What is the next step in managing a suspected case of cardiac amyloidosis in an adult patient with equivocal scintigraphic findings, a heart to contralateral lung ratio of 1-1.5, and potential risk factors such as hypertension, chronic kidney disease, or a family history of amyloidosis?

Management of Equivocal Scintigraphic Findings in Suspected Cardiac Amyloidosis

With an H/CL ratio of 1.0-1.5, you must first confirm diffuse myocardial uptake on SPECT imaging and then use the visual grading system (comparing myocardial uptake to rib uptake) to determine the next diagnostic step, as the H/CL ratio alone cannot establish or exclude the diagnosis of ATTR cardiac amyloidosis. 1

Step 1: Confirm Myocardial Uptake on SPECT

The critical first step is to carefully review SPECT images to differentiate true myocardial radiotracer uptake from residual blood pool activity or overlapping bone structures 1. This is essential because:

• If excess blood pool activity is present at 1 hour, repeat SPECT imaging at 3 hours to maximize specificity and reduce false positive interpretations 1
• The addendum to the 2021 consensus guidelines specifically warns against incorrect diagnosis of ATTR-CA based on planar imaging and H/CL ratio without SPECT confirmation of diffuse myocardial uptake 1
• SPECT/CT fusion imaging substantially reduces equivocal and false positive cases by providing anatomical landmarks 2

Step 2: Apply Semi-Quantitative Visual Grading

Once myocardial uptake is confirmed on SPECT, compare the myocardial tracer uptake to rib uptake using this grading scale 1:

• Grade 0: No myocardial uptake → Not suggestive of ATTR-CA
• Grade 1: Myocardial uptake less than rib uptake → Equivocal; requires further evaluation
• Grade 2: Myocardial uptake equal to rib uptake → Strongly suggestive of ATTR-CA (if monoclonal protein excluded)
• Grade 3: Myocardial uptake greater than rib uptake with mild/absent rib uptake → Strongly suggestive of ATTR-CA (if monoclonal protein excluded)

Step 3: Interpret the H/CL Ratio in Context

Your H/CL ratio of 1.0-1.5 falls in an indeterminate zone that requires careful interpretation 1:

• An H/CL ratio ≥1.5 at 1 hour is diagnostic for ATTR-CA (when myocardial uptake is confirmed on SPECT and AL amyloidosis is excluded) 1
• An H/CL ratio ≥1.3 at 3 hours is diagnostic for ATTR-CA 1
• The H/CL ratio is most useful when the visual grade is equivocal (Grade 1 vs Grade 2) to help classify the case as positive or negative 1
• The H/CL ratio should NOT be used alone to make the diagnosis and is not recommended if there is absence of myocardial uptake on SPECT 1

Step 4: Exclude AL Amyloidosis (Critical)

All patients with suspected cardiac amyloidosis must undergo screening for monoclonal plasma cell dyscrasia before confirming ATTR-CA diagnosis 1:

• Obtain serum and urine immunofixation electrophoresis
• Obtain serum free light chain assay
• This is mandatory because Grade 2 or 3 uptake can be seen in >20% of patients with AL cardiac amyloidosis 1
• Grade 0 and Grade 1 uptake may also be observed in AL cardiac amyloidosis and warrants further evaluation 1

Step 5: Consider Additional Diagnostic Testing

If your case remains equivocal after the above steps, consider 1, 3:

• Cardiac MRI if echocardiography shows suggestive findings, looking for diffuse subendocardial late gadolinium enhancement (88% sensitivity, 100% specificity for AL amyloidosis) and elevated extracellular volume (>0.40) 3
• Endomyocardial biopsy if non-invasive testing remains inconclusive and clinical suspicion is high
• Referral to an amyloidosis expert or hematologist is recommended when imaging is equivocal or discordant with clinical findings 1

Important Caveats

Technical Considerations

• H/CL ratios may be falsely low in patients with prior large myocardial infarction because tracer uptake is limited to non-infarcted zones 1
• Careful SPECT evaluation with non-planar image display is recommended to visualize regional uptake patterns 1
• Ensure proper ROI placement to avoid sternal overlap and maximize heart coverage without including adjacent lung 1

Alternative Causes of Uptake

99mTc-PYP/DPD/HMDP uptake can occur in other conditions 1:

• Pericarditis
• Myocardial infarction (regional uptake pattern)
• Chemotherapy or drug-associated myocardial toxicity

Clinical Integration

• Review echocardiographic findings for supportive features: LV wall thickness ≥12 mm, apical sparing pattern on strain imaging, biatrial enlargement 3
• Check for voltage-to-mass discordance (low QRS voltage on ECG with increased LV wall thickness) 3
• Assess for clinical red flags: bilateral carpal tunnel syndrome, lumbar spinal stenosis, autonomic neuropathy, or unexplained heart failure with preserved ejection fraction 3

Reporting Recommendation

Your report should categorize the findings as 1:

• Equivocal for ATTR cardiac amyloidosis if diffuse myocardial uptake is confirmed on SPECT but visual grade is 1 or there is interpretive uncertainty between Grade 1 and Grade 2
• Include a statement that AL amyloidosis evaluation is recommended in all patients
• Recommend referral to an amyloidosis expert if findings remain equivocal after complete workup 1