Anthracycline chemotherapy‐mediated vascular dysfunction as a model of accelerated vascular aging

Abstract

Cardiovascular diseases (CVD) are the leading cause of death worldwide, and age is by far the greatest risk factor for developing CVD. Vascular dysfunction, including endothelial dysfunction and arterial stiffening, is responsible for much of the increase in CVD risk with aging. A key mechanism involved in vascular dysfunction with aging is oxidative stress, which reduces the bioavailability of nitric oxide (NO) and induces adverse changes to the extracellular matrix of the arterial wall (e.g., elastin fragmentation/degradation, collagen deposition) and an increase in advanced glycation end products, which form crosslinks in arterial wall structural proteins. Although vascular dysfunction and CVD are most prevalent in older adults, several conditions can "accelerate" these events at any age. One such factor is chemotherapy with anthracyclines, such as doxorubicin (DOXO), to combat common forms of cancer. Children, adolescents, and young adults treated with these chemotherapeutic agents demonstrate impaired vascular function and an increased risk of future CVD development compared with healthy age-matched controls. Anthracycline treatment also worsens vascular dysfunction in midlife (50-64 years of age) and older (65 and older) adults such that endothelial dysfunction and arterial stiffness are greater compared to agematched controls. Collectively, these observations indicate that use of anthracycline chemotherapeutic agents induces a vascular aging-like phenotype and that the latter contributes to premature CVD in cancer survivors exposed to these agents. Here, we review the existing literature supporting these ideas, discuss potential mechanisms as well as interventions that may protect arteries from these adverse effects, identify research gaps, and make recommendations for future research.

Inflammation as A Precursor of Atherothrombosis, Diabetes and Early Vascular Aging

“…Among the secreted proteins, IL-6, IL1-α and β, IL8, IFNγ, Vascular endothelial growth factor (VEGF), ROS and TNFα are involved in endothelial dysfunction or atherosclerosis [131,173]. Vascular senescence is also produced by certain chemotherapies [174]. Vascular senescence and chemotherapy are linked through low levels of sirtuins (mainly SIRT1, but also SIRT6), proteins known to be protective molecules against inflammation and aging [175].…”

“…Vascular senescence and chemotherapy are linked through low levels of sirtuins (mainly SIRT1, but also SIRT6), proteins known to be protective molecules against inflammation and aging [175]. Moreover, chemotherapy (anthracyclines) can promote AS through vascular inflammation, inducing cytokine production ( NFκB, TGF-β, matrix metalloproteinases (MMPs), ROS, peroxynitrite and nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) [174].…”

Promoting healthy cardiovascular aging: emerging topics

“…Promising strategies for improving CV health with aging should be translated to other populations characterized by accelerated vascular aging as a result of clinical disease (e.g., CKD [57,63] , Type 2 Diabetes [64,65] , COVID-19 [254][255][256][257] ) and/or disease treatment (e.g., chemotherapy-treated cancer survivors [258] , patients living with HIV on antiretroviral therapy [259] ). Furthermore, there is an increasing body of literature suggesting that Alzheimer's disease and related dementias manifest partly as a result of CV dysfunction [57,260] ; as such, cognitive and/or cerebrovascular function should be assessed in parallel with peripheral CV function.…”

Breast cancer chemotherapy vascular toxicity: a review of mediating mechanisms and exercise as a potential therapeutic

“…Furthermore, most exercise studies have investigated anthracyclines despite the multiplicity of chemotherapy drugs utilized in breast cancer care. A full review of the mechanisms by which exercise may improve vascular function in the specific setting of anthracycline chemotherapy is discussed in depth elsewhere ( 65 ). Despite gaps in the literature, these studies show promise for the potential inclusion of exercise therapy during cancer treatment.…”