Original Investigation
Genotype and Phenotype of Transthyretin Cardiac Amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey)

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Abstract

Background

Transthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis.

Objectives

The goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry.

Methods

Demographic, clinical, and genetic features of patients enrolled in the THAOS registry in the United States (n = 390) were compared with data from patients from other regions of the world (ROW) (n = 2,140). The focus was on the phenotypic expression and survival in the majority of U.S. subjects with valine-to-isoleucine substitution at position 122 (Val122Ile) (n = 91) and wild-type ATTR (n = 189).

Results

U.S. subjects are older (70 vs. 46 years), more often male (85.4% vs. 50.6%), and more often of African descent (25.4% vs. 0.5%) than the ROW. A significantly higher percentage of U.S. patients with ATTR amyloid seen at cardiology sites had wild-type disease than the ROW (50.5% vs. 26.2%). In the United States, 34 different mutations (n = 201) have been reported, with the most common being Val122Ile (n = 91; 45.3%) and Thr60Ala (n = 41; 20.4%). Overall, 91 (85%) of 107 patients with Val122Ile were from the United States, where Val122Ile subjects were younger and more often female and black than patients with wild-type disease, and had similar cardiac phenotype but a greater burden of neurologic symptoms (pain, numbness, tingling, and walking disability) and worse quality of life. Advancing age and lower mean arterial pressure, but not the presence of a transthyretin mutation, were independently associated with higher mortality from a multivariate analysis of survival.

Conclusions

In the THAOS registry, ATTR in the United States is overwhelmingly a disorder of older adult male subjects with a cardiac-predominant phenotype. Val122Ile is the most common transthyretin mutation, and neurologic phenotypic expression differs between wild-type disease and Val122Ile, but survival from enrollment in THAOS does not. (Transthyretin-Associated Amyloidoses Outcome Survey [THAOS]; NCT00628745)

Key Words

aging
amyloid
transthyretin

Abbreviations and Acronyms

ATTR
transthyretin amyloidosis
BMI
body mass index
EDV
end-diastolic volume
HFpEF
heart failure in the setting of a preserved ejection fraction
LV
left ventricular
LVEDD
left ventricular end-diastolic dimension
mBMI
modified body mass index
MCF
myocardial contraction fraction
mt-ATTR
mutated or hereditary transthyretin amyloidosis
QOL
quality of life
ROW
other regions of the world
SV
stroke volume
TTR
transthyretin
TTR-CM
transthyretin cardiomyopathy
Val122Ile
valine-to-isoleucine substitution at position 122
wt-ATTR
wild-type transthyretin amyloidosis

Cited by (0)

Data for this manuscript were derived from the THAOS registry, which is sponsored by Pfizer Inc. Dr. Coelho's institution received support from FoldRx Pharmaceuticals, which was acquired by Pfizer in October 2010; has served on the scientific advisory board of Pfizer and received funding from Pfizer for scientific meeting expenses (travel, accommodation, and registration); currently serves on the scientific advisory board of THAOS. Dr. Damy has received grants and consulting fees from Pfizer. Dr. Dispenzieri has received research dollars from Celgene, Millennium, Pfizer, and Janssen; she has also received funding from Pfizer for meeting expenses (travel). Dr. Witteles has served as a site Principal Investigator for transthyretin trials for Pfizer and Alnylam. Drs. Gottlieb and Hummel have received research funding from Pfizer. Dr. Judge has served as an advisor to Pfizer and GlaxoSmithKline. Dr. Kristen has received research support from and served on advisory boards for Pfizer; and currently serves on the scientific advisory board of THAOS. Dr. Maurer has received support from FoldRx Pharmaceuticals as a clinical investigator and for scientific meeting expenses; his institution has received grant support from Pfizer; has served on the scientific advisory board of and received funding from Pfizer for scientific meeting expenses (travel, accommodation, and registration). Dr. Planté-Bordeneuve received support from FoldRx Pharmaceuticals as a clinical investigator and serves on the THAOS scientific advisory board but did not receive compensation for this involvement. Dr. Rapezzi received research grants and consultant and speaker honoraria from Pfizer. Dr. Shah has received consulting fees from Alnylam. Dr. Silver is a speaker for Amgen and serves on the advisory board for Legacy Heart Care. Dr. Suhr receives support as a clinical investigator financed by Pfizer and Alnylam; his department has received payment for lecturing and participating in educational activities financed by Pfizer. Dr. Waddington Cruz received support from FoldRx Pharmaceuticals as a clinical investigator and has served on the scientific advisory board of Pfizer; currently serves on the THAOS scientific advisory board. Mr. Mundayat is an employee of and holds stock options in Pfizer. Dr. Ventura’s institution has received support from Pfizer for a clinical trial. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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