An increase in myocardial 18-fluorodeoxyglucose uptake is associated with left ventricular ejection fraction decline in Hodgkin lymphoma patients treated with anthracycline

Abstract

BackgroundDoxorubicin (DOX)-based chemotherapy for Hodgkin lymphoma (HL) yields excellent disease-free survival, but poses a substantial risk of subsequent left ventricular (LV) dysfunction and heart failure, typically with delayed onset. At the cellular level, this cardiotoxicity includes deranged cardiac glucose metabolism.MethodsBy reviewing the hospital records from January 2008 through December 2016, we selected HL patients meeting the following criteria: ≥ 18 year-old; first-line DOX-containing chemotherapy; no diabetes and apparent cardiovascular disease; 18-fluoro-deoxyglucose positron emission tomography (18FDG-PET) scans before treatment (PETSTAGING), after 2 cycles (PETINTERIM) and at the end of treatment (PETEOT); at least one echocardiography ≥ 6 months after chemotherapy completion (ECHOPOST). We then evaluated the changes in LV 18FDG standardized uptake values (SUV) during the course of DOX therapy, and the relationship between LV-SUV and LV ejection fraction (LVEF), as calculated from the LV diameters in the echocardiography reports with the Teicholz formula.ResultsForty-three patients (35 ± 13 year-old, 58% males) were included in the study, with 26 (60%) also having a baseline echocardiography available (ECHOPRE). LV-SUV gradually increased from PETSTAGING (log-transformed mean 0.20 ± 0.27) to PETINTERIM (0.27 ± 0.35) to PETEOT (0.30 ± 0.41; P for trend < 0.001). ECHOPOST was performed 22 ± 17 months after DOX chemotherapy. Mean LVEF was normal (68.8 ± 10.3%) and only three subjects (7%) faced a drop below the upper normal limit of 53%. However, when patients were categorized by median LV-SUV, LVEF at ECHOPOST resulted significantly lower in those with LV-SUV above than below the median value at both PETINTERIM (65.5 ± 11.8% vs. 71.9 ± 7.8%, P = 0.04) and PETEOT (65.6 ± 12.2% vs. 72.2 ± 7.0%, P = 0.04). This was also the case when only patients with ECHOPRE and ECHOPOST were considered (LVEF at ECHOPOST 64.7 ± 8.9% vs. 73.4 ± 7.6%, P = 0.01 and 64.6 ± 9.3% vs. 73.5 ± 7.0%, P = 0.01 for those with LV-SUV above vs. below the median at PETINTERIM and PETEOT, respectively). Furthermore, the difference between LVEF at ECHOPRE and ECHOPOST was inversely correlated with LV-SUV at PETEOT (P < 0.01, R2 = − 0.30).ConclusionsDOX-containing chemotherapy causes an increase in cardiac 18FDG uptake, which is associated with a decline in LVEF. Future studies are warranted to understand the molecular basis and the potential clinical implications of this observation.

Evidence for a cardiac metabolic switch in patients with Hodgkin's lymphoma

“…Interestingly, these findings were not explained by differences in serum glucose levels or prior chemotherapy, which were in turn associated with a significant decrease in cardiac FDG uptake. 15,16 This increase was associated with a decrease in left ventricular function. Of note, 'metabolic remodelling' and substrate utilization characterize the transition to heart failure.…”

“…3 In line with findings on heart failure, two studies analysing the effects of anthracyclines on FDG uptake in a total of 113 Hodgkin's lymphoma patients found a gradual increase in FDG uptake over time while on anthracycline treatment. 15,16 This increase was associated with a decrease in left ventricular function. 15 Furthermore, a low left ventricular FDG uptake before doxorubicin treatment was associated with the development of chemotherapy-induced cardiotoxicity.…”

“…15,16 This increase was associated with a decrease in left ventricular function. 15 Furthermore, a low left ventricular FDG uptake before doxorubicin treatment was associated with the development of chemotherapy-induced cardiotoxicity. 16 The reason why a low cardiac left ventricular FDG uptake at baseline is associated with the development of chemotherapy-induced cardiotoxicity is yet not quite understood.…”

“…This effect was not linked to systemic cachexia, and alterations in skeletal muscle glucose metabolism were mainly correlated with other factors, such as age and obesity. 15 Furthermore, a low left ventricular FDG uptake before doxorubicin treatment was associated with the development of chemotherapy-induced cardiotoxicity. 13,14 Moreover, metabolic changes towards more glucose uptake were shown to be sufficient to induce cardiac dysfunction.…”

Towards pre-treatment imaging prediction of chemotherapy-related cardiotoxicity

“…The processes that have been evaluated comprise sympathetic innervation through 123 I-MIBG or PET tracers, myocardial cell injury and necrosis through 111 In-antimyosin, apoptosis and cell death through 99m Tc-annexin V, glucose metabolism through 18 F-FDG and fatty acid metabolism through 123 I-BMIPP. 13,14 Despite promising preliminary results in many cases, large-scale clinical studies to translate these techniques to routine clinical use are still pending. Standardization of technical protocols and development of simple and reproducible methods for quantification will be previously needed, and availability and cost issues will also need consideration.…”