July 25, 2025

422. Diagnosis of Transthyretin Amyloid Cardiomyopathy (ATTR-CM) with Dr. Venkatesh Murthy

13 minutes

Drs. Rick Ferraro and Sneha Nandy discuss ‘Diagnosis of ATTR Cardiac Amyloidosis’ with Dr. Venkatesh Murthy. In this episode, we explore the diagnosis of ATTR cardiac amyloidosis, a condition once considered rare but now increasingly recognized due to advances in imaging and the availability of effective therapies. Dr. Venkatesh Murthy, a leader in multimodality imaging, discusses key clinical and laboratory features that should raise suspicion for the disease. We also examine the role of nuclear imaging and genetic testing in confirming the diagnosis, as well as the importance of early detection. Tune in for expert insights on navigating this challenging diagnosis and look out for our next episode on treatment approaches for cardiac amyloidosis! Audio editing for this episode was performed by CardioNerds Intern, Julia Marques Fernandes.

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Pearls: – Diagnosis of Transthyretin amyloid cardiomyopathy

1. Recognizing the Red Flags – ATTR cardiac amyloidosis often presents with subtle but telling signs, such as bilateral carpal tunnel syndrome, low-voltage ECG, and a history of lumbar spinal stenosis or biceps tendon rupture. If you see these features in a patient with heart failure symptoms, think amyloidosis!

2. “Vanilla Ice Cream with a Cherry on Top” – On strain echocardiography, apical sparing is a classic pattern for cardiac amyloidosis. While helpful, it’s not foolproof—multimodal imaging and clinical suspicion are key!

3. Nuclear Imaging is a Game-Changer – When suspicion for cardiac amyloidosis is high à a positive PYP scan with SPECT imaging (grade 2 or 3 myocardial uptake) in the absence of monoclonal protein (ruled out by SPEP, UPEP, and free light chains) is diagnostic for ATTR amyloidosis—no biopsy needed!

4. Wild-Type vs. Hereditary? Know the Clues – Older patients (70+) are more likely to have wild-type ATTR, while younger patients (40s-60s), especially those with neuropathy and a family history of heart failure, should raise suspicion for hereditary ATTR. Genetic testing is crucial for distinguishing between the two. Note that some ATTR variants may predispose to a false negative PYP scan!

5. Missing Amyloidosis = Missed Opportunity – With multiple disease-modifying therapies now available, early diagnosis is critical. If you suspect cardiac amyloidosis, don’t delay the workup—early treatment improves outcomes!

Notes – Diagnosis of Transthyretin amyloid cardiomyopathy

What clinical features should raise suspicion for ATTR cardiac amyloidosis?

ATTR cardiac amyloidosis is underdiagnosed because symptoms overlap with other forms of heart failure.

Red flags include bilateral carpal tunnel syndrome (often years before cardiac symptoms), low-voltage ECG despite increased LV wall thickness, heart failure with preserved ejection fraction (HFpEF) with a restrictive pattern, and history of lumbar spinal stenosis, biceps tendon rupture, and/or peripheral neuropathy, including possible autonomic dysfunction (e.g., orthostatic hypotension).

Remember: If an older patient presents with heart failure and unexplained symptoms like neuropathy or musculoskeletal issues, think amyloidosis!

What is the differential diagnosis for a thick left ventricle (LVH) and how does ATTR amyloidosis fit into it?

Hypertension: Most common cause of LVH, typically with a history of uncontrolled high blood pressure.

Aortic stenosis: May present with concentric LVH.

Hypertrophic cardiomyopathy (HCM): Genetic disorder typically presenting with asymmetric LVH, especially in younger patients.

Infiltrative cardiomyopathy: Often due to amyloidosis, sarcoidosis, or hemochromatosis.

Storage disorder: Fabry’s, Danon, Pompe, etc.

What are the key imaging modalities used to diagnose ATTR cardiac amyloidosis?

Echocardiography: Thickened LV walls (>12 mm) with a restrictive filling pattern, Speckled appearance on 2D echo (not specific), apical sparing on strain imaging (“Vanilla ice cream with a cherry on top”).

Cardiac MRI (CMR): Late gadolinium enhancement (LGE) in a global subendocardial pattern, T1 mapping & extracellular volume (ECV) expansion are supportive findings.

Nuclear Scintigraphy (99mTc-PYP scan): Gold standard noninvasive test for ATTR. Grade 2 or 3 uptake (equal to or greater than bone uptake) is diagnostic if monoclonal protein is absent in the right clinical scenario.

What lab tests are used to diagnose ATTR cardiac amyloidosis?

Check troponin and NTproBNP (useful for staging)

Rule out AL amyloidosis with monoclonal protein studies like serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) with immunofixation and serum free light chain (FLC) assay (to detect clonal plasma cell disorders)

Why is ruling out AL amyloidosis critical before diagnosing ATTR?

They are treated very differently- AL amyloidosis is an oncologic emergency requiring chemotherapy, while ATTR is treated with medications.

If workup for AL amyloidosis, such as SPEP/UPEP or serum free light chains ratio, comes back positive, you do not need to pursue further testing for ATTR amyloidosis.

When should genetic testing be performed in suspected ATTR amyloidosis?

All patients diagnosed with ATTR amyloidosis should undergo genetic testing to distinguish wild-type from hereditary forms.

Wild-type ATTR: More common in older men (≥70 years), no known mutation, sporadic occurrence, often presents with predominantly cardiac involvement

Familial ATTR: Autosomal dominant inheritance, more common in Black patients (V122I mutation), more likely to have neuropathy and earlier onset of heart failure (4th or 5th decade). Specific variants have typical geographic distribution and predilection to causing neuropathy and/or cardiomyopathy.

When is a biopsy necessary to confirm ATTR amyloidosis?

Biopsy is not needed if PYP scan is positive (Grade 2-3) and AL amyloidosis is ruled out.

If the diagnosis remains uncertain, a biopsy can be performed of either a fat pad or salivary gland biopsy (easier, lower sensitivity) or an endomyocardial biopsy (gold standard but invasive).

References – Diagnosis of Transthyretin amyloid cardiomyopathy

Dorbala S, Ando Y, Bokhari S, et al. ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: Part 1 of 2-evidence base and standardized methods of imaging [published correction appears in J Nucl Cardiol. 2021 Aug;28(4):1761-1762. doi: 10.1007/s12350-021-02711-w.]. J Nucl Cardiol. 2019;26(6):2065-2123. doi:10.1007/s12350-019-01760-6

https://pubmed.ncbi.nlm.nih.gov/31468376

Writing Committee, Kittleson MM, Ruberg FL, et al. 2023 ACC Expert Consensus Decision Pathway on Comprehensive Multidisciplinary Care for the Patient With Cardiac Amyloidosis: A Report of the American College of Cardiology Solution Set Oversight Committee [published correction appears in J Am Coll Cardiol. 2023 Mar 21;81(11):1135. doi: 10.1016/j.jacc.2023.02.013.]. J Am Coll Cardiol. 2023;81(11):1076-1126. doi:10.1016/j.jacc.2022.11.022

https://pubmed.ncbi.nlm.nih.gov/36697326

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