
==== Front
JACC CardioOncol
JACC CardioOncol
JACC: CardioOncology
2666-0873
Elsevier

S2666-0873(24)00151-0
10.1016/j.jaccao.2024.04.006
State-of-the-Art Review
Cancer Therapy and Exercise Intolerance: The Heart Is But a Part
JACC: CardioOncology State-of-the-Art Review
Dillon Hayley T. BExSci (hon) @HayleyTDillon
ab
Foulkes Stephen J. PhD @S_FoulkesAEP
acd∗
Baik Alan H. MD @baik_alan
e
Scott Jessica M. PhD @cardiac_fitness
f
Touyz Rhian M. MBBCh, PhD g
Herrmann Joerg MD h
Haykowsky Mark J. PhD ac
La Gerche André MBBS, PhD dij
Howden Erin J. PhD erin.howden@baker.edu.au
@erin_howden
ak∗
a Baker Heart and Diabetes Institute, Melbourne, Australia
b Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Geelong, Australia
c Faculty of Nursing, College of Health Sciences, University of Alberta, Edmonton, Alberta, Canada
d Heart Exercise and Research Trials (HEART) Lab, St Vincent’s Institute, Fitzroy, Victoria, Australia
e Division of Cardiovascular Medicine, Department of Medicine, University of California, San Francisco, San Francisco, California, USA
f Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
g Research Institute of McGill University Health Centre, Department of Medicine, McGill University, Montreal, Quebec, Canada
h Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
i Cardiology Department, St. Vincent’s Hospital Melbourne, Fitzroy, Australia
j HEART Lab, Victor Chang Cardiovascular Research Institute, Darlinghurst, NSW, Australia
k Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
∗ Address for correspondence: Associate Professor Erin Howden, Baker Heart and Diabetes Institute, Alfred Centre, Level 4, 99 Commercial Road, Melbourne VIC 3004, Australia. erin.howden@baker.edu.au@erin_howden
∗ Ms Dillon and Dr Foulkes contributed equally to this work.

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https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
The landscape of cancer therapeutics is continually evolving, with successes in improved survivorship and reduced disease progression for many patients with cancer. Improved cancer outcomes expose competing comorbidities, some of which may be exacerbated by cancer therapies. The leading cause of disability and death for many early-stage cancers is cardiovascular disease (CVD), which is often attributed to direct or indirect cardiac injury from cancer therapy. In this review, the authors propose that toxicities related to conventional and novel cancer therapeutics should be considered beyond the heart. The authors provide a framework using the oxygen pathway to understand the impact of cancer treatment on peak oxygen uptake, a marker of integrative cardiopulmonary function and CVD risk. Peripheral toxicities and the impact on oxygen transport are discussed. Consideration for the broad effects of cancer therapies will improve the prediction and identification of cancer survivors at risk for CVD, functional disability, and premature mortality and those who would benefit from therapeutic intervention, ultimately improving patient outcomes.

Central Illustration

Highlights

• CVD is a major contributor to morbidity and mortality in cancer survivors.

• Peripheral toxicities contribute to CVD risk via their effect on exercise tolerance.

• The oxygen pathway can help understand the effect of cancer treatments.

Key Words

cardiorespiratory fitness
cardiotoxicity
cardiovascular
exercise
hematology
metabolic
oncology
skeletal muscle function
Abbreviations and Acronyms

CVD cardiovascular disease

DMO2 muscle oxygen diffusive conductance

HCT hematopoietic cell transplantation

ICI immune checkpoint inhibitor

mAb monoclonal antibody

SMD standardized mean difference

TKI tyrosine kinase inhibitor

VEGF vascular endothelial growth factor

VEGFR vascular endothelial growth factor receptor

Vo2peak peak oxygen consumption

V/Q ventilation/perfusion
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pmcImproved 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 (Vo2peak), provide additional insight into CVD prognosis for cancer survivors. Vo2peak 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 Vo2peak 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, Vo2peak 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 Vo2peak 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 Vo2peak as organized by the noncardiac components of the oxygen cascade (Table 1).Table 1 Overview of Cancer Therapies That Affect the Noncardiac Components of the Oxygen Cascade

Therapy	Cancer Indications (On and Off Label)	Toxicities Affecting the Noncardiac Components of the Oxygen Cascade	
Diffusive Oxygen Loading	Convective Oxygen Delivery	Diffusive Oxygen Conductance and Metabolism	
Antitumor antibiotics					
 Anthracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin)	Breast, Wilms’ tumor, neuroblastoma, soft tissue sarcoma, osteosarcoma, ovarian, bladder, thyroid, gastric, bronchogenic, ALL, AML, HL, NHL		Arterial stiffening,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 arterial thrombosis,88 endothelial dysfunction, systemic HTN144	Microvascular rarefaction,95 capillary leak,103 decreased muscle oxidative capacity,95,105,106 reduced mitochondrial biogenesis, number and/or function,95,106 muscle atrophy,105,110,112 myosteatosis110, 111, 112, 113	
 Bleomycin	Head, HL, neck, testicular	Pulmonary HTN,145 pulmonary fibrosis145			
Alkylating agents					
 Platinum-based (carboplatin, cisplatin, oxaliplatin)	Bladder, breast, cervical, endometrial carcinoma, head, neck, HL, pleural mesothelioma, MM, NHL, esophageal, gastric, osteosarcoma, ovarian, penile, SCLC, testicular, CRC, ovarian		Arterial stiffening,48, 49, 50 arterial thrombosis,146 endothelial dysfunction, systemic HTN,18,87 arterial vasospasm,18,30,31 atherosclerotic disease18,30	Capillary leak,103 myosteatosis112	
 Non-platinum-based (busulfan, cyclophosphamide, ifosfamide)	ALL, breast, CLL, Ewing sarcoma, HL, MM, NHL, SCLC, HCT conditions including AML, ALL, CLL, CML, MDS, and MPN	Pulmonary HTN,18,31 pulmonary fibrosis144	Arterial stiffening,45 systemic HTN87	Capillary leak103	
Antimetabolites					
 5-fluorouracil, capecitabine, gemcitabine	Anal carcinoma, bladder, breast, cervical, CRC, gastric, hepatobiliary, esophageal, pancreatic, squamous cell carcinomas, ovarian, peritoneal, adenocarcinoma of unknown primary, head, neck, HL, NHL, malignant pleural mesothelioma, SCLC, NSCLC, testicular, uterine	Pulmonary embolism30	Arterial stiffening,49 arterial thrombosis,107 endothelial dysfunction,72 systemic HTN,30 arterial vasospasm18,30	Capillary leak, decreased muscle oxidative capacity108	
Taxanes					
 Paclitaxel, docetaxel, cabazitaxel	Adenocarcinoma of unknown primary, bladder, breast, cervical, head, neck, Kaposi sarcoma, NSCLC, esophageal, gastric, ovarian, penile, SCLC, soft tissue sarcoma, testicular germ cell tumors, thymoma	Pulmonary embolism18,30	Arterial stiffening,38,56 endothelial dysfunction,73 systemic HTN,18,30 arterial vasospasm18,30	Microvascular rarefaction,95 capillary leak,103 decreased muscle oxidative capacity,95,106 reduced mitochondrial biogenesis, number and/or function,95,106 muscle atrophy,147 myosteatosis110, 111, 112, 113,147	
Vinka alkaloids					
 Vincristine	ALL, CNS tumors, HL, Ewing sarcoma, gestational trophoblastic tumors, MM, NHL, ovarian, primary CNS lymphoma, SCLC, thymoma		Systemic HTN18	Capillary leak103	
Topoisomerase I inhibitors					
 Irinotecan	CRC		Arterial stiffening52		
 Monoclonal antibodies					
 Anti-VEGF (bevacizumab, ramucirumab)	NSCLC, breast, glioblastoma, RCC, ovarian, cervical, CRC, peritoneal, fallopian tube, HCC, gastric, HCC, NSCLC, esophageal	Pulmonary embolism18,30	Arterial stiffening,57 arterial thrombosis,81,88 endothelial dysfunction,57,69 systemic HTN,30 atherosclerotic disease81	Microvascular rarefaction,57,69 capillary leak103	
 Anti-EGFR (trastuzumab, panitumumab)	CRC		Arterial stiffening38,42,52	Capillary leak103	
 Anti-CD20 (rituximab)	NHL, CLL		Systemic HTN,30 arterial vasospasm18,30	Capillary leak101,103	
TKIs					
 VEGFR TKIs (axitinib, cabozantinib, cediranib, lenvatinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, telatinib, vandetanib, vatalanib)	RCC, thyroid, HCC, NSCLC, ovarian, soft tissue carcinoma, GIST, CRC, MDS, Angiosarcoma, pancreatic, neuroendocrine tumors, soft tissue sarcoma	Pulmonary embolism30	Arterial stiffening,38,52, 53, 54, 55 arterial thrombosis,82,146 endothelial dysfunction,67,97,148,149 systemic HTN,18,87 arterial vasospasm18,30	Microvascular rarefaction54,97	
 BCR-ABL1 TKIs (dasatinib, imatinib, nilotinib, ponatinib)	GIST, ALL, CML, MDS, MPN	Pulmonary HTN,18 interstitial lung disease,19 pulmonary embolism18,30	Arterial stiffening,58,59 arterial thrombosis,88 endothelial dysfunction,76 systemic HTN,18,30 arterial vasospasm,150 atherosclerotic disease18,30,80		
 BTK inhibitors (ibrutinib, acalabrutinib)	CLL, mantel cell lymphoma, Waldenström macroglobulinemia		Systemic HTN18,87		
Fusion proteins					
 Aflibercept	CRC	Pulmonary embolism18,30	Systemic HTN18,30	Microvascular rarefaction67	
Proteasome inhibitors					
 Carfilzomib, bortezomib	MM	Pulmonary HTN,18 pulmonary embolism18	Arterial stiffness,60 arterial thrombosis,146 endothelial dysfunction,70,151 systemic HTN,18,30,87 atherosclerotic disease30	Capillary leak103	
HIF-2α inhibitors					
 Belzutifan	RCC, pancreatic neuroendocrine tumors, central nervous system hemangioblastomas	Hypoxia21			
Immune checkpoint inhibitors					
 Atezolizumab, avelumab, ipilimumab, pembrolizumab, nivolumab, cemiplimab, durvalumab	Melanoma, head, neck, HL, mediastinal large B-cell lymphoma, gastric, cervical, breast, NSCLC, SCLC, urothelial, esophageal, HCC, Merkel cell carcinoma, RCC, endometrial, malignant pleural mesothelioma, cutaneous basal cell carcinoma, cutaneous squamous cell carcinoma	Hemolytic anemia,27 pulmonary embolism152	Arterial thrombosis,83 atherosclerotic disease86	Capillary leak103	
Immunomodulatory agents					
 Cytokines (IL-2, IFNα)	Hairy cell leukemia, Kaposi sarcoma, lymphoma, malignant melanoma	Pulmonary HTN,18 pulmonary embolism27,30	Systemic HTN,30 atherosclerotic disease18,30	Capillary leak101,103	
 Lenalidomide	CLL, diffuse large B-cell lymphoma, mantle cell lymphoma, MM, MDS	Pulmonary embolism30	Arterial thrombosis,153 endothelial dysfunction,154 systemic HTN30		
 CAR T-cell therapy	ALL, diffuse large B-cell lymphoma, follicular lymphoma, mantel cell lymphoma, MM			Capillary leak102,103	
 Hematopoietic cell transplantation					
 Autologous and allogeneic	Aplastic anemia, AML, ALL, CML, CLL, lymphomas, MM, MDS, MPN	Pulmonary HTN,155 hemolytic anemia26	Arterial stiffening,66 arterial thrombosis,156,157 endothelial dysfunction,71 systemic HTN,158 atherosclerotic disease156,157	Capillary leak, decreased muscle oxidative capacity,12,109,159 muscle atrophy12,159	
 Radiation therapy	Breast, head, neck, cervical, prostate, thyroid, osteosarcoma, esophageal, CRC, pancreatic, HCC, neuroblastoma, meningioma, soft tissue carcinoma, HL, NHL, MM, AML, ALL, CLL, CML, MDS, and MPN	Pulmonary HTN,160 pulmonary fibrosis160	Arterial stiffening,51 endothelial dysfunction,75,161 arterial vasospasm,18,30 atherosclerotic disease84		
Hormone therapy					
 Aromatase inhibitors (anastrozole, exemestane, letrozole)	Breast		Arterial stiffening,61,62 endothelial dysfunction,61,74 systemic HTN87		
 Androgen deprivation therapy	Prostate		Arterial stiffening,63, 64, 65 systemic HTN87	Muscle atrophy,114 myeosteatosis115,116	
This list is not all encompassing but serves to highlight the strongest clinical evidence linking cancer therapies with impairments in the noncardiac components of the oxygen cascade. Cancer indications are based on reported indications from the U.S. Food and Drug Administration or, where not possible, treatment guidelines.

ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; BTK = Bruton tyrosine kinase; CAR = chimeric antigen receptor; CLL = chronic lymphocytic leukemia; CML = chronic myeloid leukemia; CNS = central nervous system; CRC = colorectal cancer; EGFR = epidermal growth factor receptor; GIST = gastrointestinal stromal tumor; HCC = hepatocellular carcinoma; HIF-2α = hypoxia-inducible transcription factor 2α; HL = Hodgkin’s lymphoma; HTN = hypertension; IFN = interferon; IL = interleukin; MDS = myelodysplastic syndrome; MM = multiple myeloma; MPN = myeloproliferative neoplasm; NHL = non-Hodgkin’s lymphoma; NSCLC = non–small cell lung cancer; RCC = renal cell carcinoma; SCLC = small cell lung cancer; TKI = tyrosine kinase inhibitor; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor.

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 Po2 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 Vo2peak (Central Illustration).Central Illustration Multifactorial Contributors and Cardiorespiratory System Impact in Cancer Survivors That Drive Exercise Tolerance

Multiple factors can contribute to poor exercise tolerance in cancer survivors. Cancer therapeutics can interact with patient cardiovascular risk factors including age, physical inactivity, comorbidities, genetic risk, and inflammation, as well as the cancer itself to potentially affect multiple steps of the oxygen pathway and limit exercise tolerance. Taking a more holistic approach to consider factors that can be affected by treatment beyond the heart provides new opportunities to treat exercise intolerance and could lead to reduced cardiovascular risk,9,111,127,133 hospitalizations,126 and fatigue142 and better quality of life (QOL)143 for cancer survivors. CVD = cardiovascular disease; DC = dissociation curve; VD = physiological dead space; Vo2peak = peak oxygen consumption; V/Q = ventilation/perfusion; VT = tidal volume.

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 Vo2peak 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 Vo2peak in healthy individuals (equivalent to a decade of age-related Vo2peak decline).24,25 On the basis of these correlations, treatment-induced reductions in hemoglobin concentration likely contribute to short-term declines in Vo2peak. 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 Po2). 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 transplantation26 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-based35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 and/or alkylating agent–based45,48, 49, 50 chemotherapy, radiation therapy,51 and VEGFR TKIs38,52, 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 Vo2peak has been observed in anthracycline-treated breast cancer survivors (R2 = 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 HCT66 (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 therapy67 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 al77,78 reported no appreciable impairment in endothelial function among anthracycline-treated breast cancer survivors despite impairment in Vo2peak. Similarly, Koelwyn et al79 observed normal endothelial function and preserved Vo2peak 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 thrombosis81, 82, 83 in cancer survivors treated with radiation therapy,84,85 chemotherapy, immunotherapy,83,86 proteasome inhibitors, hormone therapy,87 and targeted therapies18,30,81,82,87,88 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 [DMO2]) 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 DMO2 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 radiotherapy91 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 muscle95 and skin,57,69,96,97 respectively (Table 1).Figure 1 Overview of Cancer Therapy–Induced Skeletal Muscle Toxicity

Skeletal muscle dysfunction can occur because of the combined and independent effects of cancer-targeted therapies and patient factors in patients with cancer. Several pathways involving mitochondrial and myocyte dysfunction likely contribute to skeletal muscle dysfunction in patients with cancer. There is growing evidence that skeletal muscle dysfunction is multifactorial and can lead to exercise intolerance and increase the risk for heart failure. ROS = reactive oxygen species.

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 DMO2. 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 fibers95,106 (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 Vo2peak (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 (R2 = 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 Vo2peak (R2 = 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 models119 and early clinical studies120 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 approach121,122 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 cardiotoxicity111 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 Vo2peak. If not feasible, alternative assessments such as a graded exercise test (estimating Vo2peak) 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 Vo2peak 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.Table 2 Proposed Therapies to Modify Noncardiac and Peripheral Function and Improve Peak Oxygen Uptake

Therapy	Potential Mechanisms	
Exercise training (aerobic ± resistance training)	Diffusive oxygen loading: improved respiratory muscle strength and increased V/Q matching.162, 163, 164, 165
Convective oxygen delivery: reduced inflammation and oxidative stress,162 increased nitric oxide availability,162,163 decreased sympathetic nerve activity contributing to decreased vascular resistance,163,165 increased arterial compliance,163 improved peripheral vasodilation.163
Diffusive oxygen conductance and oxidative metabolism: increased capillarity,162,163,166 improved microvascular function,162,163,166 increased proportion of oxidative muscle fibers,162 decreased myosteatosis, increased mitochondrial number and oxidative enzymes.162	
Physical activity and sedentary behavior reduction (wearable activity trackers ± behavioral counseling)	Convective oxygen delivery: improved endothelial function, decreased vascular stiffness, improved peripheral vasodilation.167
Diffusive oxygen conductance and oxidative metabolism: improved microvascular function and oxidative enzymes.168,169	
Diet (eg, diet quality, consumption of unsaturated fatty acids, supplementation, caloric restriction)	Convective oxygen delivery: decreased inflammation and oxidative stress, and improved nitric oxide bioavailability resulting in decreased vascular resistance, increased arterial compliance, improved peripheral vasodilation.170
Diffusive oxygen conductance and oxidative metabolism: improved microvascular function, decreased myosteatosis and intramuscular triglyceride content.171	
Sodium-glucose transport protein 2 inhibitors	Convective oxygen delivery: decreased vascular stiffness, increased arterial compliance, improved peripheral vasodilation.172,173
Diffusive oxygen conductance and oxidative metabolism: preferential fatty acid oxidation for substrate utilization.174	
Iron supplementation/blood transfusion	Convective oxygen delivery and diffusive oxygen conductance: increased hemoglobin and affects cellular oxygen storage and metabolism in cardiomyocytes and skeletal muscle.175,176	
PDE5 inhibitors	Diffusive oxygen loading and convective oxygen delivery: inhibition of PDE3, PDE4, and PDE5 preventing cGMP or cAMP degradation increasing their levels in smooth muscle cells causing vasodilation.177	
Inorganic nitrates	Convective oxygen delivery and diffusive oxygen conductance: vasodilator, improved mitochondrial energetics, protection against oxidative damage and activation of cyclic guanosine monophosphate.178	
Elamipretide	Diffusive oxygen conductance and oxidative metabolism: decreased mitochondrial reactive oxygen species generation and improved ATP production.179	
ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; PDE = phosphodiesterase; V/Q = ventilation/perfusion.

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 factors131,132 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 Vo2peak 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 DMO2) 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 cancer134 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 Vo2peak 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 Vo2peak (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 al95 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 Vo2peak (+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 Vo2peak 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 nitrates141) may help address factors such as ectopic fat accumulation, chronic inflammation, and oxidative stress that contribute to the underlying peripheral toxicities.Table 3 Future Directions

Dynamics of and populations at risk for exercise intolerance	
• Broader use of direct measures of exercise tolerance in clinical trials and cohort studies.

	
• Determine accuracy of wearable technology to capture changes in exercise tolerance during and following cancer therapy.

	
Physiological mechanisms underlying exercise intolerance	
• Characterizing the impact of cancer therapy on oxygen cascade combining exercise testing with imaging, metabolic gas exchange, or hemodynamic assessment (eg, exercise stress, CPET, right heart catheterization, heart rhythm monitoring).

	
• Comprehensive assessment of exercise tolerance and clinical and physiological measures of pulmonary, cardiac, vascular, hematologic, and skeletal muscle parameters.

	
• Use of bioinformatics and multiomics to determine molecular signature of toxicities and exercise intolerance phenotypes.

	
Therapeutic strategies	
• Understand the impact of current cardiovascular pharmacotherapy on noncardiac drivers of exercise intolerance.

	
• Evaluate the effects of periphery-targeted therapeutics on exercise tolerance and the oxygen cascade.

	
• Assess the potential benefits of systemic therapies targeting multiple steps of the oxygen cascade (eg, exercise ± nutrition).

	
CPET = cardiopulmonary exercise testing.

Conclusions

Exercise intolerance is an important, but underappreciated marker of the increased cardiovascular risk and functional limitations experienced by cancer survivors. Traditionally, impairments in Vo2peak 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.Perspectives 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.

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.
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References

1 Siegel R.L. Miller K.D. Wagle N.S. Jemal A. Cancer statistics, 2023 CA Cancer J Clin 73 2023 17 48 36633525
2 Global Burden of Disease 2019 Cancer CollaborationKocarnik J.M. Compton K. Dean F.E. 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 8 2022 420 444 34967848
3 Miller K.D. Nogueira L. Devasia T. Cancer treatment and survivorship statistics, 2022 CA Cancer J Clin 72 2022 409 436 35736631
4 Florido R. Daya N.R. Ndumele C.E. Cardiovascular disease risk among cancer survivors: the Atherosclerosis Risk in Communities (ARIC) study J Am Coll Cardiol 80 2022 22 32 35772913
5 Lyon A.R. López-Fernández T. Couch L.S. 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 43 2022 4229 4361 36017568
6 Curigliano G. Lenihan D. Fradley M. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations Ann Oncol 31 2020 171 190 31959335
7 Cardinale D. Colombo A. Bacchiani G. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy Circulation 131 2015 1981 1988 25948538
8 Howden E.J. Foulkes S. Dillon H.T. 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 22 2021 451 458 33543256
9 Groarke J.D. Payne D.L. Claggett B. Association of post-diagnosis cardiorespiratory fitness with cause-specific mortality in cancer Eur Heart J Qual Care Clin Outcomes 6 2020 315 322 32167560
10 Forman D.E. Arena R. Boxer R. 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 135 2017 e894 e918 28336790
11 Cramer L. Hildebrandt B. Kung T. Cardiovascular function and predictors of exercise capacity in patients with colorectal cancer J Am Coll Cardiol 64 2014 1310 1319 25257631
12 Dillon H.T. Foulkes S. Horne-Okano Y.A. Rapid cardiovascular aging following allogeneic hematopoietic cell transplantation for hematological malignancy Front Cardiovasc Med 9 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 2 2019 e192535
14 Shang J. Zhou L. Huang L. 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 13 2023 e069645
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 17 2021 e1811 e1820 33961496
16 Yao D. Yu L. He W. Antineoplastic prescription among patients with colorectal cancer in eight major cities of China, 2015-2019: an observational retrospective database analysis BMJ Open 11 2021 e046166
17 Haykowsky M.J. Kirkham A.A. Li T. Determinants of oxygen utilization in breast cancer: similarities between heart failure with preserved ejection fraction Prog Cardiovasc Dis 74 2022 45 52 36279949
18 Herrmann J. Yang E.H. Iliescu C.A. Vascular toxicities of cancer therapies: the old and the new—an evolving avenue Circulation 133 2016 1272 1289 27022039
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 11 2016 71 79 26922746
20 King T.E. Jr. Clinical advances in the diagnosis and therapy of the interstitial lung diseases Am J Respir Crit Care Med 172 2005 268 279 15879420
21 Jonasch E. Donskov F. Iliopoulos O. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease N Engl J Med 385 2021 2036 2046 34818478
22 Baik A.H. Hypoxia signaling and oxygen metabolism in cardio-oncology J Mol Cell Cardiol 165 2022 64 75 34979102
23 Ludwig H. Van Belle S. Barrett-Lee P. 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 40 2004 2293 2306 15454256
24 Fleg J.L. Pina I.L. Balady G.J. 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 102 2000 1591 1597 11004153
25 Ekblom B. Goldbarg A.N. Gullbring B. Response to exercise after blood loss and reinfusion J Appl Physiol 33 1972 175 180 5054420
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 6 2022 2707 2721 34972204
27 Leaf R.K. Ferreri C. Rangachari D. Clinical and laboratory features of autoimmune hemolytic anemia associated with immune checkpoint inhibitors Am J Hematol 94 2019 563 574 30790338
28 Howden E.J. Bigaran A. Beaudry R. Exercise as a diagnostic and therapeutic tool for the prevention of cardiovascular dysfunction in breast cancer patients Eur J Prev Cardiol 26 2019 305 315 30376366
29 Foulkes S. Costello B.T. Howden E.J. Exercise cardiovascular magnetic resonance reveals reduced cardiac reserve in pediatric cancer survivors with impaired cardiopulmonary fitness J Cardiovasc Magn Reson 22 2020 64 32892749
30 Herrmann J. Vascular toxic effects of cancer therapies Nat Rev Cardiol 17 2020 503 522 32218531
31 Campia U. Moslehi J.J. Amiri-Kordestani L. Cardio-oncology: vascular and metabolic perspectives: a scientific statement from the American Heart Association Circulation 139 2019 e579 e602 30786722
32 Bosman M. Favere K. Neutel C.H.G. Doxorubicin induces arterial stiffness: a comprehensive in vivo and ex vivo evaluation of vascular toxicity in mice Toxicol Lett 346 2021 23 33 33895255
33 Soultati A. Mountzios G. Avgerinou C. Endothelial vascular toxicity from chemotherapeutic agents: preclinical evidence and clinical implications Cancer Treat Rev 38 2012 473 483 21982720
34 Zieman S.J. Melenovsky V. Kass D.A. Mechanisms, pathophysiology, and therapy of arterial stiffness Arterioscler Thromb Vasc Biol 25 2005 932 943 15731494
35 Daskalaki M. Makris T. Vassilakopoulos T. Effects of anthracyclines on aortic distensibility in patients with lymphomas: a prospective study Hellenic J Cardiol 55 2014 191 196 24862610
36 Chaosuwannakit N. D’Agostino Jr R. Hamilton C.A. Aortic stiffness increases upon receipt of anthracycline chemotherapy J Clin Oncol 28 2010 166 19901105
37 Drafts B.C. Twomley K.M. D’Agostino R. Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease J Am Coll Cardiol Img 6 2013 877 885
38 Grover S. Lou P. Bradbrook C. Early and late changes in markers of aortic stiffness with breast cancer therapy Intern Med J 45 2015 140 147 25404097
39 Militaru A. Avram A. Cimpean A.M. The assessment of left ventricle function and subclinical atherosclerosis in patients with acute myeloid leukemia In Vivo 32 2018 1599 1607 30348722
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 9 2020 e015598
41 Kirkham A.A. Paterson D.I. Haykowsky M.J. Aerobic fitness is related to myocardial fibrosis post–anthracycline therapy Med Sci Sports Exerc 53 2021 267 274 32826630
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 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 35 2011 389 395 21755708
44 Budinskaya K. Puchnerová V. Svačinová J. Non-invasive assessment of vascular system function and damage induced by anthracycline treatment in the pediatric cancer survivors Physiol Res 66 suppl 4 2017 S553 S560 29355384
45 Jenei Z. Bárdi E. Magyar M.T. Anthracycline causes impaired vascular endothelial function and aortic stiffness in long term survivors of childhood cancer Pathol Oncol Res 19 2013 375 383 23242567
46 Frye J.N. Sutterfield S.L. Caldwell J.T. Vascular and autonomic changes in adult cancer patients receiving anticancer chemotherapy J Appl Physiol 125 2018 198 204 29565770
47 Krystal J.I. Reppucci M. Mayr T. Fish J.D. Sethna C.J. Arterial stiffness in childhood cancer survivors Pediatr Blood Cancer 62 2015 1832 1837 25895119
48 Sekijima T. Tanabe A. Maruoka R. Impact of platinum-based chemotherapy on the progression of atherosclerosis Climacteric 14 2011 31 40 21067421
49 Visvikis A. Kyvelou S.M. Pietri P. Cardiotoxic profile and arterial stiffness of adjuvant chemotherapy for colorectal cancer Cancer Manag Res 12 2020 1175 1185 32104097
50 Nuver J. Smit A.J. van der Meer J. Acute chemotherapy-induced cardiovascular changes in patients with testicular cancer J Clin Oncol 23 2005 9130 9917 16301596
51 Vallerio P. Sarno L. Stucchi M. Long-term effects of radiotherapy on arterial stiffness in breast cancer women Am J Cardiol 118 2016 771 776 27392510
52 Res E. Kyvelou S.M. Vlachopoulos C. Metastatic malignancies and the effect on arterial stiffness and blood pressure levels: the possible role of chemotherapy Onco Targets Ther 11 2018 6785 6793 30349311
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 33 2015 1310 1317 25715093
54 Mäki-Petäjä K.M. McGeoch A. Yang L.L. Mechanisms underlying vascular endothelial growth factor receptor inhibition–induced hypertension: the HYPAZ trial Hypertension 77 2021 1591 1599 33775123
55 Veronese M.L. Mosenkis A. Flaherty K.T. Mechanisms of hypertension associated with BAY 43-9006 J Clin Oncol 24 2006 1363 1369 16446323
56 Florescu M. Mihalcea D. Enescu O.A. Taxanes-induced cardiotoxicity is related to increased arterial stiffness and oxidative stress Eur Heart J 34 suppl 1 2013 P3006
57 Steeghs N. Rabelink T. Op’t Roodt J. Reversibility of capillary density after discontinuation of bevacizumab treatment Ann Oncol 21 2010 1100 1105 19854721
58 Kim T.D. Rea D. Schwarz M. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib Leukemia 27 2013 1316 1321 23459449
59 Rattanathammethee T. Tantiworawit A. Rattarittamrong E. Peripheral artery occlusive disease among patients with chronic myeloid leukemia receiving tyrosine kinase inhibitors: a cross-sectional case-control study Clin Med Insights Cardiol 11 2017 1179546817747258
60 Astarita A. Mingrone G. Airale L. 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) 15 3 2023 955 36765915
61 Blaes A. Beckwith H. Florea N. Vascular function in breast cancer survivors on aromatase inhibitors: a pilot study Breast Cancer Res Treat 166 2017 541 547 28801846
62 Maor R. Sara J.D.S. Wanous A.A. Attenuated peripheral endothelial function among women treated with aromatase inhibitors for breast cancer Coron Artery Dis 29 2018 687 693 30379695
63 Smith J. Bennett S. Evans L. The effects of induced hypogonadism on arterial stiffness, body composition, and metabolic parameters in males with prostate cancer J Clin Endocrinol Metab 86 2001 4261 4267 11549659
64 Oka R. Utsumi T. Endo T. 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 21 2016 389 396 26296528
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 30 2009 410 415 19168445
66 Climie R.E. Dillon H.T. Horne-Okano Y. Vascular aging is accelerated in hematological cancer survivors who undergo allogeneic stem cell transplant Hypertension 80 2023 1881 1889 37476996
67 Terwoord J.D. Beyer A.M. Gutterman D.D. Endothelial dysfunction as a complication of anti-cancer therapy Pharmacol Ther 237 2022 108116
68 Venkatesulu B.P. Mahadevan L.S. Aliru M.L. Radiation-induced endothelial vascular injury: a review of possible mechanisms J Am Coll Cardiol Basic Trans Science 3 2018 563 572
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 19 2008 927 934 18056916
70 Kastritis E. Laina A. Georgiopoulos G. Carfilzomib-induced endothelial dysfunction, recovery of proteasome activity, and prediction of cardiovascular complications: a prospective study Leukemia 35 2021 1418 1427 33589757
71 Poreba M. Gac P. Usnarska-Zubkiewicz L. Endothelial function in patients with hematologic malignancies undergoing high-dose chemotherapy followed by hematopoietic stem cell transplantation Cardiovasc Toxicol 16 2016 156 162 25855515
72 Hammond S.T. Baumfalk D.R. Parr S.K. Impaired microvascular reactivity in patients treated with 5-fluorouracil chemotherapy regimens: potential role of endothelial dysfunction Int J Cardiol Heart Vasc 49 2023 101300
73 Vassilakopoulou M. Mountzios G. Papamechael C. Paclitaxel chemotherapy and vascular toxicity as assessed by flow-mediated and nitrate-mediated vasodilatation Vasc Pharmacol 53 2010 115 121
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 9 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 37 2001 761 765 11693749
76 Kaneko T. Miyazaki S. Kurita A. Endothelial function measured by peripheral arterial tonometry in patients with chronic myeloid leukemia on tyrosine kinase inhibitor therapy: a pilot study Cardio-Oncology 9 2023 11 36814340
77 Jones L.W. Fels D.R. West M. Modulation of circulating angiogenic factors and tumor biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy Cancer Prev Res (Phila) 6 2013 925 937 23842792
78 Jones L.W. Haykowsky M. Peddle C.J. 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 16 2007 1026 1031 17507633
79 Koelwyn G.J. Lewis N.C. Ellard S.L. Ventricular-arterial coupling in breast cancer patients after treatment with anthracycline-containing adjuvant chemotherapy Oncologist 21 2016 141 149 26764251
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 2 2016 625 632 26847662
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 6 8 2017 e006278
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 80 2017 487 495 28695268
83 Ma Z. Sun X. Zhang Y. Risk of thromboembolic events in cancer patients treated with immune checkpoint inhibitors: a meta-analysis of randomized controlled trials Thromb Haemost 122 2022 1757 1766 35772727
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 9 2014 e110389
85 McCready R.A. Hyde G.L. Bivins B.A. Mattingly S.S. Griffen W.O.J.S. Radiation-induced arterial injuries Surgery 93 1983 306 312 6823669
86 Dolladille C. Akroun J. Morice P.M. Cardiovascular immunotoxicities associated with immune checkpoint inhibitors: a safety meta-analysis Eur Heart J 42 2021 4964 4977 34529770
87 Cohen J.B. Brown N.J. Brown S.-A. Cancer therapy–related hypertension: a scientific statement from the American Heart Association Hypertension 80 3 2023 e46 e57 36621810
88 Grover S.P. Hisada Y.M. Kasthuri R.S. Reeves B.N. Mackman N. Cancer therapy–associated thrombosis Arterioscler Thromb Vasc Biol 41 2021 1291 1305 33567864
89 Coumbe B.G.T. Groarke J.D. Cardiovascular autonomic dysfunction in patients with cancer Curr Cardiol Rep 20 2018 69 29971575
90 Poole D.C. Musch T.I. Colburn T.D. Oxygen flux from capillary to mitochondria: integration of contemporary discoveries Eur J Appl Physiol 122 2022 7 28 34940908
91 Korpela E. Liu S.K. Endothelial perturbations and therapeutic strategies in normal tissue radiation damage Radiat Oncol 9 2014 266 25518850
92 Kamba T. Tam B.Y. Hashizume H. VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature Am J Physiol Heart Circ Physiol 290 2006 H560 H576 16172168
93 Inai T. Mancuso M. Hashizume H. 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 165 2004 35 52 15215160
94 Rasanen M. Degerman J. Nissinen T.A. VEGF-B gene therapy inhibits doxorubicin-induced cardiotoxicity by endothelial protection Proc Natl Acad Sci U S A 113 2016 13144 13149 27799559
95 Mijwel S. Cardinale D.A. Norrbom J. Exercise training during chemotherapy preserves skeletal muscle fiber area, capillarization, and mitochondrial content in patients with breast cancer FASEB J 32 2018 5495 5505 29750574
96 Coschignano M.A. De Ciuceis C. Agabiti-Rosei C. Microvascular structural alterations in cancer patients treated with antiangiogenic drugs Front Cardiovasc Med 8 2021 651594
97 Steeghs N. Gelderblom H. Roodt Jot Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor Clin Cancer Res 14 2008 3470 3476 18519779
98 Lesterhuis W.J. Rennings A.J. Leenders W.P. Vascular endothelial growth factor in systemic capillary leak syndrome Am J Med 122 2009 e5 e7
99 Siddall E. Khatri M. Radhakrishnan J. Capillary leak syndrome: etiologies, pathophysiology, and management Kidney Int 92 2017 37 46 28318633
100 Druey K.M. Greipp P.R. Narrative review: the systemic capillary leak syndrome Ann Intern Med 153 2010 90 98 20643990
101 Jeong G.H. Lee K.H. Lee I.R. Incidence of capillary leak syndrome as an adverse effect of drugs in cancer patients: a systematic review and meta-analysis J Clin Med 8 2 2019 143 30691103
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 57 2022 661 663 35091688
103 Izzedine H. Mathian A. Amoura Z. Ng J.H. Jhaveri KDJKIR Anticancer drug-induced capillary leak syndrome Kidney Int Rep 7 5 2022 945 953 35570987
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 26 2023 210 218 36942895
105 Gamble D.T. Ross J. Khan H. Impaired cardiac and skeletal muscle energetics following anthracycline therapy for breast cancer Circ Cardiovasc Imaging 16 2023 e015782
106 Mallard J. Hucteau E. Charles A.L. Chemotherapy impairs skeletal muscle mitochondrial homeostasis in early breast cancer patients J Cachexia Sarcopenia Muscle 13 2022 1896 1907 35373507
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 76 2013 338 347 23834355
108 West M.A. Loughney L. Lythgoe D. 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 9 2014 e111526
109 Wakasugi T. Morishita S. Kaida K. Impaired skeletal muscle oxygenation following allogeneic hematopoietic stem cell transplantation is associated with exercise capacity Support Care Cancer 26 2018 2149 2160 29372395
110 Kirkham A.A. Haykowsky M.J. Beaudry R.I. Cardiac and skeletal muscle predictors of impaired cardiorespiratory fitness post-anthracycline chemotherapy for breast cancer Sci Rep 11 2021 14005
111 Bellissimo M.P. Reding K.W. O’Connell N.S. Intermuscular fat changes are related to reduced left ventricular ejection fraction during cancer therapy (PREVENT-WF-98213) J Am Coll Cardiol CardioOnc 5 2023 409 411
112 Kirkham A.A. Pituskin E. Thompson R.B. Cardiac and cardiometabolic phenotyping of trastuzumab-mediated cardiotoxicity: a secondary analysis of the MANTICORE trial Eur Heart J Cardiovasc Pharmacol 8 2021 130 139
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 25 2020 e852 e860 31951302
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 4 2010 128 139 20091248
115 Chang D. Joseph D.J. Ebert M.A. Effect of androgen deprivation therapy on muscle attenuation in men with prostate cancer J Med Imaging Radiat Oncol 58 2014 223 228 24118850
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 11 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 30 2021 1424 1432 33879451
118 Christensen Holz S. Aromatase inhibitor musculoskeletal syndrome and bone loss: a review of the current literature Curr Oncol Rep 25 2023 825 831 37052869
119 Dorchies O.M. Reutenauer-Patte J. Dahmane E. The anticancer drug tamoxifen counteracts the pathology in a mouse model of Duchenne muscular dystrophy Am J Pathol 182 2013 485 504 23332367
120 Tsabari R. Simchovitz E. Lavi E. Safety and clinical outcome of tamoxifen in Duchenne muscular dystrophy Neuromuscul Disord 31 2021 803 813 34304968
121 Houstis N.E. Eisman A.S. Pappagianopoulos P.P. Exercise intolerance in heart failure with preserved ejection fraction: diagnosing and ranking its causes using personalized O2 pathway analysis Circulation 137 2018 148 161 28993402
122 Howden E.J. Ruiz-Carmona S. Claeys M. Oxygen pathway limitations in patients with chronic thromboembolic pulmonary hypertension Circulation 143 2021 2061 2073 33853383
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 10 2020 18473
124 Aimo A. Saccaro L.F. Borrelli C. The ergoreflex: how the skeletal muscle modulates ventilation and cardiovascular function in health and disease Eur J Heart Fail 23 2021 1458 1467 34268843
125 Piepoli M.F. Crisafulli A. Pathophysiology of human heart failure: importance of skeletal muscle myopathy and reflexes Exp Physiol 99 2014 609 615 24293507
126 Suzuki T. Palus S. Springer J. Skeletal muscle wasting in chronic heart failure ESC Heart Fail 5 2018 1099 1107 30548178
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 145 2020 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 38 2020 2824 2829 32584631
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 2 2020 e85 e93 33334565
130 Schubert C. Archer G. Zelis J.M. Wearable devices can predict the outcome of standardized 6-minute walk tests in heart disease NPJ Digit Mad 3 2020 92
131 Nayor M. Shah R.V. Miller P.E. Metabolic architecture of acute exercise response in middle-aged adults in the community Circulation 142 2020 1905 1924 32927962
132 Contrepois K. Wu S. Moneghetti K.J. Molecular choreography of acute exercise Cell 181 2020 1112 1130.e16 32470399
133 Shah R.V. Miller P. Colangelo L.A. Blood-based fingerprint of cardiorespiratory fitness and long-term health outcomes in young adulthood J Am Heart Assoc 11 2022 e026670
134 Gongora C.A. Drobni Z.D. Quinaglia Araujo Costa Silva T. Sodium-glucose co-transporter-2 inhibitors and cardiac outcomes among patients treated with anthracyclines J Am Coll Cardiol HF 10 2022 559 567
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 44 suppl 2 2023 ehad655.981
136 Nassif M.E. Windsor S.L. Borlaug B.A. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial Nat Med 27 2021 1954 1960 34711976
137 Foulkes S.J. Howden E.J. Haykowsky M.J. Exercise for the prevention of anthracycline-induced functional disability and cardiac dysfunction: the BREXIT study Circulation 147 2023 532 545 36342348
138 Scott J.M. Zabor E.C. Schwitzer E. Efficacy of exercise therapy on cardiorespiratory fitness in patients with cancer: a systematic review and meta-analysis J Clin Oncol 36 2018 2297 2305 29894274
139 Padilha C.S. Marinello P.C. Galvão D.A. 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 11 2017 339 349 28054255
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 11 2022 184 193 34314878
141 Eggebeen J. Kim-Shapiro D.B. Haykowsky M. 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 4 2016 428 437
142 Cramp F. Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults Cochrane Database Syst Rev 11 11 2012 CD006145 23152233
143 Herrero F. Balmer J. San Juan A.F. Is cardiorespiratory fitness related to quality of life in survivors of breast cancer? J Strength Condition Res 20 2006 535 540
144 Zamorano J.L. Lancellotti P. Rodriguez Munoz D. 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 37 2016 2768 2801 27567406
145 Reinert T. Baldotto CSdR. Nunes F.A.P. Scheliga AAdS. Bleomycin-induced lung injury J Cancer Res 2013 2013 480608
146 Levi M. Sivapalaratnam SJTr An overview of thrombotic complications of old and new anticancer drugs Thromb Res 191 2020 S17 S21 32736772
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 4 2022 192 194
148 Lai S. Amabile M.I. Mazzaferro S. Effects of sunitinib on endothelial dysfunction, metabolic changes, and cardiovascular risk indices in renal cell carcinoma Cancer Med 9 2020 3752 3757 32270594
149 Mayer E.L. Dallabrida S.M. Rupnick M.A. Contrary effects of the receptor tyrosine kinase inhibitor vandetanib on constitutive and flow-stimulated nitric oxide elaboration in humans Hypertension 58 2011 85 92 21482957
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 11 2020 543070
151 Gavazzoni M. Lombardi C.M. Vizzardi E. Irreversible proteasome inhibition with carfilzomib as first line therapy in patients with newly diagnosed multiple myeloma: Early in vivo cardiovascular effects Eur J Pharmacol 838 2018 85 90 30201379
152 Wang T.-F. Carrier M.J.C.O. Immune checkpoint inhibitors-associated thrombosis: incidence, risk factors and management Curr Oncol 30 2023 3032 3046 36975443
153 Li P. Xu B. Xu J. Lenalidomide promotes thrombosis formation, but does not affect platelet activation in multiple myeloma Int J Mol Sci 24 18 2023 14097
154 Aue G. Nelson Lozier J. Tian X. Inflammation, TNFα and endothelial dysfunction link lenalidomide to venous thrombosis in chronic lymphocytic leukemia Am J Hematol 86 2011 835 840 21812019
155 Dandoy C.E. Hirsch R. Chima R. Davies S.M. Jodele S. Pulmonary hypertension after hematopoietic stem cell transplantation Biol Blood Marrow Transplant 19 2013 1546 1556 23891748
156 Tichelli A. Bucher C. Rovó A. Premature cardiovascular disease after allogeneic hematopoietic stem-cell transplantation Blood 110 2007 3463 3471 17664354
157 Vasbinder A. Hoeger C.W. Catalan T. Cardiovascular events after hematopoietic stem cell transplant: incidence and risk factors J Am Coll Cardiol CardioOnc 5 2023 821 832
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 15 2009 1100 1107 19660723
159 Dillon H.T. Foulkes S. Horne-Okano Y.A. Reduced cardiovascular reserve capacity in long-term allogeneic stem cell transplant survivors Sci Rep 13 2023 2112 36747066
160 Hanania A.N. Mainwaring W. Ghebre Y.T. Hanania N.A. Ludwig M.J.C. Radiation-induced lung injury: assessment and management Chest 156 2019 150 162 30998908
161 Banister H.R. Hammond S.T. Parr S.K. Lower endothelium-dependent microvascular function in adult breast cancer patients receiving radiation therapy Cardio-Oncology 7 2021 18 33985593
162 Furrer R. Hawley J.A. Handschin C. The molecular athlete: exercise physiology from mechanisms to medals Physiol Rev 103 2023 1693 1787 36603158
163 Hellsten Y. Nyberg M. Cardiovascular adaptations to exercise training Compr Physiol 6 2016 1 32
164 Davey P. Meyer T. Coats A. Ventilation in chronic heart failure: effects of physical training Br Heart J 68 1992 473 477 1467031
165 Coats A.J. Adamopoulos S. Radaelli A. Controlled trial of physical training in chronic heart failure. Exercise performance, hemodynamics, ventilation, and autonomic function Circulation 85 1992 2119 2131 1591831
166 Charles M. Charifi N. Verney J. Effect of endurance training on muscle microvascular filtration capacity and vascular bed morphometry in the elderly Acta Physiol (Oxf) 187 2006 399 406 16776665
167 Paterson C. Fryer S. Zieff G. The effects of acute exposure to prolonged sitting, with and without interruption, on vascular function among adults: a meta-analysis Sports Med 50 2020 1929 1942 32757163
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 100 2015 829 838 25929229
169 Pinto A.J. Bergouignan A. Dempsey P.C. Physiology of sedentary behavior Physiol Rev 103 2023 2561 2622 37326297
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 24 2014 929 939 24787907
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 30 2010 13 34 20373917
172 Patoulias D. Papadopoulos C. Kassimis G. Effect of sodium-glucose co-transporter-2 inhibitors on arterial stiffness: a systematic review and meta-analysis of randomized controlled trials Vasc Med 27 2022 433 439 35754338
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) 13 2022 826604
174 Packer M. SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism Nat Rev Cardiol 20 2023 443 462 36609604
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 116 2010 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 18 2016 762 773 26800032
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 177 2020 5467 5488 31721165
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 33 2024 230183
179 Obi C. Smith A.T. Hughes G.J. Adeboye A.A. Targeting mitochondrial dysfunction with elamipretide Heart Fail Rev 27 2022 1925 1932 35037146
