Cancer Therapy-Induced Cardiotoxicity-A Metabolic Perspective on Pathogenesis, Diagnosis and Therapy

Abstract

Long-term cardiovascular complications of cancer therapy are becoming ever more prevalent due to increased numbers of cancer survivors. Cancer therapy-induced cardiotoxicity (CTIC) is an incompletely understood consequence of various chemotherapies, targeted anti-cancer agents and radiation therapy. It is typically detected clinically by a reduction in cardiac left ventricular ejection fraction, assessed by echocardiography. However, once cardiac functional decline is apparent, this indicates irreversible cardiac damage, highlighting a need for the development of diagnostics which can detect CTIC prior to the onset of functional decline. There is increasing evidence to suggest that pathological alterations to cardiac metabolism play a crucial role in the development of CTIC. This review discusses the metabolic alterations and mechanisms which occur in the development of CTIC, with a focus on doxorubicin, trastuzumab, imatinib, ponatinib, sunitinib and radiotherapy. Potential methods to diagnose and predict CTIC prior to functional cardiac decline in the clinic are evaluated, with a view to both biomarker and imaging-based approaches. Finally, the therapeutic potential of therapies which manipulate cardiac metabolism in the context of adjuvant cardioprotection against CTIC is examined. Together, an integrated view of the role of metabolism in pathogenesis, diagnosis and treatment is presented.

Keywords: cardioprotection; cardiotoxicity; chemotherapy; heart failure; metabolism.

Figure 1

Overview of metabolic changes within the cardiomyocyte in the pathogenesis of cancer therapy-induced cardiotoxicity. Cartoon representation of some explored targets of cancer therapies, with potential diagnostic techniques and therapeutics highlighted. Doxorubicin (DOX) has been linked to widespread metabolic dysfunction throughout the cell. Doxorubicin, trastuzumab and sunitinib have all been linked to the inhibition of adenosine monophosphate-activated protein kinase (AMPK), leading to downstream metabolic dysfunction. Glucose uptake into cells can be detected by ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) imaging clinically. Circulating TCA cycle metabolites have been detected in patients and proposed as blood biomarkers. ¹³C hyperpolarised magnetic resonance imaging (MRI) has been used to measure the flux through PDH, both preclinically and in patients. Metformin may provide cardioprotection through activation of AMPK. The sodium-glucose cotransporter 2 (SGLT2) inhibitors may provide an alternative cardiac substrate of ketones to avoid bioenergetic failure. Ac-CoA, acetyl-CoA; ANT, adenine nucleotide translocator; CK, creatine kinase; CPT I, carnitine palmitoyltransferase I; Cr, creatine; ER, endoplasmic reticulum; ETC, electron transport chain; FA, fatty acid; FA-CoA, acyl-CoA; FAT, fatty acid transporters; G6P, glucose 6-phosphate; GLUT, glucose transporter; PDH, pyruvate dehydrogenase; PGC-1α, peroxisome proliferator-activated receptor gamma coactivater-1α; PPARα, peroxisome proliferator-activated receptor alpha; ROS, reactive oxygen species.