Subclinical Transthyretin Cardiac Amyloidosis in V122I TTR Carriers

NCT05489549 | Recruiting

• 2 other identifiers: STU-2022-04041R01HL160892-01A1
• Study Type: observational
• Target: 500
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

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

Keywords

Amyloidosis; Transthyretin Amyloidosis; V122I TTR; p.Val142Ile TTR; Cardiac magnetic resonance imaging

Outcome Measures

Primary Outcomes (2)

• (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

Secondary Outcomes (20)

• (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)

Other Outcomes (1)

• (Sub-aim 2) Associations between each biomarker from Aim 2 and CMRI measurements from Aim 1 and Sub-aim 1

  At baseline for all 3 cohorts and Visit 2 for V122I TTR carriers and age-, sex-, and race-matched controls

Study Arms (3)

V122I TTR carriers

Carriers and controls will undergo standardized, detailed CMRI assessments to test the hypothesis that V122I TTR carrier status will be associated with greater evidence of pathological amyloid progression in comparison with non-carriers. In addition to the CMRI assessments, carriers and controls enrolled at UT Southwestern will undergo standardized exercise CMRI assessments during the same study visit. V122I TTR carriers will undergo detailed biomarker assessments. These will be compared with controls and patients with symptomatic V122I hATTR-CA .

Age-, sex-, and race-matched non-carrier controls

Carriers and controls will undergo standardized, detailed CMRI assessments to test the hypothesis that V122I TTR carrier status will be associated with greater evidence of pathological amyloid progression in comparison with non-carriers. In addition to the CMRI assessments, carriers and controls enrolled at UT Southwestern will undergo standardized exercise CMRI assessments during the same study visit. Controls will undergo detailed biomarker assessments. These will be compared with V122I TTR carriers and patients with symptomatic V122I hATTR-CA .

Patients with symptomatic V122I hATTR-CA

Patients with symptomatic V122I hATTR-CA will undergo detailed biomarker assessments. These will be compared with V122I TTR carriers and controls.

Eligibility Criteria

• Age: 30 Years - 80 Years
• Sex: all
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

For Aim 1, the will be a cross-sectional cohort study of 200 V122I TTR carriers and 200 age-, sex- and race-matched non-carrier controls without heart failure. For Sub-aim 1, this will be a cross-sectional sub-study of the 2 groups enrolled in Aim 1 at UT Southwestern. For Aim 2, this will be a cross-sectional cohort study of 200 V122I TTR carriers without HF (see Aim 1, Approach), 200 age-, sex-, and race-matched controls (see Aim 1), and 100 patients with symptomatic V122I hATTR-CA who will undergo detailed biomarker assessments.

You may qualify if:

• 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
• Signed informed consent

You may not qualify if:

• 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})
• Cardiac transplantation
• 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 suspected symptomatic V122I hATTR-CA from the three study sites.)
• 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 or suspected 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 that is pending or that is confirming the V122I variant
• Signed informed consent
• Other known causes of cardiomyopathy
• History of light-chain cardiac amyloidosis

Sponsors & Collaborators

• University of Texas Southwestern Medical Center: lead
• The Cleveland Clinic: collaborator
• Columbia University: collaborator
• The University of Texas at Arlington: collaborator
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (3)

Columbia University Medical Center

New York, New York, 10032, United States

RECRUITING

Cleveland Clinic

Cleveland, Ohio, 44195, United States

RECRUITING

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

RECRUITING

Biospecimen

Retention: SAMPLES WITH DNA

Venous blood will be collected by phlebotomy at enrollment for all participants. Both plasma and serum will be isolated and aliquoted for storage. Peripheral blood mononuclear cells will also be aliquoted in CPT tubes for generation of human-induced pluripotent stem cells and blood will also be aliquoted into PAXgene blood RNA tubes for future studies. All samples will be immediately frozen and stored until use.

MeSH Terms

Conditions

Amyloidosis, Familial; Amyloid Neuropathies, Familial; Amyloidosis; Amyloidosis, Hereditary, Transthyretin-Related

Condition Hierarchy (Ancestors)

Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Metabolic Diseases; Nutritional and Metabolic Diseases; Proteostasis Deficiencies; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Amyloid Neuropathies; Peripheral Nervous System Diseases; Neuromuscular Diseases

Study Officials

• Justin L Grodin, MD MPH

  UT Southwestern

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Amy Browning

CONTACT

214-645-8040; Amy.Browning@utsouthwestern.edu

Lori R Roth, MS, PAC

CONTACT

214-645-1043; Lori.Roth@utsouthwestern.edu

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: July 29, 2022
• First Posted: August 5, 2022
• Study Start: November 21, 2022
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027
• Last Updated: June 4, 2025

Record last verified: 2025-06

Locations

US (3)