Background: Cardiac transthyretin (ATTR) amyloidosis was shown to be highly prevalent in all comers with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR) with even higher rates among males and patients with low-flow, low-gradient stenosis. The objective of the current study was to investigate if known amyloid “red-flags” and comorbidities are associated with higher incidence of ATTR amyloidosis among patients receiving TAVR for severe AS.

Methods: The study prospectively enrolled patients > 65 years referred for TAVR due to severe AS. Patients who fulfilled ≥1 major (carpal tunnel syndrome, ruptured biceps tendon, spinal stenosis, N-terminal pro B-type natriuretic peptide ≥1000 pg/ml, high-sensitivity cardiac troponin >99th percentile upper reference limit) or ≥2 minor criteria (diastolic dysfunction ≥2 II. grade or e’ of the lateral mitral valve annulus < 10 cm/s, atrial fibrillation, atrioventricular conduction disease i.e. second or third grade atrioventricular block or previously implanted pacemaker) received Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (^99mTc-DPD) scintigraphy and biochemical analysis of serum and urine for monoclonal disease/light-chain amyloidosis. Patients with arterial hypertension at admission (>140/90 mmHg) or interventricular septal thickness <13 mm were excluded from screening. Diagnosis was based on established criteria: Perugini grade 2 or 3 tracer uptake and absence of laboratory indices of light-chain amyloidosis. Endomyocardial biopsy was performed if non-invasive diagnosis was not feasible to confirm amyloidosis.

Results: During an 18-month period, 85 of 263 screened patients met inclusion criteria and provided written consent to the study. Mean age was 82 years, 61% were male. Scintigraphy detected any degree of myocardial uptake (Perugini grade ≥ 1) in 9 patients (11%). Endomyocardial biopsy was performed in 4 patients with Perugini grade <2 or abnormal light-chain / immunofixation assays to confirm the diagnosis. In 3 patients no amyloid was found by biopsy yielding an overall ATTR prevalence of 7% (n=6 out of 86). All patients with ATTR amyloidosis were male. No differences were observed between ATTR amyloidosis and non-amyloidosis patients regarding major and minor criteria/ “red flags” except for carpal tunnel syndrome that was more prevalent in patients with amyloidosis (83% vs. 23%, p = 0.003). There were no significant differences in hemodynamic measures of AS (aortic valve area 0.63 vs. 0.71, p = 0.26, mean pressure gradient 31 vs. 40mmHg, p = 0.19, peak aortic valve velocity 3.4 vs. 4.1 m/sec, p = 0.07) and the rate of low-flow, low-gradient AS (50% vs. 34%, p = 0.84). No differences were observed in left ventricular systolic function (ejection fraction 52 vs. 51%, p = 0.96, global longitudinal strain -12 vs. -13%, p = 0.64) and hypertrophy (left ventricular mass index 163 vs. 151, p = 0.52, septum thickness 1.8 vs. 1.6, p = 0.09).

Conclusion: This preliminary analysis demonstrates that traditional amyloid features and comorbidities that were shown to be associated with ATTR amyloidosis may not be of equal predictive value in patients with AS. The true prevalence of ATTR in AS remains unclear and has to be investigated in large prospective studies, ideally with a diagnostic method ensuring the highest possible diagnostic accuracy such as endomyocardial biopsy or myocardial imaging with amyloid-specific radiotracers.