Unexplained cardiomegaly

Cardiomegaly is enlargement of the cardiac silhouette: a cardiothoracic ratio over 0.50 on a posteroanterior chest radiograph taken in full inspiration, or increased chamber size or wall thickness on imaging. It is found incidentally on chest radiography or reflects symptomatic heart disease. Unexplained cardiomegaly is enlargement without an evident cause after history and examination, which needs systematic evaluation to find structural heart muscle, valve, pericardial, congenital or systemic disease.

Clinical relevance. Cardiomegaly on a radiograph is not a diagnosis; it can be a false alarm (technique, body habit, pericardial fat) or the first sign of cardiomyopathy, heart failure, a pericardial effusion or a treatable cause (hypertension, thyroid disease, anaemia, alcohol, valve disease). Early identification of dilated cardiomyopathy, hypertrophic cardiomyopathy and infiltrative disease allows disease modifying treatment, family screening and prevention of sudden death.

Classification.

• Apparent cardiomegaly (normal heart): anteroposterior or supine film, poor inspiration, rotation, obesity, pregnancy, pectus excavatum and straight back syndrome, epicardial fat pad, mediastinal fat or mass, elevated diaphragm, athletic heart.
• True cardiomegaly by chamber: left ventricular dilatation or hypertrophy, right ventricular enlargement, left or right atrial enlargement, biventricular enlargement.
• True cardiomegaly by cause: myocardial (dilated, hypertrophic, restrictive, infiltrative), valvular (regurgitation, stenosis), pericardial effusion, congenital heart disease, hypertensive, ischaemic, high output states, endocrine and metabolic, infective and inflammatory, toxic, genetic, tumour.

Mechanism. Volume overload causes chamber dilatation (eccentric remodelling), pressure overload causes hypertrophy (concentric remodelling), and myocardial injury leads to dilatation and systolic dysfunction.

Pericardial effusion enlarges the silhouette with a globular shape without chamber enlargement.

History.

• Symptoms: breathlessness, exercise intolerance, orthopnoea, oedema, fatigue, palpitations, chest pain, syncope, cough, weight gain, abdominal swelling, or none (incidental finding).
• Duration, prior chest radiographs for comparison, previous cardiac investigations, family history of cardiomyopathy, heart failure, sudden death, pacemaker or defibrillator, muscular dystrophy, haemochromatosis, amyloidosis.
• Hypertension (duration, control), diabetes, thyroid disease, renal disease, sleep apnoea, obesity, pregnancy and peripartum history, anaemia.
• Alcohol quantity and duration, recreational drugs (cocaine, amphetamines), anabolic steroids, smoking.
• Infection: viral illness, HIV, Chagas disease (residence in endemic areas, triatomine bugs, blood transfusion), rheumatic fever, tuberculosis, Lyme disease, hepatitis.
• Drugs and treatment: anthracyclines, trastuzumab, cyclophosphamide, immune checkpoint inhibitors, radiotherapy to the chest, hydroxychloroquine, antiretrovirals, lithium, antipsychotics.
• Autoimmune disease (lupus, scleroderma, rheumatoid arthritis, sarcoidosis, myositis), neuromuscular disease, iron overload (thalassaemia, haemochromatosis, repeated transfusion).
• Dietary deficiency (thiamine, selenium, carnitine), cancer.
• Athletic training and intensity.

Examination.

• Vital signs, blood pressure in both arms and legs, pulse (rate, rhythm, character), saturation, weight, height, body mass index.
• Jugular venous pressure, apex beat (displaced and diffuse in dilatation, heaving in hypertrophy), heaves and thrills, heart sounds (S3, S4, loud P2, splitting, opening snap, rub), murmurs (aortic and mitral valve disease, outflow obstruction, septal defects, functional mitral and tricuspid regurgitation).
• Signs of heart failure: crackles, effusion, hepatomegaly, ascites, oedema.
• Signs of systemic disease: thyroid, anaemia, jaundice, skin pigmentation (haemochromatosis), macroglossia and periorbital purpura (amyloidosis), xanthomata, neuromuscular disease (muscle weakness, myotonia, calf hypertrophy), clubbing, cyanosis, Marfan features, rheumatological signs, lymph nodes.
• Evidence of alcohol use, injection marks.

Red flags.

• Syncope, presyncope, sustained palpitations or family history of sudden death (arrhythmic risk).
• Breathlessness at rest, pulmonary oedema, shock, hypotension.
• New heart failure with fever or recent viral illness (myocarditis).
• Chest pain, ischaemic ECG changes, raised troponin.
• Rapidly increasing heart size (pericardial effusion, tamponade).
• Peripartum onset in the last month of pregnancy or within 5 months after delivery.
• Heart block, ventricular arrhythmia or low voltage ECG with thick walls (sarcoidosis, amyloidosis).
• Cardiomegaly with cyanosis, cachexia or constitutional symptoms.
• Young age (under 40) with ventricular enlargement.

Cardiomyopathies.

• Dilated cardiomyopathy: ischaemic, hypertensive, valvular, alcoholic, viral (myocarditis), peripartum, tachycardia induced, genetic (titin, lamin A/C, dystrophin), Chagas, HIV, thyrotoxic, hypothyroid, haemochromatosis, sarcoidosis, drug induced (anthracyclines, trastuzumab), stress (Takotsubo), thiamine deficiency (beriberi), selenium deficiency, autoimmune.
• Hypertrophic cardiomyopathy (obstructive and non obstructive), athlete's heart, hypertensive heart disease, aortic stenosis, Fabry disease, Pompe disease, Friedreich ataxia, Noonan syndrome.
• Restrictive and infiltrative: cardiac amyloidosis (light chain and transthyretin), sarcoidosis, haemochromatosis, endomyocardial fibrosis (tropical), Loeffler endocarditis, radiation, scleroderma.
• Arrhythmogenic cardiomyopathy and left ventricular non compaction.

Valvular and congenital. Aortic and mitral regurgitation or stenosis, tricuspid regurgitation, rheumatic valve disease, atrial and ventricular septal defects, patent ductus arteriosus, Ebstein anomaly, Eisenmenger syndrome, coarctation, tetralogy of Fallot (repaired).

Pericardial. Pericardial effusion (idiopathic, viral, tuberculous, malignant, uraemic, hypothyroid, autoimmune, post infarction, post surgery), constrictive pericarditis, pericardial cyst, pericardial tumour.

High output and endocrine. Anaemia, thyrotoxicosis, arteriovenous fistula, beriberi, Paget disease, pregnancy, cirrhosis, severe obesity, acromegaly, phaeochromocytoma, Cushing syndrome, hypothyroidism.

Tumours and mediastinal causes. Cardiac tumours (myxoma, sarcoma, metastasis), mediastinal mass, thymoma, lymphoma, pleural and diaphragmatic causes.

Pulmonary and right sided. Pulmonary hypertension (chronic lung disease, chronic thromboembolic disease, sleep apnoea), cor pulmonale, pulmonary valve stenosis, pulmonary embolism, right ventricular infarction. Pseudo cardiomegaly. Expiratory or supine film, obesity and epicardial fat, pectus excavatum, straight back syndrome, rotation, kyphoscoliosis, elevated diaphragm, athletic remodelling.

1. Confirm true cardiomegaly: posteroanterior erect film in full inspiration (cardiothoracic ratio over 0.50 in adults; over 0.60 in neonates); compare with old films; echocardiography is the next step for any real concern.
2. 12 lead ECG: look for left ventricular hypertrophy, strain, bundle branch block (left bundle branch block with dilated cardiomyopathy), atrioventricular block, Q waves, low voltage with thick walls (amyloid), epsilon waves, pre-excitation, atrial fibrillation and long QT. Use ambulatory ECG for arrhythmia (24 hour to 14 day); exercise testing as indicated.
3. Transthoracic echocardiography (the key test): chamber sizes, wall thickness, ejection fraction and global longitudinal strain, valve disease, diastolic function, pericardial effusion, congenital defects, pulmonary pressure, thrombus and masses.
4. Blood tests: full blood count, ferritin and transferrin saturation, urea, creatinine, electrolytes, liver function, thyroid stimulating hormone, glucose and HbA1c, lipids, creatine kinase, troponin, natriuretic peptide, calcium, phosphate, HIV test, hepatitis serology, autoimmune screen.
5. Further blood tests: serum and urine protein electrophoresis with free light chains, serum angiotensin converting enzyme, Chagas serology (two methods), selenium, thiamine and carnitine as indicated, toxicology.
6. Cardiac MRI with late gadolinium enhancement and T1 and T2 mapping (myocarditis, infarct scar, fibrosis, amyloid, sarcoid, iron overload, non compaction, arrhythmogenic cardiomyopathy, hypertrophic cardiomyopathy).
7. CT coronary angiography or invasive angiography for coronary disease in dilated cardiomyopathy; nuclear imaging (technetium pyrophosphate for transthyretin amyloid, FDG PET for sarcoid).
8. Endomyocardial biopsy when giant cell myocarditis, amyloid, sarcoid, eosinophilic myocarditis or fulminant myocarditis is suspected and the result will change treatment.
9. Genetic testing and family screening (first degree relatives with ECG and echocardiography) for dilated, hypertrophic and arrhythmogenic cardiomyopathies, muscular dystrophy, Fabry disease (alpha galactosidase A level), and amyloidosis (transthyretin gene).
10. Chest CT for mediastinal, pericardial and lung causes; sleep study; right heart catheterisation for pulmonary hypertension; cardiopulmonary exercise testing to quantify limitation.
11. Pericardial effusion: echocardiography, pericardiocentesis with fluid analysis when large, suspected cancer, infection or tamponade.
12. Assess for the commonest reversible causes first: blood pressure control, alcohol history, thyroid function, anaemia, coronary disease, tachyarrhythmia, valve disease.

Limits. Cardiothoracic ratio is poorly reproducible and does not measure chamber volumes. Echocardiography quality depends on acoustic windows and operator. Genetic testing finds a pathogenic variant in only 20% to 50% of familial cardiomyopathy. Even after full investigation, about 25% to 30% of dilated cardiomyopathy remains idiopathic.

Immediate priorities. Treat emergencies (tamponade, acute pulmonary oedema, shock, ventricular arrhythmia) at once; stop cardiotoxic agents (alcohol, cocaine, amphetamines, anabolic steroids), and review drugs.

Heart failure with reduced ejection fraction (40% or under), any cause.

• ACE inhibitor: ramipril 1.25 to 2.5 mg twice daily, doubling every 1 to 2 weeks to 5 mg twice daily (or 10 mg daily).
• Alternatively sacubitril-valsartan 24/26 mg twice daily increasing every 2 to 4 weeks to 97/103 mg twice daily (36 hour washout from an ACE inhibitor).
• Angiotensin receptor blocker (candesartan 4 mg daily increasing to 32 mg) if ACE inhibitor not tolerated. Check creatinine and potassium at 1 to 2 weeks.
• Beta blocker when euvolaemic: bisoprolol 1.25 mg daily increasing every 2 weeks to 10 mg daily, or carvedilol 3.125 mg twice daily to 25 mg twice daily, or nebivolol 1.25 mg daily to 10 mg daily.
• Mineralocorticoid receptor antagonist: spironolactone 25 mg daily or eplerenone 25 mg increasing to 50 mg daily; potassium and creatinine at 1 and 4 weeks, then every 3 to 6 months; stop if potassium over 5.5 mmol/L.
• Sodium glucose co-transporter 2 inhibitor: dapagliflozin 10 mg daily or empagliflozin 10 mg daily.
• Diuretic for congestion: furosemide 20 to 80 mg daily (or bumetanide 1 to 5 mg, torasemide 10 to 40 mg), adjusting to a dry weight.
• Add ivabradine 5 mg twice daily (up to 7.5 mg twice daily) in sinus rhythm with rate 70 beats/minute or more on maximum beta blocker.
• Add hydralazine 25 mg three times daily with isosorbide dinitrate 20 mg three times daily if renin angiotensin blockers are not tolerated.
• Other add-ons: digoxin 62.5 to 250 micrograms daily for atrial fibrillation or persistent symptoms; vericiguat; intravenous iron for iron deficiency.
• Devices: implantable cardioverter defibrillator for ejection fraction 35% or less after at least 3 months of optimal therapy. Cardiac resynchronisation therapy for QRS 150 ms or more with left bundle branch block and ejection fraction 35% or less. In lamin A/C and high risk genetic disease or arrhythmic syncope, earlier defibrillator.
• Anticoagulation for atrial fibrillation, intracardiac thrombus and embolism (apixaban 5 mg twice daily, or 2.5 mg twice daily if two of age 80 or more, weight 60 kg or less, creatinine 133 micromol/L or more).
• Exercise rehabilitation, vaccinations, sodium moderation, daily weights.
• Advanced disease: transplantation or mechanical circulatory support assessment, palliative care.

Specific causes.

• Hypertensive heart disease: blood pressure under 130/80 mmHg with ACE inhibitor or angiotensin receptor blocker, calcium channel blocker and thiazide like diuretic (indapamide 1.5 mg modified release daily or chlortalidone 12.5 to 25 mg), regression of left ventricular hypertrophy.
• Alcohol: complete abstinence, thiamine 100 mg daily (200 to 300 mg daily with intravenous thiamine in deficiency states), recovery over 3 to 6 months.
• Coronary disease: antiplatelet (aspirin 75 mg), atorvastatin 40 to 80 mg, revascularisation as indicated.
• Thyroid disease: thyrotoxicosis (carbimazole 20 to 40 mg daily, beta blocker for rate control), hypothyroidism (levothyroxine 1.6 micrograms/kg, starting at 25 micrograms in older adults or coronary disease).
• Anaemia and iron overload: iron replacement (ferrous sulphate 200 mg daily) or transfusion; chelation (deferasirox 20 to 30 mg/kg daily) or venesection for haemochromatosis.
• Tachycardia induced: rate or rhythm control, ablation, with recovery of function.
• Peripartum cardiomyopathy: usual heart failure drugs adapted to pregnancy and lactation (furosemide, hydralazine, nitrate, beta blocker). Give bromocriptine 2.5 mg twice daily for 1 week then 2.5 mg daily for 6 weeks with anticoagulation. Avoid future pregnancy if ejection fraction does not recover.
• Myocarditis: supportive therapy, avoid exercise for 3 to 6 months, treat heart failure. Use immunosuppression for giant cell myocarditis (methylprednisolone, ciclosporin) and autoimmune or sarcoid disease (prednisolone 0.5 mg/kg daily with taper).
• Chagas cardiomyopathy: benznidazole 5 to 7 mg/kg daily in two doses for 60 days (nifurtimox is the alternative) in indeterminate or early disease, and heart failure drugs.
• Chagas cardiomyopathy, arrhythmia and conduction disease: amiodarone and pacemaker or defibrillator. Anticoagulation for apical aneurysm or atrial fibrillation.
• HIV cardiomyopathy: antiretroviral therapy and heart failure drugs.
• Amyloidosis, light chain: chemotherapy with bortezomib, cyclophosphamide and dexamethasone, then stem cell transplantation.
• Amyloidosis, transthyretin: tafamidis 61 mg daily, or acoramidis; diuretics; avoid beta blockers, digoxin and calcium channel blockers in advanced disease.
• Sarcoidosis: prednisolone and immunosuppression, defibrillator. Haemochromatosis: venesection.
• Hypertrophic cardiomyopathy: beta blocker (metoprolol succinate 50 to 200 mg daily) or verapamil, disopyramide 100 to 250 mg twice daily, mavacamten 2.5 to 5 mg daily (specialist). Also septal reduction, defibrillator by risk score, avoid dehydration and vasodilators, family screening.
• Valve disease: diuretics, surgical or transcatheter repair or replacement at the right time (by symptoms and echocardiographic thresholds).
• Pericardial effusion: drainage when haemodynamically significant, and treat the cause.
• Tuberculous pericardial effusion: isoniazid 5 mg/kg to a maximum of 300 mg, rifampicin 10 mg/kg to a maximum of 600 mg, pyrazinamide 25 mg/kg to a maximum of 2 g, ethambutol 15 mg/kg for 2 months, then isoniazid and rifampicin for 4 months, with pyridoxine.
• Pericarditis: ibuprofen 600 mg three times daily with colchicine 500 micrograms twice daily.
• Congenital heart disease: referral for closure or surgery.
• Athlete's heart: reassure after evaluation (wall thickness under 13 mm, normal function, normal ECG pattern for athletes, regression after detraining).
• Cardiotoxic cancer drugs: stop or switch, start heart failure therapy early (ACE inhibitor and beta blocker, for example carvedilol), cardio oncology referral. Protect with dexrazoxane for anthracyclines in selected patients.

Pseudo cardiomegaly. Reassure and repeat a proper posteroanterior film; no further investigation if echocardiography is normal.

Family screening and prevention. Clinical screening of first degree relatives for dilated, hypertrophic and arrhythmogenic cardiomyopathy every 1 to 3 years until age 50 or genetic test result; genetic counselling; avoid cardiotoxins; control hypertension, diabetes and obesity.

Monitoring. Symptoms, weight, blood pressure, pulse and jugular venous pressure at each visit. Echocardiography at diagnosis, 3 to 6 months after optimal therapy and when status changes. Natriuretic peptide; renal function and potassium; ECG and device checks; Holter for arrhythmia; cardiac MRI for response in selected cases.

Referral and escalation. Cardiology for all true unexplained cardiomegaly with abnormal echocardiography. Heart failure clinic and specialist cardiomyopathy service for genetic, infiltrative and inflammatory disease. Electrophysiology for arrhythmias and devices. Haematology for amyloidosis, haemochromatosis and anaemia. Endocrinology for thyroid and metabolic disease.

Also refer to infectious diseases for Chagas disease, HIV and tuberculosis; cardio oncology; transplant centre for refractory failure; genetics.

Admission. Heart failure with respiratory distress or hypoxia, syncope, ventricular arrhythmia, heart block, tamponade, myocarditis with instability, new heart failure with shock, or inability to titrate treatment safely.

Safety netting. Return urgently for breathlessness at rest, fainting, chest pain, sustained palpitations, fever, rapid weight gain over 2 kg in 3 days, new leg or abdominal swelling, or reduced urine. Avoid heavy alcohol, stimulants and NSAIDs, take medicines daily and attend follow up.

Special groups. Pregnancy: peripartum cardiomyopathy, mitral stenosis and pre-existing cardiomyopathy need joint cardiac and obstetric care. Avoid ACE inhibitors, angiotensin receptor blockers, sacubitril-valsartan, spironolactone and warfarin. Use furosemide, hydralazine with nitrate, beta blocker and enoxaparin. Children and young adults: congenital heart disease, myocarditis, genetic cardiomyopathy and muscular dystrophy; screen the family.

Older adults: hypertensive heart disease, amyloid, valve disease and ischaemic cardiomyopathy predominate. Athletes: distinguish physiological remodelling from cardiomyopathy before sport. Endemic regions: rheumatic heart disease, Chagas disease, HIV cardiomyopathy, tuberculous pericardial disease, endomyocardial fibrosis, severe anaemia, beriberi, uncontrolled hypertension and peripartum cardiomyopathy are leading causes.