Yan Ma
Feng Cao
Dong Han- National Clinical Research Center for Geriatric Diseases, The Second Medical Center, Chinese PLA General Hospital, Beijing, China
Editorial on the Research Topic
Cardio-oncology: mechanisms and therapeutics
Cancer and cardiovascular disease share similar risk factors and are both prevalent among aging populations. Individuals with a history of cancer are exposed to a 2–3 times higher chance of getting acute coronary syndrome (ACS), which can persist for up to 10 years after a cancer diagnosis (1). Cancer patients with cardiovascular comorbidity have worse survival rates than cancer patients alone (2, 3). Reciprocally, myocardial infarction also hastens the spread of cancer and worsens the prognosis of cancer patients (4, 5). In this regard, understanding the interaction between cancer and cardiovascular disease may help avoid tackling diseases in a siloed approach and improve the outcome of these patients with comorbidity.
In addition, novel cancer therapies have tremendously improved the survival of cancer patients but also increased treatment-related side effects (6, 7). Cardiovascular toxicities are the most common adverse effects, threatening survival and impairing life quality of the cancer survivors (8). Cancer survivors' early morbidity and death are largely affected by these side effects (9). Understanding the mechanisms underlying anticancer treatment-induced cardiotoxicity can help develop novel therapeutics to avoid or lessen it.
The purpose of this research topic is to bring together a collection of works that provide novel insights into interactions between cancer and cardiovascular disease as well as mechanisms and therapeutics of anticancer treatment-induced cardiotoxicity. All contributions to this research topic concentrate on one or more of the above-mentioned study topics and several studies referenced below are representative.
N6-Methyladenosine in cyclophosphamide-induced cardiotoxicity
The RNA epitranscriptomics represented by N6-Methyladenosine (m6A) are increasingly recognized to play important roles in physiology and disease (10). Cyclophosphamide is frequently prescribed to treat various types of cancers and autoimmune conditions. Accumulated doses of this drug may result in fatal hemorrhagic myocarditis (11). Zhu et al. demonstrated that the pathogenesis of cyclophosphamide-induced cardiotoxicity involves the downregulation of Junctophilin 2 (JPH2) levels. The proper structure and function of junctophilin-2 (JPH2) are recognized to be indispensable for proper excitation-contraction coupling in cardiomyocytes (12). The increased m6A level of JPH2 mRNA induced by N6-Methyladenosine writer METTL3 decreased its expression levels, and consequently dysregulated calcium signaling in cardiomyocytes. These results identified a novel epitranscriptomic mechanism regulating JPH2 expression and offers novel approaches to the management of cyclophosphamide-induced cardiotoxicity.
miR-194-5p contributes to doxorubicin-induced cardiotoxicity
Doxorubicin is a popular anticancer agent but is well-known for its cardiotoxicity in many patients. The mechanisms underlying doxorubicin (DOX)-induced cardiotoxicity remain not fully understood. miRNAs are widely involved in the progression of various cardiovascular diseases (13). Fa et al. revealed the important role of miR-194-5p in the pathogenesis of DOX-induced cardiotoxicity. MiR-194-5p silencing reduced doxorubicin (DOX)-induced cardiotoxicity in vitro and in vivo by upregulating PAK2 and XBP1s. Overexpression of PAK2 or XBP1s reduced miR-194-5p- exacerbated cardiomyocyte apoptosis. This work was the first to identify a novel pathogenic miR-194-5p/PAK2/XBP1s axis in DOX-induced cardiotoxicity, hence proposing a potential target for the prevention and treatment of DOX-induced cardiotoxicity.
NT-proBNP can predict cardiovascular symptoms caused by Pd-1 inhibitor therapy
In recent years, immunotherapy has achieved great success in cancer treatment. Unfortunately, cardiotoxicity appears to have emerged as an unneglectable issue recently (14). The work by Peng et al. suggested that NT-proBNP could predict cardiovascular symptoms in individuals with myocardial damage following PD-1 inhibitor therapy, while highly sensitive troponin T (hsTnT) is the best cardiac biomarker for mortality prediction in symptomatic patients. This study may help medics to perform risk stratification for patients at an earlier time and to implement effective interventions at the early stage of PD-1 inhibitor-related myocarditis.
A large-scale observation in cancer patients suffering from infective endocarditis
Infective endocarditis (IE) occurs more frequently in cancer patients as compared with the general population (15). IE was predominantly community-acquired (74.8%) in cancer patients, according to Cosyns et al. The most common complications were acute renal failure (25.9%), embolic events (21.7%), and congestive heart failure (18.1%). This is a sizable observational cohort of IE patients with cancer. It sheds light on current IE cancer patient profiles, treatment, and outcomes. Considering the lack of randomized and large-scale observational data on IE cancer patients, this registry provides a unique viewpoint on IE management in cancer patients.
D-Dimer is a predictive factor for cancer therapeutics-related cardiac dysfunction
Improved early detection methods have allowed a larger number of cancer patients with cancer therapeutics-related cardiac dysfunction (CTRCD) to live longer (16). Oikawa et al. consecutively enrolled 169 patients who planned to receive cardiotoxic chemotherapy for 12 months of follow-up and found that the incidence of CTRCD was greater in the high D-dimer group than in the low D-dimer group (16.2 vs. 4.5%, p = 0.0146). High D-dimer levels at baseline were an independent predictor of the development of CTRCD, according to multivariable logistic regression analysis [odds ratio 3.93, 95% CI (1.00–15.82), p = 0.047]. It is suggested that D-dimer may be a potential predictor of CTRCD and has clinical practical value.
Low LVEF after chemotherapy was associated with blood RNA viruses
It has been hypothesized that immunosuppression after chemotherapy increases opportunistic viral infections (17). Varkoly et al. performed high-throughput sequencing analysis of RNA obtained from blood samples of 28 patients with hematological malignancies who had undergone chemotherapy. The result suggested that patients with low LVEF had influenza orthomyxovirus, avian paramyxovirus, and retrovirus sequences present. This is the first study to use high-throughput, blinded, unbiased sequencing to test for RNA viruses in circulating blood and associate those findings with abnormalities in heart function in patients who have recently finished chemotherapy. This study raises attention to RNA virus infections in individuals with chemotherapy-related cardiomyopathy.
Cardiovascular outcomes in patients with colorectal cancer
Colorectal cancer (CRC) patients are potentially at high cardiovascular risk (18). Hang et al. followed up 197, 699 colorectal cancer patients for 37 months and examined the risks of cardiovascular death (CVD) in patients with CRC. They revealed that CVD ranked first and accounted for 41.69% of the major cause of non-cancer deaths. In addition, the nomogram for CVD prediction in CRC patients was created. This nomogram performed quite well and might assist physicians in providing customized care in clinical settings.
Perspectives
With the generous support from all editors, publishers, reviewers, and authors involved in this research topic, we have successfully finalized this wonderful collection focusing on mechanisms and therapeutic in Cardio-Oncology. Future studies on the mechanism and management of cardio-oncology are expected to continually improve the survival and life quality of cancer survivors. The enormous issues posed by tumor-cardiovascular comorbidity, however, deserve more attention given its rising incidence and the continuously aging population. There is substantial opportunity for the collaboration between oncologists and cardiologists to work together to improve the outcome of cancer patients with cardiovascular comorbidity.
Author contributions
YM drafted the manuscript. DH and FC revised the paper. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Lucà F, Parrini I, Abrignani MG, Rao CM, Piccioni L, Di Fusco SA, et al. Management of acute coronary syndrome in cancer patients: it's high time we dealt with it. J Clin Med. (2022) 11(7):1792. doi: 10.3390/jcm11071792
2. Carlson LE, Watt GP, Tonorezos ES, Chow EJ, Yu AF, Woods M, et al. Coronary artery disease in young women after radiation therapy for breast cancer: the WECARE study. JACC CardioOncol. (2021) 3:381–92. doi: 10.1016/j.jaccao.2021.07.008
3. Kwok CS, Wong CW, Kontopantelis E, Barac A, Brown S-A, Velagapudi P, et al. Percutaneous coronary intervention in patients with cancer and readmissions within 90 days for acute myocardial infarction and bleeding in the USA. Eur Heart J. (2021) 42:1019–34. doi: 10.1093/eurheartj/ehaa1032
4. Romero D. Myocardial infarction promotes breast cancer recurrence. Nat Rev Clin Oncol. (2020) 17:520. doi: 10.1038/s41571-020-0418-7
5. Koelwyn GJ, Newman AAC, Afonso MS, van Solingen C, Corr EM, Brown EJ, et al. Myocardial infarction accelerates breast cancer via innate immune reprogramming. Nat Med. (2020) 26:1452–8. doi: 10.1038/s41591-020-0964-7
6. Li M, Goldman DP, Chen AJ. Spending on targeted therapies reduced mortality in patients with advanced-stage breast cancer. Health Aff (Millwood). (2021) 40:763–71. doi: 10.1377/hlthaff.2020.01714
7. Seton-Rogers S. Cardiovascular disease and cancer communicate. Nat Rev Cancer. (2020) 20:552. doi: 10.1038/s41568-020-0294-6
8. Florido R, Daya NR, Ndumele CE, Koton S, Russell SD, Prizment A, et al. Cardiovascular disease risk among cancer survivors: the atherosclerosis risk in communities (ARIC) study. J Am Coll Cardiol. (2022) 80:22–32. doi: 10.1016/j.jacc.2022.04.042
9. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. (2022) 72(1):7–33. doi: 10.3322/caac.21708
10. Yang C, Hu Y, Zhou B, Bao Y, Li Z, Gong C, et al. The role of m(6)A modification in physiology and disease. Cell Death Dis. (2020) 11:960. doi: 10.1038/s41419-020-03143-z
11. Dhesi S, Chu MP, Blevins G, Paterson I, Larratt L, Oudit GY, et al. Cyclophosphamide-Induced cardiomyopathy: a case report, review, and recommendations for management. J Investig Med High Impact Case Rep. (2013) 1:2324709613480346. doi: 10.1177/2324709613480346
12. Garbino A, Wehrens XH. Emerging role of junctophilin-2 as a regulator of calcium handling in the heart. Acta Pharmacol Sin. (2010) 31:1019–21. doi: 10.1038/aps.2010.116
13. Barwari T, Joshi A, Mayr M. MicroRNAs in cardiovascular disease. J Am Coll Cardiol. (2016) 68:2577–84. doi: 10.1016/j.jacc.2016.09.945
14. Varricchi G, Galdiero MR, Tocchetti CG. Cardiac toxicity of immune checkpoint inhibitors: cardio-oncology meets immunology. Circulation. (2017) 136:1989–92. doi: 10.1161/CIRCULATIONAHA.117.029626
15. Grable C, Yusuf SW, Song J, Viola GM, Ulhaq O, Banchs J, et al. Characteristics of infective endocarditis in a cancer population. Open Heart. (2021) 8(2):e001664. doi: 10.1136/openhrt-2021-001664
16. Xiao H, Wang X, Li S, Liu Y, Cui Y, Deng X. Advances in biomarkers for detecting early cancer treatment-related cardiac dysfunction. Front Cardiovasc Med. (2021) 8:753313. doi: 10.3389/fcvm.2021.753313
17. Badrinath A, Bhatta S, Kloc A. Persistent viral infections and their role in heart disease. Front Microbiol. (2022) 13:1030440. doi: 10.3389/fmicb.2022.1030440
Keywords: cardio-oncolody, editoral, mechanisms, cardiotoxcity, prognosis
Citation: Ma Y, Cao F and Han D (2023) Editorial: Cardio-oncology: mechanisms and therapeutics. Front. Cardiovasc. Med. 10:1198617. doi: 10.3389/fcvm.2023.1198617
Received: 1 April 2023; Accepted: 21 April 2023;
Published: 3 May 2023.
Edited and Reviewed by: Jun-ichi Abe, University of Texas MD Anderson Cancer Center, United States
© 2023 Ma, Cao and Han. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Dong Han handong123566@163.com