Carpal tunnel syndrome in cardiac amyloidosis: implications for early diagnosis and prognostic role across the spectrum of aetiologies.

AIMS: We aimed to assess carpal tunnel syndrome (CTS) prevalence in transthyretin (TTR)-related and light-chain amyloidosis (AL), comparing it to the general population, adjusted for age and gender. In TTR-related amyloidosis (ATTR) we investigated (i) CTS prevalence in relation to genotype, cardiac amyloidosis (CA), age and gender; (ii) CTS role as an incremental risk factor for CA; (iii) temporal relationship between CTS and CA; and (iv) CTS prognostic role. METHODS AND RESULTS: Data from 538 subjects (166 hereditary ATTR, 107 wild-type ATTR, 196 AL amyloidosis, and 69 TTR mutation carriers; 64% male, median age 62.4 years), evaluated at our centre (Bologna, Italy), were analysed and compared to a published cohort of 14.9 million people, in which incidence rates of CTS had been estimated. CTS prevalence was highest in ATTR patients with CA (20.3% vs. 4.1% in the general population), while it was comparable to the general population when CA was absent and in AL patients. CTS standardized incidence rates were markedly elevated in ATTR males in the eighth decade of life (13.08 in hereditary ATTR, 15.5 in wild-type ATTR). The risk of developing CA was greater in ATTR patients with CTS; the probability of having CTS was highest 5-9 years prior to CA diagnosis. CTS was an independent mortality risk factor in ATTR. CONCLUSIONS: Compared to general population the adjusted prevalence of CTS is higher among elderly men with ATTR; CTS is a prognostic marker in ATTR, independently of cardiac involvement, and precedes CA diagnosis by 5-9 years. The awareness of this association and time delay offers the possibility of an early pre-clinical ATTR-CA diagnosis.

Phenotypic profile of Ile68Leu transthyretin amyloidosis: an underdiagnosed cause of heart failure.

AIMS: Cardiac amyloidosis remains a great challenge for the cardiologist. One of the three main aetiological forms, transthyretin-related hereditary amyloidosis (ATTRm), can present with several phenotypes, depending mainly on the specific mutation. We aimed to characterize the phenotype of patients with ATTRm due to Ile68Leu mutation, comparing them to patients with wild-type transthyretin amyloidosis (ATTRwt). METHODS AND RESULTS: Data of 67 Ile68Leu ATTRm patients from two Italian referral centres (Bologna and Florence) were retrospectively analysed and compared to those of 82 ATTRwt patients. Fifty-five unaffected mutation carriers were also analysed. Cumulative disease onset was 50% at age 71. A total of 56/67 (84%) patients had a predominantly cardiac phenotype at presentation with concentric increase in left ventricular wall thickness [median 17 mm], and normal or near normal left ventricular ejection fraction (79% of patients). Low QRS voltages were present only in 29% of patients but voltage/mass ratio was low (0.5). Carpal tunnel syndrome was noted in 43%. The overall phenotypic profile was similar to ATTRwt but Ile68Leu ATTRm patients typically presented younger (median 71 vs. 78 years) and were more likely to have (mild) symptomatic neurological involvement (19% vs. 2%). Male prevalence was 44% in unaffected mutation carriers and 78% in affected patients. Age-adjusted survival was comparable between groups. CONCLUSIONS: Ile68Leu ATTRm is a cause of familial amyloidotic cardiomyopathy endemic in central-northern Italy and presents as hypertrophic/restrictive cardiomyopathy quite similar to ATTRwt. Male preponderance is present in affected patients but not in unaffected mutation carriers. Age-adjusted survival is similar to ATTRwt.

Clinical characteristics of wild-type transthyretin cardiac amyloidosis: disproving myths.

AIMS: Wild-type transthyretin amyloidosis (ATTRwt) is mostly considered a disease predominantly of elderly male, characterized by concentric LV hypertrophy, preserved LVEF, and low QRS voltages. We sought to describe the characteristics of a large cohort of ATTRwt patients to better define the disease. METHODS AND RESULTS: Clinical findings of consecutive ATTRwt patients diagnosed at 2 centres were reviewed. ATTRwt was diagnosed histologically or non-invasively (LV hypertrophy ≥12 mm, intense cardiac uptake at 99mTc-DPD scintigraphy and AL exclusion). Mutations in TTR were excluded in all cases. The study cohort comprised 108 patients (78.6 ± 8 years); 67 (62%) diagnosed invasively and 41 (38%) non-invasively. Twenty patients (19%) were females. An asymmetric hypertrophy pattern was observed in 25 (23%) patients. Mean LVEF was 52 ± 14%, with 39 patients (37%) showing a LVEF < 50%. Atrial fibrillation (56%) and a pseudo-infarct pattern (63%) were the commonest ECG findings. Only 22 patients fulfilled QRS low-voltage criteria while 10 showed LV hypertrophy on ECG. Although heart failure was the most frequent profile leading to diagnosis (68%), 7% of individuals presented with atrioventricular block and 11% were diagnosed incidentally. Almost one third (35; 32%) were previously misdiagnosed. CONCLUSION: The clinical spectrum of ATTRwt is heterogeneous and differs from the classic phenotype: women are affected in a significant proportion; asymmetric LV hypertrophy and impaired LVEF are not rare and only a minority have low QRS voltages. Clinicians should be aware of the broad clinical spectrum of ATTRwt to correctly identify an entity for which a number of disease-modifying treatments are under investigation.