As the most reliable citation-based database that is extensively used for bibliometric analysis, WoSCC was used to download the literature on doxorubicin-induced cardiotoxicity in our study (Lin et al., 2022; Mu et al., 2022). The search term was TS= (“Cardiac” OR “Cardiomyocyte” OR “Cardiac dysfunction” OR “Cardiomyopathy” OR “Cardiopathic” OR “Cardiotoxicity” OR “Myocardial” OR “myocardium” OR “heart”) AND (“Doxorubicin” OR “Adriamycin”). For this study, articles and reviews published in the English language and published between 1 January 2000, and 1 September 2022 were included.

We downloaded the “Plain Text” versions of relevant records from WoSCC. Our analysis utilized WoSCC’s literature analysis wire to identify the top 20 highly cited publications and ten high-yield countries/regions, journals, authors, and institutions. We employed VOSviewer 1.6.16 software to perform a co-occurrence analysis of all keywords and determine the co-authorship of organizations, authors, and countries/regions (van Eck and Waltman, 2010). CiteSpace 5.1.3 is used to perform burst detection of keywords.

According to the search criteria, a total of 7,021 documents were identified in the study. The search flow was displayed in Figure 1. For time periods, the documents can be classified into two phases: the documents published before 2006 were in the first phase, and in this phase, the number of documents was small (no more than 200 publications annually). The second phase was 2015-2022, and in this phase, the overall trend for the number of documents was increased annually, and it is estimated that the publications of Doxorubicin-Induced Cardiotoxicity will continue to increase due the importance of this topic. For types of publications, there are 6,164 articles (87.8%) and 857 reviews (12.2%). For the subject area of documents, the top two subject categories were pharmacology pharmacy (1,732 documents, 24.7%) and oncology (1,584 documents, 22.6%), which was displayed in Figure 2.

In the field of doxorubicin-induced cardiotoxicity, 37,152 contributors are involved. Bonnie Ky is the most productive author with 35 documents (h-index 23), followed by Paulo J Oliveira with 31 documents (h-index 22), Steven E Lipshultz with 30 publications documents (h-index 20), Leontien M Kremer with documents (h-index 20), and Carlo Gabriele Tocchetti with 23 documents (h-index 19). The most frequently cited authors are Michael S Ewer, Daniela Cardinale, and Bonnie Ky. The co-authorship map is shown in Figure 3A. In general, Bonnie Ky and Steven E Lipshultz are among both the top 10 productive and top 10 most cooperative authors.

A total of 6,659 organizations and 101 countries/regions are related to all publications. The most productive institutions are the University of Texas (190 documents/16072 citations), the Harvard University (182 documents/14186 citations), and the University of California System (132 documents/16284 citations). The network visualization map is shown in Figure 3B. For Countries/Regions, the United States has the most publications (1,912 publications), followed by China (1,613 publications), Italy (555 publications), Canada (368 publications), and Japan (331 publications). Figure 3C displays the network visualization map, while Table 1 provides a summary of the top 10 high-yield countries/regions, institutions, and authors. In general, United States, Peoples R China, Italy, Canada, Germany, and England are among both the top 10 productive and top 10 most cooperative countries/regions, and the university of Texas and the Harvard University are among both the top 10 productive and top 10 most cooperative institutions.

All documents are from 1,323 journals, and the highest-cited journal is Journal of Clinical Oncology with 12,428 citations. The top 3 productive journals are PLOS ONE with 120 documents (3,755 citations), Journal of Clinical Oncology with 96 documents (12,428 citations), and Cardiovascular Toxicology with 90 documents (1,364 citations). Figure 4A illustrates the network visualization map of all journals, and Table 2 presents a summary of the top 10 high-yield journals. In general, Journal of Clinical Oncology, PLOS ONE and Annals of Oncology are among the top 10 productive and top 10 most high-cited journals.

Table 3 contains a list of the top 20 highest-cited documents (Armenian et al., 2017; Cardinale et al., 2015; Cardinale et al., 2010; Cardinale et al., 2004; Chatterjee et al., 2010; Demaria et al., 2017; Fang et al., 2019; Gabizon et al., 2003; Minotti et al., 2004; O'Brien et al., 2004; Octavia et al., 2012; Plana et al., 2014; Sawaya et al., 2012; Schneeweiss et al., 2013; Slamon et al., 2011; Slamon et al., 2001; Swain et al., 2003; Tacar et al., 2013; Zamorano et al., 2016; Zhang et al., 2012). Among these publications, 10 studies were clinical trials. The main observations of the clinical trials were summarized in Table 4. Among these clinical trials, nine were completed through collaboration between different institutes. The top 3 high-cited documents are as follows: the first high-cited article was published in NEJM with 8,134 citations authored by Slamon et al., 2001. In this article, they found that concurrent treatment with doxorubicin increased the risk of cardiac dysfunction significantly. The second article was published in Pharmacological Reviews with 2,630 citations authored by Minotti et al. (2004). In this article, they summarized the molecular mechanisms of cardiotoxic synergism between doxorubicin and other anticancer agents, and the clinical recommendations for using cardio-protectants without interfering the tumor response. The third article was published in NEJM with 1,738 citations authored by Slamon et al., 2011. In this study, they randomly assigned 3,222 patients with HER2-positive early-stage breast cancer to receive cyclophosphamide and doxorubicin, and found that the addition of 1 year of adjuvant trastuzumab could lower risks of cardiotoxicity. The network visualization map is displayed in Figure 4B. Figure 5 showed the co-citation reference in the field of Doxorubicin-Induced Cardiotoxicity. Co-cited references are defined as one publication is cited by more than one article of the 7,021 extracted list. The first high-co-cited reference was Minotti et al. (2004), Pharmacological Reviews in 2004 (736 co-citations), which was described above. The second high-co-cited reference was Singal and Iliskovic, 1998, NEJM in 1998 (668 co-citations) (WU et al., 2017). In this review, they discussed the cause, diagnosis, management of doxorubicin-induced cardiomyopathy. The third high-co-cited reference was Swain et al. (2003), Cancer in 2003 (634 co-citations). In this article, they concluded that doxorubicin-related congestive heart failure (CHF) occurred at a lower cumulative dose and with greater frequency than previously reported. In general, there are 11 references among both top 20 high-cited and high-co-cited documents.

Figure 6 displays the network visualization map of keywords, with four clusters (red, green, blue, and purple) depicted in distinct directions. The keywords in red cluster are oxidative stress, apoptosis, cardiomyopathy, and expression. The keywords in green cluster are cardiotoxicity, heart failure, and anthracycline. The keywords in blue cluster are chemotherapy, trastuzumab, and paclitaxel. The keywords in purple cluster are doxorubicin, adriamycin, and cancer. We conducted the burst detection analysis for twenty prominent words from 2010, and displayed in Figure 7. The keywords that begin to burst from 2018 are particularly emphasized, including “inflammation” (burst strength 25.92), “Doxorubicin-Induced Cardiotoxicity” (burst strength 12.55), “autophagy” (burst strength 8.25), suppression (burst strength 7.9), cardiac dysfunction (burst strength 7.46), and nrf2 (burst strength 7.19), which is shown in Figure 7.

A total of 7,021 publications are included, and 37,152 authors contribute to this field, which are distributed from 6,659 organizations, 1,323 journals, and 101 countries/regions. The most productive author, institution, country and journal were Bonnie Ky with 35 publications, University of Texas with 190 documents, the United States with 1,912 publications, and PLOS ONE with 120 documents. The first high-cited article was published in the NEJM with 8,134 citations authored by Slamon et al., 2001. For keyword analysis, the clusters of red, green, blue and purple, indicate 4 directions. The keywords in red cluster are oxidative stress, apoptosis, cardiomyopathy. The keywords in green cluster are cardiotoxicity, heart failure, and anthracycline. The keywords in blue cluster are chemotherapy, trastuzumab, and paclitaxel. The keywords in purple cluster are doxorubicin, adriamycin, and cancer. Most of the documents were derived from the United States, China and Italy (4,080/7,021, 58.1%). Of the top 10 institutions, five were from the United States. Of the top 10 productive authors, four were from the United States and three were from Italy. Among cooperative relationships of countries/regions institutions and authors, the United States, China and Italy are also prominent. The number of studies from other countries should be increased.

Based on the most highly cited publications and significant keywords, the current frontiers and hotspots in this field can be summarized as follows: 1) The role of doxorubicin in cardiotoxicity. Among the 20 highest-cited references, ten articles explored the role of doxorubicin in cardiotoxicity, (Swain et al., 2003; Cardinale et al., 2010; Chatterjee et al., 2010; Octavia et al., 2012; Tacar et al., 2013; Cardinale et al., 2015; Zamorano et al., 2016; Armenian et al., 2017), and the important keywords of cardiotoxicity, heart failure, and anthracycline were in green cluster, chemotherapy and trastuzumab were in blue cluster, and doxorubicin, adriamycin, and cancer were in purple cluster. The doxorubicin-induced cardiotoxicity is the common adverse effect of cancer treated with doxorubicin, which is usually composed of myocarditis and heart failure/cardiomyopathy, hypertension and vascular toxicity, and QTc prolongation and arrhythmias. 2) The mechanisms of doxorubicin-induced cardiotoxicity. Among the 20 highest-cited references, six articles explored the mechanisms of doxorubicin-induced acute cardiotoxicity (Chatterjee et al., 2010; Octavia et al., 2012; Sawaya et al., 2012; Zhang et al., 2012; Tacar et al., 2013; Cardinale et al., 2015), and the important keywords of oxidative stress, apoptosis, and expression were in red cluster. Oxidative stress and apoptosis play pivotal roles in cardiotoxicity, and several signaling pathways are implicated in mediating these processes (Paradies et al., 2018; Ikeda et al., 2019; Tian et al., 2020; Timm and Tyler, 2020; Wallace et al., 2020; Ahsan et al., 2021; Borisov et al., 2021; Li et al., 2021; Mishra et al., 2021; Rawat et al., 2021; Yang et al., 2021; Chen et al., 2022; Herrmann et al., 2022; Ikeda et al., 2022; Kong et al., 2022; Sangweni et al., 2022; Wu et al., 2022). Understanding these pathways can provide insights into potential therapeutic targets. Here are the major signaling pathways involved in cardiotoxicity under oxidative stress and apoptosis, include: