A 2013 narrative review provides a comprehensive overview of cyclophosphamide-induced cardiomyopathy, emphasizing its potential for acute, rapidly progressive, and sometimes fatal cardiac toxicity, particularly at high doses. The authors describe proposed mechanisms, including direct myocardial and endothelial injury, inflammation, and hemorrhagic myocarditis, and outline strategies for early detection using echocardiography, electrocardiographic changes, cardiac MRI, and circulating biomarkers such as BNP and cardiac troponins. Management is largely supportive and consistent with standard heart failure therapy, including diuretics, angiotensin-converting enzyme inhibitors, and beta-blockers, with escalation to intensive care, mechanical circulatory support, or extracorporeal membrane oxygenation in severe cases. Limited anecdotal experience with adjunctive therapies, such as ascorbic acid and theophylline, is noted, but the review highlights the lack of robust evidence for targeted cardioprotective interventions. Of note, the use of N-acetylcysteine (NAC) in this context is not discussed within the review. [1]
A 2020 retrospective study conducted in India examined outcomes of haploidentical hematopoietic stem cell transplantation (HSCT) with post-transplant cyclophosphamide (PTCy) in children with Fanconi anemia, a population particularly sensitive to chemotherapy. The study included 19 children undergoing 21 transplants and evaluated engraftment, graft failure, acute and chronic graft-versus-host disease, and regimen-related toxicities. NAC was infused concomitantly during cyclophosphamide in 13 children, and its use was associated with lower rates of mucositis and liver enzyme elevations, suggesting a role in mitigating oxidative tissue injury. While NAC appeared to reduce certain chemotherapy-related toxicities, this study did not assess cardiotoxicity specifically and provides no evidence regarding NAC’s effects on cyclophosphamide-induced cardiac injury. [2]
Several preclinical studies, including animal models and in vitro experiments, have investigated the protective effects of NAC and its amide derivative (NACA) against cyclophosphamide-induced cardiotoxicity and endothelial injury. In mouse and rat models, high doses of cyclophosphamide were associated with oxidative and nitrosative stress, increased cardiac enzymes (CK, LDH, troponins), DNA damage, lipid peroxidation, and impaired antioxidant defenses (GSH, catalase, SOD, glutathione peroxidase). NAC administration ameliorated these biochemical and histologic changes, improved cardiac function markers, and reduced oxidative damage, with one rat model using a dosing regimen of 200 mg/kg intraperitoneally for 5 days prior to cyclophosphamide or 0.2% NAC in feed for 14 days. Though not specific to cardiotoxicity, one investigation utilizing pig models found that N-acetylcysteine reduced cyclophosphamide-induced immunosuppression, liver injury, and oxidative stress; treatment also improved immune cell counts, modulated inflammatory cytokines, and normalized antioxidant and liver enzyme levels. [3], [4], [5], [6]
Mechanistically, NAC/NACA decreased caspase-dependent apoptosis, rebalanced endothelial nitric oxide synthase (eNOS) and arginase I, preserved angiogenic capacity, and scavenged the toxic cyclophosphamide metabolite acrolein. In H9c2 cardiomyocyte cultures, exposure to cyclophosphamide metabolites (4-hydroxy-cyclophosphamide and acrolein) increased reactive oxygen species (ROS) and cytotoxicity, while NAC reduced ROS, decreased acrolein levels, and enhanced aldehyde dehydrogenase (ALDH) activity, mitigating metabolite-induced cell injury. Overall, these findings suggest that oxidative stress and toxic cyclophosphamide metabolites are central to cyclophosphamide-induced cardiotoxicity, and that NAC/NACA has consistent protective effects in both in vivo and in vitro models, supporting its potential as a cardioprotective intervention. However, given the lack of clinical data in humans, the relevance of these findings remains unclear. [3], [4], [5], [6], [7]