Novel Therapeutics for Anthracycline Induced Cardiotoxicity

Abstract

Anthracyclines remain an essential component of the treatment of many hematologic and solid organ malignancies, but has important implications on cardiovascular disease. Anthracycline induced cardiotoxicity (AIC) ranges from asymptomatic LV dysfunction to highly morbid end- stage heart failure. As cancer survivorship improves, the detection and treatment of AIC becomes more crucial to improve patient outcomes. Current treatment modalities for AIC have been largely extrapolated from treatment of conventional heart failure, but developing effective therapies specific to AIC is an area of growing research interest. This review summarizes the current evidence behind the use of neurohormonal agents, dexrazoxane, and resynchronization therapy in AIC, evaluates the clinical outcomes of advanced therapy and heart transplantation in AIC, and explores future horizons for treatment utilizing gene therapy, stem cell therapy, and mechanism-specific targets.

Keywords: anthracyclines; cardio-oncology; cardiomyopathy; cardiotoxicity; heart failure.

FIGURE 1

Central illustration. Summary of anthracycline induced cardiotoxicity (AIC) and treatment options. AIC on a cellular level is mediated by cytoplasmic vacuolization, cardiac fibrosis, and myofibril loss and is associated with echocardiographic of decreased systolic function, increased diastolic dysfunction, and decreased global longitudinal strain. Potentially preventative and/or investigational therapies for AIC associated systolic dysfunction include dexrazoxane, neurohormonal pharmacologic therapy, and aerobic exercise. Moderate to end stage therapy considerations include cardiac resynchronization therapy, mechanical circulatory support, and orthotopic heart transplantation. Therapies such as stem cell therapy, gene therapy, and targeting of AIC-specific mechanisms (such as apoptosis, reactive oxygen species production, and inflammation) are under ongoing investigation. Created with BioRender.com.

FIGURE 2

Mechanisms of anthracycline cardiotoxicity and effects of therapies. Mitochondrial effects of anthracycline induced cardiotoxicity include production of reactive oxygen species, calcium dysregulation, impaired mitochondrial biogenesis, and disruption in mitochondrial membrane integrity, leading to release of apoptotic molecules such as bcl-2-associated X protein (Bax). The effects of anthracycline induced cardiotoxicity on nuclei include DNA intercalation and binding to Topoisomerase 2β to cause double stranded DNA breaks. DNA damage releases pro-apoptotic factors such as p53. Anthracyclines increase the expression of pro-inflammatory cytokines such as NF-kB, IL-6, NLRP3, IL-1β, and TNF-α. Proposed therapies have inhibitory effects on inflammation, reactive oxygen species production, DNA damage and apoptosis. Solid lines indicate mechanisms of anthracycline cardiotoxicity and dotted lines indicate mechanisms of proposed therapies. ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BAI1, BAX activation inhibitor 1; Bax, bcl-2-associated X protein; Ca, calcium; Fe2+/3+, iron; IL, interleukin; mPTP, mitochondrial permeability transition pore; mtDNA, mitochondrial DNA; NF-kB, nuclear factor kappa B; NLRP3, NLR family pyrin domain containing 3; ox phos, oxidative phosphorylation; ROS, reactive oxygen species; TNFα, tumor necrosis factor alpha; Top2β, topoisomerase 2β; SGLT2i, sodium glucose cotransporter 2 inhibitor; PI3K, phosphinositide 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin. Created with BioRender.com.

FIGURE 3

Algorithm of clinical management for prevention and treatment of anthracycline induced cardiotoxicity. All patients should undergo baseline cardiovascular risk assessment, including an echocardiogram. Initiation of cardioprotective medications should be considered in patients with increased cardiovascular risk or abnormal baseline LVEF assessment. Patients with high-risk anthracycline therapy due to high dose (250 mg/m² doxorubicin) and concomitant anti-HER2 treatments should undergo serial cardiovascular monitoring during treatment. All patients should undergo post-treatment LVEF monitoring for detection of long-term cardiovascular sequelae. Adapted from ESMO 2020 guidelines (75). ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; BB, beta blocker; CV, cardiovascular; GLS, global longitudinal strain; HF, heart failure; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist. Created with BioRender.com.