Anthracycline chemotherapy, vascular dysfunction and cognitive impairment: burgeoning topics and future directions

Abstract

Anthracyclines, chemotherapeutic agents used to treat common forms of cancer, increase cardiovascular (CV) complications, thereby necessitating research regarding interventions to improve the health of cancer survivors. Vascular dysfunction, which is induced by anthracycline chemotherapy, is an established antecedent to overt CV diseases. Potential treatment options for ameliorating vascular dysfunction have largely been understudied. Furthermore, patients treated with anthracyclines have impaired cognitive function and vascular dysfunction is an independent risk factor for the development of mild cognitive impairment. Here, we will focus on: anthracycline chemotherapy associated CV diseases risk; how targeting mechanisms underlying vascular dysfunction may be a means to improve both CV and cognitive health; and research gaps and potential future directions for the field of cardio-oncology.

Plain language summary

Cancer and cardiovascular diseases are highly prevalent in the USA and are inter-related issues. Drugs that are used to treat common cancers effectively destroy harmful cancer cells but negatively impact the function of the heart and blood vessels. Cancer patients treated with these drugs are at a high risk of developing problems within the blood vessels that prevent the vessels from dilating properly. Cancer treatments are also associated with impaired memory and brain function later in life. It is important to understand how and why these cancer treatments increase the risk of developing cardiovascular diseases and cognitive impairment. Current research is examining the mechanisms (i.e., potential therapeutic targets) underlying the negative effects of these drugs with the goal of developing interventions and additional treatments to improve the quality of life of cancer survivors.

The two major causes of death in the USA are cardiovascular diseases (CVDs) and cancer [1]. Research conducted over approximately the last two decades has demonstrated that CVD and cancer may be more inter-related than once previously thought. For example, cancer diagnosis itself, independent of treatment regimen, is an independent risk factor for the development of CVD [2] and CVD increase the risk of developing cancer [3]. Taken together, cancer and CVD are not only related conditions, but they may be mutually reinforcing, which has given rise to the burgeoning field of cardio-oncology.

CVD and cancer are highly prevalent in the USA and are associated with significant healthcare and economic burdens [4]. A first-line treatment strategy for cancer is chemotherapy, and unfortunately, many chemotherapeutic agents are linked to increased prevalence of CVD. Furthermore, chemotherapy treatment is highly associated with reduced cognitive function, which also places a significant economic burden on our society. In this review, we will primarily describe: the chemotherapeutic agents used to treat the commons forms of cancer; the elevated CVD risk associated with these common treatment options; how targeting vascular dysfunction induced by these common chemotherapeutic agents may be a means to reduce CVD risk in cancer survivors; the mechanisms by which these chemotherapeutic agents induce vascular dysfunction; and research gaps and potential future directions. Additionally, there will be select discussion regarding the influence of common chemotherapeutic agents on cognitive function and the inter-related nature of vascular dysfunction and cognitive impairment. The broad goal of this review is to promote further understanding of the vascular impacts of anthracycline chemotherapy treatment and to foster the development of novel targeted therapeutics that could improve both vascular and cognitive health, and ultimately improve the quality of life of cancer survivors.

Cancer & CVD: major causes of death in the USA

As stated above, CVD and cancer are the two most prominent causes of death in the USA. CVD include numerous conditions such as cardiac dysfunction (e.g., heart failure), diseased vessels (e.g., atherosclerosis), adverse structural remodeling in the heart (e.g., fibrosis) [5,6] and strokes [7], with heart failure and occlusive strokes being the two leading causes of CV-related mortality [8,9]. Cancer is a multifaceted process that occurs when abnormal cells proliferate in an uncontrolled manner [10,11]. Cancer is a highly prevalent condition with numerous underlying causes, including dysfunctional tumor suppressor genes, mutated proto-oncogenes and dysfunctional DNA repair genes [12]. Cancer can occur as a result of genetic risk factors, environmental exposures and lifestyle choices [13]. Both CVD and cancer can appreciably reduce maximal lifespan and ‘healthspan’, the period of life free from serious chronic diseases and disability [14].

Significant time and effort have been dedicated to studying the independent mechanisms underlying the development of CVD and cancer with the goal of establishing effective treatment options. However, the inter-related nature of CVD and cancer creates a barrier for developing effective therapeutic strategies. To overcome this barrier, it is essential to identify the common pathways that could be utilized to treat or prevent CVD and cancer. This challenge is actively being met and overcome by cardio-oncologists and integrative physiologists in both the clinical and basic science research environments.

CVD & cancer: prevalence & associated economic burden

According to the CDC, 697,000 people in the USA died from heart disease in 2020, which equates to one in every five deaths [15]. CVD impart a significant economic burden on the USA, and the combined cost of healthcare services, medications and premature death due to CVD cumulates to a staggering US$219 billion each year (Figure 1) [16].

Figure 1. . Cancer and cardiovascular diseases markedly increase the economic burden of healthcare in the USA.

The cumulative cost of cardiovascular disease treatment and cancer care is an astonishing US$240 billion per year.

Although recent advances in cancer treatment technology and prevention have improved cancer diagnosis and management, cancer incidence and related mortality remain pressing biomedical issues [17]. In 2019, approximately 1.7 million new cancer cases were reported and approximately 600,000 people suffered from cancer related mortality [18]. Furthermore, the cumulative cost of cancer care was greater than US$21 billion, and US out of pocket costs were particularly high for certain cancers (e.g., breast cancer) [18]. This indicates that cancer not only impacts physical well-being, but also financial welfare (Figure 1).

Chemotherapy as a first-line defense strategy to treat cancer: risk of future CVD

A first-line defense strategy for treating cancers is chemotherapy. Approximately 650,000 people are anticipated to undergo chemotherapy treatment this year [19].

Chemotherapeutic agents act by causing cell death and/or cell growth arrest via a variety of mechanisms, including apoptosis, autophagy, senescence and necrosis [20,21]. The specific mechanism by which chemotherapeutic agents function to reduce cancer varies depending on the patient, cell type, cancer type, as well as the concentration and duration of the treatment [22]. Although chemotherapy treatment is a well-established method to treat cancer, these drugs tend to nonspecifically target and damage healthy non cancerous cells, which can ultimately reduce one’s quality of life, characterized in part by chronic nausea, vomiting, neuropathy, bruising, shortness of breath, rashes and overall pain [23,24]. In addition, chemotherapy has severe side effects on the CV system, which are collectively termed ‘chemotherapy related CV toxicity.’

Anthracyclines: the most common chemotherapeutic agents & future CVD risk

The category of chemotherapeutic agents used to treat the most common forms of cancer – in other words, breast cancer, lymphomas and leukemias [25] – are anthracyclines, which are a type of antibiotic that originate from certain strains of Streptomyces peucetius bacterium [26]. Examples of anthracyclines include doxorubicin (DOXO), daunorubicin, epirubicin, idarubicin, mitoxantrone (an anthracendione) and valrubicin [27]. Anthracyclines are primary candidates to combat common cancers due to their high treatment efficacy (e.g., 90% 5-year survival rate in breast cancer patients treated with anthracyclines) [28]. The primary mechanisms of action of anthracyclines on cancer cells are intercalation into DNA, inhibiting topoisomerase II, releasing cytochrome C from mitochondria and generating free radicals to increase oxidative stress [29], while these drugs also inhibit cancer by inducing cellular senescence [20]. Unfortunately; however, there is a significant rise in CV dysfunction following treatment with these drugs [30]. For example, following the cessation of treatment, there is a disproportionate increase in the incidence of congestive heart failure relative to the cumulative dose of anthracycline chemotherapy received throughout the treatment period – for example, approximately tenfold higher incidence of heart failure with only a doubling of the cumulative dose [31]. As such, the National Cancer Institute has stated, “The cancer patient of today is the CV patient of tomorrow.”

In an attempt to mitigate the adverse effects of anthracyclines on the CV system, oncologists often administer these drugs using a high frequency/low dose approach. However, the cumulative dose of chemotherapy throughout the treatment period is most associated with CVD later in life, rather than the concentration of an acute dose [32]. Accordingly, it is clear that anthracycline chemotherapy is effective at treating the cancer, but the treatment efficacy comes at the cost of reducing CV function. Thus, it is imperative to understand the mechanisms by which anthracyclines induce CV dysfunction, as these mechanisms can serve as therapeutic targets that can be targeted to improve CV function following the cessation of cancer treatment.

Although anthracycline chemotherapy treatments typically include a cocktail of numerous anthracyclines, DOXO is most associated with subsequent CV dysfunction in patients undergoing cancer treatment with anthracyclines and DOXO can induce both acute and chronic CV toxicity (Figure 2) [27,33]. In light of this, the majority of the research to date has focused on understanding the molecular and cellular processes underlying DOXO-induced cardiac dysfunction [34], which has been reviewed in detail elsewhere [35]. Previously, doxorubicin cardiotoxicity has been studied in the context of cardiomyocytes; however, recent evidence supports the role of doxorubicin damaged endothelial cells in the progression of cardiotoxicity [36].

Figure 2. . Anthracycline chemotherapy increases the risk of developing cardiovascular diseases.

Patients who have undergone cancer treatment with anthracycline chemotherapy (e.g., doxorubicin) have a greater risk of developing cardiovascular diseases relative to age- and sex-matched healthy controls.

Vascular dysfunction as an antecedent to CV dysfunction with anthracycline chemotherapy

One way to develop interventions for improving CV function following anthracycline/DOXO chemotherapy treatment is to first understand the key risk factors for overt CVD. Vascular dysfunction is a well-established independent predictor of future adverse CV events [37]. Anthracycline/DOXO chemotherapy is administered intravenously, and thus, the vasculature is the first point of contact for these drugs. Indeed, patients who receive cancer treatment with DOXO have marked vascular dysfunction relative to age- and sex-matched healthy controls [38–40]. The two main clinical manifestations of vascular dysfunction include vascular endothelial dysfunction and stiffening of the large elastic arteries, both of which have been observed in cancer survivors treated with anthracycline/DOXO chemotherapy [41–43]. Thus, it is possible that vascular dysfunction may precede overt CVD following anthracycline/DOXO chemotherapy treatment (Figure 3).

Figure 3. . Vascular dysfunction may be an antecedent to the development of cardiovascular diseases with anthracycline chemotherapy.

Treatment with anthracycline chemotherapeutic agents increases the risk of developing cardiovascular disease (CVD). Vascular dysfunction is a well-established risk factor for the development of overt CVD and the vasculature is the first point of contact for anthracyclines. As such, vascular dysfunction may precede CVD with anthracycline chemotherapy treatment.

Vascular endothelial function

Vascular endothelial dysfunction is considered one of the earliest precursors in the development and progression of CVD [44] and is an independent risk factor for occlusive strokes [45], which as mentioned above are a primary cause of CV related mortality nationwide [7]. The vascular endothelium is a single-cell layer that lines the innermost portion of blood vessels [46]. The vascular endothelium synthesizes and releases a variety of vasoactive molecules that act in autocrine and/or paracrine manners. Nitric oxide (NO) is a vasodilatory and primarily vaso-protective molecule that is released by the endothelium in response to chemical (e.g., acetylcholine) or mechanical (e.g., shear stress) stimuli. Furthermore, at normal physiological levels, NO is anticoagulative and anti-inflammatory [46]. NO-mediated endothelium dependent dilation (EDD) is measured in preclinical models by assessing changes in diameter of isolated artery segments ex vivo in response to mechanical or pharmacological stimuli [47–50]. In clinical settings, NO-mediated EDD is measured in vivo using brachial artery flow-mediated dilation (FMD_BA), in which the change in brachial artery diameter is assessed in response to an increased blood flow (shear rate) induced production of NO [51]. Impaired FMD_BA is an independent predictor of CV related morbidity and mortality (Figure 3) [52].

Large elastic artery stiffness

Large elastic artery stiffening refers to the stiffening of the aorta and carotid arteries. As the nomenclature suggests, these arteries are designed to expand as they accept the left ventricular stroke volume with each contraction of the heart, and then recoil to create the necessary kinetic energy to drive the blood distally to tissues and cells [53]. Moreover, the elastic recoil of the aorta aids in maintaining perfusion of the heart during diastole. The stiffening of these arteries leads to numerous pathophysiological effects that collectively increase risk of CVD, including increases in arterial systolic and pulse pressures, left ventricular hypertrophy (caused by repeatedly ejecting blood out into stiff arteries) and tissue damage as a result of microvascular damage due to increases in pulsatile pressure (Figure 3) [37], especially in high-flow vital organs, such as the brain [54,55] and kidneys [56].

Large elastic artery stiffening occurs due to structural changes in the extracellular matrix of arteries including: collagen deposition, elastin fragmentation/degradation and the formation of advanced glycation end products which crosslink collagen fibers leading to a stiffer matrix. Increased vascular smooth muscle tone can also contribute to arterial stiffening. Arterial stiffening is assessed in both clinical and preclinical settings by measuring aortic pulse wave velocity (PWV). PWV is a measure of the speed of the pulse wave generated by the heart when blood is injected into the arterial system [53]. In rodents, PWV is measured between the aortic arch and abdominal aorta [53]. Additionally, the intrinsic mechanical wall stiffness of the large elastic arteries, most commonly the aorta, can be determined ex vivo in preclinical models via stress strain testing, using the principle of Young’s modulus [57]. Human carotid-femoral PWV is the reference standard measure for aortic stiffness in preclinical models [53]. Similar to FMD_BA, elevated PWV is also an independent predictor of CV related morbidity and mortality (Figure 3). The local distensibility of the carotid artery can be determined in humans by measuring carotid artery compliance (the change in artery diameter for a given change in arterial pressure) and is expressed inversely as carotid β stiffness [58].

Alterations in vascular function with anthracycline chemotherapy

As mentioned above, cancer survivors who have undergone treatment with anthracycline/DOXO chemotherapy have endothelial dysfunction and increased arterial stiffness relative to age- and sex-matched healthy controls [38,59]. Although cardiac dysfunction can occur years after therapy, DOXO treatment induces endothelial dysfunction acutely and can be detected as early as 48 h after treatment [40,59,60]. Endothelial dysfunction has also been identified weeks, months and years after treatment [61–65]. Anticancer therapy can also produce >50% increases in arterial stiffness within 4–6 months of treatment [38,66]. However, until recently the mechanisms underlying vascular dysfunction in these patients were not completely understood. To address this, we and others have performed reverse translational studies in mice to determine causal mechanisms by which DOXO induces vascular dysfunction. Below, we will describe our (and others’) previous findings and how these results could be used to inform future therapeutic strategies to treat vascular dysfunction in anthracycline/DOXO chemotherapy treated cancer survivors.

Reverse translational insight: DOXO-induced vascular dysfunction

Endothelial dysfunction

We have shown that DOXO induces oxidative stress (an imbalance between reactive oxygen species and antioxidant defenses) and endothelial dysfunction in conduit arteries in mice [47]. Specifically, carotid arteries from DOXO-treated mice exhibited impaired EDD to acetylcholine compared with vehicle (saline) treated mice. This was primarily due to a reduction in NO bioavailability. Additionally, DOXO-treated animals had vascular mitochondrial dysfunction, as evidenced by higher mitochondrial reactive oxygen species (mtROS) production in arteries compared with vehicle treated animals. Dysfunctional mitochondria can release reactive oxygen species and contribute to inflammation and oxidative stress in a feedforward fashion [67]. Excessive mtROS production can lead to reductions in NO bioavailability and ultimately result in impaired vascular function. Moreover, dysfunctional mitochondria can produce excessive amounts of mtROS due to DOXO treatment and this deleterious increase is thought to be sustained after the conclusion of the treatment [68]. Thus, we next sought to determine the causal role of excess mtROS in mediating endothelial dysfunction with DOXO. To accomplish this, we treated carotid arteries ex vivo with the mitochondria targeted antioxidant MitoQ. We found that acute MitoQ exposure normalized EDD to levels observed in the vehicle treated animals. Together, these results established excess mtROS as a viable therapeutic target for treating DOXO-induced endothelial dysfunction. Indeed, we found that 4 weeks of oral MitoQ supplementation (in the drinking water) immediately following DOXO administration could fully prevent DOXO-induced endothelial dysfunction, which confirmed that excess mtROS was a mechanism underlying DOXO-induced vascular endothelial dysfunction (Figure 4).

Figure 4. . Mechanisms mediating doxorubicin-induced vascular dysfunction.

The anthracycline chemotherapeutic agent doxorubicin causes vascular endothelial dysfunction and large elastic artery stiffening, in part, via an increase in mitochondria derived reactive oxygen species and TNF-α-mediated inflammation.

MitoQ has previously shown to be safe, tolerable and effective for improving endothelial function in other clinical settings of vascular dysfunction (i.e., mid-life/older adults) [69]. Thus, MitoQ supplementation following the completion of anthracycline/DOXO chemotherapy treatment might be a viable approach for improving endothelial function in this patient population. This is currently being studied (NCT05146843), but results are pending.

In addition to mitochondrial specific oxidative stress, numerous novel mitochondrial mechanisms have been identified as potential contributors to CV toxicity with anthracyclines, including mitochondrial epigenetic regulation, innate immunity, signaling via noncoding RNAs, and mitochondrial hormones, all of which have been reviewed in detail elsewhere [70]. Additionally, damaged mitochondria release DNA which circulates and can activate toll-like receptors on the vascular endothelium which leads to the activation of the NF-κB pathway to induce inflammation [71]. This is an additional mechanism by which vascular endothelial dysfunction can be induced by chemotherapy.

Arterial stiffness

We have also shown that TNF-α-mediated inflammation is a mechanism by which DOXO induces aortic stiffness [72]. First, we found that DOXO-treated mice exhibited higher aortic PWV in comparison to animals treated with the vehicle control. Next, we found that isolated aortic segments from DOXO treated animals had higher levels of intrinsic wall stiffness, which was associated with a greater abundance of aortic TNF-α. We determined that DOXO can directly cause aortic stiffness, demonstrated by exposing aortic rings isolated from young adult treatment naive mice to DOXO ex vivo and subsequently assessing intrinsic mechanical stiffness. We found that DOXO could induce stiffening of the aortic rings, which was prevented by concomitant exposure with the small molecule TNF-α inhibitor, C87 (Figure 4).

Acute [73] and chronic [74] inhibition of TNF-α with the drug etanercept has led to reductions in stiffness of the large elastic arteries in other settings of excess vascular inflammation and arterial stiffness (i.e., estrogen deficient postmenopausal women [73] and rheumatoid arthritis [74]). Thus, inhibition of TNF-α may be a viable therapeutic approach for reducing arterial stiffness in anthracycline/DOXO treated cancer survivors.

Collectively, these results demonstrate that excess vascular mtROS and TNF-α-mediated inflammation contribute to vascular dysfunction with DOXO (Figure 4). Considering inhibition of mtROS and TNF-α have been shown to improve vascular function in mid-life/older adults and models of accelerated aging (e.g., rheumatoid arthritis), in conjunction with the fact that anthracycline/DOXO chemotherapy is viewed as a model of early vascular aging [75], excess mtROS and TNF-α-mediated inflammation may be viable therapeutic targets to improve vascular function and ultimately reduce the risk of developing overt CVD in anthracycline/DOXO-treated cancer survivors.

Following our series of studies investigating the roles of excess mtROS and inflammation in mediating vascular dysfunction with DOXO, we next sought to determine a potential integrative mechanistic event that could mediate excess mtROS, inflammation and ultimately vascular dysfunction with DOXO. Although both cellular senescence and autophagy are potential mechanistic events mediating excess ROS and inflammation [76,77], we chose to explore the role of cellular senescence based on the National Cancer Institute’s position statement which suggests that cellular senescence should be viewed as a therapeutic target following the completion of chemotherapy treatment [78]. As mentioned above, one of the mechanisms by which anthracycline chemotherapeutic agents inhibit cancer growth is through the induction of cellular senescence (a permanent state of cell cycle arrest) in cancer cells [20,21]. Furthermore, DOXO increases cellular senescence in a variety of cell and tissue types [79]. Senescent cells secrete a variety of proinflammatory factors which are collectively referred to as the senescence-associated secretory phenotype (SASP) [80]; thus, cellular senescence and the SASP may be a source of excess inflammation and may induce excess mtROS following anthracycline/DOXO chemotherapy treatment, as inflammation can independently increase ROS [81]. Below, we will summarize our work conducted to date on the role of cellular senescence in mediating vascular dysfunction with DOXO (Figure 5).

Figure 5. . Cellular senescence may be an integrative mechanistic event linking doxorubicin chemotherapy with excess mitochondrial reactive oxygen species and inflammation-mediated vascular dysfunction and the subsequent elevated risk in developing cardiovascular diseases.

Cellular senescence is increased in arteries following administration of doxorubicin. Increased cellular senescence with doxorubicin induces excess mitochondrial ROS and inflammation, in part via the SASP, which together can drive vascular dysfunction and increase the risk of developing cardiovascular diseases.

ROS: Reactive oxygen species; SASP: Senescence-associated secretory phenotype.

Cellular senescence: an integrative mechanistic event that mediates vascular dysfunction with DOXO chemotherapy

To determine whether excess cellular senescence induced by DOXO is a mechanism by which DOXO induces excess mtROS, inflammation and ultimately vascular dysfunction, we have utilized the highly innovative gold-standard p16-3MR mouse model. The p16-3MR mouse model allows for selective clearance of p16+ senescent cells with the antiviral prodrug ganciclovir [82]. Early results suggest that DOXO induces cellular senescence in the vasculature, which increases mtROS and ultimately causes vascular dysfunction (Figure 5) [83]. More specifically, targeting cellular senescence following DOXO chemotherapy may be a viable approach to improve vascular function and ultimately reduce the risk of subsequent development of CVD [76]. In support of the notion that cellular senescence could be a possible therapeutic target for treating vascular dysfunction, we have shown that clearance of senescent cells with synthetic [84] and natural [85] senolytics (compounds that can clear senescent cells) can improve vascular function in old mice – an established model of excess vascular cell senescence.

Anthracycline chemotherapy treatment & cognitive impairment

In addition to vascular dysfunction, anthracycline treatment regimens are also associated with declines in cognitive function, a phenomenon referred to as chemotherapy-induced cognitive impairment (CICI) (Figure 6) [86]. Cognitive impairment is an important biomedical issue that greatly affects one’s well-being and functional capacity [87], and according to the 2020 US consensus it affects approximately 23% of individuals nationwide [88]. Moreover, the number of people in the US with mild cognitive impairment is expected to increase by approximately 76% from 2020 to 2060 [88]. These projections would likely be even higher if the statistics accounted for patients undergoing chemotherapeutic treatment.

Figure 6. . Anthracycline chemotherapy increases the risk of developing cognitive impairment.

Patients who have undergone cancer treatment with anthracycline chemotherapy (e.g., doxorubicin) have reduced cognitive function relative to age- and sex-matched healthy controls. Cognitive dysfunction with anthracycline chemotherapy generally manifests as memory loss, language problems, impaired complex decision making, reasoning and judgement errors and attention deficits.

Cognitive impairment is a broad term that encompasses a wide range of dysfunctions, ranging from mild cognitive impairment to dementias, which has been reviewed elsewhere [89]. Mild cognitive impairment is defined as an early stage of memory loss and reduced cognitive ability and is considered an intermediate stage between normal cognitive function and dementia [90]. Furthermore, mild cognitive impairment is associated with a greater utilization of inpatient and palliative health services in comparison to cognitively normal individuals [91].

Clinical manifestations of mild cognitive impairment include memory loss, language problems, impaired complex decision-making, reasoning and judgement errors and attention deficits (Figure 6) [92]. To date, the exact mechanisms mediating the induction of mild cognitive impairment are not completely understood; however, the mechanisms underlying cognitive impairment have been shown to be similar to those that mediate vascular dysfunction [93]. Furthermore, multiple large cohort studies have shown that vascular dysfunction is an independent predictor of cognitive impairment (Figure 7) [55,94]. As such, therapies aimed at improving vascular function hold promise for both directly and indirectly eliciting concomitant improvements in cognitive function.

Figure 7. . Large elastic artery stiffness is an independent risk factor for cognitive impairment.

Stiffening of the large elastic arteries results in increased pulse pressure in the microvasculature of the brain, which can subsequently cause cerebral microvascular damage and dysfunction, and ultimately result in cognitive impairment.

Below, we will further discuss the relation between vascular dysfunction and cognitive impairment, and redundant mechanisms mediating these important biomedical issues.

Cognitive impairment with anthracycline chemotherapy: relation to vascular dysfunction

Dysfunction of the peripheral and central vasculature have been implicated in cognitive impairment [94]. For example, large elastic artery stiffness has been identified as an independent predictor of cognitive impairment and dementias in multiple large cohort studies of healthy individuals (Figure 7) [95,96]. As discussed previously, the inherent elasticity of the large elastic arteries helps to dampen the pulsatility of blood released from the heart during systole, ultimately reducing the pulse pressure entering the microvasculature of end organs (e.g., the brain) [54–56]. With stiffening of the large elastic arteries, there is impaired dampening of blood pulsatility, which can damage the cerebral microvasculature, leading to cognitive impairment and dementias (Figure 7). Furthermore, reduced cerebral vascular function (i.e., impaired cerebrovascular endothelial function) has been directly linked to cognitive impairment in other patient populations (e.g., Alzheimer’s disease) [97]. Anthracycline-based cancer treatments have been associated with reduced cerebral blood flow, which is a known precursor to cognitive decline [98]. Early changes in systemic vascular stiffness and endothelial function may contribute to altered cerebrovascular hemodynamics and impaired cognitive function [99]. However, to date, the relation between vascular dysfunction and cognitive impairment in patients receiving cancer treatment with anthracyclines/DOXO has not been clearly established. Early findings from White et al. suggest that arterial stiffness can predict reductions in cognitive function in cancer survivors [100]; however, more work is necessary to determine the causal relation between large elastic artery stiffness and cognitive impairment in patients receiving cancer treatment with anthracycline/DOXO chemotherapy.

Redundant mechanisms underlying vascular dysfunction & cognitive impairment

Although vascular dysfunction and cognitive impairment are multifaceted processes, there are numerous underlying mechanisms that are redundant between the two conditions. Mechanisms mediating vascular dysfunction have also been shown to regulate cognitive impairment (Figure 8) [101]. Below, we will discuss mitochondrial dysfunction, oxidative stress, inflammation and cellular senescence in the context of cognitive impairment.

Figure 8. . Vascular dysfunction and cognitive impairment induced by anthracycline chemotherapy may share similar underlying mechanisms.

Anthracycline chemotherapy (e.g., doxorubicin) causes mitochondrial dysfunction, excess oxidative stress, chronic inflammation and an increase in cellular senescence and the associated secretome the SASP, and all of these processes have been implicated in both vascular dysfunction and cognitive impairment.

SASP: Senescence-associated secretory phenotype.

Mitochondrial dysfunction

The mitochondrial targeted antioxidant MitoQ (described above) has been shown to prevent memory loss and neuropathology in a preclinical mouse model of Alzheimer’s disease [102]. Furthermore, we have shown that oral supplementation with MitoQ following exposure to DOXO can markedly prevent DOXO-mediated changes in the transcriptome of the mouse hippocampus (memory center of the brain) [103]. Thus, mitochondrial dysfunction, specifically excess mtROS, is a mechanism underlying cognitive impairment and Alzheimer’s disease [104] at both the physiological and biological levels. Ameliorating mitochondrial dysfunction may hold promise for improving cognitive function (Figure 8).

Redox balance: oxidative stress & antioxidant status

Reduced levels of circulating antioxidants (e.g., glutathione) have been shown to predict cognitive impairment – i.e., lower antioxidant status was associated with impaired cognitive function [105]. Furthermore, select antioxidant compounds (e.g., vitamin E and idebenone) have led to improvements in cognitive function in a variety of patient populations with established cognitive impairment, which has previously been reviewed in detail [106]. However, an equal number of trials have reported no difference in cognitive function following antioxidant supplementation [106]; thus, targeting overall redox balance may not be the most effective approach for improving cognitive function (Figure 8).

Inflammation

Systemic inflammation is another underlying mechanism that may contribute to cognitive impairment [107,108]. Elevation in common circulating biomarkers of inflammation, such as circulating C-reactive protein and neutrophil lymphocyte ratio, have been associated with elevated odds of cognitive impairment in elderly cancer survivors [108]. Moreover, neuroinflammation is also thought to contribute to neurodegenerative diseases and subsequent cognitive impairment [109]. As such, targeting excess inflammation may be an effective therapeutic strategy for preventing/treating cognitive impairment (Figure 8).

Cellular senescence

Global clearance of senescent cells in old mice can improve cognitive function with an associated reduction in neuroinflammation, suggesting cellular senescence is a mechanism underlying age related cognitive impairment [110]. In addition, accelerated aging induced by the common cancer treatment, irradiation, can lead to reduced cognitive function and increased neuroinflammation in young mice by increasing cellular senescence [111]. Moreover, the clearance of senescent glial cells can prevent cognitive decline in a mouse model of tau dependent neurodegenerative disease [112]. The induction of senescence in astrocytes and glial cells and their relation to dementia is currently being examined in humans, which is funded by a large multiyear program project grant funded by the National Institutes of Health (P01 AG066591). Findings from this study will provide the most conclusive evidence to date regarding whether or not cellular senescence can be targeted to improve cognitive function in humans (Figure 8).

Research gaps

Monitoring vascular health in cancer survivors

In order to gain further insight into the relation between chemotherapeutic use and vascular function, we posit that there should be more consistent monitoring of vascular health for anthracycline/DOXO-treated cancer survivors. Many cardio-oncology clinics currently assess cardiovascular function via exercise testing, which could be considered a secondary but nonspecific indicator of vascular function [113]. The inclusion of FMD_BA and PWV measures, to allow for more accurate and consistent monitoring of vascular health, could provide additional data to inform future therapeutic strategies aimed at reducing CVD risk in this patient population (Figure 9).

Figure 9. . Future directions.

The field of cardio-oncology is actively pursuing interventions to improve the lives of cancer survivors. To help achieve this goal, it would be advantageous to monitor the vascular health of cancer survivors (e.g., vascular endothelial function via flow-mediated dilation [left side of far-left image] and large elastic artery stiffness via carotid-femoral pulse wave velocity [right side of far-left image]) in order to gain further insight into the CV impacts of cancer and cancer treatments. Future cardio-oncology research should consider sex differences and the effect of other chemotherapeutic agents (other than doxorubicin) on CV and cognitive function. Furthermore, a next phase of cardio-oncology research could include the implementation of interventions known (or have shown promise) to broadly improve CV health and cognitive function. These interventions could be aerobic exercise, resistance training, HIIT, IMST, chronic passive heat therapy and natural senolytics. Together, these recommendations have the potential to elucidate novel effects of chemotherapeutic agents on health and promote improvements in vascular and cognitive function.

CV: Cardiovascular; HIIT: High-intensity interval training; IMST: Inspiratory muscle strength training.

Sex differences

There is evidence to suggest that estrogen can protect against DOXO-induced vascular dysfunction. Specifically, women treated with anthracycline/DOXO chemotherapy to combat breast cancer exhibit vascular dysfunction, but not to the same magnitude as age matched men [114,115]. The potential link between anthracycline/DOXO ‘resistance’ and estrogen receptor status has been examined [116,117], but the literature lacks well-controlled, vascular-focused studies that directly assess the relation between estrogen status and anthracycline/DOXO chemotherapy treatment. Understanding sex differences as they relate to the adverse effects of anthracycline chemotherapy on vascular function, and CV health in general, is a key biomedical research priority as this type of information could pave the way for more individualized treatment approaches.

Self-reported cognitive impairment rates in cancer survivors are higher in women than in men [118]. Preclinical evidence suggests that DOXO leads to long-lasting impairment in spatial memory in female, but not male mice [119]. Accordingly, it is essential to examine potential sex differences regarding CICI in appropriately powered randomized controlled trials in humans.

Additionally, it is critical to examine the influence of being transgender/gender diverse in the context of cardio-oncology research, as medical interventions require a thorough understanding of sex and gender [120]. Gender affirming therapies may have independent effects on vascular function and therefore could also influence the effect of anthracycline chemotherapy on the CV system. A recent preclinical study explored the relation between testosterone replacement therapy and vascular function in young female mice [121] and found that testosterone replacement therapy-induced vascular endothelial dysfunction in young female mice. Therefore, future research is also warranted to better understand the integrative effects of gender affirming therapy and anthracycline chemotherapy treatment on vascular and cognitive function (Figure 9).

Additional chemotherapeutic agents & cardiovascular targeted therapy

Although much of the work to date regarding the CV toxic effects of chemotherapeutic drugs have centered around anthracyclines and DOXO, it is also important to understand the influence of other chemotherapeutic drugs on vascular and cognitive function. For example, there is recent evidence suggesting that the anti-lung cancer drug 5-fluorouracil causes CV toxicity [122]. Much of the anthracycline work to date, especially preclinical work, has focused only on doxorubicin, but doxorubicin is rarely given in isolation. Future preclinical studies should consider giving anthracycline cocktails that are comparable to what humans receive during treatment. It is also important to consider the CV toxic effects of other categories of chemotherapeutic agents – for example, 5-fluorouracil. Thus, future work should consider experimental opportunities to determine the independent and interactive effects of additional common chemotherapeutic agents on vascular and cognitive function during cancer treatment and in cancer survivors.

Dexrazoxane is a cardiovascular targeted mitochondrial DNA damage inhibitor that is given concomitantly with anthracyclines. It acts by reducing mitochondrial reactive oxygen species production. Dexrazoxane has been shown to prevent cardiomyopathy in anthracycline treated adolescents and results in less left ventricle dysfunction in comparison to anthracycline treatment alone [123,124]. However, it is unclear if dexrazoxane directly impacts vascular function in anthracycline treated individuals. It is plausible that the beneficial reductions in cardiotoxicity could be attributed to improvements in vascular function (Figure 9).

Implementing interventions that improve both vascular & cognitive function in anthracycline/DOXO treated cancer survivors

It is important to actively pursue interventions that could lead to broad health improvements in anthracycline/DOXO treated cancer survivors. Therapies aimed at improving both vascular and cognitive function could be a means to accomplish these goals.

Traditional aerobic exercise interventions

Traditional aerobic exercise could be an effective strategy to mitigate both chemotherapy-induced vascular dysfunction and cognitive impairment. Voluntary aerobic exercise is a first-line strategy for improving CV health [21,125–130] and has been shown to improve cognitive function [131,132]; thus, voluntary aerobic exercise may be an effective intervention for improving vascular and cognitive function in anthracycline chemotherapy/DOXO treated cancer survivors. Exercise training also leads to improvements in the physical fitness and subjective quality of life of cancer survivors [133]. Aerobic exercise is a well-established therapeutic strategy for improving vascular endothelial function in anthracycline treated cancer survivors [134]; however, more work is needed to determine its effect on large elastic artery stiffness. Furthermore, aerobic exercise can improve cognitive function in other populations with cognitive impairment (e.g., mid-life/older adults) [135]. Preliminary clinical evidence also suggests that aerobic exercise can mitigate cancer related cognitive impairment in postmenopausal women [136]. In the context of preclinical models, exercise can reduce cognitive impairment in rats treated with the chemotherapeutic drugs 5-fluorouracil and methotrexate [137]. Accordingly, aerobic exercise is a promising intervention that has the potential to improve both vascular and cognitive health in anthracycline/DOXO treated cancer survivors (Figure 9).

Resistance training interventions

Resistance-based exercise interventions in breast cancer survivors have been reviewed elsewhere [138] and report improvements in muscle strength and quality of life and reductions in pain and fatigue. Additionally, exercise interventions combining both aerobic and resistance training have the potential to reduce the risk for developing CVD in patients with breast cancer [139]. However, future studies are needed to systematically determine the influence of resistance training on vascular and cognitive function in cancer survivors that have undergone treatment with anthracycline/DOXO chemotherapy (Figure 9).

Time-efficient exercise training

Although traditional aerobic exercise training can lead to improvements in vascular and cognitive function, patients undergoing cancer treatment and cancer survivors face numerous barriers that lower and/or prevent adherence to exercise guidelines [140]. The American Cancer Society and American College of Sports Medicine have exercise guidelines that are specifically tailored to cancer survivors (150 min of aerobic exercise and 2–3 days of resistance exercise training per week) [141]. Adhering to these recommendations is not always feasible for patients with cancer, as cancer therapy is often associated with lack of time, shortness of breath, muscle weakness, fatigue, lack of motivation and a general lack of interest [140,142]. Thus, implementing time- and resource-efficient forms of exercise training may be an effective approach for cancer survivors that have undergone anthracycline/DOXO chemotherapy treatment (Figure 9).

High-intensity interval training

As mentioned above, cancer survivors face numerous barriers to exercise participation. The most commonly cited barrier to exercise adherence is lack of time [143,144]. As such, time-efficient exercise training could be considered as a more realistic option for these patients in comparison to traditional forms of exercise. High-intensity interval training (HIIT) is a promising type of exercise structure that may be feasible for individuals undergoing cancer treatment and in cancer survivors. Recently, Lee et al. found that HIIT (20 min protocol of seven bouts of 1 min high intensity exercise followed by 2 min of active recovery) can improve vascular endothelial function in patients with breast cancer [61]. Thus, short duration exercise programs have the potential to both overcome barriers to traditional aerobic exercise and improve vascular function in cancer survivors. To build upon these findings, future studies could consider the influence of HIIT on large elastic artery stiffness and cognitive function. Furthermore, additional work is needed to determine the minimal effective dose of exercise necessary for eliciting improvements in vascular function in cancer survivors (Figure 9).

Inspiratory muscle strength training

An additional form of time-efficient exercise training is inspiratory muscle strength training (IMST). Recently, Craighead et al. demonstrated that high resistance IMST (30 breaths/day for 6 weeks) could improve vascular endothelial function in a population with established vascular dysfunction (e.g., mid-life/older adults) [145]. Since anthracycline chemotherapy-mediated vascular dysfunction is considered a model of accelerated vascular aging [75], it is plausible that high-resistance IMST could exert beneficial effects within the vasculature of patients undergoing cancer treatment with chemotherapy and in anthracycline/DOXO treated cancer survivors. Recent findings also suggest that IMST can improve cerebrovascular function [146]; thus, IMST may be a candidate therapeutic strategy for improving both vascular and cognitive function in anthracycline/DOXO treated cancer survivors (Figure 9).

Exercise mimicking interventions

Chronic passive heat therapy – also referred to as repeated full body hot water immersion – can elicit many similar effects on arteries that are observed with traditional aerobic exercise (e.g., improved NO bioavailability). Heat therapy has led to improvements in vascular function in other populations (e.g., sedentary young adults [147] and mid-life/older adults [148]). Specifically, 8 weeks of heat therapy (4–5-times per week) in a 40.5°C bath sufficient to maintain rectal temperature above 38.5°C for 60 min per session improves vascular endothelial function and reduces large elastic artery stiffness [147,148]. Heat therapy also has the potential to improve cognitive function in individuals with age-related diseases such as Alzheimer’s disease (reviewed elsewhere) [149]. Thus, heat therapy via hot water immersion is a promising avenue for future cardio-oncology research, as it has the potential to positively impact the CV and cognitive health of cancer survivors (Figure 9).

Novel & safe senolytic strategies

Work is needed to determine the influence of novel and safe senolytic strategies for improving vascular and cognitive function in anthracycline/DOXO treated cancer survivors. This approach may also influence other mechanisms discussed throughout this review (e.g., excess oxidative stress and inflammation); thus, we believe that senolytic treatments (among others) should be considered as a first-line therapeutic strategy for improving vascular and cognitive function following anthracycline/DOXO chemotherapy. Considerable preclinical data support a negative impact of cellular senescence on vascular endothelial cells [150–154], and early results suggest that cellular senescence can impair vascular function in the setting of DOXO chemotherapy [83]. Therefore, we believe that the clearance of excess senescent cells in chemotherapy treated cancer survivors should elicit beneficial effects on the vasculature. The treatment approach should be tailored to the individual based on the type of cancer, age, comorbidities and cancer treatment regimen and dosing. It is important that senolytic treatment begins after the conclusion of chemotherapeutic treatment so as not to interfere with the anticancer properties of the chemotherapy. Fisetin, a flavonoid found in many commonly consumed foods – for example, strawberries and cucumbers – has been shown to improve healthspan in old mice by targeting cellular senescence and has a favorable safety profile in humans [155–157]. Recent findings from our group suggest that intermittent oral fisetin supplementation can improve vascular function in old mice by directly targeting cellular senescence [84]. Thus, it is highly possible that supplementing anthracycline/DOXO treated cancer survivors with fisetin could be a viable and safe therapeutic approach to improve vascular function. It is currently unknown, in any setting, if fisetin can improve cognitive function (Figure 9).

Conclusion

Vascular dysfunction and cognitive impairment are common side effects of anthracycline chemotherapy treatment, and these two pathological states share many underlying mechanisms. However, potential treatment options for preventing and/or treating vascular dysfunction and cognitive impairment in anthracycline chemotherapy-treated cancer survivors have largely been understudied. Thus, future studies aimed at establishing novel, effective, safe, and tolerable interventions for improving vascular and cognitive function are likely to have a significant biomedical/public health impact.

Future perspective

Vascular dysfunction, defined primarily by vascular endothelial dysfunction and large elastic artery stiffening, is an independent risk factor for the development of CVD and in part, cognitive impairment. It is well known that anthracycline chemotherapeutic agents, particularly DOXO, increase the risk of developing CVD. In this review, we have described: the effect of anthracycline chemotherapeutic agents, specifically DOXO, on vascular endothelial dysfunction and large elastic artery stiffness; how targeting vascular dysfunction may be an effective approach for mitigating elevated CVD risk with DOXO; cellular/molecular mechanisms mediating DOXO-induced vascular dysfunction that could be viewed as therapeutic targets for novel treatment strategies; the relation between vascular dysfunction and cognitive impairment and how targeting improvements in vascular function may be a strategy to prevent or mitigate CICI; and how the mechanisms mediating vascular dysfunction and cognitive impairment are similar, and thus, therapeutic strategies aimed at improving vascular function may directly or indirectly, improve cognitive function. We described current research gaps and possible future directions that the field of cardio-oncology could consider as a means for improving vascular and cognitive function in anthracycline/DOXO treated cancer survivors, and ultimately improving their quality of life.

Executive summary.

• Cancer and cardiovascular diseases (CVD) are highly prevalent and interrelated biomedical issues.

• Common chemotherapeutic agents such as anthracyclines dramatically increase the risk of developing CVD.

  • Endothelial dysfunction is a key antecedent to the development of overt CVD and is induced by anthracycline chemotherapy treatment.

  • Arterial stiffness is an independent predictor of cardiovascular is induced by anthracycline chemotherapy treatment.

  • Chemotherapy-induced cognitive impairment is a pressing issue that is associated with common cancer treatments such as anthracyclines.

• Reverse translational research has revealed that excessive mitochondrial reactive oxygen species, inflammation and cellular senescence contribute to anthracycline chemotherapy-mediated vascular dysfunction.

• Potential therapeutic strategies and future perspectives

  • It is imperative to further examine interventions that are intended to improve both cardiovascular and cognitive function in anthracycline chemotherapy treated cancer survivors.

  • Aerobic exercise, resistance training, high-intensity interval training, inspiratory muscle strength training, heat therapy and natural senolytics have the potential to beneficially impact the vascular and cognitive health of anthracycline treated cancer survivors.