How to diagnose

Diagnostics

There are a number of clues or “red flags” that should warrant screening for ATTR-CM.[3][4] Several systemic symptoms should raise suspicion of ATTR-CM, such as a history of bilateral carpal tunnel syndrome.

Tools such as electrocardiograms (ECGs), echocardiography (ECHO), and cardiac magnetic resonance imaging (cMRI) scans can provide valuable insight.[3][4] If patients display any of these “red flags”, they should be referred for nuclear scintigraphy.[4]

 

Systemic symptoms

Patients with other non-cardiac symptoms may be at greater risk for ATTR-CM.[4]

Electrocardiogram/echocardiography/cardiac magnetic resonance imaging

ECG and ECHO can show QRS voltages and a hypertrophic phenotype.[3][4]

Cardiac biomarkers

N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin T are often elevated in ATTR-CM patients.[3]

Electrocardiogram

Normal to low QRS voltage in combination with increased left ventricular (LV) thickness is a classic feature of cardiac amyloidosis (CA) and should raise suspicion.[3][7]

Normal (or low) QRS voltage is usually correlated to ATTR-CM. Low QRS voltage is typically correlated to AL amyloidosis but might also occur relatively late in ATTR-CM.[3][13][14] Other common findings include LV hypertrophy,[3] left bundle branch block,[3][15] intraventricular conduction delay,[3][16] and atrial arrhythmia.[16]

 

Pseudo-infarction patterns

Pseudo-infarction patterns have been identified in up to 70% of cases.[3][7]

Atrioventricular block

Atrioventricular block has been identified in up to 22% of cases.[3][7]

Show ECG image

Echocardiogram

Nearly all ECHO signals are non-specific, but in context, they can be highly suggestive of CA.[3]

A discrepancy between increased LV thickness and normal (or low) QRS voltage is an important “red flag” in CA.[3][7] Other classical signs of CA on an ECHO include impairment of relaxation and normal or near-normal LV ejection fraction and and apical sparing of longitudinal strain.[3][15]

 

Increased left ventricular wall thickness

Characteristic findings are thickened left ventricles, LV posterior wall hypertrophy, and increased septal thickness (≥14 mm).[3][4][17]

Hypertrophy

Evidence of infiltrative features such as increased thickness of the atrioventricular values is a “red flag” for ATTR-CM.[3][4]

Longitudinal strain

A base-to-apex strain gradient with relative apical sparing of longitudinal strain is another “red flag”.[3][4]

Show ECHO image

Cardiac magnetic resonance imaging

cMRI is an imaging tool that is generally performed with and without contrast and shows the cardiac structure, function, and tissue characteristics but cannot distinguish cardiac AL from ATTR amyloidosis.[18]

Late gadolinium enhancement (LGE), quantitative T1 mapping and extracellular volume (ECV) calculation are techniques that can be used to increase the suspicion of ATTR-CM.[18][19] LGE accumulation of gadolinium contrast due to increased extracellular volume as a result of the infiltration of amyloid fibrils, as well as long native T1 times are indications of CA.[18][19]

 

Late gadolinium enhancement

LGE accumulation of gadolinium contrast could be indicative “red flag” for ATTR-CM.[18]

Quantitative T1 mapping and extracellular volume

These are techniques that could be useful for early suspicion and clinical follow up for ATTR-CM patients.[18]

Show cMRI image

Ruling out light-chain amyloidosis

The combination of serum and urine tests for monoclonal proteins gives 99% sensitivity for identifying AL amyloidosis.[4][10] This is important because AL amyloidosis is characterized by a rapidly progressive clinical course which, if untreated, has a median survival of <6 months.[4]

If the results from one or more of these tests are abnormal, a bone marrow-, and fat biopsy (alternative target organ) is needed for definite diagnosis.[4][10] Patients diagnosed with AL amyloidosis should be referred to hematology.

 

Free light-chain assay in serum and urine

Abnormal if serum κ/λ FLC ratio is <0.26 or >1.65.[4]

Serum and urine protein electrophoresis with immunofixation

Abnormal if monoclonal protein (M-spike) is detected in serum/urine.[4]

Nuclear bone tracer scintigraphy of the heart

Alongside concomitant testing for light chains, nuclear scintigraphy has high sensitivity and specificity for achieving a definitive diagnosis of ATTR-CM.[2][3][23]

Assessment is accomplished by semiquantitative (comparing heart to rib uptake) or quantitative (comparing a region of interest placed over the heart with a similar-sized region of intensity placed over the contralateral chest) approaches.[25] Biopsy may be required if clinical suspicion remains high for ATTR-CM despite a negative or inconclusive scintigraphy result.[2]

 

Non-invasive

Nuclear scintigraphy can negate the need for a biopsy.[2]

Safe in elderly patients

Has shown to be safe to detect wild-type ATTR amyloidosis (ATTRwt amyloidosis) among elderly patients admitted due to HF with preserved ejection fraction.[26]

Combine with serum and urine tests

To avoid false-positive results and differentiate from AL amyloidosis.[2][10][24]

Show scintigraphy image

Cardiac biomarkers

Plasma concentration of natriuretic peptides (NP) can be used as an initial test for heart failure (HF), but as there are many cardiovascular and non-cardiovascular causes of elevated NP, other tests must also be used.[20]

Biomarker levels can be used to stratify patients with HF and predict risk of hospitalization and mortality[21] and have also been used to predict prognosis in patients with certain types of CA.[22][23]

 

N-terminal pro-B-type natriuretic peptide

Elevated levels of NT-proBNP can be prognostic in ATTR-CM.[22]

Troponin

Elevated levels of troponin I/T and/or troponin I can be prognostic in ATTR-CM.[23]

Biopsy

Biopsy is an invasive diagnostic test used to make a definitive diagnosis if clinical suspicion remains high for ATTR-CM, despite a negative or inconclusive scintigraphy scan.[2]

Although the gold standard of CA has been endomyocardial biopsy, this requires sufficient expertise and carries potential risk, meaning that extracardiac biopsy (such as from the abdominal fat pad) may be preferred, particularly in elderly patients.[3][7][28] Fibril typing can be performed by immunohistochemistry or proteomic analysis by mass spectrometry.[10]

 

Amyloid staining and Immunohistochemistry

CA deposits, when stained with Congo red dye and viewed under polarized light, show apple-green birefingence, in parallel specific antibodies could be used for amyloid fibril typing.[3]

Mass spectrometry

Mass spectrometry is considered the new gold standard for fibril typing.[3]

Negative biopsy

A negative biopsy does not rule out CA, as the distribution of amyloid deposits is variable.[29]

Show biopsy image

Genetic testing

If ATTR-CM is identified, genetic sequencing of the transthyretin (TTR) gene is required to confirm whether the patient has ATTRv or ATTRwt amyloidosis.[3]

Not only does this provide important information regarding prognosis, but it is also critical because confirmation of ATTRv amyloidosis should trigger genetic counselling and potential screening of family members.[3]

 

In all cases

TTR gene sequencing and genetic counselling are recommended in all forms of confirmed ATTR-CM.[3]

In healthy relatives

Genetic counselling should be offered to at-risk relatives of patients with ATTRv amyloidosis.[30]