Dataset Information

Sex Differences in the Phenotype of Transthyretin Cardiac Amyloidosis Due to Val122Ile Mutation: Insights from Noninvasive Pressure-Volume Analysis.

ABSTRACT:

Background

Transthyretin cardiac amyloidosis (ATTR-CA) is an under-recognized cause of heart failure with preserved ejection fraction. In the United States, the valine-to-isoleucine substitution (Val122Ile) is the most common inherited variant. Data on sex differences in presentation and outcomes of Val122Ile associated ATTR-CA are lacking.

Methods and results

In a retrospective, single-center study of 73 patients diagnosed with Val122Ile associated ATTR-CA between 2001 and 2018, sex differences in clinical and echocardiographic data at the time of diagnosis were evaluated. Pressure-volume analysis using noninvasive single beat techniques was used to compare chamber performance. Compared with men (n = 46), women (n = 27) were significantly older at diagnosis, 76 years vs 69 years; P < .001. The end-systolic pressure-volume relationship, 5.1 mm Hg*m²/mL vs 4.3 mm Hg*m²/mL; P = .27, arterial elastance, 5.5 mm Hg*m²/mL vs 5.7 mm Hg*m²/mL; P = .62, and left ventricular capacitance were similar between sexes as was pressure-volume areas indexed to a left ventricular end-diastolic pressure of 30 mm Hg, a measure of overall pump function. The 3-year mortality rates were also similar, 34% vs 43%; P = .64.

Conclusions

Despite being significantly older at time of diagnosis with Val122Ile associated ATTR-CA, women have similar overall cardiac chamber function and rates of mortality to men, suggesting a less aggressive disease trajectory. These findings should be confirmed with longitudinal studies.

SUBMITTER: Batra J

PROVIDER: S-EPMC7869136 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Sex Differences in the Phenotype of Transthyretin Cardiac Amyloidosis Due to Val122Ile Mutation: Insights from Noninvasive Pressure-Volume Analysis.

Batra Jaya J Rosenblum Hannah H Defilippis Ersilia M EM Griffin Jan M JM Saith Sunil E SE Gamino Danilo D Teruya Sergio S Santos Jeffeny De Los JL Helmke Stephen S Burkhoff Daniel D Maurer Mathew S MS

Journal of cardiac failure 20200820 1

<h4>Background</h4>Transthyretin cardiac amyloidosis (ATTR-CA) is an under-recognized cause of heart failure with preserved ejection fraction. In the United States, the valine-to-isoleucine substitution (Val122Ile) is the most common inherited variant. Data on sex differences in presentation and outcomes of Val122Ile associated ATTR-CA are lacking.<h4>Methods and results</h4>In a retrospective, single-center study of 73 patients diagnosed with Val122Ile associated ATTR-CA between 2001 and 2018, ...[more]

PMID: 32829019

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Project description:BackgroundTransthyretin amyloidosis (ATTR) is a heterogeneous disorder with multiorgan involvement and a genetic or nongenetic basis.ObjectivesThe goal of this study was to describe ATTR in the United States by using data from the THAOS (Transthyretin Amyloidosis Outcomes Survey) registry.MethodsDemographic, 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).ResultsU.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.ConclusionsIn 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).

Project description:AimCardiac troponins and natriuretic peptides are established for risk stratification in light-chain amyloidosis. Data on cardiac biomarkers in transthyretin amyloidosis (ATTR) are lacking.Methods and resultsPatients (n = 1617) with any of the following cardiac biomarkers, BNP (n = 1079), NT-proBNP (n = 550), troponin T (n = 274), and troponin I (n = 108), available at baseline in the Transthyretin Amyloidosis Outcomes Survey (THAOS) were analyzed for differences between genotypes and phenotypes and their association with survival. Median level of BNP was 68.0 pg/mL (IQR 30.5-194.9), NT-proBNP 337.9 pg/mL (IQR 73.0-2584.0), troponin T 0.03 μg/L (IQR 0.01-0.05), and troponin I 0.08 μg/L (IQR 0.04-0.13). NT-proBNP and BNP were higher in wild-type than mutant-type ATTR, troponin T and I did not differ, respectively. Non-Val30Met patients had higher BNP, NT-proBNP and troponin T levels than Val30Met patients, but not troponin I. Late-onset Val30Met was associated with higher levels of troponin I and troponin T compared with early-onset. 115 patients died during a median follow-up of 1.2 years. Mortality increased with increasing quartiles (BNP/NT-proBNP Q1 = 1.7%, Q2 = 5.2%, Q3 = 21.7%, Q4 = 71.3%; troponin T/I Q1 = 6.5%, Q2 = 14.5%, Q3 = 33.9%, Q4 = 45.2%). Three-year overall-survival estimates for BNP/NT-proBNP and troponin T/I quartiles differed significantly (p<0.001). Stepwise risk stratification was achieved by combining NT-proBNP/BNP and troponin T/I. From Cox proportional hazards model, age, modified body mass index, mutation (Val30Met vs. Non-Val30Met) and BNP/NT-proBNP (Q1-Q3 pooled vs. Q4) were identified as independent predictors of survival in patients with mutant-type ATTR.ConclusionsIn this ATTR patient cohort, cardiac biomarkers were abnormal in a substantial percentage of patients irrespective of genotype. Along with age, mBMI, and mutation (Val30Met vs. Non-Val30Met), cardiac biomarkers were associated with surrogates of disease severity with BNP/NT-proBNP identified as an independent predictor of survival in ATTR.Trial registrationClinicalTrials.gov NCT00628745.

Project description:ImportanceA genetic variant in the TTR gene (rs76992529; Val122Ile), present more commonly in individuals with African ancestry (population frequency: 3%-4%), causes misfolding of the tetrameric transthyretin protein complex that accumulates as extracellular amyloid fibrils and results in hereditary transthyretin amyloidosis.ObjectiveTo estimate the association of the amyloidogenic Val122Ile TTR variant with the risk of heart failure and mortality in a large, geographically diverse cohort of Black individuals.Design, setting, and participantsRetrospective population-based cohort study of 7514 self-identified Black individuals living in the US participating in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study with genetic data available and without heart failure at baseline. The participants were enrolled at the baseline visit (2003-2007). The end of follow-up for the majority of outcomes was on December 31, 2018. All-cause mortality data were available through December 31, 2020.ExposuresTTR Val122Ile (rs76992529) genotype.Main outcome and measuresThe primary outcome was incident heart failure (first hospitalization for heart failure or death due to heart failure). The secondary outcomes were heart failure mortality, cardiovascular mortality, and all-cause mortality. The multivariable Cox proportional hazards regression analyses were adjusted for genetic ancestry and demographic, clinical, and social factors.ResultsAmong 7514 Black participants (median age, 64 years [IQR, 57-70 years]; 61% women), the population frequency of the TTR Val122Ile variant was 3.1% (232 variant carriers and 7282 noncarriers). During a median follow-up of 11.1 years (IQR, 5.9-13.5 years), incident heart failure occurred in 535 individuals (34 variant carriers and 501 noncarriers) and the incidence of heart failure was 15.64 per 1000 person-years among variant carriers vs 7.16 per 1000 person-years among noncarriers (adjusted hazard ratio [HR], 2.43 [95% CI, 1.71-3.46]; P < .001). Deaths due to heart failure occurred in 141 individuals (13 variant carriers and 128 noncarriers) and the incidence of heart failure mortality was 6.11 per 1000 person-years among variant carriers vs 1.85 per 1000 person-years among noncarriers (adjusted HR, 4.19 [95% CI, 2.33-7.54]; P < .001). Deaths due to cardiovascular causes occurred in 793 individuals (34 variant carriers and 759 noncarriers) and the incidence of cardiovascular death was 15.18 per 1000 person-years among variant carriers vs 10.61 per 1000 person-years among noncarriers (adjusted HR, 1.69 [95% CI, 1.19-2.39]; P = .003). Deaths due to any cause occurred in 2715 individuals (100 variant carriers and 2615 noncarriers) and the incidence of all-cause mortality was 41.46 per 1000 person-years among variant carriers vs 33.94 per 1000 person-years among noncarriers (adjusted HR, 1.46 [95% CI, 1.19-1.78]; P < .001). There was no significant interaction between TTR variant carrier status and sex on incident heart failure and the secondary outcomes.Conclusions and relevanceAmong a cohort of Black individuals living in the US, being a carrier of the TTR Val122Ile variant was significantly associated with an increased risk of heart failure.

Dataset Information

Sex Differences in the Phenotype of Transthyretin Cardiac Amyloidosis Due to Val122Ile Mutation: Insights from Noninvasive Pressure-Volume Analysis.

Background

Methods and results

Conclusions

Publications

Sex Differences in the Phenotype of Transthyretin Cardiac Amyloidosis Due to Val122Ile Mutation: Insights from Noninvasive Pressure-Volume Analysis.

Similar Datasets

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