Transthyretin-Related Cardiac Amyloidosis: A Case of Delayed Diagnosis in the Comorbid Patient and Literature Review

Abstract

We report the case of an 82-year-old male with a history of bronchiectasis, asthma, and atrial fibrillation, who presented with progressive exertional dyspnoea, peripheral oedema, and recurrent heart failure exacerbations. Initial management targeted presumed pulmonary decompensation. Elevated natriuretic peptides, echocardiographic evidence of concentric left ventricular hypertrophy with preserved ejection fraction, and progressive conduction abnormalities prompted further evaluation. A 99mTc-DPD scintigraphy scan revealed Perugini grade 3 myocardial uptake consistent with wild-type transthyretin (ATTRwt) cardiac amyloidosis. Serum and urine studies excluded light-chain amyloidosis. Despite the presence of classical ‘red flag’ features, including atrial fibrillation, carpal tunnel syndrome, and unexplained left ventricular hypertrophy, diagnosis was significantly delayed by approximately 18 months, from initial symptom onset to definitive diagnosis, during which recurrent hospitalisations and progressive functional decline occurred. Earlier features were overlooked due to the attribution of symptoms to coexistent pulmonary disease and chronic kidney dysfunction. This case highlights the diagnostic challenges posed by ATTRwt, particularly in multimorbid older adults. Overlapping features with respiratory and renal pathology, as well as age-associated cardiovascular changes, obscure the clinical picture. Awareness of hallmark extracardiac features, systematic use of cardiac imaging, and prompt nuclear scintigraphy are essential for timely diagnosis. Early identification may enable consideration of disease-modifying therapy and improved symptom management.

Introduction

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases and is increasingly recognised as a heterogeneous clinical syndrome with diverse underlying aetiologies. Among these, transthyretin-related cardiac amyloidosis (ATTR-CA) is an important and often underdiagnosed cause, particularly in older adults with unexplained HFpEF, atrial arrhythmias, and increased left ventricular wall thickness without a history of hypertension or aortic stenosis [1].

ATTR-CA results from the deposition of misfolded transthyretin proteins in the myocardial extracellular matrix, leading to progressive diastolic dysfunction, conduction abnormalities, and heart failure symptoms. It exists in two forms: hereditary (ATTRv), associated with TTR gene mutations, and wild-type (ATTRwt), previously known as senile systemic amyloidosis, which occurs in elderly individuals without a genetic predisposition [2]. ATTRwt has a male predominance and is often associated with comorbid conditions such as carpal tunnel syndrome, lumbar spinal stenosis, and atrial fibrillation, frequently leading to delayed or missed diagnosis [3]. Epidemiological studies suggest that ATTRwt may be present in up to 13-16% of HFpEF patients with increased wall thickness, yet median diagnostic delays of one to three years are common and are associated with progressive functional decline, worsening heart failure, and reduced survival [4]. We present a case of wild-type ATTR cardiac amyloidosis in an elderly male with coexisting pulmonary disease and recurrent decompensated heart failure, in whom the diagnosis was delayed due to overlapping clinical features.