Curr Treat Options Cardio Med (2015) 17: 38 DOI 10.1007/s11936-015-0396-8
Cardio-oncology (S Francis, Section Editor)
Detection of Cardiac Toxicity Due to Cancer Treatment: Role of Cardiac MRI Nandini (Nina) M. Meyersohn, MD1,* Amit Pursnani, MD1,2 Tomas G. Neilan, MD1,2 Address *,1 Department of Radiology, Cardiac MR PET CT Program, Massachusetts General Hospital, Boston, MA, USA Email: [email protected] 2 Department of Medicine, Division of Cardiology, Cardio-Oncology Program, Massachusetts General Hospital, Boston, MA, USA
Published online: 3 July 2015 * Springer Science+Business Media New York 2015
This article is part of the Topical Collection on Cardio-oncology Keywords Anthracyclines I Cardiac magnetic resonance I Cardiotoxicity I Chemotherapy I Echocardiography I Ejection fraction
Opinion statement Common cancer treatments including anthracycline-based chemotherapy, tyrosine kinase inhibitors, and thoracic radiation therapy can result in short- and long-term cardiovascular complications with a significant impact on morbidity and mortality. Anthracycline-based chemotherapy and tyrosine kinase inhibitors are associated with left ventricular systolic dysfunction and heart failure. Radiation therapy is associated with restrictive cardiomyopathy, coronary artery disease, as well as pericardial and valvular disease. The current standard surveillance of oncology patients for cardiotoxicity involves echocardiography, radionuclide cardiac blood pool imaging, and cardiac magnetic resonance (CMR) imaging. CMR can be used to evaluate ventricular structure and function, which is important for management decisions to prevent further cardiac injury. In patients for whom standard surveillance imaging demonstrates a drop in systolic function with or without symptoms, the use of CMR is an appropriate next step for further evaluation due to the accuracy and reproducibility of measurements of function and volumes combined with the additive information provided by tissue characterization through imaging of myocardial edema and myocardial fibrosis, although the clinical applications of these latter are as yet unclear. Overall, detection of early cardiotoxicity is important since therapeutic response is improved with prompt initiation of medical treatment.
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Curr Treat Options Cardio Med (2015) 17: 38
Introduction As mortality rates for cancer patients have fallen in recent years, there has been a shift in physicians’ focus toward issues of survivorship including long-term complications of oncologic therapy. Among the most significant of these for long-term morbidity and mortality is an increased incidence of cardiovascular disease [1•]. Cardiovascular complications are of particular concern in pediatric and young adult oncology patients, whose potential survivorship may be several decades in length [2•, 3]. Surveillance for complications is typically performed with echocardiography, radionuclide cardiac blood pool imaging, and cardiac magnetic resonance imaging (CMR) [4]. Cardiac magnetic resonance imaging utilizes the inherent magnetic vectors or Bspins^ of protons within tissue by initially aligning them with a strong external magnetic field within the bore of the machine. The vectors of these spins are then altered using
radiofrequency pulses, and the processes by which the spins return to their original alignment provide signal that can be interpreted to provide information about the tissue in which the protons are located. Magnetic resonance imaging does not utilize ionizing radiation, has excellent spatial resolution, and can provide detailed information regarding soft tissue characteristics [5]. CMR is the reference standard for assessing left ventricular systolic function and volumes and plays an important role in the detection and monitoring of cardiotoxicity from chemotherapy and radiation therapy [6]. CMR has the additional capability to noninvasively provide information regarding tissue characterization and valvular function [7]. This review will address recent developments and current practice in the applications of CMR to the detection of cardiotoxicity in oncology patients.
Cancer treatments and cardiotoxicity An important distinction to be made for the purposes of this review is between the terms Bcardiotoxicity^ and Bcardiac dysfunction.^ Cardiotoxicity is a broad term that can be used to include the entire spectrum of cardiac injury secondary to myocyte damage, with or without associated physiologic abnormalities. Cardiac dysfunction has been defined more specifically as a measurable decline in systolic function, with proposed quantification including a symptomatic 95 % drop in left ventricular ejection fraction (LVEF) or an asymptomatic 910 % drop to less than 55 % [8]. Significant cardiotoxicity can occur at a histologic level without measurable cardiac dysfunction [9]. Relying on LVEF alone, therefore, even with the assumption that measurements are accurate, will not identify all patients with cardiotoxicity but only those who have advanced to extensive myocardial injury. This distinction is important since it has been demonstrated that early detection of cardiotoxicity and the initiation of appropriate therapy can improve cardiovascular outcomes [10•].
Anthracyclines The most commonly encountered chemotherapeutic agents resulting in cardiovascular complications are the anthracyclines, a group that includes doxorubicin (trade name Adriamycin), daunorubicin, and epirubicin. There are several hypotheses regarding the mechanism of cardiotoxicity from anthracyclines, but the generation of free radicals and subsequent cellular damage is accepted as a central cause. Other proposed mechanisms of injury include effects on intracellular adenosine triphosphate production and on cardiac topoisomerase enzymes [11]. The result of this cellular damage is myocyte death and myocardial fibrosis with
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subsequent left ventricular dysfunction. The typical clinical presentation of anthracycline-associated cardiac dysfunction is non-ischemic dilated cardiomyopathy with impaired left ventricular systolic function.
Tyrosine kinase inhibitors Monoclonal antibodies targeted to human cell surface receptors that function via inhibition of tyrosine kinase signal cascade pathways are increasingly used in the treatment of multiple oncologic conditions. The most commonly utilized tyrosine kinase inhibitor (TKI) in clinical practice that results in cardiotoxicity is trastuzumab (trade name Herceptin) targeted at HER-2 receptor positive breast cancer. The mechanism of trastuzumab-induced cardiotoxicity is also not clearly defined but is distinct from the mechanism of injury in anthracyclineassociated cardiotoxicity and appears to involve inhibition of human epidermal growth factor resulting in myocyte injury and impaired systolic function [12]. Trastuzumab-induced cardiotoxicity can often be transient. The incidence of systolic dysfunction in patients receiving trastuzumab is significantly increased with prior or concomitant use of anthracyclines.
Radiation therapy Radiation induced cardiotoxicity most commonly present as pericardial or valvular disease in patients who have received mediastinal, thoracic, or breast radiation [13]. Pericardial manifestations include acute pericarditis, pericardial effusion in the acute setting, and constrictive pericarditis in the chronic setting [14]. Valvular complications are more common in the left heart and include chronic aortic and mitral stenosis. Mediastinal radiation can also result in restrictive cardiomyopathy with diastolic dysfunction, which can be compounded in patients with constrictive pericarditis. Premature coronary artery disease is an additional chronic complication of cardiac exposure to radiation, however is better assessed by invasive or CT coronary angiography.
Surveillance for cardiotoxicity In the pediatric population, routine surveillance has been recommended to detect cardiotoxicity due to anthracycline chemotherapy [4, 15]. Recommendations include baseline ECG, two-dimensional (2D) echocardiogram, and radionuclide blood pool study if available, followed by repeat echocardiography at 3 to 6 months, 12 months, and every 2 to 3 years thereafter with additional radionuclide studies every 5 years [15]. Similarly, in adult oncology, patients’ recommendations have been provided in both Europe and the USA for serial surveillance of patients receiving anthracycline-based chemotherapy. Current consensus recommendations include baseline echocardiography followed by serial gated cardiac radionuclide blood pool studies or echocardiography to estimate and follow left ventricular ejection fraction (LVEF) [16]. A drawback to surveillance regimens that rely solely on repeated LVEF estimation is that myocardial injury can occur far earlier than demonstrable loss of systolic function [17•, 18]. Studies utilizing endomyocardial biopsy have demonstrated that cardiotoxicity is present in a significant number of patients with normal systolic function on 2D echocardiography [19]. Additionally, variability in the measurement of LVEF from examination to examination is a potential drawback.
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Curr Treat Options Cardio Med (2015) 17: 38 Variability in LVEF measurement can be as high as 8–9 % for 2D echocardiography versus 2 % for CMR [19]. Radionuclide cardiac blood pool imaging has good reproducibility but involves exposure to ionizing radiation, which is problematic for repeated examination of young patients over a long period of time. In addition to highly reproducible measurement of function and comprehensive structural evaluation, CMR has the capability for tissue characterization, the only other strategy for which is invasive endomyocardial biopsy. For these reasons, CMR is a potential next step in evaluation after early detection of an abnormality on surveillance via echocardiography or radionuclide blood pool imaging.
Cardiotoxicity imaging findings Early findings in chemotherapy Early CMR findings of cardiotoxicity secondary to anthracyclines and trastuzumab manifest within weeks to months of administration [20]. These include myocardial edema and a drop in left ventricular systolic function that can be asymptomatic [21]. CMR is the most sensitive imaging modality for the detection of myocardial edema, a finding which cannot be visualized using echocardiography or radionuclide imaging and which appears to be correlated with later loss of cardiac function. Short axis T2-weighted images of the left ventricle can evaluate for visible areas of abnormal signal hyperintensity in the myocardium consistent with edema [22]. T2 images are performed with a dual echo technique at our institution to improve potential detection of signal abnormality relative to normal myocardium. Global evaluation of T2 signal relative to skeletal muscle with a calculation of myocardial to skeletal muscle T2 ratio can also be performed to identify edema that may not be visually apparent. CMR can play an important role in the accurate evaluation of declining left ventricular systolic function. A study of oncology patients who received anthracyclines demonstrated that 2D echo overestimated LVEF by an average of 5 % as compared to CMR. Additionally, 11 % of survivors had an EF G50 % by CMR but were misidentified as normal by 2D echocardiography [19]. Given that 14 % of the overall study population had an abnormal LVEF, CMR may play an important role in providing more accurate evaluation of patients who are identified to have a drop in LVEF on echocardiography during chemotherapy. Threedimensional (3D) echocardiography demonstrates improved accuracy in measurement of ventricular volumes, although CMR remains the gold standard [23]. It is important to note that while LVEF is a marker of adverse outcomes related to heart failure, measurement is affected by varying physiological conditions. Murine models and initial human studies have also suggested that global myocardial T1 signal intensity after contrast administration increases after exposure to chemotherapy [24, 25•]. The utility of early relative global enhancement ratio as compared to skeletal muscle has not been clearly established and remains an area of active study.
Late findings in chemotherapy Late CMR findings of cardiotoxicity secondary to chemotherapy manifest within months to years of administration (Fig. 1). These include decreased left ventricular systolic function, myocardial fibrosis, and decreased left ventricular mass index.
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Myocardial fibrosis is universally present in patients with anthracyclineinduced left ventricular systolic dysfunction [21]. The presence of late gadolinium enhancement (LGE), however, is uncommon in these patients and does not present in well-defined characteristic patterns [17•]. Other novel strategies for assessing chronic diffuse fibrosis may therefore be potentially useful in these patients, including intrinsic myocardial T1 analysis and T1 mapping before and after the administration of gadolinium-based contrast. The T1 measurements can be used to provide a quantitative index of the extent of diffuse fibrosis. From a pre- and a post-contrast T1 measurement, the extracellular volume (ECV) fraction can be calculated and has been shown to be markedly elevated in patients after anthracyclines and to have a strong association with the degree of cardiac dysfunction [26]. Myocardial strain analysis has additionally been identified as a potential marker of abnormality in patients who have received anthracyclines. Although these imaging strategies provide conceptual corroboration of pathologic findings and are areas of active study, they do not currently contribute to clinical decision-making. A decrease in left ventricular mass index (LVMI) can also indicate myocyte loss due to injury from treatment that may result in eventual loss of function [27]. CMR is the gold standard for the measurement of LVMI and provides more accurate quantitation than echocardiography. Loss of LVMI is associated with long-term major adverse cardiac events, and therefore, serial evaluation may play a future role in the early detection of cardiotoxicity. The relatively higher cost of serial MRI as compared to echocardiography, however, must be taken into consideration. Comparative effectiveness studies will be necessary to further elucidate the appropriate role of these two imaging modalities.
Radiation therapy Patients with mediastinal malignancies or lymphoma who receive mediastinal or Bmantle^ radiation are at high risk for cardiovascular complications, particularly if received during childhood [28]. Emerging evidence suggests that older women with breast cancer who receive radiation therapy are also at an increased long-term risk of cardiovascular morbidity and mortality [29]. In the acute setting, the most common complication is asymptomatic pericardial effusion. Acute pericarditis is much less common and presents with similar symptoms as nonspecific pericarditis. In the chronic setting, constrictive pericarditis can develop which is difficult to distinguish clinically from restrictive cardiomyopathy as both present with diastolic dysfunction. Tagged cine gradient echo CMR sequences are useful for the distinction of the two as constrictive pericarditis will demonstrate a lag of tag line deformation between the myocardium and pericardium [30]. Cine balanced steady-state free precession (bSSFP) CMR images in a four-chamber view are also useful to demonstrate the characteristic early diastolic Bbounce^ of constrictive pericarditis, which is secondary to ventricular interdependence in a fixed pericardial volume. Chronic valvular complications are also seen after radiation therapy, most commonly aortic and mitral stenosis [28]. CMR can quantitate valvular gradients and regurgitant fractions, when applicable, as well as provide evaluation of ventricular mass and function that may affect management decisions regarding valve replacement. Coronary artery disease in the absence of traditional risk factors is another potential chronic complication of radiation therapy, however
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Curr Treat Options Cardio Med (2015) 17: 38 Fig. 1. Anthracycline-based chemotherapy and cardiac dysfunction.
is better evaluated by other imaging modalities including coronary invasive or CT angiography.
Management After cardiotoxicity has been identified, chemotherapy courses can be modified and medical treatment can be initiated to prevent further deterioration of systolic function [31]. A drop in LVEF reduction of ≥15 % with preserved function (LVEF ≥50 %) is not a contraindication to continuing anthracyclines [16]. If the LVEF declines to less than 50 %, reassessment is recommended at 3 weeks with discontinuation of anthracyclines and initiation of medical therapy if the abnormality persists. If the LVEF declines to less than 40 %, immediate discontinuation of chemotherapy and medical treatment of left ventricular dysfunction is recommended. Echocardiography screening intervals for long-term reassessment of cardiac function after anthracycline therapy in children is dependent on age at time of treatment, the presence of concomitant chest radiation therapy, and the cumulative anthracycline dose. Although consensus statements exist for screening intervals in adults treated with anthracycline therapy, debate still exists regarding the appropriate level and frequency of screening. Studies have demonstrated that systolic dysfunction related to trastuzumab administration has a higher incidence when administered concurrently with anthracycline chemotherapy [32]. As a result, trastuzumab is now routinely administered after the completion of anthracycline and other cytoxic chemotherapeutic agents [33]. The time course and criteria for discontinuation and medical treatment of patients receiving trastuzumab is similar to that for anthracyclines. As trastuzumab-associated cardiac dysfunction is often transient, however, many patients are able to resume treatment after resolution of functional deficits. Medical therapy in the treatment of chemotherapy-associated heart failure includes the use of angiotensin converting enzyme (ACE) inhibitors and beta blockers. A recent study evaluating clinical response of anthracycline-associated heart failure to therapy demonstrated complete response in 42 % of patients
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and partial response in 13 % [10•]. The most important predictor of response was the time interval from the discontinuation of chemotherapy to the initiation of medical therapy, with a 64 % incidence of complete recovery when initiated within 2 months after chemotherapy. No cases of complete recovery were observed when the interval was greater than 6 months, and no cases of partial recovery were observed with an interval greater than 12 months. These results reinforce the clinical importance of early detection of cardiotoxicity with or without symptomatic systolic dysfunction for which cardiac MRI has a central role. Areas of future study include the prospective use of medical therapy in cancer patients to prevent cardiotoxicity [34•]. Treatment is limited for radiation-induced restrictive cardiomyopathy and includes symptomatic treatment of heart failure and heart transplantation. If constrictive pericarditis is identified and is symptomatic, therapeutic pericardiectomy can be performed. Radiation-induced valvular disease with hemodynamic significance can be treated with percutaneous or open surgical interventions including valvuloplasty and valve replacement.
Summary Surveillance of oncology patients who receive chemotherapy or radiation therapy with a significant cardiac dose is a common clinical practice to identify patients for whom early intervention can improve long-term cardiovascular outcomes. CMR is the most sensitive and reproducible measure of left ventricular systolic function. In patients with abnormalities identified on routine surveillance imaging, CMR can be an appropriate next step for further characterization of structure and function. The potential utility of CMR tissue characterization strategies is an area of active study.
Compliance with Ethics Guidelines Conflict of Interest Nandini (Nina) M. Meyersohn, Amit Pursnani, and Tomas G. Neilan each declare no potential conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance 1.•
Oliveira GH, Mukerji S, Hernandez AV, Qattan MY, Banchs J, Durand JB, et al. Incidence, predictors, and impact on survival of left ventricular systolic dysfunction and recovery in advanced cancer patients. Am J Cardiol. 2014;113D11]:1893–8.
Retrospective study of largest cohort of patients who developed LV systolic dysfunction with examination of factors related to recovery and survival. 2.• Toro-Salazar OH, Gillan E, O’Loughlin MT, Burke GS, Ferranti J, Stainsby J, et al. Occult cardiotoxicity in
38 Page 8 of 9 childhood cancer survivors exposed to anthracycline therapy. Circ Cardiovasc Imaging. 2013;6D6]:873–80. Study of pediatric oncology patients demonstrating abnormal myocardial characteristics and strain parameters by CMR despite normal global systolic function. 3. Chen MH, Colan SD, Diller L. Cardiovascular disease: cause of morbidity and mortality in adult survivors of childhood cancers. Circ Res. 2011;108(5):619–28. 4. Steinherz LJ, Graham T, Hurwitz R, Sondheimer HM, Schwartz RG, Shaffer EM, et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the cardiology committee of the childrens cancer study group. Pediatrics. 1992;89(5 Pt 1):942–9. 5. Pennell DJ. Cardiovascular magnetic resonance. Circulation.121:692–705. 6. American College of Cardiology Foundation Task Force on Expert Consensus Documents, Hundley WG, Bluemke DA, Finn JP, Flamm SD, Fogel MA, et al. ACCF/ACR/AHA/NASCI/SCMR 2010 expert consensus document on cardiovascular magnetic resonance: a report of the American College of Cardiology Foundation Task Force on expert consensus documents. J Am Coll Cardiol. 2010;55(23):2614–62. 7. Thavendiranathan P, Wintersperger BJ, Flamm SD, Marwick TH. Cardiac MRI in the assessment of cardiac injury and toxicity from cancer chemotherapy: a systematic review. Circ Cardiovasc Imaging. 2013;6(6):1080–91. 8. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20(5):1215– 21. 9. Ewer MS, Ali MK, Mackay B, Wallace S, Valdivieso M, Legha SS, et al. A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving adriamycin. J Clin Oncol. 1984;2(2):112–7. 10.• 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. J Am Coll Cardiol. 2010;55D3]:213–20. Study of 201 patients with anthracycline-based chemotherapy induced cardiac dysfunction and response to medical therapy with beta blocker and ACE inhibitor. 11. Chen B, Peng X, Pentassuglia L, Lim CC, Sawyer DB. Molecular and cellular mechanisms of anthracycline cardiotoxicity. Cardiovasc Toxicol. 2007;7(2):114–21. 12. Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007;7(5):332–44. 13. Heidenreich PA, Hancock SL, Lee BK, Mariscal CS, Schnittger I. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol. 2003;42(4):743–9. 14. Filopei J, Frishman W. Radiation-induced heart disease. Cardiol Rev. 2012;20(4):184–8. 15. Shankar SM, Marina N, Hudson MM, Hodgson DC, Adams MJ, Landier W, et al. Monitoring for
Curr Treat Options Cardio Med (2015) 17: 38 cardiovascular disease in survivors of childhood cancer: report from the cardiovascular disease task force of the children’s oncology group. Pediatrics. 2008;121(2):e387–96. 16. Curigliano G, Cardinale D, Suter T, Plataniotis G, de Azambuja E, Sandri MT, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO clinical practice guidelines. Ann Oncol. 2012;23 Suppl 7:vii155–66. 17.• Drafts BC, Twomley KM, D’Agostino Jr R, Lawrence J, Avis N, Ellis LR, et al. Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease. JACC Cardiovasc Imaging. 2013;6D8]:877–85. Low to moderate doses of anthracycline-based chemotherapy found to be associated with early cardiac function abnormalities while still subclinical. 18. 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(22):2263–70. 19. 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 resonance imaging. J Clin Oncol. 2012;30(23):2876–84. 20. Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 2009;53(24):2231– 47. 21. Bernaba BN, Chan JB, Lai CK, Fishbein MC. Pathology of late-onset anthracycline cardiomyopathy. Cardiovasc Pathol. 2010;19(5):308–11. 22. Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang G, Alakija P, Cooper LT, et al. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol. 2009;53(17):1475–87. 23. Ylanen K, Eerola A, Vettenranta K, Poutanen T. Threedimensional echocardiography and cardiac magnetic resonance imaging in the screening of long-term survivors of childhood cancer after cardiotoxic therapy. Am J Cardiol. 2014;113(11):1886–92. 24. Lightfoot JC, D’Agostino Jr RB, Hamilton CA, Jordan J, Torti FM, Kock ND, et al. Novel approach to early detection of doxorubicin cardiotoxicity by gadoliniumenhanced cardiovascular magnetic resonance imaging in an experimental model. Circ Cardiovasc Imaging. 2010;3(5):550–8. 25.• Jordan JH, D’Agostino Jr RB, Hamilton CA, Vasu S, Hall ME, Kitzman DW, et al. Longitudinal assessment of concurrent changes in left ventricular ejection fraction and left ventricular myocardial tissue characteristics after administration of cardiotoxic chemotherapies using T1-weighted and T2-weighted cardiovascular
Curr Treat Options Cardio Med (2015) 17: 38 magnetic resonance. Circ Cardiovasc Imaging. 2014;7D6]:872–9. Patients receiving cardiotoxic chemotherapy demonstrate T1weighted signal abnormalities and small decreases in LVEF within 3 months of concluding therapy. 26. Neilan TG, Coelho-Filho OR, Shah RV, Feng JH, PenaHerrera D, Mandry D, et al. Myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline-based chemotherapy. Am J Cardiol. 2013;111(5):717–22. 27. Neilan TG, Coelho-Filho OR, Pena-Herrera D, Shah RV, Jerosch-Herold M, Francis SA, et al. Left ventricular mass in patients with a cardiomyopathy after treatment with anthracyclines. Am J Cardiol. 2012;110(11):1679–86. 28. Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease following treatment of Hodgkin’s disease in children and adolescents. J Clin Oncol. 1993;11(7):1208–15. 29. McGale P, Darby SC, Hall P, Adolfsson J, Bengtsson NO, Bennet AM, et al. Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden. Radiother Oncol. 2011;100(2):167–75. 30. Walker CM, Saldana DA, Gladish GW, Dicks DL, Kicska G, Mitsumori LM, et al. Cardiac complications of oncologic therapy. Radiographics. 2013;33(6):1801–15.
Page 9 of 9 38 31.
Sieswerda E, van Dalen EC, Postma A, Cheuk DK, Caron HN, Kremer LC. Medical interventions for treating anthracycline-induced symptomatic and asymptomatic cardiotoxicity during and after treatment for childhood cancer. Cochrane Database Syst Rev. 2011;7;(9):CD008011. doi(9):CD008011. 32. Saeed MF, Premecz S, Goyal V, Singal PK, Jassal DS. Catching broken hearts: pre-clinical detection of doxorubicin and trastuzumab mediated cardiac dysfunction in the breast cancer setting. Can J Physiol Pharmacol. 2014;92(7):546–50. 33. Hahn VS, Lenihan DJ, Ky B. Cancer therapy-induced cardiotoxicity: basic mechanisms and potential cardioprotective therapies. J Am Heart Assoc. 2014;3(2):e000665. 34.• Bosch X, Rovira M, Sitges M, Domenech A, Ortiz-Perez JT, de Caralt TM, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial DpreventiOn of left ventricular dysfunction with enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of malignant hEmopathies]. J Am Coll Cardiol. 2013;61D23]:2355–62. Combined therapy enalapril and carvedilol decreases the incidence of LV systolic dysfunction in patients with hematologic malignancies receiving chemotherapy.
Cardio-oncology (S Francis, Section Editor)
Detection of Cardiac Toxicity Due to Cancer Treatment: Role of Cardiac MRI Nandini (Nina) M. Meyersohn, MD1,* Amit Pursnani, MD1,2 Tomas G. Neilan, MD1,2 Address *,1 Department of Radiology, Cardiac MR PET CT Program, Massachusetts General Hospital, Boston, MA, USA Email: [email protected] 2 Department of Medicine, Division of Cardiology, Cardio-Oncology Program, Massachusetts General Hospital, Boston, MA, USA
Published online: 3 July 2015 * Springer Science+Business Media New York 2015
This article is part of the Topical Collection on Cardio-oncology Keywords Anthracyclines I Cardiac magnetic resonance I Cardiotoxicity I Chemotherapy I Echocardiography I Ejection fraction
Opinion statement Common cancer treatments including anthracycline-based chemotherapy, tyrosine kinase inhibitors, and thoracic radiation therapy can result in short- and long-term cardiovascular complications with a significant impact on morbidity and mortality. Anthracycline-based chemotherapy and tyrosine kinase inhibitors are associated with left ventricular systolic dysfunction and heart failure. Radiation therapy is associated with restrictive cardiomyopathy, coronary artery disease, as well as pericardial and valvular disease. The current standard surveillance of oncology patients for cardiotoxicity involves echocardiography, radionuclide cardiac blood pool imaging, and cardiac magnetic resonance (CMR) imaging. CMR can be used to evaluate ventricular structure and function, which is important for management decisions to prevent further cardiac injury. In patients for whom standard surveillance imaging demonstrates a drop in systolic function with or without symptoms, the use of CMR is an appropriate next step for further evaluation due to the accuracy and reproducibility of measurements of function and volumes combined with the additive information provided by tissue characterization through imaging of myocardial edema and myocardial fibrosis, although the clinical applications of these latter are as yet unclear. Overall, detection of early cardiotoxicity is important since therapeutic response is improved with prompt initiation of medical treatment.
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Curr Treat Options Cardio Med (2015) 17: 38
Introduction As mortality rates for cancer patients have fallen in recent years, there has been a shift in physicians’ focus toward issues of survivorship including long-term complications of oncologic therapy. Among the most significant of these for long-term morbidity and mortality is an increased incidence of cardiovascular disease [1•]. Cardiovascular complications are of particular concern in pediatric and young adult oncology patients, whose potential survivorship may be several decades in length [2•, 3]. Surveillance for complications is typically performed with echocardiography, radionuclide cardiac blood pool imaging, and cardiac magnetic resonance imaging (CMR) [4]. Cardiac magnetic resonance imaging utilizes the inherent magnetic vectors or Bspins^ of protons within tissue by initially aligning them with a strong external magnetic field within the bore of the machine. The vectors of these spins are then altered using
radiofrequency pulses, and the processes by which the spins return to their original alignment provide signal that can be interpreted to provide information about the tissue in which the protons are located. Magnetic resonance imaging does not utilize ionizing radiation, has excellent spatial resolution, and can provide detailed information regarding soft tissue characteristics [5]. CMR is the reference standard for assessing left ventricular systolic function and volumes and plays an important role in the detection and monitoring of cardiotoxicity from chemotherapy and radiation therapy [6]. CMR has the additional capability to noninvasively provide information regarding tissue characterization and valvular function [7]. This review will address recent developments and current practice in the applications of CMR to the detection of cardiotoxicity in oncology patients.
Cancer treatments and cardiotoxicity An important distinction to be made for the purposes of this review is between the terms Bcardiotoxicity^ and Bcardiac dysfunction.^ Cardiotoxicity is a broad term that can be used to include the entire spectrum of cardiac injury secondary to myocyte damage, with or without associated physiologic abnormalities. Cardiac dysfunction has been defined more specifically as a measurable decline in systolic function, with proposed quantification including a symptomatic 95 % drop in left ventricular ejection fraction (LVEF) or an asymptomatic 910 % drop to less than 55 % [8]. Significant cardiotoxicity can occur at a histologic level without measurable cardiac dysfunction [9]. Relying on LVEF alone, therefore, even with the assumption that measurements are accurate, will not identify all patients with cardiotoxicity but only those who have advanced to extensive myocardial injury. This distinction is important since it has been demonstrated that early detection of cardiotoxicity and the initiation of appropriate therapy can improve cardiovascular outcomes [10•].
Anthracyclines The most commonly encountered chemotherapeutic agents resulting in cardiovascular complications are the anthracyclines, a group that includes doxorubicin (trade name Adriamycin), daunorubicin, and epirubicin. There are several hypotheses regarding the mechanism of cardiotoxicity from anthracyclines, but the generation of free radicals and subsequent cellular damage is accepted as a central cause. Other proposed mechanisms of injury include effects on intracellular adenosine triphosphate production and on cardiac topoisomerase enzymes [11]. The result of this cellular damage is myocyte death and myocardial fibrosis with
Curr Treat Options Cardio Med (2015) 17: 38
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subsequent left ventricular dysfunction. The typical clinical presentation of anthracycline-associated cardiac dysfunction is non-ischemic dilated cardiomyopathy with impaired left ventricular systolic function.
Tyrosine kinase inhibitors Monoclonal antibodies targeted to human cell surface receptors that function via inhibition of tyrosine kinase signal cascade pathways are increasingly used in the treatment of multiple oncologic conditions. The most commonly utilized tyrosine kinase inhibitor (TKI) in clinical practice that results in cardiotoxicity is trastuzumab (trade name Herceptin) targeted at HER-2 receptor positive breast cancer. The mechanism of trastuzumab-induced cardiotoxicity is also not clearly defined but is distinct from the mechanism of injury in anthracyclineassociated cardiotoxicity and appears to involve inhibition of human epidermal growth factor resulting in myocyte injury and impaired systolic function [12]. Trastuzumab-induced cardiotoxicity can often be transient. The incidence of systolic dysfunction in patients receiving trastuzumab is significantly increased with prior or concomitant use of anthracyclines.
Radiation therapy Radiation induced cardiotoxicity most commonly present as pericardial or valvular disease in patients who have received mediastinal, thoracic, or breast radiation [13]. Pericardial manifestations include acute pericarditis, pericardial effusion in the acute setting, and constrictive pericarditis in the chronic setting [14]. Valvular complications are more common in the left heart and include chronic aortic and mitral stenosis. Mediastinal radiation can also result in restrictive cardiomyopathy with diastolic dysfunction, which can be compounded in patients with constrictive pericarditis. Premature coronary artery disease is an additional chronic complication of cardiac exposure to radiation, however is better assessed by invasive or CT coronary angiography.
Surveillance for cardiotoxicity In the pediatric population, routine surveillance has been recommended to detect cardiotoxicity due to anthracycline chemotherapy [4, 15]. Recommendations include baseline ECG, two-dimensional (2D) echocardiogram, and radionuclide blood pool study if available, followed by repeat echocardiography at 3 to 6 months, 12 months, and every 2 to 3 years thereafter with additional radionuclide studies every 5 years [15]. Similarly, in adult oncology, patients’ recommendations have been provided in both Europe and the USA for serial surveillance of patients receiving anthracycline-based chemotherapy. Current consensus recommendations include baseline echocardiography followed by serial gated cardiac radionuclide blood pool studies or echocardiography to estimate and follow left ventricular ejection fraction (LVEF) [16]. A drawback to surveillance regimens that rely solely on repeated LVEF estimation is that myocardial injury can occur far earlier than demonstrable loss of systolic function [17•, 18]. Studies utilizing endomyocardial biopsy have demonstrated that cardiotoxicity is present in a significant number of patients with normal systolic function on 2D echocardiography [19]. Additionally, variability in the measurement of LVEF from examination to examination is a potential drawback.
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Curr Treat Options Cardio Med (2015) 17: 38 Variability in LVEF measurement can be as high as 8–9 % for 2D echocardiography versus 2 % for CMR [19]. Radionuclide cardiac blood pool imaging has good reproducibility but involves exposure to ionizing radiation, which is problematic for repeated examination of young patients over a long period of time. In addition to highly reproducible measurement of function and comprehensive structural evaluation, CMR has the capability for tissue characterization, the only other strategy for which is invasive endomyocardial biopsy. For these reasons, CMR is a potential next step in evaluation after early detection of an abnormality on surveillance via echocardiography or radionuclide blood pool imaging.
Cardiotoxicity imaging findings Early findings in chemotherapy Early CMR findings of cardiotoxicity secondary to anthracyclines and trastuzumab manifest within weeks to months of administration [20]. These include myocardial edema and a drop in left ventricular systolic function that can be asymptomatic [21]. CMR is the most sensitive imaging modality for the detection of myocardial edema, a finding which cannot be visualized using echocardiography or radionuclide imaging and which appears to be correlated with later loss of cardiac function. Short axis T2-weighted images of the left ventricle can evaluate for visible areas of abnormal signal hyperintensity in the myocardium consistent with edema [22]. T2 images are performed with a dual echo technique at our institution to improve potential detection of signal abnormality relative to normal myocardium. Global evaluation of T2 signal relative to skeletal muscle with a calculation of myocardial to skeletal muscle T2 ratio can also be performed to identify edema that may not be visually apparent. CMR can play an important role in the accurate evaluation of declining left ventricular systolic function. A study of oncology patients who received anthracyclines demonstrated that 2D echo overestimated LVEF by an average of 5 % as compared to CMR. Additionally, 11 % of survivors had an EF G50 % by CMR but were misidentified as normal by 2D echocardiography [19]. Given that 14 % of the overall study population had an abnormal LVEF, CMR may play an important role in providing more accurate evaluation of patients who are identified to have a drop in LVEF on echocardiography during chemotherapy. Threedimensional (3D) echocardiography demonstrates improved accuracy in measurement of ventricular volumes, although CMR remains the gold standard [23]. It is important to note that while LVEF is a marker of adverse outcomes related to heart failure, measurement is affected by varying physiological conditions. Murine models and initial human studies have also suggested that global myocardial T1 signal intensity after contrast administration increases after exposure to chemotherapy [24, 25•]. The utility of early relative global enhancement ratio as compared to skeletal muscle has not been clearly established and remains an area of active study.
Late findings in chemotherapy Late CMR findings of cardiotoxicity secondary to chemotherapy manifest within months to years of administration (Fig. 1). These include decreased left ventricular systolic function, myocardial fibrosis, and decreased left ventricular mass index.
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Myocardial fibrosis is universally present in patients with anthracyclineinduced left ventricular systolic dysfunction [21]. The presence of late gadolinium enhancement (LGE), however, is uncommon in these patients and does not present in well-defined characteristic patterns [17•]. Other novel strategies for assessing chronic diffuse fibrosis may therefore be potentially useful in these patients, including intrinsic myocardial T1 analysis and T1 mapping before and after the administration of gadolinium-based contrast. The T1 measurements can be used to provide a quantitative index of the extent of diffuse fibrosis. From a pre- and a post-contrast T1 measurement, the extracellular volume (ECV) fraction can be calculated and has been shown to be markedly elevated in patients after anthracyclines and to have a strong association with the degree of cardiac dysfunction [26]. Myocardial strain analysis has additionally been identified as a potential marker of abnormality in patients who have received anthracyclines. Although these imaging strategies provide conceptual corroboration of pathologic findings and are areas of active study, they do not currently contribute to clinical decision-making. A decrease in left ventricular mass index (LVMI) can also indicate myocyte loss due to injury from treatment that may result in eventual loss of function [27]. CMR is the gold standard for the measurement of LVMI and provides more accurate quantitation than echocardiography. Loss of LVMI is associated with long-term major adverse cardiac events, and therefore, serial evaluation may play a future role in the early detection of cardiotoxicity. The relatively higher cost of serial MRI as compared to echocardiography, however, must be taken into consideration. Comparative effectiveness studies will be necessary to further elucidate the appropriate role of these two imaging modalities.
Radiation therapy Patients with mediastinal malignancies or lymphoma who receive mediastinal or Bmantle^ radiation are at high risk for cardiovascular complications, particularly if received during childhood [28]. Emerging evidence suggests that older women with breast cancer who receive radiation therapy are also at an increased long-term risk of cardiovascular morbidity and mortality [29]. In the acute setting, the most common complication is asymptomatic pericardial effusion. Acute pericarditis is much less common and presents with similar symptoms as nonspecific pericarditis. In the chronic setting, constrictive pericarditis can develop which is difficult to distinguish clinically from restrictive cardiomyopathy as both present with diastolic dysfunction. Tagged cine gradient echo CMR sequences are useful for the distinction of the two as constrictive pericarditis will demonstrate a lag of tag line deformation between the myocardium and pericardium [30]. Cine balanced steady-state free precession (bSSFP) CMR images in a four-chamber view are also useful to demonstrate the characteristic early diastolic Bbounce^ of constrictive pericarditis, which is secondary to ventricular interdependence in a fixed pericardial volume. Chronic valvular complications are also seen after radiation therapy, most commonly aortic and mitral stenosis [28]. CMR can quantitate valvular gradients and regurgitant fractions, when applicable, as well as provide evaluation of ventricular mass and function that may affect management decisions regarding valve replacement. Coronary artery disease in the absence of traditional risk factors is another potential chronic complication of radiation therapy, however
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Curr Treat Options Cardio Med (2015) 17: 38 Fig. 1. Anthracycline-based chemotherapy and cardiac dysfunction.
is better evaluated by other imaging modalities including coronary invasive or CT angiography.
Management After cardiotoxicity has been identified, chemotherapy courses can be modified and medical treatment can be initiated to prevent further deterioration of systolic function [31]. A drop in LVEF reduction of ≥15 % with preserved function (LVEF ≥50 %) is not a contraindication to continuing anthracyclines [16]. If the LVEF declines to less than 50 %, reassessment is recommended at 3 weeks with discontinuation of anthracyclines and initiation of medical therapy if the abnormality persists. If the LVEF declines to less than 40 %, immediate discontinuation of chemotherapy and medical treatment of left ventricular dysfunction is recommended. Echocardiography screening intervals for long-term reassessment of cardiac function after anthracycline therapy in children is dependent on age at time of treatment, the presence of concomitant chest radiation therapy, and the cumulative anthracycline dose. Although consensus statements exist for screening intervals in adults treated with anthracycline therapy, debate still exists regarding the appropriate level and frequency of screening. Studies have demonstrated that systolic dysfunction related to trastuzumab administration has a higher incidence when administered concurrently with anthracycline chemotherapy [32]. As a result, trastuzumab is now routinely administered after the completion of anthracycline and other cytoxic chemotherapeutic agents [33]. The time course and criteria for discontinuation and medical treatment of patients receiving trastuzumab is similar to that for anthracyclines. As trastuzumab-associated cardiac dysfunction is often transient, however, many patients are able to resume treatment after resolution of functional deficits. Medical therapy in the treatment of chemotherapy-associated heart failure includes the use of angiotensin converting enzyme (ACE) inhibitors and beta blockers. A recent study evaluating clinical response of anthracycline-associated heart failure to therapy demonstrated complete response in 42 % of patients
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and partial response in 13 % [10•]. The most important predictor of response was the time interval from the discontinuation of chemotherapy to the initiation of medical therapy, with a 64 % incidence of complete recovery when initiated within 2 months after chemotherapy. No cases of complete recovery were observed when the interval was greater than 6 months, and no cases of partial recovery were observed with an interval greater than 12 months. These results reinforce the clinical importance of early detection of cardiotoxicity with or without symptomatic systolic dysfunction for which cardiac MRI has a central role. Areas of future study include the prospective use of medical therapy in cancer patients to prevent cardiotoxicity [34•]. Treatment is limited for radiation-induced restrictive cardiomyopathy and includes symptomatic treatment of heart failure and heart transplantation. If constrictive pericarditis is identified and is symptomatic, therapeutic pericardiectomy can be performed. Radiation-induced valvular disease with hemodynamic significance can be treated with percutaneous or open surgical interventions including valvuloplasty and valve replacement.
Summary Surveillance of oncology patients who receive chemotherapy or radiation therapy with a significant cardiac dose is a common clinical practice to identify patients for whom early intervention can improve long-term cardiovascular outcomes. CMR is the most sensitive and reproducible measure of left ventricular systolic function. In patients with abnormalities identified on routine surveillance imaging, CMR can be an appropriate next step for further characterization of structure and function. The potential utility of CMR tissue characterization strategies is an area of active study.
Compliance with Ethics Guidelines Conflict of Interest Nandini (Nina) M. Meyersohn, Amit Pursnani, and Tomas G. Neilan each declare no potential conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance 1.•
Oliveira GH, Mukerji S, Hernandez AV, Qattan MY, Banchs J, Durand JB, et al. Incidence, predictors, and impact on survival of left ventricular systolic dysfunction and recovery in advanced cancer patients. Am J Cardiol. 2014;113D11]:1893–8.
Retrospective study of largest cohort of patients who developed LV systolic dysfunction with examination of factors related to recovery and survival. 2.• Toro-Salazar OH, Gillan E, O’Loughlin MT, Burke GS, Ferranti J, Stainsby J, et al. Occult cardiotoxicity in
38 Page 8 of 9 childhood cancer survivors exposed to anthracycline therapy. Circ Cardiovasc Imaging. 2013;6D6]:873–80. Study of pediatric oncology patients demonstrating abnormal myocardial characteristics and strain parameters by CMR despite normal global systolic function. 3. Chen MH, Colan SD, Diller L. Cardiovascular disease: cause of morbidity and mortality in adult survivors of childhood cancers. Circ Res. 2011;108(5):619–28. 4. Steinherz LJ, Graham T, Hurwitz R, Sondheimer HM, Schwartz RG, Shaffer EM, et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the cardiology committee of the childrens cancer study group. Pediatrics. 1992;89(5 Pt 1):942–9. 5. Pennell DJ. Cardiovascular magnetic resonance. Circulation.121:692–705. 6. American College of Cardiology Foundation Task Force on Expert Consensus Documents, Hundley WG, Bluemke DA, Finn JP, Flamm SD, Fogel MA, et al. ACCF/ACR/AHA/NASCI/SCMR 2010 expert consensus document on cardiovascular magnetic resonance: a report of the American College of Cardiology Foundation Task Force on expert consensus documents. J Am Coll Cardiol. 2010;55(23):2614–62. 7. Thavendiranathan P, Wintersperger BJ, Flamm SD, Marwick TH. Cardiac MRI in the assessment of cardiac injury and toxicity from cancer chemotherapy: a systematic review. Circ Cardiovasc Imaging. 2013;6(6):1080–91. 8. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, et al. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20(5):1215– 21. 9. Ewer MS, Ali MK, Mackay B, Wallace S, Valdivieso M, Legha SS, et al. A comparison of cardiac biopsy grades and ejection fraction estimations in patients receiving adriamycin. J Clin Oncol. 1984;2(2):112–7. 10.• 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. J Am Coll Cardiol. 2010;55D3]:213–20. Study of 201 patients with anthracycline-based chemotherapy induced cardiac dysfunction and response to medical therapy with beta blocker and ACE inhibitor. 11. Chen B, Peng X, Pentassuglia L, Lim CC, Sawyer DB. Molecular and cellular mechanisms of anthracycline cardiotoxicity. Cardiovasc Toxicol. 2007;7(2):114–21. 12. Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007;7(5):332–44. 13. Heidenreich PA, Hancock SL, Lee BK, Mariscal CS, Schnittger I. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol. 2003;42(4):743–9. 14. Filopei J, Frishman W. Radiation-induced heart disease. Cardiol Rev. 2012;20(4):184–8. 15. Shankar SM, Marina N, Hudson MM, Hodgson DC, Adams MJ, Landier W, et al. Monitoring for
Curr Treat Options Cardio Med (2015) 17: 38 cardiovascular disease in survivors of childhood cancer: report from the cardiovascular disease task force of the children’s oncology group. Pediatrics. 2008;121(2):e387–96. 16. Curigliano G, Cardinale D, Suter T, Plataniotis G, de Azambuja E, Sandri MT, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO clinical practice guidelines. Ann Oncol. 2012;23 Suppl 7:vii155–66. 17.• Drafts BC, Twomley KM, D’Agostino Jr R, Lawrence J, Avis N, Ellis LR, et al. Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease. JACC Cardiovasc Imaging. 2013;6D8]:877–85. Low to moderate doses of anthracycline-based chemotherapy found to be associated with early cardiac function abnormalities while still subclinical. 18. 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(22):2263–70. 19. 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 resonance imaging. J Clin Oncol. 2012;30(23):2876–84. 20. Yeh ET, Bickford CL. Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. J Am Coll Cardiol. 2009;53(24):2231– 47. 21. Bernaba BN, Chan JB, Lai CK, Fishbein MC. Pathology of late-onset anthracycline cardiomyopathy. Cardiovasc Pathol. 2010;19(5):308–11. 22. Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang G, Alakija P, Cooper LT, et al. Cardiovascular magnetic resonance in myocarditis: a JACC white paper. J Am Coll Cardiol. 2009;53(17):1475–87. 23. Ylanen K, Eerola A, Vettenranta K, Poutanen T. Threedimensional echocardiography and cardiac magnetic resonance imaging in the screening of long-term survivors of childhood cancer after cardiotoxic therapy. Am J Cardiol. 2014;113(11):1886–92. 24. Lightfoot JC, D’Agostino Jr RB, Hamilton CA, Jordan J, Torti FM, Kock ND, et al. Novel approach to early detection of doxorubicin cardiotoxicity by gadoliniumenhanced cardiovascular magnetic resonance imaging in an experimental model. Circ Cardiovasc Imaging. 2010;3(5):550–8. 25.• Jordan JH, D’Agostino Jr RB, Hamilton CA, Vasu S, Hall ME, Kitzman DW, et al. Longitudinal assessment of concurrent changes in left ventricular ejection fraction and left ventricular myocardial tissue characteristics after administration of cardiotoxic chemotherapies using T1-weighted and T2-weighted cardiovascular
Curr Treat Options Cardio Med (2015) 17: 38 magnetic resonance. Circ Cardiovasc Imaging. 2014;7D6]:872–9. Patients receiving cardiotoxic chemotherapy demonstrate T1weighted signal abnormalities and small decreases in LVEF within 3 months of concluding therapy. 26. Neilan TG, Coelho-Filho OR, Shah RV, Feng JH, PenaHerrera D, Mandry D, et al. Myocardial extracellular volume by cardiac magnetic resonance imaging in patients treated with anthracycline-based chemotherapy. Am J Cardiol. 2013;111(5):717–22. 27. Neilan TG, Coelho-Filho OR, Pena-Herrera D, Shah RV, Jerosch-Herold M, Francis SA, et al. Left ventricular mass in patients with a cardiomyopathy after treatment with anthracyclines. Am J Cardiol. 2012;110(11):1679–86. 28. Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease following treatment of Hodgkin’s disease in children and adolescents. J Clin Oncol. 1993;11(7):1208–15. 29. McGale P, Darby SC, Hall P, Adolfsson J, Bengtsson NO, Bennet AM, et al. Incidence of heart disease in 35,000 women treated with radiotherapy for breast cancer in Denmark and Sweden. Radiother Oncol. 2011;100(2):167–75. 30. Walker CM, Saldana DA, Gladish GW, Dicks DL, Kicska G, Mitsumori LM, et al. Cardiac complications of oncologic therapy. Radiographics. 2013;33(6):1801–15.
Page 9 of 9 38 31.
Sieswerda E, van Dalen EC, Postma A, Cheuk DK, Caron HN, Kremer LC. Medical interventions for treating anthracycline-induced symptomatic and asymptomatic cardiotoxicity during and after treatment for childhood cancer. Cochrane Database Syst Rev. 2011;7;(9):CD008011. doi(9):CD008011. 32. Saeed MF, Premecz S, Goyal V, Singal PK, Jassal DS. Catching broken hearts: pre-clinical detection of doxorubicin and trastuzumab mediated cardiac dysfunction in the breast cancer setting. Can J Physiol Pharmacol. 2014;92(7):546–50. 33. Hahn VS, Lenihan DJ, Ky B. Cancer therapy-induced cardiotoxicity: basic mechanisms and potential cardioprotective therapies. J Am Heart Assoc. 2014;3(2):e000665. 34.• Bosch X, Rovira M, Sitges M, Domenech A, Ortiz-Perez JT, de Caralt TM, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial DpreventiOn of left ventricular dysfunction with enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of malignant hEmopathies]. J Am Coll Cardiol. 2013;61D23]:2355–62. Combined therapy enalapril and carvedilol decreases the incidence of LV systolic dysfunction in patients with hematologic malignancies receiving chemotherapy.
