Guideline sources The following summarized guidelines for the evaluation and management of cardiac amyloidosis are prepared by our editorial team based on guidelines from the Heart Failure Society of America (HFSA/AHA/ACC 2022), the European Society of Cardiology (ESC 2021), the Canadian Heart Failure Society (CHFS/CCS 2020), the Amyloidosis Research Consortium (ARC 2019), the Heart Rhythm Society (HRS 2019), and the American Heart Association (AHA/HRS/ACC 2019). 1 2 3 4 5 6 7 7 7 8 Definition Cardiac amyloidosis refers to infiltration of the heart muscle by amyloid proteins, resulting in cardiomyopathy. 7 Epidemiology https://web.pathway.md/diseases/recRGSRWKNUQefP0x 1/8 6/29/23, 3:44 AM Cardiac amyloidosis Pathway Cardiac amyloidosis is caused by extracellular accumulation of misfolded protein fragments (immunoglobulin light-chain and transthyretin protein) in the heart muscle. 7 Disease course Clinical manifestations are related to the development of restrictive cardiomyopathy and include angina, myocardial infarction, and HF. An increased risk of thromboembolic complications is also present. 7 Prognosis and risk of recurrence Unadjusted 5-year mortality rates are estimated at 65% in patients with AL cardiac amyloidosis and 44% in patients with ATTR cardiac amyloidosis. 8 Calculator NYHA functional classification f Guidelines 1. Screening and diagnosis Indications for testing: As per CCS 2020 guidelines, obtain diagnostic workup for cardiac amyloidosis in patients presenting with signs and symptoms of HF having 1 of the following features: unexplained increased LV wall thickness > 60 years of age with low-flow low-gradient aortic stenosis and LVEF > 40% unexplained peripheral sensorimotor neuropathy and/or dysautonomia history of bilateral carpal tunnel syndrome established light chain or transthyretin amyloidosis. B As per ARC 2019 guidelines: Suspect transthyretin amyloid cardiomyopathy in older persons who have been hospitalized for HF, elevated troponin levels, or levels of N-terminal pro-BNP that are out of proportion to the clinical context. E Consider evaluation of myocardial uptake on bone scintigraphy in patients with HF, unexplained neuropathy, a family history of amyloidosis, or unexplained increased LV wall thickness. E 2. Classification and risk stratification https://web.pathway.md/diseases/recRGSRWKNUQefP0x 2/8 6/29/23, 3:44 AM Cardiac amyloidosis Pathway Risk stratification: use a validated serum biomarker-based staging system, including troponin and/or BNP/N-terminal pro-BNP, to risk-stratify patients with cardiac amyloidosis. A 3. Diagnostic investigations Clinical history: Recognize the following history/examination diagnostic clues to ATTR cardiomyopathy: evidence of right-sided HF (e.g., hepatomegaly, ascites, and lower extremity edema) HFpEF, particularly in men intolerance to ACE inhibitors or -blockers bilateral carpal tunnel syndrome lumbar spinal stenosis biceps tendon rupture unexplained peripheral neuropathy (e.g., loss of warm/cold discrimination), particularly if associated with autonomic dysfunction (e.g., postural hypotension, alternating bowel pattern) unexplained atrial arrhythmias or conduction system disease/need for a pacemaker. E Testing for monoclonal protein: As per ACC 2022 guidelines, screen for serum and urine monoclonal light chains with serum and urine immunofixation electrophoresis and sFLC in patients with a clinical suspicion for cardiac amyloidosis. B As per CCS 2020 guidelines, obtain serum and urine protein electrophoresis with immunofixation and sFLC in all patients with suspected cardiac amyloidosis to evaluate for possible light chain amyloidosis or other plasma cell dyscrasia. B As per ARC 2019 guidelines: Obtain testing for monoclonal protein followed by scintigraphy or biopsy as part of the evaluation of patients with suspected cardiac amyloidosis. E Obtain the following three tests to screen for the presence of a monoclonal protein in patients with symptoms, ECG, echocardiography, MRI or biomarkers suggestive of cardiac amyloidosis: serum kappa/lambda free light chain ratio (abnormal if ratio is < 0.26 or > 1.65) serum protein immunofixation (abnormal if monoclonal protein is detected) urine protein immunofixation (abnormal if monoclonal protein is detected). E Evaluation for heart failure: Obtain routine investigations for the evaluation of HF including 12-lead ECG, troponin, and BNP/N-terminal pro-BNP in patients presenting with suspected cardiac amyloidosis. B Obtain echocardiography with longitudinal LV strain measurement or cardiac MRI with late gadolinium enhancement and T1 mapping in all patients with suspected cardiac amyloidosis to evaluate for characteristic features of cardiac amyloidosis or alternative causes of HF. B Radionuclide imaging: https://web.pathway.md/diseases/recRGSRWKNUQefP0x 3/8 6/29/23, 3:44 AM Cardiac amyloidosis Pathway As per ACC 2022 guidelines, obtain bone scintigraphy to confirm the presence of transthyretin cardiac amyloidosis in patients with high clinical suspicion for cardiac amyloidosis without evidence of serum or urine monoclonal light chains. B As per CCS 2020 guidelines, obtain nuclear scintigraphy with bone-seeking radiotracer, if available, to evaluate for cardiac involvement when transthyretin cardiac amyloidosis is suspected after exclusion of light chain amyloidosis. B As per ARC 2019 guidelines, obtain noninvasive evaluation with bone scintigraphy in patients with negative screening for the presence of a monoclonal protein. E Show 3 more ATTR genotyping: As per ACC 2022 guidelines, obtain genetic testing with transthyretin gene sequencing to differentiate hereditary variant from wild-type transthyretin cardiac amyloidosis in patients diagnosed with transthyretin cardiac amyloidosis. B As per CCS 2020 guidelines, obtain genetic testing to differentiate hereditary transthyretin from wild-type transthyretin amyloidosis in patients with a diagnosis of transthyretin cardiac amyloidosis. B As per ARC 2019 guidelines, perform TTR genotyping in patients in whom a diagnosis of ATTR amyloidosis is made on biopsy. E 4. Diagnostic procedures Endomyocardial biopsy: As per CCS 2020 guidelines, perform endomyocardial biopsy for diagnosis and subtyping with mass spectrometry or immunohistochemistry/immunofluorescence, if available, when the existing diagnostic workup for cardiac amyloidosis is equivocal or discordant with clinical suspicion. B As per ARC 2019 guidelines: Perform an endomyocardial biopsy to definitively diagnose ATTR cardiomyopathy in patients with monoclonal gammopathy of unknown significance. E Consider performing endomyocardial biopsy in patients with negative screening for the presence of a monoclonal protein, if bone scintigraphy is negative or indeterminate, but suspicion of cardiac amyloidosis is high. E Tissue biopsy: Perform a tissue biopsy from a clinically affected organ (endomyocardial biopsy if the heart is clinically affected), abdominal fat, or bone marrow biopsy if a monoclonal protein is detected, depending on availability and expertise at the clinic. E Perform biopsy of an involved organ in patients with negative fat pad biopsy. E 5. Medical management https://web.pathway.md/diseases/recRGSRWKNUQefP0x 4/8 6/29/23, 3:44 AM Cardiac amyloidosis Pathway General principles: provide comprehensive interdisciplinary management in patients with established cardiac amyloidosis. B Transthyretin tetramer stabilizer therapy: As per ACC 2022 guidelines: Initiate transthyretin tetramer stabilizer therapy (tafamidis) to reduce cardiovascular morbidity and mortality in selected patients with wild-type or variant transthyretin cardiac amyloidosis and NYHA class I-III HF symptoms. B Recognize that tafamidis provides low economic value (> $180,000 per quality-adjusted life year; as of 2020 list prices) in patients with HF with wild-type or variant transthyretin cardiac amyloidosis. B As per ESC 2021 guidelines: Initiate tafamidis to reduce symptoms, cardiovascular hospitalization and mortality in patients with genetic testing proven hereditary transthyretin cardiac amyloidosis and NYHA class I or II symptoms. B Initiate tafamidis to reduce symptoms, cardiovascular hospitalization and mortality in patients with wild-type transthyretin cardiac amyloidosis and NYHA class I or II symptoms. B As per CCS 2020 guidelines: Initiate tafamidis, if available, in patients with transthyretin cardiac amyloidosis and NYHA class I-III symptoms. A Initiate transthyretin RNA silencing agent (patisiran or inotersen) in patients with hereditary transthyretin amyloidosis with ambulatory polyneuropathy. A Anticoagulation therapy: As per AHA 2022 guidelines, consider initiating anticoagulation to reduce the risk of stroke regardless of the CHA2DS2-VASc score in patients with cardiac amyloidosis and AF. C As per CCS 2020 guidelines, initiate therapeutic anticoagulation in the absence of contraindications in patients with cardiac amyloidosis and AF/atrial flutter regardless of the calculated risk of stroke or systemic embolism. B Digoxin: consider initiating digoxin with caution due to the high risk of toxicity in patients with cardiac amyloidosis. C 6. Therapeutic procedures Implantable cardioverter-defibrillator: Place an ICD in patients with cardiac amyloidosis survived a cardiac arrest, if the expected meaningful survival is > 1 year. B Consider placing a prophylactic ICD in patients with AL-type cardiac amyloidosis with nonsustained ventricular arrhythmias, if the expected meaningful survival is > 1 year. C Permanent cardiac pacing: https://web.pathway.md/diseases/recRGSRWKNUQefP0x 5/8 6/29/23, 3:44 AM Cardiac amyloidosis Pathway As per ACC 2019 guidelines, consider permanent pacing with additional defibrillator capability if needed and meaningful survival of > 1 year is expected in patients with cardiac amyloidosis and second-degree Mobitz type II AV block, high-grade AV block, or third-degree AV block. C As per HRS 2019 guidelines, implant a permanent pacemaker in both symptomatic and asymptomatic patients with cardiac amyloidosis and second-degree AV block type II, high-grade AV block or third-degree AV block. B Catheter ablation: consider performing cardiac ablation in patients with cardiac amyloidosis and symptomatic atrial arrhythmias. C 7. Surgical interventions Heart transplantation: consider offering heart transplantation in selected patients with advanced HF due to cardiac amyloidosis if significant extracardiac manifestations are absent and the risk of disease progression is considered low and/or amenable to DMT. B 8. Follow-up and surveillance Indications for hematology referral: refer patients with a monoclonal protein to hematology. E Serial imaging and laboratory assessment: obtain serial imaging with echocardiography or cardiac MRI in addition to measuring BNP/N-terminal pro-BNP levels to monitor cardiac disease progression and/or response to therapy in patients with cardiac amyloidosis. B Clinical findings Patient demographics Symptoms Male sex Ankle swelling Excessive urination at night Past medical history Fatigue Leg swelling Cardiomyopathy Lightheadedness Genetic abnormality Palpitations Inflammation Swelling Respiratory exam Family history Dyspnea Genetic predispositions Imaging findings ECG findings Findings of cardiac amyloidosis Cardiac arrhythmias Severe diastolic dysfunction Low voltages Speckled myocardium https://web.pathway.md/diseases/recRGSRWKNUQefP0x 6/8 6/29/23, 3:44 AM Cardiac amyloidosis Pathway Pr depression or diffuse ST Likelihood Ratios Pertinent positives The following findings increase the probability of cardiac amyloidosis in adults. 8 9 Finding LR+ Value Presence of findings of cardiac amyloidosis 17.6 Presence of low electrical voltages and LV septum thickness > 1.98 cm 7.89 Presence of speckled myocardium 6.5 Presence of low voltages 4.31 Show 2 more Pertinent negatives The following findings decrease the probability of cardiac amyloidosis in adults. 8 9 Finding LR- Value Absence of findings of cardiac amyloidosis 0.13 Absence of low electrical voltages and LV septum thickness > 1.98 cm 0.31 Absence of low voltages 0.51 Absence of PR depression or diffuse ST elevation 0.63 Show 2 more Studies 2018 ATTR-ACT In patients with transthyretin amyloid cardiomyopathy, tafamidis, as compared to placebo, reduced all-cause mortality (29.5% vs. 42.9%; HR 0.70, 95% CI 0.51-0.96) and reduced the rate of cardiovascular-related hospitalizations (0.48 per year vs. 0.70 per year; RR 0.68, 95% CI 0.56- 0.81). Tafamidis also reduced the decline in distance for the 6 minute walk test (p < 0.001) and reduced the rate of decline in KCCQ-OS score (p < 0.001). The incidence and types of adverse events were similar in the two groups. Maurer MS et al. N Engl J Med. 2018 Sep 13. References 1. Paul A Heidenreich, Biykem Bozkurt, David Aguilar et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association https://web.pathway.md/diseases/recRGSRWKNUQefP0x 7/8 6/29/23, 3:44 AM Cardiac amyloidosis Pathway Joint Committee on Clinical Practice Guidelines. Circulation. 2022 Apr 1;101161CIR0000000000001063. Open 2. Nowell M Fine, Margot K Davis, Kim Anderson et al. Canadian Cardiovascular Society/Canadian Heart Failure Society Joint Position Statement on the Evaluation and Management of Patients With Cardiac Amyloidosis. Can J Cardiol. 2020 Mar;36 3 322 334. Open 3. Maurer MS, Bokhari S, Damy T et al. 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