Cancer Therapy-Related Cardiovascular Toxicity (CTR-CVT)

Definition

CTR-CVT encompasses the full spectrum of cardiovascular (CV) complications that arise directly or indirectly from cancer therapy — including chemotherapy, targeted agents, immune therapies, and radiation. The term CTRCD (Cancer Therapy-Related Cardiac Dysfunction) is used specifically for cardiomyopathy and HF, capturing the broad spectrum of presentations and the aetiological link with anticancer therapy. CTR-CVT risk is a dynamic variable that changes throughout the cancer care continuum (before, during, and after treatment); the absolute risk depends on both baseline patient risk and cumulative exposure to cardiotoxic therapies over time.

Key Concepts

Epidemiology and Incidence

• Cancer and CVD are the two leading causes of mortality in developed countries. Declining cancer mortality since the 1990s has produced a growing population of cancer survivors with increasing CTR-CVT burden. (sources/Cardio-Oncology-ESC-2022, rating: very high)
• Anthracyclines: CTRCD is dose-dependent and cumulative; risk increases significantly above doxorubicin cumulative doses of 250 mg/m². (sources/Cardio-Oncology-ESC-2022)
• HER2-targeted therapies: LV dysfunction in up to 15–20% of patients; reversible on drug discontinuation. (sources/Cardio-Oncology-ESC-2022)
• VEGFi: Hypertension in 20–80% of patients (class effect). (sources/Cardio-Oncology-ESC-2022)
• Fluoropyrimidines (5-FU, capecitabine): Myocardial ischaemia in up to 10%; mechanism is coronary vasospasm + endothelial injury. (sources/Cardio-Oncology-ESC-2022)
• ICI myocarditis: Rare (0.1–1.1%) but high fatality (~25–50%); most cases occur in the first 12 weeks. (sources/Cardio-Oncology-ESC-2022)
• Dasatinib PAH: 5% vs. 0.4% with imatinib (DASISION trial). (sources/Cardio-Oncology-ESC-2022)
• CAR-T CRS: Arrhythmias in 77.6%, HF in 14.3%, MI/VTE in ~0.5% of CRS-affected patients. (sources/Cardio-Oncology-ESC-2022)
• BTK inhibitors (ibrutinib): AF is the major cardiovascular toxicity; significant incidence in older patients and those with prior AF history. (sources/Cardio-Oncology-ESC-2022)

Risk Stratification (HFA-ICOS Framework)

• The HFA-ICOS tool (Class IIa/C) categorises patients into Low / Moderate / High / Very High baseline CV toxicity risk before initiating potentially cardiotoxic anticancer therapy. Applied separately for six treatment categories: anthracyclines, HER2-targeted therapies, VEGFi, BCR-ABL TKIs, multiple myeloma therapies, and RAF/MEK inhibitors. (sources/Cardio-Oncology-ESC-2022, rating: very high)
• Very High: Any single VH risk factor (e.g. pre-existing HF/cardiomyopathy/CTRCD, prior trastuzumab, cardiac amyloidosis in MM).
• High: Any single H risk factor (e.g. LVEF <50%, age ≥80, prior mediastinal RT, MI/PCI/CABG, severe VHD, prior anthracycline).
• Moderate: Scored risk factors: M2 = 2 points (LVEF 50–54%, elevated baseline NP/cTn, prior arrhythmia); M1 = 1 point (age 65–79, hypertension, CKD, DM, obesity, smoking). Total 2–4 pts = Moderate; ≥5 pts = High.
• Low: No risk factors OR one M1 factor.
• Actions by risk level: Low = proceed without delay; Moderate = consider cardiology referral (Class IIb); High/VH = mandatory cardiology referral before treatment (Class I) + MDT risk/benefit discussion + cardioprotective strategies (Class IIa). (sources/Cardio-Oncology-ESC-2022)
• Baseline risk stratification result must be communicated to the patient and documented (Class I). (sources/Cardio-Oncology-ESC-2022)

CTRCD Severity Classification

• Symptomatic CTRCD: Mild (HF symptoms, no therapy intensification needed) → Moderate (outpatient diuretic/HF therapy intensification) → Severe (HF hospitalisation) → Very Severe (inotropes/mechanical circulatory support/transplant consideration). (sources/Cardio-Oncology-ESC-2022, rating: very high)
• Asymptomatic CTRCD:
  • Mild: LVEF ≥50% AND new relative GLS decline >15% from baseline AND/OR new rise in cardiac biomarkers.
  • Moderate: New LVEF reduction by ≥10 percentage points to LVEF 40–49%; OR new LVEF reduction <10 pp to LVEF 40–49% AND new relative GLS decline >15% OR new biomarker rise.
  • Severe: New LVEF reduction to <40%.
• (sources/Cardio-Oncology-ESC-2022)

Diagnosis and Monitoring

Baseline Assessment

• ECG: Class I for all patients starting cancer therapy. (sources/Cardio-Oncology-ESC-2022)
• Echocardiography (3D-TTE preferred): Class I at baseline for high/VH risk — assess 3D-LVEF + GLS. (sources/Cardio-Oncology-ESC-2022)
• Cardiac biomarkers (cTn + NP): Class I at baseline in all patients at risk of CTRCD if biomarkers will be tracked during treatment. (sources/Cardio-Oncology-ESC-2022)

Monitoring Methodology

• Same imaging modality throughout treatment (3D-TTE, 2D-TTE, or CMR): mandatory to minimise inter-technique variability (Class I). (sources/Cardio-Oncology-ESC-2022, rating: very high)
• GLS threshold: Relative decline >15% from baseline is the recommended cut-off for asymptomatic mild CTRCD — maximises specificity and minimises overdiagnosis. Use the same vendor for serial GLS measurements throughout treatment. (sources/Cardio-Oncology-ESC-2022)
• Cardiac biomarkers (cTn + NP): No established cancer-specific reference values — interpret in clinical context (treatment timing, comorbidities, age, sex, renal function, obesity, AF, PE). (sources/Cardio-Oncology-ESC-2022)
• CMR: Should be considered when TTE is unavailable or non-diagnostic (including fast strain-encoded CMR when available). (sources/Cardio-Oncology-ESC-2022)
• MUGA: Third-line modality only. (sources/Cardio-Oncology-ESC-2022)
• Perform cardiac imaging at any time if patients receiving cardiotoxic therapies develop new cardiac symptoms. (sources/Cardio-Oncology-ESC-2022)

ICI Myocarditis Diagnosis

• Diagnosed pathohistologically (EMB: multifocal inflammatory infiltrates + cardiomyocyte loss) or clinically (cTn elevation + ≥1 major criterion [CMR diagnostic for myocarditis] or ≥2 minor criteria; after ACS exclusion). (sources/Cardio-Oncology-ESC-2022)
• CMR in ICI myocarditis: LGE and T2-weighted STIR are diagnostic imaging criteria; native T1 elevation is highly predictive of future MACE (n=136); T1/T2 mapping serves as prognostic biomarker beyond diagnostic criteria. (sources/ai-cardiooncology-aha-2025, rating: high)
• Serial hsTnI screening: Prospective longitudinal study demonstrated serial hsTnI can detect ICI myocarditis in both symptomatic and asymptomatic patients; relative elevation in cardiac troponin T prognostic for MACE. (sources/ai-cardiooncology-aha-2025)

Multimodality Imaging Framework (AHA 2023)

The AHA 2023 Scientific Statement establishes an evidence-based multimodal imaging framework extending well beyond LVEF, mapped by therapy type and clinical presentation. (sources/imaging-cardio-oncology-aha-2024, rating: high)

Echocardiography — First-Line

• First-line modality for all patients; 3D acquisition preferred for LVEF; RV function should be obtained at baseline.
• GLS thresholds: Absolute GLS <16% or relative decline >15% from baseline (even with LVEF ≥53%) triggers closer surveillance and possible cardioprotection.
• SUCCOUR trial: strain-guided vs. LVEF-guided therapy did not show advantage for its LVEF endpoint — strain likely most useful when LVEF is low-normal.
• Routine echocardiography not required for ICI; indicated if HF symptoms or myocarditis suspected. LVEF usually decreased when echo performed during CAR-T–related HF episodes.
• (sources/imaging-cardio-oncology-aha-2024)

CMR — Second-Line

• Reserved for: difficult sonographic windows; borderline/abnormal LVEF; complex differentials (toxic vs. ischaemic vs. inflammatory cardiomyopathy); suspected myocarditis; ventricular arrhythmias; scar burden assessment.
• T1/T2 mapping: diagnostic and prognostic in ICI myocarditis (T1/T2 elevation predicts MACE; n=136); native T1 and ECV capture fibrotic change with various anticancer agents.
• CMR provides pericardial assessment via hemodynamic data, pericardial thickness, edema, and fibrosis imaging.
• Machine learning integration anticipated to reduce cost and enable rapid CMR protocols in cardio-oncology.
• (sources/imaging-cardio-oncology-aha-2024)

CCT — Specific Indications

• Coronary artery calcium (CAC) scoring: re-stratifies ASCVD risk in cancer survivors; statin underused when CAC incidentally identified on staging CT.
• ACS mimickers (fluoropyrimidines, ICI): CCTA has extremely high negative predictive value; preferred over invasive angiography in patients with high bleeding risk or haematologic derangements.
• Valvular disease pre-planning (TAVR/TMVR) before high-risk cancer treatment.
• LVEF assessment with ECG-triggered acquisition when echo and CMR are unavailable.
• (sources/imaging-cardio-oncology-aha-2024)

Nuclear Imaging

• MUGA scan: Third-line only — reserve when CMR, CCTA, and quality echocardiography unavailable.
• 99mTc-PYP SPECT: Strong evidence (+++) for suspected cardiac transthyretin amyloidosis in cancer patients (see concepts/Cardiac-Amyloidosis-Imaging).
• FDG-PET: Did not differentiate ICI myocarditis outcomes; useful for tumour burden correlation with CAR-T CRS toxicity.
• Novel PET tracers: ⁶⁸Ga-DOTATOC and ⁶⁸Ga-FAPI show promise in ICI myocarditis (uptake associated with histological disease; small series).
• (sources/imaging-cardio-oncology-aha-2024)

Imaging by Therapy Type (Table 1 Summary)

Imaging by Clinical Presentation (Table 2 Summary)

Disparities in Cardio-Oncology Imaging

• Black patients with breast cancer: 4.61× higher cardiotoxicity causing incomplete HER2 therapy vs. White patients.
• Black individuals and women: 3-fold increase in ICI-related cardiac events; RR 1.68 for cardiotoxicity in childhood cancer survivors.
• Medicare data: transthoracic echocardiography use significantly lower in Black women (RR 0.92).
• Dedicated cardio-oncology referral with meticulous serial imaging may mitigate disparities — demonstrated in a safety-net hospital cohort.
• (sources/imaging-cardio-oncology-aha-2024)

Prevention

Primary Prevention (Section 5.2)

• General principles: CVD and cancer share common modifiable risk factors. Optimise lifestyle (smoking cessation, alcohol ≤100 g/week, physical activity) before and during cancer therapy. Electrolyte correction (hypokalaemia, hypomagnesaemia) throughout treatment. Intensive management of hypertension, DM, dyslipidaemia required. (sources/Cardio-Oncology-ESC-2022, rating: very high)
• CVRF management per 2021 ESC CVD Prevention Guidelines before, during, and after cancer therapy (without delaying cancer treatment): Class I/C. (sources/Cardio-Oncology-ESC-2022)
• Dexrazoxane (iron chelator): Should be considered in high/VH CTRCD risk patients receiving anthracyclines: Class IIa/B. Dosing: 10:1 ratio (e.g. 500 mg/m² per 50 mg/m² doxorubicin), infused ≥30 min before each cycle. EMA threshold: ≥350 mg/m²; FDA threshold: ≥300 mg/m² doxorubicin equivalent. (sources/Cardio-Oncology-ESC-2022)
• Liposomal anthracyclines (pegylated and non-pegylated liposomal doxorubicin): Less cardiotoxic vs. conventional doxorubicin (meta-analysis of 19 trials): Class IIa/B for high/VH risk. (sources/Cardio-Oncology-ESC-2022)
• ACE-I/ARB + beta-blockers at HF doses: Class IIa/B for high/VH risk receiving anthracyclines and/or anti-HER2 therapies. Class IIa/C for high/VH risk receiving VEGFi, bevacizumab, RAF/MEK inhibitors, PI, dasatinib, ponatinib, or osimertinib. Preferred beta-blocker: carvedilol; alternatives: bisoprolol, metoprolol succinate, nebivolol. (sources/Cardio-Oncology-ESC-2022)
• Statins: Class IIa/B for adult patients at high/VH CV toxicity risk (per HFA-ICOS). (sources/Cardio-Oncology-ESC-2022)
• RT primary prevention: Modern heart-sparing techniques (intensity-modulated RT, deep-inspiration breath-hold, proton beam therapy) reduce mean heart dose. No proven drug prophylaxis for RT-induced CV toxicity; tight CVRF control is the cornerstone. (sources/Cardio-Oncology-ESC-2022)

Secondary Prevention (Section 5.3)

• Targets patients with pre-existing CVD (including prior CTR-CVT) and those developing new CTR-CVT during therapy. (sources/Cardio-Oncology-ESC-2022, rating: very high)
• CVD and comorbidities should receive optimal guideline-based therapy before and during cancer treatment — without delaying cancer therapy: Class I/C. (sources/Cardio-Oncology-ESC-2022)
• Regular clinical assessments, 12-lead ECG, TTE, and cardiac biomarkers; frequency guided by baseline risk and emergence of new CTR-CVT. (sources/Cardio-Oncology-ESC-2022)

Management

CTRCD — Anthracycline

• Severe symptomatic: Discontinue anthracycline (Class I/C); rare rechallenge via MDT only. (sources/Cardio-Oncology-ESC-2022, rating: very high)
• Moderate symptomatic: Interrupt (Class I/C); MDT restart after LV recovery. (sources/Cardio-Oncology-ESC-2022)
• Mild symptomatic: MDT decision on interrupt vs. continue (Class I/C). (sources/Cardio-Oncology-ESC-2022)
• Severe asymptomatic (LVEF <40%): Interrupt + full HF therapy: ACE-I/ARNi + BB + SGLT2i + MRA (Class I/C). (sources/Cardio-Oncology-ESC-2022)
• Moderate asymptomatic (LVEF 40–49%): Interrupt + HF therapy (Class I/C). (sources/Cardio-Oncology-ESC-2022)
• Mild asymptomatic (LVEF ≥50% + GLS decline >15% and/or biomarker rise): Continue anthracycline + ACE-I/ARB ± BB (Class IIa/B for GLS decline or troponin rise; IIb/C for NP rise only). (sources/Cardio-Oncology-ESC-2022)
• Rechallenge strategies: Dose minimisation; switch to liposomal anthracycline (Class IIb/C); pre-treatment dexrazoxane (Class IIb/C); monitor every 1–2 cycles. (sources/Cardio-Oncology-ESC-2022)

CTRCD — HER2-Targeted Therapy

• Moderate-to-severe symptomatic: Interrupt HER2 therapy + HF therapy (Class I). (sources/Cardio-Oncology-ESC-2022, rating: very high)
• Moderate asymptomatic (LVEF 40–49%): Continue HER2 therapy + ACE-I/ARB + BB + frequent monitoring (Class IIa/B). Major departure from prior guidance that mandated interruption. (sources/Cardio-Oncology-ESC-2022)
• Mild asymptomatic (LVEF ≥50% + GLS decline/biomarker rise): Continue HER2 + consider ACE-I/ARB ± BB (Class IIa/B). (sources/Cardio-Oncology-ESC-2022)
• Restart protocol: Resume when LVEF ≥40% and asymptomatic; echo + biomarkers every 2 cycles × 4 cycles, then reduce. (sources/Cardio-Oncology-ESC-2022)

End-of-Therapy Weaning

• Full recovery criteria: No HF symptoms + LVEF >50% + GLS normal/baseline + biomarkers normal/baseline. (sources/Cardio-Oncology-ESC-2022, rating: very high)
• Low-risk for weaning (Class IIa): Low/moderate baseline risk, reversible-type drug (e.g. trastuzumab-only), mild CTRCD, early recovery (3–6 months), no cardiomyopathy family history. (sources/Cardio-Oncology-ESC-2022)
• Continue long-term HF therapy (Class I): Severe/very severe CTRCD, incomplete LV recovery, high baseline risk, irreversible-type drug, cardiomyopathy family history. (sources/Cardio-Oncology-ESC-2022)
• Reassess TTE + biomarkers after medication withdrawal. End-of-treatment assessment within 1 year of completing cardiotoxic therapy: Class I for all. Long-term surveillance TTE at years 1, 3, 5, then every 5 years for high/VH risk. (sources/Cardio-Oncology-ESC-2022)

ICI Myocarditis Management

• Interrupt ICI in all suspected cases; permanent cessation in confirmed myocarditis (Class I/C). (sources/Cardio-Oncology-ESC-2022, rating: very high)
• Classification: Fulminant (haemodynamic instability, HF requiring ventilation, complete AV block, significant VA) vs. Non-fulminant. (sources/Cardio-Oncology-ESC-2022)
• Methylprednisolone 500–1000 mg IV daily × 3–5 days (Class I/C). Switch to oral prednisolone 1 mg/kg/day after improvement (cTn >50% reduction from peak); wean 10 mg/week. (sources/Cardio-Oncology-ESC-2022)
• Steroid-refractory: Second-line immunosuppression (Class IIa/C) — mycophenolate, anti-thymocyte globulin, IVIG, plasma exchange, tocilizumab, abatacept, alemtuzumab, tofacitinib. Caution: infliximab is associated with cardiac toxicity. (sources/Cardio-Oncology-ESC-2022)
• Fulminant: ICU (level 3) + IV methylprednisolone + optimal CV treatment including MCS (Class I/C). (sources/Cardio-Oncology-ESC-2022)

Coronary Artery Disease in Cancer

• Mechanisms: accelerated atherosclerosis (ADT, ICI, nilotinib, ponatinib, RT, VEGFi), vasospasm (bleomycin, fluoropyrimidines, taxanes, vinca alkaloids), coronary thrombosis (cisplatin, cyclophosphamide, erlotinib, ICI, IMiDs). (sources/Cardio-Oncology-ESC-2022, rating: very high)
• Invasive strategy: STEMI/high-risk NSTE-ACS with life expectancy ≥6 months: Class I/B. Conservative strategy for poor prognosis <6 months: Class IIa/C. (sources/Cardio-Oncology-ESC-2022)
• DAPT: Aspirin + clopidogrel preferred; short duration (1–3 months). Thrombocytopaenia thresholds: aspirin >10K/μL, clopidogrel >30K/μL, prasugrel/ticagrelor >50K/μL. (sources/Cardio-Oncology-ESC-2022)

Pericardial Disease in Cancer

• Causes: radiation, anthracyclines, bleomycin, cyclophosphamide, cytarabine, dasatinib, ICI, all-trans retinoic acid. Must differentiate from progressive cancer and infection. (sources/Cardio-Oncology-ESC-2022, rating: very high)
• ICI pericarditis: Median onset 30 days; severe cases require ICI discontinuation + methylprednisolone 1 mg/kg/day ± colchicine (Class I/C). (sources/Cardio-Oncology-ESC-2022)
• Malignant effusions: >30% of tamponade cases. Echo-guided pericardiocentesis for tamponade; surgical window for recurrence (Class IIa/C). (sources/Cardio-Oncology-ESC-2022)

Pulmonary Hypertension in Cancer

• All 5 PH groups can occur in cancer patients. (sources/Cardio-Oncology-ESC-2022, rating: very high)
• Dasatinib-induced PAH: 5% vs. 0.4% with imatinib (DASISION trial). Peak TRV >3.4 m/s → RHC + dasatinib discontinuation (Class I/C). TRV 2.9–3.4 m/s → dose reduction + TTE every 4 weeks (Class IIa/C). Switch to alternative BCR-ABL TKI after TRV recovery. (sources/Cardio-Oncology-ESC-2022)

Vascular Mechanisms of Traditional Chemotherapy

Detailed mechanisms sourced from the 2019 AHA Vascular Cardio-Oncology Statement. (sources/cardio-oncology-vascular-metabolic-aha-2019, rating: very high)

VEGF Inhibitor Hypertension — Mechanism and Management

Detailed from 2019 AHA Vascular Cardio-Oncology Statement. (sources/cardio-oncology-vascular-metabolic-aha-2019, rating: very high)

• Mechanisms of VEGF inhibitor-induced hypertension:
  • ↓ eNOS activity → ↓ NO bioavailability (NO is the pivotal vasodilator + antithrombotic + anti-inflammatory molecule)
  • ↑ Endothelin-1 (potent vasoconstrictor)
  • Capillary rarefaction → ↑ microcirculatory resistance
  • Rightward shift of renal pressure-natriuresis curve → impaired sodium excretion + fluid retention → salt-dependent hypertension
• Incidence: ≥25% (class effect); newer agents >50% (pazopanib 57% in treatment-naïve mRCC)
• Drug-drug interactions: Avoid diltiazem and verapamil (non-DHP CCBs act as CYP3A4 inhibitors → ↑ VEGF inhibitor plasma levels)
• Preferred antihypertensives: ACE-I (small studies suggest superior oncological outcomes in renal cell carcinoma) + amlodipine (DHP CCB — no CYP3A4 interaction)
• VEGF inhibitor cardiomyopathy mechanism: Capillary rarefaction → myocardial hypoxia → HIF stabilisation → reversible cardiomyopathy (consistent with myocardial hibernation, not necrosis)
• Preeclampsia parallel: sFlt-1 (soluble VEGF decoy receptor secreted by placenta) may mediate preeclampsia via identical mechanism (HTN + proteinuria + thrombotic angiopathy); on-target effects of VEGF inhibition

Metabolic Complications of Cancer Therapy

From 2019 AHA Vascular Cardio-Oncology Statement. (sources/cardio-oncology-vascular-metabolic-aha-2019, rating: very high)

• ADT (GnRH agonism): Increases incident DM +44%, CAD +16%, MI +11%, sudden cardiac death +16% (population-based study); mechanisms: ↑ LDL-C/triglycerides, ↑ visceral fat, ↑ insulin resistance; endothelial function paradoxically preserved with ADT; metabolic changes return to baseline on cessation; randomised oncology trial data show ADT increases mortality only in men with pre-existing CAD or HF
• PI3K inhibitors (copanlisib, alpelisib): Hyperglycemia (GLUT4 upregulation requires insulin-mediated PI3K activation); copanlisib: commonly associated; alpelisib + fulvestrant: grade 3 hyperglycemia in 36.6% vs. 0.7% (SOLAR-1)
• VEGF/PDGF TKIs (sunitinib, sorafenib): Improve glycemia — counter-intuitive given cardiometabolic effects
• CML glycemic divergence: Imatinib improves glycemia; nilotinib worsens glycemia — opposite effects within the same drug class; highlights complexity of off-target kinase effects on metabolism
• mTOR inhibitors (everolimus + exemestane): Metabolic syndrome in >30% — class effect (BOLERO-2)

Drug-Specific Profiles

Anthracyclines

• Toxicities: CTRCD (dose-dependent and cumulative; irreversible myocardial injury); risk increases above 250 mg/m² doxorubicin equivalent. (sources/Cardio-Oncology-ESC-2022)
• Monitoring: Baseline TTE (I/B) + cTn/NP (I/B for high/VH risk); TTE every 2 cycles + within 3 months post-treatment (I/C for high/VH risk); TTE within 12 months of treatment completion (I/B for all adults). Serial cTn + NP before every cycle (I/B for high/VH risk), every 2 cycles (IIa/C for moderate risk). Additional TTE after cumulative dose ≥250 mg/m² (IIa/C for moderate risk). (sources/Cardio-Oncology-ESC-2022)
• Prevention: Dexrazoxane (IIa/B), liposomal anthracyclines (IIa/B), ACE-I + carvedilol (IIa/B) for high/VH risk.

HER2-Targeted Therapies (Trastuzumab, Pertuzumab, TDM-1)

• Toxicities: LVD in up to 15–20%; reversible on drug discontinuation — does NOT cause permanent myocardial injury unlike anthracyclines. CTRCD risk markedly higher with concurrent anthracycline; sequential use preferred. (sources/Cardio-Oncology-ESC-2022)
• Monitoring: Baseline TTE (I/B); TTE every 3 months (neoadjuvant/adjuvant I/B; metastatic year 1 I/C); may reduce to every 4 months if low-risk and normal at 3 months (IIb/C). Baseline cTn post-anthracycline pre-trastuzumab (IIa/A — elevated cTn predicts higher CTRCD risk). (sources/Cardio-Oncology-ESC-2022)

Fluoropyrimidines (5-FU, Capecitabine)

• Toxicities: Angina, ischaemia-related ECG changes, hypertension, Takotsubo, MI (even with normal coronaries), myocarditis, arrhythmias; incidence of myocardial ischaemia up to 10%. (sources/Cardio-Oncology-ESC-2022)
• Monitoring: CV risk assessment + ECG + lipid profile + HbA1c (I/C); baseline TTE in symptomatic CVD history (I/C). (sources/Cardio-Oncology-ESC-2022)
• Rechallenge after vasospasm: Controversial; requires monitored unit + prophylactic long-acting nitrates + CCBs after excluding severe CAD.

VEGFi (Bevacizumab, Sunitinib, Sorafenib, Pazopanib)

• Toxicities: Hypertension (20–80%, class effect); arterial/venous thromboembolism; CTRCD; QTc prolongation (sunitinib, sorafenib, vandetanib). (sources/Cardio-Oncology-ESC-2022)
• Monitoring: Daily home BP monitoring first cycle + after dose increases (I/C); QTc monthly × 3 months then every 3–6 months if prolongation risk (I/C); TTE every 3 months (high/VH risk, IIa/C) or 4 months (moderate risk, IIb/C) during year 1. When VEGFi stops, anticipate BP drop and pre-emptively reduce antihypertensives. (sources/Cardio-Oncology-ESC-2022)

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

• Toxicities: Drug-specific — dasatinib: PAH (5%), HF, pleural/pericardial effusion; nilotinib + ponatinib: arterial occlusive events, PAD, MI; second/third-generation agents more cardiotoxic than imatinib; QTc prolongation. (sources/Cardio-Oncology-ESC-2022)
• Monitoring: Baseline CV risk assessment (I/C); CV risk assessment every 3 months year 1 (I/C); dasatinib: mandatory baseline TTE (I/C), TTE every 3 months year 1 in high/VH risk (IIa/C); nilotinib: QTc at baseline, 2 and 4 weeks, after dose increases (IIa/C), serial lipid profile + HbA1c; ponatinib: serial ankle-brachial index (IIb/C). (sources/Cardio-Oncology-ESC-2022)

BTK Inhibitors (Ibrutinib, Acalabrutinib)

• Toxicities: AF (major toxicity); ventricular arrhythmias (without QT prolongation); hypertension; HF. Acalabrutinib: lower symptomatic CV events but comparable grade ≥3 AF in elderly/prior AF patients. (sources/Cardio-Oncology-ESC-2022)
• Monitoring: Baseline CV risk assessment + ECG + BP; serial BP monitoring; ECG if palpitations/syncope; TTE in symptomatic HF. (sources/Cardio-Oncology-ESC-2022)

Multiple Myeloma Therapies (Carfilzomib, Bortezomib, IMiDs)

• Toxicities: Carfilzomib: HF/CTRCD, hypertension, VTE. IMiDs (thalidomide/lenalidomide): VTE, bradyarrhythmia. Proteasome inhibitors risk AL-cardiac amyloidosis. (sources/Cardio-Oncology-ESC-2022)
• Monitoring: Baseline TTE including AL-CA assessment (I/C); NP every cycle during first 6 cycles for carfilzomib/bortezomib (IIa/B); TTE every 3 cycles in high/VH risk carfilzomib (IIa/B). VTE prophylaxis with PI+IMiD: therapeutic LMWH if prior VTE (I/B); prophylactic LMWH if VTE risk factors (I/A); aspirin if low/no risk factors (IIa/B). (sources/Cardio-Oncology-ESC-2022)

RAF/MEK Inhibitors (Vemurafenib, Trametinib, Cobimetinib)

• Toxicities: QTc prolongation; CTRCD (onset 1 month to 2 years); hypertension; peripheral vascular disease. (sources/Cardio-Oncology-ESC-2022)
• Monitoring: BP at every visit + weekly home monitoring × 3 months (I/C); cobimetinib/vemurafenib: ECG at 2 and 4 weeks, then every 3 months (I/C); TTE every 4 months year 1 in high/VH risk (IIa/C). (sources/Cardio-Oncology-ESC-2022)

ICI (Pembrolizumab, Nivolumab, Ipilimumab)

• Toxicities: Myocarditis (0.1–1.1%; mortality ~25–50%); pericarditis; vasculitis; ventricular arrhythmias; Takotsubo; non-inflammatory LVD; ACS; dyslipidaemia (OR 3.68). (sources/Cardio-Oncology-ESC-2022)
• Monitoring: Baseline ECG + cTn + NP for all (I/B); baseline TTE for high-risk (I/B). Serial ECG + cTn before cycles 2, 3, 4 → if normal, reduce to every 3 cycles (IIa/B). Long-term ICI (>12 months): CV assessment every 6–12 months in high-risk (I/C). Any new cTn rise → urgent cardio-oncology evaluation + TTE + CMR. (sources/Cardio-Oncology-ESC-2022)

CDK 4/6 Inhibitors (Ribociclib, Palbociclib, Abemaciclib)

• Toxicities: QTc prolongation (ribociclib primarily; palbociclib/abemaciclib lower risk); neutropenia (indirect CV risk via infection). (sources/Cardio-Oncology-ESC-2022)
• Monitoring: Ribociclib: QTc at baseline, day 14, day 28 (I/A); repeat with any dose increase (I/B). EMA thresholds: interrupt if QTcF >480 ms; dose-reduce if ≥481 ms recurs. Avoid with strong CYP3A inhibitors and tamoxifen (synergistic QTc risk). (sources/Cardio-Oncology-ESC-2022)

EGFR-TKIs / Osimertinib

• Toxicities: QTc prolongation; CTRCD; hypomagnesaemia (osimertinib → QTc amplification). (sources/Cardio-Oncology-ESC-2022)
• Monitoring: Baseline TTE + ECG (I/B); TTE every 3 months during therapy (IIa/B). Monitor magnesium closely. (sources/Cardio-Oncology-ESC-2022)

CAR-T / TIL Therapies

• Toxicities: CRS → arrhythmias (77.6%), HF (14.3%), MI/VTE (~0.5%). High mortality in fulminant CRS. (sources/Cardio-Oncology-ESC-2022)
• Monitoring: Baseline ECG + NP + cTn (I/C); baseline TTE in pre-existing CVD (I/C). CRS grade ≥2: NP + cTn + TTE (I/C). Manage CRS with tocilizumab ± dexamethasone. (sources/Cardio-Oncology-ESC-2022)

Radiotherapy

• Toxicities: CAD; valvular disease (aortic/mitral); pericardial disease; conduction abnormalities; cardiomyopathy. Mean heart dose (MHD) is the key dosimetric risk parameter. (sources/Cardio-Oncology-ESC-2022)
• Risk by MHD: Very high >25 Gy; High 15–25 Gy; Moderate 5–15 Gy; Low <5 Gy.
• Monitoring: Baseline CV risk assessment + SCORE2/SCORE2-OP (I/B). Long-term surveillance of radiation fields (coronary, valvular, pericardial) after high-dose thoracic RT. (sources/Cardio-Oncology-ESC-2022)

HSCT (Haematopoietic Stem Cell Transplantation)

• Toxicities: HF, arterial events, cardiac tamponade, arrhythmias (AF, atrial flutter, SVT); GVHD → thrombosis, myocarditis, conduction abnormalities. (sources/Cardio-Oncology-ESC-2022)
• Monitoring: Baseline TTE (I/C) + NP (IIa/C) + CV risk assessment; serial TTE at 3 and 12 months in high-risk recipients. (sources/Cardio-Oncology-ESC-2022)

Androgen Deprivation Therapy (ADT)

• Toxicities: Hypertension, diabetes, IHD, CTRCD; QTc prolongation (uncommon). GnRH antagonists have significantly lower CV event rates vs. agonists. (sources/Cardio-Oncology-ESC-2022)
• GnRH agonist cardiometabolic effects: ↑ LDL-C and triglycerides, ↑ visceral fat, ↓ lean mass, ↑ insulin resistance — metabolic syndrome-like; population studies show stroke HR 1.2, MI HR 1.20 vs. no ADT. (sources/Hormonal-Rx-AHA-2021, rating: high)
• GnRH antagonists preferred in men with pre-existing symptomatic CAD (ESC Class IIa/B): HERO trial — major CV events 2.9% vs. 6.2% leuprolide (HR 0.46); pooled analysis 6 RCTs HR 0.44 for CV events with antagonists. (sources/Hormonal-Rx-AHA-2021)
• Newer AR-directed therapies (abiraterone, enzalutamide): Meta-analysis RR 1.36 (95% CI 1.13–1.64) for adverse CV events; patients with ≥3 CV comorbidities have 1.56× higher all-cause mortality. (sources/Hormonal-Rx-AHA-2021)
• Monitoring: SCORE2/SCORE2-OP at baseline; serial lipid profile, BMI, waist-to-hip ratio, HbA1c, blood pressure; AHA secondary prevention guidelines for men with pre-existing CVD. (sources/Cardio-Oncology-ESC-2022, sources/Hormonal-Rx-AHA-2021)

Endocrine Therapies (Aromatase Inhibitors, Tamoxifen, CDK4/6 Inhibitor Combinations)

• Aromatase inhibitors: Dyslipidaemia, accelerated atherosclerosis, HF; pooled RR 1.19 vs. tamoxifen for overall CVD; 30% higher MI risk; OR 1.18 for CV events when extended beyond 5 years. (sources/Cardio-Oncology-ESC-2022, sources/Hormonal-Rx-AHA-2021)
• Tamoxifen: VTE risk significantly elevated (41% higher vs. AIs); net cardioprotective for arterial CVD vs. placebo (pooled RR 0.67); not recommended with pre-existing thrombotic risk factors; toremifene/high-dose tamoxifen: QTc prolongation. (sources/Cardio-Oncology-ESC-2022, sources/Hormonal-Rx-AHA-2021)
• CDK4/6 inhibitor combinations: Ribociclib + AI or fulvestrant → QTc >480 ms in 3.3–5.6%; ribociclib + tamoxifen → QTc >480 ms in >5% (MONALEESA-7) — this combination should be avoided; palbociclib + AI → hypertension 6%; abemaciclib — no significant CV effects. (sources/Hormonal-Rx-AHA-2021)
• mTOR inhibitors (everolimus + exemestane): Metabolic syndrome in >30% — class effect; especially high risk with type 2 diabetes (BOLERO-2). (sources/Hormonal-Rx-AHA-2021)
• PI3K inhibitors (alpelisib + fulvestrant): Grade 3 hyperglycemia in 36.6% vs. 0.7% placebo (SOLAR-1). (sources/Hormonal-Rx-AHA-2021)
• Monitoring: Serial lipid profile; baseline CV risk assessment; baseline ECG before CDK4/6 inhibitor initiation; QTc monitoring with ribociclib (day 14, day 28); GLS on echocardiography during AI therapy. (sources/Cardio-Oncology-ESC-2022, sources/Hormonal-Rx-AHA-2021)
• See concepts/Hormonal-Therapy-CV-Risk for comprehensive detail.

Therapy-Related Clonal Hematopoiesis (t-CH)

• Cytotoxic chemotherapy selects for DNA damage response (DDR) pathway variants — TP53, PPM1D, CHEK2, ATM — via a fitness advantage under genotoxic stress. t-CH prevalence up to 30% in relatively young cancer survivors. (sources/ch-aha-2026, rating: very high)
• Radiation → 2–4× increased CH risk, dependent on modality and intensity. (sources/ch-aha-2026)
• TP53-CH: Amplified by doxorubicin (promotes Tp53-variant HSC expansion) → worse anthracycline-induced cardiomyopathy in mouse models. (sources/ch-aha-2026)
• PPM1D-CH: → increased IL-1β + myocardial fibrosis after angiotensin II infusion in mice; effects reversed by NLRP3 inhibitor — mechanistic overlap with canonical TET2-CH. (sources/ch-aha-2026)
• All t-CH variants tested (TP53, PPM1D, CHEK2, ATM) amplify IL-1β expression — a shared mechanism with canonical CH genes, suggesting IL-1β/NLRP3 as a potential therapeutic axis. (sources/ch-aha-2026)
• ATM/CHEK2 variants: Associated with increased CVD risk in t-CH context; mechanistic data less developed. (sources/ch-aha-2026)
• t-CH is not routinely screened in clinical cardio-oncology practice; its contribution to late cardiotoxicity in cancer survivors is an active area of investigation. See concepts/Clonal-Hematopoiesis for full detail. (sources/ch-aha-2026)

Multi-Omics Biomarkers in Cardiotoxicity

• Genomics: TTNtv (anthracycline cardiomyopathy overlap with DCM) and RARG variants identified in anthracycline cardiotoxicity; insufficient for routine clinical use. (sources/ai-cardiooncology-aha-2025, rating: high)
• Transcriptomics: scRNA-seq identified pathogenic α-myosin–specific T-cell populations in ICI myocarditis tissue. (sources/ai-cardiooncology-aha-2025)
• Proteomics: Hemopexin identified as biomarker in anthracycline cardiotoxicity; CSK kinase in ibrutinib-associated AF. (sources/ai-cardiooncology-aha-2025)
• Metabolomics: Early TCA cycle metabolite changes differentiated subsequent anthracycline cardiotoxicity before LVEF change; purine/pyrimidine metabolism alterations in cardiotoxic patients. (sources/ai-cardiooncology-aha-2025)
• All multi-omics biomarkers remain at pilot/research stage; large prospective cohorts with serial sampling are lacking. (sources/ai-cardiooncology-aha-2025)

AI-Based Risk Prediction and ECG Algorithms

• Integrative models combining cancer + CV risk factors + troponin + BNP achieved risk discrimination in the 90% range for multiple cohorts. (sources/ai-cardiooncology-aha-2025)
• AI-ECG detected LV systolic dysfunction/HF risk in anthracycline/trastuzumab patients in studies of 3,364 and 889 patients. (sources/ai-cardiooncology-aha-2025)
• AI-ECG predicted life-threatening arrhythmias and mortality in ICI myocarditis (125 cases, 49 institutions, 11 countries). (sources/ai-cardiooncology-aha-2025)
• See concepts/AI-in-Cardio-Oncology for full detail.

Paediatric Imaging Considerations

• 50% of children with cancer receive cardiotoxic therapies; cardiotoxicity is a key long-term outcome limitation.

• Paediatric echo should include a segmental approach including extracardiac anatomical relationships.
• Emphasise minimisation of radiation and contrast exposure in CCT and PET.
• CMR: prospective data show CMR-biomarker correlation after anthracycline administration in children. (sources/imaging-cardio-oncology-aha-2024, rating: high)

Arrhythmias — Dedicated Framework

For the complete drug-by-drug arrhythmia framework, see concepts/Cancer-Associated-Arrhythmia.

Arrhythmia Types and Scope

• AF is the most common arrhythmia (2–16% during active treatment); QT prolongation in up to 22% (arsenic trioxide 26–93%); ventricular arrhythmias and bradyarrhythmias are less common but potentially fatal. (sources/arrhythmia-cardio-oncology-aha-2021, rating: very high)
• Ibrutinib carries the highest AF burden of any targeted agent: RR 4.69 (meta-analysis 8 RCTs, n=2,580). Newer BTKi (acalabrutinib 4.1%, zanubrutinib 2%) are safer alternatives for patients at high AF risk. (sources/arrhythmia-cardio-oncology-aha-2021)
• ICI-associated AV block may be the first manifestation of ICI myocarditis (overall fatality ~50%); conduction disorders carry 80% cardiovascular mortality in ICI cardiotoxicity cohorts. (sources/arrhythmia-cardio-oncology-aha-2021)
• MADIT-CHIC trial: CRT is effective in chemotherapy-induced cardiomyopathy + LVEF ≤35% + LBBB — significant LVEF improvement and LV volume reduction at 6 months. CRT-pacemaker appropriate even if life expectancy <1 year for symptom palliation. (sources/arrhythmia-cardio-oncology-aha-2021)

Anticoagulation Complexity in Cancer-AF

• CHA₂DS₂-VASc underestimates thromboembolic risk in cancer; HAS-BLED is unreliable (does not capture thrombocytopenia or intracranial metastases). Cancer-specific validated risk algorithms are urgently needed. (sources/arrhythmia-cardio-oncology-aha-2021)
• DOACs preferred — ARISTOTLE cancer subgroup (n=1,236): apixaban superior to warfarin for stroke/SE; ENGAGE AF-TIMI 48 similar result for edoxaban. All DOACs interact with P-glycoprotein; rivaroxaban/apixaban also CYP 3A4 substrates — ibrutinib interaction requires care. (sources/arrhythmia-cardio-oncology-aha-2021)
• Aspirin not recommended for cancer-AF stroke prevention — excess bleeding risk from thrombocytopenia and ibrutinib platelet dysfunction. (sources/arrhythmia-cardio-oncology-aha-2021)

Autonomic Dysfunction

• AD (decreased HRV, orthostatic hypotension, IST, POTS) is prevalent in cancer survivors, particularly those with haematological malignancies; it is associated with mortality in Hodgkin lymphoma survivors and bone marrow transplant recipients. (sources/arrhythmia-cardio-oncology-aha-2021)
• Structured aerobic exercise reverses AD; ivabradine is an emerging option for IST. See concepts/Autonomic-Dysfunction-in-Cancer for full detail. (sources/arrhythmia-cardio-oncology-aha-2021)

Contradictions / Open Questions

• Most recommendations are Level of Evidence C due to the lack of dedicated cardio-oncology RCTs — the evidence base is largely derived from small trials, subgroup analyses, and registry data. (sources/Cardio-Oncology-ESC-2022, rating: very high)
• Optimal timing and duration of cardioprotective medications (ACE-I, beta-blockers) initiated for CTR-CVT is not established by RCT evidence. (sources/Cardio-Oncology-ESC-2022)
• Whether cardioprotective medications should be given prophylactically to all high-risk patients (primary prevention) or only when subclinical CTRCD is detected (secondary prevention) is debated. (sources/Cardio-Oncology-ESC-2022)
• ICI myocarditis immunosuppression: Optimal regimen and duration is undefined. Infliximab is cautioned against despite being a common second-line immunosuppressive in other inflammatory conditions — small case series show cardiac toxicity. (sources/Cardio-Oncology-ESC-2022)
• Fluoropyrimidine vasospasm rechallenge: No RCT data; only case series support rechallenge with prophylactic nitrates + CCBs in a monitored setting. (sources/Cardio-Oncology-ESC-2022)
• PRECISE-DAPT bleeding risk score performs poorly in cancer patients for predicting bleeding; no validated cancer-specific bleeding score exists. (sources/Cardio-Oncology-ESC-2022)
• GnRH antagonist vs. agonist CV benefit: HERO trial suggests lower CV events with antagonists; PRONOUNCE trial showed no MACE difference (stopped early, optimal CVRF management). (sources/Cardio-Oncology-ESC-2022)
• HFA-ICOS tools are based on retrospective data and have not been prospectively validated in large RCTs; applicability across different cancer types requires caution. (sources/Cardio-Oncology-ESC-2022)
• Biomarker-guided cardioprotection not proven superior: Troponin-guided enalapril initiation showed no benefit over universal enalapril (n=276 RCT); hsTnI-guided candesartan/carvedilol did not prevent LV dysfunction in a multicenter RCT — both limited by small size and low cardiotoxicity event rates. (sources/ai-cardiooncology-aha-2025)
• No AI cardiotoxicity prediction models have been prospectively validated; inconsistent cardiotoxicity definitions across studies hinder algorithm development and comparison. (sources/ai-cardiooncology-aha-2025)
• SUCCOUR trial limitation: Strain-guided cardioprotection did not improve the 2D LVEF endpoint vs. LVEF-guided therapy — but the endpoint itself (2D LVEF) may be insensitive; clinical HF event data are lacking. GLS remains the most useful marker in low-normal LVEF patients. (sources/imaging-cardio-oncology-aha-2024, rating: high)
• LVEF insufficiency for ICI and targeted therapy toxicities: LVEF does not detect ICI-associated myocarditis (LVEF normal in up to 50% of cases) or targeted therapy–associated arrhythmias. T1/T2 mapping and GLS add sensitivity, but prospective validation with clinical endpoints is lacking. (sources/imaging-cardio-oncology-aha-2024)
• Novel PET tracers for ICI myocarditis (⁶⁸Ga-DOTATOC/FAPI): Promising histological correlation in small series, but FDG-PET did not differentiate myocarditis outcomes — the role of PET in routine cardiotoxic management remains undefined. (sources/imaging-cardio-oncology-aha-2024)

Connections

• Related to concepts/Cardio-Oncology
• Related to concepts/AI-in-Cardio-Oncology
• Related to concepts/HFA-ICOS-Risk-Stratification
• Related to concepts/Cardiac-Amyloidosis-Imaging
• Related to concepts/Late-Gadolinium-Enhancement
• Related to entities/Heart-Failure
• Related to entities/Atrial-Fibrillation
• Related to entities/DCM
• Related to entities/ATTR-Amyloidosis
• Related to sources/Cardio-Oncology-ESC-2022
• Related to sources/ai-cardiooncology-aha-2025
• Related to sources/imaging-cardio-oncology-aha-2024
• Related to concepts/Cancer-Associated-Arrhythmia
• Related to concepts/Autonomic-Dysfunction-in-Cancer
• Related to sources/arrhythmia-cardio-oncology-aha-2021
• Related to concepts/Hormonal-Therapy-CV-Risk
• Related to sources/Hormonal-Rx-AHA-2021
• Related to concepts/Cancer-Associated-VTE
• Related to concepts/Clonal-Hematopoiesis — t-CH (TP53/PPM1D/CHEK2/ATM) selected by chemotherapy/radiation; amplifies anthracycline cardiomyopathy and myocardial fibrosis via NLRP3/IL-1β
• Related to sources/cardio-oncology-vascular-metabolic-aha-2019
• Related to sources/ch-aha-2026

Sources

• sources/Cardio-Oncology-ESC-2022
• sources/Hormonal-Rx-AHA-2021
• sources/ai-cardiooncology-aha-2025
• sources/arrhythmia-cardio-oncology-aha-2021
• sources/cardio-oncology-vascular-metabolic-aha-2019
• sources/ch-aha-2026
• sources/imaging-cardio-oncology-aha-2024