Subclinical Transthyretin Cardiac Amyloidosis in V122I TTR Carriers | oneAMYLOIDOSISvoice
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Subclinical Transthyretin Cardiac Amyloidosis in V122I TTR Carriers

information clé

numéro d'identification de l'étude : NCT05489549

condition: Amyloidosis, Hereditary, Amyloidosis Cardiac, Amyloidosis, Familial, Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy, Transthyretin Gene Mutation

statut: Recrutement

objectif:

Approximately 1.5 million of the 44 million Blacks in the United States are carriers of the valine-to-isoleucine substitution at position 122 (V122I) in the transthyretin (TTR) protein. Virtually exclusive to Blacks, this is the most common cause of hereditary cardiac amyloidosis (hATTR-CA) worldwide. hATTR-CA leads to worsening heart failure (HF) and premature death. Fortunately, new therapies that stabilize TTR improve morbidity and mortality in hATTR-CA, especially when prescribed early in the disease. However, hATTR-CA is often diagnosed at an advanced stage and conventional diagnostic tools lack diagnostic specificity to detect early disease.

The overall objectives of this study are to determine the presence of subclinical hATTR-CA and to identify biomarkers that indicate amyloid progression in V122I TTR carriers. The central hypothesis of this proposal is that hATTR-CA has a long latency period that will be detected through subclinical amyloidosis imaging and biomarker phenotyping.

The central hypothesis will be tested by pursuing 2 specific aims: Aim 1) determine the association of V122I TTR carrier status with CMRI evidence of amyloid infiltration; Sub-aim 1) determine the association of V122I TTR carrier status with cardiac reserve; Aim 2) determine the association between amyloid-specific biomarkers and V122I TTR carrier status; and Sub-aim 2) determine the association of amyloid-specific biomarkers with imaging-based parameters and evaluate their diagnostic utility for identifying subclinical hATTR-CA. In Aim 1, CMRI will be used to compare metrics associated with cardiac amyloid infiltration between a cohort of V122I TTR carriers without HF formed by cascade genetic testing and age-, sex-, and race-matched non-carrier controls. For Sub-Aim 1, a sub-sample of carriers and non-carrier controls enrolled in Aim 1 will undergo novel exercise CMRI to measure and compare cardiac systolic and diastolic reserve. Aim 2 involves measuring and comparing amyloid-specific biomarkers in V122I TTR carriers without HF with samples matched non-carriers (both from Aim 1) and individuals with symptomatic V122I hATTR-CA from our clinical sites. These biomarkers detect and quantify different processes of TTR amyloidogenesis and include circulating TTR, retinol binding protein 4, TTR kinetic stability, and misfolded TTR oligomers. Sub-aim 2 will establish the role of these biomarkers to detect imaging evidence of subclinical hATTR-CA disease.

résultats: https://clinicaltrials.gov/ct2/show/results/NCT05489549

dernière mise à jour: 22 février 2024

détails de l'étude

date de début: 21 novembre 2022

achèvement estimée: Le 30 juin 2027

dernière mise à jour: 1 août 2023

taille / inscription: 500

résultats principaux :

  • (Aim 1) Evidence of amyloid infiltration as measured by ECV
    ECV expansion represents interstitial expansion from amyloid infiltration and greater levels can distinguish amyloidosis from other hypertrophic cardiomyopathies and correlate with cardiac amyloidosis disease severity.
  • At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
    (Sub-aim 1) Δ stroke volume index (ΔSVi)
    We will measure and compare ΔSVi (%) from rest to peak stress in V122I TTR carriers and non-carrier controls. Participants will exercise within the bore of the magnet using an MR compatible ergometer with adjustable electronic resistance (Ergospect Cardio-Stepper, Ergospect). Cardiac imaging will be performed at rest and during exercise at 25% (low intensity), 50% (moderate intensity), and 66% (heavy intensity) of maximal predicted work rate. Workloads will be maintained for ~5 min at each stage - 3 min to achieve a physiological steady-state and then 2 minutes for image acquisition.
  • At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern

résultats secondaires :

  • (Aim 1) Late gadolinium enhancement
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
  • (Aim 1) Native T1 and T2 mapping
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
  • (Aim 1) Post-gadolinium T1 signal intensity
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
  • (Aim 1) High resolution cardiac cine imaging for cardiac morphology
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
  • (Aim 1) High resolution cardiac cine imaging for global systolic function as ejection fraction
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
  • (Aim 1) High resolution cardiac cine imaging for global systolic function as fractional area change
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
  • (Aim 1) High resolution cardiac cine imaging for global systolic function via novel feature tracking
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
  • (Aim 1) High resolution cardiac cine imaging for global diastolic function via novel feature tracking.
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
  • (Aim 1) LV strain from magnetic resonance tissue tagging
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
  • (Aim 1) Phase contrast MRI to assess diastolic function by measurement of mitral inflow velocities.
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
  • (Aim 1) Phase contrast MRI to assess diastolic function by calculating the E/e' strain rate.
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
  • (Sub-aim 1) End diastolic volume index (EDVi, ml/m2) in all 4 chambers
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
  • (Sub-aim 1) End systolic volume index (ESVi, ml/m2) in all 4 chambers
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
  • (Sub-aim 1) Stroke volume index (SVi, ml/m2, ΔSVi is the primary outcome) in all 4 chambers
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
  • (Sub-aim 1) Ejection fraction (LVEF, %) in all 4 chambers
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
  • (Sub-aim 1) Longitudinal strain (LS, %)
    At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
  • (Aim 2) TTR concentration
    At baseline for all three cohorts
  • (Aim 2) RBP4 concentration
    At baseline for all three cohorts
  • (Aim 2) Concentration of circulating misfolded TTR oligomers
    At baseline for all three cohorts
  • (Aim 2) TTR kinetic stability
    At baseline for all three cohorts

Critère d'intégration:

• Âges admissibles : 30 - 80
• Sexes admissibles : tous
(V122I TTR carriers (or matched non-carriers))

Critère d'intégration:

Men and women ages 30-80 who are V122I TTR carriers (or matched non-carriers) without history of HF (this will be assessed by study personnel) and defined as: a) No history of hospitalization within the previous 12 months for management of HF; b) Without an elevated B-type natriuretic peptide level ≥100 pg/mL or NT-proBNP ≥360 pg/mL within the previous 12 months; or c) No clinical diagnosis of HF from a treating clinician
Consentement éclairé signé

critère d'exclusion: Critères:

A self-reported history or clinical history of HF
Other known causes of cardiomyopathy
History of light-chain cardiac amyloidosis
Prior type 1 myocardial infarction (non-ST segment elevation myocardial Infarction {NSTEMI} or ST-elevation myocardial infarction {STEMI})
Transplantation cardiaque
Body weight >250 lbs
Estimated glomerular filtration rate ≤30 mL/min/1.73 m2
Inability to safely undergo CMRI

(For participants with symptomatic V122I hATTR-CA, we will enroll probands with HF from Aim 1 or patients with symptomatic V122I hATTR-CA from the three study sites.)

Critère d'intégration:

Men and women ages 30-80 who have symptomatic V122I hATTR-CA as determined by a history of HF (this will be assessed by study personnel) and defined as: a) History of hospitalization within the previous 12 months for management of HF; b) An elevated B-type natriuretic peptide level ≥100 pg/mL or NT-proBNP ≥360 pg/mL within the previous 12 months; or c) A clinical diagnosis of HF from a treating clinician.
Have an established diagnosis of hATTR-CA based on either a) Biopsy confirmed by Congo red (or equivalent) staining with tissue typing with immunohistochemistry or mass spectrometric analysis or immunoelectron microscopy, OR b) positive technetium-99m (99mTc)-pyrophosphate or -bisphosphonate scan, combined with accepted laboratory criteria without abnormal M-protein.
TTR gene sequencing confirming the V122I variant
Consentement éclairé signé

parrainer: Université de Southwestern Medical Center

contacts: Carolyn Kelly, RN MPH CCRC, 214-645-8040, [email protected]

les enquêteurs: Justin L Grodin, MD MPH,UT Southwestern

emplacements des centres d'essai : États-Unis

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