V122I TTR Cardiac Amyloidosis in Patients of African Descent

Alexander, Kevin M.; Falk, Rodney H.

doi:10.1161/circheartfailure.116.003489

Cited by 7 publications

(8 citation statements)

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“…Indeed, large scale genomic studies have demonstrated a 3-4% mutation carrier rate in populations of African descent. 3 The UK National Amyloidosis Centre is the single nationwide centre specially commissioned for the assessment, diagnosis, and treatment of all patients with suspected amyloidosis. The Centre's database therefore represents a de facto national registry.…”

Section: Discussionmentioning

confidence: 99%

“…4 It is thus difficult to exclude a contribution to poor outcomes in p.(V142I)-ATTRv-CM from inequitable access to health care. 3,4 We hypothesized that p.(V142I)-associated ATTRv-CM has a biologically aggressive clinical phenotype and undertook a deep phenotyping study utilizing multiple modalities including, but not limited to, echocardiography, cardiac magnetic resonance (CMR), blood biomarkers and histology in the largest known cohort of patients with p.(V142I)-ATTRv-CM. A matched ATTRwt-CM comparator group was utilized to elicit any phenotypic differences between the two groups.…”

Section: Introductionmentioning

confidence: 99%

“…Over 130 pathogenic TTR mutations are known to cause ATTRv amyloidosis which is inherited in an autosomal dominant fashion 2 . The p.(V142I) variant is most often seen in patients of African ancestry, with a large scale genomic study undertaken in over 9000 African American individuals from the United States demonstrating a p.(V142I) carrier rate of 3.2% 3,4 . The exact disease penetrance of the mutation is unknown, but based on a carrier rate of 3.2% in tandem with estimates of the United States population, there are approximately 1.6 million African Americans that carry the p.(V142I) variant 5 …”

Section: Introductionmentioning

confidence: 99%

“…This is relevant in the context of novel therapies for ATTR amyloidosis for which the annual cost per patient ranges from $225 000 to $450 000 4 . It is thus difficult to exclude a contribution to poor outcomes in p.(V142I)‐ATTRv‐CM from inequitable access to health care 3,4 …”

Section: Introductionmentioning

confidence: 99%

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Deep phenotyping of p.(V142I)‐associated variant transthyretin amyloid cardiomyopathy: Distinct from wild‐type transthyretin amyloidosis?

Razvi,

Ioannou,

Patel

et al. 2024

European J of Heart Fail

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AimsTransthyretin amyloid cardiomyopathy (ATTR‐CM) is an increasingly recognised cause of heart failure. 3‐4% of individuals of African descent carry a TTR gene mutation encoding the p.(V142I) variant, a powerful risk factor for development of variant ATTR‐CM; this equates to 1.6 million carriers in the USA. We undertook deep phenotyping of p.(V142I)‐ATTRv‐CM and comparison with wild‐type ATTR‐CM (ATTRwt‐CM).Methods & ResultsA retrospective study of 413 patients with p.(V142I)‐associated ATTR‐CM (ATTRv‐CM) who attended the UK National Amyloidosis Centre was conducted. Patients underwent evaluation at time of diagnosis, including clinical, echocardiography, and biomarker analysis; a subgroup had cardiac magnetic resonance imaging (CMR). Four hundred and thirteen patients with wild‐type ATTR‐CM (ATTRwt‐CM), matched for independent predictors of prognosis (age, NAC Stage, decade of first presentation), were used as a comparator group.At time of diagnosis, patients with ATTRv‐CM had significant functional impairment by NYHA classification (NHYA ≥ III; 38%) and 6‐minute walk test distance (median 276 metres). Median 5‐year survival in ATTRv‐CM patients was 31 months vs 59 months in matched patients with ATTRwt‐CM (p<0.001). Patients with ATTRv‐CM had significant impairment of functional parameters by echocardiography including biventricular impairment, high burden of regurgitant valvular disease and low cardiac output. Multivariable analysis revealed the prognostic importance of RV dysfunction. CMR and histological analysis revealed myocyte atrophy and widespread myocardial infiltration in ATTRv‐CM.Conclusionp.(V142I)‐ATTRv‐CM has an aggressive phenotype characterised by myocyte loss and widespread myocardial infiltration which may account for frequent biventricular failure and poor prognosis in this ATTR‐CM genotypic subgroup.This article is protected by copyright. All rights reserved.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Deep phenotyping of p.(V142I)‐associated variant transthyretin amyloid cardiomyopathy: Distinct from wild‐type transthyretin amyloidosis?

Razvi,

Ioannou,

Patel

et al. 2024

European J of Heart Fail

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“…Affected patients with this genotype display a variable disease penetrance which is influenced by origin, gender, parental gene transmission, and age [ 1 , 15 ]. The most common variant involved in the cardiac form of hATTR is NM_000371.3:c.424G > A (p.Val142Ile) [ 16 , 17 ]. The NM_000371.3:c.238A > G (p.Thr80Ala) variant is another frequent cause of amyloid PNP and CM [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Hereditary transthyretin-related amyloidosis is frequent in polyneuropathy and cardiomyopathy of no obvious aetiology

et al. 2021

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Background Hereditary Transthyretin-Related Amyloidosis, a clinically heterogeneous autosomal dominant disease caused by pathogenic variants in the TTR gene, is characterized by the deposition of insoluble misfolded protein fibrils. The diagnosis, especially in non-endemic areas, is typically delayed by 4–5 years; a misdiagnosis due to clinical heterogeneity is common. The study objective was to define the prevalence of Hereditary Transthyretin-Related Amyloidosis in patients with polyneuropathy and/or cardiomyopathy of no obvious aetiology. Method A multicenter observational “Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis”—TRAM study was performed in Germany, Austria, and Switzerland. Results A total of 5141 participants were recruited by 50 neurologic and 27 cardiologic specialized centres. Genetic analysis demonstrated a 1.1% Hereditary Transthyretin-Related Amyloidosis positivity rate among patients with polyneuropathy and/or cardiomyopathy of not obvious aetiology. Twenty-one various TTR variants ( TTR -positive) were identified. Body Mass Index was lower in the TTR -positive patients as an indicator for the involvement of the autonomic nervous system; the age of onset of clinical manifestations was higher in TTR -positive patients. There were no other genotype-phenotype correlations or the prevalence of specific clinical manifestations in TTR -positive patients. Conclusions Our data support the fact that Hereditary Transthyretin-Related Amyloidosis is underdiagnosed in polyneuropathy and cardiomyopathy patients. Routine implementation of genetic testing is recommended in patients with unexplained polyneuropathy and/or cardiomyopathy to accelerate the earlier diagnosis and the time-sensitive treatment initiation. KEY MESSAGES More than 5.000 participants with CM and/or PNP of no obvious aetiology were recruited in the observational “Epidemiological analysis for the hereditary Transthyretin-Related AMyloidosis” TRAM study and screened for pathogenic TTR variants. The study demonstrated >1% of patients with CM and/or PNP of unclear aetiology are positive for a pathogenic TTR variant. Routine genetic testing is recommended in patients with unexplained CM and/or PNP to accelerate the initial diagnosis and timely treatment initiation.

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OBSOLETE: Stage A Heart Failure: Identification and Management of Heart Failure Risk Factors

Alexander¹,

Nayor²

2018

Reference Module in Biomedical Sciences

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V122I TTR Cardiac Amyloidosis in Patients of African Descent

Cited by 7 publications

References 10 publications

Deep phenotyping of p.(V142I)‐associated variant transthyretin amyloid cardiomyopathy: Distinct from wild‐type transthyretin amyloidosis?

Deep phenotyping of p.(V142I)‐associated variant transthyretin amyloid cardiomyopathy: Distinct from wild‐type transthyretin amyloidosis?

Hereditary transthyretin-related amyloidosis is frequent in polyneuropathy and cardiomyopathy of no obvious aetiology

OBSOLETE: Stage A Heart Failure: Identification and Management of Heart Failure Risk Factors

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