Radiation Induced Heart Disease

Radiation induced heart disease (RIHD) is damage to the heart and great vessels after thoracic radiotherapy for Hodgkin lymphoma, breast, lung, oesophageal, mediastinal and thymic cancers, and some paediatric tumours.

It includes pericardial disease (acute pericarditis, delayed effusion, constriction), myocardial disease (restrictive and dilated cardiomyopathy) and coronary artery disease (premature, with ostial and proximal lesions in the left main, left anterior descending and right coronary arteries).

It also includes valve disease (aortic and mitral, with fibrosis, calcification and later stenosis or regurgitation, especially on the left side), conduction disease (sinus node dysfunction, AV block, right bundle branch block), carotid and subclavian artery stenosis, and autonomic dysfunction.

Risk rises with mean heart dose: the relative risk of major coronary events increases by about 7% for each 1 Gy of mean heart dose, with no clear threshold. Whole heart doses over 30 Gy carry high risk. Modern breast radiotherapy delivers a mean heart dose of about 1 to 2 Gy, and mediastinal lymphoma fields deliver more.

Risk is higher with young age at treatment, previous or concurrent anthracyclines or trastuzumab, left sided or internal mammary fields, and cardiovascular risk factors. Pericarditis occurs within weeks to months, and coronary, valve and myocardial disease usually appears 10 to 30 years later.

Pathophysiology. Radiation causes endothelial injury, microvascular loss, inflammation, fibrosis (transforming growth factor beta signalling) and accelerated atherosclerosis with fibrotic, calcified and often ostial plaques. Pericardium, valves and myocardium become fibrotic and stiff.

Fibrosis of the mediastinum, lungs and chest wall coexists, which complicates surgery.

• Dyspnoea, fatigue, orthopnoea, oedema, and chest pain. Angina may be absent or atypical because of neural injury.
• Constriction: raised venous pressure with Kussmaul sign, ascites, oedema, pericardial knock. Restrictive features are common and may coexist with constriction.
• Valve murmurs (aortic stenosis or regurgitation, mitral regurgitation), bradycardia, syncope and palpitations.
• Previous history of thoracic radiotherapy, stroke or transient ischaemic attack, claudication of the upper limb, and hypothyroidism after neck radiotherapy.

Red flags.

• Chest pain or ischaemia on a stress test, particularly with a left main or ostial lesion
• Syncope, high grade AV block or sinus pauses
• Heart failure with preserved or reduced ejection fraction
• Severe valve disease
• Tamponade or constriction
• New neurological deficit (carotid disease)
• Previous radiotherapy with dose over 30 Gy to the heart, young age at treatment, or anthracycline exposure

• Exposure history. Dose to the heart, fields, date and anthracycline or trastuzumab use (from the treatment summary).
• ECG for conduction and ischaemic change. Ambulatory ECG for bradycardia and pauses.
• Echocardiography. Pericardial thickening and effusion, constrictive physiology (septal bounce, respiratory ventricular interdependence, annulus reversus), restrictive filling, valve thickening with calcification of the aortic root, aortic mitral curtain and mitral base, ejection fraction and strain.
• Cardiac MRI and CT. Pericardial thickness and enhancement, myocardial fibrosis, calcification, mediastinal and lung fibrosis, porcelain aorta, internal mammary artery status before surgery.
• Coronary assessment. Stress imaging or coronary CT with calcium score, then invasive angiography when ischaemia is likely. Screening of high risk patients (heart dose of 15 Gy or more, or combined anthracycline) is started at 5 to 10 years after radiotherapy and repeated about every 5 years.
• Right and left heart catheterisation with simultaneous pressures to separate constriction from restriction.
• Carotid ultrasound in patients treated to the neck. Lipids, glucose, TSH yearly after neck or mediastinal radiotherapy.
• Surveillance echocardiography at 5 years in patients with high risk treatment, and every 5 years at 10 years or more in others.

Differential diagnosis.

• Idiopathic or other constrictive pericarditis, and restrictive cardiomyopathy (cardiac amyloidosis)
• Anthracycline and trastuzumab cardiotoxicity
• Malignant pericardial effusion or recurrent tumour
• Age related calcific aortic stenosis
• Atherosclerotic coronary disease unrelated to radiotherapy
• Rheumatic and other valve disease
• Hypothyroid heart disease and pericardial effusion
• Constriction from tuberculosis (in endemic regions)

• Control cardiovascular risk strictly. Blood pressure under 130/80 mm Hg, no smoking, glycaemic control, weight control and exercise.
• Statin. Atorvastatin 40 to 80 mg orally once daily for coronary disease or high risk, with a target LDL cholesterol under 1.4 mmol/L (55 mg/dL) and a fall of at least 50%. Check liver enzymes at baseline and 3 months, and reduce the dose with interacting drugs (clarithromycin, ciclosporin) or in liver impairment. Contraindicated in pregnancy. Add ezetimibe 10 mg orally once daily when not at target.
• Antiplatelet therapy for established coronary disease: aspirin 75 to 100 mg orally once daily (usual maximum 325 mg daily).
• Coronary revascularisation. Percutaneous intervention is preferred when anatomy allows. Coronary artery bypass surgery carries higher risk because of mediastinal fibrosis, a porcelain aorta, injured internal mammary arteries and poor healing, and early mortality is higher. Choose by the heart team.
• Valve disease. Intervene by the usual thresholds for symptoms and severity, with a heart team assessment. Operative mortality is higher than in other patients, and transcatheter aortic valve implantation is often preferred for severe aortic stenosis at elevated surgical risk. Multivalve disease and combined coronary disease need joint planning.
• Pericardial disease.
  • Pericarditis: ibuprofen 600 mg orally every 8 hours (maximum 2.4 g daily) with gastric protection and colchicine 0.5 mg orally once daily under 70 kg or twice daily at 70 kg or over (reduce to once daily at eGFR 30 to 50 mL/min/1.73 m2, avoid under 30). Avoid anti-inflammatory drugs in kidney impairment and coronary disease with caution.
  • Tamponade: pericardiocentesis or surgical drainage.
  • Constriction: diuretics for congestion (furosemide 40 mg orally once daily in the morning, increased to 80 to 120 mg daily as needed, higher doses in renal impairment under specialist care, with sodium, potassium and creatinine monitoring). Pericardiectomy for refractory symptoms, with a high operative mortality (about 10 to 20%) and poor long term survival because of myocardial and lung involvement.
• Heart failure. Restrictive and preserved ejection fraction disease: diuretics, spironolactone 25 mg once daily (12.5 mg at eGFR 30 to 49 mL/min/1.73 m2), and dapagliflozin 10 mg once daily (start at eGFR 25 mL/min/1.73 m2 or more; contraindicated in type 1 diabetes; withhold during acute illness with poor oral intake). Reduced ejection fraction: add sacubitril/valsartan 24/26 mg orally twice daily, doubled at 2 to 4 weeks to the target 97/103 mg twice daily, and bisoprolol 1.25 mg orally once daily, increased every 1 to 4 weeks to 10 mg once daily, titrating cautiously and checking potassium and creatinine 1 to 2 weeks after each change.
• Conduction disease. Pacemaker for symptomatic sinus node dysfunction and for second degree type II or third degree block. Choose a device that minimises right ventricular pacing.
• Carotid and subclavian disease. Antiplatelet therapy, statin and revascularisation by symptoms and severity.
• Atrial fibrillation: apixaban 5 mg orally twice daily, reduced to 2.5 mg twice daily when at least two of age 80 years or over, weight 60 kg or under and serum creatinine 133 micromol/L or over are present. Also 2.5 mg twice daily at creatinine clearance 15 to 29 mL/min, and avoided under 15 mL/min. Maximum 10 mg daily. Long term.
• Hypothyroidism. Levothyroxine 1.6 microgram/kg orally once daily on an empty stomach (25 to 50 microgram in older adults or with coronary disease, increased every 4 to 6 weeks), aiming for a normal TSH.

Special groups.

• Children and young adults: lifelong surveillance and early risk factor control.
• Pregnancy: assess before conception, because restrictive disease, valve disease and prior anthracycline raise risk. Stop statins, ACE inhibitors, sacubitril/valsartan and spironolactone.

Monitoring. Echocardiography at 5 years and every 5 years in lower risk patients, and every 1 to 2 years with established dysfunction or valve disease. Stress testing or CT at 5 to 10 years after radiotherapy in high risk patients. Lipids yearly, TSH yearly, blood pressure at each visit. Device checks as scheduled.

Referral and escalation. Refer to cardio oncology or a cardiology service with imaging expertise. Urgent for tamponade, ischaemia, syncope, heart failure admission or severe valve disease.