P.R.
      • Meikle S.R.
      • et al.
      Two-dimensional myocardial strain imaging detects changes in left ventricular systolic function immediately after anthracycline chemotherapy.
      circumferential strain have also been reported early after anthracycline treatment. The magnitude of the decrease in longitudinal strain appears to average between 10% and 20% over the length of the treatment, depending on the population, the analysis, and the treatment studied.
      The regionality of the impairment of LV systolic function was assessed in 19 children at the midpoint and at the end of their anthracycline treatment. The investigators reported mainly a septal and apical pattern, which was partially improved at the end of the treatment.
      • Poterucha J.T.
      • Kutty S.
      • Lindquist R.K.
      • Li L.
      • Eidem B.W.
      Changes in left ventricular longitudinal strain with anthracycline chemotherapy in adolescents precede subsequent decreased left ventricular ejection fraction.
      There does not appear to be preferential impairment of one particular layer (subendocardial, midmyocardial, or subepicardial) by anthracyclines, as both longitudinal and radial (and, when studied, circumferential) strain was altered. This result is concordant with experimental models of doxorubicin-induced CTRCD, in which cardiomyocyte apoptosis is present throughout the myocardial layers.
      • Neilan T.G.
      • Jassal D.S.
      • Perez-Sanz T.M.
      • Raher M.J.
      • Pradhan A.D.
      • Buys E.S.
      • et al.
      Tissue Doppler imaging predicts left ventricular dysfunction and mortality in a murine model of cardiac injury.
      Interestingly, Hare et al.
      • Hare J.L.
      • Brown J.K.
      • Leano R.
      • Jenkins C.
      • Woodward N.
      • Marwick T.H.
      Use of myocardial deformation imaging to detect preclinical myocardial dysfunction before conventional measures in patients undergoing breast cancer treatment with trastuzumab.
      did not report any change in longitudinal or radial global systolic strain (but a slight decrease in longitudinal and radial strain rate) in patients treated by anthracyclines and trastuzumab. Strain rate measurements may be more sensitive than strain to subtle changes in cardiac function. However, use of strain rate appears to be more challenging in clinical practice.
      The prognostic value of early measurement of systolic deformation indices in the prediction of subsequent LV systolic function has been evaluated in several studies, both in animals
      • Neilan T.G.
      • Jassal D.S.
      • Perez-Sanz T.M.
      • Raher M.J.
      • Pradhan A.D.
      • Buys E.S.
      • et al.
      Tissue Doppler imaging predicts left ventricular dysfunction and mortality in a murine model of cardiac injury.
      and humans.
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Cohen V.
      • et al.
      Early detection and prediction of cardiotoxicity in chemotherapy-treated patients.
      • Fallah-Rad N.
      • Walker J.R.
      • Wassef A.
      • Lytwyn M.
      • Bohonis S.
      • Fang T.
      • et al.
      The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy.
      • Poterucha J.T.
      • Kutty S.
      • Lindquist R.K.
      • Li L.
      • Eidem B.W.
      Changes in left ventricular longitudinal strain with anthracycline chemotherapy in adolescents precede subsequent decreased left ventricular ejection fraction.
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Tan T.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      In 81 patients with breast cancer treated with anthracyclines followed by taxanes and trastuzumab who were followed for 15 months with quarterly echocardiography, the average of the basal and midventricular peak systolic longitudinal strain measured in apical four- and two-chamber views using STE after the completion of anthracyclines predicted subsequent CTRCD. CTRCD was defined in this study as a decrease in LVEF of >10% to <55% during the remainder of the treatment (12 months thereafter). Longitudinal strain calculated with EchoPAC software (GE Healthcare, Milwaukee, Wisconsin) was >−19% in all patients who later developed HF (Figures 8a–8d). Although reductions were seen in all three layers, neither radial nor circumferential strain was predictive of subsequent CTRCD.
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Tan T.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      A predictive value of regional strain was also reported in smaller studies with shorter follow-up periods.
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Cohen V.
      • et al.
      Early detection and prediction of cardiotoxicity in chemotherapy-treated patients.
      • Fallah-Rad N.
      • Walker J.R.
      • Wassef A.
      • Lytwyn M.
      • Bohonis S.
      • Fang T.
      • et al.
      The utility of cardiac biomarkers, tissue velocity and strain imaging, and cardiac magnetic resonance imaging in predicting early left ventricular dysfunction in patients with human epidermal growth factor receptor II-positive breast cancer treated with adjuvant trastuzumab therapy.
      • Poterucha J.T.
      • Kutty S.
      • Lindquist R.K.
      • Li L.
      • Eidem B.W.
      Changes in left ventricular longitudinal strain with anthracycline chemotherapy in adolescents precede subsequent decreased left ventricular ejection fraction.
      Importantly, although the decrease in longitudinal strain and LVEF appears to at least partially persist throughout the duration of the treatment,
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Tan T.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      it is unknown what their evolution will be in subsequent years, and whether early deformation measurements will predict persistent decreases in LVEF or symptomatic HF.
      Figure thumbnail gr8
      Figure 8Speckle-tracking echocardiographic images illustrating GLS obtained from the apical long-axis view (A), four-chamber-view (B), and two-chamber-view (C) and strain curves and bull’s-eye plot in a patient with breast cancer who developed CTRCD after receiving doxorubicin followed by trastuzumab. Each segment has a numeric and color-coded strain value. The cardiac dysfunction appears to be regional, with some segments more involved than others.
      Negishi et al.
      • Negishi K.
      • Negishi T.
      • Hare J.L.
      • Haluska B.A.
      • Plana J.C.
      • Marwick T.H.
      Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity.
      recently published a study looking for the optimal myocardial deformation index to predict CTRCD at 12 months in 81 women with breast cancer treated with trastuzumab, with or without anthracyclines. The strongest predictor of CTRCD was ΔGLS measured at the 6-month visit. An 11% reduction (95% confidence interval, 8.3%–14.6%) was the optimal cutoff, with sensitivity of 65% and specificity of 94%. Of note, ΔGLS was superior to changes in the count of abnormal segments, s′ and e′ velocities. They concluded that in patients with baseline strain measurements, the 95% confidence interval suggests that reductions of GLS of <8% compared with baseline appear not to be clinically meaningful, whereas those >15% are very likely to be of clinical significance (see Figures 9a and 9b for example of calculation). They confirmed the findings of Sawaya et al.,
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Tan T.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      this time using the conventional calculation of GLS averaging the 18 segments from the three apical views. They showed that in patients without baseline strain measurements, the proposed cutoff of −19% conforms to the confidence interval around −20.5% found in their study. Nevertheless the area under the curve for absolute strain value is less, making the change in strain the preferable approach.
      Figure thumbnail gr9
      Figure 9Bull’s-eye plot showing GLS of the patient shown in . (A) GLS and regional longitudinal strain at baseline. (B) GLS and regional longitudinal strain 3 months during trastuzumab-based therapy after anthracyclines. GLS has decreased from −20.6% to −14.4% (30% decrease). The decrease in GLS is therefore considered of clinical significance (>15% vs baseline).
      Finally, four studies evaluated the deformation parameters in long-term cancer survivors (range, 2–30 years after treatment).
      • Ho E.
      • Brown A.
      • Barrett P.
      • Morgan R.B.
      • King G.
      • Kennedy M.J.
      • et al.
      Subclinical anthracycline- and trastuzumab-induced cardiotoxicity in the long-term follow-up of asymptomatic breast cancer survivors: a speckle tracking echocardiographic study.
      • Ganame J.
      • Claus P.
      • Uyttebroeck A.
      • Renard M.
      • D’hooge J.
      • Bijnens B.
      • et al.
      Myocardial dysfunction late after low-dose anthracycline treatment in asymptomatic pediatric patients.
      • Cheung Y.F.
      • Hong W.J.
      • Chan G.C.
      • Wong S.J.
      • Ha S.Y.
      Left ventricular myocardial deformation and mechanical dyssynchrony in children with normal ventricular shortening fraction after anthracycline therapy.
      • Tsai H.R.
      • Gjesdal O.
      • Wethal T.
      • Haugaa K.H.
      • Fossa A.
      • Fossa S.D.
      • et al.
      Left ventricular function assessed by two-dimensional speckle tracking echocardiography in long-term survivors of Hodgkin’s lymphoma treated by mediastinal radiotherapy with or without anthracycline therapy.
      In two of the studies with longer follow-up and/or higher doses of anthracyclines, the LVEF (or fractional shortening) was slightly decreased.
      • Cheung Y.F.
      • Hong W.J.
      • Chan G.C.
      • Wong S.J.
      • Ha S.Y.
      Left ventricular myocardial deformation and mechanical dyssynchrony in children with normal ventricular shortening fraction after anthracycline therapy.
      • Tsai H.R.
      • Gjesdal O.
      • Wethal T.
      • Haugaa K.H.
      • Fossa A.
      • Fossa S.D.
      • et al.
      Left ventricular function assessed by two-dimensional speckle tracking echocardiography in long-term survivors of Hodgkin’s lymphoma treated by mediastinal radiotherapy with or without anthracycline therapy.
      In contrast, all four studies detected decreases in longitudinal and radial (and circumferential when studied) parameters compared with age-matched control patients, underlining the sensitivity of these parameters in the detection of subclinical LV dysfunction. STE appears therefore as the imaging technique of choice for detection of subclinical LV dysfunction. Normal values for GLS depend on the measurement position in the myocardium, the vendor, and the version of the analysis software, resulting in considerable heterogeneity in the published literature. Two recently published large studies evaluating the normal ranges of LV 2D strain have shown an effect of gender in LV myocardial deformation.
      • Kocabay G.
      • Muraru D.
      • Peluso D.
      • Cucchini U.
      • Mihaila S.
      • Padayattil-Jose S.
      • et al.
      Normal left 1 ventricular mechanics by two-dimensional speckle tracking echocardiography. Reference values in healthy adults.
      • Takigiku K.
      • Takeuchi M.
      • Izumi C.
      • Yuda S.
      • Sakata K.
      • Ohte N.
      • et al.
      Normal range of left ventricular 2-dimensional strain: Japanese Ultrasound Speckle Tracking of the Left Ventricle (JUSTICE) study.
      The study of Kocabay et al.
      • Kocabay G.
      • Muraru D.
      • Peluso D.
      • Cucchini U.
      • Mihaila S.
      • Padayattil-Jose S.
      • et al.
      Normal left 1 ventricular mechanics by two-dimensional speckle tracking echocardiography. Reference values in healthy adults.
      reported a mean normal GLS of −20.7 ± 2 for men and −22.1 ± 1.8 for women. These values are almost identical to the ones reported by the Japanese Ultrasound Speckle Tracking of the Left Ventricle (JUSTICE) study
      • Takigiku K.
      • Takeuchi M.
      • Izumi C.
      • Yuda S.
      • Sakata K.
      • Ohte N.
      • et al.
      Normal range of left ventricular 2-dimensional strain: Japanese Ultrasound Speckle Tracking of the Left Ventricle (JUSTICE) study.
      for the same vendor. There is also concern that strain values may decrease with age.
      • Takigiku K.
      • Takeuchi M.
      • Izumi C.
      • Yuda S.
      • Sakata K.
      • Ohte N.
      • et al.
      Normal range of left ventricular 2-dimensional strain: Japanese Ultrasound Speckle Tracking of the Left Ventricle (JUSTICE) study.
      • Kuznetsova T.
      • Herbots L.
      • Richart T.
      • D’hooge J.
      • Thijs L.
      • Fagard R.H.
      • et al.
      Left ventricular strain and strain rate in a general population.
      As a result, it is not possible to recommend universal normal values or lower limits of normal. We refer the reader to Table 5, which summarizes the findings of the Japanese Ultrasound Speckle Tracking of the Left Ventricle study, providing mean values for GLS according to vendor, gender, and age. Cheng et al.
      • Cheng S.
      • Larson M.G.
      • McCabe E.L.
      • Osypiuk E.
      • Lehman B.T.
      • Stanchev P.
      • et al.
      Reproducibility of Speckle-Tracking-Based Strain Measures of Left Ventricular Function in a Community-Based Study.
      recently evaluated the reproducibility of 2D STE in the Offspring Cohort of the Framingham Heart Study. The interobserver intraclass correlation coefficient was ≥0.84 for all global strain measurements, with an average coefficient of variation for GLS of ≤4%. The intraobserver intraclass correlation coefficient was ≥0.91 among time points spanning a total 8-month period, with an average of ≤6% for GLS. The authors concluded that 2D STE is reproducible when performed by trained operators. However, the technique has important limitations (Table 6). There are no data currently available as to the reproducibility of GLS at nonacademic centers or community hospitals. The presence of a learning curve for sonographers and interpreting physicians makes dedicated training and monitoring of quality (i.e., intra- and interobserver and test-retest variability) essential. When setting a strain program, it is recommended to initially designate one physician and, where available, one technician to perform, interpret, and compare studies over time. As experience is gained with the technique, the effort may be expanded to include other physicians, technicians, and trainees. Nevertheless, the most important limitation is intervendor variability.
      • Takigiku K.
      • Takeuchi M.
      • Izumi C.
      • Yuda S.
      • Sakata K.
      • Ohte N.
      • et al.
      Normal range of left ventricular 2-dimensional strain: Japanese Ultrasound Speckle Tracking of the Left Ventricle (JUSTICE) study.
      • Risum N.
      • Ali S.
      • Olsen N.T.
      • Jons C.
      • Khouri M.G.
      • Lauridsen T.K.
      • et al.
      Variability of global left ventricular deformation analysis using vendor dependent and independent two-dimensional speckle-tracking software in adults.
      Different echocardigoraphy machines or software packages can in fact produce different results, in particular for circumferential and radial strain, making problematic intraindividual comparisons over time. Recognizing the critical need for standardization in strain imaging, the EACVI and ASE invited technical representatives from all interested vendors to participate in a concerted effort to reduce intervendor variability in strain measurement.
      A Unique Collaboration to Advance Strain Imaging.
      Until that is achieved, it is recommended to use the same vendor’s machine and software version to compare individual patients with cancer when using 2D STE for the serial evaluation of systolic function.
      Table 5Effect of vendor age and gender on GLS
      VendorAge group (y)P
      0–1920–2930–3940–4950–59≥60
      V1
       Overall−22.1 ± 2.4−21.2 ± 1.9−21.1 ± 2.1−21.4 ± 2.0−21.0 ± 2.2−20.3 ± 1.9.0218
       Male−21.7 ± 3.1−20.9 ± 1.9−20.6 ± 1.9−20.9 ± 1.8−21.0 ± 1.9−19.7 ± 1.4.1982
       Female−22.4 ± 1.6−22.3 ± 1.6−22.8 ± 1.8−22.6 ± 2.1−23.3 ± 1.9−20.9 ± 2.1.0348
      P (male vs female).4292.0316<.0001.0178.0029.1381
      V2
       Overall−19.9 ± 2.5−19.0 ± 2.1−19.5 ± 2.2−18.2 ± 2.5−17.6 ± 2.5−16.7 ± 2.1<.0001
       Male−19.4 ± 2.7−18.8 ± 2.0−19.1 ± 2.3−17.9 ± 2.8−16.9 ± 2.3−15.8 ± 1.4.0019
       Female−20.5 ± 2.2−20.6 ± 2.3−20.2 ± 2.0−19.3 ± 0.9−20.4 ± 1.5−17.3 ± 2.3.0002
      P (male vs female).1349.0248.1083.4316.0294.0928
      V3
       Overall−21.4 ± 1.7−20.2 ± 2.1−20.4 ± 2.3−19.4 ± 2.2−18.5 ± 2.6−17.8 ± 2.8<.0001
       Male−21.6 ± 2.0−20.2 ± 2.0−20.4 ± 2.2−19.8 ± 2.3−18.7 ± 2.6−16.3 ± 3.1<.0001
       Female−21.2 ± 1.5−20.2 ± 2.4−20.4 ± 2.8−18.7 ± 1.8−18.3 ± 2.8−18.6 ± 2.3.0141
      P (male vs female).6076.9787.9201.1415.7374.0668
      V1, Vivid 7 or Vivid E9 (GE Healthcare); V2, iE33 (Philips Medical Systems); V3, Artida or Aplio (Toshiba Medical Systems).
      Reproduced with permisssion from Circulation Journal.
      • Takigiku K.
      • Takeuchi M.
      • Izumi C.
      • Yuda S.
      • Sakata K.
      • Ohte N.
      • et al.
      Normal range of left ventricular 2-dimensional strain: Japanese Ultrasound Speckle Tracking of the Left Ventricle (JUSTICE) study.
      Table 6Strengths and limitations of GLS
      GLS
      Strengths
      • Superiority in the prediction of all-cause mortality in the general population compared with LVEF
        • Stanton T.
        • Leano R.
        • Marwick T.H.
        Prediction of all-cause mortality from global longitudinal speckle strain: comparison with ejection fraction and wall motion scoring.
      • Improved risk stratification in patients with HF
        • Cho G.Y.
        • Marwick T.H.
        • Kim H.S.
        • Kim M.K.
        • Hong K.S.
        • Oh D.J.
        Global 2-dimensional strain as a new prognosticator in patients with heart failure.
      • Ability to recognize early LV dysfunction in patients undergoing cardiotoxic therapy and prognosticate subsequent CTRCD
        • Negishi K.
        • Negishi T.
        • Hare J.L.
        • Haluska B.A.
        • Plana J.C.
        • Marwick T.H.
        Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity.
        • Sawaya H.
        • Sebag I.A.
        • Plana J.C.
        • Januzzi J.L.
        • Ky B.
        • Tan T.C.
        • et al.
        Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      • Reproducible when performed by trained operators
      Limitations
      • Heavy dependence on the quality of the 2D echocardiographic images
      • Influenced by loading conditions
      • Lack of long-term randomized clinical trials evaluating the ability of GLS to predict persistent decreases in LVEF or symptomatic HF
      • Lack of data as to the reproducibility of GLS in nonacademic centers or community hospitals
      • Vendor and software specific
      Individual echocardiographic laboratories following patients with cancer should strive to incorporate strain assessment in their echocardiography laboratory protocols.

       Key Points

      • Myocardial deformation (strain) can be measured using DTI or 2D STE. The latter is favored because of a lack of angle dependency.
      • GLS is the optimal parameter of deformation for the early detection of subclinical LV dysfunction.
      • Ideally, the measurements during chemotherapy should be compared with the baseline value. In patients with available baseline strain measurements, a relative percentage reduction of GLS of <8% from baseline appears not to be meaningful, and those >15% from baseline are very likely to be abnormal.
      • When applying STE for the longitudinal follow-up of patients with cancer, the same vendor-specific ultrasound machine should be used.

      Detection of Subclinical LV Dysfunction Using Biomarkers

      Biomarkers have the potential to fulfill a critical unmet need as a robust diagnostic tool for the early identification, assessment, and monitoring of CTRCD. A biomarker approach is minimally invasive and can be readily repeated without significant risk. Despite intrinsic assay variability, standardized assays typically have acceptable coefficients of variation of <10%, potentially minimizing intra- and interobserver variability.
      • Cardinale D.
      • Sandri M.T.
      Role of biomarkers in chemotherapy-induced cardiotoxicity.

      Troponins

      Cardiac troponins are the gold-standard biomarkers for the diagnosis of myocardial injury.
      • Reichlin T.
      • Hochholzer W.
      • Bassetti S.
      • Steuer S.
      • Stelzig C.
      • Hartwiger S.
      • et al.
      Early diagnosis of myocardial infarction with sensitive cardiac troponin assays.
      • Wright R.S.
      • Anderson J.L.
      • Adams C.D.
      • Bridges C.R.
      • Casey Jr., D.E.
      • Ettinger S.M.
      • et al.
      2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American Academy of Family Physicians, Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons.
      Troponin I (TnI) is a sensitive and specific marker for myocardial injury in adults treated with anthracycline chemotherapy, and studies suggest that an elevation of troponin identifies patients at risk for the subsequent development of CTRCD.
      The largest of these studies was performed in 703 patients with cancer, in whom TnI was determined with each cycle of high-dose chemotherapy and 1 month after chemotherapy.
      • Cardinale D.
      • Sandri M.T.
      • Colombo A.
      • Colombo N.
      • Boeri M.
      • Lamantia G.
      • et al.
      Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy.
      Patients were classified into three subgroups on the basis of the combined presence of any detectable TnI either within 72 hours (early) or 1 month after the last administration of chemotherapy (late). In 495 patients, both early (within 72 hours) and late TnI values were <0.08 ng/mL; in 145, there was only an early increase; and in 63 patients, both values increased. These troponin release patterns identified patients at different levels of risk for CTRCD, with the majority of events occurring in TnI-positive patients. Furthermore, a persistent TnI increase was associated with an increase in the severity of CTRCD and a higher incidence or cardiac events compared with transient increases. The correlation between TnI positivity and LVEF maximal reduction ranged from 0.78 to 0.92, with positive and negative predictive values of 84% and 99%, respectively. The advantage of this high negative predictive value is the identification of patients at low risk for CTRCD. However, a persistent TnI increase was associated with an increased severity of CTRCD and a higher incidence of cardiac events compared with transient increases. Additional smaller studies have also demonstrated correlations between troponin elevations and subsequent LVEF decline.
      • Auner H.W.
      • Tinchon C.
      • Linkesch W.
      • Tiran A.
      • Quehenberger F.
      • Link H.
      • et al.
      Prolonged monitoring of troponin T for the detection of anthracycline cardiotoxicity in adults with hematological malignancies.
      • Specchia G.
      • Buquicchio C.
      • Pansini N.
      • Di Serio F.
      • Liso V.
      • Pastore D.
      • et al.
      Monitoring of cardiac function on the basis of serum troponin I levels in patients with acute leukemia treated with anthracyclines.
      • Kilickap S.
      • Barista I.
      • Akgul E.
      • Aytemir K.
      • Aksoyek S.
      • Aksoy S.
      • et al.
      cTnT can be a useful marker for early detection of anthracycline cardiotoxicity.
      Troponins may be also be used to identify early cardiac injury in patients undergoing treatment with newer targeted anticancer drugs. The largest of these studies, performed in 251 patients with breast cancer treated with trastuzumab, demonstrated that TnI positivity was associated with an increased incidence of cardiac events and lower likelihood of recovery.
      • Cardinale D.
      • Colombo A.
      • Torrisi R.
      • Sandri M.T.
      • Civelli M.
      • Salvatici M.
      • et al.
      Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation.
      Other investigators have also studied the changes in TnI in patients with breast cancer receiving doxorubicin followed by trastuzumab therapy.
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Tan T.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      In women who developed cardiotoxicity at the completion of anthracyclines, the mean ultrasensitive TnI concentration was 32 pg/mL (range, 10–56 pg/mL), compared with 17 pg/ml (range, 5–35 pg/ml) in women who did not. Furthermore, a value > 30 pg/mL was associated with specificity of 73% and negative predictive value of 77% for subsequent CTRCD. In contrast, Morris et al.
      • Morris P.G.
      • Chen C.
      • Steingart R.
      • Fleisher M.
      • Lin N.
      • Moy B.
      • et al.
      Troponin I and C-reactive protein are commonly detected in patients with breast cancer treated with dose-dense chemotherapy incorporating trastuzumab and lapatinib.
      demonstrated that TnI increases in patients receiving both trastuzumab and the tyrosine kinase inhibitor lapatinib were common, occurring in 67% of individuals; these elevations were not associated with subsequent CTRCD as detected by serial MUGA scans.
      Schmidinger et al.
      • Schmidinger M.
      • Zielinski C.C.
      • Vogl U.M.
      • Bojic A.
      • Bojic M.
      • Schukro C.
      • et al.
      Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma.
      also reported an increase in troponin T in 10% of patients with metastatic renal cancer treated with sunitinib or sorafenib. Here, troponin T was used as a surrogate marker for subclinical dysfunction. These data suggest that troponins may be a useful tool for assessing CTRCD in patients treated with both conventional and newer anticancer therapies.
      The role of TnI has been evaluated in patients with solid metastatic tumors treated with new anti-VEGF monoclonal inhibitors and tyrosine kinase inhibitors.
      • Ederhy S.
      • Massard C.
      • Dufaitre G.
      • Balheda R.
      • Meuleman C.
      • Rocca C.G.
      • et al.
      Frequency and management of troponin I elevation in patients treated with molecular targeted therapies in phase I trials.
      Eleven percent of patients showed increases in TnI during treatment. Normalization of TnI values was obtained with β-blockers and aspirin, allowing patients to be rechallenged with the study drug. No patient experienced any subsequent increase in TnI or cardiac events during the subsequent observation period (mean follow-up period, 3 months).
      Currently, there are a number of barriers to the widespread application of troponin as a clinical biomarker in CTRCD. First, the determination of the optimal timing of troponin assessment remains in question, as it is unclear if a single measurement with each cycle of chemotherapy has sufficient predictive value to be of utility or if multiple measurements are needed. Moreover, defining the cutoff point for positivity that maximizes the positive and negative predictive value, determining the optimal assay platform, and minimizing the coefficient of variation at the lower detection limit remain important goals.

      Other Biomarkers

      Natriuretic peptides, such as brain-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP), have also been measured in adults undergoing chemotherapy, with elevations typically reflective of abnormal filling pressures, but conclusions regarding their utility are conflicting and less consistent.
      In a study using point-of-care testing, serial assessment of natriuretic peptides in 109 patients undergoing anthracycline-based therapy showed that a BNP elevation of >200 pg/mL conferred a significantly increased risk for subsequent CTRCD, as observed in 11 patients.
      • Lenihan D.J.
      • Massey M.R.
      • Baysinger K.B.
      • Adorno C.L.
      • Warneke C.L.
      • Steinert D.
      • et al.
      Superior Detection of Cardiotoxicity during Chemotherapy Using Biomarkers.
      In smaller retrospective studies, patients with persistent BNP elevations 72 hours after high-dose chemotherapy had worsening of LV diastolic and systolic function indices from baseline to 12 months, with the mean LVEF decreasing from 62.8 ± 3.4% to 45.6 ± 11.5%.
      • Romano S.
      • Fratini S.
      • Ricevuto E.
      • Procaccini V.
      • Stifano G.
      • Mancini M.
      • et al.
      Serial measurements of NT-proBNP are predictive of not-high-dose anthracycline cardiotoxicity in breast cancer patients.
      In contrast, a study of 100 patients demonstrated transient increases in NT-proBNP in 13 patients treated with anthracycline chemotherapy but no association with LV systolic or diastolic function.
      • Dodos F.
      • Halbsguth T.
      • Erdmann E.
      • Hoppe U.C.
      Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline-induced cardiotoxicity in adults.
      Other small studies have also demonstrated a lack of association
      • Wann S.
      • Passen E.
      Echocardiography in pericardial disease.
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Tan T.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      • Knobloch K.
      • Tepe J.
      • Lichtinghagen R.
      • Luck H.J.
      • Vogt P.M.
      Monitoring of cardiotoxicity during immunotherapy with Herceptin using simultaneous continuous wave Doppler depending on N-terminal pro-brain natriuretic peptide.
      • Knobloch K.
      • Tepe J.
      • Rossner D.
      • Lichtinghagen R.
      • Luck H.J.
      • Busch K.H.
      • et al.
      Combined NT-pro-BNP and CW-Doppler ultrasound cardiac output monitoring (USCOM) in epirubicin and liposomal doxorubicin therapy.
      or only cross-sectional associations between BNP and LV diastolic function.
      • Nousiainen T.
      • Jantunen E.
      • Vanninen E.
      • Remes J.
      • Vuolteenaho O.
      • Hartikainen J.
      Natriuretic peptides as markers of cardiotoxicity during doxorubicin treatment for non-Hodgkin’s lymphoma.
      A larger scale study, the Effectiveness of Using Biomarkers to Detect and Identify Cardiotoxicity and Describe Treatment trial,

      Fish M, Lenihan DJ. Effectiveness of using biomarkers to detect and identify cardiotoxicity and describe treatment (PREDICT). 2013;(Accessed 2014 Mar 11) http://clinicaltrials.gov/ct2/show/NCT01311843.

      is currently under way, aiming to comprehensively determine the role of point-of-care biomarker testing in predicting cardiotoxicity in patients being treated with anthracyclines.

       Key Points

      • Elevated troponins in patients receiving cardiotoxic chemotherapy may be a sensitive measurement for the early detection of toxicity.
      • In contrast to troponins, serum concentrations of natriuretic peptides, although likely reflective of elevated filling pressures, may be less consistent in the early identification of CTRCD.

      An Integrated Approach of Imaging and Biomarkers

      An integrated approach combining echocardiographic data and biomarkers may be of utility and provide incremental value in predicting subsequent CTRCD. It may also provide a strategy for more aggressive surveillance if used in parallel or reduction in the frequency of imaging when used in series (i.e., alternating imaging with biomarkers). Sawaya et al.
      • Sawaya H.
      • Sebag I.A.
      • Plana J.C.
      • Januzzi J.L.
      • Ky B.
      • Tan T.C.
      • et al.
      Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab.
      published findings in the anthracycline and trastuzumab breast cancer population suggesting that the assessment of ultrasensitive troponin levels at the same time as STE-derived strain imaging obtained after anthracycline exposure has improved specificity of 93%, in comparison with either parameter alone (73%). An elevation in ultrasensitive TnI or a decrease in GLS of >−19% was associated with sensitivity of 87% compared with 48% or 74% for each parameter alone. Some centers use an integrated approach with the use of echocardiography at standardized, clinical preselected intervals (e.g., every 3 months during trastuzumab therapy) with biomarker assessment before each cycle of trastuzumab (e.g., every 3 weeks) in patients at high risk for CTRCD. However, there is a critical need for additional research to further strengthen the validity of this approach.

       Key Point

      • An integrated approach may provide incremental value in predicting subsequent CTRCD.

      Implications of Early Detection on Therapeutic Approaches

      Although combination regimens for HF therapy have been reported to be effective, HF due to CTRCD is often resistant to therapy if diagnosed late in its course. Therefore, efforts have been directed at HF prevention. The possible approaches to HF prevention are prophylaxis in all patients or early identification and treatment.
      Recognition of the availability of prophylaxis against subclinical LV dysfunction is an important step in developing a screening strategy; there would be no purpose in screening if there were no therapeutic implications. Pretreatment with a variety of agents (i.e., iron chelators, angiotensin-converting enzyme inhibitors, β-blockers, or statins) may be helpful in reducing the risk for cardiotoxicity.
      • Kalam K.
      • Marwick T.H.
      Role of cardioprotective therapy for prevention of cardiotoxicity with chemotherapy: A systematic review and meta-analysis.
      The most effective agents appear to be dexrazoxane
      • Lipshultz S.E.
      • Rifai N.
      • Dalton V.M.
      • Levy D.E.
      • Silverman L.B.
      • Lipsitz S.R.
      • et al.
      The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia.
      • van Dalen E.C.
      • Caron H.N.
      • Dickinson H.O.
      • Kremer L.C.
      Cardioprotective interventions for cancer patients receiving anthracyclines.
      and statin therapy.
      • Seicean S.
      • Seicean A.
      • Plana J.C.
      • Budd G.T.
      • Marwick T.H.
      Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study.
      • Acar Z.
      • Kale A.
      • Turgut M.
      • Demircan S.
      • Durna K.
      • Demir S.
      • et al.
      Efficiency of atorvastatin in the protection of anthracycline-induced cardiomyopathy.
      The use of vasoactive medications may be limited by the risk for side effects (especially dizziness and hypotension)
      • Silber J.H.
      • Cnaan A.
      • Clark B.J.
      • Paridon S.M.
      • Chin A.J.
      • Rychik J.
      • et al.
      Enalapril to prevent cardiac function decline in long-term survivors of pediatric cancer exposed to anthracyclines.
      and is supported by limited evidence for angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and β-blockers.
      • Blaes A.H.
      • Gaillard P.
      • Peterson B.A.
      • Yee D.
      • Virnig B.
      Angiotensin converting enzyme inhibitors may be protective against cardiac complications following anthracycline chemotherapy.
      • Seicean S.
      • Seicean A.
      • Alan N.
      • Plana J.C.
      • Budd G.T.
      • Marwick T.H.
      Cardioprotective Effect of Beta-Adrenoceptor Blockade in Breast Cancer Patients Undergoing Chemotherapy: A Follow-Up Study of Heart Failure.
      • Kalay N.
      • Basar E.
      • Ozdogru I.
      • Er O.
      • Cetinkaya Y.
      • Dogan A.
      • et al.
      Protective effects of carvedilol against anthracycline-induced cardiomyopathy.
      • Nakamae H.
      • Tsumura K.
      • Terada Y.
      • Nakane T.
      • Nakamae M.
      • Ohta K.
      • et al.
      Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone.
      • Cadeddu C.
      • Piras A.
      • Mantovani G.
      • Deidda M.
      • Dessi M.
      • Madeddu C.
      • et al.
      Protective effects of the angiotensin II receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress, and early ventricular impairment.
      Given the frequency of asymptomatic LV dysfunction and the potential side effects associated with the proposed regimens, early identification and treatment may be the optimal path.
      Treatment of subclinical LV dysfunction is based on a strategy of early detection of myocardial disease with either biomarkers or imaging. The attraction of this approach is that there is potential benefit for any patient, and those without dysfunction are not burdened by the treatment. The disadvantages are that screening has to be sufficiently accurate to identify as closely as possible all at-risk patients and that some patients may have progressed to sufficient damage that treatment may provide only a partial response.
      TnI release after high-dose chemotherapy in patients treated by anthracyclines was investigated by Cardinale and Sandri.
      • Cardinale D.
      • Sandri M.T.
      Role of biomarkers in chemotherapy-induced cardiotoxicity.
      This team demonstrated the usefulness of enalapril in this population,
      • Cardinale D.
      • Colombo A.
      • Torrisi R.
      • Sandri M.T.
      • Civelli M.
      • Salvatici M.
      • et al.
      Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation.