Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 1: Definitions, Pathophysiology, Risk Factors, and Imaging

Abstract

Advances in cancer therapy have resulted in significant improvement in long-term survival for many types of cancer but have also resulted in untoward side effects associated with treatment. One such complication that has become increasingly recognized is the development of cardiomyopathy and heart failure. Whether a previously healthy person from a cardiovascular perspective develops cancer therapy-related cardiac dysfunction or a high-risk cardiovascular patient requires cancer therapy, the team of oncologists and cardiologists must be better equipped with an evidence-based approach to care for these patients across the spectrum. Although the toxicities associated with various cancer therapies are well recognized, limitations to our understanding of the appropriate course of action remain. In this first of a 2-part review, we discuss the epidemiologic, pathophysiologic, risk factors, and imaging aspects of cancer therapy-related cardiac dysfunction and heart failure. In a subsequent second part, we discuss the prevention and treatment aspects, concluding with a section on evidence gap and future directions. We focus on adult patients in all stages of cancer therapy from pretreatment surveillance, to ongoing therapy, and long-term follow-up.

Keywords: anthracyclines; cardiomyopathies; cardiotoxicity; chemotherapy; heart failure; trastuzumab; ventricular dysfunction, left.

Figure 1

Pathophysiology of Cardiac Toxicity from Various Chemotherapeutics and Role of Preventative Therapies. Alkylating agents inhibit DNA transcription, impairing protein synthesis. Human epidermal receptor 2 (HER2/ErbB)-targeted therapy inhibits the activation of HER2 resulting in the inhibition of a signal transduction pathway that ultimately impairs DNA transcription. Anthracyclines intercalate into DNA, impairing protein synthesis, generate reactive oxygen species (ROS) resulting in DNA damage as well as inhibit topoisomerase II-beta (Top2B), impairing DNA repair. Taxanes impair microtubule function needed for cell division. Vascular endothelial growth factor (VEGF)-inhibitors blocks the activation of kinases resulting in the downstream inhibition of angiogenesis. Dexrazoxane, an iron-chelating agent may decrease the formation of ROS through prevention of anthracycline-iron complex formation as well as inhibit the formation of Top2B–DNA cleavage complexes which impair DNA repair. Beta-blockers, statins, and angiotensin converting enzyme inhibitors (ACE-I), through anti-oxidant properties, may inhibit the production of ROS. ACE-I’s may decrease angiotensin-induced blockade of the neuregulin-1 (NRG-1)/ErbB pathway. Statins have also been shown to inhibit Top2B–mediated DNA damage. The various cellular effects of these chemotherapy agents may ultimate result in cardiovascular manifestations in the form of left ventricular dysfunction, heart failure, hypertension, and atherosclerosis.