Cancer Therapy and Exercise Intolerance: The Heart Is But a Part: JACC: CardioOncology State-of-the-Art Review.

Improved understanding of cancer biology and the discovery of novel therapeutic targets have led to remarkable progressions in cancer therapy efficacy in recent decades. 1 The discovery of targeted agents and immunotherapies has facilitated a paradigm shift in cancer management and contributed to a steady increase in survivorship. 2 Five-year survival rates are rising, and projections forecast that cancer survivor prevalence will grow to 22.5 million by 2032 in the United States alone. 3 This improved survival, however, is associated with a 37% greater risk for cardiovascular disease (CVD), 4 posing a threat to quality of life and longevity in this vulnerable population.

Among cancer survivors, excess CVD risk has been largely ascribed to cancer therapy–induced damage to the heart (ie, cardiotoxicity), giving rise to the medical subspecialty of “cardio-oncology.” In line with this cardiocentric focus, the primary means for diagnosis and risk stratification of cancer survivors with suspected cardiotoxicity are resting cardiac imaging measurements of left ventricular systolic function, primarily left ventricular ejection fraction and global longitudinal strain. 5 , 6 However, there is growing recognition that resting left ventricular ejection fraction is a less robust predictor of adverse CVD outcomes in cancer survivors, 7 and it does not correlate with objective measures of exercise intolerance, 8 a hallmark feature of CVD. Indeed, it is increasingly apparent that the adverse consequences of cancer therapeutics often extend beyond the heart to affect all components of the oxygen cascade (ie, lungs, blood, vasculature, and skeletal muscle). Therefore, current monitoring strategies, which are intended primarily to quantify cardiac dysfunction as a marker of cancer therapy–related toxicity and CVD risk, do not fully capture the breadth of toxicities that affect the oxygen transport system. We propose that integrative measures of global cardiovascular and skeletal muscle function that are highly adaptive and sensitive, such as peak oxygen consumption (V o 2 peak), provide additional insight into CVD prognosis for cancer survivors. V o 2 peak encapsulates the interaction between both central (ie, cardiac output and pulmonary gas diffusion) and peripheral (ie, blood oxygen-carrying capacity, vascular function, and skeletal muscle function) components of the oxygen cascade and is a powerful independent predictor of mortality from CVD (HR: 0.41; 95% CI: 0.16-1.05), cancer (HR: 0.16; 95% CI: 0.09-0.28), and all causes (HR: 0.17; 95% CI: 0.11-0.27) in post-treatment patients with adult-onset cancers (for high vs low cardiorespiratory fitness, respectively). 9 Furthermore, limitations in V o 2 peak can affect one’s ability to perform activities of daily living, thereby also serving as an indicator of functional independence and quality of life. 10 Notably, V o 2 peak is reduced in many cancer survivors and is not entirely explained by declines in cardiac function. 9 , 10 , 11 , 12

In this review, we use the oxygen cascade as a framework to systematically highlight the peripheral toxicities of conventional (ie, chemotherapy and radiation therapy) and novel cancer therapies (ie, hematopoietic cell transplantation [HCT], immune therapy, targeted therapy, and hormone therapy) and their subsequent impact on V o 2 peak and CVD risk. We focus primarily on evidence from commonly prescribed cancer therapies such as chemotherapies (eg, anthracyclines, alkylating agents, antimetabolites, taxanes) and radiation therapy given their widespread use and large evidence base. Where possible, we highlight emerging evidence relating to novel targeted agents. The focus on targeted and immune therapies is important as their use is rapidly increasing because of expanding treatment indications, as well as growing data on their efficacy, and cost-benefit analyses. For example, the proportion of U.S.-based patients with cancer eligible for immune checkpoint inhibitors (ICIs) increased from 1.54% in 2011 to 43.63% in 2018, 13 and similar trends have been seen for tyrosine kinase inhibitors (TKIs), monoclonal antibodies (mAbs), and vascular endothelial growth factor receptor (VEGFR) inhibitors. 14 , 15 , 16 The review also draws upon evidence from preclinical and clinical studies to provide an overview of underpinning mechanisms and clinical implications. We propose that phenotyping the effects of cancer therapy beyond the heart (ie, peripheral toxicities) will more accurately identify cancer survivors at risk for CVD, functional disability, and premature mortality who might benefit from therapeutic intervention, ultimately improving patient outcomes.

Overview of the Oxygen Transport Cascade

The oxygen transport cascade describes the physiological steps involved in transporting oxygen from the atmosphere to muscle mitochondria where the efficient production of energy in addition to numerous other enzymatic reactions that require molecular oxygen occur. During aerobic exercise, the increase in metabolic demand requires more oxygen uptake through convective and diffusive processes coupled with mitochondrial respiration to meet the adenosine triphosphate requirement of the exercising muscles. The convective steps involve the movement of oxygen into the lungs (alveolar ventilation) and transport from the lungs into the periphery via the circulatory system (hemoglobin and cardiac output). The diffusive steps occur as oxygen moves across the alveolar-pulmonary capillary membrane in the lung and during the unloading of oxygen from hemoglobin into capillaries, where cells use oxygen for a variety of biological functions. Importantly, most of the oxygen is consumed by mitochondria to generate adenosine triphosphate via oxidative phosphorylation. Although prior reviews focused on cardiac-specific toxicities, 5 , 17 we focus on the impact cancer therapies have on the factors peripheral to the heart (lungs, blood, vasculature, and skeletal muscle) and subsequently V o 2 peak as organized by the noncardiac components of the oxygen cascade ( Table 1 ).

Diffusive Oxygen Loading

The pulmonary system performs 2 important roles in the oxygen cascade: ventilation, allowing the movement of air molecules from the atmosphere into the alveoli, and gas exchange, which includes the diffusion of oxygen from the alveoli to the pulmonary capillaries. Ventilation increases in response to exercise to enable greater movement of oxygen into the alveoli, where oxygen diffuses into the pulmonary capillary membrane and binds to hemoglobin. Impairment in the efficiency of gas exchange (alveolar to arterial P o 2 difference) can occur during exercise when there is a mismatch in the ventilation/perfusion (V/Q) ratio or changes to oxygen tension. For example, pulmonary embolism, which is a common complication among patients with cancer, can be provoked by multiple agents ( Table 1 ) 18 and is associated with profound exercise intolerance due to V/Q mismatch. There have been a few case reports of interstitial lung disease following treatment with the BCR-ABL TKIs imatinib and nilotinib, which are first-line therapy for chronic myelogenous leukemia, although this is an uncommon complication (estimated at <1%). 19 Interstitial lung diseases are characterized by alveolar and interstitial space damage, pulmonary inflammation, and fibrosis, resulting in decreased pulmonary capacity and impaired gas exchange. 20 Novel hypoxia-inducible transcription factor inhibitors (eg, belzutifan) can cause severe hypoxia for unclear reasons, but it is thought to be related to pulmonary arterial vasoconstriction and V/Q mismatch. 21 Thus, this severe complication of cancer therapy can affect oxygen diffusion capacity within the lungs and likely affects V o 2 peak ( Central Illustration ).

Following the initial convective step of oxygen movement through the lungs to the alveolar capillary membrane, oxygen is loaded to hemoglobin via diffusion in red blood cells and then is distributed throughout the body via the circulatory system. To facilitate the optimal transfer of oxygen, sufficient hemoglobin must be available. As such, factors that reduce hemoglobin levels, such as defective erythropoiesis or hemolysis, can impair V o 2 peak through a reduction in arterial blood oxygen content and, subsequently, reduced skeletal muscle oxygenation ( Central Illustration ). Several cancer chemotherapies (eg, anthracyclines, platinum-based therapies, antimicrotubule agents) cause anemia by their myelosuppressive effects on erythroid progenitor cells, bone marrow activity, and renal function. 22 The severity of chemotherapy-induced anemia is affected by the type and dose of cancer therapy, and it can affect 20% to 100% of patients with lung, breast, hematological, and colorectal cancer undergoing treatment. 23 Fortunately for most patients, anemia is transient, but even small reductions in hemoglobin concentration (ie, 13%-14%, values commonly seen in patients on cancer therapy) have been associated with 9% to 10% reductions in V o 2 peak in healthy individuals (equivalent to a decade of age-related V o 2 peak decline). 24 , 25 On the basis of these correlations, treatment-induced reductions in hemoglobin concentration likely contribute to short-term declines in V o 2 peak. The longer-term impacts are less clear, with persistent anemia beyond myelosuppressive treatment rarely reported in the literature. Oxygen loading can also be influenced by shifts in the oxygen-hemoglobin dissociation curve. Under hypoxic settings, there is a leftward shift in the oxygen-hemoglobin dissociation curve, which leads to tighter binding of oxygen to hemoglobin (eg, greater arterial oxygen content for a given P o 2 ). In contrast, acidosis or hyperthermia can cause a rightward shift in the curve, which increases oxygen extraction in the peripheral tissues.

Autoimmune hemolytic anemia occurs because of increased destruction of red blood cells by autoantibodies and complement and other cell types within the immune system. The condition can occur following allogeneic stem cell transplantation 26 and after treatment with ICI therapy in melanomas and lung cancers. 26 , 27 This severe complication is typically responsive to steroid treatment, with improvement of hemoglobin levels in about 89 days. 27 Although rare (incidence rates are estimated to be <1%), as the use of ICI therapy becomes more widespread, there is the potential that this severe complication might contribute to cardiovascular morbidity and exercise intolerance in patients with cancer.

Convective Oxygen Delivery

Oxygenated blood is distributed to the various capillary plexi in accordance with the metabolic demand of the organ or tissue they supply. The regulation of blood flow depends on the neural, endocrine, and local control of vascular tone and perfusion pressure in distal conduit arteries and arterioles. Importantly, limitations in oxygen delivery have been observed in cancer survivors and are associated with exercise intolerance. 28 , 29 In this setting, impaired oxygen delivery has been associated with cardiac dysfunction, alterations in the structural and mechanical properties of the vasculature, and autonomic dysfunction. The impact of conventional and novel cancer therapies on the noncardiac factors mediating oxygen delivery is highlighted in the Central Illustration and Table 1 .

Vascular toxicities are a frequent complication of a broad range of cancer therapies and contribute to CVD morbidity in cancer survivors. 30 , 31 Arterial stiffening could theoretically limit oxygen delivery by way of blunting the Windkessel effect (which refers to the elastic reservoir properties of a blood vessel and typically dampens the variations in pulse pressure throughout the cardiac cycle) and increasing systemic vascular resistance, while hypertension could contribute to capillary and tissue malperfusion. Preclinical evidence has shown that chemotherapy (eg, anthracyclines, platinum compounds, 5-Fluorouracil), 32 radiation, proteasome inhibitors, and anti–vascular endothelial growth factor (VEGF) therapies can promote pathologic structural and functional alteration of the vascular wall that prelude or reflect arterial stiffening. 33 The mechanisms underpinning cancer therapy–induced vascular toxicities are emerging, with accumulating evidence implicating oxidative stress and inflammation because of their deleterious impacts on nitric oxide signaling, the elastin/collagen ratio, and smooth muscle cell senescence. 34 A pathophysiologic link between cancer therapy and arterial stiffness has been reported, with a recent meta-analysis demonstrating increased arterial stiffness (aortic distensibility, β-stiffness index, pulse-wave velocity) in patients with cancer following exposure to various cancer therapies (ie, anthracycline-based 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 and/or alkylating agent–based 45 , 48 , 49 , 50 chemotherapy, radiation therapy, 51 and VEGFR TKIs 38 , 52 , 53 , 54 , 55 ) compared with both pretreatment values and noncancer controls ( Table 1 ). 40 Subgroup analyses have further demonstrated that anthracycline-based therapies exert a greater vascular toxic effect. Importantly, an inverse relationship between arterial stiffness and V o 2 peak has been observed in anthracycline-treated breast cancer survivors ( R 2 = 0.32-0.38). 41 Arterial stiffening has also been reported in patients with cancer treated with antimetabolite- and taxane-based chemotherapies, 38 , 49 , 56 anti–epidermal growth factor receptor and VEGF mAbs, 38 , 42 , 52 , 57 BCR-ABL1 TKIs, 58 , 59 proteasome inhibitors, 60 aromatase inhibitors, 61 , 62 androgen deprivation therapy, 63 , 64 , 65 and HCT 66 ( Table 1 ). The effects of immunotherapy on arterial stiffness awaits investigation.

Endothelial dysfunction, characterized by reduced vasodilator bioavailability (ie, nitric oxide and prostacyclin) and increased endothelium-derived vasoconstrictor activity (ie, endothelin-1, prostaglandin, and thromboxane), might impair oxygen delivery by increasing peripheral resistance and blunting dilation of arterioles in response to vasoactive stimuli. Preclinical studies have shown that all classes of chemotherapeutic agents, 67 radiation therapy, 68 and select targeted therapy 67 can damage the vascular endothelium and smooth muscle (culminating in impaired vasodilation) via myriad on- and off-target mechanisms. These include DNA damage, down-regulation of critical signaling pathways (eg, VEGF), altered gene expression (eg, redox-regulated transcription factors), as well as oxidative stress, immune system activation, and up-regulation of proinflammatory pathways (all of which are exacerbated in the context of immunotherapy and HCT-mediated cytokine release syndrome). 67 , 68 Cancer therapy–induced endothelial toxicity has also been documented in the clinical setting ( Table 1 ). Longitudinal studies have demonstrated reductions in endothelium-dependent vasodilation of the brachial artery and microcirculatory vessels in patients with cancer treated with VEGFR TKIs or VEGF mAbs (28%-50% and 39%-49% for macrocirculation and microcirculation, respectively), 67 , 69 proteasome inhibitors (35% and 24%), 70 HCT (37% for macrocirculation), 71 and various chemotherapeutics (eg, anthracyclines, antimetabolites, 72 taxanes, 73 and platinum-based alkylating agents; 35%-95% and 24%-29%). 67 Evidence of vascular endothelial dysfunction has also been documented in cross-sectional studies in patients with breast and hematological cancer treated with aromatase inhibitors, 61 , 74 radiation therapy, 75 and BCR-ABL TKIs. 76 It is important to note that not all findings have been concordant. 67 Jones et al 77 , 78 reported no appreciable impairment in endothelial function among anthracycline-treated breast cancer survivors despite impairment in V o 2 peak. Similarly, Koelwyn et al 79 observed normal endothelial function and preserved V o 2 peak in anthracycline-treated breast cancer survivors relative to age-matched noncancer control subjects. Further research is warranted to understand the impact of cancer treatments (particularly anthracyclines) on endothelial function and exercise tolerance, as these findings may be limited by small sample sizes, 77 , 78 potential survivor bias in longer-term investigations, 78 , 79 and selection bias for more physically active patients. 77 In addition, the impact of novel therapeutics such as immunotherapies (eg, ICI, chimeric antigen receptor T-cell therapy, immunomodulatory agents) on endothelial function has yet to be investigated.

The harmful effects of cancer therapy–associated endothelial dysfunction and arterial stiffening on oxygen delivery may be compounded by the coexistence of hypertension, atherosclerosis, thrombosis, or vasospasm. Mechanistically, endothelial dysfunction denotes a state of endothelial activation characterized by vasoconstriction, inflammation, proliferation, coagulation, and thrombosis, while arterial stiffening can evoke similar vascular toxicities through disruptions in laminar blood flow and decreases in wall shear stress. Recent guideline documents, meta-analyses and systemic reviews report increased risks for systemic hypertension, atherosclerotic disease, 80 , 81 and/or arterial thrombosis 81 , 82 , 83 in cancer survivors treated with radiation therapy, 84 , 85 chemotherapy, immunotherapy, 83 , 86 proteasome inhibitors, hormone therapy, 87 and targeted therapies 18 , 30 , 81 , 82 , 87 , 88 compared with the general population ( Table 1 ). Furthermore, cancer therapy–induced vascular dysfunction may facilitate the development of coronary artery vasospasm. 18 , 30 Classical examples include 5-fluorouracil and its oral prodrug capecitabine, as well as cisplatin, paclitaxel, gemcitabine, rituximab, sorafenib, nilotinib, and radiation therapy. 18 , 30 However, whether this phenomenon affects other vascular beds (ie, peripheral arteries) and compromises oxygen delivery and exercise tolerance needs clarification.

Beyond local pathologic vascular alterations, cardiovascular autonomic dysfunction has emerged as a particularly deleterious complication of chemotherapy and radiation. 89 It is not yet known if cancer therapies increase sympathetic outflow, which could compromise oxygen delivery during exercise by counteracting the protective inhibition of sympathetic vasoconstriction in exercising muscle (ie, functional sympatholysis).

Diffusion of Oxygen From Capillaries to Mitochondria and Cells and Metabolism

Oxygen diffusion from the microcirculation to the cells and mitochondria (where oxygen is the final electron acceptor in oxidative phosphorylation) represents the final steps of oxygen use in skeletal muscle and tissues. The pressure gradient for oxygen between the capillary and cells, and the capacity for oxygen diffusion into skeletal muscle (muscle oxygen diffusive conductance [DMO 2 ]) governs oxygen diffusion into tissues. Importantly, exercise intolerance in individuals with chronic cardiopulmonary disease is driven not solely by limited oxygen delivery. Exercise intolerance is also caused by impairment in skeletal muscle oxygen diffusion, secondary to pathologic reductions in hemoglobin levels, density of the skeletal muscle capillary network, and the oxidative capacity of skeletal muscle. 17

A dysfunctional microvascular network resulting from cancer therapy may contribute to impaired DMO 2 by reducing the surface area for the diffusion of oxygen from red blood cells to the myocyte ( Central Illustration , Figure 1 ). 90 Preclinical studies have shown that first-line (neo)adjuvant therapies for several tumor streams, including radiotherapy 91 anthracycline chemotherapy (eg, doxorubicin), but also emerging targeted therapies, including VEGFR TKIs and fusion proteins (eg, axitinib, aflibercept), cause microvascular rarefaction (ie, reduced density of the capillary network). 92 , 93 This reduction in capillarity has the flow-on effect of reducing the surface area for oxygen diffusion into skeletal muscle (and other cells) and contributes to tissue hypoxia. In the context of small molecule TKIs and fusion proteins that directly inhibit VEGFR and platelet-derived growth factor receptor signaling, capillary rarefaction results from accelerated microvascular endothelial cell death and endothelial dysfunction, which precipitates thrombosis and a further decrease in vascular perfusion and consequential microvessel destruction. 93 The mechanisms underlying anthracycline-induced capillary rarefaction are incompletely understood, but reports that VEGF-B gene therapy inhibits doxorubicin-induced capillary rarefaction suggest that similar antiangiogenic mechanisms may also contribute. 94 These findings are confirmed by studies of adult patients with cancer demonstrating that anthracycline-taxane-containing chemotherapy and VEGFR TKIs (eg, pazopanib, sunitinib, telatinib) and mAbs (eg, bevacizumab) provoke capillary rarefaction in the skeletal muscle 95 and skin, 57 , 69 , 96 , 97 respectively ( Table 1 ).

Cancer therapies can also impair microvessel permeability and integrity ( Table 1 ). Capillary leak syndrome is an example of this process and is characterized by capillary hyperpermeability to protein, resulting in edema, hemoconcentration, and hypoalbuminemia. The resultant reductions in local blood volume and increase in oxygen diffusion distance may impair skeletal muscle perfusion and DMO 2 . The pathogenesis of capillary leak syndrome remains unclear, but preclinical and clinical evidence suggests that it may be a consequence of poor endothelial integrity secondary to an increase in cytokines and up-regulation of angiopoietin-2 and VEGF, 98 , 99 but it could also develop from direct toxicity of the anticancer agents on the capillary system. 100 Capillary leak syndrome is a common side effect of HCT and various cancer immunotherapies (eg, interleukin-2, interferon-α, chimeric antigen receptor T-cell therapy), with estimated incidences of 6.8% to 52.7% 101 and 11.8% to 85.5%, 101 , 102 , 103 respectively. Capillary leak syndrome has also been reported following exposure to select targeted therapies (eg, axitinib, bevacizumab, bortezomib, imatinib, rituximab, trastuzumab) and all major classes of chemotherapeutics. 101 , 103 Currently, there is no targeted treatment for this syndrome, though emerging evidence suggests that tocilizumab, an interluekin-6 inhibitor, and dexamethasone may reduce the risk for cytokine release storm and consequently capillary leak syndrome. 103 Accordingly, deleterious effects of anticancer agents on microvascular integrity could persist long after treatment cessation, contributing to abnormal oxygen uptake in skeletal muscles. 98 , 99

Despite the critical nature of skeletal muscle oxidative capacity for aerobic energy production, the impact of cancer therapy on skeletal muscle has received relatively scant attention in clinical studies. There is strong preclinical evidence that many common cancer therapies (most chemotherapies, VEGF-targeted therapies, immunotherapy) can negatively affect skeletal muscle protein synthesis and oxidative capacity via increased reactive oxygen species production, long-term activation of proinflammatory pathways, and direct damage to mitochondria, sarcoplasmic reticulum, and contractile proteins. 104 Clinical studies of patients undergoing anthracycline- and/or taxane-based chemotherapy have shown skeletal muscle degradation, 12 , 105 reductions in high-energy phosphate metabolism, 105 decreased mitochondrial number and/or enzymes, 95 , 106 down-regulation in mitochondrial biogenesis and quality control pathways, 82 , 107 and a reduced proportion of the highly oxidative type I fibers 95 , 106 ( Table 1 ). These could result in changes in oxygen metabolism in peripheral tissues, which could be compounded by additional toxicities due to anemia and venoarterial thrombosis. Moreover, a small study of colorectal cancer survivors undergoing capecitabine chemotherapy combined with radiation therapy coincided with a 20% reduction in V o 2 peak (equivalent to 2 decades of age-related decline) and a 26% reduction in in vivo measures of muscle oxidative capacity (measured using phosphorous spectroscopy). 108 Similarly, a longitudinal study of patients with hematologic cancer undergoing allogeneic HCT reported a 7% reduction in exercise tolerance (measured by the 6-minute walk test) that was significantly correlated with a decline in muscle oxygenation ( R 2 = 0.42). 109

Cancer therapy is also associated with increased fat infiltration in muscle between muscle fibers (termed myosteatosis) ( Table 1 ). Myosteatosis may act as a barrier that impedes oxygen diffusion from capillary to muscle mitochondria. Several longitudinal studies have demonstrated that many chemotherapy regimens commonly used for breast and hematologic malignancies (often including an anthracycline, taxane, and/or platinum compound with our without radiotherapy and/or human epidermal growth factor receptor 2) are associated with increases in myosteatosis ranging from 2% to 28%. 110 , 111 , 112 Importantly, myosteatosis in anthracycline-treated cancer survivors was associated with reductions in V o 2 peak ( R 2 = 0.30-0.68) and reduced gastrocnemius oxygen extraction during plantar flexion exercise. 110 , 113 Given the important regulatory functions of sex hormones on skeletal muscle, gonadal suppression related to chemotherapy, surgical intervention (eg, hysterectomy, oophorectomy) or pharmacologic hormonal therapy may also have an important impact on muscle composition and myosteatosis. Indeed, androgen deprivation therapy for prostate cancer is associated with muscle atrophy (2%-4% reduction in lean body mass) 114 and increased myosteatosis (8%-19% increase), 115 , 116 with noticeable changes that can develop within 12 to 15 weeks of therapy. In women, surgically induced menopause from hysterectomy (with or without oophorectomy) is also associated with lower lean body mass (−0.9% to −1.5%), 117 likely due to marked and rapid declines in circulating estrogens and androgens. Although aromatase inhibitors are associated with significant myalgias and muscle weakness, there is no clear evidence that these symptoms are secondary to muscle atrophy or myosteatosis. 118 Similarly, selective estrogen receptor modulators (eg, tamoxifen) do not appear to induce adverse changes in muscle composition, and paradoxically, preclinical models 119 and early clinical studies 120 of Duchenne muscular dystrophy suggest that tamoxifen may have muscle protective effects (possibly due to an agonistic estrogen receptor effect in skeletal muscle).

Integration of the Oxygen Pathways in Cardio-Oncology

Although the field of cardio-oncology has traditionally sought to understand the complications of cancer therapy through a cardiac-centric lens, there is a clear need for a more integrative conceptualization. The oxygen pathway is an “in-series” system, whereby each step interacts with both preceding and subsequent steps. This means that focusing on only one step in isolation can lead to an underappreciation of the pathobiological causes of a patient’s limitations. Applications of this integrative approach 121 , 122 have provided important insights into the pathobiology of exercise limitations in patients with chronic thromboembolic pulmonary hypertension and heart failure with preserved ejection fraction, respectively. These studies revealed that most patients had defects in multiple steps of the oxygen pathway, and the traditional culprits of reduced oxygen delivery (ie, cardiopulmonary dysfunction) explained a modest degree of impairment in exercise performance. Consequently, a clearer understanding of the multifactorial causes of cardiotoxicity and exercise intolerance in cancer survivors may require a similar integrative approach to patient assessment and therapeutic strategies. For instance, emerging evidence highlights the presence and contribution of altered ventricular-arterial coupling to cardiotoxicity in chemotherapy-treated cancer survivors. 123 Similarly, there is a growing understanding that coronary microvascular dysfunction and/or rarefaction related to chemotherapy, chest-targeted radiation and VEGF-targeted therapies may contribute to cardiotoxicity and heart failure. 30

Evidence from heart failure populations suggests that skeletal muscle plays a role in cardiovascular dysfunction, disability, and clinical outcomes. For example, the effects of chronic inflammation and oxidative stress seen among patients with heart failure are thought to up-regulate the skeletal muscle metaboreflex (ergo- and mechanoreflex). 124 The metaboreflex refers to the neural reflex system that senses changes in local mechanical and metabolites to aid in the regulation and matching muscle blood flow to metabolic demands. 124 Excessive activation of this reflex, which has been reported in individuals with heart failure, results in increases in sympathetic nerve activity and increased systemic vascular resistance that contributes to increased symptoms of breathlessness and, chronically, might also drive subsequent cardiovascular dysfunction. 125 Importantly, the evidence highlighted in the preceding sections suggests that these same pathophysiologic processes may also be at play in the cancer setting. Moreover skeletal muscle alterations associated with cancer and cancer therapy, such as reduced muscle mass and/or increased myosteatosis, are emerging as important predictors of frailty, rehospitalization, and mortality in patients with heart failure. 126 A similar association has also been observed in cancer survivors, in whom measures of muscle mass and/or myosteatosis have been predictive of cardiotoxicity 111 and cancer-related and all-cause mortality. 127

The integrative approach proposed in this review also highlights the need to understand the pathology of cardiotoxicity from a holistic viewpoint. Cardiotoxicity is likely a consequence of multiple hits to the cardiovascular system prior to, during, and following cancer therapy. In addition to the direct insults to the oxygen cascade induced by cancer therapy, there are numerous other processes (beyond the cardiotoxic agents) contributing to dysfunction. Just as in heart failure, this likely reflects the additional direct and indirect insults from cardiovascular risk factors including age, sex, physical inactivity, sedentary behavior, obesity, hypertension, smoking status, and diet, as well as biological processes such as chronic inflammation, oxidative stress, and gonadal/ovarian suppression that could be accelerated by cancer, its treatment (eg, androgen deprivation therapy), and additional risk factors.

Future Directions and Clinical Implications

Identification of exercise intolerance and its physiological underpinnings

An important clinical question is how best to identify those with or at risk for reduced exercise intolerance across the cancer treatment and survivorship continuum ( Table 2 ). The current approach to assess functional capacity from an oncology perspective is to evaluate performance status using the Karnofsky performance status and Eastern Cooperative Oncology Group scales. Although this approach is routinely used in contemporary clinical practice, the utility of these scales is limited to identifying those patients with severe impairment. 128 Thus, given that the impact of functional status is an important predictor of survival in patients with cancer, more accurate quantification of functional status in at-risk populations is warranted. The current gold-standard approach to measure exercise tolerance is cardiopulmonary exercise testing with gas exchange measurement to directly quantify V o 2 peak. If not feasible, alternative assessments such as a graded exercise test (estimating V o 2 peak) or a 6-minute walk test can provide more accessible but less sensitive measures of exercise capacity. The growing use of wearable smart technology that captures measures of exercise performance (eg, walking speed, physical activity) alongside physiological measures (eg, resting and exercise heart rate) may be an untapped resource to understand temporal changes in exercise capacity, functional performance, and disease risk on a large scale. 129 , 130 Regardless, these methods may identify the presence of exercise intolerance but alone are unable to provide a clear diagnosis as to the unique defects in the oxygen pathway contributing to this. Given that the symptoms of exercise intolerance occur during exertion, reliance on resting or nonexercise measures of cardiac, vascular, and pulmonary function also may provide limited insight. The combination of cardiopulmonary exercise testing, to quantify V o 2 peak and respiratory limitations with concurrent measurements of hemodynamic and blood gases is a promising approach for the integrative evaluation of individual and combined oxygen pathway defects. 121 , 122 Combining cardiopulmonary exercise testing with echocardiographic measures of cardiac output allows the assessment of the Fick determinants of oxygen consumption (cardiac output and subsequent back-calculation of arteriovenous oxygen difference), and this may be more scalable approach that has been applied in the assessment of the overarching central and peripheral factors contributing to unexplained dyspnea and heart failure.

A limitation of these approaches is that because of the necessary expertise and equipment, these assessments may not be feasible at all centers. Furthermore, in a setting in which fatigue and shortness of breath are common side effects of treatment, further work is needed to understand which patients may benefit the most from these time- and labor-intensive approaches. Moreover, validated thresholds are needed to better classify the presence of central vs peripheral limitations. Technological advances in bioinformatics, multiomics, and machine learning are making it increasingly possible to characterize the complex molecular changes that underlie the acute and chronic responses to exercise. Indeed, recent findings highlight the potential of this approach to identify particular phenotypes, whereby metabolomic exercise biomarker signatures have been found to be associated with cardiometabolic risk factors 131 , 132 and independently predict long-term CVD and mortality. 133 Whether these approaches can identify exercise intolerance and provide insight into the physiological underpinnings remains to be determined. Application of these approaches (and their insights) in the cancer setting may be an additional pathway toward a personalized understanding of exercise limitations across the cancer treatment continuum.

Therapeutic strategies

Therapeutic guidelines for the prevention and management of cancer treatment–induced CVD are focused on the use of standard pharmacotherapies (eg, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-adrenergic blockers, calcium-channel blockers, statins) for cancer treatment–induced CVD. 5 , 87 Although these approaches could address some steps in the oxygen cascade, such as convective oxygen delivery, the impact of cardiovascular pharmacotherapy on V o 2 peak or the individual components of the oxygen cascade in cancer survivors remains unclear. Modeling of the oxygen cascade in individuals with other forms of cardiovascular pathology has shown that correcting isolated defects in oxygen delivery (such as improving cardiac output and vascular conductance) without addressing other steps (such as impaired DMO 2 ) limits improvement in exercise intolerance. 121 , 122 These findings highlight the importance of evaluating alternative therapies (such as sodium-glucose transport protein 2 inhibitors, phosphodiesterase 5 inhibitors, inorganic nitrates, and elamipretide) that may be able to target these less considered toxicities induced by cancer treatment ( Table 2 ). Indeed, sodium-glucose transport protein 2 inhibitors have shown promising results in terms of improving cardiovascular outcomes in patients with cancer 134 and exercise tolerance in some patients with heart failure, 135 , 136 though the mechanisms of benefit are unclear, and there is currently limited evidence of therapeutic effectiveness for cancer survivors. The lack of evidence for effective therapies to improve exercise tolerance is an area of research that requires urgent attention. Furthermore, addressing these systemic effects through pharmacotherapy alone introduces challenges from the perspective of polypharmacy and economic burden to the individual and health care system. Consequently, lower cost approaches that have the capacity to address multiple defects such as exercise training, physical activity, and dietary interventions may also be worth investigating. Indeed, structured exercise training is considered a cornerstone for improving V o 2 peak across the continuum of both CVD and cancer, 137 with a meta-analysis of 48 randomized controlled trials (encompassing 3,632 patients with cancer) demonstrating a clinically meaningful improvement in V o 2 peak (2.13 mL/kg/min) with structured aerobic with or without resistance exercise training compared with usual care. 138 A key feature of exercise training (defined as planned, structured, and purposeful movement of moderate intensity or greater at a sufficient volume or dose to improve physical fitness) is its ability to systemically target multiple steps in the oxygen cascade, including one of the few efficacious strategies for targeting the microvasculature and skeletal muscle ( Table 2 ). For example, Mijwel et al 95 demonstrated that 16 weeks of moderate- to high-intensity aerobic exercise with or without resistance training during anthracycline-paclitaxel chemotherapy prevented reductions in skeletal muscle capillarity, mitochondrial content, muscle fiber area, and the proportion of oxidative muscle fibers. Similarly, 12 months of combined progressive aerobic and resistance training markedly improved V o 2 peak (+3.5 mL/kg/min) and cardiac output (increasing convective oxygen delivery) in women undergoing treatment for breast cancer. 137 The optimal exercise dose and modality to address deficits in the oxygen pathway are unclear, with very few studies directly comparing aerobic exercise with resistance exercise and evaluating relevant outcomes. In studies evaluating resistance training alone during anticancer treatment, it was shown to favorably affect body composition (increasing lean mass and decreasing fat mass) and to improve strength. 139 Whether these benefits translate to improvements in skeletal muscle diffusion capacity and intracellular oxidative function remains to be determined and is an important area for future research ( Table 3 ). Alternatively, physical activity interventions (focused on increasing general daily activity and reducing sedentary time) are another approach to improving cardiometabolic health that may counter the acceleration of peripheral toxicity induced by sedentary behavior during and after cancer therapy. Indeed, a meta-analysis of 35 randomized controlled trials investigating the impact of physical activity interventions using wearable technology (pedometers and/or physical activity monitors such as Fitbits) with or without behavioral counseling in cancer survivors demonstrated moderate to large effects on the weekly volume of total (standardized mean difference [SMD] = 0.62) and moderate to vigorous physical activity (SMD = 0.61) and increases in cardiorespiratory fitness (SMD = 0.51). 140 However, the mechanisms in the oxygen pathway mediating this improvement are yet to be established. Although the direct impact of dietary interventions on V o 2 peak remains unclear, strategies such as caloric restriction, time-restricted feeding, increased diet quality (eg, Mediterranean diet, Dietary Approaches to Stop Hypertension diet) or more targeted supplementation (eg, inorganic nitrates 141 ) may help address factors such as ectopic fat accumulation, chronic inflammation, and oxidative stress that contribute to the underlying peripheral toxicities.

Conclusions

Exercise intolerance is an important, but underappreciated marker of the increased cardiovascular risk and functional limitations experienced by cancer survivors. Traditionally, impairments in V o 2 peak are attributed to cardiac limitations, but there is growing evidence that current and emerging cancer therapy induce substantial impairment on the noncardiac components of oxygen uptake, delivery, and use. Improving our understanding of and appreciation for these noncardiac effects may yield critical insights necessary for targeted, multifaceted diagnostic and therapeutic strategies necessary to address functional limitation and adverse cardiovascular outcomes in this complex population.

COMPETENCY IN MEDICAL KNOWLEDGE: Cancer therapy related peripheral toxicities in cardio-oncology are routinely considered as contributors to patient CVD risk.

TRANSLATIONAL OUTLOOK: Treating the effects of cancer therapy on the periphery could lower the future risk of CVD and improve cancer survivorship.

Funding Support and Author Disclosures

Dr Howden is supported by the National Heart Foundation of Australia Future Leader Fellowship (102536) and the National Health and Medical Research Council (GNT 1119955). Dr Touyz is supported by a Canada Research Chair, Canadian Institutes of Health Research, and the Dr Phil Gold Chair, McGill University. Dr Herrmann is supported by the National Cancer Institute (CA 233601) and the Miami Heart Research Institute; has received consulting fees from Pfizer, AstraZeneca, and Astellas; and has received royalties from Elsevier. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Footnotes

The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center .

References

1. Siegel R.L., Miller K.D., Wagle N.S., Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17–48. doi: 10.3322/caac.21763.

2. Global Burden of Disease 2019 Cancer Collaboration. Kocarnik J.M., Compton K., Dean F.E., et al. Cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 29 cancer groups from 2010 to 2019: a systematic analysis for the Global Burden of Disease Study 2019. JAMA Oncol. 2022;8:420–444. doi: 10.1001/jamaoncol.2021.6987.

3. Miller K.D., Nogueira L., Devasia T., et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 2022;72:409–436. doi: 10.3322/caac.21731.

4. Florido R., Daya N.R., Ndumele C.E., et al. Cardiovascular disease risk among cancer survivors: the Atherosclerosis Risk in Communities (ARIC) study. J Am Coll Cardiol. 2022;80:22–32. doi: 10.1016/j.jacc.2022.04.042.

5. Lyon A.R., López-Fernández T., Couch L.S., et al. 2022 ESC guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS) developed by the task force on cardio-oncology of the European Society of Cardiology (ESC) Eur Heart J. 2022;43:4229–4361. doi: 10.1093/eurheartj/ehac244.

6. Curigliano G., Lenihan D., Fradley M., et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol. 2020;31:171–190. doi: 10.1016/j.annonc.2019.10.023.

7. Cardinale D., Colombo A., Bacchiani G., et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131:1981–1988. doi: 10.1161/CIRCULATIONAHA.114.013777.

8. Howden E.J., Foulkes S., Dillon H.T., et al. Traditional markers of cardiac toxicity fail to detect marked reductions in cardiorespiratory fitness among cancer patients undergoing anti-cancer treatment. Eur Heart J Cardiovasc Imaging. 2021;22:451–458. doi: 10.1093/ehjci/jeaa421.

9. Groarke J.D., Payne D.L., Claggett B., et al. Association of post-diagnosis cardiorespiratory fitness with cause-specific mortality in cancer. Eur Heart J Qual Care Clin Outcomes. 2020;6:315–322. doi: 10.1093/ehjqcco/qcaa015.

10. Forman D.E., Arena R., Boxer R., et al. Prioritizing functional capacity as a principal end point for therapies oriented to older adults with cardiovascular disease: a scientific statement for healthcare professionals from the American Heart Association. Circulation. 2017;135:e894–e918. doi: 10.1161/CIR.0000000000000483.

11. Cramer L., Hildebrandt B., Kung T., et al. Cardiovascular function and predictors of exercise capacity in patients with colorectal cancer. J Am Coll Cardiol. 2014;64:1310–1319. doi: 10.1016/j.jacc.2014.07.948.

12. Dillon H.T., Foulkes S., Horne-Okano Y.A., et al. Rapid cardiovascular aging following allogeneic hematopoietic cell transplantation for hematological malignancy. Front Cardiovasc Med. 2022;9 doi: 10.3389/fcvm.2022.926064.

13. Haslam A., Prasad V. Estimation of the percentage of US patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Netw Open. 2019;2 doi: 10.1001/jamanetworkopen.2019.2535.

14. Shang J., Zhou L., Huang L., et al. Trends in antineoplastic drug use, cost and prescribing patterns among patients with lung cancer in nine major cities of China, 2016-2020: a retrospective observational study based on inpatient and outpatient hospital data. BMJ Open. 2023;13 doi: 10.1136/bmjopen-2022-069645.

15. Talon B., Calip G.S., Lee T.A., Sharp L.K., Patel P., Touchette D.R. Trend in tyrosine kinase inhibitor utilization, price, and out-of-pocket costs in patients with chronic myelogenous leukemia. JCO Oncol Pract. 2021;17:e1811–e1820. doi: 10.1200/OP.20.00967.

16. Yao D., Yu L., He W., et al. Antineoplastic prescription among patients with colorectal cancer in eight major cities of China, 2015-2019: an observational retrospective database analysis. BMJ Open. 2021;11 doi: 10.1136/bmjopen-2020-046166.

17. Haykowsky M.J., Kirkham A.A., Li T., et al. Determinants of oxygen utilization in breast cancer: similarities between heart failure with preserved ejection fraction. Prog Cardiovasc Dis. 2022;74:45–52. doi: 10.1016/j.pcad.2022.10.005.

18. Herrmann J., Yang E.H., Iliescu C.A., et al. Vascular toxicities of cancer therapies: the old and the new—an evolving avenue. Circulation. 2016;133:1272–1289. doi: 10.1161/CIRCULATIONAHA.115.018347.

19. Caldemeyer L., Dugan M., Edwards J., Akard L. Long-term side effects of tyrosine kinase inhibitors in chronic myeloid leukemia. Curr Hematol Malig Rep. 2016;11:71–79. doi: 10.1007/s11899-016-0309-2.

20. King T.E., Jr. Clinical advances in the diagnosis and therapy of the interstitial lung diseases. Am J Respir Crit Care Med. 2005;172:268–279. doi: 10.1164/rccm.200503-483OE.

21. Jonasch E., Donskov F., Iliopoulos O., et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med. 2021;385:2036–2046. doi: 10.1056/NEJMoa2103425.

22. Baik A.H. Hypoxia signaling and oxygen metabolism in cardio-oncology. J Mol Cell Cardiol. 2022;165:64–75. doi: 10.1016/j.yjmcc.2021.12.013.

23. Ludwig H., Van Belle S., Barrett-Lee P., et al. The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer. 2004;40:2293–2306. doi: 10.1016/j.ejca.2004.06.019.

24. Fleg J.L., Pina I.L., Balady G.J., et al. Assessment of functional capacity in clinical and research applications: an advisory from the Committee on Exercise, Rehabilitation, and Prevention, Council on Clinical Cardiology, American Heart Association. Circulation. 2000;102:1591–1597. doi: 10.1161/01.cir.102.13.1591.

25. Ekblom B., Goldbarg A.N., Gullbring B. Response to exercise after blood loss and reinfusion. J Appl Physiol. 1972;33:175–180. doi: 10.1152/jappl.1972.33.2.175.

26. Migdady Y., Pang Y., Kalsi S.S., Childs R., Arai S. Post-hematopoietic stem cell transplantation immune-mediated anemia: a literature review and novel therapeutics. Blood Adv. 2022;6:2707–2721. doi: 10.1182/bloodadvances.2021006279.

27. Leaf R.K., Ferreri C., Rangachari D., et al. Clinical and laboratory features of autoimmune hemolytic anemia associated with immune checkpoint inhibitors. Am J Hematol. 2019;94:563–574. doi: 10.1002/ajh.25448.

28. Howden E.J., Bigaran A., Beaudry R., et al. Exercise as a diagnostic and therapeutic tool for the prevention of cardiovascular dysfunction in breast cancer patients. Eur J Prev Cardiol. 2019;26:305–315. doi: 10.1177/2047487318811181.

29. Foulkes S., Costello B.T., Howden E.J., et al. Exercise cardiovascular magnetic resonance reveals reduced cardiac reserve in pediatric cancer survivors with impaired cardiopulmonary fitness. J Cardiovasc Magn Reson. 2020;22:64. doi: 10.1186/s12968-020-00658-4.

30. Herrmann J. Vascular toxic effects of cancer therapies. Nat Rev Cardiol. 2020;17:503–522. doi: 10.1038/s41569-020-0347-2.

31. Campia U., Moslehi J.J., Amiri-Kordestani L., et al. Cardio-oncology: vascular and metabolic perspectives: a scientific statement from the American Heart Association. Circulation. 2019;139:e579–e602. doi: 10.1161/CIR.0000000000000641.

32. Bosman M., Favere K., Neutel C.H.G., et al. Doxorubicin induces arterial stiffness: a comprehensive in vivo and ex vivo evaluation of vascular toxicity in mice. Toxicol Lett. 2021;346:23–33. doi: 10.1016/j.toxlet.2021.04.015.

33. Soultati A., Mountzios G., Avgerinou C., et al. Endothelial vascular toxicity from chemotherapeutic agents: preclinical evidence and clinical implications. Cancer Treat Rev. 2012;38:473–483. doi: 10.1016/j.ctrv.2011.09.002.

34. Zieman S.J., Melenovsky V., Kass D.A. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol. 2005;25:932–943. doi: 10.1161/01.ATV.0000160548.78317.29.

35. Daskalaki M., Makris T., Vassilakopoulos T., et al. Effects of anthracyclines on aortic distensibility in patients with lymphomas: a prospective study. Hellenic J Cardiol. 2014;55:191–196.

36. Chaosuwannakit N., D’Agostino Jr R., Hamilton C.A., et al. Aortic stiffness increases upon receipt of anthracycline chemotherapy. J Clin Oncol. 2010;28:166. doi: 10.1200/JCO.2009.23.8527.

37. Drafts B.C., Twomley K.M., D’Agostino R., et al. Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease. J Am Coll Cardiol Img. 2013;6:877–885. doi: 10.1016/j.jcmg.2012.11.017.

38. Grover S., Lou P., Bradbrook C., et al. Early and late changes in markers of aortic stiffness with breast cancer therapy. Intern Med J. 2015;45:140–147. doi: 10.1111/imj.12645.

39. Militaru A., Avram A., Cimpean A.M., et al. The assessment of left ventricle function and subclinical atherosclerosis in patients with acute myeloid leukemia. In Vivo. 2018;32:1599–1607. doi: 10.21873/invivo.11420.

40. Parr S.K., Liang J., Schadler K.L., Gilchrist S.C., Steele C.C., Ade C.J. Anticancer therapy-related increases in arterial stiffness: a systematic review and meta-analysis. J Am Heart Assoc. 2020;9 doi: 10.1161/JAHA.119.015598.

41. Kirkham A.A., Paterson D.I., Haykowsky M.J., et al. Aerobic fitness is related to myocardial fibrosis post–anthracycline therapy. Med Sci Sports Exerc. 2021;53:267–274. doi: 10.1249/MSS.0000000000002469.

42. Yersal Ö., Eryilmaz U., Akdam H., Meydan N., Barutca S. Arterial stiffness in breast cancer patients treated with anthracycline and trastuzumab-based regimens. Cardiol Res Pract. 2018;2018 doi: 10.1155/2018/5352914.

43. Herceg-Čavrak V., Ahel V., Batinica M., Matec L., DJCa Kardoš. Increased arterial stiffness in children treated with anthracyclines for malignant disease. Coll Antropol. 2011;35:389–395.

44. Budinskaya K., Puchnerová V., Svačinová J., et al. Non-invasive assessment of vascular system function and damage induced by anthracycline treatment in the pediatric cancer survivors. Physiol Res. 2017;66(suppl 4):S553–S560. doi: 10.33549/physiolres.933794.

45. Jenei Z., Bárdi E., Magyar M.T., et al. Anthracycline causes impaired vascular endothelial function and aortic stiffness in long term survivors of childhood cancer. Pathol Oncol Res. 2013;19:375–383. doi: 10.1007/s12253-012-9589-6.

46. Frye J.N., Sutterfield S.L., Caldwell J.T., et al. Vascular and autonomic changes in adult cancer patients receiving anticancer chemotherapy. J Appl Physiol. 2018;125:198–204. doi: 10.1152/japplphysiol.00005.2018.

47. Krystal J.I., Reppucci M., Mayr T., Fish J.D., Sethna C.J. Arterial stiffness in childhood cancer survivors. Pediatr Blood Cancer. 2015;62:1832–1837. doi: 10.1002/pbc.25547.

48. Sekijima T., Tanabe A., Maruoka R., et al. Impact of platinum-based chemotherapy on the progression of atherosclerosis. Climacteric. 2011;14:31–40. doi: 10.3109/13697137.2010.522278.

49. Visvikis A., Kyvelou S.M., Pietri P., et al. Cardiotoxic profile and arterial stiffness of adjuvant chemotherapy for colorectal cancer. Cancer Manag Res. 2020;12:1175–1185. doi: 10.2147/CMAR.S223032.

50. Nuver J., Smit A.J., van der Meer J., et al. Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer. J Clin Oncol. 2005;23:9130–9917. doi: 10.1200/JCO.2005.01.4092.

51. Vallerio P., Sarno L., Stucchi M., et al. Long-term effects of radiotherapy on arterial stiffness in breast cancer women. Am J Cardiol. 2016;118:771–776. doi: 10.1016/j.amjcard.2016.06.001.

52. Res E., Kyvelou S.M., Vlachopoulos C., et al. Metastatic malignancies and the effect on arterial stiffness and blood pressure levels: the possible role of chemotherapy. Onco Targets Ther. 2018;11:6785–6793. doi: 10.2147/OTT.S156318.

53. Alivon M., Giroux J., Briet M., Goldwasser F., Laurent S., Boutouyrie PJJoh. Large artery stiffness and hypertension after antiangiogenic drugs: influence on cancer progression. J Hypertens. 2015;33:1310–1317. doi: 10.1097/HJH.0000000000000550.

54. Mäki-Petäjä K.M., McGeoch A., Yang L.L., et al. Mechanisms underlying vascular endothelial growth factor receptor inhibition–induced hypertension: the HYPAZ trial. Hypertension. 2021;77:1591–1599. doi: 10.1161/HYPERTENSIONAHA.120.16454.

55. Veronese M.L., Mosenkis A., Flaherty K.T., et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol. 2006;24:1363–1369. doi: 10.1200/JCO.2005.02.0503.

56. Florescu M., Mihalcea D., Enescu O.A., et al. Taxanes-induced cardiotoxicity is related to increased arterial stiffness and oxidative stress. Eur Heart J. 2013;34(suppl 1)

57. Steeghs N., Rabelink T., Op’t Roodt J., et al. Reversibility of capillary density after discontinuation of bevacizumab treatment. Ann Oncol. 2010;21:1100–1105. doi: 10.1093/annonc/mdp417.

58. Kim T.D., Rea D., Schwarz M., et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia. 2013;27:1316–1321. doi: 10.1038/leu.2013.70.

59. Rattanathammethee T., Tantiworawit A., Rattarittamrong E., et al. Peripheral artery occlusive disease among patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors: a cross-sectional case-control study. Clin Med Insights Cardiol. 2017;11 doi: 10.1177/1179546817747258.

60. Astarita A., Mingrone G., Airale L., et al. Carfilzomib-based regimen and cardiotoxicity in multiple myeloma: incidence of cardiovascular events and organ damage in carfilzomib-dexamethasone versus carfilzomib-lenalidomide-dexamethasone. A real-life prospective study. Cancers (Basel) 2023;15(3):955. doi: 10.3390/cancers15030955.

61. Blaes A., Beckwith H., Florea N., et al. Vascular function in breast cancer survivors on aromatase inhibitors: a pilot study. Breast Cancer Res Treat. 2017;166:541–547. doi: 10.1007/s10549-017-4447-6.

62. Maor R., Sara J.D.S., Wanous A.A., et al. Attenuated peripheral endothelial function among women treated with aromatase inhibitors for breast cancer. Coron Artery Dis. 2018;29:687–693. doi: 10.1097/MCA.0000000000000666.

63. Smith J., Bennett S., Evans L., et al. The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer. J Clin Endocrinol Metab. 2001;86:4261–4267. doi: 10.1210/jcem.86.9.7851.

64. Oka R., Utsumi T., Endo T., et al. Effect of androgen deprivation therapy on arterial stiffness and serum lipid profile changes in patients with prostate cancer: a prospective study of initial 6-month follow-up. Int J Clin Oncol. 2016;21:389–396. doi: 10.1007/s10147-015-0891-7.

65. Dockery F., Bulpitt C.J., Agarwal S., Vernon C., Rajkumar CJJoa. Effect of androgen suppression compared with androgen receptor blockade on arterial stiffness in men with prostate cancer. J Androl. 2009;30:410–415. doi: 10.2164/jandrol.108.006924.

66. Climie R.E., Dillon H.T., Horne-Okano Y., et al. Vascular aging is accelerated in hematological cancer survivors who undergo allogeneic stem cell transplant. Hypertension. 2023;80:1881–1889. doi: 10.1161/HYPERTENSIONAHA.123.21115.

67. Terwoord J.D., Beyer A.M., Gutterman D.D. Endothelial dysfunction as a complication of anti-cancer therapy. Pharmacol Ther. 2022;237 doi: 10.1016/j.pharmthera.2022.108116.

68. Venkatesulu B.P., Mahadevan L.S., Aliru M.L., et al. Radiation-induced endothelial vascular injury: a review of possible mechanisms. J Am Coll Cardiol Basic Trans Science. 2018;3:563–572. doi: 10.1016/j.jacbts.2018.01.014.

69. Mourad J.J., des Guetz G., Debbabi H., Levy B.I. Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol. 2008;19:927–934. doi: 10.1093/annonc/mdm550.

70. Kastritis E., Laina A., Georgiopoulos G., et al. Carfilzomib-induced endothelial dysfunction, recovery of proteasome activity, and prediction of cardiovascular complications: a prospective study. Leukemia. 2021;35:1418–1427. doi: 10.1038/s41375-021-01141-4.

71. Poreba M., Gac P., Usnarska-Zubkiewicz L., et al. Endothelial function in patients with hematologic malignancies undergoing high-dose chemotherapy followed by hematopoietic stem cell transplantation. Cardiovasc Toxicol. 2016;16:156–162. doi: 10.1007/s12012-015-9324-0.

72. Hammond S.T., Baumfalk D.R., Parr S.K., et al. Impaired microvascular reactivity in patients treated with 5-fluorouracil chemotherapy regimens: potential role of endothelial dysfunction. Int J Cardiol Heart Vasc. 2023;49 doi: 10.1016/j.ijcha.2023.101300.

73. Vassilakopoulou M., Mountzios G., Papamechael C., et al. Paclitaxel chemotherapy and vascular toxicity as assessed by flow-mediated and nitrate-mediated vasodilatation. Vasc Pharmacol. 2010;53:115–121. doi: 10.1016/j.vph.2010.05.002.

74. Broberg O., Ora I., Wiebe T., Weismann C.G., Liuba P. Characterization of cardiac, vascular, and metabolic changes in young childhood cancer survivors. Front Pediatr. 2021;9 doi: 10.3389/fped.2021.764679.

75. Beckman J.A., Thakore A., Kalinowski B.H., Harris J.R., Creager M.A. Radiation therapy impairs endothelium-dependent vasodilation in humans. J Am Coll Cardiol. 2001;37:761–765. doi: 10.1016/s0735-1097(00)01190-6.

76. Kaneko T., Miyazaki S., Kurita A., et al. Endothelial function measured by peripheral arterial tonometry in patients with chronic myeloid leukemia on tyrosine kinase inhibitor therapy: a pilot study. Cardio-Oncology. 2023;9:11. doi: 10.1186/s40959-023-00164-3.

77. Jones L.W., Fels D.R., West M., et al. Modulation of circulating angiogenic factors and tumor biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy. Cancer Prev Res (Phila) 2013;6:925–937. doi: 10.1158/1940-6207.CAPR-12-0416.

78. Jones L.W., Haykowsky M., Peddle C.J., et al. Cardiovascular risk profile of patients with HER2/neu-positive breast cancer treated with anthracycline-taxane–containing adjuvant chemotherapy and/or trastuzumab. Cancer Epidemiol Biomarkers Prev. 2007;16:1026–1031. doi: 10.1158/1055-9965.EPI-06-0870.

79. Koelwyn G.J., Lewis N.C., Ellard S.L., et al. Ventricular-arterial coupling in breast cancer patients after treatment with anthracycline-containing adjuvant chemotherapy. Oncologist. 2016;21:141–149. doi: 10.1634/theoncologist.2015-0352.

80. Douxfils J., Haguet H., Mullier F., Chatelain C., Graux C., Dogné J.-M. Association between BCR-ABL tyrosine kinase inhibitors for chronic myeloid leukemia and cardiovascular events, major molecular response, and overall survival: a systematic review and meta-analysis. JAMA Oncol. 2016;2:625–632. doi: 10.1001/jamaoncol.2015.5932.

81. Totzeck M., Mincu R.I., Rassaf T. Cardiovascular adverse events in patients with cancer treated with bevacizumab: a meta-analysis of more than 20 000 patients. J Am Heart Assoc. 2017;6(8) doi: 10.1161/JAHA.117.006278.

82. Liu B., Ding F., Zhang D., Wei G.H. Risk of venous and arterial thromboembolic events associated with VEGFR-TKIs: a meta-analysis. Cancer Chemother Pharmacol. 2017;80:487–495. doi: 10.1007/s00280-017-3386-6.

83. Ma Z., Sun X., Zhang Y., et al. Risk of thromboembolic events in cancer patients treated with immune checkpoint inhibitors: a meta-analysis of randomized controlled trials. Thromb Haemost. 2022;122:1757–1766. doi: 10.1055/s-0042-1749185.

84. Bashar K., Healy D., Clarke-Moloney M., Burke P., Kavanagh E., Walsh S.R. Effects of neck radiation therapy on extra-cranial carotid arteries atherosclerosis disease prevalence: systematic review and a meta-analysis. PLoS One. 2014;9 doi: 10.1371/journal.pone.0110389.

85. McCready R.A., Hyde G.L., Bivins B.A., Mattingly S.S., Griffen W.O.J.S. Radiation-induced arterial injuries. Surgery. 1983;93:306–312.

86. Dolladille C., Akroun J., Morice P.M., et al. Cardiovascular immunotoxicities associated with immune checkpoint inhibitors: a safety meta-analysis. Eur Heart J. 2021;42:4964–4977. doi: 10.1093/eurheartj/ehab618.

87. Cohen J.B., Brown N.J., Brown S.-A., et al. Cancer therapy–related hypertension: a scientific statement from the American Heart Association. Hypertension. 2023;80(3):e46–e57. doi: 10.1161/HYP.0000000000000224.

88. Grover S.P., Hisada Y.M., Kasthuri R.S., Reeves B.N., Mackman N. Cancer therapy–associated thrombosis. Arterioscler Thromb Vasc Biol. 2021;41:1291–1305. doi: 10.1161/ATVBAHA.120.314378.

89. Coumbe B.G.T., Groarke J.D. Cardiovascular autonomic dysfunction in patients with cancer. Curr Cardiol Rep. 2018;20:69. doi: 10.1007/s11886-018-1010-y.

90. Poole D.C., Musch T.I., Colburn T.D. Oxygen flux from capillary to mitochondria: integration of contemporary discoveries. Eur J Appl Physiol. 2022;122:7–28. doi: 10.1007/s00421-021-04854-7.

91. Korpela E., Liu S.K. Endothelial perturbations and therapeutic strategies in normal tissue radiation damage. Radiat Oncol. 2014;9:266. doi: 10.1186/s13014-014-0266-7.

92. Kamba T., Tam B.Y., Hashizume H., et al. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature. Am J Physiol Heart Circ Physiol. 2006;290:H560–H576. doi: 10.1152/ajpheart.00133.2005.

93. Inai T., Mancuso M., Hashizume H., et al. Inhibition of vascular endothelial growth factor (VEGF) signaling in cancer causes loss of endothelial fenestrations, regression of tumor vessels, and appearance of basement membrane ghosts. Am J Pathol. 2004;165:35–52. doi: 10.1016/S0002-9440(10)63273-7.

94. Rasanen M., Degerman J., Nissinen T.A., et al. VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection. Proc Natl Acad Sci U S A. 2016;113:13144–13149. doi: 10.1073/pnas.1616168113.

95. Mijwel S., Cardinale D.A., Norrbom J., et al. Exercise training during chemotherapy preserves skeletal muscle fiber area, capillarization, and mitochondrial content in patients with breast cancer. FASEB J. 2018;32:5495–5505. doi: 10.1096/fj.201700968R.

96. Coschignano M.A., De Ciuceis C., Agabiti-Rosei C., et al. Microvascular structural alterations in cancer patients treated with antiangiogenic drugs. Front Cardiovasc Med. 2021;8 doi: 10.3389/fcvm.2021.651594.

97. Steeghs N., Gelderblom H., Roodt Jot, et al. Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clin Cancer Res. 2008;14:3470–3476. doi: 10.1158/1078-0432.CCR-07-5050.

98. Lesterhuis W.J., Rennings A.J., Leenders W.P., et al. Vascular endothelial growth factor in systemic capillary leak syndrome. Am J Med. 2009;122:e5–e7. doi: 10.1016/j.amjmed.2009.01.020.

99. Siddall E., Khatri M., Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management. Kidney Int. 2017;92:37–46. doi: 10.1016/j.kint.2016.11.029.

100. Druey K.M., Greipp P.R. Narrative review: the systemic capillary leak syndrome. Ann Intern Med. 2010;153:90–98. doi: 10.1059/0003-4819-153-2-201007200-00005.

101. Jeong G.H., Lee K.H., Lee I.R., et al. Incidence of capillary leak syndrome as an adverse effect of drugs in cancer patients: a systematic review and meta-analysis. J Clin Med. 2019;8(2):143. doi: 10.3390/jcm8020143.

102. Feng J., Shao M., Hu Y., Huang H. Profile of capillary-leak syndrome in patients received chimeric antigen receptor T cell therapy. Bone Marrow Transplant. 2022;57:661–663. doi: 10.1038/s41409-022-01562-4.

103. Izzedine H., Mathian A., Amoura Z., Ng J.H., Jhaveri KDJKIR. Anticancer drug-induced capillary leak syndrome. Kidney Int Rep. 2022;7(5):945–953. doi: 10.1016/j.ekir.2022.02.014.

104. Klassen P., Schiessel D.L., Baracos V.E. Adverse effects of systemic cancer therapy on skeletal muscle: myotoxicity comes out of the closet. Curr Opin Clin Nutr Metab Care. 2023;26:210–218. doi: 10.1097/MCO.0000000000000922.

105. Gamble D.T., Ross J., Khan H., et al. Impaired cardiac and skeletal muscle energetics following anthracycline therapy for breast cancer. Circ Cardiovasc Imaging. 2023;16 doi: 10.1161/CIRCIMAGING.123.015782.

106. Mallard J., Hucteau E., Charles A.L., et al. Chemotherapy impairs skeletal muscle mitochondrial homeostasis in early breast cancer patients. J Cachexia Sarcopenia Muscle. 2022;13:1896–1907. doi: 10.1002/jcsm.12991.

107. Qi W.X., Lin F., Sun Y.J., Tang L.N., Shen Z., Yao Y. Risk of venous and arterial thromboembolic events in cancer patients treated with gemcitabine: a systematic review and meta-analysis. Br J Clin Pharmacol. 2013;76:338–347. doi: 10.1111/bcp.12203.

108. West M.A., Loughney L., Lythgoe D., et al. The effect of neoadjuvant chemoradiotherapy on whole-body physical fitness and skeletal muscle mitochondrial oxidative phosphorylation in vivo in locally advanced rectal cancer patients—an observational pilot study. PLoS One. 2014;9 doi: 10.1371/journal.pone.0111526.

109. Wakasugi T., Morishita S., Kaida K., et al. Impaired skeletal muscle oxygenation following allogeneic hematopoietic stem cell transplantation is associated with exercise capacity. Support Care Cancer. 2018;26:2149–2160. doi: 10.1007/s00520-017-4036-6.

110. Kirkham A.A., Haykowsky M.J., Beaudry R.I., et al. Cardiac and skeletal muscle predictors of impaired cardiorespiratory fitness post-anthracycline chemotherapy for breast cancer. Sci Rep. 2021;11 doi: 10.1038/s41598-021-93241-5.

111. Bellissimo M.P., Reding K.W., O’Connell N.S., et al. Intermuscular fat changes are related to reduced left ventricular ejection fraction during cancer therapy (PREVENT-WF-98213) J Am Coll Cardiol CardioOnc. 2023;5:409–411. doi: 10.1016/j.jaccao.2023.01.006.

112. Kirkham A.A., Pituskin E., Thompson R.B., et al. Cardiac and cardiometabolic phenotyping of trastuzumab-mediated cardiotoxicity: a secondary analysis of the MANTICORE trial. Eur Heart J Cardiovasc Pharmacol. 2021;8:130–139. doi: 10.1093/ehjcvp/pvab016.

113. Beaudry R.I., Kirkham A.A., Thompson R.B., Grenier J.G., Mackey J.R., Haykowsky M.J. Exercise intolerance in anthracycline-treated breast cancer survivors: the role of skeletal muscle bioenergetics, oxygenation, and composition. Oncologist. 2020;25:e852–e860. doi: 10.1634/theoncologist.2019-0777.

114. Haseen F., Murray L.J., Cardwell C.R., O’Sullivan J.M., Cantwell M.M. The effect of androgen deprivation therapy on body composition in men with prostate cancer: systematic review and meta-analysis. J Cancer Surviv. 2010;4:128–139. doi: 10.1007/s11764-009-0114-1.

115. Chang D., Joseph D.J., Ebert M.A., et al. Effect of androgen deprivation therapy on muscle attenuation in men with prostate cancer. J Med Imaging Radiat Oncol. 2014;58:223–228. doi: 10.1111/1754-9485.12124.

116. Chiang P.-K., Tsai W.-K., Chiu A.W.-H., Lin J.-B., Yang F.-Y., Lee J. Muscle loss during androgen deprivation therapy is associated with higher risk of non-cancer mortality in high-risk prostate cancer. Front Oncol. 2021;11 doi: 10.3389/fonc.2021.722652.

117. Karia P.S., Joshu C.E., Visvanathan K. Association of oophorectomy and fat and lean body mass: evidence from a population-based sample of U.S. women. Cancer Epidemiol Biomarkers Prev. 2021;30:1424–1432. doi: 10.1158/1055-9965.EPI-20-1849.

118. Christensen Holz S. Aromatase inhibitor musculoskeletal syndrome and bone loss: a review of the current literature. Curr Oncol Rep. 2023;25:825–831. doi: 10.1007/s11912-023-01413-5.

119. Dorchies O.M., Reutenauer-Patte J., Dahmane E., et al. The anticancer drug tamoxifen counteracts the pathology in a mouse model of Duchenne muscular dystrophy. Am J Pathol. 2013;182:485–504. doi: 10.1016/j.ajpath.2012.10.018.

120. Tsabari R., Simchovitz E., Lavi E., et al. Safety and clinical outcome of tamoxifen in Duchenne muscular dystrophy. Neuromuscul Disord. 2021;31:803–813. doi: 10.1016/j.nmd.2021.05.005.

121. Houstis N.E., Eisman A.S., Pappagianopoulos P.P., et al. Exercise intolerance in heart failure with preserved ejection fraction: diagnosing and ranking its causes using personalized O2 pathway analysis. Circulation. 2018;137:148–161. doi: 10.1161/CIRCULATIONAHA.117.029058.

122. Howden E.J., Ruiz-Carmona S., Claeys M., et al. Oxygen pathway limitations in patients with chronic thromboembolic pulmonary hypertension. Circulation. 2021;143:2061–2073. doi: 10.1161/CIRCULATIONAHA.120.052899.

123. Mihalcea D., Florescu M., Bruja R., Patrascu N., Vladareanu A.M., Vinereanu D. 3D echocardiography, arterial stiffness, and biomarkers in early diagnosis and prediction of CHOP-induced cardiotoxicity in non-Hodgkin’s lymphoma. Sci Rep. 2020;10 doi: 10.1038/s41598-020-75043-3.

124. Aimo A., Saccaro L.F., Borrelli C., et al. The ergoreflex: how the skeletal muscle modulates ventilation and cardiovascular function in health and disease. Eur J Heart Fail. 2021;23:1458–1467. doi: 10.1002/ejhf.2298.

125. Piepoli M.F., Crisafulli A. Pathophysiology of human heart failure: importance of skeletal muscle myopathy and reflexes. Exp Physiol. 2014;99:609–615. doi: 10.1113/expphysiol.2013.074310.

126. Suzuki T., Palus S., Springer J. Skeletal muscle wasting in chronic heart failure. ESC Heart Fail. 2018;5:1099–1107. doi: 10.1002/ehf2.12387.

127. Aleixo G.F.P., Shachar S.S., Nyrop K.A., Muss H.B., Malpica L., Williams G.R. Myosteatosis and prognosis in cancer: systematic review and meta-analysis. Crit Rev Oncol Hematol. 2020;145 doi: 10.1016/j.critrevonc.2019.102839.

128. Scott J.M., Stene G., Edvardsen E., Jones L.W. Performance status in cancer: not broken, but time for an upgrade? J Clin Oncol. 2020;38:2824–2829. doi: 10.1200/JCO.20.00721.

129. Radin J.M., Wineinger N.E., Topol E.J., Steinhubl S.R. Harnessing wearable device data to improve state-level real-time surveillance of influenza-like illness in the USA: a population-based study. Lancet Digit Health. 2020;2:e85–e93. doi: 10.1016/S2589-7500(19)30222-5.

130. Schubert C., Archer G., Zelis J.M., et al. Wearable devices can predict the outcome of standardized 6-minute walk tests in heart disease. NPJ Digit Mad. 2020;3:92. doi: 10.1038/s41746-020-0299-2.

131. Nayor M., Shah R.V., Miller P.E., et al. Metabolic architecture of acute exercise response in middle-aged adults in the community. Circulation. 2020;142:1905–1924. doi: 10.1161/CIRCULATIONAHA.120.050281.

132. Contrepois K., Wu S., Moneghetti K.J., et al. Molecular choreography of acute exercise. Cell. 2020;181:1112–1130.e16. doi: 10.1016/j.cell.2020.04.043.

133. Shah R.V., Miller P., Colangelo L.A., et al. Blood-based fingerprint of cardiorespiratory fitness and long-term health outcomes in young adulthood. J Am Heart Assoc. 2022;11 doi: 10.1161/JAHA.122.026670.

134. Gongora C.A., Drobni Z.D., Quinaglia Araujo Costa Silva T., et al. Sodium-glucose co-transporter-2 inhibitors and cardiac outcomes among patients treated with anthracyclines. J Am Coll Cardiol HF. 2022;10:559–567. doi: 10.1016/j.jchf.2022.03.006.

135. Coppo E., Giraldez Valpuesta A., Gamaza Chulian S. Effect of sodium-related glucose transporter 2-inhibitors on exercise capacity in heart failure patients with reduced ejection fraction, does etiology matter? Eur Heart J. 2023;44(suppl 2)

136. Nassif M.E., Windsor S.L., Borlaug B.A., et al. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat Med. 2021;27:1954–1960. doi: 10.1038/s41591-021-01536-x.

137. Foulkes S.J., Howden E.J., Haykowsky M.J., et al. Exercise for the prevention of anthracycline-induced functional disability and cardiac dysfunction: the BREXIT study. Circulation. 2023;147:532–545. doi: 10.1161/CIRCULATIONAHA.122.062814.

138. Scott J.M., Zabor E.C., Schwitzer E., et al. Efficacy of exercise therapy on cardiorespiratory fitness in patients with cancer: a systematic review and meta-analysis. J Clin Oncol. 2018;36:2297–2305. doi: 10.1200/JCO.2017.77.5809.

139. Padilha C.S., Marinello P.C., Galvão D.A., et al. Evaluation of resistance training to improve muscular strength and body composition in cancer patients undergoing neoadjuvant and adjuvant therapy: a meta-analysis. J Cancer Surviv. 2017;11:339–349. doi: 10.1007/s11764-016-0592-x.

140. Singh B., Zopf E.M., Howden E.J. Effect and feasibility of wearable physical activity trackers and pedometers for increasing physical activity and improving health outcomes in cancer survivors: A systematic review and meta-analysis. J Sport Health Sci. 2022;11:184–193. doi: 10.1016/j.jshs.2021.07.008.

141. Eggebeen J., Kim-Shapiro D.B., Haykowsky M., et al. One week of daily dosing with beetroot juice improves submaximal endurance and blood pressure in older patients with heart failure and preserved ejection fraction. J Am Coll Cardiol HF. 2016;4:428–437. doi: 10.1016/j.jchf.2015.12.013.

142. Cramp F., Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev. 2012;11(11):CD006145. doi: 10.1002/14651858.CD006145.pub3.

143. Herrero F., Balmer J., San Juan A.F., et al. Is cardiorespiratory fitness related to quality of life in survivors of breast cancer? J Strength Condition Res. 2006;20:535–540. doi: 10.1519/r-18215.1.

144. Zamorano J.L., Lancellotti P., Rodriguez Munoz D., et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for Cancer Treatments and Cardiovascular Toxicity of the European Society of Cardiology (ESC) Eur Heart J. 2016;37:2768–2801. doi: 10.1093/eurheartj/ehw211.

145. Reinert T., Baldotto CSdR., Nunes F.A.P., Scheliga AAdS. Bleomycin-induced lung injury. J Cancer Res. 2013;2013

146. Levi M., Sivapalaratnam SJTr. An overview of thrombotic complications of old and new anticancer drugs. Thromb Res. 2020;191:S17–S21. doi: 10.1016/S0049-3848(20)30391-1.

147. Kirkham A.A., Power C., Pituskin E. Physical inactivity, adverse body composition, and cardiac function in breast cancer survivors: triple jeopardy? J Am Coll Cardiol CardioOnc. 2022;4:192–194. doi: 10.1016/j.jaccao.2022.03.001.

148. Lai S., Amabile M.I., Mazzaferro S., et al. Effects of sunitinib on endothelial dysfunction, metabolic changes, and cardiovascular risk indices in renal cell carcinoma. Cancer Med. 2020;9:3752–3757. doi: 10.1002/cam4.2910.

149. Mayer E.L., Dallabrida S.M., Rupnick M.A., et al. Contrary effects of the receptor tyrosine kinase inhibitor vandetanib on constitutive and flow-stimulated nitric oxide elaboration in humans. Hypertension. 2011;58:85–92. doi: 10.1161/HYPERTENSIONAHA.110.168120.

150. Jin Y., He Q., Yang X., Luo PJFiP. A comprehensive review of clinical cardiotoxicity incidence of FDA-approved small-molecule kinase inhibitors. Front Pharmacol. 2020;11 doi: 10.3389/fphar.2020.00891.

151. Gavazzoni M., Lombardi C.M., Vizzardi E., et al. Irreversible proteasome inhibition with carfilzomib as first line therapy in patients with newly diagnosed multiple myeloma: Early in vivo cardiovascular effects. Eur J Pharmacol. 2018;838:85–90. doi: 10.1016/j.ejphar.2018.09.014.

152. Wang T.-F., Carrier M.J.C.O. Immune checkpoint inhibitors-associated thrombosis: incidence, risk factors and management. Curr Oncol. 2023;30:3032–3046. doi: 10.3390/curroncol30030230.

153. Li P., Xu B., Xu J., et al. Lenalidomide promotes thrombosis formation, but does not affect platelet activation in multiple myeloma. Int J Mol Sci. 2023;24(18) doi: 10.3390/ijms241814097.

154. Aue G., Nelson Lozier J., Tian X., et al. Inflammation, TNFα and endothelial dysfunction link lenalidomide to venous thrombosis in chronic lymphocytic leukemia. Am J Hematol. 2011;86:835–840. doi: 10.1002/ajh.22114.

155. Dandoy C.E., Hirsch R., Chima R., Davies S.M., Jodele S. Pulmonary hypertension after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2013;19:1546–1556. doi: 10.1016/j.bbmt.2013.07.017.

156. Tichelli A., Bucher C., Rovó A., et al. Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation. Blood. 2007;110:3463–3471. doi: 10.1182/blood-2006-10-054080.

157. Vasbinder A., Hoeger C.W., Catalan T., et al. Cardiovascular events after hematopoietic stem cell transplant: incidence and risk factors. J Am Coll Cardiol CardioOnc. 2023;5:821–832. doi: 10.1016/j.jaccao.2023.07.007.

158. Majhail N.S., Challa T.R., Mulrooney D.A., Baker K.S., Burns L.J. Hypertension and diabetes mellitus in adult and pediatric survivors of allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2009;15:1100–1107. doi: 10.1016/j.bbmt.2009.05.010.

159. Dillon H.T., Foulkes S., Horne-Okano Y.A., et al. Reduced cardiovascular reserve capacity in long-term allogeneic stem cell transplant survivors. Sci Rep. 2023;13:2112. doi: 10.1038/s41598-023-28320-w.

160. Hanania A.N., Mainwaring W., Ghebre Y.T., Hanania N.A., Ludwig M.J.C. Radiation-induced lung injury: assessment and management. Chest. 2019;156:150–162. doi: 10.1016/j.chest.2019.03.033.

161. Banister H.R., Hammond S.T., Parr S.K., et al. Lower endothelium-dependent microvascular function in adult breast cancer patients receiving radiation therapy. Cardio-Oncology. 2021;7:18. doi: 10.1186/s40959-021-00104-z.

162. Furrer R., Hawley J.A., Handschin C. The molecular athlete: exercise physiology from mechanisms to medals. Physiol Rev. 2023;103:1693–1787. doi: 10.1152/physrev.00017.2022.

163. Hellsten Y., Nyberg M. Cardiovascular adaptations to exercise training. Compr Physiol. 2016;6:1–32. doi: 10.1002/cphy.c140080.

164. Davey P., Meyer T., Coats A., et al. Ventilation in chronic heart failure: effects of physical training. Br Heart J. 1992;68:473–477. doi: 10.1136/hrt.68.11.473.

165. Coats A.J., Adamopoulos S., Radaelli A., et al. Controlled trial of physical training in chronic heart failure. Exercise performance, hemodynamics, ventilation, and autonomic function. Circulation. 1992;85:2119–2131. doi: 10.1161/01.cir.85.6.2119.

166. Charles M., Charifi N., Verney J., et al. Effect of endurance training on muscle microvascular filtration capacity and vascular bed morphometry in the elderly. Acta Physiol (Oxf) 2006;187:399–406. doi: 10.1111/j.1748-1716.2006.01585.x.

167. Paterson C., Fryer S., Zieff G., et al. The effects of acute exposure to prolonged sitting, with and without interruption, on vascular function among adults: a meta-analysis. Sports Med. 2020;50:1929–1942. doi: 10.1007/s40279-020-01325-5.

168. Restaino R.M., Holwerda S.W., Credeur D.P., Fadel P.J., Padilla J. Impact of prolonged sitting on lower and upper limb micro- and macrovascular dilator function. Exp Physiol. 2015;100:829–838. doi: 10.1113/EP085238.

169. Pinto A.J., Bergouignan A., Dempsey P.C., et al. Physiology of sedentary behavior. Physiol Rev. 2023;103:2561–2622. doi: 10.1152/physrev.00022.2022.

170. Schwingshackl L., Hoffmann G.J.N. Mediterranean dietary pattern, inflammation and endothelial function: a systematic review and meta-analysis of intervention trials. Nutr Metab Cardiovasc Dis. 2014;24:929–939. doi: 10.1016/j.numecd.2014.03.003.

171. Shaw C.S., Clark J., Wagenmakers A.J. The effect of exercise and nutrition on intramuscular fat metabolism and insulin sensitivity. Annu Rev Nutr. 2010;30:13–34. doi: 10.1146/annurev.nutr.012809.104817.

172. Patoulias D., Papadopoulos C., Kassimis G., et al. Effect of sodium-glucose co-transporter-2 inhibitors on arterial stiffness: a systematic review and meta-analysis of randomized controlled trials. Vasc Med. 2022;27:433–439. doi: 10.1177/1358863X221101653.

173. Wei R., Wang W., Pan Q., Guo L. Effects of SGLT-2 inhibitors on vascular endothelial function and arterial stiffness in subjects with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Front Endocrinol (Lausanne) 2022;13 doi: 10.3389/fendo.2022.826604.

174. Packer M. SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism. Nat Rev Cardiol. 2023;20:443–462. doi: 10.1038/s41569-022-00824-4.

175. Gafter-Gvili A., Rozen-Zvi B., Vidal L., Gafter U., Vansteenkiste J.F., Shpilberg O. Intravenous Iron Supplementation for the treatment of cancer-related anemia—systematic review and meta-analysis. Blood. 2010;116 doi: 10.3109/0284186X.2012.702921. 4249-4249.

176. Stugiewicz M., Tkaczyszyn M., Kasztura M., Banasiak W., Ponikowski P., Jankowska E.A. The influence of iron deficiency on the functioning of skeletal muscles: experimental evidence and clinical implications. Eur J Heart Fail. 2016;18:762–773. doi: 10.1002/ejhf.467.

177. Tzoumas N., Farrah T.E., Dhaun N., Webb D.J. Established and emerging therapeutic uses of PDE type 5 inhibitors in cardiovascular disease. Br J Pharmacol. 2020;177:5467–5488. doi: 10.1111/bph.14920.

178. Benza R.L., Grünig E., Sandner P., Stasch J.-P., Simonneau G. The nitric oxide–soluble guanylate cyclase–cGMP pathway in pulmonary hypertension: from PDE5 to soluble guanylate cyclase. Eur Respir Rev. 2024;33 doi: 10.1183/16000617.0183-2023.

179. Obi C., Smith A.T., Hughes G.J., Adeboye A.A. Targeting mitochondrial dysfunction with elamipretide. Heart Fail Rev. 2022;27:1925–1932. doi: 10.1007/s10741-021-10199-2.