Anthracycline-induced cardiotoxicity: From pathobiology to identification of molecular targets for nuclear imaging

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  FIGURE 1. Current nuclear molecular imaging strategies targeting pathways and cell injury mechanisms activated in anthracycline-induced cardiotoxicity. Nuclear probes studied to date target anthracycline-mediated cardiomyocyte injury mechanisms such as apoptosis, necrosis, reactive oxygen species, and mitochondrial dysfunction; downstream consequences such as cardiac fibrosis; and more global changes such as sympathetic drive, myocardial blood flow, and left ventricular ejection fraction. Bax, Bcl2 associated X protein; Bak, Bcl2 antagonist/killer; Bcl2, B-cell CLL/lymphoma 2; dsDNA, double-stranded DNA; GLUT1, glucose transporter 1; γ-H2AX, phosphorylated histone variant H2AX; MCT, monocarboxylate transporter; ΔΨM, mitochondrial membrane potential; mPTP, mitochondrial permeability transition pore; PS, phosphatidylserine; ROS, reactive oxygen species; Top IIβ, topoisomerase IIβ.

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  FIGURE 2. Additional anthracycline cardiotoxicity mechanisms for the development of novel molecular nuclear probes. Highlighted mechanisms have not yet been targeted using a nuclear imaging strategy, and certain key molecular or biochemical targets are presented for the potential development of new SPECT/PET tracers. (A) Anthracyclines impair autophagy by compromising lysosomal acidification, increasing beclin-1 expression, inhibiting mTOR, and inhibiting transcription factor EB, thereby blocking autophagic flux and causing an accumulation of autolysosomes that leads to increased ROS production. New probes may be developed to target molecules implicated in the accumulation of undegraded autolysosomes. (B) Anthracycline-induced ferroptosis is caused by iron overload through upregulation of TfR, inactivation of ferritin, inhibition of ABC-B8, and downregulation of GPX4, which may be targets for probe development. (C) Anthracycline induces pyroptosis by upregulating TINCR, which increases the expression of NLRP3 and caspase 1 activation. Future probes may for example target NLRP3 or caspase1. ABC-B8, ATP binding cassette subfamily B member 8; Dox, doxorubicin; GPX4, glutathione peroxidase 4;…

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  FIGURE 3. Potential clinical applications of nuclear molecular imaging in predicting and reclassifying cardiotoxicity in cancer patients undergoing anthracycline treatment. Different clinical algorithms may be followed according to the mechanistic pathway targeted for imaging – whether expression of cardiac injury related proteins, or alternatively activation of cardioprotective pathways – and the presence or absence of abnormal echocardiographic features suggestive of cardiotoxicity. (A) Molecular imaging may be used to predict the risk of developing cardiotoxicity during and/or following anthracycline treatment in patients with a normal echocardiogram. (B) In patients with an abnormal echocardiogram suggesting a new impairment in cardiac function, molecular imaging may be able to finetune the cardiotoxicity diagnosis with implications on the duration of anthracycline-induced cardiac dysfunction, or to reclassify the echocardiographic diagnosis, thereby providing oncologists and cardiologists greater diagnostic certainty with ensuing clinical implications.