As advancements in cancer treatment lead to increased survival rates, the long-term cardiovascular side effects of chemotherapy, particularly anthracyclines used in the treatment of various cancers such as breast cancer, have become a significant concern due to their dose-dependent cardiotoxicity 1.
To effectively address the development of chemotherapy-related cardiotoxicity (CTRCD), it is imperative to gain a comprehensive understanding of the underlying mechanisms. Among the various factors contributing to anthracycline-induced cardiotoxicity, lipid peroxidation of the cell membrane emerges as a primary cause. The generation of reactive oxygen species through iron-dependent pathways is identified as the predominant source of anthracycline-induced cardiotoxicity 5. Research indicates that inhibition of anthracycline exacerbates the production of reactive oxygen species and disrupts mitochondrial biogenesis 20. Willis et al 21 demonstrated subacute anthracycline-induced myocyte atrophy in both mice and humans. MuRF1 (muscle-specific ubiquitin ligase muscle ring finger-1) was required for doxorubicin-induced cardiac atrophy in mice.
In this study, we examined the prophylactic properties of Sac/Val in mitigating Dox-induced cardiotoxicity and elucidated the potential underlying mechanisms. Our findings demonstrate that pre-treatment with Sac/Val can mitigate myocardial inflammation, fibrosis, and apoptosis, while promoting autophagy and improving heart function in mice with Dox-induced cardiotoxicity through modulation of the AMPKα-mTORC1 signaling pathway. These results offer a molecular rationale for the inhibition of apoptosis by Sac/Val via regulation of the AMPKα-mTORC1 signaling pathway in the context of Dox-induced cardiotoxicity.
In the context of cardio-oncology, treatment-induced cardiotoxicity poses a significant risk to patient health. Sac/Val regimens are recommended for managing this complication. A retrospective case study documented successful outcomes with Sac/Val treatment in two individuals with anthracycline-related cardiomyopathy and heart failure with reduced ejection fraction (HFrEF) who had previously shown poor responses to conventional evidence-based medications 22. Both patients experienced improvements in heart failure symptoms, normalization of NT-proBNP levels, and avoided rehospitalization for their condition 22.
In their study, Canale et al. 23 presented a case series involving four patients diagnosed with cancer therapy-related cardiac dysfunction (CTRCD) and severe heart failure with reduced ejection fraction (HFrEF). The patients received Sacubitril/Valsartan (Sac/Val) treatment while wearing an automatic defibrillator until their cardiac function normalized. A subsequent study conducted by researchers in six Spanish hospitals with specialized cardio-oncology clinics followed up on 67 cancer survivors, the majority of whom had received anthracycline-based chemotherapy 24. Among patients with HFrEF, Sac/Val therapy was found to be well-tolerated and associated with improvements in NT-proBNP levels, NYHA functional class, and echocardiographic findings 24. Renato et al.25 reported anthracycline cardiomyopathy was treated with Sac/Val in two clinical cases where symptoms and echocardiographic parameters improved in response to the treatment. Ana et al.26 evaluated ten consecutive patients suffering from cardiotoxicity-related HFrEF were evaluated by comprehensive multiparametric cardiac magnetic resonance (CMR) for the therapeutic effect of Sac/Val. When Sac/Val was administered, LV volumes were markedly reduced and LVEF was significantly improved. NYHA functional class also improved in association with a marked decrease in NT-proBNP concentration 26. LV dysfunction within CTRCD is partly restorable, but this strongly dependeds on timely treatment with Sac/Val 26. After failing to respond to conventional evidence-based drug therapy, Sac/Val was introduced to 28 patients with breast cancer and refractory cardiotoxicity-related HFrEF 27. The NYHA cardiac function grade, six-minute walking distance, LVEF, LV diastolic function, LV end-diastolic diameter, and mitral regurgitation assessment significantly improved after captopril or valsartan was replaced with ARNI. While several small observational studies have found that Sac/Val improves cardiac structure and function in CTRCD patients, large-scale prospective clinical trials are needed to confirm these findings.
Studies on the efficacy of Sac/Val in mitigating doxorubicin-induced cardiotoxicity in animal experimental models are limited. Following administration of doxorubicin, mice exhibited impaired heart function, abnormal mitochondrial structure, and compromised respiratory function, all of which were significantly improved with Sac/Val treatment 11. Additionally, it is suggested that sacubitril/valsartan may enhance dynamin-related protein 1 (Drp1)-mediated mitochondrial dysfunction caused by doxorubicin 11. In a preclinical model of prophylactic treatment, Sacubitril/Valsartan demonstrated efficacy in mitigating oxidative stress damage, inflammation, and apoptosis associated with doxorubicin-induced heart failure and arrhythmia 12. Furthermore, compared to doxorubicin alone, Sacubitril/Valsartan attenuated matrix metalloproteinase (MMP) activity in rats, thereby safeguarding against doxorubicin-induced cardiac systolic dysfunction and left ventricular remodeling 13. Rats administered with Sacubitril/Valsartan exhibited significant amelioration of doxorubicin-induced cardiac dysfunction through the downregulation of endoplasmic reticulum stress and apoptosis-related proteins 14. The mitigation of cardiotoxicity induced by doxorubicin in rat hearts and H9C2 cardiomyocytes was achieved through the reduction of oxidative stress by Sac/Val 15. These findings suggest that the cardiotoxic effects of doxorubicin may have been attenuated by the anti-inflammatory, anti-apoptotic, and antioxidant properties of Sac/Val.
Based on the data presented, it is suggested that the cardiotoxic effects induced by DOX may have been mitigated by the anti-inflammatory, anti-apoptotic, and antioxidant properties 28. Activation of autophagy at a moderate level may support cellular energy and nutrient provision, thereby safeguarding cardiomyocytes 28. Notably, our findings demonstrate for the first time that Sac/Val treatment could ameliorate autophagy suppression in mice with DOX-induced cardiotoxicity.
AMPK, a heterotrimeric enzyme, plays a crucial role in regulating cardiac energy homeostasis 29. The serine/threonine-specific protein kinase, mTOR, consists of two distinct multi-complexes, mTORC1, which is involved in regulating cardiac autophagy in response to oxidative stress 19. The deficiency of soluble epoxide hydrolase has been shown to reduce myocardial lipid accumulation by enhancing AMPK-mTORC mediated autophagy 29. Our study demonstrates that Sac/Val exhibits cardioprotective effects against Dox-induced cardiotoxicity through its anti-apoptotic and de-autophagy properties, which are mediated by the regulation of the AMPKα-mTORC1 signaling pathway.
This study is subject to several limitations. Future research is required to establish the generalizability of the findings in a murine model to human subjects. Moreover, a deeper understanding of anthracycline-induced cardiomyopathy could be achieved through experimentation with human cardiomyocyte models. Additionally, the lack of comparison between Sac/Val and valsartan in the experiments prevents a definitive conclusion regarding whether the beneficial effects of Sac/Val are solely attributed to valsartan or if sacubitril also plays a role.