Cardiac Amyloidosis: Evolving Diagnosis and Management

Kittleson MM, Maurer MS, Ambardekar AV, et al.
Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association. Circulation 2020;Jun 1:[Epub ahead of print].

The following are key points to remember from this American Heart Association Scientific Statement on Cardiac Amyloidosis: Evolving Diagnosis and Management:

  1. Cardiac amyloidosis is caused mainly by misfolded monoclonal immunoglobulin light chains (ALs) from an abnormal clonal proliferation of plasma cells or transthyretin (TTR) amyloidosis (ATTR), a liver synthesized protein previously that is normally involved in the transportation of the hormone thyroxine and retinol-binding protein. ATTR can be inherited as an autosomal dominant trait caused by pathogenic variants in the transthyretin gene TTR (ATTRv) or by the deposition of ATTRwt (wild-type transthyretin protein), previously called senile cardiac amyloidosis.
  2. ATTR amyloid protein can infiltrate other organs, most often the autonomic and peripheral nervous systems, but cardiac involvement, when present, is the principal determinant of survival. ATTR deposition is seen in up to 16% of patients with degenerative aortic stenosis and 13-17% of patients with heart failure with preserved ejection fraction. Median survival after diagnosis in untreated patients is poor: 2.5 years for ATTRv caused by the TTR Val122Ile (or pV142I) mutation and 3.6 years for ATTRwt.
  3. Clues that should prompt investigation of ATTR-CM include sensorimotor peripheral neuropathy (paraesthesias and weakness), autonomic dysfunction (orthostatic hypotension, postprandial diarrhea/alternating with constipation, gastroparesis, urinary retention, and incontinence), orthopedic manifestations (carpal tunnel syndrome, lumbar spinal stenosis, unprovoked biceps tendon rupture, hip and knee arthroplasty), black race, familial history of polyneuropathy, intolerance to antihypertensive or heart failure medications because of hypotension or orthostasis, persistent low elevation in serum troponin, discordance between QRS voltage and wall thickness, unexplained left ventricular (LV) or right ventricular (RV) or atrial thickening, or family history of cardiomyopathy.
  4. Echocardiography and cardiac magnetic resonance imaging are not diagnostic for ATTR cardiomyopathy (CM) but can suggest the diagnosis and may be useful when infiltrative cardiomyopathy, constrictive pericarditis, or myocarditis is suspected. The presence of moderate to severe LV thickening (wall thickness ≥14 mm) should trigger consideration of ATTR-CM, especially if there is discordance between wall thickness on echocardiogram and QRS voltage on electrocardiogram.
  5. The use of 99mtechnetium (99mTc) bone-avid compounds represents a paradigm shift because these scans allow the noninvasive diagnosis of ATTR-CM, although the basis for binding to amyloid deposits remains unknown but the results of the 99mtechnetium-pyrophosphate (99mTc-PYP) scan should be interpreted only in the context of a negative monoclonal light chain screen. Single-photon emission computed tomography imaging is required if there is grade 1 or higher 99mTc-PYP to distinguish blood pool from myocardial retention. Note that mild elevations in the serum free light chain kappa/lambda ratio frequently occur in patients with renal disease, and in the setting of normal immunofixation, a kappa/lambda ratio of up to 3.0 can be normal. Consultation with a hematologist can be considered in such circumstances.
  6. Endomyocardial biopsy may be necessary, in some instances, to establish the diagnosis: 1) a positive 99mTc-PYP scan and evidence of a plasma cell dyscrasia by serum/urine immunofixation electrophoresis or serum free light chain analysis to exclude AL-CM (because AL-CM and ATTR-CM may very rarely occur together in the same patient, such that patients with biopsy-proven AL-CM, especially if older, may also have superimposed ATTRwt-CM deposits); 2) a negative or equivocal 99mTc-PYP scan despite a high clinical suspicion to confirm ATTR-CM; and 3) unavailability of 99mTc-PYP scanning.
  7. Therapy of cardiac amyloidosis focuses on three areas: management of heart failure, management of arrhythmias, and initiation of disease-modifying agents. As a result of atrial dysfunction in ATTR-CM, anticoagulation is indicated for atrial fibrillation/flutter regardless of CHA2DS2-VASc score; amiodarone is the agent of choice for both rhythm and rate control.
  8. Targets for disease-modifying therapies in cardiac amyloidosis include TTR silencing (patisiran/inotersen), TTR stabilization (tafamidis, diflunisal, green tea, AG10), and TTR disruption/resorption (doxycycline/tauroursodeoxycholic acid), monoclonal antibodies). TTR stabilizers bind to the TTR tetramer and prevent misfolding and thus deposition of amyloid fibrils. TTR silencers target TTR hepatic synthesis; although not explicitly tested, there is evidence that TTR silencers may have beneficial cardiac effects. TTR disruptors target the clearance of amyloid fibrils from tissues.
  9. Tafamidis is a TTR stabilizer that binds the thyroxine binding site of TTR. In the ATTR-ACT randomized trial (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy) of patients with ATTRwt-CM or ATTRv-CM, tafamidis was associated with a significantly lower all-cause mortality (29.5% vs. 42.9%) and lower cardiovascular-related hospitalization (0.48 vs. 0.70 per year) after 30 months. In patients with predominantly cardiac disease resulting from ATTRv or ATTRwt, tafamidis is indicated in those with New York Heart Association class I-III symptoms, and early initiation appears to slow disease progression. The benefit of tafamidis has not been observed in patients with class IV symptoms, severe aortic stenosis, or impaired renal function (glomerular filtration rate <25 ml/min−1/1.73 m−2 body surface area).
  10. Despite advances in the management of ATTR-CM, areas of uncertainty remain in screening, disease progression, role of TTR silencers in patients with ATTR-CM, timing of therapy initiation, and financial burden of new treatments.


This is an outstanding Scientific Statement and is a must-read for those managing heart failure patients.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardio-Oncology, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Pericardial Disease, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Acute Heart Failure, Echocardiography/Ultrasound

Keywords: Amyloidosis, Anticoagulants, Arrhythmias, Cardiac, Antihypertensive Agents, Atrial Fibrillation, Cardiomyopathies, Cardiotoxicity, Diagnostic Imaging, Echocardiography, Geriatrics, Heart Failure, Hypotension, Orthostatic, Myocarditis, Paresthesia, Pericarditis, Constrictive, Technetium Tc 99m Pyrophosphate, Troponin

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