2023 ACC Expert Consensus on Cardiac Amyloidosis: Key Points

Kittleson MM, Ruberg FL, Ambardekar AV, 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. J Am Coll Cardiol 2023;Jan 23:[Epub ahead of print].

The following are key points to remember from a new Expert Consensus Decision Pathway document on comprehensive multidisciplinary care for the patient with cardiac amyloidosis:

  1. Amyloid cardiomyopathy is caused by misfolding of (i) monoclonal immunoglobulin light chain produced in bone marrow plasma cell disorders called AL, or (ii) transthyretin (TTR) protein called ATTR. ATTR-cardiomyopathy (ATTR-CM) can occur in the context of genetically normal protein (wild type or ATTRwt-CM) or due to genetic mutations (most commonly isoleucine substitution for valine at position 122), rendering the protein abnormal (ATTRv-CM).
  2. Since amyloid fibrils can deposit in multiple organs, multidisciplinary care is a requisite.
  3. Cardiac clues to diagnosis of amyloidosis includes increased left ventricular hypertrophy in the absence of hypertension or valvular heart disease, heart failure symptoms, diastolic dysfunction, atrial fibrillation, conduction system disease, and elevated cardiac biomarkers. Extracardiac manifestations include carpal tunnel syndrome, spinal stenosis, hip or knee replacement, prior shoulder surgery, proteinuria, and peripheral or autonomic neuropathy causing orthostatic hypotension. Pathognomonic extracardiac findings for AL include macroglossia, periorbital purpura, and acquired factor X deficiency. Findings unique to ATTR are spontaneous biceps rupture and spinal stenosis.
  4. Low voltage electrocardiography and presence of hypertrophy on echocardiography is only present in 30% of amyloid patients. Other echo findings include left ventricular hypertrophy, atrioventricular valve/right ventricular free wall/interatrial septum thickening, diastolic dysfunction, biatrial enlargement, and decreased global longitudinal strain with apical sparing.
  5. Cardiac magnetic resonance imaging can help differentiate amyloidosis from other infiltrative diseases. Findings include extracellular volume expansion and diffuse late gadolinium enhancement.
  6. The first step in identifying type of amyloidosis is a monoclonal protein screen involving: serum free light chain assay, serum and urine immunofixation electrophoresis. If all are negative, AL has been ruled out. If any are positive, the next step is biopsy of the involved organ with mass spectrometry to confirm AL deposition. A negative fat pad biopsy does not rule out AL or ATTR, and biopsy of the involved organ (heart or kidneys) should be considered.
  7. A serum/urine protein electrophoresis should not be used to rule out monoclonal protein due to lower accuracy relative to immunofixation. In chronic kidney disease, elevated serum free light chain ratios of K/L are common but with a normal serum and urine immunofixation electrophoresis.
  8. If AL has been ruled out, a technetium pyrophosphate scan can be used to diagnose ATTR-CM. Genetic testing is warranted to distinguish between ATTRwt-CM or ATTRv-CM.
  9. Tafamidis is a TTR stabilizer and is the only Food and Drug Administration approved medication available for all ATTR-CM. It delays disease progression but does not result in regression, and in trials, reduced all-cause mortality and cardiovascular hospitalizations. It has minimal side effects but has a high cost, needing copay assistance programs for patients.
  10. Alternatives to tafamidis include diflunisal, also a TTR stabilizer, which is less effective but significantly cheaper. It is a nonsteroidal anti-inflammatory drug and should be avoided in chronic kidney disease, decompensated heart failure, and gastrointestinal (GI) bleeding.
  11. Beta-blockers should be used with caution and may worsen outcomes. Angiotensin inhibitors may be poorly tolerated due to orthostatic hypotension. Retrospective analysis of trials suggests a beneficial effect of spironolactone. There is no evidence to guide use of SGLT-2 inhibitors in amyloidosis.
  12. If atrial fibrillation is present, anticoagulation is recommended regardless of CHA2DS2-VASc score, and prior to cardioversion, a transesophageal echocardiogram should always be performed regardless of anticoagulation status due to high risk for intracardiac thrombus.
  13. There should be close monitoring for conduction disease and ventricular arrhythmias, both being very common in amyloid cardiomyopathy. However, defibrillators have not consistently demonstrated improved survival for amyloidosis and hence should be considered based on standard heart failure guidelines for amyloid patients.
  14. If aortic stenosis is present with cardiac amyloidosis, aortic valve replacement (AVR) may help improve symptoms and referral for transcatheter AVR (TAVR) should be considered.
  15. Emerging therapies not yet approved for cardiac amyloidosis include TTR silencers such as patisiran or vutisiran (approved for ATTRv polyneuropathy) and inotersen. These are currently only approved for amyloid polyneuropathy. Data on green tea derivatives are lacking and not recommended.
  16. GI mucosa involvement can cause protein losing enteropathy, GI dysmotility, abdominal pain, constipation, or diarrhea and bleeding. Treatment is supportive and should include collaboration with a GI specialist.
  17. Treatment for multiple myeloma with AL amyloidosis includes either high-dose melphalan with stem cell transplant daratumumab with cyclophosphamide, bortezomib, and dexamethasone. For AL-CM, a stem cell transplant followed by cardiac transplant would be ideal, but in some cases, sequential heart transplant followed by stem cell transplantation may be considered.
  18. Kidney involvement is very common with AL and ATTR amyloidosis. Treatment is supportive and includes low salt diet, use of diuretics for fluid overload, and angiotensin antagonists for proteinuria.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Cardiovascular Care Team, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Valvular Heart Disease, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Heart Transplant, Interventions and Imaging, Interventions and Structural Heart Disease, Interventions and Vascular Medicine, Echocardiography/Ultrasound, Magnetic Resonance Imaging

Keywords: Aortic Valve Stenosis, Arrhythmias, Cardiac, Atrial Fibrillation, Amyloid Neuropathies, Amyloidosis, Amyloidosis, Familial, Angiotensins, Anticoagulants, Biomarkers, Digestive System Diseases, Cardiomyopathy, Restrictive, Cerebral Amyloid Angiopathy, Consensus, Cost of Illness, Diagnostic Imaging, Echocardiography, Electrocardiography, Factor X Deficiency, Genetic Testing, Heart Failure, Heart Transplantation, Hypotension, Orthostatic, Hypertrophy, Immunoglobulin Light-chain Amyloidosis, Kidney Diseases, Macroglossia, Magnetic Resonance Imaging, Multiple Myeloma, Nervous System Diseases, Palliative Care, Patient Care Team, Spironolactone, Stem Cell Transplantation, Telemedicine, Transcatheter Aortic Valve Replacement

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