We aimed to ascertain the real-world diagnostic accuracy of bone scintigraphy in combination with free light chain (FLC) assessment for transthyretin (ATTR) cardiac amyloidosis (CA) using the histopathological diagnosis derived from endomyocardial biopsy (EMB) as a reference standard. We retrospectively analyzed 102 patients (22% women) with suspected CA from seven Austrian amyloidosis referral centers. The inclusion criteria comprised the available results of bone scintigraphy, FLC assessment, and EMB with histopathological analysis. ATTR and AL were diagnosed in 60 and 21 patients (59%, 21%), respectively, and concomitant AL and ATTR was identified in one patient. The specificity and positive predictive value (PPV) of Perugini score ≥ 2 for ATTR CA were 95% and 96%. AL was diagnosed in three out of 31 patients (10%) who had evidence of monoclonal proteins and a Perugini score ≥ 2. When excluding all patients with detectable monoclonal proteins (n = 62) from analyses, the PPV of Perugini score ≥ 2 for ATTR CA was 100% and the NPV of Perugini score < 2 for ATTR CA was 79%. Conclusively, ATTR CA can be diagnosed non-invasively in the case of a Perugini score ≥ 2 and an unremarkable FLC assessment. However, tissue biopsy is mandatory in suspected CA in any other constellation of non-invasive diagnostic work-up.

We identified two patients with transthyretin (ATTR) amyloid myopathy (one ATTR variant amyloidosis, ATTRv; one wild-type ATTR amyloidosis, ATTRwt). Myopathy was the initial manifestation in ATTRwt, whereas it followed neuropathy and cardiomyopathy in ATTRv. The ATTRwt patient showed muscular tracer uptake on 99mTc-DPD planar scintigraphy at the time of initial diagnosis, consistent with ATTR amyloid myopathy. The ATTRv patient underwent heart transplantation because of progressive heart failure. Within the next two years, progressive myopathic symptoms and extracardiac tracer uptake on 99mTc-DPD planar scintigraphy were documented, attributable to ATTR amyloid myopathy. Interstitial amyloid deposits were confirmed by muscle biopsy in both patients, with a particularly high amyloid burden in the adipose tissue. This case report highlights the frequent concomitant presence of cardiac ATTR amyloidosis and ATTR amyloid myopathy. ATTR amyloid myopathy may precede cardiac manifestation in ATTRwt or occur after heart transplantation in ATTRv. Due to the high diagnostic accuracy of 99mTc-DPD scintigraphy for detecting ATTR amyloid myopathy and the emergence of novel therapeutics, it is important to increase the awareness of its presence.

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Background Cardiac transthyretin (ATTR) amyloidosis is an infiltrative disease caused by the extracellular deposition of misfolded ATTR protein in the myocardium. Early disease recognition and accurate description of cardiac involvement are fundamental, as cardiac ATTR amyloidosis is associated with poor prognosis. Although endomyocardial biopsy (EMB) remains the gold standard in amyloid detection and typing, non-invasive imaging can provide an accurate diagnostic tool. Bone scintigraphy enables early disease detection with high accuracy. However, it remains to be determined whether the degree of cardiac tracer uptake on bone scintigraphy correlates with the extent of histologic amyloid burden in EMB. Aim This single center observational study aimed to compare the histological amyloid load in endomyocardial biopsies with the quantification of cardiac tracer uptake on 99mTechnetium-3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD) scintigraphy in cardiac ATTR amyloidosis. Methods 23 patients with cardiac ATTR amyloidosis were enrolled. Diagnosis was obtained with a combination of invasive and non-invasive methods. Perugini score, mean left ventricular tracer uptake (LV uptake) and left ventricular to corpus sterni uptake ratio (LV/CS ratio) on 99mTc-DPD-scintigraphy were measured, while histological amyloid load was quantified as percentage of the analysed myocardial tissue using Sulfated Alcian Blue staining and the Fiji-ImageJ programme. Bivariate correlation and Pearson correlation coefficient were used to study the relationship between EMB and 99mTc-DPD-scintigraphy findings. Results We found a statistically significant correlation between histological amyloid load and Perugini score (r=0.47 p=0.02), as well as between Perugini score and LV/CS ratio (r=0.31 p=0.046). Mean LV tracer uptake showed a trend for correlation with histological amyloid load (r=0.37 p=0.08), without reaching statistical significance. Conclusion We found a correlation between the extent of histologic amyloid burden in EMB and the degree of cardiac tracer uptake on 99mTc-DPD-scintigraphy. Our results underline the reliability of 99mTc-DPD-scintigraphy as a surrogate of histological amyloid load in the diagnosis of cardiac ATTR amyloidosis. Possible implications for the assessment of prognosis are subject to future studies with a larger number of patients. FUNDunding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Pfizer

Background Previous studies indicated that amyloid scintigraphy in combination with free light chain (FLC) assessment yields an excellent diagnostic accuracy for cardiac transthyretin (ATTR) amyloidosis (1). As a consequence, the diagnosis of ATTR amyloidosis is increasingly made without the actual gold-standard method endomyocardial biopsy (EMB). Whether this leads to misdiagnosis in real-world practice is currently underinvestigated. We aimed to describe the diagnostic accuracy of amyloid scintigraphy in a real world setting. Methods Seven tertiary care centers throughout Austria agreed to participate in the study and performed a systematic retrospective medical records search from 2017 to 2020. Patients were included in case of available results of amyloid scintigraphy, FLC assessment and EMB, respectively. Amyloid scintigraphy was performed using a 99m-technetium-labelled tracer. Histological analysis was performed using immunohistochemistry. The number of submitted subjects with complete data per center ranged from 2 to 46. The patient number increased with years, with 15 patients investigated in 2017 and 32 in 2020. Results We enrolled 101 patients (21% women) with a mean age of 73±9 years and median NT-proBNP (IQR) of 2694 (1601–5239) pg/ml (Table 1). An abnormal Perugini Score (ie. grade II or III) was present in 57 patients (56%) and FLC assessment was overall indicative of monoclonal protein in 60 patients (59%). Among patients with abnormal Perugini Score, 29 had FLC assessment indicative of monoclonal protein. The most common histopathological diagnoses were ATTR in 60 patients (59%) and cardiac light chain (AL) amyloidosis in 20 patients (20%). One further patient was diagnosed with concomitant AL and ATTR amyloidosis. Further diagnoses included ApoA4 (n=2) and AA amyloidosis (n=1), while cardiac amyloidosis was ruled out in 17 patients (17%). ATTR was diagnosed in 54 patients with Perugini Score II or III compared with 6 patients with Perugini &lt; II, yielding a sensitivity of abnormal Perugini score for ATTR amyloidosis of 90%. Among patients with abnormal Perugini Score (n=57), ATTR was diagnosed in 55 patients, and AL amyloidosis in 3 (one had concomitant ATTR and AL), yielding a positive predictive value (PPV) of abnormal Perugini Score of 97% (Table 2). Two AL patients had Perugini Score of II and one had Perugini Score of III. When excluding patients with monoclonal gammopathy, the PPV of abnormal Perugini Score was 100%. Conclusion Our data confirm a PPV of abnormal amyloid scintigraphy of 100% for cardiac ATTR amyloidosis when monoclonal gammopathy was excluded. mong patients with monoclonal gammopathy, one of ten patients with abnormal scintigraphy had AL amyloidosis as the underlying condition. Our data underscore that tissue biopsy and histopathological analysis should be performed in every patient with suspected amyloidosis and monoclonal gammopathy even in case of Perugini Score II or III. Funding Acknowledgement Type of funding sources: None.

Background Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal disease caused by the extracellular deposition of misfolded ATTR protein in the myocardium. In an era where new therapies are rapidly emerging, development of non-invasive imaging modalities to quantify amyloid burden over time is of utmost importance. Although endomyocardial biopsy (EMB) remains the gold standard in amyloid detection and typing, 99mTc-DPD scintigraphy is a widely available and accurate tool for non-invasive diagnosis of cardiac ATTR amyloidosis. However, it remains to be determined whether the degree of cardiac 99mTc-DPD uptake correlates with the histological amyloid infiltration on EMB – thus, justifying 99mTc-DPD scintigraphy as a disease monitoring tool. Aim This single-centre observational study aimed to compare the extent of histologic amyloid burden on EMB with the quantification of cardiac 99mTc-DPD uptake on scintigraphic planar images and SPECT/CT acquisitions in cardiac ATTR amyloidosis. Methods 26 patients with cardiac ATTR amyloidosis were enrolled. Patients were included in case of (1) EMB-proven ATTR amyloidosis and (2) availability of 99mTc-DPD scintigraphy (reference activity: 550 MBq). Visual interpretation using the Perugini score, quantitative analysis of cardiac 99mTc-DPD uptake by planar whole-body imaging and SPECT/CT using regions of interest (ROI) were performed, and heart to whole-body ratio (H/WB) was measured. Histological amyloid load was quantified as percentage of the analysed myocardial tissue using Sulfated Alcyan Blue staining and the Fiji-ImageJ programme. Pearson's and Spearman's correlation were used for correlation analysis and assessment of agreement. Results ATTR patients had a median age of 77 [73–79] years and were predominantly male (85%). An abnormal Perugini score (i.e. 2 or 3) was present in 25 patients (96%), whereas 1 patient was assigned Perugini score 1 (4%). Increased cardiac tracer uptake was documented in all patients, both on 99mTc-DPD planar scintigraphy (ROImean 129±37) and SPECT/CT (ROImean 369±142). Histologic amyloid burden on EMB was 32±19% on average. It significantly correlated with Perugini score (r=0.56 p=0.003), as well as with cardiac 99mTc-DPD uptake (planar: r=0.54 p=0.006, SPECT/CT: r=0.48 p=0.018) and H/WB (r=0.41 p=0.046). Conclusion We have demonstrated a good correlation between histological amyloid infiltration on EMB and cardiac 99mTc-DPD uptake on scintigraphic planar images and SPECT/CT scans, illustrating the potential of 99mTc-DPD scintigraphy to yield reliable quantitative information on cardiac amyloid burden. Further investigations with a larger number of patients are needed to confirm our findings and to implement thresholds in cardiac 99mTc-DPD uptake for being used for guiding disease and therapy management. Funding Acknowledgement Type of funding sources: None.