Neprilysin Inhibition in the Prevention of Anthracycline-Induced Cardiotoxicity

Simple Summary Anthracycline-induced cardiotoxicity (AIC) poses a significant clinical challenge in the management of cancer patients. Thus, the development of effective preventive measures for AIC is a heavily studied subject in the field of cardio-oncology. A new class of agents, namely angiotensin receptor/neprilysin inhibitors (ARNi; sacubitril/valsartan), recently incorporated into the management of heart failure with reduced ejection fraction, were found to possess robust cardioprotective effects in preclinical models of a wide range of cardiovascular pathologies. This review discusses the cardioprotective mechanisms of action of sacubitril/valsartan in relation to the pathophysiologic processes involved in the cardiotoxicity of anthracyclines: myocardial remodeling, cardiomyocyte DNA damage, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, inflammatory response, and renin-angiotensin-aldosterone system dysregulation. Additionally, the available data on the effectiveness of sacubitril/valsartan administration in the prevention of AIC were summarized. Several reports on sacubitril/valsartan administration in animal models of AIC published at the time of writing have shown promising results, as ARNi prevented anthracycline-induced myocardial systolic dysfunction and remodeling by alleviating oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and the inflammatory response. Human data remain limited—an ongoing PRADAII trial, aimed to assess the efficacy of sacubitril/valsartan in patients receiving chemotherapy for breast cancer, is expected to be completed in 2025. Abstract Anthracycline-induced cardiotoxicity (AIC) poses a clinical challenge in the management of cancer patients. AIC is characterized by myocardial systolic dysfunction and remodeling, caused by cardiomyocyte DNA damage, oxidative stress, mitochondrial dysfunction, or renin-angiotensin-aldosterone system (RAAS) dysregulation. In the past decade, after positive results of a PARADIGM-HF trial, a new class of drugs, namely angiotensin receptor/neprilysin inhibitors (ARNi), was incorporated into the management of patients with heart failure with reduced ejection fraction. As demonstrated in a variety of preclinical studies of cardiovascular diseases, the cardioprotective effects of ARNi administration are associated with decreased oxidative stress levels, the inhibition of myocardial inflammatory response, protection against mitochondrial damage and endothelial dysfunction, and improvement in the RAAS imbalance. However, data on ARNi’s effectiveness in the prevention of AIC remains limited. Several reports of ARNi administration in animal models of AIC have shown promising results, as ARNi prevented ventricular systolic dysfunction and electrocardiographic changes and ameliorated oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, and the inflammatory response associated with anthracyclines. There is currently an ongoing PRADAII trial aimed to assess the efficacy of ARNi in patients receiving breast cancer treatment, which is expected to be completed by late 2025.