Suspected ATTR Amyloid Cardiomyopathy Diagnostic Workup

Authored by Open Medicine, published on 2026-09-24 15:38:09.0

Clinical suspicion of cardiac amyloidosis

Consider cardiac amyloidosis in patients with otherwise unexplained heart failure or increased ventricular wall thickness, particularly when cardiac and extracardiac red flags coexist. Cardiac clues may include: heart failure, often with preserved or mildly reduced ejection fraction unexplained increased left or right ventricular wall thickness restrictive physiology or diastolic dysfunction atrial fibrillation or other atrial arrhythmias conduction disease, bradyarrhythmia or pacemaker requirement syncope low-flow, low-gradient aortic stenosis persistently elevated natriuretic peptides or troponin without another clear explanation Extracardiac clues may include: bilateral carpal tunnel syndrome lumbar or cervical spinal stenosis spontaneous biceps tendon rupture peripheral sensory neuropathy autonomic dysfunction family history of cardiomyopathy, heart failure or neuropathy Echocardiography and cardiac magnetic resonance may support the suspicion of cardiac amyloidosis but cannot reliably distinguish ATTR-CM from AL amyloidosis
- Exclude AL amyloidosis first
  
  Perform a complete monoclonal protein screen: serum free light chains with κ/λ ratio serum immunofixation electrophoresis urine immunofixation electrophoresis Interpret the κ/λ free light chain ratio using age-, kidney function– and assay-appropriate reference intervals. Suggested iStopMM/FreeLite reference intervals: eGFR ≥60 and age <70 years: 0.44–2.16 eGFR ≥60 and age ≥70 years: 0.46–2.59 eGFR 45–59: 0.46–2.62 eGFR 30–44: 0.48–3.38 eGFR <30: 0.54–3.30 Do not use serum or urine protein electrophoresis alone to exclude AL amyloidosis. If the FLC result is borderline or discordant, consider renal function, assay methodology and hematology input before classifying the monoclonal screen as abnormal.
  - Is the monoclonal protein screen abnormal?
    
    Consider the monoclonal protein screen abnormal if: serum immunofixation identifies a monoclonal protein; urine immunofixation identifies a monoclonal protein; or the serum κ/λ FLC ratio remains outside the appropriate age-, kidney function– and assay-adjusted reference interval. YES: do not establish ATTR-CM by scintigraphy alone; proceed to tissue confirmation and definitive amyloid typing. NO: proceed to bone-avid tracer scintigraphy.
    - Possible AL or coexisting monoclonal gammopathy
      
      An abnormal monoclonal protein screen prevents a secure non-biopsy diagnosis of ATTR-CM. Refer for hematologic/amyloidosis evaluation and obtain tissue confirmation with definitive amyloid typing. A positive bone scintigraphy scan does not establish ATTR-CM when a monoclonal gammopathy is present. Tissue may be obtained from an appropriate surrogate or clinically involved site. If surrogate-site biopsy is negative but cardiac amyloidosis remains strongly suspected, biopsy of the affected organ, including endomyocardial biopsy when appropriate, may be required. Amyloid type should be established using a validated typing method, preferably mass spectrometry when available.
    - Bone-avid tracer scintigraphy (PYP/DPD/HMDP)
      
      In patients with a negative monoclonal protein screen, perform bone-avid radionuclide scintigraphy using an accepted tracer: 99mTc-PYP 99mTc-DPD 99mTc-HMDP Include SPECT or SPECT/CT imaging to confirm that tracer uptake is truly myocardial and not due to residual blood-pool activity or overlying bone. Interpret the scan together with the cardiac phenotype and monoclonal protein assessment.
      - Interpret myocardial tracer uptake (Perugini grade)
        
        Grade myocardial uptake after confirming true myocardial localization: Grade 0: no myocardial uptake Grade 1: myocardial uptake less intense than rib uptake Grade 2: myocardial uptake similar to rib uptake Grade 3: myocardial uptake greater than rib uptake Grade 2–3 uptake may support non-biopsy ATTR-CM only when the monoclonal protein screen is negative. Grade 0–1 uptake does not meet established non-biopsy diagnostic criteria for ATTR-CM.
        
        Grade 2–3 uptake
        
        In the setting of a compatible cardiac phenotype and a negative monoclonal protein screen, Grade 2 or 3 true myocardial uptake fulfills the scintigraphic criterion for non-biopsy diagnosis of ATTR-CM.
        
        ATTR-CM confirmed without biopsy
        
        Non-biopsy ATTR-CM diagnosis requires: Compatible cardiac phenotype negative monoclonal protein screen Grade 2–3 true myocardial uptake confirmed by SPECT/SPECT-CT When all three conditions are met, ATTR-CM can be diagnosed without histologic confirmation. Proceed to TTR genetic testing.
        
        TTR genetic testing
        
        Perform TTR gene sequencing in every patient with confirmed ATTR-CM, regardless of age or apparent family history. Genetic testing distinguishes variant ATTR (ATTRv) from wild-type ATTR (ATTRwt) and has important implications for family counseling and cascade testing. Genetic counseling should accompany testing when available. A variant of uncertain significance should not by itself be considered diagnostic of hereditary ATTR; interpret uncertain variants with appropriate genetics/amyloidosis expertise.
        
        Pathogenic or likely pathogenic TTR variant identified: ATTRv-CM
        
        Confirm variant transthyretin amyloid cardiomyopathy (ATTRv-CM). Provide genetic counseling and discuss cascade genetic testing for appropriate at-risk relatives. Assess for extracardiac manifestations, particularly peripheral and autonomic neuropathy, because phenotype can vary substantially by TTR variant.
        
        No pathogenic or likely pathogenic TTR variant identified: ATTRwt-CM
        
        In a patient with confirmed ATTR-CM and no pathogenic or likely pathogenic TTR variant, classify the disease as wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). Proceed to disease staging, multidisciplinary clinical assessment and ATTR-CM treatment selection.
        
        Grade 1 uptake
        
        Grade 1 myocardial uptake does not meet established non-biopsy diagnostic criteria for ATTR-CM. Review the clinical phenotype, echocardiography and CMR findings. If cardiac amyloidosis remains clinically likely, proceed to specialist assessment and tissue confirmation with definitive amyloid typing.
        
        Non-biopsy ATTR-CM criteria not met
        
        Grade 1 uptake is insufficient to establish ATTR-CM without histology. If suspicion for cardiac amyloidosis remains significant, proceed to specialist evaluation and tissue confirmation rather than labeling the scan as diagnostic ATTR-CM. The biopsy strategy should be individualized according to the suspected amyloid type, involved organs and diagnostic yield.
        
        Specialist assessment and tissue confirmation
        
        Obtain tissue confirmation when the non-biopsy ATTR-CM criteria are not fulfilled and cardiac amyloidosis remains clinically suspected. Demonstrate amyloid deposition and establish the precursor protein using definitive amyloid typing, preferably mass spectrometry when available. A positive surrogate-site biopsy may establish the diagnosis; however, a negative fat-pad or bone marrow biopsy does not reliably exclude cardiac amyloidosis. If suspicion remains high despite a negative surrogate-site biopsy, biopsy of the affected organ, including endomyocardial biopsy when appropriate, should be considered. If tissue typing confirms ATTR, proceed to TTR genetic testing.
        
        Grade 0 uptake
        
        No definite myocardial tracer uptake is identified. Typical ATTR-CM is less likely, but a negative bone scintigraphy scan does not absolutely exclude ATTR-CM in every clinical setting.
        
        Typical ATTR-CM unlikely
        
        Grade 0 scintigraphy makes typical ATTR-CM unlikely. If clinical suspicion is low, reassess for alternative causes of the cardiac phenotype. If suspicion remains high: review echocardiography and CMR; reassess the monoclonal protein evaluation; consider disease stage and hereditary phenotype; consider referral to an amyloidosis specialist and tissue diagnosis. False-negative bone scintigraphy may occur in very early disease and with certain TTR variants.
Clinical pearl: monoclonal gammopathy and ATTR can coexist

An abnormal monoclonal proteA monoclonal gammopathy does not exclude ATTR-CM. Conversely, a positive bone scan does not establish ATTR-CM when the monoclonal protein screen is abnormal. When both are present, tissue confirmation with definitive amyloid typing is required to determine the amyloid precursor protein.in screen requires tissue typing.

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