What is the diagnostic approach for cardiac amyloidosis?

Diagnosis of Cardiac Amyloidosis

Diagnostic Algorithm

The diagnosis of cardiac amyloidosis follows a structured pathway beginning with clinical suspicion based on red flags, followed by echocardiography as first-line imaging, then monoclonal protein screening to differentiate subtypes, and finally either nuclear imaging or cardiac MRI for confirmation—with biopsy reserved for equivocal cases. 1, 2

Step 1: Recognize Clinical Red Flags

Specific clinical features should immediately trigger suspicion for cardiac amyloidosis:

Cardiac manifestations:

• Heart failure with preserved ejection fraction (HFpEF) with unexplained left ventricular wall thickness ≥12 mm 2
• Low QRS voltage on ECG despite ventricular wall thickening on imaging (voltage-to-mass discordance) 1, 2
• Pseudoinfarct pattern on ECG (Q waves without coronary disease) 1, 2
• Atrial fibrillation with restrictive physiology 1
• Atrioventricular conduction abnormalities 1

Extracardiac red flags:

• Bilateral carpal tunnel syndrome without rheumatoid arthritis or trauma 1, 2, 3
• Spontaneous biceps tendon rupture without heavy lifting 1, 2, 3
• Lumbar spinal stenosis requiring surgery 2
• Unexplained peripheral or autonomic neuropathy 2, 3
• Macroglossia 3
• Unexplained proteinuria or hepatomegaly 3

Biomarker abnormalities:

• Disproportionately elevated NT-proBNP or BNP relative to degree of heart failure (sensitivity 93%, specificity 90%) 1, 2
• Elevated troponin (T, I, or high-sensitivity) without acute coronary syndrome 1, 2

Step 2: Perform Echocardiography (First-Line Imaging)

Echocardiography must be performed in all patients with suspected cardiac amyloidosis or systemic amyloidosis with heart failure. 1, 2

Key echocardiographic findings:

• Left ventricular wall thickness >12 mm with small cavity size 1, 2
• Biatrial enlargement disproportionate to ventricular dysfunction 2
• Thickened cardiac valves without significant stenosis 2
• Restrictive transmitral Doppler filling pattern (grade ≥2 diastolic dysfunction) 1, 2
• Apical sparing pattern on longitudinal strain with apical-to-basal strain ratio >2.1 (highly specific finding) 1, 2
• LV ejection fraction-to-strain ratio >4 2
• Pericardial effusion 1, 2
• Increased atrial septal thickness 2

Critical limitation: Echocardiography cannot distinguish AL from ATTR subtypes—further testing is mandatory. 2

Step 3: Monoclonal Protein Screening (Mandatory for All Cases)

Immediately obtain monoclonal protein screening to differentiate AL from ATTR amyloidosis: 2, 3

• Serum free light chain (sFLC) assay 3
• Serum immunofixation electrophoresis (SIFE) 3
• Urine immunofixation electrophoresis (UIFE) 3

This step is critical because treatment differs dramatically between subtypes, and misdiagnosis leads to inappropriate therapy and patient harm. 3

Step 4: Subtype-Specific Diagnostic Pathways

For ATTR Amyloidosis (Monoclonal Protein Screening Negative):

Nuclear bone scintigraphy with 99mTc-PYP/DPD/HMDP is diagnostic without biopsy when all three criteria are met: 1, 2, 3

1. Grade 2 or 3 myocardial uptake of radiotracer 1
2. Absence of monoclonal plasma cell process (negative sFLC, SIFE, UIFE) 1
3. Typical cardiac imaging features on echo or CMR 1

Important caveat: A Perugini score of 2 or 3 is only "indicative" of cardiac amyloidosis, not "confirmative" for ATTR subtype until monoclonal protein screening is negative. 4

After confirming ATTR, perform TTR gene sequencing to differentiate:

• ATTRwt (wild-type, formerly "senile" amyloidosis) 1
• ATTRv (hereditary variant) 1

This distinction has therapeutic implications and genetic counseling requirements. 1

For AL Amyloidosis (Monoclonal Protein Screening Positive):

AL cardiac amyloidosis diagnosis requires: 1, 3

• Demonstration of tissue amyloid deposits (cardiac or extracardiac biopsy) AND 3
• Evidence of plasma cell dyscrasia (positive monoclonal protein screening) AND 3
• Either typical cardiac imaging features OR abnormal cardiac biomarkers (NT-proBNP or troponin) with other causes excluded 1

Collaborate immediately with hematology to determine if findings represent spurious results, MGUS, AL amyloidosis, or multiple myeloma. 3

Step 5: Cardiac MRI (When Echo is Suggestive or Equivocal)

Cardiac MRI should be performed when echocardiography shows suggestive but not definitive findings. 2

Diagnostic CMR features (any one is sufficient): 1

• LV wall thickness > upper limit of normal for sex on SSFP cine imaging 1
• Global extracellular volume (ECV) >0.40 1, 2
• Diffuse late gadolinium enhancement (LGE), particularly circumferential subendocardial pattern 1, 2
• Abnormal gadolinium kinetics with myocardial nulling before blood pool nulling 1, 2
• Elevated native T1 values (>1020-1044 ms depending on technique) 2

CMR diagnostic performance: Sensitivity 80-92%, specificity 87-94% for cardiac amyloidosis. 2 The diffuse subendocardial LGE pattern has 88% sensitivity and 100% specificity for AL amyloidosis specifically. 2

Critical contraindication: Gadolinium is contraindicated in patients with estimated GFR <30 ml/min/1.73 m² due to nephrogenic systemic fibrosis risk. 1, 3

Step 6: Endomyocardial Biopsy (Gold Standard, When Needed)

Endomyocardial biopsy remains the definitive diagnostic test when non-invasive methods are equivocal or when precise tissue diagnosis is required. 1, 3

Biopsy technique and interpretation:

• Congo red staining showing apple-green birefringence under polarized light confirms amyloid 1, 3
• Mass spectrometry-based analysis (LC-MS/MS) is the gold standard for amyloid typing (88% sensitivity, 96% specificity) 3
• Immunohistochemistry is less reliable than mass spectrometry and should only be performed at experienced centers 3

Alternative biopsy sites (less invasive):

• Abdominal fat pad aspiration: 84% sensitivity for AL, but only 45% for ATTRv and 15% for ATTRwt 3
• Bone marrow biopsy: 69% sensitivity for AL amyloidosis 3
• Rectum, gingiva, liver, kidney 1

Step 7: Assess Extent of Organ Involvement

Once cardiac amyloidosis is diagnosed, systematic evaluation of all potentially affected organs is mandatory because extent of involvement determines treatment strategy and prognosis. 1

Common Diagnostic Pitfalls to Avoid

Do not rely solely on clinical features without histological or imaging confirmation when monoclonal gammopathy is present—not all monoclonal proteins indicate AL amyloidosis. 3

Do not assume ATTR diagnosis based on nuclear imaging alone—must confirm absence of monoclonal protein. 1, 4

Do not use digoxin or calcium channel blockers in suspected cardiac amyloidosis, as these drugs bind to amyloid fibrils causing toxicity and exaggerated hypotensive responses even at therapeutic levels. 1

Do not overlook the voltage-to-mass discordance—low QRS voltage with increased wall thickness is one of the most specific ECG findings. 1, 2

Do not perform cardiac MRI in patients with severe renal dysfunction (GFR <30) without careful risk-benefit assessment due to gadolinium contraindication. 1, 3

Integration of Diagnostic Modalities

The 2021 ASNC/AHA/ASE expert consensus provides the most comprehensive and recent diagnostic framework, emphasizing that diagnosis can be established through three pathways: 1

1. Histological diagnosis via endomyocardial biopsy (definitive for all subtypes) 1
2. Histological diagnosis via extracardiac biopsy plus typical cardiac imaging features 1
3. Non-invasive diagnosis of ATTR via nuclear imaging (grade 2-3 uptake) plus negative monoclonal protein screening plus typical cardiac imaging 1

The 2016 AHA statement notes uncertainty about CMR accuracy for diagnosis, though acknowledges its value for assessing extent of involvement. 1 However, the more recent 2021 consensus and contemporary evidence support CMR as a robust diagnostic tool with well-defined criteria. 1, 2

The key is recognizing that early diagnosis is crucial because effective, life-saving treatments now exist for both AL and ATTR amyloidosis, making timely and accurate diagnosis more important than ever. 5, 6, 7