Identifying Subclinical Transthyretin Cardiac Amyloidosis in Asymptomatic Carriers of the V122I TTR Allele
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 500
- 试验地点
- 3
- 主要终点
- (Sub-aim 1) Δ stroke volume index (ΔSVi)
研究概览
简要总结
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Case Control
- 时间视角
- Cross Sectional
入排标准
- 年龄范围
- 30 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •(V122I TTR carriers and carriers of other pathogenic TTR alleles (or matched non-carriers))
- •Inclusion Criteria:
- •Men and women ages 30-80 who are carriers of pathogenic TTR alleles (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
排除标准
- •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 hATTR-CA, we will enroll probands with HF from Aim 1 or patients with suspected symptomatic hATTR-CA from the three study sites.)
- •Inclusion Criteria:
- •Men and women ages 30-80 who have symptomatic 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 pathogenic TTR variant
- •Signed informed consent
- •Exclusion Criteria:
- •Other known causes of cardiomyopathy
- •History of light-chain cardiac amyloidosis
- •Cardiac transplantation
- •Liver transplantation
- •Previous treatment with a TTR stabilizer (tafamidis, acoramidis) within the prior 14 days or TTR any silencer (inotersen, patisiran, eplontersen)
- •Estimated glomerular filtration rate ≤30 mL/min/1.73 m2
研究组 & 干预措施
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.
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 .
结局指标
主要结局
(Sub-aim 1) Δ stroke volume index (ΔSVi)
时间窗: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
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.
(Aim 1) Evidence of amyloid infiltration as measured by ECV
时间窗: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
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.
次要结局
- (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))
- (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)
- (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))
- (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) 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)
- (Aim 1) Native T1 and T2 mapping(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 diastolic function via novel feature tracking.(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))
- (Aim 1) Late gadolinium enhancement(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 2) TTR kinetic stability(At baseline for all three cohorts)
- (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 global systolic function as ejection fraction(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))
- (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)
- (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)
- (Aim 2) Concentration of circulating misfolded TTR oligomers(At baseline for all three cohorts)
研究者
Justin Grodin
Associate Professor of Medicine
University of Texas Southwestern Medical Center