Remarkable progress has been made in the development of new therapies for cancer, dramatically changing the landscape of treatment approaches for several malignancies and continuing to increase patient survival. Accordingly, adverse effects of cancer therapies that interfere with the continuation of best-possible care, induce life-threatening risks or lead to long-term morbidity are gaining increasing importance. Cardiovascular toxic effects of cancer therapeutics and radiation therapy are the epitome of such concerns, and proper knowledge, interpretation and management are needed and have to be placed within the context of the overall care of individual patients with cancer. Furthermore, the cardiotoxicity spectrum has broadened to include myocarditis with immune checkpoint inhibitors and cardiac dysfunction in the setting of cytokine release syndrome with chimeric antigen receptor T cell therapy. An increase in the incidence of arrhythmias related to inflammation such as atrial fibrillation can also be expected, in addition to the broadening set of cancer therapeutics that can induce prolongation of the corrected QT interval. Therefore, cardiologists of today have to be familiar not only with the cardiotoxicity associated with traditional cancer therapies, such as anthracycline, trastuzumab or radiation therapy, but even more so with an ever-increasing repertoire of therapeutics. This Review provides this information, summarizing the latest developments at the juncture of cardiology, oncology and haematology.

Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia

Molecular mechanism involved in cyclophosphamide-induced cardiotoxicity: Old drug with a new vision

Investigation of the effect of hepatic metabolism on off-target cardiotoxicity in a multi-organ human-on-a-chip system.

The dose-limiting toxic effect of cyclophosphamide (CY) is cardiotoxicity. The pathogenesis of myocardial damage is poorly understood, and there is no established means of prevention. In previous studies, we suggested that for CY-induced cardiotoxicity, whereas acrolein is the key toxic metabolite, carboxyethylphosphoramide mustard (CEPM) is protective. We sought to verify that acrolein is the main cause of cardiotoxicity and to investigate whether aldehyde dehydrogenase (ALDH), which is associated with greater CEPM production, is involved in the protective effect for cardiotoxicity. We also evaluated the protective effect of N-acetylcysteine (NAC), an amino acid with antioxidant activity and a known acrolein scavenger. H9c2 cells were exposed to CY metabolites HCY (4-hydroxy-cyclophosphamide), acrolein or CEPM. The degree of cytotoxicity was evaluated by MTT assay, lactate dehydrogenase (LDH) release, and the production of reactive oxygen species (ROS). We also investigated how the myocardial cellular protective effects of CY metabolites were modified by NAC. To quantify acrolein levels, we measured the culture supernatants using high performance liquid chromatography. We measured ALDH activity after exposure to HCY or acrolein and the same with pre-treatment with NAC. Exposure of H9c2 cells to CEPM did not cause cytotoxicity. Increased ROS levels and myocardial cytotoxicity, however, were induced by HCY and acrolein. In cell cultures, HCY was metabolized to acrolein. Less ALDH activity was observed after exposure to HCY or acrolein. Treatment with NAC reduced acrolein concentrations. Increased ROS generation and decreased ALDH activity confirmed that CY metabolites HCY and acrolein are strongly implicated in cardiotoxicity. By inhibiting ROS generation, increasing ALDH activity and decreasing the presence of acrolein, NAC has the potential to prevent CY-induced cardiotoxicity.

https://link.springer.com/content/pdf/10.1186%2Fs13104-017-2726-2.pdf

Role of metabolites of cyclophosphamide in cardiotoxicity

Protective effects of silymarin and curcumin on cyclophosphamide-induced cardiotoxicity.

Cyclophosphamide is increasingly used to treat various types of cancers and autoimmune conditions. Higher doses of this drug may produce significant cardiac toxicity, including fatal hemorrhagic myocarditis. In this review, we present a case of cyclophosphamide-induced cardiomyopathy requiring mechanical circulatory support. We also describe the pathophysiology, clinical manifestations, and risk factors for this important clinical entity and propose early detection and management strategies.

https://journals.sagepub.com/doi/pdf/10.1177/2324709613480346

Michael P. Chu

Papers

Cyclophosphamide-Induced Cardiomyopathy: A Case Report, Review, and Recommendations for Management