Subclinical Transthyretin Cardiac Amyloidosis in V122I TTR Carriers

Identifying Subclinical Transthyretin Cardiac Amyloidosis in Asymptomatic Carriers of the V122I TTR Allele

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.

(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

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