**3. Cancer Treatment-Induced Cardiovascular Toxicity**

The two major causes of death worldwide, accounting for approximately 50% of all deaths, are cancer and cardiovascular disease [61]. Recent cancer treatment strategies have improved patient survival rates. Nonetheless, many cancer therapies have undesired deleterious side effects on the cardiovascular system [62,63]. For example, breast cancer survivors have been shown to be at a significantly higher risk of death due to cardiovascular disease, outweighing the mortality risk of the original cancer or its recurrence [64]. Through an interdisciplinary approach involving cardiologists and oncologists, the cardio-oncology field is working to develop optimal strategies for patients with cardiovascular disease or risk factors from cancer diagnosis throughout the rest of their lives, even after treatment ends. Heart failure, myocardial ischemia, and myocardial infarction are just a few of the conditions that fall under the umbrella term "cardiotoxicity", which also covers a wide range of other conditions. Increasing therapeutic effectiveness has increased cancer patient survival; however, the long-term cardiovascular effects of these therapies have gained clinical significance. With more than 3.5 million breast cancer survivors in the US, both conventional chemotherapy (such as anthracyclines and radiotherapy) and targeted medicines (such as HER2 inhibitors and CDK4/6 inhibitors) have significantly improved patient care. Since then, cardiovascular disease has overtaken other conditions as the main killer and morbidity factor in this group [65,66]. Owing to their well-known cardiovascular side effects and comparatively high incidence of heart failure, anthracyclines have been the most extensively researched medication for decades [67]. Hoffmann et al. [68] reported that doxorubicin and trastuzumab treatment of nude mice in an orthotopic mouse model of human breast cancer led to a cardiovascular defect. In order to effectively treat cancer, new strategies are urgently needed to prevent potential cardiovascular diseases. Changes may occur years after therapy is over, and may be abrupt or persistent [69].

### **4. Gut Microbiota and Cardiovascular Toxicity**

Heart failure has long been associated with impaired intestinal barrier function, which leads to gut dysbiosis and bacterial translocation [70–72]. Interestingly, the gut microbiome is increasingly reported to influence cancer development and progression in different ways [73]; for example, on one hand, several types of cancers result in altered gut microbiota, whereas the efficacy of cancer therapies, chemo- and immunotherapy, for example, is found to be strongly influenced by microbiome composition [74,75]. The chemo–gut study, a cross-sectional survey exploring physical, mental, and gastrointestinal health outcomes in cancer survivors, has recently provided novel insights into the strong association between chemotherapy and chronic, moderate-to-severe gastrointestinal symptoms lasting for years after cancer treatment, which are associated with worse mental and physical health [76,77]. Thus, is the gut microbiome a common link between cancer therapy and cardiotoxicity? The answer to this question is still not clear, due to the lack of concrete data on the relationship among microbiota, vascular damage, and heart failure in cancer patients after therapy; however, a few recent studies have suggested that the postulated link is not far-fetched. For example, Huang et al. [78] and Liu et al. [79] have recently shown that an imbalance in the gut microbiome composition and its functional alterations are likely to be among the major etiological mechanisms underlying doxorubicin-induced cardiotoxicity. Importantly, Huang et al. [78] showed that the gut dysbiosis due to doxorubicin contributes to the development of cardiotoxicity, by altering doxorubicin metabolism and increasing inflammation. Furthermore, they observed improved cardiac function and reduced doxorubicin-induced cardiotoxicity upon microbial depletion with the use of antibiotics. Overall, these results strongly suggests that the gut microbiota may potentially serve as new therapeutic target for cardiotoxicity and cardiovascular diseases. Similarly, Zhao et al. [80] observed that cisplatin, one of the chemotherapy drugs that is known to cause cardiotoxicity, led to a dramatic reduction in *Firmicutes* and elevated levels of pathogenic bacteria. On the other hand, *Lactobacillus* supplementation in cisplatin-treated mice increased body weight, improved cardiac function, and attenuated inflammation. The study thus showed that probiotics may help avoid cardiotoxicity brought on by chemotherapy, but additional validation studies are required in order to establish the best probiotic strain, dosage, and duration for this usage.

Similarly, Lin et al. demonstrated that yellow wine polyphenolic compounds protect against doxorubicin-induced cardiotoxicity by modulating the composition and metabolic function of gut microbiota [81]. Thus, it will not be surprising if researchers in the near future consider the gut microbiota as a new target for the treatment of cardiotoxicity and cardiovascular diseases. Large-scale cancer survivor microbiome investigations may help identify individuals at cardiovascular risk who could benefit from more specialized microbiome-mediated treatment. Furthermore, a deeper understanding of the connection between gut microbiota and cardiotoxicity caused by cancer therapies may pave the way for lowering the risk of these grave and potentially deadly side effects.
