Doxorubicin exposure significantly reduced the cardiac clearance rate of [3-11C]pyruvate in mice at 4 weeks compared to controls (decay constant 0.00266 vs 0.00409, p=0.0117), indicating impaired pyruvate metabolism.
Does [3-11C]pyruvate PET detect doxorubicin-induced alterations in cardiac pyruvate metabolism in mice?
[3-11C]Pyruvate PET can detect early maladaptive changes in cardiac pyruvate metabolism induced by doxorubicin, offering a potential non-invasive imaging biomarker for anthracycline cardiotoxicity.
Absolute Event Rate: 0.00266% vs 0.00409%
p-value: p=0.0117
Changes in cardiac metabolism typically precede cardiac dysfunction and therefore represent an important target for diagnosis and treatment designed to prevent progression to heart failure, a leading cause of death. Profound changes in pyruvate metabolism, including reduced expression of the mitochondrial pyruvate carrier (MPC), are increasingly recognized as early maladaptive alterations in cardiomyopathies, but no methods currently exist to determine MPC expression in vivo. We exposed mice to doxorubicin (DOX), an anthracycline chemotherapeutic known to perturb pyruvate metabolism, and demonstrated that cardiac tissue levels of MPC decrease within 4 weeks of initial DOX exposure. Using a combination of stable isotope tracing metabolomics, hyperpolarized 1-13Cpyruvate magnetic resonance imaging (MRI), and 3-11Cpyruvate positron emission tomography (PET), we found that loss of MPC and monocarboxylate transporter 1 (MCT1) resulted in decreased utilization of pyruvate for mitochondrial oxidative metabolism and resulted in decreased cardiac carbon-11 clearance. Despite recovery of expression levels of pyruvate transporters, including MPC, 16 weeks after initial DOX exposure, cardiac carbon-11 clearance still trends towards differences between control mice and the mice exposed to this chemotherapeutic. 3-11CPyruvate PET is therefore a promising approach to imaging cardiac pyruvate transport with potential applications to the identification of early maladaptive changes in pyruvate metabolism and monitoring response to therapy.
Lee et al. (Thu,) conducted a other in Doxorubicin-induced cardiotoxicity. Doxorubicin vs. Vehicle/Control was evaluated on Decay constant (k) of [3-11C]pyruvate cardiac clearance from 2 to 10 min post-injection at 4 weeks (p=0.0117). Doxorubicin exposure significantly reduced the cardiac clearance rate of [3-11C]pyruvate in mice at 4 weeks compared to controls (decay constant 0.00266 vs 0.00409, p=0.0117), indicating impaired pyruvate metabolism.