Amyloidosis Cardiac, Amyloidosis, Familial, Amyloidosis, Hereditary, Transthyretin Gene Mutation, Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy
Conditions
Keywords
Amyloidosis, Transthyretin Amyloidosis, V122I TTR, p.Val142Ile TTR, Cardiac magnetic resonance imaging
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.
Interventions
None listed
Sponsors
University of Texas Southwestern Medical Center
The Cleveland Clinic
Columbia University
The University of Texas at Arlington
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Observational model
CASE_CONTROL
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
30 Years to 80 Years
Inclusion criteria
(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
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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| (Aim 1) Evidence of amyloid infiltration as measured by ECV | 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. |
| (Sub-aim 1) Δ stroke volume index (ΔSVi) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| (Aim 2) TTR concentration | At baseline for all three cohorts | 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. |
| (Aim 2) RBP4 concentration | At baseline for all three cohorts | 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. |
| (Aim 2) Concentration of circulating misfolded TTR oligomers | At baseline for all three cohorts | 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. |
| (Aim 2) TTR kinetic stability | At baseline for all three cohorts | Venous blood will be collected by phlebotomy at enrollment for all participants. TTR kinetic stability will be measured by using Western Blot techniques. |
| (Aim 1) Late gadolinium enhancement | At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) | 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. |
| (Aim 1) Native T1 and T2 mapping | At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) | 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. |
| (Aim 1) Post-gadolinium T1 signal intensity | At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) | 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. |
| (Aim 1) High resolution cardiac cine imaging for cardiac morphology | At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) | High resolution cardiac cine imaging will measure cardiac morphology in all 4 chambers of the heart. |
| (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) | High resolution cardiac cine imaging will measure cardiac systolic function in all 4 chambers of the heart by assessing ejection fraction. |
| (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) | High resolution cardiac cine imaging will measure cardiac systolic function in all 4 chambers of the heart by assessing fractional area change. |
| (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) | High resolution cardiac cine imaging will measure cardiac systolic function in all 4 chambers of the heart using novel feature tracking methods. |
| (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) | High resolution cardiac cine imaging will measure cardiac diastolic function in all 4 chambers of the heart using novel feature tracking methods. |
| (Aim 1) LV strain from magnetic resonance tissue tagging | At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) | 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. |
| (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) | 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. |
| (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) | 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. |
| (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 | Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome. |
| (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 | Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome. |
| (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 | Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome. |
| (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 | Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome. |
| (Sub-aim 1) Longitudinal strain (LS, %) | At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern | Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome. |
Countries
United States
Contacts
CONTACTAmy Browning
CONTACTLori R Roth, MS, PAC
PRINCIPAL_INVESTIGATORJustin L Grodin, MD MPH
UT Southwestern
Outcome results
None listed