The use of PYP scan for evaluation of ATTR cardiac amyloidosis at a tertiary medical centre

Cardiac transthyretin amyloidosis (ATTR) is an often underdiagnosed disease that can lead to significant morbidity and mortality for patients. In recent years, technetium-99m pyrophosphate scintigraphy (PYP) imaging has become a standard of care diagnostic tool to help clinicians identify this disease. With newly emerging therapies for ATTR cardiomyopathy, it is critical to identify patients who are eligible for therapy as early as possible. At our institution, we sought to describe the frequency of PYP scanning and how it has impacted the management of a patient suspected to have amyloid cardiomyopathy.

Between 1 January 2017 and 31 December 2020, we identified 273 patients who completed PYP scanning for evaluation of cardiac amyloidosis at Tufts Medical Center, a tertiary care centre. We reviewed pertinent clinical data for all study subjects. A PYP scan was considered positive when the heart to contralateral lung ratio was greater than or equal to 1.5, with a visual grade of 2 or 3, and confirmation with single-photon emission computerised tomography (SPECT) imaging.

In total there were 55 positive, 202 negative, and 16 equivocal PYP scans. Endomyocardial biopsies were rarely performed following PYP results. Of the seven patients with a positive PYP scan who underwent biopsy, five were positive for ATTR amyloid; of the patients with a negative scan who were biopsied, none were positive for ATTR amyloidosis and two were positive for amyloid light-chain (AL) amyloidosis. The biomarkers troponin I, B-type naturietic peptide (BNP), and N-terminal pro-BNP (NT-proBNP), as well as the interventricular septal end-diastolic thickness (IVSd) seen on echocardiogram, were all found to be statistically higher in the PYP positive cohort than in the PYP negative cohort using Mann-Whitney U statistical analysis. In total, 27 out of the 55 patients with a positive PYP scan underwent therapy specific for cardiac amyloid.

In conclusion, this study reinforces the clinical significance of the PYP scan in the diagnosis and management of cardiac amyloidosis. A positive scan allowed physicians to implement early amyloid-directed treatment while a negative scan encouraged physicians to pursue an alternative diagnosis.


Transthyretin (ATTR) cardiac amyloidosis is a disorder characterised by the deposition of amyloid fibrils into the heart’s extracellular space.1,2 Over time, this condition leads to restrictive cardiomyopathy and heart failure. Most cases are caused by abnormal plasma cell proliferation leading to misfolded light chains (AL amyloidosis) or misaggregation of the transthyretin protein (ATTR).3,4

Cardiac amyloidosis is widely considered to be underdiagnosed as patients often present in the late stages of disease.2,5 Endomyocardial biopsy can be utilised to diagnose ATTR cardiomyopathy by demonstrating amyloid proteins on Congo red staining. While considered a gold standard for diagnosis, this procedure poses potential risks including pericardial tamponade, arrhythmia, haematoma and other morbidity. The frequency of such events, as reported by institution, ranges anywhere from <1% to 6%.6 Thus, non-invasive studies are crucial to evaluate patients for the presence of cardiac amyloidosis. Findings, such as increased ventricular wall thickness on echocardiography, delayed enhancement pattern on cardiac magnetic resonance imaging (MRI), and elevations in cardiac biomarkers, have been associated with cardiac amyloidosis, but on their own are not diagnostic.

In recent years, technetium-99m pyrophosphate scintigraphy (PYP) imaging has emerged as a sensitive and specific imaging modality to diagnose ATTR cardiac amyloidosis.7-9 This non-invasive nuclear imaging study poses little to no risk to the patient while also providing important information.

In this retrospective study, we reviewed all patients who underwent PYP imaging from 1 January 2017 to 31 December 2020 at Tufts Medical Center, to better understand how this imaging study is being used at a major tertiary academic centre. The purpose of this analysis is to examine the trends of PYP use, identify predictive factors associated with a positive result, and observe how this imaging study has changed clinical practice in recent years.


Study population

The population of interest for this study included all patients who underwent a PYP scan for suspected cardiac amyloidosis at Tufts Medical Center between 1 January 2017 and 31 December 2020. Of the 278 PYP scans performed, three were excluded as they were performed for indications other than suspicion of cardiac amyloidosis and two were excluded as the tests were not completed due to patient discomfort. Therefore, a total of 273 patients were included in the study.

PYP scan

All PYP scans were performed by injection of 15mCi technetium-99-pyrophosphate. Cardiac images in the supine position were captured one hour following injection of the radioisotope. Single-photon emission computed tomography (SPECT) imaging was obtained immediately following static imaging. Repeat imaging was obtained at three hours following injection if there was persistent blood pool activity at one hour. Qualitative grade of myocardial uptake was obtained ranging from 0 to 3, with 0 representing no cardiac uptake, 1 representing cardiac uptake less than rib uptake, and 2 and 3 representing cardiac uptake equal to or greater than rib uptake.10 Heart to contralateral lung ratios (H:L) were obtained by measuring the circular target region of interest over the heart relative to the contralateral chest. Additionally, qualitative visual assessment of SPECT imaging was performed by an expert nuclear cardiologist or nuclear medicine radiologist to assess for radionuclide uptake in the myocardium versus the blood pool. A scan was considered positive with a H:L ratio of >1.5 and grade of myocardial uptake 2 or 3, with SPECT confirmation of uptake in the myocardium. A scan was considered negative with a H:L ratio of <1.5 with a grade of 0 or 1. A scan was considered equivocal with a H:L ratio of 1.3–1.5, a grade of 2, and an inconclusive qualitative assessment of myocardial uptake as determined by the interpreting physician.

Data collection

Patient demographics, clinical characteristics, laboratory studies, imaging results, biopsy results, and therapy-related information were identified via retrospective chart review of the electronic medical record. Troponin I, B-type natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP), and echocardiography measurements were collected from the medical record of each enrolled patient when available; these values were from the time closest to the completion of the PYP scan. All data were collected by trained study staff. The study was approved by the Institutional Review Board at Tufts Medical Center. The Institutional Review Board at Tufts Medical Center granted a waiver of consent and a HIPAA (Health Insurance Portability and Accountability Act) waiver of research authorisation for this study in accordance with 45 CFR (Code of Federal Regulations) 46.116(d) and HIPAA.

Statistical analysis

Troponin I, BNP, and NT-proBNP, as well interventricular septal end-diastolic thickness (IVSd) from echocardiography were obtained when available in the medical chart. Given the non-normal distribution of values within each cohort, medians for these variables were measured. Statistical analysis was performed using the Mann-Whitney U two-tailed approach to compare the medians of each variable in the positive PYP scan group to the same variable of the negative PYP scan group. Gaussian approximation p values are reported. Patients with an equivocal scan were not included in this analysis as the number in the cohort was too small to assess for statistical significance.


Patient characteristics

Background data of the study population are presented in table 1. The median age of participants ranged from 71 in the negative group to 79 in the equivocal group. The majority of patients who underwent a PYP scan were men and were white.

Table 1. Patient characteristics

Baseline characteristic Positive PYP scan Equivocal PYP scan Negative PYP scan
Number of patients 55 16 202
Median age, years 76 79 71
Gender, n (%) Female 8 (14.5%) 11 (68.8%) 88 (43.6%)
Male 47 (85.5%) 5 (31.2%) 114 (56.4%)
Race, n (%) White 46 (83.6%) 13 (81.3%) 145 (71.8%)
Black 1 (1.8%) 1 (6.25%) 21 (10.4%)
Hispanic 1 (1.8%) 0 4 (2%)
Asian 1 (1.8%) 0 14 (6.9%)
Other 6 (10.9%) 2 (12.5%) 18 (8.9%)
Key: PYP scan = technetium pyrophosphate scintigraphy

Scan positivity rate

Of the 273 patients evaluated in the study, 55 patients (20%) had a positive scan. Of the 202 negative scans, four were considered negative in the setting of a H:L ratio of greater than 1.5 but a visual grade of 1 and negative SPECT imaging, indicating uptake in the blood pool rather than myocardial uptake. Only 16 were considered equivocal.

Tissue confirmation

Table 2 outlines available biopsy results for the study population. A total of 27 patients in the study group underwent endomyocardial biopsy, which was pursued if the patient harboured a monoclonal protein to differentiate between ATTR and AL amyloidosis. Within the PYP positive group, five biopsies were positive for ATTR and two were negative for amyloid. Those that were positive had H:L ratios ranging from 1.7 to 2.8; four demonstrated grade 3 uptake and one demonstrated grade 2 uptake. The two patients with a negative endomyocardial biopsy had H:L ratios of 1.7 and 1.75, and both had grade 2 uptake.

Table 2. Biopsy results

Result Positive PYP scan Equivocal PYP scan Negative PYP scan
Endomyocardial biopsy
Number performed 7 2 18
Positive for ATTR amyloid (%) 5 (71.4%) 1 (50%) 0
Positive for AL amyloid (%) 0 0 2 (11.1%)
Fat-pad biopsy
Number performed 12 2 61
Positive for ATTR amyloid (%) 4 (33.3%) 0 1 (1.6%)
Positive for AL amyloid (%) 0 0 0
Key: AL = amyloid light-chain; ATTR = transthyretin; PYP scan = technetium pyrophosphate scintigraphy

Within the PYP negative group, two of the biopsies were positive for AL amyloid. These patients had H:L ratios of 1.2 and 1.43, and both had grade 1 uptake. Of the two equivocal patients who underwent endomyocardial biopsy, one was positive for ATTR. Scan results revealed an H:L ratio of 1.13 with grade 2 uptake.

Predictive markers

Table 3 outlines analysis of available predictive markers taken at the time of the scan result. Patients with a positive scan were found to have a statistically significantly higher measurement in troponin, BNP and pro-BNP, as well as IVSd measurement on echocardiography compared with those with a negative result.

Table 3. Predictive markers, Mann-Whitney analysis

Marker Positive PYP scan Negative PYP scan Mann-Whitney U score p value*
Median IVSd, cm 1.5 1.2 1,166.500 <0.001
Median BNP, pg/ml 330 114 2,154.500 <0.001
Median NT-proBNP, pg/ml 1,144 191.5 714.500 <0.001
Median troponin I, ng/ml 0.06 0.01 1,062.500 <0.001
*Gaussian approximation p values are reported.
Key: BNP = B-type naturietic peptide; IVSd = interventricular septal end-diastolic thickness; NT-proBNP = N-terminal pro-B-type naturietic peptide; PYP scan = technetium pyrophosphate scintigraphy
Treatment choices

Of the 55 patients with positive scans, 23 were treated with tafamidis and three were treated with an investigational agent as part of a clinical trial. One patient was treated with doxycycline for off-label management of cardiac amyloidosis. Seven were treated with diuretics alone for management of heart failure symptoms due to poor functional status. The remaining patients were treated expectantly or declined therapy.

Of the patients with equivocal scans, only one received tafamidis after endomyocardial biopsy was positive for ATTR amyloidosis. The remaining patients did not receive amyloid-directed therapy. Both patients with negative PYP scans but positive endomyocardial biopsies were treated for infiltrative AL cardiomyopathy with anti-plasma cell chemotherapy.


Here we report on 273 patients who underwent PYP scanning to evaluate for cardiac amyloidosis at a tertiary care centre. This imaging modality has evolved as a critical diagnostic tool in the evaluation of cardiac amyloidosis, and a positive scan often leads the medical team to pursue therapeutic options for this disease entity.

Based on these data, we have been able to identify a number of factors that may help predict a positive scan. In our analysis, we found that patients who ultimately were found to have a positive PYP scan had statistically higher biomarkers (troponin, BNP and NT-proBNP) at the time of their PYP scan, as well as statistically thicker IVSd on echocardiogram.

Previous studies have revealed the PYP scan to be highly accurate in detection of cardiac amyloidosis, with a reported sensitivity of 99% and specificity of 86% in the absence of evidence of monoclonal gammopathy.11 This has led to adoption of the PYP scan as a non-invasive method for evaluation of cardiac ATTR. These data from our institution demonstrate that following these guidelines when evaluating patients limited the number of endomyocardial biopsies performed to a low number of cases. Of the 273 patients evaluated here, only 27 underwent biopsy, all due to the concomitant presence of a monoclonal gammopathy, which necessitated the need for biopsy confirmation. It has been well documented that AL amyloid can lead to a false-positive PYP scan, requiring biopsy to differentiate between AL and ATTR amyloidosis.11,12

In the PYP positive group, seven patients underwent biopsies of which five were positive for ATTR amyloid. Of the two that were negative, one patient was felt to have a very high clinical suspicion for ATTR and was managed accordingly, with the negative biopsy felt to be a false negative, possibly due to sampling error in the setting of patchy infiltration. The second patient did not have clinical or biochemical evidence of ATTR amyloid; the patient’s BNP and troponin were negative and she did not have signs or symptoms of heart failure on examination, but did have a monoclonal gammopathy on serum protein electrophoresis (SPEP). This patient was diagnosed with IgA lambda monoclonal gammopathy of undetermined significance (MGUS) and is being clinically monitored. Thus, patients with a positive PYP scan but negative clinical or biochemical signs of cardiac amyloid may need a confirmatory biopsy to help elucidate the diagnosis. This further supports the concept that a patient’s clinical exam and laboratory evaluations are important factors to consider in the context of PYP scan results.

In the negative group, 18 patients underwent biopsy, none of which were positive for ATTR amyloid while two were positive for AL amyloidosis. These results support the high accuracy of the imaging study when evaluating for this condition.

Tafamidis, a medication that stabilises the transthyretin tetramer, has been shown to reduce all-cause mortality and rate of cardiovascular hospitalisations among patients with ATTR cardiomyopathy.13,14 The encouraging results of treatment with this agent have elevated the importance of recognising and diagnosing cardiac amyloidosis earlier in the disease course. Within our study population, 23 of the patients in the PYP positive group were ultimately treated with tafamidis.

There are some limitations to this study due to its retrospective nature. Not all patients evaluated with a PYP scan had cardiac biomarkers and echocardiographic parameters available in the clinical record, making trends less conclusive. Similarly, a large cohort of patients were referred to Tufts Medical Center for amyloid consultation, underwent imaging and were ultimately lost to follow-up upon return to outside medical settings.

Furthermore, this study was unable to capture the patients who were considered for, but ultimately did not undergo, cardiac PYP scanning. At this time, the decision to pursue a cardiac PYP scan remains a clinical one, integrating the patient’s findings on diagnostic and clinical evaluation. Medical teams must consider a patient’s overall clinical status including symptoms, physical exam findings, laboratory and imaging results when deciding whether cardiac amyloidosis needs to be considered and whether a PYP scan would be indicated. Understanding the process behind forgoing the scan would be helpful in understanding how this disease remains underdiagnosed.


The PYP scan has emerged as a low-risk imaging study that helps medical teams diagnose ATTR cardiomyopathy. As demonstrated here, higher biomarker values and increased IVSd on echocardiogram can correlate with positive scans, and, thus, can help the medical team in deciding to pursue this study. PYP scan results have greatly impacted clinical decision making when diagnosing and treating cardiac amyloid. These data demonstrate that the high sensitivity and specificity of the test have resulted in limited need for endomyocardial biopsy, reinforcing this imaging modality to be a lower risk alternative for diagnosis. A positive result would justify the early introduction of disease-modifying agents for management of ATTR, and considering this test early, when there is an index of suspicion, could lead to improved overall outcomes for patients.

Key messages

  • Pyrophosphate scintigraphy (PYP scanning) is a clinically significant and effective imaging modality for use in the diagnosis and management of transthyretin (ATTR) cardiac amyloidosis
  • Positive PYP scan results were correlated with elevated cardiac biomarkers and larger interventricular septal diameter on echocardiography
  • Positive PYP scanning led to early amyloid-directed treatment in a real-world environment

Conflicts of interest

None declared.



Study approval

All data for the study were collected by trained study staff. All data were de-identified to maintain the confidentiality of the subjects involved. The study was approved by the Institutional Review Board at Tufts Medical Center. The Institutional Review Board at Tufts Medical Center granted a waiver of consent and a HIPAA waiver of research authorisation for this study in accordance with 45 CFR 46.116(d) and HIPAA.


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