CardioNerds (Drs. Rick Ferraro and Georgia Vasilakis Tsatiris) discuss ATTR cardiac amyloidosis with expert Dr. Justin Grodin. This episode is a must-listen for all who want to know how to diagnose and treat ATTR with current available therapies, as well as management of concomitant diseases through a multidisciplinary approach. We take a deep dive into the importance of genetic testing, not only for patients and families, but also for gene-specific therapies on the horizon. Dr. Grodin draws us a roadmap, guiding us through new experimental therapies that may reverse the amyloidosis disease process once and for all. Audio editing by CardioNerds academy intern, Christiana Dangas.
This episode was developed in collaboration with the American Society of Preventive Cardiology and supported by an educational grant from BridgeBio.
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Pearls:
You must THINK about your patient having amyloid to recognize the pattern and make the diagnosis. Start with a routine ECG and TTE, and look for a disproportionately large heart muscle with relatively low voltages on the ECG.
Before you diagnose ATTR amyloidosis, AL amyloidosis must be ruled out (or ruled in) with serum light chains, serum/urine immunofixation, and/or tissue biopsy.
Genetic testing is standard of care for all patients and families with ATTR amyloidosis, and the future is promising for gene-specific treatments. Current FDA-approved treatments for TTR amyloidosis are TTR stabilizers and TTR silencers, but TTR fibril-depleting agents are on their way.
Early diagnosis of ATTR affords patients maximal benefit from current amyloidosis therapies.
TTR amyloidosis patients require a multidisciplinary approach for success, given the high number of concomitant diseases with cardiomyopathy.
Notes:
Notes: Notes drafted by Dr. Georgia Vasilakis Tsatiris.
What makes you most suspicious of a diagnosis of cardiac amyloidosis from the typical heart failure patient?
You must have a strong index of suspicion, meaning you THINK that the patient could have cardiac amyloidosis, to consider it diagnostically. Some characteristics or “red flags” to not miss:
Disproportionately thick heart muscle with a relatively low voltages on EKG
Bilateral carpal tunnel syndrome – estimated that 1 in 10 people >65 years old will have amyloidosis
Previously tolerated antihypertensive medications
Atraumatic biceps tendon rupture
Bilateral carpal tunnel syndrome
Spinal stenosis
Concomitant with other diseases: HFpEF, low-flow low-gradient aortic stenosis
How would you work up a patient for cardiac amyloidosis?
Start with a routine ECG (looking for disproportionally low voltage) and routine TTE (looking for thick heart muscle)
CBC, serum chemistries, hepatic function panel, NT proBNP, and troponin levels
NOTE: It is critical to differentiate between amyloid light chain (AL amyloidosis) and transthyretin ATTR amyloidosis, as both make up 95-99% of amyloidosis cases.
Obtain serum free light chains, serum & urine electrophoresis, and serum & urine immunofixation to rule out AL amyloidosis. (See table below)
AL Amyloidosis ATTR Amyloidosis → Positive serum free light chains and immunofixation (Abnormal M protein) → Tissue biopsy (endomyocardial, fat pad) to confirm diagnosis → Negative serum free light chains and immunofixation (ruled out AL amyloidosis) → Cardiac scintigraphy (Technetium pyrophosphate with SPECT imaging)
What treatment options do we have to offer now for ATTR CM, and how has this compared to prior years?
Before 2019, treatment options were limited outside of cardiac transplantation and prophylactic liver transplants for hereditary ATTR amyloidosis.
Treatments since 2019 have utilized the amyloidogenic cascade:
TTR protein is formed in the liver and circulates in the bloodstream.
Current treatments aim to either slow ATTR progression by stopping deposition or clearing amyloid deposits
Only FDA-approved treatments are for stopping deposition, while agents that clear amyloid deposits remain investigational. Two classes of agents that stop amyloid deposition are TTR stabilizers and TTR Silencers. (See table below)
TTR Stabilizers TTR Silencers Tafamidis (ATTR-ACT, 2018) Acoramidis (ATTRibute-CM, 2024) Inotersen (Clinical Trial, 2018) Eplontersen (Clinical Trial, 2023) Patisiran (Clinical Trial, 2018) Vutrisiran* (Clinical Trial, 2022) Mechanism: prevents dissociation of, or stabilizes, the TTR tetramer to halt disease progression Mechanism: inhibit the liver’s production of TTR in the bloodstream via small interfering RNAs (