Chagas Cardiomyopathy

Chagas cardiomyopathy is the chronic cardiac form of infection with the protozoan Trypanosoma cruzi. About 6 to 7 million people are infected worldwide, mostly in Latin America, with imported disease in North America, Europe, Australia and other regions through migration.

Transmission is by contact with the faeces of triatomine bugs, and also by contaminated food or drink, blood transfusion, organ transplantation and the placenta. The acute phase is usually mild or silent.

Most people then enter an indeterminate (asymptomatic) phase lasting life, and 20 to 30% develop cardiac disease 10 to 30 years later (annual progression about 2 to 5%). A smaller share develop megaoesophagus or megacolon.

It is the commonest infectious cardiomyopathy and carries a worse prognosis than other non-ischaemic cardiomyopathies. Reactivation occurs with immunosuppression (HIV infection with CD4 count under 200 cells/microlitre, transplantation, chemotherapy).

Staging used in practice is: A (infected, normal ECG and echocardiogram), B1 (ECG abnormality, normal ejection fraction), B2 (reduced ejection fraction, no symptoms), C (heart failure symptoms) and D (refractory heart failure).

Pathophysiology. Parasite persistence, chronic immune mediated inflammation, microvascular damage and autonomic neuronal loss produce fibrosis, mainly of the apex and inferolateral wall, with conduction system destruction.

This explains apical aneurysm, ventricular tachycardia, sinus node dysfunction, AV block and right bundle branch block. Thrombus forms in the aneurysm and in the dilated atria and ventricles, and causes stroke.

• Palpitations, presyncope and syncope from bradyarrhythmia or ventricular tachycardia. Sudden death is common, and may be the first event.
• Heart failure, with right sided signs (oedema, hepatomegaly, raised venous pressure) often prominent.
• Embolic stroke, atypical chest pain, and dysphagia or constipation from megaoesophagus or megacolon.
• ECG: right bundle branch block with left anterior fascicular block (the classic combination), AV block, sinus bradycardia, frequent ventricular ectopy, Q waves and low QRS voltage.
• Acute phase or reactivation: fever, hepatosplenomegaly, myocarditis, pericardial effusion and meningoencephalitis.

Red flags.

• Syncope, non-sustained or sustained ventricular tachycardia
• Second degree or third degree AV block
• Ejection fraction under 40%, or an apical aneurysm
• Embolic stroke
• NYHA class III or IV symptoms
• Reactivation in an immunosuppressed patient or after transplantation
• Infant of an infected mother

• Chronic infection. IgG serology with two tests that use different antigens (enzyme immunoassay, immunofluorescence or indirect haemagglutination). A third test resolves discordance.
• Acute phase, congenital infection and reactivation. Microscopy of fresh blood or buffy coat and PCR. Monitor PCR weekly after transplantation and in profound immunosuppression.
• ECG and 24 to 48 hour ambulatory ECG for ectopy, non-sustained ventricular tachycardia and bradyarrhythmia. Exercise testing for chronotropic response and arrhythmia.
• Echocardiography. Apical or posterior wall aneurysm, inferolateral hypokinesia, ejection fraction, right ventricular function and thrombus.
• Cardiac MRI. Late gadolinium enhancement (a strong marker of arrhythmic risk) and thrombus.
• Risk score (Rassi). NYHA class III or IV 5 points, cardiomegaly on chest X-ray 5, segmental or global wall motion abnormality 3, non-sustained ventricular tachycardia 3, low QRS voltage 2, male sex 2. A total of 0 to 6 is low risk, 7 to 11 intermediate and 12 to 20 high risk (10-year mortality about 10%, 44% and 84%).
• Digestive disease. Barium swallow or enema in symptomatic patients. Coronary angiography or CT to exclude coexisting coronary disease when chest pain is present.

Differential diagnosis.

• Idiopathic dilated cardiomyopathy and ischaemic cardiomyopathy
• Cardiac sarcoidosis and other infiltrative disease
• Rheumatic heart disease and hypertensive heart disease
• Degenerative conduction disease
• Endomyocardial fibrosis, myocarditis from other causes and arrhythmogenic cardiomyopathy
• Lyme carditis
• Right bundle branch block from other causes

Antitrypanosomal therapy.

• Benznidazole 5 to 7 mg/kg/day orally in 2 divided doses for 60 days (usual adult maximum 300 mg daily; children 5 to 10 mg/kg/day). Alternative: nifurtimox 8 to 10 mg/kg/day orally in 3 doses with food for 60 days in adults (children 10 to 20 mg/kg/day).
• Indications: acute infection, congenital infection, reactivation, and chronic infection in children and in adults up to about 50 years without advanced cardiomyopathy (stages A and B1). Treatment is individualised in stages B2 and C, because it did not reduce clinical progression in established cardiomyopathy.
• Monitoring: full blood count, liver enzymes and creatinine at baseline, 2 weeks, 4 weeks and at the end. Stop for severe dermatitis with fever or mucosal lesions, neutrophils under 1.0 x 109/L, peripheral neuropathy, or transaminases over 5 times the upper limit (or over 3 times with symptoms). Contraindicated in pregnancy. Avoid alcohol. Use cautiously at creatinine clearance under 30 mL/min because data are limited. Contraindicated in severe liver impairment.
• Reactivation in HIV infection or transplantation: treat with benznidazole 5 to 7 mg/kg/day orally in 2 divided doses for 60 days (usual adult maximum 300 mg daily), with antiretroviral therapy.

Heart failure with reduced ejection fraction. Full tolerated therapy, started at low doses because of bradycardia and low blood pressure.

• Sacubitril/valsartan 49/51 mg orally twice daily, doubled at 2 to 4 weeks to the target 97/103 mg twice daily (maximum 194/206 mg daily). Start 24/26 mg twice daily if not on an ACE inhibitor or angiotensin receptor blocker, on low doses, with eGFR under 30 mL/min/1.73 m2, or with moderate liver impairment. Stop any ACE inhibitor 36 hours before. Contraindicated with previous angio oedema, severe liver impairment and pregnancy. Check potassium and creatinine 1 to 2 weeks after each change.
• Bisoprolol 1.25 mg orally once daily, increased every 1 to 4 weeks to the target 10 mg once daily, maximum 10 mg daily in heart failure. Contraindicated in cardiogenic shock, second degree or third degree AV block without a pacemaker, sick sinus syndrome and severe asthma. Often needs a pacemaker to allow titration.
• Spironolactone 25 mg orally once daily (12.5 mg at eGFR 30 to 49 mL/min/1.73 m2), up to 50 mg daily. Check potassium and creatinine at 1 week and 4 weeks, then every 3 months. Withhold at potassium over 5.5 mmol/L and avoid at eGFR under 30 mL/min/1.73 m2.
• Dapagliflozin 10 mg orally once daily, long term. Start at eGFR 25 mL/min/1.73 m2 or more. Withhold during acute illness with poor oral intake. Contraindicated in type 1 diabetes.
• 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). Monitor sodium, potassium and creatinine.

Arrhythmia and conduction disease.

• Amiodarone for symptomatic or recurrent ventricular tachycardia and for ectopy with ventricular dysfunction: orally 200 mg three times daily for 1 week, 200 mg twice daily for 1 week, then 200 mg once daily (maintenance 100 to 200 mg once daily), maximum 600 mg daily during loading. Thyroid and liver function every 6 months, with baseline chest X-ray and lung function. Halve digoxin and reduce warfarin by 30 to 50%. Contraindicated in severe sinus node disease and high grade AV block without pacing.
• Implantable cardioverter defibrillator for survivors of cardiac arrest and sustained ventricular tachycardia, with amiodarone to limit shocks. Primary prevention is individualised for ejection fraction under 40% with non-sustained ventricular tachycardia, because benefit is uncertain.
• Pacemaker for symptomatic bradycardia, sinus node dysfunction and second degree type II or third degree AV block. Catheter ablation for recurrent ventricular tachycardia (epicardial access is often needed) in a specialist centre.
• Resynchronisation is considered for left bundle branch block with ejection fraction 35% or less. Evidence is limited in right bundle branch block.

Anticoagulation.

• Atrial fibrillation or flutter: 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.
• Left ventricular thrombus, apical aneurysm with thrombus, or previous cardioembolic stroke: warfarin 5 mg orally once daily at the start (2 to 3 mg in older adults, liver impairment or interacting drugs), adjusted to an INR of 2.0 to 3.0, no fixed maximum. INR every 2 to 3 days at the start, weekly until stable, then every 4 to 12 weeks. Warfarin is preferred in Chagas disease because data on direct oral anticoagulants for ventricular thrombus are limited.

Advanced disease. Mechanical support and transplantation in stage D. After transplantation, give benznidazole for reactivation and monitor PCR weekly.

Special groups.

• Pregnancy: antitrypanosomal drugs are deferred until after delivery and breastfeeding is usually continued. Screen all pregnant women from endemic regions and test newborns at birth and at 9 months. Treat infected infants with benznidazole 10 mg/kg/day orally in 2 doses for 60 days, which cures over 90%.
• Region: outside the Americas, disease is imported. Screen donors and recipients from endemic areas.

Monitoring. Indeterminate form: ECG yearly and echocardiography every 1 to 2 years. Stage B1 or B2: ECG, echocardiography and ambulatory ECG yearly. Full blood count, liver enzymes and creatinine at 2 weeks, 4 weeks and the end of benznidazole, potassium and creatinine after each heart failure titration, and thyroid and liver function every 6 months on amiodarone. Device interrogation every 3 to 6 months.

Referral and escalation. Refer to a cardiology centre with Chagas expertise and an infectious disease team. Urgent for syncope, ventricular tachycardia, high grade block, embolism, or heart failure with NYHA class III or IV symptoms.