Cardio-Oncology: Vascular and Metabolic Perspectives — AHA Scientific Statement 2019

Authors, Journal, Affiliations, Type, DOI

• Umberto Campia, Javid J. Moslehi, Laleh Amiri-Kordestani, Ana Barac, Joshua A. Beckman, David D. Chism, Paul Cohen, John D. Groarke, Joerg Herrmann, Carolyn M. Reilly, Neal L. Weintraub
• On behalf of the AHA Council on Peripheral Vascular Disease; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing
• Circulation 2019;139:e579–e602
• AHA Scientific Statement — comprehensive narrative review with expert consensus
• DOI: 10.1161/CIR.0000000000000641

Overview

This 2019 AHA Scientific Statement addresses the vascular and metabolic dimensions of cardio-oncology — an underrepresented complement to the cardiac dysfunction (CTRCD) focus of most cardio-oncology literature. It maps vascular toxicity mechanisms for traditional chemotherapies (fluoropyrimidines, taxanes, platinums, anthracyclines), radiation-induced vasculopathy (premature CAD, carotid disease, autonomic dysfunction), and targeted therapies (VEGF inhibitors causing hypertension and VTE, ABL kinase inhibitors with disparate vascular profiles, ICI vasculitis). It covers cancer-associated VTE — the most common cardiovascular complication of malignancy — including the Ottawa recurrence score and emerging DOAC evidence. A distinct section addresses metabolic complications (ADT cardiometabolic risk, PI3K inhibitor hyperglycemia, nilotinib vs. imatinib glycemic divergence). The statement concludes with the paradigm that cancer and CVD share common risk factors including clonal hematopoiesis of indeterminate potential (CHIP), and with practical guidance on cardio-oncology service structure.

Keywords

Cardio-oncology, vascular toxicity, venous thromboembolism, cancer-associated thrombosis, metabolic complications, androgen deprivation therapy, VEGF inhibitors, clonal hematopoiesis, radiation vasculopathy, fluoropyrimidines

Key Takeaways

Vascular Complications of Traditional Therapies

Fluoropyrimidines (5-FU, Capecitabine)

• Myocardial ischaemia via coronary vasospasm — mechanisms: endothelial cytolysis, ↑ endothelin-1, vascular smooth muscle hypercontractility
• Incidence: up to 5.4% with continuous infusion 5-FU; 2.4% with short-term 5-FU/leucovorin; 2.9% ischaemia/infarction with capecitabine
• Toxicity predominantly within 72h of first cycle; high relapse risk on rechallenge; death can occur despite reversibility of vasospasm
• Rechallenge: only if no alternative — requires informed consent, aspirin, CCB + nitrates, continuous ECG monitoring (CCU), bolus (not continuous) infusion

Taxanes

• Antiangiogenic effects at sub-cytotoxic concentrations via endothelial/smooth muscle cytoskeletal disruption
• Toxicities: capillary hyperpermeability (fluid retention), peripheral neuropathy (vasa nervorum damage), myocardial ischaemia; dose-response relationship

Vinca Alkaloids

• Caspase-mediated apoptosis + inhibition of endothelial cell proliferation
• Toxicities: chest pain, MI, hypertension, Raynaud phenomenon, thromboembolism

Platinum Compounds (Cisplatin)

• Direct endothelial toxicity + platelet activation + ↓ NO bioavailability
• Toxicities: Raynaud phenomenon, hypertension, MI, stroke, arterial thrombosis, acute limb ischaemia, DVT, PE
• Chest pain in up to 38% of testicular cancer patients treated with cisplatin + vinca alkaloids + bleomycin

Cyclophosphamide

• Similar mechanisms to platinums; particularly at high doses pre-bone marrow transplant
• Toxicities: cerebrovascular events, hepatic veno-occlusive disease, hypertension, MI, pulmonary hypertension, Raynaud

Anthracyclines

• Endothelial dysfunction via ROS production, DNA double-strand breaks, mitochondrial dysfunction
• Endothelial toxicity can occur immediately; endothelial dysfunction persists months–years after exposure
• Current practice focuses on LV dysfunction surveillance; vascular toxicity under-investigated

Bleomycin

• Inhibits endothelial cell proliferation/migration; induces endothelial apoptosis
• Toxicities: Raynaud phenomenon (3-fold increased risk in testicular cancer survivors; dose-related), MI, pulmonary hypertension
• Bleomycin alone or with vinca alkaloids/cisplatin/etoposide

Radiation Vasculopathy

• 50% of patients receive RT; any vascular structure in the field is vulnerable

• Acute effects: endothelial dysfunction, inflammatory infiltration → persistent microvasculature and conduit artery damage; radiation injury to vasa vasorum
• Premature CAD in Hodgkin lymphoma and breast cancer survivors — linear dose-response relationship
• Head/neck RT: significantly increased carotid disease, TIA, ischaemic stroke
• Large/medium-vessel vasculopathy: axillary artery stenosis (breast RT), porcelain aorta (mediastinal RT)
• DVT, venous stenosis, renal artery stenosis from non-selective field exposure
• Autonomic dysfunction (cranial/neck/mediastinal RT): labile BP and HR, orthostatic intolerance
  • Hodgkin lymphoma survivors (n=263, median 19 years post-RT): 4× higher resting HR, 5× higher abnormal HRR after exercise; 4-fold increased all-cause mortality with abnormal HRR
• Surveillance: Expert groups recommend stress testing 5–10 years post-mediastinal RT, then every 5 years; carotid ultrasound post-neck RT
• Outcomes after intervention worse: PCi/CABG/carotid intervention outcomes inferior to non-radiation cohorts; higher in-stent restenosis
• Risk reduction: lower cumulative dose, cardiac shielding, tangential fields, 3D image-guided planning, respiratory gating

Vascular Complications of Targeted Therapies

VEGF Inhibitors (Bevacizumab, Sunitinib, Sorafenib, Pazopanib, Axitinib, Regorafenib, etc.)

• Hypertension in ≥25% (class effect); newer agents >50% (pazopanib 57% in treatment-naïve mRCC)
• Mechanisms: ↓ NO bioavailability (↓ eNOS activity) + ↑ endothelin-1 + capillary rarefaction + ↓ renal natriuresis → salt-dependent hypertension
• VTE: Bevacizumab highest incidence (~12% vs. 2–6% for TKIs); nearly half are high-grade
• Additional events: aortic dissection, stroke, arterial and venous thrombosis
• Drug-drug interactions: Avoid diltiazem and verapamil (CYP3A4 induction → ↑ VEGF inhibitor levels); preferred antihypertensives: ACE-I + dihydropyridine CCB (amlodipine)
• VEGF inhibitor-associated cardiomyopathy: capillary rarefaction → myocardial hypoxia → HIF activation → reversible cardiomyopathy (often recovers, consistent with hibernation not necrosis)
• Parallels with preeclampsia: sFlt-1 (soluble VEGF receptor) may mediate preeclampsia; VEGF inhibitor toxicities parallel preeclampsia (HTN + proteinuria + thrombotic angiopathy on renal biopsy)

BCR-ABL TKIs (Imatinib/Nilotinib/Ponatinib/Dasatinib)

• Imatinib: Safe vascular profile; possible vascular protective effect
• Nilotinib: Peripheral and coronary artery events; ankle-brachial index reductions → atherosclerosis mechanism; worsens glycemia
• Ponatinib: Significant peripheral + coronary ischaemic events in ≥27% (PACE trial); temporary FDA withdrawal → reintroduction with REMS; off-target vascular effects (distinct from ABL1 target)
• Dasatinib: PAH + slightly higher MI/stroke vs. imatinib; vascular toxicities = "off-target" effects dissociable from cancer target

Immunomodulators (Thalidomide, Lenalidomide)

• VTE predominantly venous; mechanism: ↑ endothelial tissue factor expression → intrinsic coagulation pathway
• Risk stratification (3 categories): Low risk (<5%) = single-agent thalidomide, no prophylaxis; Standard risk (up to 20%) = no/1 risk factor, not receiving multiagent chemo/high-dose dex → aspirin 81 mg/day; High risk = ≥2 risk factors OR multiagent chemo/high-dose dex → LMWH or warfarin

Proteasome Inhibitors (Bortezomib, Carfilzomib)

• Vascular oxidative stress + endothelial dysfunction + inhibition of EC proliferation
• Toxicities: cerebrovascular events, MI, systemic + pulmonary hypertension, VTE

Immune Checkpoint Inhibitors (ICI)

• Mechanism: T-cell activation → vasculitis (immune-mediated)
• Case reports of vasculitis; fulminant myocarditis (rare but fatal)
• Expanding indications + combination with agents of known vascular toxicity require vigilance

CAR-T Cells

• CRS: ↑ IFN-γ, GM-CSF, IL-10, IL-6 → vascular leak syndrome, QT prolongation, tachycardia, arrhythmias, troponin elevation, LV systolic dysfunction in small subsets

Metabolic Complications

Androgen Deprivation Therapy (ADT)

• GnRH agonism increases: incident DM +44%, CAD +16%, MI +11%, sudden cardiac death +16% (large population-based study)
• Mechanisms: ↑ LDL-C + triglycerides, ↑ visceral fat, ↓ lean mass, ↑ insulin resistance; BUT endothelial function preserved or enhanced with ADT
• Metabolic + vascular changes return to baseline on ADT cessation
• Randomised oncology trial data show ADT increases mortality only in men with pre-existing CAD or HF

PI3K Inhibitors

• PI3K mediates insulin response → inhibition impairs GLUT4 upregulation → hyperglycemia
• Copanlisib: commonly associated with hyperglycemia (relapsed follicular lymphoma)

VEGF/PDGF TKIs (Sunitinib, Sorafenib)

• Improve glycemia — opposite effect to PI3K inhibitors

CML Glycemic Divergence

• Imatinib: improves glycemia
• Nilotinib: worsens glycemia — within same drug class, opposite metabolic effects

Cancer-Associated VTE

• Most common cardiovascular complication of malignancy
• Cancer increases VTE risk 7–8× vs. general population (Dutch series n=3,220; Danish study n=57,951)
• Hematological malignancies: 28× increased odds; lung and GI tumors: >20×
• Risk highest in first year after diagnosis (15-fold); increases with metastatic stage
• Patients with cancer represent ~20% of all VTE; annual incidence 0.5% (vs. 0.1% general population)
• High clot burden in cancer VTE: bilateral DVT, iliocaval thrombosis, upper limb DVT more common
• VTE recurrence rate in cancer ~21% at 1 year vs. 7% without malignancy
• Cancer-associated VTE increases mortality 1.6–4.2× within cancer populations; 5–6× vs. non-cancer VTE
• Ottawa Score (recurrent VTE prediction): Female (+1), Lung cancer (+1), Breast cancer (−1), TNM stage I (−2), Prior VTE (+1); Score ≤0 = low risk (<4.5%); Score ≥1 = high risk (19%); 100% sensitivity, 98.1% NPV
• Anticoagulation: Extended/indefinite (no scheduled stop date) even with high bleeding risk (ACCP)
• LMWH preferred over VKA: Dalteparin and enoxaparin superior to VKA for recurrent VTE prevention (CLOT, LITE trials)
• Emerging DOAC data (as of 2019): Edoxaban vs. dalteparin (n=1,050): primary outcome (recurrent VTE or major bleeding) 12.8% vs. 13.5% (P=0.006 noninferiority); Rivaroxaban vs. dalteparin (pilot): VTE recurrence HR 0.43 but clinically relevant non-major bleeding HR 3.76; Apixaban vs. dalteparin (abstract): VTE recurrence 3.4% vs. 14.1% (HR 0.26, P=0.0182) with superior QoL and very low bleeding

Common Risk Factors Between Cancer and CVD

• ARIC study: AHA 7-metric cardiovascular health adherence inversely associated with cancer (strongest for breast, colorectal, lung) AND CVD
• Tobacco: Established shared risk factor
• Hyperlipidemia and breast cancer: Top quartile dietary cholesterol → 48% ↑ breast cancer risk; 27-hydroxycholesterol acts as direct estrogen receptor agonist in breast cancer cells
• Inflammation (IL-1β): CANTOS trial — canakinumab reduced cardiac events AND lung cancer incidence/mortality
• Clonal Hematopoiesis of Indeterminate Potential (CHIP): Expanded somatic blood cell clone without hematologic abnormality; common in older populations; driver mutations in DNMT3A, ASXL1, TET2; associated with hematologic cancer risk AND increased MI, stroke, all-cause mortality; each of the 3 genes individually associated with coronary heart disease; basic models implicate them in atherosclerosis pathogenesis

Cardio-Oncology Service Structure

• Three proposed models: (1) cardiologist-led with oncology communication; (2) oncologist-led with cardiology communication; (3) truly multidisciplinary (resource-intensive, preferred for large centres)
• Cancer survivorship: projected 20 million survivors by 2026; limited cardiovascular screening recommendations outside RT and anthracycline-treated childhood cancer survivors
• Key operational elements: patient-centred care, proximity of services, timely scheduling, patient education, physician extenders for routine follow-up, cardiac rehabilitation referral, lifestyle modification
• Fellowship training: Cardio-oncology in 2019 is a general cardiology specialty (not just HF subspecialty); needs formal Core Cardiovascular Training Statement modelled training programme

Limitations of the Document

• Narrative review with expert consensus; not a systematic review/meta-analysis
• Many vascular complication estimates are from small retrospective observational studies
• DOAC cancer-VTE data were emerging/incomplete at time of publication (only pilot/abstract results available for apixaban; rivaroxaban trials still ongoing)
• Cardio-oncology service recommendations are descriptive and lack prospective outcome data
• Mechanisms of vascular toxicity (e.g. ponatinib) largely unexplored — unclear whether events represent atherosclerosis, thromboembolism, or vasospasm

Key Concepts Mentioned

• concepts/Cardio-Oncology — clinical discipline; vascular + metabolic perspectives add to CTRCD framework
• concepts/Cancer-Therapy-Related-CV-Toxicity — vascular mechanisms of traditional and targeted therapies
• concepts/Cancer-Associated-VTE — 7–8× risk; Ottawa score; LMWH preference; DOAC emergence
• concepts/Clonal-Hematopoiesis — CHIP as shared cancer/CVD risk factor; DNMT3A/ASXL1/TET2
• concepts/Radiation-Vasculopathy — radiation-induced CAD, carotid, peripheral vascular, and autonomic disease
• concepts/Preeclampsia — sFlt-1/VEGF inhibitor parallel mechanism

Key Entities Mentioned

• entities/Pulmonary-Hypertension — bleomycin-associated PAH; cyclophosphamide-associated PAH; dasatinib PAH

Wiki Pages Updated

• wiki/sources/cardio-oncology-vascular-metabolic-aha-2019.md (created)
• wiki/concepts/Cancer-Associated-VTE.md (created)
• wiki/concepts/Clonal-Hematopoiesis.md (created)
• wiki/concepts/Cancer-Therapy-Related-CV-Toxicity.md (updated — vascular mechanisms, VEGF HTN detail, metabolic complications)
• wiki/concepts/Cardio-Oncology.md (updated — shared cancer-CVD risk section)
• wiki/entities/Pulmonary-Hypertension.md (updated — bleomycin/cyclophosphamide PAH)
• wiki/sourceindex.md (updated)
• wiki/wikiindex.md (updated)