What is the diagnostic approach for an older adult suspected of having cardiac amyloidosis presenting with symptoms of heart failure or arrhythmias?

Diagnostic Approach for Cardiac Amyloidosis

Begin with simultaneous monoclonal protein screening (serum and urine immunofixation electrophoresis plus serum free light chains) in all patients with suspected cardiac amyloidosis, as this obligate first step determines whether you pursue the AL or ATTR diagnostic pathway. 1, 2

Clinical Recognition: When to Suspect Cardiac Amyloidosis

Suspect cardiac amyloidosis in older adults presenting with:

• Left ventricular wall thickness ≥12-14 mm with low QRS voltage on ECG (voltage-to-mass discordance is a critical red flag) 1, 2, 3
• Heart failure with preserved ejection fraction (HFpEF) with unexplained LV hypertrophy 1, 2
• Bilateral carpal tunnel syndrome, particularly in males without rheumatoid arthritis or trauma 1, 2, 4
• Disproportionately elevated NT-proBNP relative to clinical heart failure severity (sensitivity 93%, specificity 90%) 2, 4
• Lumbar spinal stenosis, spontaneous biceps tendon rupture, or prior orthopedic procedures 1, 2, 4
• Autonomic or sensory polyneuropathy without clear etiology 1, 2, 4
• Concomitant aortic stenosis (particularly low-flow, low-gradient) with unexplained LV hypertrophy 1, 4
• Intolerance to ACE inhibitors, ARBs, or beta-blockers with resolving hypertension over time 1

Step 1: Monoclonal Protein Screening (Mandatory First Step)

Order all three tests simultaneously before any other diagnostic testing: 1, 2, 4

• Serum immunofixation electrophoresis (SIFE)
• Urine immunofixation electrophoresis (UIFE)
• Serum free light chain assay (sFLC) with kappa/lambda ratio

Critical pitfall: Never interpret bone scintigraphy without concomitant monoclonal protein screening, as >10% of AL amyloidosis cases show positive cardiac uptake on nuclear imaging. 1

Step 2: Initial Cardiac Imaging with Echocardiography

Perform transthoracic echocardiography as the first-line cardiac imaging modality in all suspected cases. 1, 2, 3

Key Echocardiographic Findings:

Structural abnormalities: 3

• LV wall thickness ≥12 mm with small cavity size
• Biatrial enlargement disproportionate to ventricular dysfunction
• Thickened cardiac valves without significant stenosis
• Increased atrial septal thickness

Functional abnormalities: 3

• Apical sparing pattern on longitudinal strain with apical-to-basal strain ratio >2.1 (highly specific for cardiac amyloidosis)
• Restrictive transmitral Doppler filling pattern
• LV ejection fraction-to-strain ratio >4

Important limitation: Echocardiography cannot distinguish AL from ATTR amyloidosis; further testing is required for subtype determination. 3

Step 3: Divergent Diagnostic Pathways Based on Monoclonal Protein Results

Pathway A: Monoclonal Protein DETECTED → Suspect AL Amyloidosis

If monoclonal protein is present, refer to hematologist-oncologist immediately for further evaluation. 1, 2, 4

Proceed with: 2

• Abdominal fat pad aspiration (first-line surrogate biopsy site; 84% sensitivity for AL cardiac amyloidosis)
• Bone marrow biopsy to demonstrate clonal plasma cells and exclude multiple myeloma or B-cell lymphoproliferative disorders
• Endomyocardial biopsy if fat pad aspiration is negative but clinical suspicion remains high 1

Pathway B: Monoclonal Protein ABSENT → Pursue ATTR Amyloidosis

Perform bone scintigraphy with 99mTc-pyrophosphate (99mTc-PYP), 99mTc-DPD, or 99mTc-HMDP. 1, 2, 4

Diagnostic criteria for ATTR cardiac amyloidosis without biopsy: 1, 2, 5

• Grade 2-3 myocardial uptake on bone scintigraphy
• AND absence of monoclonal protein on screening
• This combination is diagnostic for ATTR cardiac amyloidosis without need for endomyocardial biopsy

If ATTR amyloidosis is confirmed, perform TTR gene sequencing to differentiate hereditary variant (ATTRv) from wild-type (ATTRwt) amyloidosis. 1, 4

Step 4: Cardiac MRI (When Indicated)

Reserve cardiac MRI for cases where echocardiography shows suggestive but not definitive findings. 1, 2, 3

Diagnostic MRI Features: 2, 3

• Diffuse subendocardial or transmural late gadolinium enhancement (LGE) distributed circumferentially (88% sensitivity, 100% specificity for AL amyloidosis)
• Elevated native T1 values (>1020-1044 ms depending on technique)
• Abnormal gadolinium kinetics with myocardial nulling occurring before blood pool nulling
• Elevated extracellular volume (ECV >0.40)

Cardiac MRI adds most value for: 3

• Tissue characterization to differentiate cardiac amyloidosis from hypertrophic cardiomyopathy or hypertensive heart disease
• Prognostication, as LGE presence and extent predict mortality (OR 2.73-19.84 depending on pattern)

Step 5: Supportive Biomarkers and ECG Findings

Biomarkers that support diagnosis: 2, 4

• NT-proBNP disproportionately elevated relative to degree of heart failure
• Elevated troponin (T, I, or high-sensitivity)

ECG findings: 2, 3

• Low QRS voltage despite increased wall thickness on echocardiography
• Pseudoinfarct pattern (Q waves without prior myocardial infarction)
• Voltage-to-mass discordance

Critical Diagnostic Pitfalls to Avoid

• Never interpret bone scintigraphy without monoclonal protein screening first – this is the most common diagnostic error. 1
• Do not delay monoclonal protein screening beyond 6 weeks, as delays are associated with increased early mortality. 2
• Avoid misdiagnosing cardiac amyloidosis as hypertrophic cardiomyopathy or generic HFpEF – maintain high clinical suspicion in older adults with the red flag features described above. 1
• Do not rely on endomyocardial biopsy when grade 2-3 uptake on bone scintigraphy plus negative monoclonal protein screen is present – this combination is diagnostic for ATTR without biopsy. 1, 2