Skip to main content

Cisplatin, environmental metals, and cardiovascular disease: an urgent need to understand underlying mechanisms

Abstract

Significantly increased risks of cardiovascular disease occur in testicular cancer survivors given cisplatin-based chemotherapy. The postulated mechanism of platinum-based chemotherapy’s vascular toxicity has been thought secondary to its different early- and late- effects on vascular injury, endothelial dysfunction, and induction of a hypercoagulable state. We highlight for the first time the similarities between platinum-associated vascular adverse events and the vascular toxicity associated with other xenobiotic-metal contaminants. The vascular toxicity seen in large epidemiologic studies of testicular cancer survivors may in part be similar and mechanistically linked to the risk seen in environmental heavy metal contaminants linked to cardiovascular disease. Future research should be directed to better understand the magnitude of the adverse cardiovascular effects of platinum and to elucidate the underlying mechanisms of action.

Short communication

Significantly increased risks of cardiovascular disease (CVD) occur in testicular cancer survivors (TCS) given platinum-based chemotherapy regimens such as bleomycin, etoposide, and cisplatin (BEP) [1,2,3].The postulated mechanism of platinum-based chemotherapy’s vascular toxicity has been thought secondary to its different early- and late- effects on vascular injury, endothelial dysfunction, and induction of a hypercoagulable state [2, 3]. Early, in the first year after therapy, TCS treated with platinum-based chemotherapy have markedly increased six-fold risks of myocardial infarction [1] and increased risks of cardiovascular mortality [2]. Further, there are also early increased risks of cerebrovascular accidents [1, 2], vascular thromboembolism [1], and new-onset hypertension [1]. Early adverse vascular effects of platinum drugs, occurring less than one year after exposure, are thought to be due to acute vasospasm (days to weeks after exposure) and acute thrombosis (weeks to months after exposure) [4], which are mechanistically linked to disruptions in vascular smooth muscle cells and endothelial cells [3].

There are also elevated risks of late, occurring typically more than ten years after treatment, atherosclerotic CVD events after platinum-based chemotherapy, including an increased risk of myocardial infarction (HR, 1.4; 95% CI, 1.0–2.0) and cardiovascular death (HR, 1.6; 95% CI, 1.0–2.5) [1]. Other late risks following BEP include the development of hypertension, hyperlipidemia, diabetes mellitus, and metabolic syndrome [1, 2]. Late adverse vascular effects of platinum drugs have been attributed to platinum-related disruptions of vascular endothelial cells [3] resulting in a proinflammatory state, leading to atherosclerosis (occurring months to years after exposure), and “accelerated vascular aging” [5].

Similarly, substantial epidemiologic evidence shows that environmental exposures to xenobiotic metal pollutants such as cadmium, lead, and arsenic are associated with increased late risks of CVD, including accelerated atherosclerotic CVD and hypertension [6]. Indeed, a large meta-analysis by Chowdhury et al. [7], including 37 studies and 348,000 participants, demonstrated that several metal contaminants (cadmium, arsenic, and lead) have a positive and direct linear dose–response with greater CVD risk (Fig. 1). For example, higher levels of cadmium were associated with a significantly increased risk of CVD, coronary heart disease, and cerebrovascular disease (relative risks [95% CI]: 1.33 (1.04–1.63); 1.29 (0.98–1.71), and 1.72 (1.29–2.28), respectively, with risk estimates based on large numbers of events (ranging from 601–3,756) and adjusted for basic demographics and CVD risk factors (age, sex, systolic blood pressure, smoking, history of diabetes, etc.). Hypothetical mechanisms of the toxicity of these metals focus on oxidative stress, lipid peroxidation, and endothelial dysfunction [6], not dissimilar to the postulated mechanisms of platinum vascular toxicity [1,2,3]. In particular, cadmium and lead, which can persist for decades in the human body similar to platinum [8], have been linked with increased risks of hypertension, hyperlipidemia, and atherosclerosis [6] via effects on blood pressure control, carbohydrate and lipid metabolism, vascular function, and atherogenesis [9].

Fig. 1
figure1

Summary of the association of environmental contaminants with cardiovascular outcomes. Pooled risk estimates were calculated using random effects meta-analyses. the relative risk compares the risk for each outcome in individuals in the top third with those in the bottom third of baseline levels of the environmental contaminants (i.e., extreme thirds). risk estimates from separate studies were typically adjusted for basic demographics (e.g., age, sex, systolic blood pressure, smoking, history of diabetes, etc.) [7]

Platinum-based treatment regimens for testicular cancer are a paradigm of success as curable systemic chemotherapies which result in high survival rates. However, despite success in testicular cancer survivorship, CVD may present an unintended risk of early- and late- vascular side effects of platinum-based therapies. We highlight for the first time the similarities between platinum-associated vascular adverse events and the vascular toxicity associated with other heavy-metal contaminants. The vascular toxicity seen in large epidemiologic studies of TCS may in part be similar and possibly mechanistically linked to the risk seen in environmental heavy metal contaminants linked to CVD. However, the therapeutic exposure levels of platinum in testicular cancer regimens are at much higher, curative doses than occupational or environmental exposures for other toxic heavy metals, leading us to conclude that the cardiovascular damage due to platinum may be more substantial.

Future research should be directed to better understand the magnitude of the adverse cardiovascular effects of platinum and to elucidate the underlying mechanisms of action, such as the role of epigenetic biomarkers that are induced by heavy metal exposure [10]. In the interim, following cisplatin-based chemotherapy for testicular cancer, health care providers should monitor and manage modifiable cardiovascular risk factors, including blood pressure, lipids, and glucose. Patients should also be counseled to adopt healthy behaviors, including increased physical activity, improvements in diet, smoking cessation, and the maintenance of optimal weight.

Availability of data and materials

None.

References

  1. 1.

    Lauritsen J, Hansen MK, Bandak M, et al. Cardiovascular risk factors and disease after male germ cell cancer. J Clin Oncol:JCO1901180, 2019

  2. 2.

    Fung C, Fossa SD, Milano MT, et al. Cardiovascular disease mortality after chemotherapy or surgery for testicular nonseminoma: A population-based study. J Clin Oncol. 2015;33:3105–15.

    CAS  Article  Google Scholar 

  3. 3.

    Herrmann J. Vascular toxic effects of cancer therapies. Nat Rev Cardiol. 2020;17:503–22.

    CAS  Article  Google Scholar 

  4. 4.

    Dieckmann KP, Gerl A, Witt J, et al. Myocardial infarction and other major vascular events during chemotherapy for testicular cancer. Ann Oncol. 2010;21:1607–11.

    Article  Google Scholar 

  5. 5.

    Stelwagen J, Lubberts S, Steggink LC, et al. Vascular aging in long-term survivors of testicular cancer more than 20 years after treatment with cisplatin-based chemotherapy. Br J Cancer. 2020;123:1599–607.

    CAS  Article  Google Scholar 

  6. 6.

    Solenkova NV, Newman JD, Berger JS, et al. Metal pollutants and cardiovascular disease: mechanisms and consequences of exposure. Am Heart J. 2014;168:812–22.

    CAS  Article  Google Scholar 

  7. 7.

    Chowdhury R, Ramond A, O’Keeffe LM, et al. Environmental toxic metal contaminants and risk of cardiovascular disease: systematic review and meta-analysis. BMJ. 2018;362:k3310.

    Article  Google Scholar 

  8. 8.

    Trendowski MR, El-Charif O, Ratain MJ, et al. Clinical and genome-wide analysis of serum platinum levels after cisplatin-based chemotherapy. Clin Cancer Res. 2019;25:5913–24.

    CAS  Article  Google Scholar 

  9. 9.

    Cosselman KE, Navas-Acien A, Kaufman JD. Environmental factors in cardiovascular disease. Nat Rev Cardiol. 2015;12:627–42.

    CAS  Article  Google Scholar 

  10. 10.

    Ryu H-W, Lee DH, Won H-R, et al. Influence of toxicologically relevant metals on human epigenetic regulation. Toxicol Res. 2015;31:1–9.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

N/A

Funding

Drs. Travis and Sesso were supported by the National Cancer Institute grant: 2 R01 CA 157823, Genetic Susceptibility and Biomarkers of Platinum-Related Toxicity. Dr. Clasen is supported via National Cancer Institute Loan Repayment Grant OYFC2282.

Author information

Affiliations

Authors

Contributions

SCC and LBT. conceived of the presented idea. PCD, LH, CF, HDS developed the theory in their subspecialty areas. The author(s) read and approved the final manuscript.

Corresponding author

Correspondence to Suparna C. Clasen.

Ethics declarations

Ethics approval and consent to participate

N/A

Consent for publication

All authors consented for publication.

Competing interests

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Clasen, S.C., Dinh, P.C., Hou, L. et al. Cisplatin, environmental metals, and cardiovascular disease: an urgent need to understand underlying mechanisms. Cardio-Oncology 7, 34 (2021). https://doi.org/10.1186/s40959-021-00120-z

Download citation

Keywords

  • Cisplatin
  • Testicular cancer
  • Survivorship
  • Vascular toxicity
  • Thrombosis
  • Heavy-metals