A bench to bedside perspective on anthracycline chemotherapy-mediated cardiovascular dysfunction: challenges and opportunities. A symposium review

Abstract

Cardiovascular diseases (CVD) are the leading cause of death worldwide and the risk of developing CVD is markedly increased following anthracycline chemotherapy treatment. Anthracyclines are an essential component of the cancer treatment regimen used for common forms of cancer in male and female children, adolescents, young adults, and older adults. Increased CVD risk with anthracyclines occurs, in part, due to vascular dysfunction—impaired endothelial function and arterial stiffening. These features of vascular dysfunction also play a major role in other common disorders observed following anthracycline treatment, including chronic kidney disease, dementia, and exercise intolerance. However, the mechanisms by which anthracycline chemotherapy induces and sustains vascular dysfunction are incompletely understood. This budding area of biomedical research is termed cardio-oncology, which presents the unique opportunity for collaboration between physicians and basic scientists. This symposium, presented at Experimental Biology 2022, provided a timely update on this important biomedical research topic. The speakers presented observations made at levels from cells to mice to humans treated with anthracycline chemotherapeutic agents using an array of translational research approaches. The speaker panel included a diverse mix of female and male investigators and unique insight from a cardio-oncology physician-scientist. Particular emphasis was placed on challenges and opportunities in this field as well as mechanisms that could be viewed as therapeutic targets leading to novel treatment strategies.

INTRODUCTION

Cardiovascular diseases (CVD) and cancer are the two leading causes of death in developed and developing nations (1). In the year 2022, the National Cancer Institute estimates there will be ∼2 million new cancer cases and ∼600,000 cancer-related deaths in the United States alone (2). Of the new cancer cases, it is estimated that 650,000 patients will undergo chemotherapy treatment (3). Although chemotherapy is a highly effective treatment strategy for particular cancers, it comes with severe CV side effects (4). As a result, CVD is the leading cause of later morbidity and early mortality among survivors of chemotherapy-treated cancer (5). Worsening CV risk factors also increase the risk of developing cancer in the future (6), which may further influence increased morbidity and mortality in this patient population. In particular, anthracyclines, which are first-line chemotherapeutic agents for several common cancers (e.g., breast, prostate, lymphomas, and leukemias), have toxic effects on the CV system (7, 8). Anthracycline chemotherapeutic agents include daunorubicin, doxorubicin (DOXO), epirubicin, idarubicin, mitoxantrone, and valrubicin (9).

The most commonly administered anthracycline chemotherapeutic agent is DOXO or alternatively referred to as Adriamycin. This compound, among other anthracyclines, is thought to be the major culprit for inducing toxic effects on the CV system (9). As such, a majority of the preclinical work in this field has used DOXO to understand the potential mechanisms by which anthracycline chemotherapeutic agents cause CV dysfunction.

A primary concern for patients exposed to chemotherapy with anthracyclines who survive their cancer is so-called “cardiotoxicity” manifesting clinically as heart failure. The overall incidence of heart failure in patients with cancer treated with DOXO is exponentially increased relative to age- and sex-matched healthy controls (10), with the risk being proportional to the cumulative dose of DOXO received throughout chemotherapy. Such effects have led the National Cancer Institute to state that “the cancer patient of today will likely be the cardiovascular patient of tomorrow.”

Given this link to heart failure, much of the work to date in the emerging field of “cardio-oncology” has understandably focused on anthracycline-induced cardiomyopathy, cardiac dysfunction (e.g., reduced cardiac output and left ventricular ejection fraction), and blood pressure. However, anthracyclines are administered as a systemic therapy and the vasculature is the first tissue exposed to the potentially toxic effects of these drugs (11). Vascular dysfunction is a key antecedent for the development of future CVD (12), so it is entirely possible that DOXO-induced damage to arteries plays an important role in the increased risk of CVD observed in patients treated with these agents (Fig. 1). Thus, understanding the impact of anthracyclines on vascular dysfunction and the underlying mechanisms of action is important in biomedical research gap, as this research could lead to the development of novel targeted therapeutics that could significantly reduce the risk of CVD in patients receiving anthracycline chemotherapy. In this review, we will highlight the work described in the symposium entitled, “A bench to bedside perspective on anthracycline chemotherapy-mediated cardiovascular dysfunction: Challenges and opportunities,” which was presented at Experimental Biology 2022 in Philadelphia, Pennsylvania (Fig. 2).

Figure 1.

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

Figure 2.

A bench to bedside perspective of anthracycline chemotherapy-related cardiovascular dysfunction. This symposium review will highlight the following four areas as it relates to anthracycline chemotherapy-mediated cardiovascular dysfunction: 1) underlying mechanisms (e.g., mitochondrial dysfunction, inflammation; and cellular senescence); 2) public health risks; 3) potential treatment strategies (e.g., exercise training); and 4) a clinical perspective on current and potential monitoring strategies.

Specifically, this review will describe: 1) methods for assessing vascular function; 2) published and emerging findings from preclinical animal studies that have sought to determine the mechanisms by which DOXO causes vascular dysfunction; 3) the need for including vascular function assessments as part of the standard-of-care procedures for monitoring CV health in patients receiving anthracycline chemotherapy for their cancer treatment; 4) lifestyle strategies for improving cardiovascular function in survivors of anthracycline chemotherapy-treated cancer; and 5) clinical insight on the challenges and opportunities in monitoring and preserving vascular function in this patient population (Fig. 2).

OVERVIEW OF VASCULAR FUNCTION

Endothelial Function and Dysfunction

Vascular dysfunction can be defined in multiple ways, but two manifestations of this dysfunction, which are highly associated with clinical CVD risk will be emphasized here. The first is impaired endothelium-dependent dilation (EDD) (13, 14). The vascular endothelium is a single-cell layer at the interface between the flow of blood and the lumen of the artery and the walls of the artery (15). Once believed to be primarily a physical barrier charged with filtering solutes moving between the blood and arterial wall, the vascular endothelium is currently understood to synthesize and release a wide array of biologically active molecules that act in autocrine and/or paracrine fashion to influence the function and health (resistance to disease) of arteries and their surrounding tissues. The most important of these endothelial-derived molecules is nitric oxide (NO), which exerts a provasodilatory and anticoagulative, antiproliferative, and anti-inflammatory protective effects on arteries (15). Experimentally, NO-mediated EDD can be evoked by either a mechanical (i.e., increase in blood flow) or a chemical (e.g., acetylcholine [ACh]) stimulus, both of which activate the enzyme NO synthase (eNOS). eNOS catalyzes the generation of NO from l-arginine and oxygen, with NO subsequently diffusing to vascular smooth muscle cells where it induces vascular smooth muscle relaxation and vasodilation (15). Endothelial dysfunction is characterized by a decline in EDD, largely as a consequence of reductions in NO bioavailability, although changes in other vasoactive factors such as prostaglandins, endothelin-1, norepinephrine, and angiotensin II also may contribute (15) (Fig. 3).

Figure 3.

Traditional mechanisms of vascular dysfunction. Two major macro-mechanistic processes that commonly underly vascular dysfunction are excess oxidative stress and chronic inflammation, which are mutually reinforcing cellular processes (i.e., they can exacerbate one another). Together, these processes induce vascular dysfunction, featuring endothelial dysfunction (bottom left) and large elastic artery stiffness (bottom right), which increase the risk for developing cardiovascular diseases.

Large Elastic Artery Function and Dysfunction

A second important clinical manifestation of vascular dysfunction is the stiffening of the large elastic arteries, that is, the aorta and carotid arteries (16, 17) (Fig. 3). 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 our tissues and cells. Moreover, the elastic recoil of the aorta aids in maintaining perfusion of the heart during diastole (18). The stiffening of these arteries leads to numerous pathophysiological effects that collectively increase the 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 flow (12), especially in high-flow vital organs such as the brain (19, 20) and kidneys (21).

Structural changes to arteries, functional influences (i.e., factors influencing vascular smooth muscle tone), and the intrinsic stiffness of vascular smooth muscle cells may all contribute to large elastic artery stiffening in any particular pathological setting (18). The primary structural changes mediating arterial stiffening occur in the extracellular matrix and include degradation/fragmentation of elastin, an increase in the deposition of collagen (fibrosis), and formation of advanced glycation end products (AGEs), which crosslink collagen fibers, further increasing their stiffness. Increased vascular smooth muscle tone is a consequence of changes in the molecules produced by endothelial cells (e.g., reductions in nitric oxide [NO] and increases in endothelin-1), increased sympathetic nervous system activity and release of norepinephrine, and renin-angiotensin-aldosterone system activity (12, 22, 23). These factors also influence the intrinsic stiffness of the vascular smooth muscle cells, which adds to the stiffness of the arterial wall (24).

MEASURING VASCULAR FUNCTION

Endothelial Function

NO-mediated EDD is measured in preclinical models by assessing changes in artery diameter in response to flow in vivo or changes in diameter of isolated artery segments ex vivo in response to mechanical or pharmacological stimuli, as mentioned earlier (25–28). In humans, the gold-standard noninvasive assessment of NO-mediated EDD is brachial artery flow-mediated dilation (FMD), in which the change in brachial artery diameter in response to blood flow (shear rate)-induced increases in NO production is determined (29). Brachial artery FMD primarily assesses macrovascular (conduit artery) function (29). Microvascular (resistance vessels) function can be determined by measuring changes in blood flow in response to intra-arterial infusions of ACh (30). Endothelial dysfunction is the major antecedent of atherosclerosis, and both reduced brachial artery FMD and resistance artery blood flow responses to ACh are independent predictors of CV events and CVD in large, community-based cohorts free from clinical disease (31) (Fig. 4).

Figure 4.

Methods for assessing vascular endothelial function and large elastic artery stiffness. Endothelial function is most commonly assessed in humans using brachial artery flow-mediated dilation (top left), whereas endothelial function in mice can be assessed using ex vivo carotid artery endothelium-dependent dilation in response to acetylcholine (ACh, top right). Large elastic artery (e.g., aorta) stiffness is assessed in humans between the carotid and femoral arteries or by assessing the distensibility of the carotid artery in response to a given transmural pressure (i.e., carotid artery compliance) (bottom left), whereas it is assessed in mice between the aortic arch and abdominal aorta (bottom right).

Large Elastic Artery Stiffness

In vivo, arterial stiffness can be assessed in preclinical settings and humans using pulse wave velocity (PWV), which is a measure of the (regional) speed of the pulse wave generated by the heart when blood is ejected into the arterial system (18). Aortic PWV, measured as the PWV between the aortic arch and the abdominal aorta, is the predominant measure used in rodents and carotid-femoral PWV is the reference standard measure of aortic stiffness in humans (18). The local distensibility of the carotid artery can also be determined in humans by measuring carotid artery compliance (the change in artery diameter for a given change in arterial pressure) and expressing inversely as carotid β stiffness (32, 33) (Fig. 4).

MECHANISTIC STUDIES IN PRECLINICAL ANIMAL MODELS

It is well established that survivors of cancer who previously received anthracycline chemotherapy have aortic stiffness (33–35) and endothelial dysfunction (36, 37) relative to sex- and age-matched healthy controls. However, until recently, the mechanisms by which these processes occur were not well understood. To address this research gap, Clayton et al. (25) adopted a reverse translation approach and utilized preclinical mouse models of DOXO-induced vascular dysfunction.

Two major macromechanistic processes underlying vascular dysfunction in other settings [e.g., advanced age (15, 38–40)] are tonic excess oxidative stress (25) and chronic sterile inflammation (41). Excess production of ROS (primarily superoxide) in combination with unchanged or decreased abundance/activity of antioxidant enzymes (e.g., superoxide dismutase, SOD) results in the development of oxidative stress in arteries (25). Excess superoxide rapidly reacts with NO to form the secondary reactive species peroxynitrite, decreasing the bioavailability of NO (42), ultimately causing endothelial dysfunction (15). Peroxynitrite also reacts with and oxidizes tetrahydrobiopterin, an essential cofactor for NO production by eNOS (43). Excess ROS also can activate proinflammatory networks such as those regulated by the transcription factor nuclear factor kappa B, which upregulates the production of proinflammatory cytokines that can impair vascular function and activate other ROS-producing systems and enzymes, creating a vicious feed-forward cycle of inflammation and oxidative stress (17, 44, 45).

This overall state of oxidative stress and inflammation also contributes to arterial stiffening by inducing remodeling of the extracellular matrix, which alters structural properties of the arterial wall (18). For example, production of collagen by fibroblasts is stimulated by superoxide-related oxidative stress (46). Furthermore, elastin content is lower in aorta of SOD-deficient mice, consistent with the observation that oxidative stress induces elastin degradation (47). AGEs interact with the receptor for AGEs to activate proinflammatory signaling pathways and oxidative stress, which ultimately perpetuates aortic stiffening and further production of AGEs (23).

Mitochondrial Health

The role of mitochondrial health in mediating vascular function has been reviewed in detail elsewhere (48). In brief, a key source of excess oxidative stress in the vasculature is mitochondria (48). Excessive production of mitochondrial ROS may contribute to vascular oxidative stress and reduce the bioavailability of NO, either directly via formation of peroxynitrite or indirectly by uncoupling of eNOS and reducing NO production due to oxidation of the eNOS cofactor tetrahydrobiopterin (48). These events are further propagated by peroxynitrite inhibition of an appropriate upregulation of the mitochondrial antioxidant enzyme manganese SOD (47). Reduced NO bioavailability leads to impairments in endothelial function (as described earlier) but may also contribute to further mitochondrial dysfunction (49) (Fig. 5).

Figure 5.

Reduced mitochondrial health can lead to vascular dysfunction. A decline in the health of the mitochondria can result in an increase in mitochondrial superoxide-mediated oxidative stress. This excess superoxide can cause endothelial dysfunction directly by interacting with nitric oxide (NO) to produce peroxynitrite (ONOO⁻), which reduces the bioavailability of NO, or by uncoupling endothelial nitric oxide synthase (eNOS) via interaction with the eNOS cofactor tetrahydrobiopterin (BH₄). Excess superoxide can also cause arterial stiffness by increasing arterial collagen deposition, degrading/fragmenting elastin or by cross-linking collagen via an upregulation of advanced glycation end products (AGEs).

For example, excessive mitochondrial ROS production in vascular smooth muscle cells may lead to overproduction of collagen and accelerated elastin degradation/fragmentation (50, 51). Furthermore, mitochondrial ROS are recognized as important activators of proinflammatory signaling in vascular smooth muscle cells implicated in mediating adverse structural changes in arteries (48, 52). Finally, excessive levels of mitochondrial ROS may also contribute to oxidative stress-driven formation of AGEs and subsequent crosslinking of collagen in the arterial wall (48) (Fig. 5).

DOXO, Mitochondrial Health, and Vascular Function

Recently, Clayton et al. (25) sought to determine the influence of mitochondrial ROS in mediating DOXO-induced vascular endothelial dysfunction. In these studies, Clayton et al. (25) showed that DOXO reduces vascular abundance of manganese SOD and that we can reverse endothelial dysfunction in carotid arteries from mice treated with DOXO via ex vivo treatment of arteries with the mitochondrial-targeted antioxidant MitoQ (alternatively referred to as mitoquinone or mitoquinol mesylate). Furthermore, we showed that chronic oral supplementation (4 wk in drinking water) with MitoQ could preserve NO bioavailability and prevent mitochondrial ROS-related suppression of EDD following DOXO treatment. Together, these findings strongly suggest that mitochondrial ROS is a promising therapeutic target for the prevention of DOXO-mediated endothelial dysfunction (Fig. 6). Importantly, MitoQ can increase brachial artery FMD in healthy mid-life/older adults free of overt CVD (53), suggesting it may be effective in treating endothelial dysfunction in survivors of DOXO-treated cancer (which is being investigated in this clinical trial: NCT05146843).

Figure 6.

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 arterial mitochondria-derived superoxide and TNF-alpha(α)-mediated inflammation.

Next, Clayton et al. (41) performed an additional study in young C57BL6/J wild-type mice to determine the mechanisms by which DOXO chemotherapy causes arterial stiffening. We demonstrated that mice administered with DOXO had higher aortic PWV (in vivo aortic stiffness) relative to vehicle (saline)-treated controls, which was mediated by greater intrinsic mechanical stiffness of the aortic wall. The latter was, at least in part, due to the combination of elastin degradation and greater formation of AGEs, inflammation, and greater mitochondrial ROS production (41, 54). Therefore, we then aimed to determine whether mitochondrial-targeted antioxidant supplementation following DOXO administration could prevent DOXO-mediated aortic stiffening. We found that DOXO-treated mice that received 4 wk of oral supplementation (in drinking water) with MitoQ had lower aortic intrinsic mechanical wall stiffness relative to DOXO-treated mice that received standard drinking water (54). These observations suggest that mitochondrial ROS may be a novel therapeutic target for prevention of DOXO-mediated arterial stiffening (Fig. 6). However, future studies are warranted to understand how MitoQ or other mitochondrial-targeted therapies influence aortic PWV following DOXO treatment. Regarding clinical translation, MitoQ is commercially available and safe for use in humans (55, 56). Furthermore, MitoQ has shown to be effective in reducing arterial stiffness in other populations [e.g., mid-life and older adults (53)], and is currently being administered to survivors with DOXO-treated cancer to determine its effect on improving CVD risk factors, such as aortic stiffness (NCT05146843).

Cellular Senescence

Cellular senescence is a multidimensional stress response that causes an essentially irreversible arrest of the cell cycle; however, senescent cells remain metabolically active and secrete a variety of proinflammatory cytokines and other signaling molecules, which are collectively referred to as the senescence-associated secretory phenotype (SASP) (57). Importantly, cellular senescence is increased in response to DOXO chemotherapy, as it is a mechanism by which DOXO suppresses cancer growth (58). However, the associated SASP may 1) lead to further cancer progression (59); 2) increase risk for future cancer development (58); and 3) induce physiological dysfunction [e.g., CVD (60)] during and following chemotherapy treatment. Regarding the latter, the National Cancer Institute recently described the increase in cellular senescence following DOXO chemotherapy as a viable therapeutic target for improving physiological function during and following the treatment period (61).

Cellular senescence has also been implicated in mitochondrial dysfunction (62). There is an established bidirectional relation between cellular senescence/SASP and mitochondrial health, such that reduced mitochondrial health can induce cellular senescence and the SASP may induce a reduction in mitochondrial health. As such, targeting the pathophysiological increase (excess) in senescent cells and the associated SASP could mitigate DOXO-associated vascular dysfunction by improving mitochondrial health. Cellular senescence can be quantified in a variety of ways, as there is a unique “signature” of up- and downregulated genes and proteins in senescent cells. A key aspect of this “signature” is the upregulation of the tumor suppressor protein p16 and p21 (63).

In a setting of vascular endothelial dysfunction (e.g., advanced age), it has been shown that higher (relative to young) arterial abundance of endothelial cell p16 and p21 was inversely related to brachial artery FMD (64). The results of the same study demonstrated that habitually exercising mid-life/older adults have lower endothelial cell p16 and p21 abundance as well as higher FMD, relative to their age-matched sedentary counterparts. Together, these findings suggest that lowering vascular cell senescence may hold promise for improving vascular endothelial function in other pathological settings (e.g., cancer survivors who received DOXO chemotherapy).

To explore the relation between DOXO, cellular senescence, mitochondrial health, and vascular dysfunction, Clayton et al. used a mouse model in which p16+ cells can be readily cleared [p16-3MR mouse (65)]. Specifically, we cleared senescent cells following DOXO administration to determine the influence of cellular senescence in mediating vascular dysfunction induced by DOXO chemotherapy. Our data suggest that clearing senescent cells following DOXO administration prevents arterial stiffening and vascular endothelial dysfunction induced by DOXO (66). This effect appeared to be mediated in part by the preservation of NO bioavailability and prevention of increased aortic intrinsic mechanical wall stiffness. Together, these data suggest that cellular senescence may be a novel therapeutic target for preventing and/or treating DOXO-induced vascular dysfunction (Fig. 7). Currently, there are no approved therapeutic strategies for reducing cellular senescence-associated vascular dysfunction in the setting of DOXO chemotherapy. Thus, a logical next step will be to develop safe and effective translational interventions that can reduce cellular senescence and improve vascular function in patients treated with DOXO chemotherapy.

Figure 7.

Cellular senescence may be a viable therapeutic target for preventing doxorubicin chemotherapy-mediated vascular dysfunction. Cellular senescence is increased in arteries following administration of doxorubicin. Increased cellular senescence with doxorubicin induces excess mitochondrial superoxide and inflammation, in part via the senescence associated secretory phenotype (SASP), which together can drive vascular dysfunction. Thus, cellular senescence may be a viable therapeutic target for preventing and/or treating vascular dysfunction following doxorubicin chemotherapy, which would subsequently reduce the risk of developing cardiovascular diseases (CVDs).

WHY VASCULAR DYSFUNCTION SHOULD BE A COMPONENT OF CVD MONITORING IN PATIENTS TREATED WITH ANTHRACYCLINE CHEMOTHERAPY

As previously mentioned, anthracycline chemotherapy has been shown to induce vascular dysfunction (25, 35, 41, 67–69) (Fig. 8). This is crucial given patients with cancer who have undergone treatment with anthracyclines have increased incidence of CV-related morbidity and mortality relative to age-matched healthy controls (70). Historically, evaluation of vascular health has not been regarded as a part of the clinical cardio-oncology arena due to our limited understanding of the relation between anthracycline chemotherapy-induced vascular dysfunction and CV-related morbidity/mortality. However, recent work provides insight into ways assessments of vascular health can enhance cardiovascular risk stratification and guide primary/primordial prevention strategies in patients following cancer treatment.

Figure 8.

Vascular dysfunction can predict cardiovascular (CV)-related mortality following anthracycline chemotherapy. It is well-established that CV-related mortality is increased following anthracycline chemotherapy treatment. It has recently been established that vascular dysfunction can predict the rate of CV-related mortality in patients treated with anthracycline chemotherapy.

In a recent systematic review and meta-analysis, Parr et al. (34) summarized the literature regarding the relation between multiple types of anticancer therapies, including anthracyclines, and arterial stiffness. This work revealed that anticancer chemotherapy was associated with an ∼1.5 m/s increased pulse wave velocity, which equates to an age-adjusted, sex-adjusted, and risk factor-adjusted 14%, 15%, and 15% greater risk for cardiovascular events, cardiovascular mortality, and all-cause mortality, respectively (71). Furthermore, subanalysis of patients given an anthracycline-based treatment regimen had greater arterial stiffening compared with nonanthracycline-based treatments. These findings expand the field’s understanding of the effects of anthracycline chemotherapy on the CV system beyond the heart, by demonstrating that arterial stiffness occurs immediately after treatment and persists years into survivorship. This is biomedically significant given that even marginal increases in arterial stiffness in otherwise healthy individuals increases the risk of CVD by >10% (71) and that there is a clear relation between arterial stiffness and the prediction of all-cause CV outcomes (72–74). Furthermore, the results highlight the need to develop therapeutic interventions to restore arterial elasticity in patients following chemotherapy and to implement monitoring arterial stiffness as a component of the CV health plan that, per its association with CVD, can be used to stratify patient risk, identify early CV injury during treatment, and detection of long-term CV injury into survivorship.

In the general population, increase in arterial stiffness is acknowledged as a surrogate end-point for cardiovascular disease, as it is a well-established predictor of all-cause and CVD mortality (18, 71, 75). However, until recently there has been a paucity of information on the relation between arterial stiffness and cardiovascular- and cancer-related mortality, in cancer survivorship. In a recent retrospective analysis of data from the Third National Health and Nutrition Examination Survey and Linked Mortality Files, Parr et al. (76) asked whether arterial stiffness [measured via pulse pressure, which is tightly associated with PWV and a clinical index of arterial stiffness (77)] is associated with CV-related mortality. This study revealed that arterial stiffness was associated with CV-related mortality in younger survivors with cancer after adjusting for traditional cardiovascular risk factors. This data was further supported by more recent work demonstrating a several-fold higher risk of CVD in survivors of cancer with elevated carotid-femoral PWVs (78). Moreover, models including measures of arterial stiffness were incrementally more predictive of cardiovascular mortality compared with traditional risk factors, which provides further support for including arterial stiffness in the CV health monitoring plan for patients who are undergoing or who have undergone chemotherapy treatment.

In addition to overall CVD risk, a consequence of increased arterial stiffness is the abnormal pulsatile hemodynamics entering the distal vasculature, which can elicit microvascular distress, structural and functional abnormalities, and end-organ damage. Although multiple organ systems are at risk, alterations within the cerebral circulation have, in recent years, emerged as an important consequence of increased arterial stiffness. Several studies in the general disease-free population have demonstrated that increased arterial stiffness is an independent predictor of cognitive decline (20, 79). However, only one study to date has evaluated this relation within the field of cardio-oncology. In a recent large-scale retrospective study of patients following cancer diagnosis, higher carotid-femoral PWV was shown to be associated with a greater rate of decline in global cognitive function and clinically defined mild cognitive impairment. Given, that many patients who survive their cancer diagnosis are at a higher risk of both cognitive decline across multiple domains (80, 81) as well as cardiovascular disease manifestation (82) compared with the general population, this work further supports continued investigation into its implementation as a risk-stratification strategy following cancer diagnosis.

Similar to arterial stiffness, noninvasive assessment of vascular endothelial dysfunction is an independent predictor of coronary heart disease, atherosclerosis, and occlusive stroke in the general population (83) and is associated with mortality in select populations with CVD or related disorders [e.g., chronic heart failure (84), type 2 diabetes (85), and kidney transplant recipients (86)]. However, the relation between vascular endothelial dysfunction and CV-related mortality in anthracycline chemotherapy-treated patients with cancer remains to be elucidated. Importantly, impaired endothelial function is a predictor of future solid tumor growth (87); thus, although there is more work to be done in this area, it is clear that the assessment of vascular endothelial function is warranted in patients with cancer undergoing anthracycline-based treatments.

Collectively, this work highlights the importance of assessing vascular function as part of the typical CV health monitoring plan in patients undergoing not only anthracycline chemotherapy treatment but also potentially all types of anticancer chemotherapy. Given that clinical assessment of vascular function in patients with cancer may have profound consequences for the management of cardiovascular health into survivorship, a continued understanding of its relation to individual aspects of various treatment regiments (i.e., type and dose) and clinically relevant outcomes should be aggressively pursued.

LIFESTYLE MODIFICATIONS AS A THERAPEUTIC STRATEGY FOR IMPROVING VASCULAR FUNCTION IN SURVIVORS OF ANTHRACYCLINE CHEMOTHERAPY-TREATED CANCER: A FOCUS ON EXERCISE

Exercise participation throughout the anthracycline treatment trajectory is a promising strategy to reduce the risk of developing cardiovascular toxicities (88–91), and as such, it was the primary focus of the “lifestyle modifications” section of this symposium. However, it is also important to note that individualized dietary interventions are recommended as a lifestyle strategy to prevent and/or treat CV dysfunction in the setting of cardio-oncology, which has been reviewed in detail elsewhere (92, 93).

Exercise elicits a multitude of benefits including cardiac strength, function, and capacity, and thus is a well-established component of the American Heart Association for CVD prevention, prehabilitation, and rehabilitation (94). Exercise interventions for cancer survivors improve cardiorespiratory fitness, physical function, quality of life, fatigue, and body composition, with indications that improvements in one or more of these outcomes may lead to better treatment tolerance and effectiveness, and improved prognosis, with larger-scale trials currently underway (95). In fact, Kang et al. (96) recently summarized the current evidence of “Exercise cardio-oncology,” and emphasized the utilization of exercise to prevent, improve, and manage anthracycline-induced CV toxicities in individuals diagnosed with cancer (Fig. 9).

Figure 9.

Exercise training is feasible for survivors with anthracycline chemotherapy-treated cancer and is effective at improving cardiovascular function. Implementing exercise training—a combination of resistance training, high intensity interval training (HIIT), and aerobic training—during or following the completion of anthracycline chemotherapy can prevent and reduce cardiovascular dysfunction, respectively.

In support of the implementation of exercise cardio-oncology, the American Heart Association (AHA) proposed Cardio-Oncology Rehabilitation (CORE) in 2019, a multidisciplinary approach to the cardiovascular rehabilitation of cancer survivors based-off the well-established cardiac rehabilitation programs for patients with noncancer cardiology (92). CORE integrates structured exercise training with a comprehensive infrastructure of nutritional counseling, weight and blood pressure control, diabetes management, assistance with smoking cessation, and psychosocial support. Specifically, CORE recommends individualized aerobic and resistance-based exercise for survivors with cancer who are identified as being at increased risk of CV toxicity development, e.g., those receiving anthracyclines.

Probable mechanisms of action by which exercise mitigates anthracycline-induced CV toxicities warrant attention. Exercise training may have direct effects on the improvements of cardiac muscle adaptation and growth through enhancing cardiomyocyte proliferation (97). In addition, exercise decreases ROS (98) and select evidence suggests exercise may suppress excess cellular senescence (64, 99, 100). Furthermore, exercise training improves the cardiometabolic risk profiles, in part by challenging the sarcopenic effects of cancer treatments or pre-existing comorbidities (101). Specifically, exercise increases CV reserve (97, 102, 103), such as by increasing peak oxygen consumption (V̇o_2peak) through improved endothelial and autonomic function (104), as well as improved cardiac perfusion (105). Importantly, exercise counteracts the fall in V̇o_2peak that typically occurs with anthracycline treatment (106). Targeted exercise may also increase CV reserve by training the diaphragm and decreasing the blood pressure against which the cardiac muscle pumps (107, 108). In addition, exercise has been shown to normalize calcium-handling proteins in cardiac rehabilitation for heart failure (109). Finally, those who are chronically exercise-trained have lower arterial stiffness relative to their sedentary age-matched counterparts (110–113).

Aerobic exercise is the most common mode prescribed to improve cardiorespiratory fitness and cardiovascular function, both surrogate measures of CVD risk (114). For example, clinical aerobic exercise reportedly increased V̇o_2peak among survivors with breast cancer receiving anthracycline chemotherapy treatment (115). In addition, acute (single bout) exercise attenuated the anthracycline-induced increase in N-terminal pro-brain natriuretic peptide (NT-proBNP), a circulating biomarker of CV toxic effects, and resulted in an increase in systolic strain rate and left ventricular ejection fraction (LVEF), suggesting exercise to improve systolic function compared with usual care when completed 24 h before anthracycline infusion on cardiac function in survivors with breast cancer (116).

High-intensity interval training (HIIT) involves alternating bouts of high (e.g., 90% of peak power output) and low (e.g., 10% of peak power output) intensity exercise and is considered an effective form of aerobic training to ameliorate CVD risk factors (117). Lee et al. (118) previously reported that HIIT is feasible (82.3% adherence) among survivors with early stage breast cancer during anthracycline treatment and maintained V̇o_2peak throughout the treatment trajectory. Lee et al. (90) further assessed vascular endothelial function, measured by brachial artery FMD, and vascular wall thickness, measured by carotid intima-media thickness (cIMT)—both of which can predict future atherosclerosis (14). Brachial artery FMD significantly increased in the HIIT group while the usual care controls experienced a significant decrease. HIIT preserved cIMT, compared with a significant decline in the usual care group. Finally, Lee et al. (119) assessed extracellular matrix-regulating enzymes and reported increased levels of matrix metalloproteinases (MMP), which at reduced levels are associated with the development of atherosclerosis (120, 121). MMP-2 significantly increased in both the HIIT and usual care groups, and MMP-9 significantly declined in the HIIT group. Thus, HIIT may be a promising intervention modality in the management of CVD-related factors with larger trials with definitive endpoints needed.

Resistance exercise is typically prescribed to improve skeletal muscle strength and hypertrophy (122), yet improvements in said outcomes can also lead to improvements in CV function (123). One trial to our knowledge to date used exclusively resistance exercise in a cohort receiving anthracycline treatment (124). The BEATE randomized clinical trial assessed a 12-wk resistance training intervention in survivors with stage I–III breast cancer (89.5% receiving adjuvant anthracycline treatment) (124) to investigate the effect of resistance training on fatigue and quality of life, compared with a supervised muscle relaxation group. Resistance exercise was deemed feasible during adjuvant chemotherapy with a 71% adherence rate and exerted significant improvements in physical fitness, assessed by muscle strength, quality of life, and fatigue.

Both aerobic and resistance exercise have independent, beneficial effects on CV-related outcomes that potentially lead to different improved effects on anthracycline-induced cardiovascular toxicities. Within the cancer exercise guidelines recommended by the American College of Sports Medicine (125), combined aerobic and resistance exercises are encouraged so that their respective benefits are collectively obtained (126). Kirkham et al. (126) completed a non-RCT (randomized clinical trial) assessing the effects of an 8–12 wk progressive combined aerobic and resistance exercise intervention on cardiac function assessed by longitudinal strain, LVEF, and longitudinal strain rates, and hemodynamic elements assessed by cardiac output, stroke volume, heart rate, blood pressure, and systemic vascular resistance, among survivors of breast cancer receiving anthracyclines. Systemic vascular resistance significantly decreased compared with baseline in both the exercise and control groups, however, the decrease in systemic vascular resistance was significantly attenuated in the exercise group. Cardiac output was preserved in the exercise group compared with a significant increase from baseline in the control group. Despite this, the exercise group had both a clinically and statistically significant decrease in V̇o_2peak.

Additional combined exercise approaches have been utilized during adjuvant treatment (106). Howden et al. (106) examined the effect of exercise on V̇o_2peak and cardiac function after an 8- to 12-wk aerobic and resistance intervention in survivors of breast cancer receiving anthracyclines (106). The usual care control experienced a 15% decline in V̇o_2peak, which was significantly different from the 4% decline noted in the exercise group. However, the exercise group had a significantly greater baseline V̇o_2peak and it is unclear if this difference was accounted for in the group × time comparison. Furthermore, anthracyclines induced a significant decline in resting measures of LVEF and hemoglobin, and an increase in troponin I, which were not attenuated by exercise (127). Mijwel et al. (127) reported results from the OptiTrain which is a RCT conducted in survivors of breast cancer receiving adjuvant chemotherapy including taxanes, anthracyclines, or a combination of the two, where survivors were randomized to one of three groups: resistance exercise + HIIT, aerobic exercise + HIIT, or usual care control. Both the resistance + HIIT and aerobic + HIIT groups maintained V̇o_2peak, whereas the usual care group had a significant decline.

Based on the current evidence, exercise is a promising nonpharmacological strategy that can be used to mitigate anthracycline-induced CV toxicities among survivors of cancer (Fig. 9). Although the optimal prescription and timing of exercise to elicit the greatest benefit are still unknown, the discussed evidence demonstrates exercise-induced positive effects on CV-related outcomes throughout the treatment trajectory.

Although it is clear that exercise training is an effective therapeutic strategy for mitigating CVD risk associated with anthracycline chemotherapy treatment (90, 96), we must consider the immediate barriers to exercise in these patients (128). Anthracycline-treated survivors with cancer often experience a shortness of breath and may have a hard time undergoing traditional exercise training (128). In addition, it may be challenging to accurately assess baseline V̇o_2peak in these patients, which often serves as the starting point for calculating workload in subsequent exercise training sessions (129). Recently, Michalski et al. (129) determined that traditional assessments of V̇o_2peak—used in healthy individuals—do not accurately predict V̇o_2peak in survivors of cancer and an oncology-specific predictive equation should be used. As such, exercise-like or exercise-mimicking strategies may be viable therapeutic options for improving CV health (similarly to traditional exercise) in anthracycline chemotherapy-treated survivors of cancer—these types of strategies have been reviewed in detail elsewhere, at least in the context of overall CV dysfunction (130).

MONITORING CARDIOVASCULAR DYSFUNCTION IN PATIENTS THAT HAVE UNDERGONE ANTHRACYCLINE CHEMOTHERAPY: CHALLENGES AND OPPORTUNITIES IN CLINICAL PRACTICE

As described earlier, assessment of cardiac function is a primary component of “standard of care” practice for patients following anthracycline chemotherapy treatment. Assessments often include—but are not necessarily limited to—cardiac output, ejection fraction, left ventricular morphology, and blood pressure. However, as outlined in this symposium, we posit that assessment of vascular function (i.e., large elastic artery stiffness and vascular endothelial function) be added to the typical cardiovascular monitoring plan for patients following anthracycline chemotherapy treatment (see Fig. 10). Though, we must understand and acknowledge the challenges of implementing these measurements in a standard treatment plan. Furthermore, if we seek to view these CV dysfunctions as “therapeutic targets” for treatment strategies, we must also recognize the challenges in implementing these treatments.

Figure 10.

A proposal of measures that could represent a comprehensive cardiovascular health monitoring plan in a cardio-oncology clinic. We propose that cardiac function, cardiorespiratory fitness, blood pressure, blood-based biomarkers, endothelial function, and arterial stiffness should all be a component of a patient’s cardiovascular health monitoring plan in a cardio-oncology clinic.

In cardio-oncology, the attending cardio-oncologist often works collaboratively with the oncologist that is overseeing the patient’s cancer treatment, with the goal of establishing a relation between the cancer treatment and cardiac function. Most commonly, cardio-oncologists are board-certified cardiologists, and as such, these individuals may have the opportunity to adjust/add to the standard CV monitoring plan as they see best fit for their patient. Thus, we posit that cardio-oncologists should consider the addition of vascular function assessments to the typical treatment plan, as these processes could be adversely influenced before any changes in cardiac function (for the reasons described earlier), which could prevent the development of, or attenuate the progression of, overt CVD.

Regarding the assessment of large elastic artery stiffness (e.g., aortic PWV), we believe this measure could be readily implemented in a standard CV monitoring plan. Aortic PWV can be accessed via applanation tonometry with simultaneous ECG gating of the R-wave to measure the time delay between the foot of the carotid and femoral arterial pressure waves (18). This technique, relative to others used throughout standard CV health monitoring, requires minimal technical skills, and time spent performing data analysis. However, the assessment of vascular endothelial function via brachial artery FMD (131) requires a trained ultrasonographer and extensive time spent performing data analysis. Thus, if a cardio-oncologist had minimal resources and could choose only one assessment of vascular function, aortic PWV would likely be the top candidate. If resources were not a limiting factor, we would highly encourage cardio-oncologists to consider the addition of both aortic PWV and brachial artery FMD to the traditional CV health monitoring plan. Interestingly, unlike in North America, aortic PWV is used clinically for CVD risk management in Europe and Asia (132); however, it is not yet part of the CV monitoring plan in these continents (133, 134).

Earlier in this symposium, it was suggested that cellular senescence may be a viable therapeutic target to mediate CV dysfunction following anthracycline chemotherapy treatment. This point was supported by preclinical data (54, 66) and a position statement put forth by the National Cancer Institute (61). Although the use of senolytic agents following chemotherapy treatment, for the purpose of targeting cellular senescence, is likely to be effective at attenuating anthracycline chemotherapy-mediated CV dysfunction, more early phase clinical trials need to be completed (and show efficacy) before this can be broadly implemented in the clinical setting.

A burgeoning area in the field of anthracycline-mediated CV dysfunction is the use of blood-based biomarkers as predictors of future CVD risk (135–137). These blood-derived factors could include, but are not limited to 1) structural proteins released by necrotic myocardium (e.g., troponin) (138); 2) cardiomyocyte-derived secreted factors that respond to increased ventricular pressure (e.g., NT-proBNP) (139, 140); 3) immune cell-originating proteins that are released in response to excess oxidative stress and inflammation (e.g., myeloperoxidase) (141); various microRNAs (142); extracellular vesicles (143); proteins involved blood vessel formation (e.g., vascular endothelial growth factor) (25); and metabolites implicated in NO signaling (e.g., arginine, citrulline, and dimethylarginine) (144). Thus, incorporating the assessment of blood-based biomarkers in the standard CV health monitoring plan for anthracycline-treated chemotherapy patients may be a way to predict future CVD and hopefully offset the progression before its onset.

CONCLUSIONS

It is clear that CVD risk is largely elevated by vascular dysfunction. As such, assessing and aiming to improve vascular function in the setting of cardio-oncology may be a strategy to reduce CVD risk in anthracycline chemotherapy-treated survivors of cancer. Moreover, understanding the mechanisms by which anthracycline chemotherapy induces vascular dysfunction could provide a basis for implementing healthy lifestyle interventions known to positively influence these mechanisms, and/or these mechanisms could be viewed as therapeutic targets that could be “aimed” at with novel treatment strategies to improve vascular function.

GRANTS

This study was supported by the National Institutes of Health Awards K99 HL159241 (to Z. S. Clayton) and UL1 TR001855 (to C. M. Dieli-Conwright).

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

Z.S.C. conceived and designed research; Z.S.C. prepared figures; Z.S.C., C.J.A., C.M.D.-C., and H.M.M. drafted manuscript; Z.S.C., C.J.A., C.M.D.-C., and H.M.M. edited and revised manuscript; Z.S.C., C.J.A., C.M.D.-C., and H.M.M. approved final version of manuscript.