Non-Invasive Diagnosis of Cardiac Amyloidosis

How to Detect Amyloidosis

Currently, there are 9 known types of cardiac amyloidosis. The most common types are immunoglobulin light chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). In the case of suspected cardiac amyloidosis, it is crucial to quickly establish a definitive diagnosis because early initiation of treatment significantly affects outcomes. Invasive diagnostics that involve examining biopsies of cardiac or extracardiac tissue can identify any type of amyloidosis. However, non-invasive methods also play a significant role in diagnostics, expanding the screening possibilities for this condition in various patient risk groups.

Non-Invasive Examinations

Echocardiography

The fundamental finding indicative of cardiac amyloidosis is otherwise unexplained thickening of the left ventricular myocardium (LV) to ≥ 12 mm.

Additionally, the following must be present

EITHER ≥ 2 other findings from the following:

• diastolic dysfunction of grade 2 or worse
• reduced s', e', and a' wave velocities in Doppler examination to < 5 cm/s
• reduced overall longitudinal strain of the LV (absolute value < -15 %)

OR a multiparametric score of ≥ 8 points:

Note: IVS – intraventricular septum size; LVEDD – LV diameter at end-diastole; PWT – posterior wall thickness of LV; TAPSE – tricuspid annular plane systolic excursion.

Scintigraphy

If echocardiographic findings are positive, the diagnosis of cardiac ATTR can be established using non-invasive methods – scintigraphy and cardiac magnetic resonance imaging (CMR). During scintigraphy, after administering radiopharmaceuticals from the phosphonate group labeled with technetium isotope ^99mTc (^99mTc-DPD and ^99mTc-HMDP), a typical image is observed in patients with ATTR. While in healthy individuals, the substance has an affinity for the skeleton, in patients with ATTR, there is either similar uptake of the radiopharmaceutical in both the skeleton and myocardium (grade 2) or even more intense myocardial uptake with minimal skeletal uptake (grade 3).

Scintigraphy should ideally be performed using single photon emission computed tomography (SPECT) to confirm that the radiopharmaceutical uptake corresponds to the presence and distribution of the substance throughout the myocardium, and not just in the ventricular cavity or a specific area damaged by, for instance, ischemia.

Immunological Examination of Blood and Urine

Examination of serum free light chains (FLC) levels and protein electrophoresis with immunofixation of serum (SPIE) and urine samples (UPIE) provides information on the presence of monoclonal gammopathy. Positive results indicate AL amyloidosis, negative results (i.e., absence of monoclonal protein) indicate ATTR. With normal immunological examination results, scintigraphy showing grade 2 or 3 radiopharmaceutical uptake in the myocardium has almost 100% specificity for ATTR.

Cardiac Magnetic Resonance

During CMR examination, diffuse subendocardial and transmural late gadolinium enhancement and abnormal gadolinium kinetics are always observed. A calculated extracellular volume (ECV) value of ≥ 0.40% supports the diagnosis but is not necessary for its establishment.

Diagnostic Algorithm

The Working Group on Myocardial and Pericardial Diseases of the European Society of Cardiology (ESC) recommends that in cases of suspected cardiac amyloidosis (left ventricular wall thickness ≥ 12 mm + at least 1 warning sign of cardiac amyloidosis), scintigraphy should initially be performed along with SPIE, UPIE, and FLC. These test results can lead to the following 4 scenarios:

• Negative scintigraphy, negative monoclonal protein: ATTR and AL are unlikely, and alternative diagnoses should be excluded. If suspicion persists, CMR and invasive diagnostic methods are recommended to exclude rare forms of hereditary ATTR.
• Positive scintigraphy, negative monoclonal protein: The likely diagnosis is ATTR. Genetic testing is recommended to differentiate between acquired and hereditary forms. If scintigraphy results show grade 1, non-invasive methods cannot be solely relied upon, and histological confirmation using invasive diagnostics is needed to verify the presence of amyloid in cardiac or extracardiac tissue.
• Negative scintigraphy, positive at least one immunological test: AL amyloidosis should be ruled out, and CMR should be performed to exclude myocardial involvement. If CMR is positive or uncertain, invasive methods are used.
• Positive scintigraphy, positive at least one immunological test: Possible diagnoses include concurrent ATTR and monoclonal gammopathy, AL amyloidosis, or coexistent ATTR and AL. Histological examination from an endomyocardial biopsy is necessary.

Conclusion

Cardiac amyloidosis should be considered in patients with unexplained LV wall thickening who have warning signs (heart failure or aortic stenosis after the age of 65, hypotension following previous hypertension, autonomic dysfunction, peripheral polyneuropathy, proteinuria, bilateral carpal tunnel syndrome, increased bruising, biceps tendon rupture), other suspicious findings on ECG, or a positive family history. Non-invasive methods facilitate the diagnosis of the most common amyloidosis types and can be sufficient for diagnosing ATTR.

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Source: Garcia-Pavia P., Rapezzi C., Adler Y. et al. Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2021; 42: 1554–1568, doi: 10.1093/eurheartj/ehab072.