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A 68-year-old man presents to the cardiology outpatient department with six months of progressive exertional dyspnoea (now NYHA III), bilateral lower-limb swelling, and two episodes of pre-syncope. He has a 20-year history of hypertension and bilateral carpal tunnel syndrome (operated five years ago), and recently underwent spinal decompression for lumbar spinal stenosis. On examination: BP 100/70 mmHg, JVP raised to the angle of the jaw with a prominent rapid y descent that rises further on inspiration (Kussmaul's sign), apex beat undisplaced and tapping, a third heart sound, soft pansystolic murmur at the apex, hepatomegaly (4 cm), and bilateral pitting ankle oedema.
ECG: atrial fibrillation at 90/min with low limb-lead voltages (under 0.5 mV QRS) and a pseudoinfarct pattern (Q waves V1-V3). Chest X-ray: bi-atrial enlargement, mild pulmonary venous congestion, no pericardial calcification. Echocardiogram: concentric LV wall thickening (septum 16 mm, posterior wall 15 mm) with granular 'sparkling' myocardial texture, LV end-diastolic dimension 42 mm, EF 52%, bi-atrial enlargement, restrictive mitral inflow (E/A 2.8, deceleration time 120 ms), tissue Doppler septal and lateral e' both 4 cm/s, E/e' 22, longitudinal strain showing apical sparing ('cherry on top'). NT-proBNP 3200 ng/L. Troponin T mildly elevated.
Questions
a) What is the most likely diagnosis, and what is the pathognomonic echocardiographic-ECG finding? (2 marks)
b) Outline the confirmatory diagnostic work-up, naming the non-invasive test that can confirm ATTR amyloidosis without biopsy. (3 marks)
c) Discuss the principles of definitive management, including one disease-modifying drug with its mechanism, dose and the trial that supports it. (3 marks)
d) Name two drugs that are specifically contraindicated in this condition and explain why. (2 marks)
Model Answers
a) The most likely diagnosis is restrictive cardiomyopathy due to cardiac amyloidosis — specifically wild-type transthyretin (ATTRwt, senile) amyloidosis, given the elderly man, bilateral carpal tunnel syndrome, lumbar spinal stenosis, and heart failure. The pathognomonic finding is voltage-mass discordance: low ECG limb-lead voltages with thickened LV walls on echo. The apical-sparing longitudinal strain pattern and granular myocardium reinforce amyloidosis.
b) Diagnostic work-up: (i) serum free light chain assay with kappa/lambda ratio, serum and urine protein electrophoresis with immunofixation to exclude AL amyloidosis (a plasma-cell dyscrasia); (ii) 99mTc-pyrophosphate (PYP), DPD, or HMDP bone scintigraphy — Perugini grade 2 or 3 cardiac uptake diagnoses ATTR amyloidosis non-invasively (sensitivity and specificity over 99%), provided monoclonal protein has been excluded — this avoids biopsy; (iii) cardiac MRI with late gadolinium enhancement, native T1 mapping and extracellular volume (ECV over 40%) to characterise the infiltrative phenotype; (iv) endomyocardial biopsy with Congo red staining and mass spectrometry typing if non-invasive work-up is inconclusive. Bone marrow biopsy if AL is confirmed.
c) Management principles: treat the underlying cause; symptom control with cautious loop diuretic (furosemide 20-40 mg) plus spironolactone 12.5-25 mg, anticoagulation for atrial fibrillation (apixaban 5 mg BD), rate control with cautious beta-blocker, and a permanent pacemaker if high-grade AV block develops. The disease-modifying therapy for ATTR-CM is tafamidis 61 mg orally once daily — a transthyretin tetramer stabiliser that prevents dissociation and amyloid fibril formation. The ATTR-ACT trial (Maurer, NEJM 2018) showed all-cause mortality reduced from 42.9% to 29.5% (hazard ratio 0.70) and a 32% reduction in cardiovascular hospitalisations over 30 months. Heart transplantation (or combined heart-liver transplant for ATTRv) is reserved for end-stage disease.
d) Two contraindicated drugs: (i) Digoxin — it binds amyloid fibrils and accumulates, producing dangerous toxicity (severe ventricular arrhythmias, hypotension, hyperkalaemia); (ii) Non-dihydropyridine calcium-channel blockers (verapamil, diltiazem) — they are negative inotropes that worsen heart failure in restrictive physiology and also bind amyloid fibrils. Both should be avoided in any form of cardiac amyloidosis.