Subclinical Transthyretin Cardiac Amyloidosis in V122I TTR Carriers

University of Texas Southwestern Medical Center500 enrolled

Overview

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.

Study Type

OBSERVATIONAL

Enrollment

Eligibility

Sex: ALLMin age: 30 YearsMax age: 80 Years

Medical Language ↔ Plain English

(V122I TTR carriers (or matched non-carriers)) Inclusion Criteria: * 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 Exclusion Criteria: * 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.) Inclusion Criteria: * 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 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

Outcomes

Primary Outcomes

(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.

Time frame: 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.

Time frame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern

Secondary Outcomes

(Aim 1) Late gadolinium enhancement

We will use a PSIR sequence, limiting operator-dependency. Global subendocardial enhancement, transmural LGE, and focal, patchy LGE are all features of cardiac amyloidosis, representing interstitial expansion. In cardiac amyloidosis, unlike other cardiomyopathies, LGE is correlated to amyloid infiltration not interstitial fibrosis.

Time frame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)

(Aim 1) Native T1 and T2 mapping

Native T1 and T2 mapping represent diffuse interstitial expansion and myocardial edema, respectively. Native T1 measurements are abnormally elevated in amyloidosis and much higher in comparison with other cardiomyopathies that may be associated with interstitial expansion.

Time frame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)

(Aim 1) Post-gadolinium T1 signal intensity

Post-gadolinium T1 signal intensity changes characteristically with myocardial signal nulling before the blood pool signal in amyloidosis (opposite of non-amyloid hearts). We will test for this characteristic pattern using a Look-Locker "TI Scout" sequence.

Time frame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)

(Aim 1) High resolution cardiac cine imaging for cardiac morphology

High resolution cardiac cine imaging will measure cardiac morphology in all 4 chambers of the heart.

Time frame: 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

High resolution cardiac cine imaging will measure cardiac systolic function in all 4 chambers of the heart by assessing ejection fraction.

Time frame: 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

High resolution cardiac cine imaging will measure cardiac systolic function in all 4 chambers of the heart by assessing fractional area change.

Time frame: 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

High resolution cardiac cine imaging will measure cardiac systolic function in all 4 chambers of the heart using novel feature tracking methods.

Time frame: 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.

High resolution cardiac cine imaging will measure cardiac diastolic function in all 4 chambers of the heart using novel feature tracking methods.

Time frame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)

(Aim 1) LV strain from magnetic resonance tissue tagging

Magnetic resonance tissue tagging is the gold-standard for measuring LV strain and strain rate, providing highly sensitive measures of subclinical systolic and diastolic function.

Time frame: 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.

Phase contrast MRI will be used to assess LV diastolic function by assessing the ratio of early (E) and late (A) mitral inflow velocities which can be abnormal in V122I TTR carriers which can be abnormal in V122I TTR carriers.

Time frame: 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.

Phase contrast MRI will be used to assess LV diastolic function by cine feature tracking and MR tissue tagging to calculate the E/e' strain rate which can be abnormal in V122I TTR carriers.

Time frame: 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

Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome.

Time frame: 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

Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome.

Time frame: 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

Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome.

Time frame: 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

Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome.

Time frame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern

(Sub-aim 1) Longitudinal strain (LS, %)

Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome.

Time frame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern

(Aim 2) TTR concentration

Venous blood will be collected by phlebotomy at enrollment for all participants. Both plasma and serum will be isolated and aliquoted for storage. Plasma TTR levels will be measured with commercially available ELISA assays.

Time frame: At baseline for all three cohorts

(Aim 2) RBP4 concentration

Venous blood will be collected by phlebotomy at enrollment for all participants. Both plasma and serum will be isolated and aliquoted for storage. Plasma RBP4 levels will be measured with commercially available ELISA assays.

Time frame: At baseline for all three cohorts

(Aim 2) Concentration of circulating misfolded TTR oligomers

Venous blood will be collected by phlebotomy at enrollment for all participants. Circulating misfolded TTR oligomers will be measured with peptide-based probes that selectively label these species in plasma.

Time frame: At baseline for all three cohorts

(Aim 2) TTR kinetic stability

Venous blood will be collected by phlebotomy at enrollment for all participants. TTR kinetic stability will be measured by using Western Blot techniques.

Time frame: At baseline for all three cohorts

Subclinical Transthyretin Cardiac Amyloidosis in V122I TTR Carriers

Overview

Conditions

Eligibility

Locations (3)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts