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

Abstract

Background: Doxorubicin (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.

Methods: By 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 (PET^STAGING), after 2 cycles (PET^INTERIM) and at the end of treatment (PET^EOT); at least one echocardiography ≥ 6 months after chemotherapy completion (ECHO^POST). 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.

Results: Forty-three patients (35 ± 13 year-old, 58% males) were included in the study, with 26 (60%) also having a baseline echocardiography available (ECHO^PRE). LV-SUV gradually increased from PET^STAGING (log-transformed mean 0.20 ± 0.27) to PET^INTERIM (0.27 ± 0.35) to PET^EOT (0.30 ± 0.41; P for trend < 0.001). ECHO^POST 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 ECHO^POST resulted significantly lower in those with LV-SUV above than below the median value at both PET^INTERIM (65.5 ± 11.8% vs. 71.9 ± 7.8%, P = 0.04) and PET^EOT (65.6 ± 12.2% vs. 72.2 ± 7.0%, P = 0.04). This was also the case when only patients with ECHO^PRE and ECHO^POST were considered (LVEF at ECHO^POST 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 PET^INTERIM and PET^EOT, respectively). Furthermore, the difference between LVEF at ECHO^PRE and ECHO^POST was inversely correlated with LV-SUV at PET^EOT (P < 0.01, R² = - 0.30).

Conclusions: DOX-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.

Keywords: 18FDG-PET; Cardiotoxicity; Doxorubicin; Heart failure; Left ventricular dysfunction.

Fig. 1

Study design and stages of anthracycline cardiotoxicity. A schematic of the timing of the ¹⁸FDG positron emission tomography (¹⁸FDG-PET) scans and echocardiograms taken into analysis is depicted in the upper panel, while the corresponding stages of anthracycline-related cardiotoxicity are presented in the lower part. DOX: doxorubicin-containing chemotherapy; ECHO^PRE: echocardiography at baseline (available only in a subgroup of patients); ECHO^POST: echocardiography after completion of DOX chemotherapy; PET^STAGING: ¹⁸FDG-PET before treatment; PET^INTERIM: ¹⁸FDG-PET after 2 cycles of doxorubicin; PET^EOT: ¹⁸FDG-PET at the end of treatment; LV: left ventricular

Fig. 2

¹⁸FDG uptake during doxorubicin treatment in the myocardium and in the longissimus thoracis muscle. Boxes are median and interquartile ranges of left ventricular and skeletal muscle ¹⁸FDG standardized uptake values (SUV) at the indicated ¹⁸FDG positron emission tomography (¹⁸FDG-PET) scans. Vertical bars indicate the highest and lowest SUV at each time point. Repeated measures ANOVA P for trend = 0.0007 and 0.02 for SUV in the heart and longissimus thoracis, respectively. STAGING: ¹⁸FDG-PET before treatment; INTERIM: ¹⁸FDG-PET after 2 cycles of doxorubicin; EOT: ¹⁸FDG-PET at the end of treatment

Fig. 3

Left ventricular ejection fraction according to categories of ¹⁸FDG uptake in patients with echocardiography at follow-up. Left ventricular ejection fraction (LVEF), as assessed by echocardiography performed after completion of anthracycline chemotherapy, in patients with myocardial ¹⁸FDG standardized uptake values (LV-SUV) below or above the median value (low and high, respectively) measured at each ¹⁸FDG positron emission tomography (¹⁸FDG-PET) scan. For each PET time point, LVEF was compared between patients with LV-SUV below vs. above the median value by unpaired t-test. * indicates P < 0.05. LV-SUV^STAGING: LV-SUV at the ¹⁸FDG-PET scan before treatment; LV-SUV^INTERIM: LV-SUV at the ¹⁸FDG-PET performed after 2 cycles of doxorubicin; LV-SUV^EOT: LV-SUV at the ¹⁸FDG-PET performed at the end of chemotherapy

Fig. 4

Left ventricular ejection fraction according to categories of ¹⁸FDG uptake in patients with echocardiography at both baseline and follow-up. Left ventricular ejection fraction (LVEF) at the baseline and follow-up echocardiography (LVEF^PRE and LVEF^POST, respectively) in patients with myocardial ¹⁸FDG standardized uptake values (LV-SUV) below or above the median value (low and high, respectively) at each ¹⁸FDG positron emission tomography (¹⁸FDG-PET) scan. LVEF was compared between patients with LV-SUV below vs. above the median value at each PET time point by unpaired t-test and * is P < 0.05. LVEF^PRE and LVEF^POST for each subgroup of patients with LV-SUV below or above the median value (e.g. LVEF^PRE and LVEF^POST in subjects with high LV-SUV at EOT) were compared by paired t-test; § and # indicate P < 0.05 and < 0.01, respectively. LV-SUV^STAGING: LV-SUV at the ¹⁸FDG-PET scan before treatment; LV-SUV^INTERIM: LV-SUV at the ¹⁸FDG-PET performed after 2 cycles of doxorubicin; LV-SUV^EOT: LV-SUV at the ¹⁸FDG-PET performed at the end of chemotherapy

Fig. 5

Relationship between left ventricular ejection fraction change and ¹⁸FDG uptake in the subsets of patients with baseline and follow-up echocardiography data available. LVEF: left ventricular ejection fraction; LV-SUV^EOT: LV ¹⁸FDG standardized uptake value at positron emission tomography performed at the end of anthracycline chemotherapy