Introduction
Numerous types of cancer treatments, ranging from immunotherapy, traditional chemotherapy (e.g., doxorubicin), and targeted therapy (e.g., tyrosine kinase inhibitors [TKIs]) are associated with vascular toxicities. As cardiovascular disease (CVD) remains the leading cause of morbidity and mortality in patients with and without cancer, there is an urgent need to better understand the mechanisms and manifestations of vascular side effects to improve the care of cancer patients. In this brief review, we will summarize the common vascular toxicities associated with cancer therapies and provide a broad overview on their management.

Systemic Hypertension
Systemic hypertension is a common vascular toxicity due to vascular endothelial growth factor (VEGF) signaling pathway inhibition and is also a clinical marker of therapy efficacy.¹ VEGF binds to VEGF receptors (VEGFR), promoting angiogenesis.^2,3 VEGF signaling pathway inhibitors (VSPi) take advantage of tumor cells' dependence on blood supply by inhibiting VEGF signaling through various mechanisms of action: VEGF antibodies (e.g., bevacizumab), VEGFR antibodies (e.g., ramucirumab), and VEGFR TKIs (e.g., sorafenib, sunitinib) (Table 1).⁴ VSPi-associated hypertension is an "on-target" effect, affecting up to 90% of patients with newer generation VSPi (e.g., lenvatinib, lucitanib, axitinib).^5,6 Life-threatening hypertensive crises, such as posterior reversible encephalopathy, are rare.⁷ Patients with pre-existing hypertension, advanced age (>60 years), tobacco use, hyperlipidemia, and obesity are at highest risk for VSPi associated hypertension.^8,9 Mechanisms have been reviewed previously^4,10 and are summarized in Table 2 below.

Table 1: VEGF Signaling Pathway (VSP) Inhibitors

Target	Name	Mechanisms	Cardiovascular Toxicities	Cancer(s)
VEGF-A	Bevacizumab (Avastin)	Monoclonal antibody (mAb); humanized anti-VEGF antibody	Hypertension Arterial and venous thromboembolism Reversible cardiomyopathy Congestive heart failure Cardiac hypertrophy Myocardial infarction Cerebral ischemia Bleeding Proteinuria	Metastatic colorectal cancer Advanced non-squamous non-small cell lung cancer Metastatic renal cell carcinoma Recurrent glioblastoma Advanced cervical cancer
VEGFR2	Ramucirumab	mAb; binds to VEGFR-2 and blocks binding of VEGFR ligands, such as VEGF-A, VEGF-C, and VEGF-D	Hypertension Reversible cardiomyopathy Arterial and venous thromboembolism Bleeding Peripheral edema Proteinuria	Advanced gastric or GE junction adenocarcinoma Metastatic NSCLC Metastatic colorectal cancer Advanced hepatocellular carcinoma
VEGFR1	Icrucumab	mAb; binds to VEGFR-1 and inhibits downstream signaling	Peripheral edema Anemia No cardiotoxicity or hypertension identified	Under clinical investigation for advanced solid cancers (e.g., small cell lung cancer, colorectal cancer)
VEGF	Ziv-aflibercept	VEGF-trap; peptide-antibody fusion protein that  binds to circulating VEGF members (VEGF-A, VEGF-B) and placental growth factor	Hypertension Arterial and venous thromboembolism Cardiomyopathy  Bleeding Proteinuria	Metastatic colorectal cancer
Multi-target Tyrosine Kinase Inhibitors (TKI)	Axitinib	VEGFR1, 2, 3; PDGFR; c-KIT	Hypertension Cardiomyopathy Arterial and venous thromboembolism Bleeding Proteinuria	Advanced RCC, advanced neuroendocrine tumors of non-pancreatic origin
	Cabozantinib	VEGFR1, 2, 3, RET, FLT3; c-MET, AXL	Hypertension Cardiomyopathy Arterial and venous thromboembolism Bleeding Proteinuria	Advanced RCC Metastatic medullary thyroid cancer Hepatocellular cancer
	Lenvatinib	VEGFR 1, 2, 3; FGFR 1-4, PDGFRA, RET	Hypertension Cardiomyopathy Arterial and venous thromboembolism Bleeding QT prolongation Proteinuria	Iodine-131-refractory thyroid cancer
	Cediranib	VEGFR1 2, 3; c-KIT; PDGFR	Hypertension Arterial and venous thromboembolism QT prolongation Proteinuria	Advanced RCC, GIST, soft tissue sarcoma, HCC, advanced non-small cell lung cancer, advanced colorectal cancer, mesothelioma, breast cancer, ovarian cancer , GBM
	Nintedanib	PDGFR, FGFR, VEGFR-1, 2, 3; FLT3	Hypertension Arterial and venous thromboembolism Myocardial infarction Bleeding Proteinuria	Locally advanced, metastatic, or locally recurring non-small cell lung cancer (in combination with docetaxel); interstitial lung disease
	Pazopanib	VEGFR 1, 2, 3, PDGFR, FGFR, c-KIT, Flt-3, RET	Hypertension Cardiomyopathy Thromboembolism QT prolongation Torsades de pointes Proteinuria	Metastatic medullary thyroid cancer Advanced renal cell carcinoma Advanced soft tissue sarcomas
	Sunitinib	VEGFR 1, 2, 3, PDGFR-A and -B, c-KIT, RET, CD114, CD135	Hypertension Reversible cardiomyopathy Arterial and venous thromboembolism Cardiac ischemia QT prolongation Proteinuria	Advanced RCC, Progressive well-differentiated pancreatic neuroendocrine tumors, GIST
	Sorafenib	RAF kinase, VEGFR 1, 2, 3, PDGFR-B, RET, c-KIT, FLT3	Hypertension Reversible cardiomyopathy Cardiac ischemia Arterial and venous thromboembolism Bleeding QT prolongation Proteinuria	Advanced RCC, advanced unresectable HCC, GIST, angiosarcoma, advanced thyroid carcinoma refractory to radioactive iodine treatment
	Apatinib	VEGFR2, c-KIT, c-SRC	Hypertension Bleeding Left ventricular dysfunction Proteinuria	Metastatic gastric carcinoma, metastatic breast cancer; advanced HCC, refractory metastatic colorectal cancer
	Lucitanib	VEGFR1, 2, 3, PGFRA/B, FGFR1 and 2	Hypertension QT prolongation Proteinuria	Advanced solid tumors (in clinical trials)
	Regorafenib	VEGFR 1, 2,3; TIE-2, RET, PDGFB, basic FGF-1, c-KIT, RAF-1, BRAF	Hypertension Thrombosis Heart failure Bleeding Proteinuria	Advanced HCC, Advanced GIST, metastatic colorectal cancer
	Vandetanib	VEGFR-2, 3, EGFR, PDGFR, RET	Hypertension Cardiomyopathy QT prolongation	Advanced RCC, medullary thyroid cancer, NSCLC
	Vatalanib	VEGFR1, 2, 3; PDGFR, c-KIT	Hypertension Heart failure Venous thromboembolism	Advanced solid tumors
	Surufatinib	VEGFR1, 2, 3; FGFR1, CSF1R	Hypertension Proteinuria Hypertriglyceridemia	Advanced solid tumors; advanced medullary thyroid cancer
	Famitinib	VEGFR2 and 3, PDGFR, c-KIT, FGFR	Hypertension	Advanced genitourinary and gynecologic cancers
	Ponatinib	BCR-ABL, FGFR, VEGFR1, 2, 3, PDGFR, c-KIT, RET, FLT3	Hypertension Arterial and venous thromboembolism Cardiac ischemia Atrial fibrillation Proteinuria	Resistant Philadelphia chromosome-positive chronic myelogenous leukemia and acute lymphocytic leukemia

Prior to initiation of VSPi, baseline blood pressures should be optimized (goal <130/80 mmHg) with lifestyle modifications and anti-hypertensive medications. During treatment with VSPi, blood pressures should be closely monitored, and hypertension should be treated with first-line medications according to the Joint National Committee (JNC 8) guidelines (Table 2).

Table 2: Proposed Mechanisms and Management of Common Vascular Toxicities

		Thromboembolism	CAD/MI	PAD	Hypertension	PAH		Arterial Vasospasm
Proposed Mechanism(s)		Traditional chemotherapies: direct cytotoxicity on endothelial cells; erosion of the superficial endothelial monolayer.68,69 VEGF signaling pathway inhibitors: alter vasodilator homeostasis and endothelial cell dysfunction due to inhibition of VEGF signaling.3,4,10 ICIs: Possibly due to vasculitis and vascular thrombotic events.32	BCL-ABL inhibitors: induce endothelial dysfunction; direct endothelial cell toxicity.70 Radiotherapy: tunica intima and media disruption; fibrosis and atrophy of endothelial cells. Toxicity related to radiation dose.71,72		VEGF signaling pathway inhibitors: increase endothelin-1 levels; induce endothelial cell dysfunction; alter nitric oxide signaling.4,10	Dasatinib: induces mitochondrial oxidative stress and endothelial apoptosis; alters normal pulmonary endothelial integrity and permeability.73,74 Bleomycin: induces pulmonary fibrosis and hypoxia -> PH (predominantly WHO group 3)	5-FU: induces endothelial dysfunction and vasoconstriction via activation of protein kinase C signaling.75 Reduces nitric oxide levels.
Management*	Step 1	ABCDEs to prevent cardiovascular heart disease in all cancer patients and survivors.76 A: Awareness of heart disease risks; B: blood pressure; C: cholesterol, cigarette/tobacco cessation; D: diet and weight management, dose of chemotherapy or radiation, DM prevention and treatment; E: exercise (+/- echocardiogram) All patients should have a detailed history and physical to evaluate for underlying ASCVD and optimize risk factors. CVD and cancer share many risk factors (e.g., hypertension, diabetes, hyperlipidemia) and have many overlapping features (e.g., tobacco use, obesity, older age, physical inactivity). Notably, patients with CVD also are more likely to develop cancer compared to the general population.77 Smoking cessation and treatment of underlying CVD and CV risk factors should be recommended for all patients regardless of their cancer therapies or underlying malignancy Assess possible drug-specific side effects for all patients High risk patients should be referred to cardio-oncology.
	Screening	Assess for asymmetric LE or UE swelling at each clinic visit ECG to assess for RV strain or RVH	Baseline ECG and every 6 months Assess for resting and exertional chest pain, CHF symptoms (orthopnea, PND, LE edema) at each visit Monitor risk factors (e.g., fasting glucose/A1C, HTN, fasting lipids) every 6 months SCORE chart –validated tool to identify patients at high risk of atherosclerotic events during nilotinib treatment.78	Baseline ECG and every 6 months ABI at baseline and every 3-6 months for patients on second generation TKI (nilotinib or ponatinib) Monitor risk factors (e.g., fasting glucose/A1C, HTN, lipid panel) every 6 months	Baseline ECG and every 6 months Urine Pr/Cr ratio Home BP monitoring Monitor blood pressure at every outpatient visit Optimize BPs before initiating cancer-directed therapy (goal 130/80 mmHg)	Baseline ECG and every 6 months Assess for right sided heart failure signs and symptoms (e.g., ascites, LE edema)	Baseline ECG Assess risk factors for coronary artery disease (A1C, HTN, lipid panel, weight, smoking history)
	Diagnosis	Venous and arterial doppler ultrasound	ECG to assess for ischemia or infarction Cardiac troponin if symptoms consistent with ACS  Exercise or nuclear stress test Consider CACs and cCTA in low-risk patients (note, these have not been validated specifically in cancer patients) Coronary angiogram in high-risk patients or if concern for ACS Cardiac MRI or PET scan to rule out myocarditis in high-risk patients taking ICI	Arterial doppler ultrasound ABI £ 0.9 CT peripheral angiography	Serial blood pressure measurements >130/80 mmHg ECG to assess for left ventricular hypertrophy Basic metabolic panel Urine Pr/Cr ratio to assess for proteinuria	If symptoms consistent with right-sided heart failure (e.g., elevated JVP, ascites, LE edema), obtain ECG, CXR and TTE Cardiac biomarkers (BNP or NT-pro BNP) CPET to differentiate between cardiac vs. pulmonary pathologies RHC: mPAP > 20mmHg, PVR >3 WU	Coronary angiogram Repeat ECG if new symptoms (e.g. angina, dyspnea, palpitations) Cardiac biomarkers (cTnI; BNP or NT-pro BNP) TTE to evaluate for WMA Genetic testing to identify patients at high risk for severe 5-FU related toxicity
	Treatment	No data to support VTE prophylaxis in cancer patients VTE: anticoagulation ATE: anticoagulation, fibrinolysis, mechanical thrombectomy Treatment should be individualized based on bleeding risk and location/severity of thromboembolism	Aggressive risk factor modification Anti-platelet therapy and high-intensity statin PCI or coronary artery bypass graft surgery if indicated	Aggressive risk factor modification Structured exercise therapy Pharmacologic therapies (high-intensity statin, cilostazol) Revascularization as indicated If severe, nilotinib should be replaced with an alternative TKI	First line anti-hypertensives per JNC guidelines (e.g., dihydropyridine CCB, ACEi/ARB, diuretic if intravascular volume overload) Note: non-dihydropyridine CCBs can increase levels of VEGF inhibitors and should be avoided.79	Discontinue the culprit drug Refer to PH specialist to initiate pulmonary vasodilator therapy (3 classes: PDE-5 inhibitors, ERAs, and prostacyclin)	Start anti-anginal therapy (CCB or nitrates); CCB preferred if concern for microvascular dysfunction If patient has history of 5-FU related vasospasm, recommend serial ECG and TTE monitoring with every 1-2 cycles

Venous and Arterial Thromboembolism
Thromboembolism is prevalent in cancer patients and is associated with high rates of morbidity and mortality.¹¹ Cancer treatment can further increase the incidence of venous- (VTE) and arterial thromboembolism (ATE), including thrombotic events such as myocardial ischemia/infarction (MI) (Figure 1). The mechanisms of increased thrombosis due to cancer therapies are proposed to include endothelial activation, endothelial cytotoxicity, platelet activation, and reduced anticoagulant activity. Here, we will focus on targeted therapies and immunotherapies.

Though TKIs result in potent antineoplastic effects by blocking downstream signaling pathways of their targets (e.g., VEGFR, platelet derived growth factor receptor [PDGFR]), their use is associated with an increased risk of thromboembolism (Table 1). For example, sunitinib and sorafenib are associated with a three-fold increase in the risk of ATE.¹² Additional VEGFR-TKIs (e.g., pazopanib, vandetanib, axitinib, etc.) are associated with an increased risk of ATE and thrombosis (1.4% vs. 0.5%, OR = 2.26), with MI being the most common.¹³ The proposed mechanisms include endothelial cell dysfunction and altered vasodilator homeostasis.⁴ Bevacizumab also increases the risk of both VTE and ATE.¹⁴ Indeed, bevacizumab almost doubles the risk of ATE in cancer patients, in part due to increased platelet activation.^15-18

BCR-ABL TKIs are currently the standard of care for chronic myeloid leukemia (CML). Second-generation TKIs (nilotinib, dasatinib, ponatinib) have a greater binding affinity for BCR-ABL1 and are more efficacious compared to first-generation TKI (imatinib).^19-21 Notably,  patients on newer generation TKIs are three times more likely to develop ATE compared to those treated with imatinib.^22,23 Preclinical studies suggest that platelet activation is the primary mechanism of ponatinib-associated ATE.^24,25

Immune checkpoint inhibitors (ICIs) are increasingly being used as first-line cancer therapies.^26,27 ICIs are monoclonal antibodies that impair tumor escape mechanisms by targeting immune checkpoints, such as CTLA-4, PD-1, and PD-L1, among others (e.g.,  LAG3). Though ATE and VTE have been reported in patients taking ICI, incidence rates are unclear due to lack of systematic toxicity monitoring.^28-30 A recent single center retrospective study reported a cumulative incidence of 12.9% (VTE) and 0.6% (ATE) in patients treated with ICIs but a control group was lacking.³¹ Proposed mechanisms include vasculitis and vascular thrombotic events.³²

The management of thromboembolism in cancer patients should be individualized based on bleeding and clotting risks. Though anticoagulation is the most common treatment, fibrinolysis, antiplatelet therapy, and mechanical thrombectomy can be considered on an individualized basis.³³ The most recent ASCO (American Society of Clinical Oncology) guidelines do not recommend routine thromboprophylaxis for all cancer patients, though can be considered in high-risk patients (Table 2).³⁴

Atherosclerosis and Peripheral Artery Disease
Peripheral artery disease (PAD) is characterized by progressive atherosclerosis and stenosis of large and medium-sized arteries. PAD commonly affects the lower extremities, resulting in claudication.³⁵ Various cancer therapies have been shown to accelerate atherosclerosis and PAD, especially in patients with underlying CVD risk factors (Figure 1).

PAD is associated with second-generation BCR-ABL TKIs (e.g. nilotinib, ponatinib). Notably, imatinib has a favorable CV side effect profile and may even reduce the risk of PAD.³⁶ Compared to imatinib, nilotinib use is associated with increased risk of pathological ankle-brachial index (ABI) values (RR = 10.3; 95% CI 2.3-61.5).³⁷ Cases of nilotinib-associated PAD can be severe and rapidly progressive, sometimes requiring angioplasty or surgical revascularization.^38-40 Ponatinib is also associated with advanced atherosclerosis, including acute MI.⁴¹ Recent meta-analyses have confirmed the increased risk of arterial vascular events (e.g. PAD, MI, CVD) with both nilotinib and ponatinib.^42,43 Potential mechanisms are summarized in Table 2.

Though clinical reports of accelerated atherosclerosis or PAD in ICIs are limited, pre-clinical studies have demonstrated that genetic deficiency of PD-L1, PD-L2, or PD1 increase inflammatory cell infiltration in atherosclerotic plaques, suggesting a potential link between ICIs and atherosclerosis.^44,45 It is thought that ICIs inhibit critical negative regulators of atherosclerosis.³² A recent single-center study showed that patients treated with ICIs are 3.3 times more likely to have an atherosclerotic CV event, defined as MI, coronary revascularization, and ischemic stroke, compared to matched controls over years.⁴⁶

Management of atherosclerotic disease in cancer patients should be individualized based on risk factors and baseline CV disease. Patients with high CVD risk profiles are more vulnerable to vascular toxicities with TKIs compared to those with low risk profiles.⁴⁷ Risk factors (e.g., obesity, smoking, diabetes, hypertension, hypercholesterolemia) should be assessed and optimized in patients prescribed BCR-ABL inhibitors. CV and metabolic parameters, including ABI measurements, should be monitored regularly. In patients taking nilotinib or ponatinib with high-grade PAD (i.e., severe claudication plus abnormal ABI or imaging), the TKI should be replaced with another if possible.⁴⁸

Pulmonary Hypertension
Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure (mPAP) >20mmHg measured during right heart catheterization (RHC).⁴⁹ Group 1 PH or pulmonary arterial hypertension (PAH) includes drug-induced, idiopathic, and toxin-induced, and results from uncontrolled growth of endothelial and smooth-muscle cells in the pulmonary vasculature.^50,51 Untreated PH can lead to increased pulmonary vascular resistance (PVR), RV hypertrophy and remodeling, culminating in RV failure.

Dasatinib (second-generation BCL-ABL TKI) has been associated with reversible PAH.^52-56 Though the incidence of dasatinib-associated PAH was initially estimated to be 0.45%,⁵⁷ recent studies report an incidence rate of up to 5%.^58-60 However, this is likely higher due to under-diagnosis of subclinical PH, as well as recently updated diagnostic criteria (i.e.., mPAP >20mmHg rather than ≥25mmHg). Though cessation of dasatinib typically decreases mPAP, long-term follow up data showed that one-third of patients had persistently elevated mPAP and PVR.⁶¹ The proposed mechanisms of dasatinib-induced PAH are summarized in Table 2.

Management of PH in cancer patients is based on guidelines in the general population.^62,63 Prior to initiation of dasatinib, patients should be evaluated for signs of underlying cardiopulmonary disease. Patients who develop dyspnea and symptoms of RV dysfunction (e.g., peripheral edema), should be evaluated with electrocardiogram (ECG) and transthoracic echocardiogram (TTE). If PAH is suspected, RHC should be considered. Once PH is confirmed, the culprit drug should be discontinued, and pulmonary vasodilators initiated.

Coronary Artery Vasospasm
Coronary artery vasospasm typically presents with angina, troponin elevation, and ischemic ECG changes. Traditional chemotherapy agents, specifically 5-fluorouracil (5-FU) and capecitabine (prodrug of 5-FU), have the highest risk of vasospasm.^64,65 Patients with underlying coronary artery disease or pre-existing endothelial dysfunction are at higher risk of coronary vasospasm.⁶⁶ Pharmacogenetic variants in DPYD (dihydropyrimidine dehydrogenase) and TYMS (thymidylate synthase) are associated with an increased risk of high grade toxicity.⁶⁷ Cases of coronary vasospasm have also been reported with other therapies (e.g., paclitaxel, bevacizumab, sorafenib, radiotherapy) (Figure 1).  Management recommendations are summarized in Table 2.

Figure 1: Common Vascular Toxicities Associated with Cancer Therapies

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Clinical Topics: Anticoagulation Management, Cardiac Surgery, Cardio-Oncology, Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Pulmonary Hypertension and Venous Thromboembolism, Stable Ischemic Heart Disease, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and Venothromboembolism, Aortic Surgery, Cardiac Surgery and Heart Failure, Cardiac Surgery and SIHD, Homozygous Familial Hypercholesterolemia, Novel Agents, Statins, Heart Failure and Cardiac Biomarkers, Pulmonary Hypertension, Interventions and Coronary Artery Disease, Interventions and Vascular Medicine, Hypertension, Smoking, Chronic Angina

Keywords: Dasatinib, Ankle Brachial Index, Angioplasty, Antihypertensive Agents, Anticoagulants, Atherosclerosis, Axitinib, B7-H1 Antigen, Bevacizumab, Blood Pressure, Brain Diseases, Brain Ischemia, Cardiac Catheterization, Capecitabine, Cardiovascular Diseases, Classification, Constriction, Pathologic, Control Groups, Coronary Artery Disease, Coronary Vasospasm, CTLA-4 Antigen, Diabetes Mellitus, Dihydrouracil Dehydrogenase (NADP), Doxorubicin, Dyspnea, Rabeprazole, Edema, Electrocardiography, Endothelial Cells, Fibrinolysis, Follow-Up Studies, Goals, Homeostasis, Hypercholesterolemia, Hyperlipidemias, Hypertension, Hypertension, Pulmonary, Hypertrophy, Imatinib Mesylate, Immune Checkpoint Inhibitors, Immune Checkpoint Inhibitors, Immunotherapy, Infarction, Ischemic Stroke, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Life Style, Lower Extremity, Medical Oncology, Muscle Cells, Myocardial Ischemia, Neoplasms, Obesity, Paclitaxel, Peripheral Arterial Disease, Pharmacogenomic Variants, Plaque, Atherosclerotic, Platelet Activation, Platelet Aggregation Inhibitors, Prodrugs, Programmed Cell Death 1 Receptor, Protein Kinase Inhibitors, Pulmonary Arterial Hypertension, Pulmonary Artery, Receptors, Platelet-Derived Growth Factor, Receptors, Vascular Endothelial Growth Factor, Retrospective Studies, Risk Factors, Signal Transduction, Smoking, Sorafenib, Standard of Care, Stroke, Sunitinib, Thrombectomy, Thrombosis, Thymidylate Synthase, Tobacco Use, Troponin, Tumor Escape, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor A, Vascular Resistance, Vasculitis, Vasodilator Agents, Venous Thromboembolism

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