Cardiac amyloidosis

Cardiac amyloidosis (plural: amyloidoses) is a significant source of morbidity among patients with systemic amyloidosis and is the most common cause of restrictive cardiomyopathy outside the tropics.

Pathology

Amyloidosis represents the extra-cellular deposition of insoluble fibrillar proteinaceous material in various organs and tissues in a variety of clinical settings. For a general discussion of the condition please refer to amyloidosis. 

Cardiac involvement is seen with most forms of amyloidosis, although it is most common and most often clinically significant with primary amyloidosis (i.e. associated with multiple myeloma or other monoclonal gammopathies).

There are 2 main forms of amyloidosis that significantly affect the heart.

• AL amyloidosis: acquired disease
• transthyretin-related (TTR) amyloidosis: there are 2 types of TTR-related amyloidosis:
  • genetic form: hereditary transthyretin-related amyloidosis (ATTR)
  • non-hereditary form: senile systemic amyloidosis (SSA)

Radiographic features

Echocardiography

Described transthoracic echocardiography findings include

• atrial septal thickening
  • considered a characteristic feature of cardiac amyloidosis
• characteristic granular/sparkling appearance of the left ventricular (LV) myocardium: not specific and need to differentiate from other infiltrative diseases
• increased LV wall thickness
  • results from amyloid infiltration of interstitial space and may relate to amyloid burden
• decreased LV end-diastolic volume
  • leads to reduced stroke volume despite near-normal LVEF
• typically preserved or mildly reduced LV ejection fraction
  • systolic dysfunction may occur in advanced disease
• transmitral flow demonstrates a restrictive filling pattern
  • exaggerated E/A ratio (E>>A) with a truncated E wave deceleration time (DT) 
    • a reduced amplitude A wave may suggest poor atrial function and a higher risk of thrombus formation
  • elevated E/e’ ratio suggestive of elevated left atrial pressure
    • pulmonary venous doppler waveforms will demonstrate a diastolic filling predominance with an S/D ratio <1
      • amplitude of atrial reversal (AR) >35 cm/s
      • duration of AR exceeds mitral A wave by >20 ms
• biatrial enlargement
  • right atrial enlargement
  • left atrial enlargement
• atrial strain:  can be significantly reduced
• longitudinal strain (LS) in the left ventricle is impaired
  • impairment more pronounced at the base and mid-ventricular regions compared to the apex
  • specific patterns of left ventricular LS may differentiate amyloid from aortic stenosis and hypertrophic cardiomyopathy
• reduced right ventricular systolic excursion velocity (S') as measured by tissue Doppler imaging
  • tricuspid annular plane systolic excursion and RV LS are early indicators of cardiac involvement in patients with systemic AL amyloidosis
• reduced tricuspid annular plane systolic excursion (TAPSE) despite normal RV end-diastolic dimension
• dynamic left ventricular outflow tract obstruction
  • distinguish from hypertrophic obstructive cardiomyopathy (HOCM)

MRI

MRI is the modality of choice for evaluating cardiac amyloidosis. Features include:

• a diffuse decrease in the T1 and T2 signal intensity of myocardium
• diffuse left ventricular wall thickening (usually multiple chambers are involved); can be associated with thickening of both atrial walls in which case, a thickening of >6 mm of the inter-atrial septum or posterior right atrial wall is specific to amyloidosis ¹⁰
• biventricular diastolic dysfunction with normal systolic function and ejection fraction
  • subsequently (later in the course of the disease) may show systolic biventricular dysfunction with a decreased ejection fraction
• restriction of diastolic filling
• disproportionate atrial enlargement
• pericardial and pleural effusions
• T1 mapping:
  • native T1 is prolonged even more in AL-amyloidosis than in ATTR-amyloidosis ^13-16
  • extracellular volume is increased especially in ATTR-amyloidosis, for which it is prognostic factor ^15,16
• T2 mapping: 
  • elevated T2 is associated with a worse prognosis in AL-amyloidosis ¹⁷
• late gadolinium enhancement (LGE)
  • diffuse sub-endocardial heterogeneous increased signal on contrast-enhanced inversion recovery T1-weighted images (a characteristic feature) ¹¹
  • transmural enhancement may be more prevalent in patients with ATTR compared to patients with AL ⁶

Nuclear Medicine

Tc-99m-DPD, Tc-99m-HMDP (hydroxymethylene diphosphonate) and Tc-99m-PYP (pyrophosphate) ²² have been shown to have high sensitivity and specificity for the diagnosis of transthyretin cardiac amyloidosis (ATTR) ^19,20.

Planar +/- SPECT-CT scintigraphy is performed to lookone hour post tracer administration. Images are assessed for the presence of abnormal increased cardiac uptake in the myocardium to indicate the presence of ATTR cardiac amyloidosis. Cardiac uptake is evaluated visually and can be scored using the Perugini scale, which compares tracer uptake in the ribs to uptake in the myocardium (if present) ^18,21. A grade 2 or 3 pattern of myocardial uptake is strongly suggestive of ATTR amyloidosis, with variable scan uptake encountered in AL amyloidosis²³. Delayed three-hour imaging can be performed if there is abnormal biodistribution of tracer (i.e. increased generalised soft tissue uptake) at the one-hour time point. 

Differential diagnosis

Cardiac amyloidosis needs to be distinguished from other forms of restrictive cardiomyopathy, including:

• hypertrophic cardiomyopathy
• cardiac sarcoidosis
• cardiac lymphoma

See also

• amyloidosis (general article)
  • renal amyloidosis
  • splenic amyloidosis
  • hepatic amyloidosis
  • pulmonary amyloidosis
  • gastrointestinal amyloidosis
  • skeletal amyloidosis
    • amyloid arthropathy