Table 2.

Conventional Cancer Therapies and Proposed Mechanisms of Cardiovascular Toxicity

Cancer therapy	Proposed pathways	Reported toxicity	Preclinical models	Unexplored questions
Anthracyclines Doxorubicin Daunorubicin Epirubicin Idarubicin Valrubicin Mitoxantrone	Multiple proposed models: DNA damage (p53) Reactive oxygen species formation DNA damage caused by disruption of Top2β¹⁰ Iron metabolism (ABCB8)¹¹ Autophagy/mitophagy (Beclin, PI3Kγ, BNIP3, p53)^12,27 Calcium signaling Mitochondrial biogenesis HIF signaling AhR/Cyp1²¹ Apoptosis and necrosis (BAX) Induction of inflammatory cytokines	Cardiomyopathy (acute and delayed onset) Arrhythmia Ultrastructural changes on endomyocardial biopsy (myofibrillar loss and disarray, dilation of the sarcoplasmic reticulum, mitochondrial swelling, cytoplasmic vacuolization)	hiPSC-CMs³ Zebrafish⁷ Rodents^12,27 Swine¹⁴	How do proposed mechanistic pathways interact to cause cardiotoxicity? What is the role of vascular dysfunction in anthracycline cardiotoxicity? How can preclinical studies be harnessed to identify novel biomarkers of anthracycline cardiotoxicity in patients? Which molecular pathways are druggable for prevention or treatment of anthracycline cardiotoxicity? What is the genetic basis for interindividual susceptibility to anthracycline cardiotoxicity?
Fluoropyrimidines 5-Flurouracil Capecitabine	DNA via thymidylate synthase Protein kinase C eNOS Metabolism to fluorocitrate, resulting in inhibition of TCA cycle Apoptosis and autophagy	Coronary vasospasm Acute coronary syndrome Cardiomyopathy Arrhythmia Sudden cardiac death Pericarditis	Rodents Rabbits	Which risk factors predispose to endothelial dysfunction and vasospasm?
Alkylating agents Cyclophosphamide Ifosfamide Bendamustine Chlorambucil Cisplatin	Heart fatty acid binding proteins Cardiomyocyte apoptosis Inflammation Endothelial dysfunction Calcium dysregulation Mitochondrial and ER damage Oxidative stress Direct DNA damage	Cardiomyopathy Capillary microthrombosis Arrhythmia Hypotension QT prolongation Pericarditis Supraventricular arrhythmias Diastolic dysfunction	Rodents	What are the genetic or metabolic factors that predispose certain patients to accumulation of toxic metabolites?
Antimicrotubule agents Paclitaxel Docetaxel	DNA damage Histamine release	Cardiomyopathy Hypertension Myocardial infarction Conduction abnormalities (QT prolongation, bradycardia, atrial fibrillation)	Rodents	Which cell types and subcellular organelles are affected by these agents?
Hormonal therapies Androgen deprivation therapy (GnRH agonists, adrenal androgen receptor inhibitors, direct androgen receptor inhibitors)	Modulation of sodium and potassium currents²⁸ Testosterone deficiency²⁹	QT prolongation Arrhythmia Metabolic syndrome Hypertension Vascular events	hiPSC-CMs Rodents Rabbits	Is there a central pathway affected by androgen deprivation that results in hypercholesterolemia, hyperinsulinemia, and obesity? What is the best preclinical model to recapitulate baseline cardiovascular risk factors that predispose to metabolic syndrome? What are the differences between classes of ADT and the risk of cardiovascular toxicity?
Chest radiation	Nuclear and mitochondrial DNA Upregulation of NF-κB Oxidative stress Inhibition of angiogenesis	Accelerated atherosclerosis Dilated or restrictive cardiomyopathy Constrictive pericarditis Microvascular disease Valvular heart disease (stenosis or regurgitation) Conduction system disease Autonomic dysfunction	Rodents³⁰ Rabbits Pigs Dogs	Are there genetic factors that predispose to radiation-induced cardiovascular toxicity? Which specific profibrotic and inflammatory pathways are induced by radiation? What is the best model of long-term cardiac complications of chest radiation? What are new therapeutic approaches to mitigate the cardiovascular toxicity of chest radiation?

ABCB8 indicates ATP-binding cassette subfamily B member 8; ADT, androgen deprivation therapy; AhR, aryl hydrocarbon receptor; BAX, Bcl-2–associated X protein; BNIP3, BCL2/adenovirus E1B 19 kd-interacting protein 3; Cyp1, cytochrome P450 family 1 enzymes; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; GnRH, gonadotropin-releasing hormone; HIF, hypoxia-inducible factor; hiPSC-CMs, human induced pluripotent stem cell–derived cardiomyocytes; NF-κB, nuclear factor-κB; PI3Kγ, phosphoinositide 3-kinase-γ; TCA, tricarboxylic acid cycle; and Top2β, topoisomerase 2β.