Cardiac Involvement in Systemic Disease: Amyloid, Sarcoid, Chagas & Lyme
When the heart is the clue to a systemic disease
Cardiac amyloidosis
What it looks like. Amyloid fibrils infiltrate the myocardium and produce a restrictive cardiomyopathy that presents as HFpEF. The signature is a mismatch: thick LV walls on echo but low QRS voltage on ECG — unlike hypertensive LVH, where voltage rises with wall thickness — often with pseudo-infarct Q waves, AV block, and AF. Echo adds biatrial enlargement, a sparkling myocardium, and apical-sparing longitudinal strain (the "cherry on top" pattern); cardiac MRI shows diffuse subendocardial late gadolinium enhancement. Troponin and NT-proBNP stay persistently elevated.
Extracardiac red flags. Bilateral carpal tunnel syndrome (often years earlier), lumbar spinal stenosis, biceps tendon rupture, neuropathy with orthostatic hypotension, and hypertension that "resolves". AL amyloidosis adds macroglossia, periorbital purpura, and nephrotic-range proteinuria.
| Feature | AL (light chain) | ATTR (transthyretin) |
|---|---|---|
| Protein | Monoclonal light chains from a plasma-cell clone | Transthyretin, the liver-made carrier of thyroxine and retinol, dissociated from its tetramer |
| Typical patient | Any adult; rapidly progressive | Wild-type: men usually over 70; hereditary V122I in ~3–4% of Black Americans |
| Distinctive clues | Macroglossia, periorbital purpura, nephrotic syndrome | Carpal tunnel, spinal stenosis, biceps rupture |
| Key test | Free light chains + serum/urine immunofixation, then tissue biopsy | Grade 2–3 Tc-99m PYP uptake with no monoclonal protein; TTR gene sequencing |
| Treatment | Urgent plasma-cell chemotherapy (e.g., daratumumab-based) ± autologous stem cell transplant | Tafamidis or acoramidis (tetramer stabilizers); vutrisiran (TTR silencer) |
Diagnostic sequence. Screen every suspected case for a monoclonal protein first — serum free light chains (κ/λ ratio) plus serum and urine immunofixation — because AL is aggressive and treatable. A monoclonal protein requires tissue confirmation: fat pad, bone marrow, or endomyocardial biopsy showing Congo red apple-green birefringence, with mass spectrometry to type the fibril. Without one, grade 2–3 myocardial uptake on technetium-99m pyrophosphate scintigraphy diagnoses ATTR with no biopsy, and TTR gene sequencing separates wild-type from hereditary disease.
ATTR therapy. Tafamidis binds TTR's thyroxine-binding sites, stabilizes the tetramer, and lowers mortality and cardiovascular hospitalization; acoramidis (2024) is a second stabilizer, and the TTR silencer vutrisiran was approved for ATTR cardiomyopathy in 2025. The hereditary V30M variant presents mainly as familial polyneuropathy, the setting in which TTR silencers (patisiran, vutrisiran) were first approved.
Amyloid hearts have a small, fixed stroke volume and depend on heart rate: beta-blockers and non-dihydropyridine CCBs cause hypotension and low output, ACE inhibitors and ARBs drop BP in patients with autonomic neuropathy, and digoxin binds fibrils and becomes toxic. Use loop diuretics for congestion and anticoagulate AF regardless of CHA2DS2-VASc; atrial thrombus can form even in sinus rhythm.
Cardiac sarcoidosis
Presentation. Noncaseating granulomas, typically in the basal septum and LV wall, cause AV block, monomorphic VT, sudden death, and HF with regional wall-motion abnormalities. Unexplained Mobitz II or complete heart block before age 60 warrants evaluation. Clues include bilateral hilar adenopathy, erythema nodosum, and uveitis; serum ACE is nonspecific.
Diagnosis. Cardiac MRI shows patchy midwall or subepicardial LGE, often in the basal septum. FDG-PET shows active inflammation and tracks response to therapy, after a high-fat, very-low-carbohydrate preparation that suppresses normal myocardial glucose uptake. Endomyocardial biopsy is insensitive because involvement is patchy, so an extracardiac site such as a mediastinal node often supplies the tissue diagnosis.
Treatment. Corticosteroids, often with methotrexate as a steroid-sparing agent. Because of the sudden-death risk, a patient who needs a pacemaker usually receives an ICD instead; sustained VT, survived arrest, or a severely reduced EF are ICD indications too.
Chagas disease and Lyme carditis
| Feature | Chagas cardiomyopathy | Lyme carditis |
|---|---|---|
| Organism | Trypanosoma cruzi; triatomine ("kissing") bug feces, transfusion, congenital | Borrelia burgdorferi; Ixodes tick |
| Setting | Latin American origin; decades after infection | Northeast or upper Midwest in summer; weeks to months after the bite |
| Heart | RBBB + left anterior fascicular block, AV block, VT, sudden death, LV apical aneurysm with thrombus and embolic stroke, dilated cardiomyopathy | AV block of fluctuating degree, usually at the AV node; myopericarditis |
| Other clues | Megaesophagus, megacolon; Romaña sign in acute infection | Erythema migrans, facial palsy, migratory arthralgias |
| Treatment | Benznidazole or nifurtimox early; GDMT, amiodarone, ICD or pacing, and anticoagulation once cardiomyopathy is established | IV ceftriaxone if admitted, then oral doxycycline or amoxicillin for 14–21 days total; temporary pacing |
Chagas. About 20–30% of chronically infected people develop cardiomyopathy decades later, and destruction of enteric ganglia causes megaesophagus and megacolon. Acute conjunctival entry can leave a Romaña sign, painless unilateral eyelid swelling. Chronic infection is diagnosed with two different IgG serologic assays because parasitemia is low. Antiparasitic drugs help acute, congenital, or reactivated infection and younger patients without advanced heart disease, but they do not reverse established cardiomyopathy.
Lyme carditis. Admit for PR ≥300 ms, second- or third-degree block, or symptoms; switch from ceftriaxone to oral therapy once block improves. Block usually resolves within about a week, so a permanent pacemaker is rarely needed. Mild carditis (PR <300 ms) is treated orally from the start.
Metabolic, endocrine and neuromuscular hearts
| Disease | Cardiac lesion | Clues and management |
|---|---|---|
| Hemochromatosis (HFE C282Y) | Dilated (early restrictive) cardiomyopathy, conduction disease | Diabetes, bronze skin, cirrhosis, hypogonadism, MCP arthropathy; MRI T2* <20 ms; phlebotomy (chelation if transfusional) can reverse it |
| Carcinoid | Tricuspid regurgitation, pulmonic stenosis, right HF | Flushing, diarrhea, wheezing, liver metastases; urine 5-HIAA; somatostatin analog, valve replacement if severe |
| Thyrotoxicosis | Sinus tachycardia, AF, high-output HF | Wide pulse pressure, low TSH; propranolol plus antithyroid therapy |
| Duchenne muscular dystrophy | Dilated cardiomyopathy, including carriers | X-linked dystrophin loss; ACE inhibitor by about age 10 |
| Myotonic dystrophy type 1 | Conduction disease, sudden death | DMPK CTG repeat; yearly ECG, low threshold for pacemaker or ICD |
| Friedreich ataxia | Concentric hypertrophic cardiomyopathy, the leading cause of death | FXN GAA repeat (frataxin); ataxia, diabetes, scoliosis |
Carcinoid. Hepatic metastases let serotonin reach the right heart unmetabolized; the lungs inactivate it, so left-sided lesions suggest a PFO or a bronchial carcinoid.
Thyroid. Excess thyroid hormone raises β-adrenergic sensitivity and lowers SVR. Check TSH in every new AF; AF often reverts once the patient is euthyroid, and anticoagulation follows CHA2DS2-VASc. Older adults may have "apathetic" hyperthyroidism, with AF or HF as the only sign.
Fabry disease (X-linked α-galactosidase A deficiency) is another infiltrative mimic of hypertrophic cardiomyopathy, with neuropathic pain, angiokeratomas, and proteinuria.