Amyloidogenic genetic variant not associated with increased mortality in blacks

1. Among black American carriers of the amyloidogenic V122I transthyretin variant, there was no increased mortality compared to noncarriers over 21.5 years of follow-up.

2. Carriers of the V122I transthyretin variant experienced slight systolic and diastolic dysfunction and higher NT-proBNP levels when compared to noncarriers. 

Evidence Rating Level: 1 (Excellent)

Study Rundown: Systemic amyloidoses are a family of diseases induced by misfolded or misassembled proteins. Extracellular deposition of these proteins as soluble or insoluble cross b-pleated sheets disrupts vital organ function. In particular, the amyloidogenic V122I transthyretin (TTR) variant has been shown to hinder adequate cardiac function and has been associated with late-onset restrictive amyloid cardiomyopathy in previous studies. This is most apparent in the elderly black population in America. These infiltrates have been linked to pathological effects in the heart including progressive diastolic and/or systolic dysfunction.

In this study, researchers assessed clinical profiles, mortality, and risk of incident heart failure in male and female elderly black Americans who were carriers for the genetically significant variant of V122I TTR. Although it is typical for heart failure to develop progressively in conventional amyloid cardiomyopathy, there are limited published resources and reports about this particular high-risk population. Importantly, contrary to the few published reports about the V122I TTR variant and the perceived higher mortality in black carriers, the researchers did not detect a higher mortality among carriers after 21.5 years of follow-up. However, researchers did find a significantly higher incidence of heart failure among carriers of the V122I variant. It is important to note the relatively low number of male carriers included in the study. Overall, there were few documented V122I carriers included in the study (in an absolute sense), which limited the analysis.

Click to read the study, published today in NEJM

Relevant Reading:Amyloid heart disease

In-Depth [prospective cohort]: In this study, researchers recruited 3,856 black participants, of whom 124 were genetically confirmed to be carriers of the nonsynonymous V122I TTR variant (rs76992529). Participants underwent periodic follow-up every 3 years through 1998. This was followed by functional and structural echocardiographic studies and collection of a broad range of laboratory data. It was observed that there were no significant differences between the non-carriers and carriers with respect to laboratory and clinical characteristics, and most importantly, no significant differences in the prevalence of cardiovascular risk factors and history of heart failure; the only exception was the finding that carriers had a significantly higher level of N-terminal pro-brain natriuretic peptide (NT-proBNP). The central finding was the fact that there was no significant difference observed between the two populations in terms of mortality (P=0.97). The hazard ratios for death and heart failure among carriers as compared with noncarriers were 1.20 (95%, CI, 0.77 to 1.86) and 1.54 (95% CI, 0.88 to 2.71), respectively, among men and 0.84 (95% CI, 0.54 to 1.32) and 1.42 (95% CI, 0.89 to 2.26), respectively, among women.

In conclusion, although black American carriers of the V122I TTR genetic variant had subtle abnormalities of systolic and diastolic dysfunction as well as a higher NT-proBNP levels than the noncarriers, this group did not experience a higher mortality rate.

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