The importance of recognition and diagnosis of cardiac amyloidosis is at an all-time high due to its high prevalence and improved therapeutic strategies. Here we discuss what CardioNerds need to know about the manifestations, diagnosis, and management of transthyretin (ATTR) and light chain (AL) cardiac amyloidosis. Join Dr. Dan Ambinder (CardioNerds Cofounder), Dr. Dinu-Valentin Balanescu (Series Cochair, Chief Resident at Beaumont Health, and soon FIT at Mayo Clinic), and Dr. Dan Davies (Episode FIT Lead and FIT at Mayo Clinic) as they discuss cardiac amyloidosis with Dr. Omar Siddiqi, cardiologist at the Boston University Amyloidosis Center and program director for the general cardiovascular fellowship program at Boston University, a CardioNerds Healy Honor Roll Program. Episode notes were drafted by Dr. Dan Davies. Audio editing by CardioNerds Academy Intern, student doctor Chelsea Amo Tweneboah.
This episode is supported by a grant from Pfizer Inc.
This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan.
Pearls and Quotes
- Cardiac amyloidosis is no longer considered a rare disease, especially transthyretin amyloidosis in older male patients with HFpEF and aortic stenosis.
- Echocardiogram is the “gate keeper” of cardiac imaging and provides initial evidence of amyloid infiltration, while cardiac MRI can help refine the presence of an infiltrative cardiomyopathy versus other causes of increased wall thickness.
- The most clinically important types of amyloid heart disease are transthyretin (ATTR) and light chain (AL) amyloidosis. The workup to differentiate these disorders includes a gammopathy panel to screen for the presence of potentially amyloidogenic light chains (serum and urine electrophoresis WITH immunofixation and serum free light chains), and cardiac scintigraphy with Technetium-99m-labeled bone-seeking tracers (PYP, DPD, etc.) to identify cardiac aTTR infiltration if the gammopathy panel is unrevealing.
- There is still a role for endomyocardial biopsy in the diagnosis of cardiac amyloidosis! All patients in whom there is concern for cardiac amyloidosis and gammopathy panel indicates the presence of monoclonal light chains should have a biopsy to obtain a tissue diagnosis of likely AL amyloidosis. Alternatively, an endocardial biopsy may prove valuable in patients who have confusing phenotypic features between amyloid types, such as a patient with abnormal monoclonal protein and positive PYP imaging.
- Be suspicious of heart failure patients that do not tolerate typical medications that lower heart rate. In the restrictive cardiomyopathy of cardiac amyloidosis, patients are reliant on higher heart rates to compensate for the inability to augment stroke volume.
- Be suspicious of amyloidosis in patients with recurrent left atrial thrombi despite anticoagulation.
1. What is cardiac amyloidosis and how common is it?
- Cardiac amyloidosis is adisorder caused by misfolding of proteins into insoluble forms which are deposited into extracellular spaces of the heart, commonly causing a stiff and thick heart with progressive diastolic dysfunction with restrictive hemodynamics and ensuing heart failure.
- The two most common types of amyloid protein that affect the heart are transthyretin (ATTR) and light chain (AL). Transthyretin amyloidosis is caused by a misfolded transporter protein produced by the liver, while light chain amyloidosis is caused by a misfolded light chain immunoglobulin produced by clonal plasma cells.
- ATTR cardiac amyloidosis may be present in 6-17% of older patients with HFpEF and increased wall thickness, as well as in 4-16% of patients undergoing intervention for severe aortic stenosis. AL amyloidosis is much rarer, with a prevalence of about 12 cases per million persons per year.
2. What are some non-cardiac clues to the presence of cardiac amyloidosis?
- Non-cardiac clinical clues for transthyretin amyloidosis (ATTR) include spinal stenosis, biceps tendon rupture, carpal tunnel syndrome (particularly when bilateral), and peripheral neuropathy.
- Bilateral carpal tunnel syndrome may be present in up to 60% of ATTR-CA patients with over 40% having a history of biceps tendon rupture.
- Non-cardiac clinical clues for light chain amyloidosis (AL) include renal disease (esp. nephrotic syndrome), macroglossia, autonomic and peripheral neuropathy, and periorbital purpura (racoon eyes).
3. What are common multimodality imaging features used for the diagnosis of cardiac amyloidosis?
- For an in-depth discussion about the use of multimodality imaging in the diagnosis of cardiac amyloidosis, enjoy CardioNerds Episode #109 – Nuclear & Multimodality Imaging: Cardiac Amyloidosis.
- Echocardiography (echo) is among the first test performed in patients for the diagnosis of cardiovascular symptoms and may provide initial clues to the diagnosis. Features of cardiac amyloidosis on echocardiogram include increased left ventricular wall thickness (>12 mm, classically concentric) with abnormal diastolic function, increased right ventricular free wall and interatrial septal thickness, as well as increased valve thickness. There may be a small pericardial effusion. Left ventricular strain is usually abnormal with a characteristic apical sparing pattern. A granular, or sparkling, appearance of the myocardium has been classically described but is poorly predictive.
- Cardiac magnetic resonance (CMR) imaging is often used for differentiation of increased left ventricular wall thickness (infiltrative cardiomyopathies, hypertrophic cardiomyopathies, etc.) and in patients at increased risk of AL cardiac amyloidosis. Common features specific to CMR include abnormal myocardial nulling (blood pool nulls before the myocardium on inversion recovery sequences), elevated native T1 value, increased extracellular volume (ECV), and late gadolinium enhancement (classically in a diffuse, non-ischemic pattern).
- Bone scintigraphy (technetium pyrophosphate [PYP] or DPD) is a nuclear imaging study used for the diagnosis of transthyretin amyloidosis. In the absence of an abnormal monoclonal protein, the sensitivity and specificity approach 100%, allowing for the “non-biopsy” diagnosis of ATTR-CA (specifically in the context of a negative gammopathy panel). The 2019 multi-society diagnostic guidelines recommend SPECT imaging be used in combination planar imaging for all cases to improve predictive characteristics.
4. How are heart failure and arrhythmias managed in patients with cardiac amyloidosis?
- The mainstay of heart failure therapy in cardiac amyloidosis is loop diuretics with or without aldosterone antagonists. Spironolactone was shown to be effective in patients with a phenotype suggesting cardiac amyloidosis in a subgroup analysis of TOPCAT.
- Patients often have poor tolerance of guideline directed medical therapies for heart failure, including beta blockers and calcium channel blockers, with ACEI/ARB/ARNI frequently limited by hypotension. The SGLT2 inhibitors appear to be tolerated in patients with cardiac amyloidosis but more research is needed to determine impact on cardiovascular outcomes.
- Rate and rhythm control strategies for atrial arrhythmias can both be successful, but patients may be intolerant of medications. The risk of cardioembolic events in amyloid patients with atrial fibrillations is elevated, independent of CHA2DS2 -VASc score, and therefore all patients should be offered anticoagulation. Be suspicious of amyloidosis in patients with recurrent left atrial appendage thrombi despite anticoagulation.
5. What specific therapies can be used for transthyretin (ATTR) amyloidosis and light chain (AL) amyloidosis?
- Tafamidis is a transthyretin stabilizer that inhibits tetramer dissociation and reduces amyloid deposition in extracellular tissue. It is the only FDA approved medication for transthyretin cardiac amyloidosis and was shown to be associated with reduced mortality and heart failure hospitalization compared to control in the ATTR-ACT trial.
- Patisiran is a small interfering RNA that works as a gene silencer for ATTR protein production and is FDA approved for patients with polyneuropathy secondary to hereditary ATTR. Analysis of cardiac outcomes in the APOLLO trial suggest early stabilization of left ventricular wall thickness and reduction in natriuretic peptides in patients with features of concomitant cardiac involvement.
- Specific therapies for AL amyloidosis are managed by hematologists with the goal of complete hematologic response to prevent further immunoglobulin production and amyloid deposition. These therapies typically include chemotherapy regimens (e.g. cyclophosphamide, bortezomib, dexamethasone [CyBorD]), daratumumab (an anti-CD38 antibody), with or without autologous stem cell transplantation.
- There are many ongoing trials with novel therapies, with specific interest in treatments targeting removal of systemically deposited amyloid fibrils.
- 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. J. Nucl. Cardiol. 26, 2065–2123 (2019). Link
- 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 2 of 2—Diagnostic criteria and appropriate utilization. J. Nucl. Cardiol. 27, 659–673 (2020). Link
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- Witteles RM, Liedtke M. AL Amyloidosis for the Cardiologist and Oncologist: Epidemiology, Diagnosis, and Management. JACC CardioOncol. 2019;1(1):117-130. Link
- Maurer MS, Schwartz JH, Gundapaneni B, Elliott PM, Merlini G, Waddington-Cruz M, Kristen AV, Grogan M, Witteles R, Damy T, Drachman BM, Shah SJ, Hanna M, Judge DP, Barsdorf AI, Huber P, Patterson TA, Riley S, Schumacher J, Stewart M, Sultan MB, Rapezzi C; ATTR-ACT Study Investigators. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018 Sep 13;379(11):1007-1016. Link
- Gertz, M. A., & Dispenzieri, A. (2020). Systemic Amyloidosis Recognition, Prognosis, and Therapy: A Systematic Review. Jama, 324(1), 79-89. https://jamanetwork.com/journals/jama/fullarticle/2767867
- Cappelli, F., Zampieri, M., Fumagalli, C., Nardi, G., Del Monaco, G., Matucci Cerinic, M., Allinovi, M., Taborchi, G., Martone, R., Gabriele, M., Ungar, A., Moggi Pignone, A., Marchionni, N., Di Mario, C., Olivotto, I., & Perfetto, F. (2021). Tenosynovial complications identify TTR cardiac amyloidosis among patients with hypertrophic cardiomyopathy phenotype. J Intern Med, 289(6), 831-839. https://pubmed.ncbi.nlm.nih.gov/33615623/
- Sperry, B. W., Hanna, M., Shah, S. J., Jaber, W. A., & Spertus, J. A. (2021). Spironolactone in Patients With an Echocardiographic HFpEF Phenotype Suggestive of Cardiac Amyloidosis: Results From TOPCAT. JACC Heart Fail, 9(11), 795-802. https://www.sciencedirect.com/science/article/pii/S2213177921003206?via%3Dihub
- Dobner, S., Bernhard, B., Asatryan, B., Windecker, S., Stortecky, S., Pilgrim, T., Gräni, C., & Hunziker, L. (2022). SGLT2 inhibitor therapy for transthyretin amyloid cardiomyopathy: early tolerance and clinical response to dapagliflozin. ESC Heart Fail. https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14188
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