Arq Bras Cardiol abc Arquivos Brasileiros de Cardiologia Arq. Bras. Cardiol. 0066-782X 1678-4170 Sociedade Brasileira de Cardiologia - SBC 4PTpMqnfnMpvbhdwhNHtXkd S0066-782X2019000300309 10.5935/abc.20190022 Review Article Early Detection and Monitoring of Cancer Chemotherapy-Related Left Ventricular Dysfunction by Imaging Methods Ribeiro Mario Luiz Jorge Antonio José Lagoeiro Nacif Marcelo Souto Martins Wolney de Andrade Universidade Federal Fluminense Niterói RJ Brazil Universidade Federal Fluminense, Niterói, RJ - Brazil Mailing Address: Antonio José Lagoeiro Jorge, Avenida Marquês do Paraná, 303. Postal Code 24033-900, Centro, Niterói, RJ - Brazil. Email: lagoeiro@cardiol.br, lagoeiro@globo.com

Author contributions

Conception and design of the research: Ribeiro ML, Martins WA; acquisition of data and analysis and interpretation of the data: Ribeiro ML; writing of the manuscript and critical revision of the manuscript for intellectual content: Jorge AJL, Ribeiro ML, Nacif MS, Martins WA.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

 21 02 2019 3 2019 112 3 309 316 05 03 2018 21 11 2018 05 12 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Keywords: Neoplasms/mortality Antineoplastic Agents/adverse effects Ventricular Dysfunction, Left/diagnostic imaging Anthracyclines/adverse effects Trastuzumab/radiation effects Introduction

Cancer has been the second leading cause of death in Brazil since 2006, and it is predicted to surpass cardiovascular disease (CVD) as the leading cause of death between 2020 and 2025.1 Cancer and CVD have risk factors in common, such as obesity, sedentarism, arterial hypertension, tobacco use, diabetes mellitus, advanced age, and dietary pattern. The co-prevalence of cancer and CVD is therefore elevated. The diagnosis and prevention of both diseases may be carried out in an integrated manner.2 Oncological treatment with chemotherapy (CT) has led to an increase in survival, but it has also led to the risk of cardiotoxicity (CTX), the incidence of asymptomatic ventricular dysfunction or even cardiomyopathy.3 Early diagnosis of CTX is important, given that the sooner this myocardial event is diagnosed, the higher the chances of recovering systolic function.4

The objective of monitoring left ventricular (LV) function during cancer treatment is to detect cardiac dysfunction during the subclinical phase, rather than when a symptomatic patient already has reduced ejection fraction. The groups of chemotherapeutic medications that most frequently cause myocardial aggression are anthracyclines (ANT), widely used in the treatment of solid tumors and hematological malignancies, and monoclonal antibodies, the typical example of which is trastuzumab (TZU).5,6 The CTX of ANT was initially described as dose-cumulative, irreversible, and caused by mitochondrial injury. In contrast, TZU-related CTX, which is not dose dependent, is irreversible and does not cause mitochondrial injury. In both aggressions, however, the possibility of reverse remodeling and recovery of ventricular function has been reported. Case series of patients undergoing treatment with ANT reported an incidence of 15% to 17% of some degree of decrease in LV ejection fraction (LVEF), calculated by Simpson's method, and 2% to 3% of severe heart failure (HF).7 More recent case series, however, have related lower incidences.

There are different definitions used for the diagnosis of ventricular dysfunction related to cancer treatment, which are extrapolated from diverse clinical situations and which have little specific validation. Currently, one of the most used definitions is as a decrease in LVEF of more than 10% of the baseline value, to values below the cutoff of 53%, with or without symptoms, it being necessary to repeat the exam 2 or 3 weeks after the initial measurement.8 According to Zamorano et al.9 this lower limit for LVEF normality is 50%, also with a 10% reduction. Other definitions quantify a decrease in LVEF of more than 10% to LVEF below 55%, in asymptomatic patients, or a decrease of more than 5% to LVEF below 55% in symptomatic patients.10 Initially, endomyocardial biopsy was the gold standard used for cardiotoxicity, but its invasive character and risk of complications led to its progressive replacement by imaging methods. Various techniques have been proposed as tools for diagnosis and prognosis of CTX associated with CT, with emphasis on serum biomarkers, conventional echocardiography, two-dimensional strain echocardiography, radionuclide ventriculography (RNV), and cardiac magnetic resonance imaging (CMRI). The objective of this review is to present clinicians with the main advantages and disadvantages of different imaging methods for diagnosing and monitoring chemotherapy-related left ventricular dysfunction, regarding critical analysis, accuracy, limitations, and clinical perspectives.

 Methods

This review followed adaptations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology principles. The bibliographic search included the databases MEDLINE, SciELO, and LILACS. The descriptors used were cardiotoxicity; left ventricular dysfunction; antineoplastics; anthracyclines; diagnostic techniques and procedures; echocardiography; Doppler echocardiography; two-dimensional/three-dimensional/contrast echocardiography; scintigraphy; nuclear medicine; computed tomography; magnetic resonance. The reference lists of the articles found in the electronic search were also consulted and relevant articles were, thus, identified. The objective was to answer the question which is the most appropriate imaging method for the early detection of ventricular dysfunction in patients submitted to cancer CT within the context of clinical practice. Two independent researchers independently analyzed all abstracts. The review considered original articles with the following study designs: clinical trial, cohort, case-control, meta-analysis, and reviews that had expert consensus; considering articles published in the period between January 1998 and June 2017, whose full texts were available in English, Spanish, or Portuguese. The studies were selected in accordance with the following criteria: (a) the underlying disease was cancer, with a diagnosis confirmed by histopathology; (b) treatment included CT with ANT, TZU, or other known myocardial depressants; and (c) diagnostic methods such as echocardiography, computed tomography, nuclear medicine, or magnetic resonance imaging were used. The following were excluded: case reports, articles with other types of oncological therapy, and duplicate articles. Two hundred and twenty-one abstracts in the databases fulfilled the search criteria, and 162 articles were excluded.

Hereafter, we will critically analyze each of the methods, highlighting their advantages, disadvantages, and clinical applicability regarding the detection of CT-induced CTX. A summary of this analysis is given in Table 1.

Advantages, disadvantages, and applicability of imaging methods for detecting chemotherapy-related cardiotoxicity
Method Advantages Disadvantages Applicability
2D ECHO • Available• Allows for serial repetition• Evaluates anatomy and function • High variability• Late detection of alterations • Screening exam• Established diagnosis of disease
2D ECHO + Simpson + Contrast • Improves accuracy with respect to 2D ECHO • Higher cost• Longer exam time • Allows for accurate evaluation with simpler, more accessible technology
3D ECHO • Accuracy and reproducibility close to that of CMRI • Low availability • Accurate detection
2D STE • Detects subclinical dysfunction • Low availability• Depends on echocardiographic window • Initial screening of patients who will need monitoring
RNV • Excellent accuracy and reproducibility • Low availability• Does not evaluate other structures, such as valves, pericardium • In doubts regarding ECHO measurements of LVEF• Inadequate ECHO image quality
CMRI • Gold standard for evaluating volumes and LVEF• Allows for diagnosis of other etiologies of cardiomyopathy• Allows for tissue characterization • Low availability• Long exam time• Cost • In etiological doubts• In doubts regarding ECHO measurements of LVEF

2D ECHO: two-dimensional echocardiography; 3D ECHO: three-dimensional echocardiography; 2D STE: ecocardiograma bidimensional com strain; RNV: radionuclide ventriculography; CMRI: cardiac magnetic resonance imaging; LVEF: left ventricular ejection fraction

 Two-dimensional echocardiography

Two-dimensional echocardiography (2D ECHO) with Doppler is the method most frequently used before, during, and after CT, given that it is not invasive; it does not use ionizing radiation; it is highly available and cost-effective. It evaluates systolic and diastolic function, cardiac valves, and the pericardium, thus offering an analysis of diverse manifestations of CTX.11 The quantification of LVEF is the most accepted for measuring LV systolic function, and it is an important parameter in the algorithm for monitoring CT-induced CTX, capable of diagnosis and prognosis of clinical results, supporting the decision to continue or stop antineoplastic therapy.8 It is important that this measure be accurate, with minimal temporal variability. However, LVEF measured by 2D ECHO has an elevated temporal variability, approximately 10% [9,1%-11,8%], and in order to be able to detect a 10% alteration in LVEF safely, the measure should have a lower temporal variability. It is thus possible to affirm that LVEF measured by 2D ECHO is less reliable.12

Reduced LVEF following CT is considered a late finding that may indicate irreversible myocardial aggression and impede evolution with adequate therapy. Diastolic dysfunction may precede and predict late systolic dysfunction; however, no parameter of diastolic function has definitively shown to be predictive of CTX, and the studies are conflicting.13-17

The right ventricle (RV) is commonly affected by CT, in an early manner, with a higher number of affected segments than the LV, predominantly in the interventricular septum.18 Its routine evaluation should follow the recommendations set forth by Lang et al.19 In this manner, the quantification of RV systolic and diastolic function would be important for serial monitoring, but there is a significant technical difficulty which restricts its routine use in clinical practice.

In summary, a disadvantage of 2D ECHO is the elevated intra- and inter-examiner variability that compromises the method's reproducibility.

 Three-dimensional echocardiography

Unlike 2D ECHO, the evaluation of LVEF volumes by 3D ECHO is not based on geometrical suppositions; it is not affected by shortened views,20 and it is quantified by an automated edge-tracking algorithm.21 Studies with CMRI have shown that evaluations of LVEF and LV volumes by 3D ECHO have better accuracy and reproducibility,22,23 as well as lower temporal variability for serial monitoring of LVEF.12

The study by Walker et al.23 evaluated the accuracy of measuring LVEF with 2D ECHO, RNV, and 3D ECHO with relation to CMRI, in patients who used Doxorubicin (DOX) and TZU. The left ventricle final diastolic volume (LVFDV) showed a modest correlation between 2D ECHO and CMRI (r = 0.64 baseline, r = 0.69 at 12 months); the correlation of LVFDV between 3D ECHO and CMRI was shown to be stronger (r = 0.87 baseline; r = 0.95 at 12 months); LVEF measured by 2D ECHO had a weak correlation with CMRI (r = 0.31 baseline, r = 0.42 at 12 months). Both 3D ECHO and RNV showed a strong correlation when comapred with CMRI (r = 0.91 baseline, r = 0.90 at 12 months). When compared with RNV, the serial measurement of LVEF via 3D ECHO was shown to be more viable, accurate, and reproducible for serial LVEF monitoring in these patients.

Echocardiography is the method of choice for serial evaluation of patients undergoing CT, considering availability, cost, and risk. Accurate LVEF calculation should be carried out with the best available method in the echocardiography laboratory, ideally 3D ECHO. In the event that 2D ECHO is used, Simpson's is the preferred method.8 When utilizing 2D ECHO, contrast should be associated to improve the accuracy and reproducibility of the measurements of LVEF and volumes.24

Myocardial two-dimensional strain echocardiography

Two-dimensional speckle tracking echocardiography (2D STE) is an accurate technique, which is easy to perform and which has good reproducibility. It measures myocardial deformation through strain and strain rate in the three spatial planes, i.e. longitudinal, circumferential, and radial. Left ventricular systolic global longitudinal strain (LVGLS) has an intra- and inter-observer variability of 4.9% to 8.6%, which is lower than the that of the measurement of LVEF.25 Its prognostic value is incremental to LVEF for the prediction of all-cause mortality in the general population.26 Strain and strain rate are attributed to have the capacity to detect subclinical LV dysfunction and cardiac dysfunction related to CT, especially with the use of ANT and TZU.

In the study by Charbonnel et al.,27 LVGLS measured before treatment and after low doses (150 mg/m2) of ANT was shown to be a predictor of alterations in LVEF 12 months after the initial dose; CTX occurred in 6 of the 86 patients (7.0%). Pre-CT evaluation of LVGLS was observed to have a predictor value with an area under the ROC curve of 0.76, with a predictor threshold of (-)19.95% for LVGLS; in the evaluation with low doses, LVGLS provided incremental predictive information on CTX with an area under the ROC curve of 0.82, for a predictor threshold of (-)17.45% for LVGLS.

The study by Mousavi et al.28 demonstrated that LVGLS was a strong predictor of symptomatic HF in pre-CT evaluation of patients undergoing CT with ANT. Age and LVGLS were also predictors of all-cause mortality. LVGLS greater than (-)16% was associated with a 4.7-fold increase in the occurrence of symptomatic HF.

Our cardio-oncology research group studied pre-CT LVGLS as a predictor of LV dysfunction and found data (yet to be published) similar to those of the above-cited authors.27,28

In 52 patients with breast cancer undergoing CT with ANT, who were studied 1 week before CT and after the complete cycle, a significant decrease in LVGLS occurred, which was not accompanied by a decrease of more than 10% in LVEF, which suggests that LVGLS is more sensitive than LVEF in detecting alterations in systolic function.17

In patients with non-Hodgkin's lymphoma, followed for 6 months, there was a significant reduction in LVGLS and an increase in cardiac troponin T (cTnT); LVEF, however, remained within reference values. When alterations in LVGLS and cTnT were included in the multivariate analysis, only the decrease in LVGLS between the baseline and the third cycle of CT was an independent predictor of CTX; there was, however, no long-term follow-up to determine the clinical relevance of these findings in predicting late cardiac events.29

Sawaya et al.30 followed 43 patients with breast cancer treated with ANT and TZU, performing 2D STE and measuring biomarkers at baseline and at 3 and 6 months. High-sensitivity cardiac troponin I (hsTnI) and LVGLS were early markers of subsequent decreases in LVEF. Patients who presented neither a decrease of more than 10% in LVGLS nor an elevation in hsTnI during the third month had a 3% probability of a decreased LVEF in the sixth month. Patients who had a decrease of more than 10% in LVGLS and/or an elevation in hsTnI presented a risk of CTX during the sixth month 9 times greater than those without either of these alterations. The authors infer that the presence of these markers does not mandate the suspension of CT but rather alerts that there is a necessity for closer cardiac monitoring, earlier initiation of “cardioprotective” measures, or the use of alternative, less cardiotoxic therapies.30

Sawaya et al.31 followed 81 patients treated with ANT, taxanes, and TZU, 26 of which developed CTX, 5 with symptoms of HF. LVGLS and hsTnI were predictors of CTX, and LVGLS greater than (-)19% was present in all of those who developed symptoms of HF.

According to Negishi et al.32 a relative reduction in LVGLS of more than 11%, with respect to the pre-CT exam, is the best predictor of CTX. In the absence of a pre-CT exam, LVGLS greater than (-)20,5% would also be a predictor of CTX, albeit, with a lower area under the ROC curve (0.67); they thus suggest using relative reduction rather than absolute value.

Forty-two patients with ANT and TZU regimes were followed for 12 months, and 10 of them developed CTX. LVGLS, left ventricular systolic global radial strain (GRS), and S' detected a pre-clinical reduction in the third month, and all 10 who developed CTX had a reduction in LVEF at 6 months.33

Even though there is a consensus regarding the need for cardiac function monitoring via non-invasive imaging after exposure to CT, the method to be utilized and the monitoring time have yet to be defined. Evidence suggests that a reduction in LVGLS precedes a decrease in LVEF; however, long-term follow-up is necessary to determine the clinical relevance of these findings.

 Radionuclide ventriculography

RNV was the first scintigraphic method for serial evaluation of LVEF in patients undergoing CT.34,35 Its advantages include excellent accuracy, an estimated intra- and inter-variability of less than 5%, independence from LV geometry, and the possibility of being performed in patients with large body surfaces.36,37 Gated single-photon emission computed tomography (SPECT) has currently been used to measure LVEF; nevertheless, the American Society of Nuclear Cardiology recommends that serial monitoring be performed by RNV as a Class I indication, whereas the gated blood-pool SPECT technique is a Class IIb indication.36 Limitations to the routine use of nuclear imaging include patients with arrhythmias; incompleteness of information on the right ventricle, the atria, the valves, and the pericardium; repeated exposure to ionizing radiation; and higher costs compared to echocardiography. In 2016, the American Society of Clinical Oncology published guidelines on the prevention and monitoring of cardiac dysfunction in adult cancer patients, recommending the use of RNV or CMRI in cases where echocardiography is not available or technically feasible, for example, in cases with inadequate ultrasound windows.38 In addition to evaluating systolic function, RNV has demonstrated value in following diastolic function in patients exposed to cardiotoxic medications.

 Radionuclide ventriculography versus echocardiography

RNV was more sensitive than echocardiography in detecting early decreases in LVEF.39,40 However, in these small studies, there was a high incidence of CTX (over 48%) without long-term follow-up. This limitation did not allow for correlations to be drawn with HF incidence. In a study of breast cancer patients who received ANT and TZU, measurements of LVEF by 3D ECHO and RNV were comparable, with CMRI used as a reference.23 A document titled “American Society of Echocardiography Expert Consensus Statement for Multimodality Imaging Evaluation of Adult Patients During and After Cancer Therapy”8 recommends the use of 2D ECHO or 3D ECHO for evaluating LVEF before, during, and after CT. In the case of inadequate image quality, the use of CMRI is recommended; RNV is not mentioned as a routine method. The specific availability of each service certainly interferes with the choice of method. There are currently new scintigraphic methods with other markers of early myocardial injury,35 which are capable of subclinically detecting LV dysfunction and which could predict the development of subsequent LV dysfunction or HF, such as sympathetic neural imaging with the 123I-meta-iodobenzylguanidine (123I-mIBG) technique, imaging of cell death (111In-antimiosina), targeted therapy imaging (111In-TZU), and molecular metabolic imaging of PET. All of these techniques have yet to be clinically validated for use in this CTX situation.

Studies with the adrenergic marker of neuronal integrity 123I-mIBG carried out in patients using ANT demonstrated that scintigraphy with mIBG is capable of identifying patients with a higher risk of CTX with great accuracy.41

Cardiac magnetic resonance imaging Functional evaluation (cine MR and tagging/strain)

CMRI is the gold standard evaluation of LVEF volumes, using the technique of cine MR with quantification by Simpson's method. Its routine utilization is limited by availability and cost.42,43 In addition to accurately evaluating left and right ventricular function, CMRI can identify other probable causes associated with cardiomyopathy, such as myocardial invasion of the tumor, amyloidosis, sarcoidosis, myocarditis, and atherosclerotic coronary disease. CMRI should always be considered the first step before endomyocardial biopsy.8

Draft et al.44 detected subclinical abnormalities in geometry and ventricular function, such as a significant increase in final systolic volume, decreased LVEF and increased average circumferential strain in patients receiving low to moderate doses of anthracyclines. These markers are not usual criteria for CTX and the relation with prediction of future events is unknown. Armstrong et al.45 also detected subclinical cardiac dysfuntion using CMRI, analyzing LVEF and LV volume. No study of CMRI to date has demonstrated that alterations in myocardial function indexes after CT with ANT were predictors of subsequent CTX or HF. An ongoing observational study is assessing whether LV function measured by CMRI in patients using ANT, with or without TZU, will be able to predict a decrease in LVEF in 24 months.46

According to Plana et al.,8 CMRI should be used to confirm alterations in LVEF reported by other techniques or when there is a conflict between measurements from different techniques. This is only justified in the event that there is a plan to modify or interrupt CT. It is of little interest to use CMRI for diastolic function analysis due to the fact that its accuracy is similar to that of echocardiography.47,48

There are few studies on the evaluation of myocardial strain by CMRI for evaluating CT-related CTX. In the trial by Draft et al.,44 there was an early increase in midwall circumferential strain, after a month of therapy with ANT, associated with subclinical abnormality in ventricular function, demonstrated by a decrease in LVEF evaluated by CMRI. It is necessary to determine if these markers are associated with cardiovascular events in survivors of cancer.

 Tissue characterization (myocardial enhancement/T1 mapping/T2 mapping)

Myocardial tissue characterization of CTX dates back to the 1980s, when necropsy and biopsy studies revealed that myocardial inflammation and cardiomyocyte edema are early findings of CTX, which occur prior to reduced myocardial function, as opposed to myocardial fibrosis, which is a late finding.49,50 In addition to its functional evaluation, CMRI is capable of performing morphological and tissue evaluation in a qualitative (visual) and quantitative manner, as percentage of muscle affected.51 Myocardial interstitial injuries may or may not be reversible, depending on different factors which include the degree of interstitial fibrosis. In this manner, CMRI is able to establish the differential diagnosis between reactive, infiltrative, and scar fibrosis.52

It is possible to evaluate CTX on the tissue level with early and late enhancement techniques.52 The main disadvantage is that, in the large majority of subclinical disease cases, there is no visually detectable fibrosis to be quantified and this technique is negative.

T1 mapping has been validated for detection of interstitial fibrosis not detected by late enhancement techniques, and the results are informed through the quantification of myocardial relaxation time in milliseconds.53 During postcontrast, the lower the myocardial T1, the higher the degree of interstitial fibrosis. T1 mapping has shown to be an independent predictor of CTX in patients treated with ANT who were followed for a period of 3 years.54 Extracellular volume (ECV) fraction which indicates the expansion of interstitial space corrected by hematocrit was also a strong imaging biomarker.54

T2 mapping is responsible for the quantification of cardiomyocyte edema, and it assists in the characterization of acute, subacute, or chronic damage.55 The results of T2 mapping are also represented by time in milliseconds. A study with 9 patients who received ANT showed that average T2 values > 59 ms were associated with CTX.56

Myocardial tissue characterization by CMRI may detect early myocardial injury during CT and identify subclinical myocardial alterations in cancer survivors; however, prospective studies are needed to confirm this hypothesis. The cost-effectiveness of using CMRI in comparison with other sequential follow-up techniques for patients undergoing CT still needs to be quantified.

 Cardiac computed tomography (coronary angiotomography)

Coronary angiotomography is a method with growing clinical applicability that uses low doses of radiation (1-2 mSv) and iodinated contrast (50 mL).57 In addition to its classical indications, it is possible to quantify the volumes and ejection fractions of both ventricles.58 After the study by Nacif et al.,59 the use of angiotomography for the quantification of myocardial interstitial fibrosis via the quantification of VEC may be of great clinical utility. VEC values greater than 35% are associated with interstitial fibrosis.

 Rational approach strategy for early detection of CTX

In Figure 1, we propose a flowchart showing the rational approach for patients undergoing CT. This algorithm is based on a review of the literature and the authors' expertise. It thus lacks validation in randomized controlled clinical trials. This approach should be adapted to the reality of each service's supply and demand conditions.8 Faced with a cancer patient, the following steps are recommended: (a) integrated actions, shared by cardiologists and oncologists, within a multidisciplinary team; (b) clinical evaluation of estimated global cardiovascular risk, previous diseases, previous chemo- or radiotherapy and, when indicated, specific intervention prior to CT; (c) within the institution's limitations, consider two-dimensional echocardiography with measurements of strain. (d) In the event that baseline cardiac evaluation is not available for all patients, prioritize those with high risks of CTX, such as those with CVD or cardiovascular risk factors; LV systolic dysfunction; over 65 years of age; a regimen with doses of ANT (DOX) greater than 350 mg/m2; or combination CT (Figure 1).

Proposal for cardiovascular monitoring of patients undergoing chemotherapy based on information in the literature and authors' expertise. ECG: electrocardiogram; CT: chemotherapy; RT: radiation therapy; 2D-ECHO: two-dimensional echocardiography; RNV: radionuclide ventriculography; CMRI: cardiac magnetic resonance imaging; ECHO: echocardiography.

If one the following is detected in a patient being monitored: LVEF < 53%, LVGLS below the lower limit of normality, or elevated troponins, in the absence of symptoms, the cardiologist should be consulted and the risk-benefit ratio related of CT discussed with the oncologist. Whether to continue or not is, however, the oncologist's decision. The healthcare flowcharts depend on the cardiotoxic potential of the CT regimen. In accordance with documents by the American and European societies of echocardiography, patients with cumulative doses below 240 mg/m2 of DOX should repeat the cardiac evaluation at the conclusion of the CT regimen and 6 months later.8 In patients with doses above 240 mg/m2 there should be a new evaluation before each additional 50 mg/m2 cycle. In patients receiving TZU, there should, ideally, be an echocardiogram every 3 months.8 Owing to the unavailability of data, in patients undergoing therapy with vascular endothelial growth factor inhibitors, evaluation with echocardiography 1 month after the initial dose and, subsequently, every 3 months, is recommended.8

Subclinical detection of left ventricular dysfunction

To date, there is no evidence regarding the treatment of asymptomatic patients with preserved LVEF and alterations exclusively in strain. However, the rationale for measuring strain is based on the possibility of frequently monitoring patients at risk and, as soon as a decrease in LVEF is detected, initiating therapy and obtaining reverse remodeling.

For the purpose of detecting subclinical dysfunction, baseline LVGLS is the marker for comparison of post-CT measurements. A relative reduction of more than 15% can confirm the dysfunction. This altered value should be confirmed by a new exam 2 or 3 weeks later. Elevated TnI with or without alterations in LVGLS is also considered a marker of myocardial injury; there are, however, multiple causes of elevations in TnI, as well as doubts regarding its prognostic value for ventricular dysfunction. Whenever the need for suspending CT is considered in asymptomatic patients, it is necessary to measure LVEF using a more accurate method, such as RNV or CMRI.8

There are no studies with safe levels of evidence demonstrating the benefits of pharmacological “cardioprotective” treatment in patients undergoing CT. When considering the hypothesis of continuing CT notwithstanding alternations in LV function, echocardiographic re-evaluation is necessary before the new cycle, with the awareness that the risk of CTX will progressively increase.

Additional imaging exams are not necessary for patients who have concomitant risk factors, in the presence of normal GLS or troponins during CT and 6 months after the last CT with ANT. Following completion of the therapeutic regimen, there should be annual clinical cardiovascular examination and the use of cardiac imaging in accordance with the services available.8

Conclusions

Monitoring LVEF by 2D ECHO is the most executable strategy for detecting CT-related cardiovascular disease in large groups of patients; this method should, however, be considered in the context of its numerous limitations. 3D ECHO is the method of choice when considering accuracy together with availability, limitations regarding repetition, and ease of execution. When this is not available, the addition of contrast to 2D ECHO should be encouraged, seeing that this increases accuracy. LVGLS is the best parameter of myocardial deformation for subclinical detection of LV dysfunction; however, there is no solid evidence showing the benefits of initiating early “cardioprotective” therapy based on its results. RNV has a high diagnostic accuracy for ventricular dysfunction and may be an alternative in the event of doubts regarding echocardiography. CMRI assists in differential diagnoses with other causes of cardiomyopathies.

The decision to interrupt or continue a chemotherapeutic regimen is clinical, joint, and multidisciplinary, and it is based on the risk-benefit ratio for each patient.

Randomized controlled clinical trials with long-term follow-up are necessary to determine whether early detection of cardiac dysfunction is a predictor of LVEF reduction and, above all, HF and major cardiovascular events.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of Doctoral submitted by Mário Luiz Ribeiro, from Universidade Federal Fluminense.

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Douglas OS Garcia MJ Haines DE Lai WW Manning WJ Patel AR ACCF/ASE/AHA/ASNC/HFSA/HRS/SCAI/SCCM/ SCCT/SCMR 2011 Appropriate Use Criteria for Echocardiography J Am Soc Echocardiogr 2011 24 229 267 12 Thavendiranathan P, Grant AD, Negishi T, Plana JC, Popovic' ZB, Marwick TH. Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy. J Am Coll Cardiol. 2013;61:77-84. Thavendiranathan P Grant AD Negishi T Plana JC Popovic' ZB Marwick TH Reproducibility of echocardiographic techniques for sequential assessment of left ventricular ejection fraction and volumes: application to patients undergoing cancer chemotherapy J Am Coll Cardiol 2013 61 77 84 13 Paraskevaidis IA, Makavos G, Tsirigotis P, Psarogiannakopoulos P, Parissis J, Gkirkas K, et al. Deformation Analysis of Myocardial Layers Detects Early Cardiac Dysfunction after Chemotherapy in Bone Marrow Transplantation Patients: A Continuous and Additive Cardiotoxicity Process. J Am Soc Echocardiogr. 2017;30(11):1091-102. Paraskevaidis IA Makavos G Tsirigotis P Psarogiannakopoulos P Parissis J Gkirkas K Deformation Analysis of Myocardial Layers Detects Early Cardiac Dysfunction after Chemotherapy in Bone Marrow Transplantation Patients: A Continuous and Additive Cardiotoxicity Process J Am Soc Echocardiogr 2017 30 11 1091 1102 14 Dorup I, Levitt G, Sullivan I, Sorensen K. Prospective longitudinal assessment of late anthracycline cardiotoxicity after childhood cancer: the role of diastolic function.2004. Heart. 2004;90(10):1214-6. Dorup I Levitt G Sullivan I Sorensen K Prospective longitudinal assessment of late anthracycline cardiotoxicity after childhood cancer: the role of diastolic function 2004 Heart 2004 90 10 1214 1216 15 Pellicori P, Calicchia A, Lococo F, Cimino G, Torromeo C. Subclinical anthracycline cardiotoxicity in patients with acute promyelocytic leucemia in long-term remission after the AIDA protocol. Cong Heart Fail. 2012;18:217-21. Pellicori P Calicchia A Lococo F Cimino G Torromeo C Subclinical anthracycline cardiotoxicity in patients with acute promyelocytic leucemia in long-term remission after the AIDA protocol Cong Heart Fail 2012 18 217 221 16 Serrano JM, Gonzalez I, Del Castillo S, Muniz J, Morales LJ, Moreno F, et al. Diastolic Dysfunction Following Anthracycline-Based Chemotherapy in Breast Cancer Patients: Incidence and Predictors. The Oncologist. 2015;20:864-72. Serrano JM Gonzalez I Del Castillo S Muniz J Morales LJ Moreno F Diastolic Dysfunction Following Anthracycline-Based Chemotherapy in Breast Cancer Patients: Incidence and Predictors The Oncologist 2015 20 864 872 17 Stoodley PW, Richards DAB, Hui R, Boyd A, Harnett PR, Meikle SR, et al. Two-dimensional myocardial strain imaging detects changes in left ventricular systolic function immediately after anthracycline chemotherapy. Euro J Echocardiogr. 2011;12:945-52. Stoodley PW Richards DAB Hui R Boyd A Harnett PR Meikle SR Two-dimensional myocardial strain imaging detects changes in left ventricular systolic function immediately after anthracycline chemotherapy Euro J Echocardiogr 2011 12 945 952 18 Barendswaard EC, Prpi H, Van der Wall EE, Camps JA, Keizer HJ, Pauwels EK. Right ventricule wall motion abnormalities in patients treated with chemotherapy. Clin Nucl Med.1991;16(7):513-6. Barendswaard EC Prpi H Van der Wall EE Camps JA Keizer HJ Pauwels EK Right ventricule wall motion abnormalities in patients treated with chemotherapy Clin Nucl Med 1991 16 7 513 516 19 Lang RM, Badano LP, MD, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28:1-39. Lang RM Badano LP Mor-Avi V Afilalo J Armstrong A Ernande L Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging J Am Soc Echocardiogr 2015 28 1 39 20 Jenkins C, Moir S, Chan J, Rakhit D, Haluska B, and Marwick TH. Left ventricular volume measurement with echocardiography: a comparison of left ventricular opacification, three-dimensional echocardiography, or both with magnetic resonance imaging. Eur Heart J. 2009;30(1):98-106. Jenkins C Moir S Chan J Rakhit D Haluska B Marwick TH Left ventricular volume measurement with echocardiography: a comparison of left ventricular opacification, three-dimensional echocardiography, or both with magnetic resonance imaging Eur Heart J 2009 30 1 98 106 21 Muraru D, Badano LP, 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. Eur J Echocardiogr. 2010;11(4):359-68. Muraru D Badano LP Piccoli G Gianfagna P Del Mestre L Ermacora D Validation of a novel automated border-detection algorithm for rapid and accurate quantitation of left ventricular volumes based on three-dimensional echocardiography Eur J Echocardiogr 2010 11 4 359 368 22 Dorosz JL, Lezotte DC, Weitzenkamp DA, Allen LA, Salcedo EE. Performance of 3-dimensional echocardiography in measuring left ventricular volumes and ejection fraction: a systematic review and meta-analysis. J Am Coll Cardiol. 2012;59(20):1799-808. Dorosz JL Lezotte DC Weitzenkamp DA Allen LA Salcedo EE Performance of 3-dimensional echocardiography in measuring left ventricular volumes and ejection fraction: a systematic review and meta-analysis J Am Coll Cardiol 2012 59 20 1799 1808 23 Walker J, Bhullar N, Fallah-Rad N, Lytwyn M, Golian M, Fang T, et al. Role of three-dimensional echocardiography in breast cancer: comparison with two-dimensional echocardiography, multiple-gated acquisition scans, and cardiac magnetic resonance imaging. J Clin Oncol. 2010;28(21):3429-36. Walker J Bhullar N Fallah-Rad N Lytwyn M Golian M Fang T Role of three-dimensional echocardiography in breast cancer: comparison with two-dimensional echocardiography, multiple-gated acquisition scans, and cardiac magnetic resonance imaging J Clin Oncol 2010 28 21 3429 3436 24 Hoffmann R, Bardeleben S, Cate F, Borges AC, Kasprzak J, Firschke C, et al. Assessment of systolic left ventricular function: a multi-centre comparison of cineventriculography, cardiac magnetic resonance imaging, unenhanced and contrast-enhanced echocardiography. Eur Heart J. 2005;26:607-16. Hoffmann R Bardeleben S Cate F Borges AC Kasprzak J Firschke C Assessment of systolic left ventricular function: a multi-centre comparison of cineventriculography, cardiac magnetic resonance imaging, unenhanced and contrast-enhanced echocardiography Eur Heart J 2005 26 607 616 25 Farsalinos KE, Daraban AM, Unlu S, Thomas JD, Badano LP, Voigt JU. Head-to-Head Comparison of Global Longitudinal Strain Measurements among Nine Different Vendors The EACVI/ASE Inter-Vendor Comparison Study. J Am Soc Echocardiogr. 2015;28:1171-81. Farsalinos KE Daraban AM Unlu S Thomas JD Badano LP Voigt JU Head-to-Head Comparison of Global Longitudinal Strain Measurements among Nine Different Vendors The EACVI/ASE Inter-Vendor Comparison Study J Am Soc Echocardiogr 2015 28 1171 1181 26 Stanton T, Leano R, Marwick TH. Prediction of All-Cause Mortality From Global Longitudinal Speckle Strain Comparison With Ejection Fraction and Wall Motion Scoring. Circ Cardiovasc Imaging.2009;2:356-364. Stanton T Leano R Marwick TH Prediction of All-Cause Mortality From Global Longitudinal Speckle Strain Comparison With Ejection Fraction and Wall Motion Scoring Circ Cardiovasc Imaging 2009 2 356 364 27 Charbonnel C, Convers-Domart R, Rigaudeau S, Taksin AL, Baron N, Lambert J, et al. Assessment of global longitudinal strain at low-dose anthracycline-based chemotherapy, for the prediction of subsequent cardiotoxicity. Eur Heart J Cardiovasc Imaging 2017;18:392-401. Charbonnel C Convers-Domart R Rigaudeau S Taksin AL Baron N Lambert J Assessment of global longitudinal strain at low-dose anthracycline-based chemotherapy, for the prediction of subsequent cardiotoxicity Eur Heart J Cardiovasc Imaging 2017 18 392 401 28 Mousavi N, Tan TC, Ali M, Halpern EF, Wang L, Scherrer-Crosbie M. Echocardiographic parameters of left ventricular size and function as predictors of symptomatic heart failure in patients with a left ventricular ejection fraction of 50-59% treated with anthracyclines. Eur Heart J Cardiovasc Imaging. 2015;16:977-84. Mousavi N Tan TC Ali M Halpern EF Wang L Scherrer-Crosbie M Echocardiographic parameters of left ventricular size and function as predictors of symptomatic heart failure in patients with a left ventricular ejection fraction of 50-59% treated with anthracyclines Eur Heart J Cardiovasc Imaging 2015 16 977 984 29 Kang Y, Xu X, Cheng L, Li L, Sun M, Chen H, et al. Two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T in early detection and prediction of cardiotoxicity during epirubicine-based chemotherapy. Eur J Heart Fail. 2014;16:300-8. Kang Y Xu X Cheng L Li L Sun M Chen H Two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T in early detection and prediction of cardiotoxicity during epirubicine-based chemotherapy Eur J Heart Fail 2014 16 300 308 30 Sawaia H, Sebag IA, Plana JC, Januzzi JL, Ky B, Cohen V, et al. Early detection and prediction of cardiotoxicity in chemotherapy-treated patients. Am J Cardiol. 2011;107(9):1375-80. Sawaia H Sebag IA Plana JC Januzzi JL Ky B Cohen V Early detection and prediction of cardiotoxicity in chemotherapy-treated patients Am J Cardiol 2011 107 9 1375 1380 31 Sawaia H, Sebag IA, Plana JC, Januzzi JL, Ky B, Tan TC, et al. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes and traztuzumab. Circ Cardiovasc Imaging. 2012;5(5):596-603. Sawaia H Sebag IA Plana JC Januzzi JL Ky B Tan TC Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes and traztuzumab Circ Cardiovasc Imaging 2012 5 5 596 603 32 Negishi K, Negishi T, Hare JL, Haluska BA, Plana JC, Marwick TH. Independent and Incremental Value of Deformation Indices for Prediction of Trastuzumab-Induced Cardiotoxicity. J Am Soc Echocardiogr. 2013;26:493-8. Negishi K Negishi T Hare JL Haluska BA Plana JC Marwick TH Independent and Incremental Value of Deformation Indices for Prediction of Trastuzumab-Induced Cardiotoxicity J Am Soc Echocardiogr 2013 26 493 498 33 Fallah-Rad N, Walker JR, 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. J Am Coll Cardiol. 2011;57:2263-70. Fallah-Rad N Walker JR Wassef A Lytwyn M Bohonis S Fang T 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 J Am Coll Cardiol 2011 57 2263 2270 34 Aiken MJ, Suhag V, Garcia CA, Acio E, Moreau S, Priebat DA, et al. Doxorubicin-induced cardiac toxicity and cardiac rest gated blood poll imaging. Clin Nucl Med. 2009;34(11):762-7. Aiken MJ Suhag V Garcia CA Acio E Moreau S Priebat DA Doxorubicin-induced cardiac toxicity and cardiac rest gated blood poll imaging Clin Nucl Med 2009 34 11 762 767 35 Schwartz RG, Jain D, Storozynsky E. Traditional and novel methods to assess and prevent chemotherapy-related cardiac dysfunction noninvasively. J Nucl Cardiol. 2013;20(3):443-64. Schwartz RG Jain D Storozynsky E Traditional and novel methods to assess and prevent chemotherapy-related cardiac dysfunction noninvasively J Nucl Cardiol 2013 20 3 443 464 36 Corbett JR, Akinboboye OO, Bacharach SL, Borer JS, Botvinick EH, DePuey EG, et al. Equilibrium radionuclide angiocardiography. J Nucl Cardiol.2006;13(6):e56-e79. Corbett JR Akinboboye OO Bacharach SL Borer JS Botvinick EH DePuey EG Equilibrium radionuclide angiocardiography J Nucl Cardiol 2006 13 6 e56 e79 37 Strashun AM, Goldsmith SJ, Horowitz SF. Gated blood pool scintigraphic monitoring of doxorubicin cardiomyopathy: comparison of camera and computerized probe results in 101 patients. J Am Coll Cardiol.1986;8(5):1082-7. Strashun AM Goldsmith SJ Horowitz SF Gated blood pool scintigraphic monitoring of doxorubicin cardiomyopathy: comparison of camera and computerized probe results in 101 patients J Am Coll Cardiol 1986 8 5 1082 1087 38 Armenian SH, Lacchetti C, Barac A, Carver J, Constine LS, Denduluri N, et al. Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;35:893-911. Armenian SH Lacchetti C Barac A Carver J Constine LS Denduluri N Prevention and Monitoring of Cardiac Dysfunction in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline J Clin Oncol 2016 35 893 911 39 Fatima N, Zaman UM, Hashmi A, Kamal S, Hameed A. Assessing adriamycin-induced early cardiotoxicity by estimating left ventricular ejection fraction using technetium-99m multiple-gated acquisition scan and echocardiography. Nucl Med Commum.2011;32(5):381-5. Fatima N Zaman UM Hashmi A Kamal S Hameed A Assessing adriamycin-induced early cardiotoxicity by estimating left ventricular ejection fraction using technetium-99m multiple-gated acquisition scan and echocardiography Nucl Med Commum 2011 32 5 381 385 40 Tantawy AA, Elmasry AO, Shaaban M, Toaima DN, Shahat AM. Radionuclide ventriculography detects early anthracycline cardiotoxity in children with Hodgkin Lymphoma. J Pediatr Hematol Oncol.2011;33:e132-e137. Tantawy AA Elmasry AO Shaaban M Toaima DN Shahat AM Radionuclide ventriculography detects early anthracycline cardiotoxity in children with Hodgkin Lymphoma J Pediatr Hematol Oncol 2011 33 e132 e137 41 Pepe A, Pizzino F, Gargiulo P, Perrone-Filardi P, Cadeddu C, Mele D, et al. Cardiovascular imaging in the diagnosis and monitoring of cardiotoxicity: cardiovascular magnetic resonance and nuclear cardiology J Cardiovasc Med 2016, 17 (suppl 1):e45-e54 Pepe A Pizzino F Gargiulo P Perrone-Filardi P Cadeddu C Mele D Cardiovascular imaging in the diagnosis and monitoring of cardiotoxicity: cardiovascular magnetic resonance and nuclear cardiology J Cardiovasc Med 2016 17 suppl 1 e45 e54 42 Debatin JF, Nadel SN, Paolini JF, Sostman HD, Coleman RE, Evans AJ, et al. Cardiac ejection fraction: phantom study comparing cine MR imaging, radionuclide blood pool imaging, and ventriculography. J Magn Reson Imaging.1992;2(2):135-42. Debatin JF Nadel SN Paolini JF Sostman HD Coleman RE Evans AJ Cardiac ejection fraction: phantom study comparing cine MR imaging, radionuclide blood pool imaging, and ventriculography J Magn Reson Imaging 1992 2 2 135 142 43 Moon JC, Lorenz CH, Francis JMm, Smith JC, Pennell DJ. Breath-hold FLASH and FISP cardiovascular MR imaging: left ventricular volume differences and reproducibility. Radiology.2002;223(3):789-97. Moon JC Lorenz CH Francis JMm Smith JC Pennell DJ Breath-hold FLASH and FISP cardiovascular MR imaging: left ventricular volume differences and reproducibility Radiology 2002 223 3 789 797 44 Drafts BC, Twomley KM, D'Agostino R Jr, Lawrence J, Avis N, Ellis LR, et al. Low to moderate dose anthracycline-based chemoterapy is associated with early noinvasive imaging evidence of subclinical cardiovascular disease. JACC Cardiovasc Imag. 2013;6(8):877-85. Drafts BC Twomley KM D'Agostino R Jr Lawrence J Avis N Ellis LR Low to moderate dose anthracycline-based chemoterapy is associated with early noinvasive imaging evidence of subclinical cardiovascular disease JACC Cardiovasc Imag 2013 6 8 877 885 45 Armstrong GT, Plana JC, Zhang N, Srivastava D, Green DM, Ness KK, et al. Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic ressonance imaging. J Clin Oncol. 2012;30:2876-84. Armstrong GT Plana JC Zhang N Srivastava D Green DM Ness KK Screening adult survivors of childhood cancer for cardiomyopathy: comparison of echocardiography and cardiac magnetic ressonance imaging J Clin Oncol 2012 30 2876 2884 46 Hundley WG. MRI in detecting heart damage in patients with cancer receiving chemotherapy. http://clinicaltrials.gov/show/NCT01719562. Accessed june 27, 2017. Hundley WG MRI in detecting heart damage in patients with cancer receiving chemotherapy http://clinicaltrials.gov/show/NCT01719562 june 27, 2017 47 Bollache E, Redheuil A, Clément-Guinaudeau S, Defrance C, Perdrix L, Ladouceur M et al. Automated left ventricular diastolic function evaluation from phase-contrast cardiovascular magnetic resonance and comparison with Doppler echocardiography. J Cardiovasc Magn Reson. 2010;12(1):63. Bollache E Redheuil A Clément-Guinaudeau S Defrance C Perdrix L Ladouceur M Automated left ventricular diastolic function evaluation from phase-contrast cardiovascular magnetic resonance and comparison with Doppler echocardiography J Cardiovasc Magn Reson 2010 12 1 63 63 48 Paelinck BP, de Roos A, Bax JJ, Bosmans JM, van Der Geest RJ, Dhondt D, et al. Feasibility of tissue magnetic resonance imaging a pilot study in comparison with tissue Doppler imaging and invasive measurement. J Am Coll Cardiol.2005;45(7);1109-16. Paelinck BP de Roos A Bax JJ Bosmans JM van Der Geest RJ Dhondt D Feasibility of tissue magnetic resonance imaging a pilot study in comparison with tissue Doppler imaging and invasive measurement J Am Coll Cardiol 2005 45 7 1109 1116 49 Friedman MA, Bozdech MJ, Billingham ME, Rider AK. Doxorubicin cardiotoxicity: Serial endomyocardilal biopsies and systolic time intervals. J Am Med Assoc. 1978;240(15):1603-6. Friedman MA Bozdech MJ Billingham ME Rider AK Doxorubicin cardiotoxicity: Serial endomyocardilal biopsies and systolic time intervals J Am Med Assoc 1978 240 15 1603 1606 50 Unverferth DV, Fetters JK, Unverferth BJ, Leier CV, Magorien RD, Arn Ar, et al. Human myocardial histologic characteristics in congestive heart failure. Circulation.1983;68(6):1194-200. Unverferth DV Fetters JK Unverferth BJ Leier CV Magorien RD Arn Ar Human myocardial histologic characteristics in congestive heart failure Circulation 1983 68 6 1194 1200 51 Souto ALM, Souto RM, Teixeira ICR, Nacif MS. Myocardial viability on cardiac magnetic ressonance. Arq Bras Cardiol.2017;108(5):458-69. Souto ALM Souto RM Teixeira ICR Nacif MS Myocardial viability on cardiac magnetic ressonance Arq Bras Cardiol 2017 108 5 458 469 52 Nathan M, Liu CY, Pierre C, David B, Lima JAC. Assessment of myocardial fibrosis with cardiac magnetic resonance. J Am Coll Cardiol.2011;57(8):891-903. Nathan M Liu CY Pierre C David B Lima JAC Assessment of myocardial fibrosis with cardiac magnetic resonance J Am Coll Cardiol 2011 57 8 891 903 53 Sibley CT, Noureldin RA, Gai N, Nacif MS, Liu S, Turkbey EB, et al. T1 Mapping in cardiomyopathy at cardiac MR: comparison with endomyocardial biopsy. Radiology.2012;265(3):724-32. Sibley CT Noureldin RA Gai N Nacif MS Liu S Turkbey EB T1 Mapping in cardiomyopathy at cardiac MR: comparison with endomyocardial biopsy Radiology 2012 265 3 724 732 54 Jordan JH, Vasu S, Morgan TM, D'Agostino Jr RB, Meléndez GC, Hamilton CA, et al. Anthracycline-Associated T1 mapping characteristics are elevated independent of the presence of cardiovascular comorbidities in cancer survivors. Circ Cardiovasc Imaging.2016;9:e004325. Jordan JH Vasu S Morgan TM D'Agostino RB Jr Meléndez GC Hamilton CA Anthracycline-Associated T1 mapping characteristics are elevated independent of the presence of cardiovascular comorbidities in cancer survivors Circ Cardiovasc Imaging 2016 9 e004325 55 Lota AS, Gatehouse PD, Mohiaddin RH. T2 mapping and T2* imaging in heart failure. Heart Fail Rev.2017;22:431-40. Lota AS Gatehouse PD Mohiaddin RH T2 mapping and T2* imaging in heart failure Heart Fail Rev 2017 22 431 440 56 Thavendiranathan P, Amir E, Bedard P, Crean A, Paul N, Nguyen ET, et al. Regional myocardial edema detected by T2 mapping is a feature of cardiotoxicity in breast cancer patients receiving sequential therapy with anthracyclines and trastuzumab. J Cardiovasc Magnet Res.2014;16(Suppl 1):P273. Thavendiranathan P Amir E Bedard P Crean A Paul N Nguyen ET Regional myocardial edema detected by T2 mapping is a feature of cardiotoxicity in breast cancer patients receiving sequential therapy with anthracyclines and trastuzumab J Cardiovasc Magnet Res 2014 16 Suppl 1 P273 P273 57 Halliburton SS, Abbara S, Chen MY, Gentry R, Mahesh M. SCCT guidelines on radiation dose and dose-optimization strategies in cardiovascular CT. J Cardiovasc Comput Tomogr.2011;5:198-224. Halliburton SS Abbara S Chen MY Gentry R Mahesh M SCCT guidelines on radiation dose and dose-optimization strategies in cardiovascular CT J Cardiovasc Comput Tomogr 2011 5 198 224 58 Man SR, Man SB, Lal MJ. Role of cardiac CTA in estimating left ventricular volumes and ejection fraction. World J Radiol.2014;6(9):669-76. Man SR Man SB Lal MJ Role of cardiac CTA in estimating left ventricular volumes and ejection fraction World J Radiol 2014 6 9 669 676 59 Nacif MS, Kawel N, Lee JJ, Chen X, Yao J, Zavodni A, et al. Interstitial myocardial fibrosis assessed as extracellular volume fraction with low-radiation-dose cardiac CT. Radiology.2012;264(3):876-83. Nacif MS Kawel N Lee JJ Chen X Yao J Zavodni A Interstitial myocardial fibrosis assessed as extracellular volume fraction with low-radiation-dose cardiac CT Radiology 2012 264 3 876 883 Artigo de Revisão Detecção Precoce e Monitoramento da Disfunção Ventricular Esquerda Secundária à Quimioterapia do Câncer pelos Métodos de Imagem Ribeiro Mario Luiz Jorge Antonio José Lagoeiro Nacif Marcelo Souto Martins Wolney de Andrade Universidade Federal Fluminense, Niterói, RJ - Brasil Correspondência: Antonio José Lagoeiro Jorge, Avenida Marquês do Paraná, 303. CEP 24033-900, Centro, Niterói, RJ - Brasil. Email: lagoeiro@cardiol.br, lagoeiro@globo.com

Contribuição dos autores

Concepção e desenho da pesquisa: Ribeiro ML, Martins WA; obtenção de dados e análise e interpretação dos dados: Ribeiro ML; redação do manuscrito e revisão crítica do manuscrito quanto ao conteúdo intelectual importante: Jorge AJL, Ribeiro ML, Nacif MS, Martins WA.

Potencial conflito de interesses

Declaro não haver conflito de interesses pertinentes.

 Palavras-chave: Neoplasias/mortalidade Antineoplásicos/efeitos adversos Disfunção Ventricular Esquerda/diagnóstico por imagem Cardiotoxicidade Antraciclinas/efeitos adversos Trastuzumab/efeitos da radiação Introdução

O câncer (CA) tornou-se a segunda causa de mortalidade no Brasil a partir de 2006 e há previsão de que ultrapasse as doenças cardiovasculares (DCV), atualmente consideradas a causa principal, entre 2020 e 2025.1 As DCV e o CA partilham fatores de risco em comum tais como a obesidade, o sedentarismo, a hipertensão arterial, o tabagismo, o diabetes mellitus, a faixa etária elevada e o padrão alimentar. Portanto, a coprevalência de CA e DCV é elevada. O diagnóstico e a prevenção de ambas as doenças devem ser realizados de forma integrada.2 O tratamento oncológico com a quimioterapia (QT) combinada trouxe aumento da sobrevida, porém também levou ao risco de cardiotoxicidade (CTX); à incidência de disfunção ventricular assintomática; ou até mesmo de miocardiopatia.3 O diagnóstico precoce da CTX é importante, posto que quanto mais precoce for o diagnóstico do acometimento miocárdico, maior é a chance de recuperação da função sistólica.4

A monitorização da função ventricular esquerda (VE) durante o tratamento do CA objetiva detectar a disfunção cardíaca em uma fase subclínica, e não quando já houver fração de ejeção reduzida em paciente sintomático. Os grupos de quimioterápicos que mais frequentemente causam agressão ao miocárdio são as antraciclinas (ANT), largamente usadas no tratamento dos tumores sólidos e doenças malignas hematológicas, e os anticorpos monoclonais, cujo exemplo típico é o trastuzumabe (TZU).5,6 A CTX das ANT foi inicialmente descrita como dose-cumulativa, irreversível e por lesão mitocondrial. Em contraste àquela relacionada ao TZU que não é dose-dependente, é reversível e não causa lesão mitocondrial, entretanto em ambas as agressões relatou-se a possibilidade do remodelamento reverso e da recuperação da função ventricular. Séries de casos de pacientes sob uso de ANT referiram incidência entre 15% e 17% de algum grau de redução da fração de ejeção do VE (FEVE) pelo método de Simpson e 2% a 3% de insuficiência cardíaca (IC) grave,7 entretanto séries mais recentes relatam incidência menor.

Há diferentes definições arbitradas para o diagnóstico de disfunção ventricular relacionada à terapêutica do CA, extrapoladas de situações clínicas diversas e com escassa validação específica. Atualmente, uma das mais usadas é a redução da FEVE em valores superiores a 10% do valor basal para valores abaixo do corte de 53%, com ou sem sintomas, repetindo-se o exame duas a três semanas após a aferição inicial.8 Para Zamorano et al.9 este limite inferior de normalidade da FEVE é de 50%, também com uma redução de 10%. Outras definições quantificam em queda da FEVE maior que 10% para FEVE abaixo de 55%, em pacientes assintomáticos, ou queda maior que 5% para FEVE menor que 55% em sintomáticos.10 Inicialmente, a biópsia endomiocárdica foi utilizada como padrão-ouro de cardiotoxicidade, mas seu caráter invasivo e o risco de complicações fizeram com que fosse progressivamente substituída pelos métodos de imagem. Várias técnicas foram propostas como ferramentas para o diagnóstico e o prognóstico da CTX associada à QT, com destaque para os biomarcadores séricos, o ecocardiograma convencional, o strain bidimensional, a ventriculografia radionuclídica (VRN) e a ressonância magnética cardíaca (RMC). O objetivo da presente revisão é trazer ao clínico as principais vantagens e desvantagens dos diversos métodos de imagem, com respeito à análise crítica, acurácia, limitações e perspectivas clínicas, no diagnóstico e monitoramento da disfunção ventricular esquerda por quimioterápicos.

 Métodos

Esta revisão seguiu adaptações dos princípios da metodologia Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A pesquisa de artigos incluiu as bases de dados MEDLINE, ScIELO e LILACS. Os descritores utilizados foram “Cardiotoxicidade”; “Disfunção Ventricular Esquerda”; “Antineoplásicos”; “Antraciclinas”; “Técnicas e Procedimentos Diagnósticos”; “Ecocardiografia”; “Ecocardiografia Doppler”; “Ecocardiografia Bidimensional/Tridimensional/de contraste”; “Cintilografia”; “Medicina nuclear”; “Tomografia computadorizada”; “Ressonância magnética”. Também foram consultadas as listas de referências dos artigos encontrados na busca eletrônica e, assim, foram identificados artigos relevantes. Objetivou-se responder qual é o método de imagem mais apropriado para a detecção precoce de disfunção ventricular em pacientes submetidos à QT do CA dentro do contexto da prática clínica. Todos os resumos foram analisados de forma independente por dois pesquisadores. Foram considerados nesta revisão os artigos originais do tipo ensaio clínico, coorte, caso-controle, meta-análises e artigos de revisão que dispusessem consenso de especialistas, publicados no período de janeiro de 1998 até junho de 2017, com textos disponíveis na íntegra, em inglês, espanhol ou português. Os estudos foram selecionados conforme os seguintes critérios: (a) a doença de base fosse CA com diagnóstico comprovado por histopatologia; (b) o tratamento incluísse QT com ANT, TZU ou outros sabidamente depressores do miocárdio; e (c) os métodos de diagnóstico como ecocardiografia, tomografia computadorizada, medicina nuclear ou ressonância magnética tivessem sido utilizados. Foram excluídos relatos de caso, artigos com outros tipos de terapia oncológica e os artigos que apresentaram duplicidade entre as bases. Duzentos e vinte e um resumos preencheram os critérios de pesquisa nas bases de dados. Foram excluídos 162 artigos.

Doravante faremos a análise crítica de cada um dos métodos, ressaltando-se suas vantagens, desvantagens e aplicabilidade clínica no tocante a detecção de CTX causada pela QT. Um resumo desta análise encontra-se na tabela 1.

Vantagens, desvantagens e aplicabilidade dos métodos de imagem na detecção de cardiotoxicidade por quimioterápicos
Método Vantagens Desvantagens Aplicabilidade
2D-ECO • Disponível• Permite repetições seriadas• Avalia anatomia e função • Elevada variabilidade• Detecta alterações tardias • Exame de triagem• Diagnóstico de doença estabelicida
2D-ECO + Simpson + Contraste • Melhora a acurácia em relação ao 2D-ECO • Eleva o custo• Maior tempo de exame • Permite avaliação acurada com tecnologia mais simples e acessível
3D-ECO • Acurácia e reprodutibilidade próximas à RMC • Baixa disponibilidade • Detecção acurada
2D-STE • Detecta disfunção subclínica • Baixa disponibilidade• Depende de janela ecocardiográfica• Variabilidade entre valores de referência • Triagem inicial dos pacientes que necessitarão de acompanhamento
VRN • Excelente acurácia e reprodutibilidade • Baixa disponibilidade• Não avalia outras estruturas como válvulas, pericárdio • Dúvidas da aferição da FEVE ao ECO• Imagens inadequadas ao ECO
RMC • Padrão-ouro para avalição de volumes e da FEVE• Permite diagnóstico de outras etiologias de miocardiopatias• Permite caracterização tecidual • Baixa disponibilidade• Tempo prolongado de exame• Custo • Nas dúvidas etiológicas• Dúvidas na aferição da FEVE ao ECO

2D ECO: ecocardiograma bidimensional; 3D ECO: ecocardiograma tridimensional; 2D STE: ecocardiograma bidimensional com strain; VRN: ventriculografia com radionuclídeos; RMC: ressonância magnética cardíaca; FEVE: fração de ejeção do ventrículo esquerdo.

 Ecocardiografia bidimensional

A ecocardiografia bidimensional (2D ECO) com Doppler é o método mais frequentemente utilizado no acompanhamento pré-, per- e pós-QT por não ser invasivo, não utilizar radiação ionizante, ter alta disponibilidade e custo-efetividade. Avalia as funções sistólica e diastólica, as valvas cardíacas e o pericárdio, oferecendo desta forma análise das diversas manifestações de CTX.11 A quantificação da FEVE é a mais aceita para a aferição da função sistólica do VE e é um importante parâmetro no algoritmo de monitorização de CTX induzida pela QT, capaz de diagnóstico e prognóstico de resultados clínicos, sustentando decisões de seguir ou parar com a terapêutica antineoplásica.8 É importante que esta medida seja acurada com mínima variabilidade temporal. No entanto, a FEVE pelo 2D ECO tem uma elevada variabilidade temporal, em torno de 10% [9,1% - 11,8%] e para que se possa detectar com segurança uma alteração na FEVE de 10%, esta medida deveria ter uma variabilidade temporal menor. Desta forma é possível afirmar que a FEVE medida pelo 2D ECO é menos confiável.12

A redução da FEVE após QT é considerada um achado tardio que pode indicar uma agressão miocárdica irreversível e impedir mudança da evolução com a terapia adequada. A disfunção diastólica poderia preceder e predizer uma disfunção sistólica tardia, entretanto nenhum parâmetro da função diastólica mostrou definitivamente ser preditivo de CTX e os estudos são conflitantes.13-17

O ventrículo direito (VD) é comumente acometido pela QT, de modo precoce, com maior número de segmentos acometidos do que o VE e com a predominância do septo interventricular.18 Sua rotina de avaliação deve seguir as recomendações de Lang et al.19 Deste modo, a quantificação da função sistólica e diastólica do VD seria importante para a monitorização seriada, porém há significativa dificuldade técnica que restringe seu uso rotineiro na prática clínica.

Em suma, pesa sobre o 2D ECO a elevada variabilidade intra- e inter-examinador que comprometem a reprodutibilidade do método.

 Ecocardiograma tridimensional

A avaliação dos volumes e da FEVE pelo 3D ECO não se baseia em suposições geométricas; não é afetada por exibições encurtadas20 e é quantificada por um algoritmo automatizado de rastreamento de borda,21 diferente do 2D ECO. Estudos com RMC mostraram que a avaliação da FEVE e dos volumes do VE através do 3D ECO tem melhor acurácia e reprodutibilidade22,23 e menor variabilidade temporal para a monitorização seriada da FEVE.12

No estudo de Walker et al.23 avaliou-se a acurácia da medida da FEVE através do 2D ECO, VRN e 3D ECO em relação à RMC, de pacientes que usaram doxorrubicina (DOXO) e TZU. O volume diastólico final do ventrículo esquerdo (VDFVE) demonstrou modesta correlação entre 2D ECO e a RMC (r = 0,64 basal, r = 0,69 aos 12 meses); a correlação do VDFVE entre 3D ECO e RMC demonstrou ser mais forte (r = 0,87 basal; r = 0,95 aos 12 meses); a FEVE pelo 2D ECO apresentou uma fraca correlação com a RMC (r = 0,31 basal, r= 0,42 aos 12 meses). Ambos 3D ECO e VRN mostraram uma forte correlação quando comparados com a RMC (r = 0,91 basal, r = 0,90 aos 12 meses). Quando comparado com a VRN, a medida seriada da FEVE através da 3D ECO mostrou ser viável, precisa e reprodutível para o monitoramento seriado da FEVE nesses pacientes.

A ecocardiografia é o método de escolha para a avaliação seriada de pacientes submetidos à QT ao se ponderar disponibilidade, custo e risco. O cálculo preciso da FEVE deve ser realizado com o melhor método disponível no laboratório de ecocardiografia, idealmente pelo 3D ECO. Caso se utilize o 2D ECO, a técnica de Simpson é a de eleição.8 Ao se utilizar o 2D ECO, dever-se-ia associar o contraste, com melhora da acurácia e reprodutibilidade das medidas dos volumes e na FEVE.24

<italic>Strain</italic> miocárdico bidimensional

O ecocardiograma bidimensional com Speckle tracking (2D STE) é uma técnica acurada, de fácil realização e boa reprodutibilidade. Mede a deformação miocárdica através do strain e do strain rate nos três planos espaciais: longitudinal, circunferencial e radial. O strain sistólico global longitudinal do VE (GLS VE) tem uma variabilidade intra e interobservadora de 4,9% a 8,6%, portanto menor do que na medida da FEVE.25 Tem um valor prognóstico incremental à FEVE para a predição de todas as causas de mortalidade na população geral.26 Ao strain e strain rate são imputadas a capacidade de detecção da disfunção subclínica do VE e a predição da disfunção cardíaca relacionada à QT, especialmente com o uso das ANT e do TZU.

No estudo de Charbonnel et al.27 o GLS VE aferido precocemente antes do tratamento e após doses baixas de ANT - 150 mg/m2 - demonstrou ser preditor de alteração na FEVE doze meses após a dose inicial. A CTX ocorreu em seis de 86 pacientes (7,0%). Observou-se um valor preditor do GLS VE na avaliação pré-QT, com uma área sob a curva ROC de 0,76 e um limiar preditor do GLS VE de (-) 19,95%; na avaliação com doses baixas, o GLS VE mostrou uma informação preditiva incremental de CTX, com uma área sob a curva ROC de 0,82, para um limiar preditor do GLS VE de (-)17,45%.

O estudo de Mousavi et al.28 demonstrou que o GLS VE foi um forte preditor de IC sintomática, na avaliação pré-QT, de pacientes submetidos a QT com ANT. A idade e o GLS VE também foram preditores de todas as causas de mortalidade. Um GLS VE maior que (-)16% esteve associado a um aumento de 4,7 vezes na ocorrência de IC sintomática.

Nosso grupo de pesquisa em cardio-oncologia estudou o GLS VE pré-QT como preditor de disfunção VE e encontrou dados, ainda não publicados, semelhantes aos dos autores supracitados.27,28

Em 52 pacientes com CA de mama submetidos à QT com ANT, estudados uma semana antes da QT e após o ciclo completo, ocorreu queda significativa do GLS VE não acompanhada por queda da FEVE maior que 10%, o que sugere ser o GLS VE mais sensível do que a FEVE em detectar alteração da função sistólica.17

Em pacientes com linfoma não-Hodgkin, seguidos por seis meses, ocorreu uma redução significativa no GLS VE e aumento da troponina T cardíaca (cTnT), porém a FEVE se manteve dentro dos valores de referência. Quando alterações no GLS VE e da cTnT foram incluídas na análise multivariada, somente a diminuição no GLS VE entre o basal e o terceiro ciclo de QT foi preditor independente de CTX, porém não houve acompanhamento em longo prazo para determinar a relevância clínica destes achados em predizer eventos cardíacos tardios.29

Sawaya et al.30 acompanharam 43 pacientes com CA de mama tratados com ANT e TZU, realizando 2D STE e medida de biomarcadores, no basal e a 3 e 6 meses. A troponina de alta sensibilidade (hsTnI) e o GLS VE foram marcadores precoces de subsequente queda da FEVE. Aqueles que não apresentaram uma queda maior que 10% do GLS VE ou elevação da hsTnI no terceiro mês tiveram 3% de probabilidade de queda da FEVE no sexto mês. Aqueles com uma queda do GLS VE acima de 10% e/ou elevação da hsTnI apresentaram risco de CTX no sexto mês nove vezes maior do que aqueles sem uma destas alterações. Os autores inferem que a presença destes marcadores não autoriza a suspender a QT, mas sim alerta para a necessidade de monitorização cardíaca mais frequente, ou início precoce de medidas “cardioprotetoras”, ou uso de terapias alternativas menos cardiotóxicas.30

Sawaya et al.31 acompanharam 81 pacientes tratados com ANT, taxanos e TZU, dos quais 26 desenvolveram CTX, cinco com sintomas de IC. O GLS VE e a hsTnI foram preditores de CTX e um GLS VE maior que (-)19% esteve presente em todos que desenvolveram sintomas de IC.

Para Negishi et al.32 uma redução relativa maior que 11% do GLS VE, em relação ao exame pré-QT, seria o melhor preditor de CTX. Na ausência do exame pré-QT um GLS VE maior que (-)20,5% também seria um preditor de CTX, porém com uma área sob a curva ROC menor (0,67); deste modo, ele sugere que se use a redução relativa e não o valor absoluto.

Quarenta e dois pacientes em regime de ANT e TZU foram seguidos por 12 meses e 10 deles desenvolveram CTX. O GLS VE, o strain sistólico global radial (GRS) do VE e o S' detectaram uma redução pré-clínica no terceiro mês, com uma redução da FEVE no sexto mês em todos que desenvolveram CTX.33

Embora exista consenso para a necessidade de monitorização da função cardíaca por imagem não invasiva após a exposição à QT, o método utilizado e o tempo de vigilância não estão definidos. As evidências sugerem que a diminuição do GLS VE precede a queda da FEVE, entretanto faz-se necessário o acompanhamento em longo prazo para determinar a relevância clínica destes achados.

 Ventriculografia radionuclídica

A VRN foi o primeiro método cintilográfico de avaliação seriada da FEVE em paciente sob QT.34,35 Ela tem como vantagens a excelente acurácia, a variabilidade inter e intraobservadora estimada em menos que 5%, a independência da geometria do VE, e o fato de ser exequível em pacientes de grande superfície corporal.36,37 Atualmente, o gated single-photon emission computed tomography (SPECT) tem sido utilizado para medir a FEVE; contudo, a American Society of Nuclear Cardiology recomenda que a monitorização seriada seja realizada por VRN como indicação classe I, enquanto que a técnica do gated blood-pool SPECT é indicação IIb.36 As limitações para o uso rotineiro da imagem nuclear incluem os pacientes com arritmias; a incompletude de informações sobre o ventrículo direito, os átrios, as valvas, e o pericárdio; a repetida exposição à radiação ionizante; e um custo mais elevado que a ecocardiografia. A American Society of Clinical Oncology publicou uma diretriz em 2016 sobre a prevenção e a monitorização da disfunção cardíaca em pacientes adultos com CA e recomendou a utilização da VRN ou da RMC quando o ecocardiograma não estiver disponível ou não for tecnicamente exequível, como em casos de janela ultrassonográfica inadequada.38 Além da avaliação da função sistólica, a VRN tem demonstrado o valor do acompanhamento da função diastólica em pacientes expostos a fármacos cardiotóxicos.

 Ventriculografia radionuclídica versus ecocardiografia

A VRN foi mais sensível do que a ecocardiografia em detectar diminuição precoce da FEVE,39,40 porém nestes pequenos estudos houve alta incidência de CTX (maior que 48%) sem seguimento em longo prazo. Tal limitação não permitiu traçar correlação com incidência de IC. Em um estudo de pacientes com CA de mama que receberam ANT e TZU a medida da FEVE por 3D ECO foi comparável à VRN, usando a RMC como referência.23 No documento intitulado "American Society of Echocardiography Expert Consensus Statement for Multimodality Imaging Evaluation of Adult Patients During and After Cancer Therapy"8 preconizam a utilização do 2D ECO ou 3D ECO para avaliação da FEVE antes, durante e após a QT. Em caso de imagem inadequada, recomenda-se a utilização da RMC, não tendo sido mencionada a VRN como método de rotina. Seguramente as disponibilidades específicas de cada serviço interferem na eleição do método. Há atualmente novos métodos cintilográficos com outros marcadores de injúria miocárdica precoce,35 capazes de detecção subclínica da disfunção VE, que poderiam predizer o desenvolvimento de subsequente disfunção VE ou IC, como a imagem neuronal simpática pela técnica do 123Metaiodobenzilguanidina (123I-mIBG), imagem de morte celular (111In antimiosina), imagem de terapêutica alvo (111In TZU), e imagem metabólica molecular do PET. Todas essas técnicas continuam ainda sem validação para uso clínico nesta situação da CTX.

Estudos com o marcador de integridade neuronal adrenérgico 123I-mIBG conduzidos em pacientes em uso de ANT demonstraram que a cintilografia com mIBG é capaz de identificar com grande acurácia os pacientes em maior risco de CTX.41

Ressonância magnética cardíaca Avaliação funcional (cine RM e <italic>tagging/strain</italic>)

A RMC é o padrão-ouro na avaliação dos volumes e da FEVE pela técnica de cine RM com a quantificação pelo método de Simpson. Sua utilização de rotina está limitada pela disponibilidade e custo.42,43 Além de avaliar com precisão a função ventricular esquerda e direita, a RMC pode identificar outras prováveis causas associadas de miocardiopatia tais como a invasão miocárdica do tumor, a amiloidose, a sarcoidose, a miocardite e a doença coronariana aterosclerótica. A RMC deve sempre ser considerada o primeiro degrau antes da biópsia endomiocárdica.8

Draft et al. 44 detectaram anormalidades subclínicas da geometria e função ventricular, como aumento significativo do volume sistólico final, redução da FEVE e aumento do strain circunferencial médio em pacientes submetidos à dose baixa ou intermediária de antracíclicos. Estes marcadores não são critérios usuais de CTX e se desconhece a relação com predição de eventos futuros. Armstrong et al.45 também detectaram disfunção cardíaca subclínica através da RMC, analisando FEVE e volume do VE. Até o momento nenhum estudo de RMC demonstrou que alteração nos índices de função miocárdica após QT com ANT fosse preditora de subsequente CTX ou IC. Um estudo observacional em andamento avalia se medidas da função do VE pela RMC, em pacientes em uso de ANT com ou sem TZU, será capaz de predizer a queda da FEVE em 24 meses.46

Para Plana et al.8 a RMC deve ser usada na confirmação de alteração na FEVE relatada por outra técnica, ou quando há conflito entre medidas de técnicas diferentes. Isto só se justificaria se houvesse um plano para modificar ou interromper a QT. O uso da RMC para análise da função diastólica é de pouco interesse devido a sua acurácia ser semelhante à de ecocardiografia.47,48

Há poucos trabalhos na avaliação do strain miocárdico pela RMC na avaliação da CTX por QT. No ensaio de Draft et al.44 houve aumento no strain circunferencial da parede média precocemente, com um mês de terapia por ANT, associado a anormalidade subclínica da função ventricular, como demonstrado por uma queda da FEVE avaliada pela RMC. Faz-se necessário determinar se estes marcadores estão associados com eventos cardiovasculares nos sobreviventes de CA.

 Caracterização tecidual (realce miocárdico/mapa T1/mapa T2)

A caracterização tecidual miocárdica da CTX remonta à década de 1980, quando os estudos de necropsia e biópsia já revelavam que a inflamação miocárdica e o edema do cardiomiócito são achados precoces de CTX, e que ocorreriam anteriormente à redução da função miocárdica, em oposição à fibrose miocárdica cujo achado é tardio.49,50 A RMC, além da avaliação funcional, é capaz de realizar a avaliação morfológica e tecidual de forma qualitativa (visual) e quantitativa em percentual do músculo acometido.51 A lesão intersticial miocárdica pode ser reversível ou não, dependendo de diversos fatores, incluindo o grau de fibrose intersticial. Desta forma, a RMC consegue estabelecer o diagnóstico diferencial entre a fibrose reacional, infiltrativa e a cicatricial.52

É possível avaliar a CTX em nível tecidual com as técnicas de realce precoce e tardio.52 O grande problema é que, na grande maioria dos casos de doença subclínica, não existe fibrose visualmente detectável para ser quantificada e esta técnica é negativa.

O mapa T1 foi validado para detecção de fibrose intersticial não detectada pelas técnicas do realce tardio e os resultados são informados mediante a quantificação do tempo de relaxamento miocárdico em milissegundos.53 No pós-contraste, quanto mais baixo o T1 do miocárdio, maior o grau de fibrose intersticial. Já no pré-contraste, quanto maior o T1 do miocárdio, maior o grau de fibrose intersticial. O mapa T1 se mostrou um preditor independente de CTX em pacientes que realizaram tratamento com ANT e foram acompanhados por um período de três anos.54 A fração do volume extracelular que demarca a expansão do espaço intersticial corrigido pelo hematócrito também foi um forte biomarcardor pela imagem.54

O mapa T2 fica responsável pela quantificação do edema do cardiomiócito e auxilia na caracterização de um dano agudo, subagudo ou crônico.55 Os resultados do mapa T2 também são representados pelo tempo em milissegundos. Estudo com nove pacientes que receberam ANT mostrou que valores médios de T2 > 59 ms foram associados à CTX.56

A caracterização do tecido miocárdico pela RMC pode detectar injúria miocárdica precoce durante a QT e identificar alterações miocárdicas subclínicas nos sobreviventes de CA, porém estudos prospectivos são necessários para a confirmação desta hipótese. A relação de custo-efetividade em usar RMC frente a outras técnicas de acompanhamento sequencial de pacientes sob QT ainda necessita ser quantificada.

 A tomografia computadorizada cardíaca (angio-TC de coronárias)

A angio-TC de coronárias é um método de aplicabilidade clínica crescente que utiliza baixas doses de radiação (1-2 mSv) e de contraste iodado (50 mL).57 Além de suas indicações clássicas, é possível a quantificação dos volumes e da fração de ejeção dos ventrículos.58 Após o estudo de Nacif et al.,59 o uso da angio-TC para a quantificação de fibrose intersticial miocárdica pela técnica de quantificação do VEC pode ser de grande utilidade clínica. Valores do VEC maiores do que 35% estão associados com fibrose intersticial.

 Estratégia de abordagem racional para a detecção precoce da cardiotoxicidade

Na Figura 1, propomos um fluxograma de abordagem racional aos pacientes submetidos à QT. Tal algoritmo é baseado na revisão da literatura e expertise dos autores. Carece, portanto, de validação em ensaios clínicos randomizados e controlados. A abordagem deve ser adaptada à realidade das condições de oferta e demanda de cada serviço.8 Frente a um paciente com CA sugere-se adotar os seguintes passos: (a) Ações integradas, partilhadas por cardiologistas e oncologistas, dentro de equipe multidisciplinar; (b) Avaliação clínica com estimativa do risco cardiovascular global, doenças prévias, tratamento quimio- ou radioterápicos prévios e intervenção específica quando indicada previamente à QT; (c) Dentro das limitações institucionais, considerar o ecocardiograma bidimensional com medida do strain; (d) Caso não seja exequível uma avaliação cardíaca basal em todos, priorizar aqueles com alto risco para CTX, tais como aqueles com doença prévia ou fatores de risco cardiovascular; disfunção sistólica do VE; idade maior que 65 anos; programação de altas doses de ANT (DOXO), maior que 350 mg/m2; ou combinação de QT (figura 1).

Proposta de acompanhamento cardiovascular aos pacientes submetidos à quimioterapia baseada em informações da literatura e experiência dos autores. ECG: eletrocardiograma; QT: quimioterapia; RT: radioterapia; 2D ECO: ecocardiograma bidimensional; VRN: ventriculografia com radionuclídeos; RMC: ressonância magnética cardíaca; ECO: ecocardiografia.

Nos pacientes sob acompanhamento, quando detectado uma FEVE < 53%, GLS VE abaixo do limite inferior da normalidade, e/ou troponinas elevadas, na ausência de sintomas, o cardiologista deve ser consultado, discutindo com o oncologista a relação risco-benéfico da QT, entretanto sua continuação ou não é uma decisão do oncologista. Os fluxogramas de atendimento dependem do potencial cardiotóxico do esquema quimioterápico. Segundo documento das sociedades norte-americana e europeia de ecocardiografia, pacientes com doses cumulativas menores que 240 mg/m2 de DOXO deveriam repetir a avaliação cardíaca após o término do esquema terapêutico e seis meses depois.8 Os pacientes com doses maiores que 240 mg/m2 deveriam passar por nova avaliação antes de cada ciclo adicional de 50 mg/m2. Os pacientes sob uso de TZU, idealmente, deveriam ter um ecocardiograma a cada três meses.8 Por indisponibilidade de dados, em pacientes com terapia por inibidores do fator de crescimento do endotélio vascular, sugere-se uma avaliação ecocardiográfica um mês depois da dose inicial e depois a cada três meses.8

Detecção subclínica da disfunção ventricular esquerda

Até o presente momento, não há evidências para o tratamento de pacientes assintomáticos com FEVE preservada e alteração exclusiva no strain. No entanto, o racional de se aferir o strain se fundamenta na possibilidade de monitorar amiúde os pacientes sob risco e, tão logo detectada a queda da FEVE, iniciar-se a terapêutica e obter-se o remodelamento reverso.

Para fins de detecção de disfunção subclínica, o GLS VE basal é o marcador para comparação com as medidas após QT. Uma redução relativa maior que 15% pode confirmar a disfunção. Este valor alterado deveria ser confirmado em um novo exame em duas a três semanas. A elevação da TnI com ou sem alteração do GLS VE também é considerada um marcador de lesão miocárdica, porém há múltiplas causas de elevação da TnI, assim como dúvidas quanto ao seu valor prognóstico de disfunção ventricular. Sempre que se cogite a necessidade de suspensão da QT em assintomáticos, faz-se necessário a medida da FEVE por outro método mais acurado como a VRN ou a RMC.8

Não há estudos com nível de evidência segura demonstrando o benefício do tratamento farmacológico “cardioprotetor” nos pacientes sob QT. Na hipótese de continuação da QT a despeito de alterações na função do VE, é necessária reavaliação ecocardiográfica antes de novo ciclo, ciente de antemão que o risco de CTX irá aumentar progressivamente.

Exames adicionais de imagem não são necessários para pacientes que não têm fatores concomitantes de risco, na presença de GLS ou troponina normais durante a QT e seis meses depois da última QT com ANT. Sugere-se que, após completar seu esquema terapêutico, deva haver avaliação clínica cardiovascular anual e o uso de imagem cardíaca condicionada à disponibilidade no serviço.8

Conclusões

A monitorização da FEVE pela 2D ECO é a estratégia mais exequível para se detectar doença cardiovascular relacionada à QT em grandes grupos de pacientes, entretanto deve ser considerada no contexto das inúmeras limitações do método. O 3D ECO é o método de escolha ao se ponderar acurácia com disponibilidade, limitações de repetição e facilidade de execução. Na sua indisponibilidade, a adição de contraste à 2D ECO deve ser recomendada, visto que isto aumenta acurácia. O GLS VE é o melhor parâmetro da deformação miocárdica para a detecção subclínica da disfunção VE, porém não há evidências sólidas mostrando o benefício de se iniciar a terapia “cardioprotetora” precoce baseada em seus resultados. A VRN tem elevada acurácia diagnóstica para disfunção ventricular e pode ser uma alternativa para os casos de dúvida à ecocardiografia. A RMC auxilia nos diagnósticos diferenciais com outras causas de miocardiopatias.

A decisão da interrupção ou manutenção de esquema quimioterápico é clínica, conjunta, multidisciplinar, fundamentada na relação risco versus benefício para cada paciente.

Ensaios clínicos randomizados, controlados, com seguimento em longo prazo, são necessários para que se possa definir se a detecção precoce da disfunção cardíaca é preditor de redução da FEVE e, sobretudo, de IC e eventos cardiovasculares maiores.

Fontes de financiamento

O presente estudo não teve fontes de financiamento externas.

Vinculação acadêmica

Este artigo é parte de tese de Doutorado de Mário Luiz Ribeiro pela Universidade Federal Fluminense.