Prevalence, characteristics and outcomes of older patients with hereditary versus wild‐type transthyretin amyloid cardiomyopathy

Abstract

Aims Transthyretin amyloid cardiomyopathy (ATTR‐CM) is often assumed to be associated with wild‐type TTR genotype (ATTRwt) in elderly patients (aged ≥70), some of whom are not offered genetic testing. We sought to estimate the prevalence, clinical characteristics and prognostic implications of transthyretin (TTR) variants among elderly patients diagnosed with ATTR‐CM. Methods and results Data from consecutive patients over 70 years of age diagnosed with ATTR‐CM at the UK National Amyloidosis Centre between January 2010 and August 2022 were retrospectively evaluated. All patients underwent clinical evaluation, biochemical tests, echocardiography and TTR genotyping. The study outcome was all‐cause mortality. The study population consisted of 2029 patients with ATTR‐CM (median age 79 years at diagnosis, 13.5% females, 80.4% Caucasian). Variant ATTR‐CM (ATTRv‐CM) was diagnosed in 20.7% (n = 421) of the study population of whom 327 (77.7%) carried V122I, 47 (11.2%) T60A, 16 (3.8%) V30M and 31 (7.3%) other pathogenic TTR variants. During a median (range) follow‐up of 29 (12–48) months, ATTRv‐CM was associated with increased all‐cause mortality compared to ATTRwt‐CM, with the poorest survival observed in V122I‐associated ATTRv‐CM (p < 0.001). Univariable and multivariable logistic regression analyses in those with ATTR‐CM showed younger age at diagnosis (odds ratio [OR] 0.85 per year, p < 0.001), female sex (OR 2.73, p < 0.001), Afro‐Caribbean ethnicity (OR 65.5, p < 0.001), atrial fibrillation (OR 0.65, p = 0.015), ischaemic heart disease (OR 0.54, p = 0.007), peripheral polyneuropathy (OR 5.70, p < 0.001) and orthostatic hypotension (OR 6.29, p < 0.001) to be independently associated with ATTRv‐CM. Conclusion Up to 20.7% of elderly patients with ATTR‐CM have a pathogenic TTR variant. These findings support routine sequencing of the TTR gene in all patients with ATTR‐CM regardless of age.

Variant and wild type transthyretin amyloidosis: two sides of the same coin or different currencies in different pockets?

“…Transthyretin amyloidosis may be hereditary, transmitted in an autosomal dominant fashion, or due to amyloid deposition derived from wild-type TTR. In this issue of the Journal, Porcari and colleagues retrospectively report an overall prevalence of 20.7% 2 The likelihood of a pathogenic TTR variant in this cohort was higher in relatively younger patients, females, patients with Afro-Caribbean ethnicity and in those with orthostatic hypotension or polyneuropathy. Importantly, patients diagnosed with the variant form of the disease (variant TTR [ATTRv]) compared with the wild-type form (wild-type TTR amyloidosis [ATTRwt]), showed higher all-cause mortality.…”

“…Transthyretin amyloidosis may be hereditary, transmitted in an autosomal dominant fashion, or due to amyloid deposition derived from wild‐type TTR. In this issue of the Journal, Porcari and colleagues retrospectively report an overall prevalence of 20.7% of a pathogenic TTR variant (with a prevalence of 7.2% in those with non‐African or Caribbean ancestry) among 2029 patients with ATTR aged 70 years or older studied between 2010 and 2022 2 . The likelihood of a pathogenic TTR variant in this cohort was higher in relatively younger patients, females, patients with Afro‐Caribbean ethnicity and in those with orthostatic hypotension or polyneuropathy.…”

April 2023 at a glance: focus on diagnosis and comorbidities

“…However, the prevalence of variant ATTR‐CA (ATTRv‐CA) was of 20.7% among 2029 patients aged ≥70 years with ATTR‐CA from the UK National Amyloidosis Centre. The ATTRv‐CA was associated with increased risk of all‐cause mortality, especially when related to the V122I mutation 18 …”

Expert Review on Contemporary Management of Common Benign Pleural Effusions

“…If suspected, once ruling out the presence of serum or urine monoclonal light chains (AL amyloidosis), a positive 99m-technetium pyrophosphate scintigraphy should lead to TTR gene sequencing to differentiate hereditary (h-ATTR) from wt-ATTR disease. 40 41 Patients with cardiac ATTR amyloidosis benefit from tafamidis, a TTR stabilizer, 42 and should generally avoid ACEi, ARB, beta blockers, calcium channel blockers, and digoxin.…”

“…39 Other clinical manifestations include carpal tunnel syndrome, orthostatic hypotension, and neuropathy. 40 The disease results from the aggregation of insoluble deposits of misfolded amyloid proteins (immunoglobulin light chains or transthyretin [ATTR]) within the myocardium. 41 In particular, wild-type ATTR (wt-ATTR) amyloidosis may be responsible for up to 15% of cases of HF in the elderly.…”