Abstract Background Transthyretin cardiac amyloidosis (ATTR-CM) is a progressive disorder caused by extracellular deposition of transthyretin (TTR) amyloid fibrils (1). It exists in 2 forms: hereditary (ATTRv), due to TTR mutations, and wild-type (ATTRwt), associated with aging. ATTRv is traditionally considered more severe and affecting younger individuals (2), leading to genetic testing being frequently omitted in elderly patients under the assumption of ATTRwt (3). Our findings challenge this paradigm, suggesting a late-onset hereditary form of ATTR-CM with distinct characteristics. Methods This multicenter retrospective study included patients ≥70 y diagnosed with ATTR-CM between 2014 and 2024 at 4 cardiomyopathy centers in our city. Patients underwent clinical evaluation, biochemical testing, Holter monitoring, echocardiography, and TTR genotyping. Statistical analysis included descriptive statistics, Student’s t-test, Chi-square test, and Mann–Whitney U test. A univariate analysis was performed to identify variables associated with ATTRv in elderly patients. Results Among 1,016 patients evaluated for suspected ATTR-CM, 331 were diagnosed. After excluding 102 patients (age 70 years or monoclonal component without biopsy confirmation), 229 remained (201 males, 28 females; mean age 82.7 ± 6.1 y. ATTRv was found in 34 patients (14.85%, 95% CI: 10.24%–19.45%), with Ile88Leu (38%) as the most frequent mutation, followed by Val50Met (26%) and Val142Ile (11%). ATTRv patients were significantly younger (75.97 ± 5.32 vs. 83.55 ± 5.98 y; p 0.001) and more frequently female (32.35% vs. 8.65%; p = 0.0018). They also had higher rates of carpal tunnel syndrome (0.73 vs. 0.45; p = 0.008) and polyneuropathy (0.50 vs. 0.24; p = 0.008). ATTRv patients exhibited fewer supraventricular extrasystoles (123.14 vs. 1,312.33; p = 0.022) and less frequent positivity on 99mTc-DPD scintigraphy (0.68 vs. 0.94; p 0.001), with lower Perugini scores (1.88 vs. 2.48; p = 0.015). Echocardiographic analysis showed a smaller indexed left atrial volume (41.3 vs. 50.0 mL/m²; p = 0.012). Among ATTRv patients, genetic testing enabled targeted therapy in 11 individuals (9 patisiran, 2 vutrisiran). Testing of 59 first-degree relatives identified 28 mutation carriers (47.5%) (19 females, 10 males; mean age 47 y), of whom 7 (25%) exhibited phenotypic expression (mean age 68 years) and initiated early therapy. Conclusions Up to 15% of elderly patients with ATTR-CM carry a pathogenic TTR mutation, with Ile88Leu being the most prevalent in central Italy. This late-onset ATTRv exhibits a distinct phenotype, differing from younger-onset ATTRv, with higher female prevalence, increased neuropathy, lower arrhythmic burden, and reduced bone scintigraphy positivity, defining a novel entity: the "ATTRv Longevity Variant." These findings support systematic genetic testing in all ATTR-CM patients, irrespective of age, to enable targeted therapy and early intervention in at-risk relatives.
Costantino et al. (Sat,) studied this question.