Minireviews
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Radiol. Jul 28, 2014; 6(7): 486-492
Published online Jul 28, 2014. doi: 10.4329/wjr.v6.i7.486
Nuclear imaging in detection and monitoring of cardiotoxicity
Carmen D’Amore, Paola Gargiulo, Stefania Paolillo, Angela Maria Pellegrino, Tiziana Formisano, Antonio Mariniello, Giuseppe Della Ratta, Elisabetta Iardino, Marianna D’Amato, Lucia La Mura, Irma Fabiani, Flavia Fusco, Pasquale Perrone Filardi
Carmen D’Amore, Stefania Paolillo, Angela Maria Pellegrino, Tiziana Formisano, Antonio Mariniello, Giuseppe Della Ratta, Elisabetta Iardino, Marianna D’Amato, Lucia La Mura, Irma Fabiani, Flavia Fusco, Pasquale Perrone Filardi, Department of Advanced Biomedical Sciences, Federico II University, 80131 Naples, Italy
Paola Gargiulo, SDN Foundation, Institute of Diagnostic and Nuclear Development, 80129 Naples, Italy
Author contributions: D’Amore C and Gargiulo P contributed to this work, generated the tables and wrote the manuscript; Paollillo S, Pellegrino AM, Formisano T and Mariniello A contributed to the writing of the manuscript; Della Ratta G, Iardino E, D’Amato M, La Mura L, Fabiani I and Fusco F contributed to med-line; and Perrone Filardi P reviewed the manuscript.
Correspondence to: Pasquale Perrone Filardi, MD, PhD, Department of Advanced Biomedical Sciences, Federico II University, Via Pansini, 5, 80131 Naples, Italy. fpperron@unina.it
Telephone: +39-81-7462224 Fax: +39-81-7462224
Received: February 21, 2014
Revised: April 21, 2014
Accepted: May 29, 2014
Published online: July 28, 2014

Abstract

Cardiotoxicity as a result of cancer treatment is a novel and serious public health issue that has a significant impact on a cancer patient’s management and outcome. The coexistence of cancer and cardiac disease in the same patient is more common because of aging population and improvements in the efficacy of antitumor agents. Left ventricular dysfunction is the most typical manifestation and can lead to heart failure. Left ventricular ejection fraction measurement by echocardiography and multigated radionuclide angiography is the most common diagnostic approach to detect cardiac damage, but it identifies a late manifestation of myocardial injury. Early non-invasive imaging techniques are needed for the diagnosis and monitoring of cardiotoxic effects. Although echocardiography and cardiac magnetic resonance are the most commonly used imaging techniques for cardiotoxicity assessment, greater attention is focused on new nuclear cardiologic techniques, which can identify high-risk patients in the early stage and visualize the pathophysiologic process at the tissue level before clinical manifestation. The aim of this review is to summarize the role of nuclear imaging techniques in the non-invasive detection of myocardial damage related to antineoplastic therapy at the reversible stage, focusing on the current role and future perspectives of nuclear imaging techniques and molecular radiotracers in detection and monitoring of cardiotoxicity.

Key Words: Cardiotoxicity, Cardiac nuclear imaging, Early diagnosis, Scintigraphy, Positron emission tomography

Core tip: Cardiomyopathy is a potential complication of various anticancer drugs, such as anthracyclines and biological therapy. Left ventricular dysfunction is the most common manifestation of cardiotoxicity and is monitored with left ventricular ejection fraction measurement, but it is a late manifestation of myocardial injury. Thus, the cardiologist and oncologist should collaborate to identify new non-invasive techniques to detect cardiac dysfunction at an early and potentially reversible stage, before the onset of clinical manifestation. To achieve this aim, nuclear imaging techniques may offer good future perspectives for early detection of myocardial damage using novel molecular tracers.



INTRODUCTION

Over the last few decades, early diagnosis and development of new antitumor agents have significantly improved the survival of cancer patients. However, conventional and new oncologic drugs frequently have a wide range of cardiac adverse effects, in particular myocardial toxicity. Anthracyclines (doxorubicin, epirubicin), cyclophosphamide, monoclonal antibodies (trastuzumab) and other tyrosine kinase inhibitors (TKIs) are antineoplastic drugs more frequently associated with cardiotoxicity[1]. These drugs may cause irreversible damage, such as that induced by anthracyclines, through free radical production, adrenergic function alteration and cardiac myocyte death due to calcium overload[2,3], or potential completely reversible dysfunction, like that related to TKI administration[4].

Left ventricular (LV) dysfunction is the most typical manifestation of cardiotoxicity and it contributes to increased mortality during chemotherapy[5]. Cardiotoxicity has been defined by the Cardiac Review and Evaluation Committee supervising trastuzumab clinical trials[6] as: (1) a decrease in cardiac LV ejection fraction (EF), either globally or more severe in the septum; (2) the onset of symptoms associated with congestive heart failure (HF); (3) the presence of signs associated with congestive HF; and (4) a reduction in LVEF from baseline of at least 5% to below 55% with signs and symptoms of congestive HF, or a decline in LVEF of at least 10% to below 55% without signs and symptoms of congestive HF. The serial assessment of LVEF is the most common modality for detection of cardiotoxicity and a reduction more than 10% from baseline or a decrease in LVEF below 50% are considered interruption criteria for anticancer drugs administration[7-9]. Notwithstanding, guidelines do not specify the timing and the duration of follow-up and what technique is preferable to assess LV function during and after cancer treatment[10].

Echocardiography (ECHO) plays an important role in evaluation and monitoring of cancer patients treated with cardiotoxic antineoplastic drugs due to its availability and repeatability. Conversely, inter- and intra-observer variability during serial measurement of LVEF and underestimation of myocardial contractile dysfunction should be considered. To overcome these limitations, novel echocardiographic techniques, such as tissue velocity imaging and strain imaging, could be used to detect the presence of myocardial contractile dysfunction before impairment of LVEF[11].

In addition, cardiac magnetic resonance imaging (CMR) is a well recognized imaging technique to screen chemotherapy-related cardiomyopathy[12]. It provides reproducible and noninvasively assessment of LV volume, mass and function[13,14]. Moreover, several studies[13,15,16] emphasized its role in early detection of myocardial damage, however high cost and low availability limit clinical routine use.

Although ECHO and CMR are the two most commonly used imaging techniques for non-invasive chemioterapic myocardial toxicity assessment, nuclear imaging may still have a role in the evaluation and monitoring of cancer patients treated with cardiotoxic drugs. Besides providing sensitive and accurate estimation of LVEF, nuclear imaging techniques using specific radiotracer molecules represent an emerging tool for non-invasive detection of biological processes preceding anatomical involvement and physiological consequences of myocardial damage induced by antineoplastic drugs (Tables 1 and 2).

Table 1 Radiotracer for cardiac nuclear imaging.
TechniqueTracer Action
SPECT
99mTc-erythrocyteContractile function
111In-antimyosinImaging necrosis/cell death
123I-MIBGNeuronal imaging(presynaptic uptake and storage)
111In-TzTherapeutic target imaging
99mTc-annessin VImaging necrosis/cell death
123I-BMIPPFatty acid use
PET
18F-FDGGlucose metabolism
Presynaptic tracersVisualize inhibition of neurotransmission
true catecholamines
18F-6-fluorodopamine
11C-epinephrine
catecholamine analogsFalse neurotransmitters
11C-HED
11C-phenylephrine
18F-6-fluoro-metaraminol
Postsynaptic tracersVisualize transmission of sympathetic signal to target tissue
11C-CGP12177
11C-CGP12388
11C-GB67
Table 2 Techniques used for detection of anticancer therapy cardiomiopathy.
MethodsAdvantagesLimits
EchocardiographyNon-invasive Absence of adverse effects Analysis of systolic and diastolic function Tissue velocity imaging and strain imaging useful for early detection of subclinical alterationInter- and intra-observer variability Low sensitivity of EF assessment for early diagnosis
Magnetic resonance imagingAccurate heart anatomic description Absence of radiation exposure Accurate and reproducible EF assessment Cardiac innervation assessmentLimited availability High costs Not applicable in patients with metallic device Low information about its role in the early detection
Multiple-gated acquisition scintigraphyHigh sensitivity and specificity EF assessment No inter- and intra-observer variabilityLow sensitivity of EF for early diagnosis Less information about diastolic function Radiation exposure
Positron emission tomographyMyocardial metabolic and perfusion evaluationLimited availability

In this review we will summarize the role of nuclear cardiology in the non-invasive detection of myocardial damage related to antineoplastic therapy, focusing on the current role and future perspectives of nuclear imaging and molecular radiotracers in the assessment of cardiac toxicity.

99MTC-MUGA

Multigated radionuclide angiography (MUGA) is a non-invasive technique using 99mTc-erythrocytes to visualize the cardiac blood pool through a γ camera with gated acquisition[17]. The series of heart planar images at each stage of the cardiac cycle permit accurate and highly reproducible quantification of LV volumes and LVEF during cancer therapy[18]. However, its use may be hampered by soft tissue attenuation artifacts and may expose patients to ionizing radiation[14,19]. In 28 patients treated with increasing cumulative doses of doxorubicin for non-Hodgkin lymphoma, Nousianen et al[20] documented that a MUGA scan had 90% sensitivity and 72% specificity for predicting development of chronic HF. However, the results of this little prospective study were not confirmed by a large retrospective study[21] conducted on 630 patients randomized to increasing dose of doxorubicin or placebo. In fact, Swain et al[21] observed that 66% of patients experiencing doxorubicin-related chronic HF showed no clinically relevant decline in LVEF value assessed by MUGA scan from baseline levels (ranging from 0 to 30% of the absolute value), suggesting that it is not accurate in HF prediction.

99mTC GBPS

99mTC gated blood-pool SPECT (single photon emission computed tomography) is a nuclear technique enabling acquisition of 3-dimensional scanned images. 99mTC gated blood-pool SPECT provides information on LVEF, right ventricular EF and wall motion useful for monitoring and personalizing therapy in HF patients[21]. A good correlation between gated blood-pool SPECT and MUGA in LVEF estimation was documented[22]. However, gated blood-pool SPECT tends to underestimate LVEF values (33% ± 13%)[23] compared with MUGA (41% ± 14%, P = 0.001), first-pass radionuclide ventriculography (45% ± 13%, P < 0.0001) and echocardiography (37% ± 15%, P = 0.004).

111IN-ANTIMYOSIN SPECT

The immunoscintigraphic agent 111In-antimyosin is a specific marker for myocardial cell injury and necrosis, binding to intracellular myosin when sarcolemma disruption occurs and the cell is irreversibly damaged. It has been studied in myocardial infarction, myocarditis, cardiac transplant rejection and anthracycline cardiotoxicity[24].

111In-antimyosin SPECT can play a role in subclinical assessment of LV dysfunction as documented in several studies[24,25]. Estorch et al[25] showed an increased uptake of 111In-antimyosin after anthracycline chemotherapy (doxorubicin or mitoxantrone) in breast cancer patients without cardiovascular risk factors or previous chemotherapy or mediastinal radiotherapy, and the degree of myocardial antimyosin uptake was associated with changes in LVEF. Moreover, the presence in some patients of radiotracer uptake not associated with a significant reduction in LVEF after chemotherapy suggested the potential use of this technique to detect cellular damage before the onset of LV functional impairment, allowing the identification of patients at risk of HF. Similar results have also been obtained by Carrió et al[24], who documented a significant reduction in LVEF after chemotherapy in patients treated with an anthracycline dose of 420-600 mg/m2 (P < 0.001) and no significant change in patients treated with a dose of 240-300 mg/m2. Moreover, patients with heart-to-lung ratio (HLR) ≥ 1.90 at a cumulative anthracycline dose of 240-300 mg/m2 developed a reduction in LVEF greater than 10% at a subsequent cumulative doxorubicin dose of 420-600 mg/m2. These data encouraged the use of antimyosin scintigraphy to identify patients with a high risk of developing systolic LV dysfunction when treated with an increasing dose of chemotherapeutic drugs. In addition, Valdés Olmos et al[26] observed that patients with a persistent reduction in LVEF after chemotherapy had a significantly higher HLR value (1.83 ± 0.37) than patients with transient LVEF decrease (1.52 ± 0.21; P < 0.01), revealing that cardiac uptake of 111In-antimyosin could also be useful in discriminating between patients with transient and persistent LV dysfunction and in guiding clinical decisions about discontinuation of anthracycline therapy.

123I-METAIODOBENZYLGUANIDINE SPECT

123I-metaiodobenzylguanidine (123I-MIBG) SPECT is a promising technique for detection of early anthracycline injury and for identification of patients at high risk of developing cardiotoxicity.

Chemotherapy-induced cardiomyopathy activates a compensatory response that increases adrenergic sympathetic and renin-angiotensin system activity to preserve organ perfusion[27]. In patients with chronic HF, increased norepinephrine (NE) release, depletion of NE deposits and downregulation of human NE transporter (hNET1) have been shown[28]. 123I-MIBG is a norepinephrine analogue, showing the same uptake, storage and release mechanisms of NE. Unlike NE, MIBG is not metabolized by catechol-o-methyl transferase and monoamine oxidase[29]; so, labelled with 123I, it can be used to generate scintigraphic images of cardiac efferent sympathetic innervation. After 123I-MIBG administration, early (15 min) and late (4 h) post injection images are acquired to determinate heart to mediastinal ratio (H/M) and washout rate (WR). Consequently, increased NE in the cardiac synaptic space and a reduction in the presynaptic space, induced by HF, reduced MIBG cardiac uptake and accelerated the washout rate.

Studies[30,31] conducted in asymptomatic patients treated with anthracyclines revealed that 123I-MIBG was useful for assessment of myocardial adrenergic derangement and identification of patients at risk of developing cardiotoxicity. In addition, in 36 patients undergoing MIBG scintigraphy who had a diagnosis of sarcoma and no history of cardiac disease or previous cancer treatment, Carrió et al[30] found an insignificant decrease in LVEF and MIBG uptake at an intermediate cumulative dose of doxorubicin (240-300 mg/mg2). However, when a high cumulative dose of doxorubicin 420-600 mg/m2 was used, the experimenters documented a significant impairment of 123I-MIBG uptake (P < 0.001) and a reduction in LVEF (P < 0.05), and proposed that the degree of H/M reduction was also correlated with the dose of anthracycline administrated.

111IN-TRASTUZUMAB SPECT

In cancer patients, anthracyclines can increase the levels of human epidermal growth factor receptor 2 (HER2) expressed by myocytes. In patients pre-treated with anthracyclines, trastuzumab, a chemotherapic agent with a direct effect on HER2, often causes cardiotoxicity, likely as a result of the inhibition of cardiac HER2 that activates the apoptotic pathways and amplifies anthracycline oxidative stress. Thus, 111In-trastuzumab (111In-Tz) SPECT can be used to evaluate the myocyte HER2 expression and the risk of development LV dysfunction in patients treated with this drug[32].

In a small study, Behr et al[33] investigated 111In-Tz scintigraphy in 20 patients with metastatic breast cancer expressing the HER2/neu receptor, pre-treated with anthracyclines and scheduled for administration of Tz as second-line therapy. They documented myocardial 111In-Tz uptake prior to Tz in 7 patients; of these, 6 developed clinical HF (II-IV NYHA class), whereas none of 13 patients without uptake had adverse cardiac events, suggesting that pre-treatment scanning with 111In-Tz could predict cardiotoxicity. In contrast to these results, Perik et al[34] documented increased 111In-Tz uptake at the start of trastuzumab therapy only in 1 of 17 studied patients, who had received extensive anthracycline pre-treatment, and normal 111In-Tz uptake at baseline scintigraphy in 3 patients who developed Tz-induced cardiomyopathy.

99MTC-ANNEXIN V SPECT

Apoptosis of myocardial cells plays a critical role in the onset of cardiomyopathy and has been observed in several conditions, such as hypoxia, ischemia, cardiac overload, acute myocardial infarction, anthracycline-induced cardiomyopathy and end-stage HF. In apoptotic cells, the early stage is characterized by activation of proteases and sphingomyelinases and consequent exposure of phosphatidyldserine molecules on the outer surface of the cell membrane. 99mTc-annexin V has a high affinity for the exposed phosphatidylserine molecule and thus allows imaging of apoptotic cell death[35].

In animals, annexin V scintigraphy has been used to assess acute and chronic doxorubicin-induced cardiomyopathy based on early apoptosis. Increased 99mTc-annexin V uptake was observed in the myocardium of doxorubicin-treated animals and cardiac oxidative stress was confirmed by histological analysis[36,37].

Further studies are needed of the clinical use of this radiotracer, in particular early identification of myocardial damage related to antineoplastic drugs.

123I-15-(P-IODOPHENYL)-3-(R,S)-METHYLPENTADECANOIC ACID SPECT

Taxanes are used in the treatment of breast, lung and ovarian cancer, and they can cause ischemia, arrhythmias and HF. Taxanes can impair the microtubular transport system in cardiomyocytes, resulting in failure to store free fatty acids in the cytosol lipid pool and impairment of mitochondrial free fatty acid uptake for beta-oxidation. 123I-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (123I-BMIPP) scintigraphy has been used to assess this biochemical perturbation in free fatty acid oxidation[38]. Saito et al[38] showed significantly lower BMIPP uptake scores after chemotherapy than those before treatment (23.4 ± 3.4 vs 26.6 ± 0.8, P < 0.001). Moreover, 6 of 25 studied patients, who developed LV dysfunction, also had a significant decrease in total BMIPP uptake scores, suggesting the use of 123I-BMIPP SPECT for detecting of taxane-induced cardiotoxicity. The value of 123I-BMIPP in prediction of cardiotoxicity was also documented in 36 patients with various malignancies treated with doxorubicin[39]. In this study, Saito et al[39] showed a significant dose-related reduction in 123I-BMIPP uptake (0.095 ± 0.25 vs 0.071 ± 0.019; P < 0.001) after doxorubicin chemotherapy and a higher rate of LV dysfunction development in patients with decreased uptake, but with normal LVEF at echocardiography.

POSITRON EMISSION TOMOGRAPHY

Positron emission tomography (PET) is the gold standard technique to assess myocardial metabolism and perfusion due to its high spatial and temporal resolution and high diagnostic sensibility and accuracy. Cardiac PET radiotracers are divided into two categories, those evaluating myocardial perfusion and those evaluating myocardial metabolism.

In the cardio-oncologic field, PET is useful for the diagnosis of metastatic lesion and assessment of the response to chemotherapy. However, fluorine-18-fluorodeoxyglucose (18F-FDG)-PET imaging is used to monitor the response to treatment of primary cardiac lymphoma[40,41] and to evaluate metastatic pericardial involvement[42]. The role of PET in the early detection of cardiotoxicity is still debated. Nony et al[43] showed a significant decrease in LVEF (P = 0.046) assessed by radionuclide angiography after treatment with doxorubicin, but no significant effect was observed in myocardial blood flow evaluated with PET in 6 female cancer patients without heart disease. Recently, Borde et al[44] analyzed changes in myocardial glucose metabolism using FDG-PET and suggested increased glucose utilization was evidence of cellular alteration preceding the cardiotoxicity cascade in patients treated with adriamycin.

Like SPECT, PET imaging can play a key role in the evaluation of cardiac autonomic dysfunction associated with HF[45]. PET provides several advantages over SPECT, with higher spatial and temporal resolution and routinely available attenuation correction. In addition, PET radiotracers more closely resemble the endogenous neurotransmitters than 123MIBG used for SPECT imaging, and the variety of available tracers may allow for more detailed analysis of neuronal signalling[46]. There are two types of presynaptic positron-emitting tracers to assess the presynaptic sympathetic integrity in the heart, radiolabeled catecholamines and radiolabeled catecholamine analogs. The first type behaves identically to endogenous neurotransmitters, thus it is metabolically active and can complicate kinetic data analysis. Catecholamine analogs work as false neurotransmitters and are incapable of following the entire metabolic pathway of true catecholamines. Instead, postsynaptic tracers transmit the sympathetic signal to target tissue. Compared with the availability of presynaptic tracers, only a small number of tracers for postsynaptic neuronal imaging are clinically used. Experimental studies showed a significant reduction in the amount of LV β-adrenoceptors[47] and 11C-hydroxyephedrine in HF catecholamine uptake[48,49] associated with LV dysfunction. Thus, studies are needed to validate this new radiotracer in the cardio-oncology field.

However, the complexity of most of the radiolabeling ligands, the requirement of laborious and specific knowledge, the high cost and the low availability limit clinical use of PET.

CONCLUSION

Cardiotoxicity is one of the principal adverse effects of anticancer therapy of clinical and prognostic importance. LVEF reduction is the most valid criterion to assess the presence of myocardial damage during or after chemotherapy. However, changes in LVEF occur when a critical amount of myocardial damage has taken place and compensatory mechanisms are exhausted[50]. Thus, cardiologists and oncologists should work together to identify new non-invasive, sensitive and non-expensive diagnostic tools that can accurately recognize cardiotoxicity at the subclinical stage to reduce cardiac morbidity and mortality in cancer patients. Further interesting future perspectives in early detection of myocardial damage are offered by nuclear imaging using new molecular tracers which may be able to identify patients at high risk of developing LV dysfunction during and after cancer treatment. Several studies are needed to validate the clinical application of new molecular markers for the identification of early cellular damage.

Footnotes

P- Reviewer: Vinh-Hung V S- Editor: Song XX L- Editor: Cant MR E- Editor: Lu YJ

References
1.  Yeh ET, Tong AT, Lenihan DJ, Yusuf SW, Swafford J, Champion C, Durand JB, Gibbs H, Zafarmand AA, Ewer MS. Cardiovascular complications of cancer therapy: diagnosis, pathogenesis, and management. Circulation. 2004;109:3122-3131.  [PubMed]  [DOI]
2.  Smith LA, Cornelius VR, Plummer CJ, Levitt G, Verrill M, Canney P, Jones A. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta-analysis of randomised controlled trials. BMC Cancer. 2010;10:337.  [PubMed]  [DOI]
3.  Olivetti G, Melissari M, Capasso JM, Anversa P. Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res. 1991;68:1560-1568.  [PubMed]  [DOI]
4.  Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol. 2005;23:2900-2902.  [PubMed]  [DOI]
5.  Kendal WS. Dying with cancer: the influence of age, comorbidity, and cancer site. Cancer. 2008;112:1354-1362.  [PubMed]  [DOI]
6.  Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D. Cardiac dysfunction in the trastuzumab clinical trials experience. J Clin Oncol. 2002;20:1215-1221.  [PubMed]  [DOI]
7.  Schwartz RG, McKenzie WB, Alexander J, Sager P, D’Souza A, Manatunga A, Schwartz PE, Berger HJ, Setaro J, Surkin L. Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography. Am J Med. 1987;82:1109-1118.  [PubMed]  [DOI]
8.  van Royen N, Jaffe CC, Krumholz HM, Johnson KM, Lynch PJ, Natale D, Atkinson P, Deman P, Wackers FJ. Comparison and reproducibility of visual echocardiographic and quantitative radionuclide left ventricular ejection fractions. Am J Cardiol. 1996;77:843-850.  [PubMed]  [DOI]
9.  Mitani I, Jain D, Joska TM, Burtness B, Zaret BL. Doxorubicin cardiotoxicity: prevention of congestive heart failure with serial cardiac function monitoring with equilibrium radionuclide angiocardiography in the current era. J Nucl Cardiol. 2003;10:132-139.  [PubMed]  [DOI]
10.  Eschenhagen T, Force T, Ewer MS, de Keulenaer GW, Suter TM, Anker SD, Avkiran M, de Azambuja E, Balligand JL, Brutsaert DL. Cardiovascular side effects of cancer therapies: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2011;13:1-10.  [PubMed]  [DOI]
11.  Yu CM, Sanderson JE, Marwick TH, Oh JK. Tissue Doppler imaging a new prognosticator for cardiovascular diseases. J Am Coll Cardiol. 2007;49:1903-1914.  [PubMed]  [DOI]
12.  Hendel RC, Patel MR, Kramer CM, Poon M, Hendel RC, Carr JC, Gerstad NA, Gillam LD, Hodgson JM, Kim RJ. ACCF/ACR/SCCT/SCMR/ASNC/NASCI/SCAI/SIR 2006 appropriateness criteria for cardiac computed tomography and cardiac magnetic resonance imaging: a report of the American College of Cardiology Foundation Quality Strategic Directions Committee Appropriateness Criteria Working Group, American College of Radiology, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, American Society of Nuclear Cardiology, North American Society for Cardiac Imaging, Society for Cardiovascular Angiography and Interventions, and Society of Interventional Radiology. J Am Coll Cardiol. 2006;48:1475-1497.  [PubMed]  [DOI]
13.  Fallah-Rad N, Lytwyn M, Fang T, Kirkpatrick I, Jassal DS. Delayed contrast enhancement cardiac magnetic resonance imaging in trastuzumab induced cardiomyopathy. J Cardiovasc Magn Reson. 2008;10:5.  [PubMed]  [DOI]
14.  Walker J, Bhullar N, Fallah-Rad N, Lytwyn M, Golian M, Fang T, Summers AR, Singal PK, Barac I, Kirkpatrick ID. 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;28:3429-3436.  [PubMed]  [DOI]
15.  Fallah-Rad N, Walker JR, Wassef A, Lytwyn M, Bohonis S, Fang T, Tian G, Kirkpatrick ID, Singal PK, Krahn M. 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.  [PubMed]  [DOI]
16.  Wassmuth R, Lentzsch S, Erdbruegger U, Schulz-Menger J, Doerken B, Dietz R, Friedrich MG. Subclinical cardiotoxic effects of anthracyclines as assessed by magnetic resonance imaging-a pilot study. Am Heart J. 2001;141:1007-1013.  [PubMed]  [DOI]
17.  Hesse B, Lindhardt TB, Acampa W, Anagnostopoulos C, Ballinger J, Bax JJ, Edenbrandt L, Flotats A, Germano G, Stopar TG. EANM/ESC guidelines for radionuclide imaging of cardiac function. Eur J Nucl Med Mol Imaging. 2008;35:851-885.  [PubMed]  [DOI]
18.  Altena R, Perik PJ, van Veldhuisen DJ, de Vries EG, Gietema JA. Cardiovascular toxicity caused by cancer treatment: strategies for early detection. Lancet Oncol. 2009;10:391-399.  [PubMed]  [DOI]
19.  Corapçioglu F, Sarper N, Berk F, Sahin T, Zengin E, Demir H. Evaluation of anthracycline-induced early left ventricular dysfunction in children with cancer: a comparative study with echocardiography and multigated radionuclide angiography. Pediatr Hematol Oncol. 2006;23:71-80.  [PubMed]  [DOI]
20.  Nousiainen T, Jantunen E, Vanninen E, Hartikainen J. Early decline in left ventricular ejection fraction predicts doxorubicin cardiotoxicity in lymphoma patients. Br J Cancer. 2002;86:1697-1700.  [PubMed]  [DOI]
21.  Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97:2869-2879.  [PubMed]  [DOI]
22.  Groch MW, DePuey EG, Belzberg AC, Erwin WD, Kamran M, Barnett CA, Hendel RC, Spies SM, Ali A, Marshall RC. Planar imaging versus gated blood-pool SPECT for the assessment of ventricular performance: a multicenter study. J Nucl Med. 2001;42:1773-1779.  [PubMed]  [DOI]
23.  Hacker M, Hoyer X, Kupzyk S, La Fougere C, Kois J, Stempfle HU, Tiling R, Hahn K, Störk S. Clinical validation of the gated blood pool SPECT QBS processing software in congestive heart failure patients: correlation with MUGA, first-pass RNV and 2D-echocardiography. Int J Cardiovasc Imaging. 2006;22:407-416.  [PubMed]  [DOI]
24.  Carrió I, Lopez-Pousa A, Estorch M, Duncker D, Berná L, Torres G, de Andrés L. Detection of doxorubicin cardiotoxicity in patients with sarcomas by indium-111-antimyosin monoclonal antibody studies. J Nucl Med. 1993;34:1503-1507.  [PubMed]  [DOI]
25.  Estorch M, Carrió I, Martínez-Duncker D, Berná L, Torres G, Alonso C, Ojeda B. Myocyte cell damage after administration of doxorubicin or mitoxantrone in breast cancer patients assessed by indium 111 antimyosin monoclonal antibody studies. J Clin Oncol. 1993;11:1264-1268.  [PubMed]  [DOI]
26.  Valdés Olmos RA, ten Bokkel Huinink WW, ten Hoeve RF, van Tinteren H, Bruning PF, van Vlies B, Hoefnagel CA. Usefulness of indium-111 antimyosin scintigraphy in confirming myocardial injury in patients with anthracycline-associated left ventricular dysfunction. Ann Oncol. 1994;5:617-622.  [PubMed]  [DOI]
27.  Francis GS, Cohn JN. The autonomic nervous system in congestive heart failure. Annu Rev Med. 1986;37:235-247.  [PubMed]  [DOI]
28.  Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J. The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol. 2009;54:1747-1762.  [PubMed]  [DOI]
29.  Strashun A. Adriamycin, congestive cardiomyopathy, and metaiodobenzylguanidine. J Nucl Med. 1992;33:215-222.  [PubMed]  [DOI]
30.  Carrió I, Estorch M, Berná L, López-Pousa J, Tabernero J, Torres G. Indium-111-antimyosin and iodine-123-MIBG studies in early assessment of doxorubicin cardiotoxicity. J Nucl Med. 1995;36:2044-2049.  [PubMed]  [DOI]
31.  Valdés Olmos RA, ten Bokkel Huinink WW, ten Hoeve RF, van Tinteren H, Bruning PF, van Vlies B, Hoefnagel CA. Assessment of anthracycline-related myocardial adrenergic derangement by [123I]metaiodobenzylguanidine scintigraphy. Eur J Cancer. 1995;31A:26-31.  [PubMed]  [DOI]
32.  de Korte MA, de Vries EG, Lub-de Hooge MN, Jager PL, Gietema JA, van der Graaf WT, Sluiter WJ, van Veldhuisen DJ, Suter TM, Sleijfer DT. 111Indium-trastuzumab visualises myocardial human epidermal growth factor receptor 2 expression shortly after anthracycline treatment but not during heart failure: a clue to uncover the mechanisms of trastuzumab-related cardiotoxicity. Eur J Cancer. 2007;43:2046-2051.  [PubMed]  [DOI]
33.  Behr TM, Béhé M, Wörmann B. Trastuzumab and breast cancer. N Engl J Med. 2001;345:995-996.  [PubMed]  [DOI]
34.  Perik PJ, Lub-De Hooge MN, Gietema JA, van der Graaf WT, de Korte MA, Jonkman S, Kosterink JG, van Veldhuisen DJ, Sleijfer DT, Jager PL. Indium-111-labeled trastuzumab scintigraphy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol. 2006;24:2276-2282.  [PubMed]  [DOI]
35.  Bennink RJ, van den Hoff MJ, van Hemert FJ, de Bruin KM, Spijkerboer AL, Vanderheyden JL, Steinmetz N, van Eck-Smit BL. Annexin V imaging of acute doxorubicin cardiotoxicity (apoptosis) in rats. J Nucl Med. 2004;45:842-848.  [PubMed]  [DOI]
36.  Panjrath GS, Jain D. Monitoring chemotherapy-induced cardiotoxicity: role of cardiac nuclear imaging. J Nucl Cardiol. 2006;13:415-426.  [PubMed]  [DOI]
37.  Panjrath GS, Patel V, Valdiviezo CI, Narula N, Narula J, Jain D. Potentiation of Doxorubicin cardiotoxicity by iron loading in a rodent model. J Am Coll Cardiol. 2007;49:2457-2464.  [PubMed]  [DOI]
38.  Saito K, Takeda K, Imanaka-Yoshida K, Imai H, Sekine T, Kamikura Y. Assessment of fatty acid metabolism in taxan-induced myocardial damage with iodine-123 BMIPP SPECT: comparative study with myocardial perfusion, left ventricular function, and histopathological findings. Ann Nucl Med. 2003;17:481-488.  [PubMed]  [DOI]
39.  Saito K, Takeda K, Okamoto S, Okamoto R, Makino K, Tameda Y, Nomura Y, Maeda H, Ichihara T, Nakano T. Detection of doxorubicin cardiotoxicity by using iodine-123 BMIPP early dynamic SPECT: quantitative evaluation of early abnormality of fatty acid metabolism with the Rutland method. J Nucl Cardiol. 2000;7:553-561.  [PubMed]  [DOI]
40.  Lee JC, Platts DG, Huang YT, Slaughter RE. Positron emission tomography combined with computed tomography as an integral component in evaluation of primary cardiac lymphoma. Clin Cardiol. 2010;33:E106-E108.  [PubMed]  [DOI]
41.  Kaderli AA, Baran I, Aydin O, Bicer M, Akpinar T, Ozkalemkas F, Yesilbursa D, Gullulu S. Diffuse involvement of the heart and great vessels in primary cardiac lymphoma. Eur J Echocardiogr. 2010;11:74-76.  [PubMed]  [DOI]
42.  Weijs LE, Arsos G, Baarslag HJ, Wittebol S, de Klerk JM. Pericardial involvement in a non-Hodgkin lymphoma patient: coregistered FDG-PET and CT imaging. Eur Heart J. 2007;28:2698.  [PubMed]  [DOI]
43.  Nony P, Guastalla JP, Rebattu P, Landais P, Lievre M, Bontemps L, Itti R, Beaune J, Andre-Fouet X, Janier M. In vivo measurement of myocardial oxidative metabolism and blood flow does not show changes in cancer patients undergoing doxorubicin therapy. Cancer Chemother Pharmacol. 2000;45:375-380.  [PubMed]  [DOI]
44.  Borde C, Kand P, Basu S. Enhanced myocardial fluorodeoxyglucose uptake following Adriamycin-based therapy: Evidence of early chemotherapeutic cardiotoxicity? World J Radiol. 2012;4:220-223.  [PubMed]  [DOI]
45.  Lautamäki R, Tipre D, Bengel FM. Cardiac sympathetic neuronal imaging using PET. Eur J Nucl Med Mol Imaging. 2007;34 Suppl 1:S74-S85.  [PubMed]  [DOI]
46.  Langer O, Halldin C. PET and SPET tracers for mapping the cardiac nervous system. Eur J Nucl Med Mol Imaging. 2002;29:416-434.  [PubMed]  [DOI]
47.  Merlet P, Delforge J, Syrota A, Angevin E, Mazière B, Crouzel C, Valette H, Loisance D, Castaigne A, Randé JL. Positron emission tomography with 11C CGP-12177 to assess beta-adrenergic receptor concentration in idiopathic dilated cardiomyopathy. Circulation. 1993;87:1169-1178.  [PubMed]  [DOI]
48.  Vesalainen RK, Pietilä M, Tahvanainen KU, Jartti T, Teräs M, Någren K, Lehikoinen P, Huupponen R, Ukkonen H, Saraste M. Cardiac positron emission tomography imaging with [11C]hydroxyephedrine, a specific tracer for sympathetic nerve endings, and its functional correlates in congestive heart failure. Am J Cardiol. 1999;84:568-574.  [PubMed]  [DOI]
49.  Hartmann F, Ziegler S, Nekolla S, Hadamitzky M, Seyfarth M, Richardt G, Schwaiger M. Regional patterns of myocardial sympathetic denervation in dilated cardiomyopathy: an analysis using carbon-11 hydroxyephedrine and positron emission tomography. Heart. 1999;81:262-270.  [PubMed]  [DOI]
50.  Popat S, Smith IE. Therapy Insight: anthracyclines and trastuzumab--the optimal management of cardiotoxic side effects. Nat Clin Pract Oncol. 2008;5:324-335.  [PubMed]  [DOI]