The Amyloidogenic V122I Transthyretin Variant in Elderly Black Americans

Abstract

BACKGROUND Approximately 4% of black Americans carry a valine-to-isoleucine substitution (V122I) in the transthyretin protein, which has been associated with late-onset restrictive amyloid cardiomyopathy and increased risks of death and heart failure. METHODS We determined genotype status for the transthyretin gene (TTR) in 3856 black participants in the Atherosclerosis Risk in Communities study and assessed clinical profiles, mortality, and the risk of incident heart failure in V122I TTR variant carriers (124 participants [3%]) versus noncarriers (3732 participants). Cardiac structure and function and features suggestive of cardiac amyloidosis were assessed in participants who underwent echocardiography during visit 5 (2011 to 2013), when they were older than 65 years of age. RESULTS After 21.5 years of follow-up, we did not detect a significant difference in mortality between carriers (41 deaths, 33%) and noncarriers (1382 deaths, 37%; age- and sex-stratified hazard ratio among carriers, 0.99; 95% confidence interval [CI], 0.73 to 1.36; P = 0.97). The TTR variant was associated with an increased risk of incident heart failure (age- and sex-stratified hazard ratio, 1.47; 95% CI, 1.03 to 2.10; P = 0.04). On echocardiography at visit 5, carriers (46 participants) had worse systolic and diastolic function, as well as a higher level of N-terminal pro–brain natriuretic peptide, than noncarriers (1194 participants), although carriers had a low prevalence (7%) of overt manifestations of amyloid cardiomyopathy. CONCLUSIONS We did not detect a significant difference in mortality between V122I TTR allele carriers and noncarriers, a finding that contrasts with prior observations; however, the risk of heart failure was increased among carriers. The prevalence of overt cardiac abnormalities among V122I TTR carriers was low. (Funded by the National Heart, Lung, and Blood Institute and others.)

Afro-Caribbean Heart Failure in the United Kingdom

“…The recently reported longitudinal Atherosclerosis Risk in Communities study failed to demonstrate a significant difference in mortality between 124 V122I TTR variant carriers (3%) and 3732 noncarriers, but the incidence of heart failure was higher in allele carriers and median age of carriers at final follow-up is younger than the median age of presentation for ATTR V122I and low proportions of men were included or followed up to visit 5. 27 Wildtype ATTR amyloidosis is reported to be an increasingly important cause of heart failure with preserved EF and has been shown to be the primary cause in up to 13% of patients of all ethnicities. 28 The geographic origins of the ATTR V122I patients reported here is consistent with a founder mutation in West Africa.…”

Cardiac amyloidosis: the great pretender

“…The largest cluster of individuals with ATTR caused by the Val30Met mutation may be found in northern Portugal [7], where the incidence is estimated to be one in 538 individuals [8]. In the USA, V122I is the most frequent cause of hereditary ATTR (prevalence ranging 3-3.9 % in African Americans) [9], leading to a late onset CA or to an increased risk of incident heart failure among African Americans [10].…”

Amyloid heart disease: genetics translated into disease-modifying therapy

“…Long-term propensity matched analysis from ARIC-evaluated cardiac structure, function and outcomes in carriers versus non-carriers—after 21.5 years of follow-up, patients carrying the Val122Ile mutation were more likely to develop incident heart failure without a difference in mortality. In addition, markers of systolic (global longitudinal strain) and diastolic function (by tissue Doppler imaging) were more impaired in Val122Ile carriers, along with greater left ventricular wall thickness and higher N-terminal pro b-type natriuretic peptide at 5 years 16. Val122Ile was also noted to be a common aetiology of heart failure in this population in Europe, where it constituted the fourth highest prevalence in Afro-Carribean patients in the United Kingdom (8.5%) and demonstrated the worst prognosis compared with other aetiologies of heart failure 17…”