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

Razvi, Yousuf; Ioannou, Adam; Patel, Rishi K.; Chacko, Liza; Karia, Nina; Riefolo, Mattia; Porcari, Aldostefano; Rauf, Muhammad Umaid; Starr, Neasa; Ganesananthan, Sashiananthan; Blakeney, Iona; Kaza, Nandita; Filisetti, Stefano; Bolhuis, Roos Eline; Rowczenio, Dorota; Gilbertson, Janet; Hutt, David; Mahmood, Shameem; Lachmann, Helen J.; Wechalekar, Ashutosh D.; Kotecha, Tushar; Knight, Daniel S.; Coghlan, John G.; Petrie, Aviva; Whelan, Carol J.; Venneri, Lucia; Martinez‐Naharro, Ana; Hawkins, Phillip; Fontana, Marianna; Gillmore, Julian D.

doi:10.1002/ejhf.3088

Cited by 7 publications

(10 citation statements)

References 27 publications

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“…Over recent years, it has become apparent that V122I-associated ATTRv-CM represents a particularly severe form of cardiac ATTR amyloidosis with poorer outcomes compared with other genotypic variants, including wild-type ATTR-CM. 19,[33][34][35] The present data need to be interpreted within the limitations of the study. This retrospective study was conducted in referral centers for the diagnosis and management of ATTR-CM.…”

Section: Discussionmentioning

confidence: 95%

Clinical and Prognostic Implications of Right Ventricular Uptake on Bone Scintigraphy in Transthyretin Amyloid Cardiomyopathy

Porcari,

Fontana,

Canepa

et al. 2024

Circulation

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BACKGROUND: The extent of myocardial bone tracer uptake with technetium pyrophosphate, hydroxymethylene diphosphonate, and 3,3-diphosphono-1,2-propanodicarboxylate in transthyretin amyloid cardiomyopathy (ATTR-CM) might reflect cardiac amyloid burden and be associated with outcome. METHODS: Consecutive patients with ATTR-CM who underwent diagnostic bone tracer scintigraphy with acquisition of whole-body planar and cardiac single-photon emission computed tomography (SPECT) images from the National Amyloidosis Centre and 4 Italian centers were included. Cardiac uptake was defined according to the Perugini classification: 0=absent cardiac uptake; 1=mild uptake less than bone; 2=moderate uptake equal to bone; and 3=high uptake greater than bone. Extent of right ventricular (RV) uptake was defined as focal (basal segment of the RV free wall only) or diffuse (extending beyond basal segment) on the basis of SPECT imaging. The primary outcome was all-cause mortality. RESULTS: Among 1422 patients with ATTR-CM, RV uptake accompanying left ventricular uptake was identified by SPECT imaging in 100% of cases at diagnosis. Median follow-up in the whole cohort was 34 months (interquartile range, 21 to 50 months), and 494 patients died. By Kaplan-Meier analysis, diffuse RV uptake on SPECT imaging (n=936) was associated with higher all-cause mortality compared with focal (n=486) RV uptake (77.9% versus 22.1%; P <0.001), whereas Perugini grade was not associated with survival ( P =0.27 in grade 2 versus grade 3). On multivariable analysis, after adjustment for age at diagnosis (hazard ratio [HR], 1.03 [95% CI, 1.02–1.04]; P <0.001), presence of the p.(V142I) TTR variant (HR, 1.42 [95% CI, 1.20–1.81]; P =0.004), National Amyloidosis Centre stage (each category, P <0.001), stroke volume index (HR, 0.99 [95% CI, 0.97–0.99]; P =0.043), E/e’ (HR, 1.02 [95% CI, 1.007–1.03]; P =0.004), right atrial area index (HR, 1.05 [95% CI, 1.02–1.08]; P =0.001), and left ventricular global longitudinal strain (HR, 1.06 [95% CI, 1.03–1.09]; P <0.001), diffuse RV uptake on SPECT imaging (HR, 1.60 [95% CI, 1.26–2.04]; P <0.001) remained an independent predictor of all-cause mortality. The prognostic value of diffuse RV uptake was maintained across each National Amyloidosis Centre stage and in both wild-type and hereditary ATTR-CM ( P <0.001 and P =0.02, respectively). CONCLUSIONS: Diffuse RV uptake of bone tracer on SPECT imaging is associated with poor outcomes in patients with ATTR-CM and is an independent prognostic marker at diagnosis.

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Section: Discussionmentioning

confidence: 95%

Clinical and Prognostic Implications of Right Ventricular Uptake on Bone Scintigraphy in Transthyretin Amyloid Cardiomyopathy

Porcari,

Fontana,

Canepa

et al. 2024

Circulation

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“…Indeed, V142Iassociated ATTRv-CA presents with greater disease severity (including lower left ventricular EF) and faster disease progression compared with both ATTRwt-CA and non-V142I ATTRv-CA. 27,28 Recent data from a clinical trial in ATTR-CA supported the presence of reduced EF in a significant proportion of patients with a tendency to progress in ATTR-CA. 29 Therefore, among Black hospitalized patients with HFrEF, suspicion for ATTR-CA should be heightened and not restricted to patients with preserved EF.…”

Section: Discussionmentioning

confidence: 99%

Cardiovascular Burden of the V142I Transthyretin Variant

Selvaraj,

Claggett,

Shah

et al. 2024

JAMA

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ImportanceIndividual cohort studies concur that the amyloidogenic V142I variant of the transthyretin (TTR) gene, present in 3% to 4% of US Black individuals, increases heart failure (HF) and mortality risk. Precisely defining carrier risk across relevant clinical outcomes and estimating population burden of disease are important given established and emerging targeted treatments.ObjectivesTo better define the natural history of disease in carriers across mid to late life, assess variant modifiers, and estimate cardiovascular burden to the US population.Design, Setting, and ParticipantsA total of 23 338 self-reported Black participants initially free from HF were included in 4 large observational studies across the US (mean [SD], 15.5 [8.2] years of follow-up). Data analysis was performed between May 2023 and February 2024.ExposureV142I carrier status (n = 754, 3.2%).Main Outcomes and MeasuresHospitalizations for HF (including subtypes of reduced and preserved ejection fraction) and all-cause mortality. Outcomes were analyzed by generating 10-year hazard ratios for each age between 50 and 90 years. Using actuarial methods, mean survival by carrier status was estimated and applied to the 2022 US population using US Census data.ResultsAmong the 23 338 participants, the mean (SD) age at baseline was 62 (9) years and 76.7% were women. Ten-year carrier risk increased for HF hospitalization by age 63 years, predominantly driven by HF with reduced ejection fraction, and 10-year all-cause mortality risk increased by age 72 years. Only age (but not sex or other select variables) modified risk with the variant, with estimated reductions in longevity ranging from 1.9 years (95% CI, 0.6-3.1) at age 50 to 2.8 years (95% CI, 2.0-3.6) at age 81. Based on these data, 435 851 estimated US Black carriers between ages 50 and 95 years are projected to cumulatively lose 957 505 years of life (95% CI, 534 475-1 380 535) due to the variant.Conclusions and RelevanceAmong self-reported Black individuals, male and female V142I carriers faced similar and substantial risk for HF hospitalization, predominantly with reduced ejection fraction, and death, with steep age-dependent penetrance. Delineating the individual contributions of, and complex interplay among, the V142I variant, ancestry, the social construct of race, and biological or social determinants of health to cardiovascular disease merits further investigation.

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“…Moreover, it was found that homozygous patients with ATTRv cardiomyopathy were diagnosed at a younger age, suggesting an early disease onset and a more aggressive disease compared to heterozygous patients. 5 However, these results should be interpreted with caution due to the low number of homozygous patients, warranting the need for large cohort studies to validate this result.…”

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confidence: 89%

“…For example, in a cohort of patients with biopsy-proven ATTR cardiomyopathy, 9.6% of patients were homozygous for the p.V142I variant. 12 Similarly, Razvi et al 5 found a higher prevalence of homozygosity among patients with ATTR cardiomyopathy, representing 5.5% of the entire cohort. Moreover, it was found that homozygous patients with ATTRv cardiomyopathy were diagnosed at a younger age, suggesting an early disease onset and a more aggressive disease compared to heterozygous patients.…”

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confidence: 92%

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Expanding the knowledge on transthyretin p.V142I variant‐related cardiomyopathy

Monda,

Limongelli

2024

European J of Heart Fail

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This article refers to 'Deep phenotyping of p.(V142I)associated variant transthyretin amyloid cardiomyopathy: Distinct from wild-type transthyretin amyloidosis?' by Y. Razvi et al., published in this issue on pages 383-393.Transthyretin amyloidosis (ATTR) is a condition characterized by the extracellular deposition of insoluble protein fibrils within various organs and tissues. 1 Two distinct forms of ATTR have been identified: variant ATTR (ATTRv) and wild-type ATTR (ATTRwt; also referred to as senile amyloidosis). 1,2 ATTRv is a genetic disorder inherited in an autosomal dominant manner, resulting from a pathogenic variant in the TTR gene. 3 To date, more than 140 gene variants have been associated with ATTRv, categorized into cardiac, neurological, and mixed forms based on the clinical phenotype. 3 A deeper understanding of genotype-phenotype correlations in ATTRv is essential for early disease identification, predicting adverse outcomes, and guiding management with approved and upcoming disease-modifying therapies.The p.V142I, the most common identified TTR variant, is significantly prevalent among individuals of African ancestry, being associated with poor outcome. 4 In recent years, significant advancements have been made in understanding the prevalence, clinical phenotypes, and outcomes in patients with p.V142I-associated ATTR (Figure 1). The paper of Razvi et al., 5 published in this issue of the Journal, represents another step forward in the comprehensive understanding of this complex disease.According to the Genome Aggregation Database (GnomAD), the prevalence of p.V142I variant in the general population is estimated to be 0.3%, making it the most common cause of ATTRv and explaining 88% of cases. 6 However, data from study cohorts and genetic biobanks suggest that the prevalence of p.V142I variant is higher among people of African descent, ranging from 1.1% to 9.8%. In a large study population consisting of 9862 non-Hispanic Black/African American women, 3.4% of individuals carried the p.V142I variant, and its presence was associated with a higher risk of coronary artery disease, stroke, acute heart failure (HF), and cardiovascular and all-cause death. 7

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

Cited by 7 publications

References 27 publications

Clinical and Prognostic Implications of Right Ventricular Uptake on Bone Scintigraphy in Transthyretin Amyloid Cardiomyopathy

Clinical and Prognostic Implications of Right Ventricular Uptake on Bone Scintigraphy in Transthyretin Amyloid Cardiomyopathy

Cardiovascular Burden of the V142I Transthyretin Variant

Expanding the knowledge on transthyretin p.V142I variant‐related cardiomyopathy

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