Cardiotoxicity of Cancer Treatments: Focus on Anthracycline Cardiomyopathy

Abstract

Significant progress has been made in developing new treatments and refining the use of preexisting ones against cancer. Their successful use and the longer survival of cancer patients have been associated with reports of new cardiotoxicities and the better characterization of the previously known cardiac complications. Immunotherapies with monoclonal antibodies against specific cancer-promoting genes, chimeric antigen receptor T cells, and immune checkpoint inhibitors have been developed to fight cancer cells, but they can also show off-target effects on the heart. Some of these cardiotoxicities are thought to be due to nonspecific immune activation and inflammatory damage. Unlike immunotherapy-associated cardiotoxicities which are relatively new entities, there is extensive literature on anthracycline-induced cardiomyopathy. Here, we provide a brief overview of the cardiotoxicities of immunotherapies for the purpose of distinguishing them from anthracycline cardiomyopathy. This is especially relevant as the expansion of oncological treatments presents greater diagnostic challenges in determining the cause of cardiac dysfunction in cancer survivors with a history of multiple cancer treatments including anthracyclines and immunotherapies administered concurrently or serially over time. We then provide a focused review of the mechanisms proposed to underlie the development of anthracycline cardiomyopathy based on experimental data mostly in mouse models. Insights into its pathogenesis may stimulate the development of new strategies to identify patients who are susceptible to anthracycline cardiomyopathy while permitting low cardiac risk patients to receive optimal treatment for their cancer.

The Role of Mitochondrial Quality Control in Anthracycline-Induced Cardiotoxicity: From Bench to Bedside

“…Secondly, anthracycline treatment promotes oxidative modifications of mitochondrial DNA (mtDNA), suppressing the replication and expression processes. The dose accumulation and reduced transcriptional level of critical respiratory metabolic enzymes lead to decreases in mtDNA copy number and mitochondrial bioenergetic impairment, which presents as reduced ATP production and increased ROS production [74]. Moreover, continuous anthracycline 3 Oxidative Medicine and Cellular Longevity chemotherapy may cause alterations in nuclear epigenetic regulation of critical redox and metabolic genes in cardiomyocytes.…”

Cross-disease communication between cancer and heart failure provides a rational approach to prevention and treatment of both diseases

“…For example, identification of a molecular basis for the downregulation of mitochondrial respiratory capacity in the PBMCs of CHF patients, which we have shown previously ( 24 ), and if such a mechanism occurs specifically in PBMCs but not in tumor cells, improving mitochondrial respiratory capacity in PBMCs may be promising for the treatment of cancer in patients who also have CHF. Such a strategy targeting immune cells’ mitochondria may also enhance tumor growth suppression in cancer treatment by immune checkpoint inhibitors, although cardiac assessment with a careful follow-up is necessary because immune checkpoint inhibitors are known to have a cardiotoxicity with low incidence rate (<1%) with single use of them ( 31 ). Furthermore, activation of immune cells is beneficial for chemotherapy ( 32 ), and thus, mitochondria-targeted treatment strategy may help chemotherapy improve outcomes of cancer patients with or without CHF, although robust clinical evidence is still lacking.…”

Precision Cardio-Oncology: Use of Mechanistic Pharmacokinetic and Pharmacodynamic Modeling to Predict Cardiotoxicities of Anti-Cancer Drugs

“…Conversely, the occurrence of heart failure, which involves both hemodynamic and pathological changes, can be chronic and acute. Additionally, heart failure could also be the consequence of the direct cardio-toxicity of anticancer drugs, such as trastuzumab and anthracyclines ( 19 , 20 ). Therefore, the modeling of heart failure is complicated and specific to a certain class of drugs.…”