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

doi:10.1067/mnc.2000.108351

Journal of Nuclear Cardiology

Volume 7, Issue 6, November 2000, Pages 553-561

https://doi.org/10.1067/mnc.2000.108351 Get rights and content

Abstract

Background. To evaluate the possibility of predicting the development of doxorubicin-induced cardiomyopathy, we performed quantitative assessment of the early kinetics of iodine-123 beta-methyl-iodophenyl-pentadecanoic acid (I-123 BMIPP) by means of dynamic myocardial SPECT. Methods. Thirty-six patients with various malignancies were examined. I-123 BMIPP dynamic myocardial SPECT was performed before chemotherapy, after chemotherapy, or both. Immediately after the injection of I-123 BMIPP (111 MBq), 30-second dynamic SPECT data were acquired successively for 15 minutes. The left ventricular (LV) myocardium was divided into 8 segments in short-axial and vertical slices. By using the time-activity curve (TAC) of each myocardial segment [Mo(t) as an output function and the TAC of the LV cavity [B(t)] as an input function, the Rutland equation, Mo(t)/B(t) = F + K ∫B(t) dt/B(t), was used as a means of assessing all segments. Results. Mo(t)/B(t) showed a good linear correlation with ∫B(t) dt/B(t) from 30 seconds to 4 minutes in all 456 segments. The mean K value of 8 LV segments was significantly lower after chemotherapy than before chemotherapy (0.071 ± 0.019 [n = 21] vs 0.095 ± 0.025 [n = 36], P < .001). In 21 patients in whom dynamic SPECT was performed both before and after chemotherapy, the mean K values of left ventricle showed a significant decrease, from 0.101 ± 0.024 to 0.071 ± 0.019 (P < .0001). The fractional change in the value of K after chemotherapy showed a significant linear correlation with the administered dose of doxorubicin (r = 0.648, P < .002). Conclusion. I-123 BMIPP dynamic myocardial SPECT may be clinically useful, because it permits the early detection of doxorubicin-induced cardiomyopathy. (J Nucl Cardiol 2000;7:553-61.)

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Cited by (27)

Activation recovery interval as an electrocardiographic repolarization index to detect doxorubicin-induced cardiotoxicity
2023, Journal of Cardiology
It has been reported that early detection and treatment of cancer therapy- related cardiac dysfunction (CTRCD) improves its prognosis. The detailed relationships between electrocardiographic repolarization indices and decreased left ventricular function in CTRCD have not been elucidated. We closely assessed such relationships in patients with doxorubicin (DOX)-induced CTRCD.
This retrospective, single-center, cohort study included 471 consecutive patients with malignant lymphoma who received chemotherapy including DOX. Of them, 17 patients with CTRCD and 68 patients without CTRCD who underwent 12‑lead electrocardiogram and an echocardiogram before and after chemotherapy were eventually analyzed. The fluctuations of the following electrocardiographic repolarization indices were evaluated in lead V5: QT, JT, T peak to T end interval (Tp-e), and activation recovery interval (ARI). These indices were corrected by heart rate with the Fridericia formula.
The median period from the end of chemotherapy to the diagnosis of the CTRCD group was 346 days (IQR 170–1283 days). After chemotherapy, the QT interval was significantly prolonged in both with and without CTRCD groups compared with that before chemotherapy (pre QTc vs. post QTc in CTRCD group, 386 ± 27 ms vs. 411 ± 37 ms, p = 0.03, pre QTc vs. post QTc in non-CTRCD group, 388 ± 24 ms vs. 395 ± 25 ms, p = 0.04, respectively). ARIc after chemotherapy was characteristically observed only in the CTRCD group (pre ARIc vs. post ARIc in CTRCD group, 258 ± 53 ms vs. 211 ± 28 ms, p = 0.03, pre ARIc vs. post ARIc in non-CTRCD group, 221 ± 19 ms vs. 225 ± 23 ms, NS, respectively) and had negative correlations with left ventricular ejection fraction (r = −0.56, p < 0.001). Using the receiver-operating characteristic curve, the relationship between ARIc and CTRCD morbidity was examined. The optimal cut-off point of ARIc prolongation between before and after chemotherapy was 18 ms (sensitivity 75 %, specificity 79 %, area under the curve 0.76).
ARIc prolongation may be useful in the early detection of developing late-onset chronic DOX-induced CTRCD and lead to early treatment for cardiac protection.
Computed Tomographic Angiography Assessment of Epicardial Coronary Vasoreactivity for Early Detection of Doxorubicin-Induced Cardiotoxicity
2020, JACC: CardioOncology
Citation Excerpt :
Cardiac magnetic resonance imaging has also been tested in animal models (36,37), and T2-weighted imaging to detect edema and T1-weighted imaging to identify early fibrosis have been applied to patients receiving anthracyclines (38), but results have been mixed. In addition, several nuclear imaging approaches have shown promise in preclinical and small clinical studies, such as tracers targeting apoptosis (39), reactive oxygen species production (24), altered fatty acid oxidation (40), and altered sympathetic innervation (41), but these findings have yet to be confirmed in larger clinical studies. To our knowledge, our study is the first to use a CTA approach for the early detection of DOX-induced cardiotoxicity.
The vascular endothelium is a novel target for the detection, management, and prevention of doxorubicin (DOX)-induced cardiotoxicity.
The study aimed to: 1) develop a methodology by computed tomography angiography (CTA) to evaluate stress-induced changes in epicardial coronary diameter; and 2) apply this to a chronic canine model of DOX-induced cardiotoxicity to assess vascular toxicity.
To develop and validate quantitative methods, sequential retrospectively gated coronary CTAs were performed in 16 canines. Coronary diameters were measured at prespecified distances during rest, adenosine (ADE) (280 μg/kg/min), rest 30 min post-ADE, and dobutamine (DOB) (5 μg/kg/min). A subgroup of 8 canines received weekly intravenous DOX (1 mg/kg) for 12 to 15 weeks, followed by rest-stress CTA at cumulative doses of ∼4-mg/kg (3 to 5 mg/kg), ∼8-mg/kg (7 to 9 mg/kg), and ∼12-mg/kg (12 to 15 mg/kg) of DOX. Echocardiograms were performed at these timepoints to assess left ventricular ejection fraction and global longitudinal strain.
Under normal conditions, epicardial coronary arteries reproducibly dilated in response to ADE (left anterior descending coronary artery [LAD]: 12 ± 2%, left circumflex coronary artery [LCx]: 13 ± 2%, right coronary artery [RCA]: 14 ± 2%) and DOB (LAD: 17 ± 3%, LCx: 18 ± 2%, RCA: 15 ± 3%). With DOX, ADE vasodilator responses were impaired after ∼4-mg/kg (LAD: –3 ± 1%, LCx: 0 ± 2%, RCA: –5 ± 2%) and ∼8-mg/kg (LAD: –3 ± 1%, LCx: 0 ± 1%, RCA: –2 ± 2%). The DOB dilation response was preserved at ∼4-mg/kg of DOX (LAD: 18 ± 4%, LCx: 11 ± 3%, RCA: 11 ± 2%) but tended to decrease at ∼8-mg/kg of DOX (LAD: 4 ± 2%, LCx: 8 ± 3%, RCA: 3 ± 2%). A significant left ventricular ejection fraction reduction was observed only at 12 to 15 mg/kg DOX (baseline: 63 ± 2%, 12-mg/kg: 45 ± 3%). Global longitudinal strain was abnormal at ∼4-mg/kg of DOX (p = 0.011).
CTA can reliably assess epicardial coronary diameter in response to pharmacological stressors, providing a noninvasive functional index of coronary vasoreactivity. Impaired epicardial vasodilation occurs early in DOX-induced cardiotoxicity.
In Vivo Reactive Oxygen Species Detection With a Novel Positron Emission Tomography Tracer, <sup>18</sup>F-DHMT, Allows for Early Detection of Anthracycline-Induced Cardiotoxicity in Rodents
2018, JACC: Basic to Translational Science
Citation Excerpt :
Magnetic resonance imaging has also been applied for evaluation of early myocardial edema and/or inflammation (T2-weighted imaging) and early cardiac fibrosis/extracellular volume changes (T1-weighted imaging) in the setting of cardiotoxic chemotherapy agents (10,43); however, the utility of these magnetic resonance indices remains controversial due to conflicting reports (43,44). A few studies have proposed radiotracer-based molecular imaging methods as highly sensitive diagnostic tools for early detection of cardiotoxicity, because these methods are able to directly target molecular (apoptosis, 99mTc-annexin V), metabolic (fatty acid oxidation, 123I-beta-methyl-p-iodo-phenyl-pentadecanoic acid), and physiological (sympathetic denervation, 123I-metaiodobenzylguanidine) alterations associated with the underlying disease pathophysiology and progression (45–47). Along these lines, we hypothesized that 18F-DHMT PET imaging of in vivo ROS production may be valuable for early detection of DOX-induced cardiotoxicity, because increased ROS production plays a critical role in DOX-induced cardiotoxicity.
Reactive oxygen species (ROS) are involved in doxorubicin-induced cardiotoxicity. The authors investigated the efficacy of ¹⁸F-DHMT, a marker of ROS, for early detection of doxorubicin-induced cardiotoxicity in rats. Echocardiography was performed at baseline and 4, 6, and 8 weeks post-doxorubicin initiation, whereas in vivo superoxide production was measured at 4 and 6 weeks with ¹⁸F-DHMT positron emission tomography. Left ventricular ejection fraction (LVEF) was not significantly decreased until 6 weeks post-doxorubicin treatment, whereas myocardial superoxide production was significantly elevated at 4 weeks. ¹⁸F-DHMT imaging detected an elevation in cardiac superoxide production before a fall in LVEF in rodents and may allow for early cardiotoxicity detection in cancer patients.
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Cardiotoxicity represents a frequent complication secondary to the intake of some classes of chemotherapeutic agents, with significant consequences on patients’ outcome. The majority of studies on cardiotoxicity focus on patients treated with anthracyclines and trastuzumab, but cardiotoxic effect has been described for classes of drugs such as inhibitors of tyrosine kinases, inhibitors of vascular endothelial growth factor or multikinase inhibitors (imatinib, dasatinib, nilotinib, sunitinib, sorafenib, and bevacizumab), antimetabolites (5-fluorouracil), alkylating agents (cisplatin, cyclophosphamide), and taxanes (docetaxel and paclitaxel). Radiotherapy (RT), that is often associated with standard chemotherapy treatment, is also associated with cardiotoxicity appearing as (acute) myocardial infarction, pericardial disease, valvular heart disease, and heart failure. The incidence of late irradiation-induced cardiac disease depends on the irradiated volume, total irradiation dose, dose per fraction, and on the presence or absence of preexisting cardiovascular risk factors. Irradiation of the mediastinum with a cumulative dose >30 Gy and a daily fractioning >2 Gy appeared to be related to a high risk of developing cardiac dysfunction. Two groups of patients, i.e., those suffering from Hodgkin’s disease and breast cancer, are particularly at risk of developing late myocardial damage, since RT treatment techniques for both patient groups may include (large) parts of the heart, and adjuvant systemic therapy, in particular anthracycline-containing chemotherapy, is frequently administered to these patient.
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2014, JACC: Cardiovascular Imaging
Citation Excerpt :
Myocardial fatty acid metabolism assessed with the SPECT radiotracers IPPA [15-(p-iodophenyl) pentadecanoic acid] and BMIPP (123I-betamethyl-p-iodophenyl pentadecanoic acid) have been measured in subjects receiving anthracycline and other chemotherapeutic agents. A study by Saito et al. (104,105) demonstrated early decreased uptake of 123I-BMIPP in patients with preserved LV function after treatment with an anthracycline; similar decreases in 123I-BMIPP uptake were observed in patients experiencing a decline in LVEF after receipt of a taxane and carboplatin. Recently, Carboni et al. (106) evaluated mitochondrial metabolism with 99mTc-sestamibi in patients receiving multiagent chemotherapy.
The introduction of multiple treatments for cancer, including chemotherapeutic agents and radiation therapy, has significantly reduced cancer-related morbidity and mortality. However, these therapies can promote a variety of toxicities, among the most severe being the ones involving the cardiovascular system. Currently, for many surviving cancer patients, cardiovascular (CV) events represent the primary cause of morbidity and mortality. Recent data suggest that CV injury occurs early during cancer treatment, creating a substrate for subsequent cardiovascular events. Researchers have investigated the utility of noninvasive imaging strategies to detect the presence of CV injury during and after completion of cancer treatment because it starts early during cancer therapy, often preceding the development of chemotherapy or cancer therapeutics related cardiac dysfunction. In this State-of-the-Art Paper, we review the utility of current clinical and investigative CV noninvasive modalities for the identification and characterization of cancer treatment-related CV toxicity.
Détection et prévention des complications cardiaques des chimiothérapies anticancéreuses
2012, Archives of Cardiovascular Diseases
Citation Excerpt :
By inhibiting the microtubular transport system, the taxanes paclitaxel and docetaxel impair storage of free fatty acid in the cytosolic lipid pool of cardiomyocytes, resulting in reduced mitochondrial uptake of free fatty acids. Myocardial perfusion scintigraphy with 123I-methylpentadecanoic acid (123I-BMIPP), a tracer of free fatty acids, has proven effective in the detection of early myocardial dysfunction associated with taxane administration, especially when taxanes are combined with carboplatin [47]. More sophisticated radionuclide imaging techniques provide potentially useful information.
Despite continuous improvements in management of patients with cancer, cardiac side-effects still account for a substantial limitation of chemotherapy. Evaluation of cardiac toxicity in patients includes consideration of biomarkers such as cardiac troponins and B-type natriuretic peptides, together with non-invasive imaging in the form of 2D-, 3D-, or strain-echocardiography, multiple gated radionuclide angiography, quantitative gated blood-pool SPECT, ¹²³I-metaiodobenzylguanidine scintigraphy, or cardiac magnetic resonance imaging. These approaches differ from each other with regards to availability, accuracy, sensitivity to detect early stages of cardiac injury, individual reliability, ease of use in a longitudinal follow-up perspective, and to related cost-effectiveness. Improving prevention of these cardiac side-effects depends on several, currently unresolved issues. Early detection and quantification of cardiac damage is required to adapt chemotherapy in progress for optimal management of patients. Whether increased availability of myocardial strain imaging and repeat blood biomarkers determinations will reliably and consistently achieve these goals remain to be confirmed. Also, protective approaches to reduce cardiac toxicity of anticancer drugs should be reconsidered according to the recently restricted approval for use of dexrazoxane. Anthracycline-based regimens, encapsulated anthracyclines and non-anthracycline regimens should be revisited with regards to antitumour efficacy and cardiac toxicity. Cardiovascular drugs that proved effective in prevention of anthracycline-induced cardiac toxicity in experimental models should be investigated in clinical trials. Finally, the efficacy of cardiovascular drugs that have already been tested in clinical settings should be confirmed and compared with each other in patients in increased numbers.
Malgré les progrès de la prise en charge des malades atteints de cancer, les effets secondaires cardiaques des chimiothérapies restent un facteur limitant non négligeable. L’évaluation de la cardiotoxicité en cours de constitution fait appel aux biomarqueurs, troponines et peptides natriurétiques, ainsi qu’à l’imagerie non invasive, échocardiographie 2D, 3D, de strain, ventriculographie isotopique, tomographie d’émission de positons, scintigraphie à la métaiodobenzylguanidine-¹²³I (MIBG) ou à l’IRM. Chacune de ces méthodes se distingue par sa disponibilité, sa précision, la sensibilité de détection des lésions cardiaques débutantes, sa reproductibilité, sa simplicité d’emploi dans le cadre d’une surveillance clinique et son rapport coût–efficacité. Améliorer la prévention de cette cardiotoxicité nécessite de pouvoir surmonter les contraintes actuelles. La détection précoce et la quantification des lésions cardiaques débutantes sont un pré-requis à l’optimisation des traitements en cours, mais il n’est pas encore certain que le développement rapide de l’échographie de strain et le recours régulier aux biomarqueurs permettront d’atteindre pleinement ces objectifs. Ce d’autant que nos méthodes de cardioprotection devront être revues, en aval de la récente restriction d’emploi du dexrazoxane, qui impacte sur les protocoles de chimiothérapies à base d’anthracyclines, encapsulées ou non, ou sur leurs alternatives, en fonction des cancers et des malades traités. Un certain nombre de médicaments qui ont montré une efficacité dans cette prévention sur des modèles expérimentaux devront être étudiés dans le cadre d’essais cliniques, en particulier les médicaments cardiovasculaires déjà utilisés dans d’autres indications et dont la cardioprotection a pu être documentée sur des études préliminaires. Leurs résultats devront être confirmés et comparés entre eux dans des études à plus grande échelle.

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Original ArticlesDetection of doxorubicin cardiotoxicity by using iodine-123 BMIPP early dynamic SPECT: Quantitative evaluation of early abnormality of fatty acid metabolism with the Rutland method

Abstract

Original Articles
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