**5.4 Cardiac magnetic resonance imaging (MRI)**

 Cardiac MRI has been used for identification of cardiac amyloidosis in patients with unexplained heart failure and arrhythmias in which echocardiographic findings are suspicious yet inconclusive [ 52 ]. It is a highly specific tool for the diagnosis of CA because of its intrinsic capacity to characterized tissue by using late gadolinium enhancement and parametric mapping techniques (T1) and its ability to assess extracellular Volume [ECV]) ( **Figure 4** ) [ 53 ]. In CA, late gadolinium

#### **Figure 4.**

 *Common cardiac MRI findings found in cardiac amyloidosis using state-of-the art cardiac MRI approach. The rights of this figure were obtained. Permission for the reproduction of the image was obtained by the authors. Magnetic Resonance Imaging, First published: 30 June 2022, DOI: 10.1002/jmri.28314 .* 

enhancement (LGE) distributes in the extracellular space not following a specific coronary distribution. Different patterns have been observed such as diffuse patterns that can progress from subendocardial to transmural. The circumferential subendocardial LGE has been more frequently seen in patients with AL-CM whereas the diffuse transmural LGE pattern has been more frequently associated with ATTR-CM [54]. The degree and severity of LGE is associated with increased mortality. Native (noncontrast) T1 or T1 time is measured without contrasts and may reflect changes in tissue composition such as in intracellular or extracellular compartments affected by collagen, protein, edema, lipids, and iron content [54]. Whereas postcontrast T1 is used to calculate ECV a which is a surrogate parameter for the extracellular matrix. Both, native T1 and ECV have demonstrated their usefulness as biomarkers for CA diagnosis [54]. A series from National Amyloidosis Centre in the United Kingdom followed hematologic-measured treatment response and correlated them with ECV findings. They concluded that cardiac MRI-detected change in ECV at 6 months to be prognostic for long-term outcomes, even after controlling for the hematologic response. Suggesting that cardiac involvement in AL amyloidosis does not walk so tightly together with hematologic involvement and that serial analysis of the presumed cardiac amyloid burden with cardiac MRI during treatment may be important to comprehensively assess treatment response [55].

#### **5.5 Bone radiotracers**

99mTc-PYP/DPD/HMDP cardiac scans have become a chief diagnostic tool used in the diagnosis and differentiation of cardiac amyloidosis. In 1980, it was observed for the first time the uptake of 99mTc-phosohate in cardiac material from patients undergoing bone scan for evaluation of bone metastasis [56]. Later in 2005, Perugini et al. demonstrated the usefulness of 99mTc-DPD scintigraphy in diagnosis and successful differentiation of TTR versus AL etiology in patients with documented cardiac amyloidosis [56]. Radiotracer uptake was attributed to possible higher calcium content un ATTR amyloid deposits [57, 58].

There are two approaches for pyrophosphate image interpretation: quantitative vs. semiquantitative evaluation (**Figure 5**). In the quantitative PYP evaluation, a circular target region of interest (ROI) is drawn over the heart on the planar images and are mirrored on the contralateral chest to account for the background of the ribs (H/CL) [52]. Total and absolute counts are measured in each ROI and a ratio of heart-to-contralateral lung determined. When myocardial uptake is visually present in 1 hour, it is considered positive for ATTR if H/CL >1.5. On the other hand, the Perugini grading scale is a semi-quantitative method of scoring cardiac uptake following injection of 99mTc-DPD, 99mTc-Pyrophosphate or 99mTc-HMDP scintigraphy in the investigation of cardiac amyloidosis (particularly ATTR amyloidosis). The grading scale visually compares tracer uptake in the myocardium and ribs and will grade it from 0 to 3 depending on the cardiac uptake compared to the rib with 0 as no cardiac uptake and 3 as cardiac uptake greater than rib uptake. Visual scores greater than 2 on planar ± SPECT/CT imaging without evidence for monoclonal proteins in blood and urine, renders a diagnosis of ATTR cardiac amyloidosis with specificity and positive predictive value >98% (**Figure 5**) [52, 59]. Substantial uptake (Grade 2 or 3) has been reported in more than 20% of patients with AL cardiac amyloidosis.

### *Cardiac Amyloidosis DOI: http://dx.doi.org/10.5772/intechopen.109522*

#### **Figure 5.**

 *Cardiac scintigraphy in cardiac amyloidosis. (A) Qualitative assessment with evident Perugini Grade 3. The Perugini visual grading rule as follows: grade 0 = cardiac uptake not visible, grade 1 = mild cardiac uptake visible but inferior to skeletal uptake, grade 2 = moderate cardiac uptake visible equal to or greater than skeletal uptake, and grade 3 = strong cardiac uptake with little or no skeletal uptake. In the (B) semi-quantitative analysis of planar images, the counts per pixel of the heart to contralateral chest have a value of 1.7 (red circle with the H denotes heart or cardiac uptake and green circle with CL denotes contralateral uptake). Semi-quantitative analysis of planar images with both anterior and lateral views planar images are evaluated, by drawing a patient-specific circular ROI on the heart and mirroring it to the contralateral chest to calculate the heart-tocontralateral (H/CL).* 

 **Figure 6.**

 *Cardiac amyloidosis diagnosis flowchart.* 

#### **5.6 Tissue biopsy**

 Tissue diagnosis with endomyocardial biopsy remains the goal standard for diagnosis CA. However, since it is invasive, it is usually reserved for those patients in which noninvasive assessment has been equivocal such as in the case of patients where plasma cell dyscrasia cannot be entirely ruled out or those with presence of low-grade uptake [55]. Diagnosis is evident with confirmation of amyloid deposition throughout with evidence of apple-green birefringence using Congo Red staining (**Figure 1**). The type of cardiac amyloidosis can also be determined using mass spectrometry and immunohistochemistry approaches. Another approach that is less invasive is the use of fat pad biopsy, however, its sensitivity is less than that of tissue biopsy (20% vs. 60–80%) [1].

#### **5.7 Genetic testing**

All the approaches described above can be used to distinguish between AL amyloidosis and ATTR amyloidosis. However, as it was discussed in Section 3.2 there are two distinct kinds of ATTR, one hereditary and one senile. Therefore, to distinguish between both and to further identify the kind of mutation that exists in the case of ATTRv, genetic testing is granted.

A summarized flowchart for ease and aid of cardiac amyloidosis diagnosis can be found in **Figure 6**.
