Attacking the Achilles heel of cardiac amyloid nuclear scintigraphy: How to reduce equivocal and false positive studies.

BACKGROUND: Planar and single-photon emission computed tomography (SPECT) nuclear imaging techniques with bone seeking radiotracers have been increasingly adopted for diagnosis of ATTR cardiac amyloidosis. However, inherent limitations of these techniques due to lack of anatomical landmarks have been recognized, with consequent high numbers of equivocal or false positive cases. SPECT/computed tomography (CT) fusion imaging offers a significant advantage to overcome these limitations by substantially reducing inaccurate interpretations. The authors present the results of a 3-year imaging quality improvement project that focused on reducing the high number of equivocal studies that were noted in the first two years of the amyloidosis program, comparing SPECT only to SPECT/CT fusion technique. METHODS: A retrospective, systematic analysis of 176 patient records was performed to test the premise that SPECT/CT fusion imaging has the potential to reduce equivocal and false positive results. RESULTS: Of a total of 176 patients, 35 equivocal (19.8%), 32 (18.18%) strongly suggestive, and 109 (61.93%) not suggestive cases were identified. Recognizing that this was not consistent with the international data, the authors set out on a comprehensive quality assessment project to reduce the number of equivocal and false positive cases. In patients who initially underwent SPECT only (Group A; n = 78), the addition of SPECT/CT fusion resulted in the net reclassification of 73% of cases: 100% of equivocal cases (n = 35) were reclassified to not suggestive (n = 34) or strongly suggestive (n = 1). 73% of strongly suggestive cases (n = 30) were reclassified to not suggestive (n = 22) while 8 strongly suggestive cases were confirmed as true positives. 13 not suggestive cases remained negative after SPECT/CT fusion. In cases where SPECT/CT fusion was utilized from the beginning (Group B; n = 98), there were no reclassification of any of the cases when these cases were reprocessed as a control group. CONCLUSION: Addition of SPECT/CT imaging reduces the false positive or equivocal studies and increases the diagnostic accuracy of the test. All false positive and equivocal studies were eliminated using the fusion technique. Utilizing the fusion imaging technique increases the spatial resolution, with the ability to localize myocardial uptake and accurately differentiate from blood pool, which is a major source of error.

Diagnostic safety of a machine learning-based automatic patient selection algorithm for stress-only myocardial perfusion SPECT.

BACKGROUND: Stress-only myocardial perfusion imaging (MPI) markedly reduces radiation dose, scanning time, and cost. We developed an automated clinical algorithm to safely cancel unnecessary rest imaging with high sensitivity for obstructive coronary artery disease (CAD). METHODS AND RESULTS: Patients without known CAD undergoing both MPI and invasive coronary angiography from REFINE SPECT were studied. A machine learning score (MLS) for prediction of obstructive CAD was generated using stress-only MPI and pre-test clinical variables. An MLS threshold with a pre-defined sensitivity of 95% was applied to the automated patient selection algorithm. Obstructive CAD was present in 1309/2079 (63%) patients. MLS had higher area under the receiver operator characteristic curve (AUC) for prediction of CAD than reader diagnosis and TPD (0.84 vs 0.70 vs 0.78, P < .01). An MLS threshold of 0.29 had superior sensitivity than reader diagnosis and TPD for obstructive CAD (95% vs 87% vs 87%, P < .01) and high-risk CAD, defined as stenosis of the left main, proximal left anterior descending, or triple-vessel CAD (sensitivity 96% vs 89% vs 90%, P < .01). CONCLUSIONS: The MLS is highly sensitive for prediction of both obstructive and high-risk CAD from stress-only MPI and can be applied to a stress-first protocol for automatic cancellation of unnecessary rest imaging.

Effects of cardiac rehabilitation with and without meditation on myocardial blood flow using quantitative positron emission tomography: A pilot study.

BACKGROUND: Psychosocial stress is recognized as a risk factor for coronary heart disease (CHD). High rates of CHD in African-Americans may be related to psychosocial stress. However, standard cardiac rehabilitation (CR) usually does not include a systematic stress-reduction technique. Previous studies suggest that the Transcendental Meditation (TM) technique may reduce CHD risk factors and clinical events. This pilot study explored the effects of standard CR with and without TM on a measure of CHD in African-American patients. METHODS: Fifty-six CHD patients were assigned to CR, CR + TM, TM alone, or usual care. Testing was done at baseline and after 12 weeks. The primary outcome was myocardial flow reserve (MFR) assessed by 13N-ammonia positron emission tomography (PET). Secondary outcomes were CHD risk factors. Based on guidelines for analysis of small pilot studies, data were analyzed for effect size (ES). RESULTS: For 37 patients who completed posttesting, there were MFR improvements in the CR + TM group (+20.7%; ES = 0.64) and the TM group alone (+12.8%; ES = 0.36). By comparison, the CR-alone and usual care groups showed modest changes (+ 5.8%; ES = 0.17 and - 10.3%; ES = - 0.31), respectively. For the combined TM group, MFR increased (+ 14%, ES = 0.56) compared to the combined non-TM group (- 2.0%, ES = - 0.08). CONCLUSIONS: These pilot data suggest that adding the TM technique to standard cardiac rehabilitation or using TM alone may improve the myocardial flow reserve in African-American CHD patients. These results may be applied to the design of controlled clinical trials to definitively test these effects. TRIAL REGISTRATION: ClinicalTrials.gov registration # NCT01810029.

99mTechnetium pyrophosphate scintigraphy with cadmium zinc telluride cameras is a highly sensitive and specific imaging modality to diagnose transthyretin cardiac amyloidosis.

BACKGROUND: Transthyretin cardiac amyloidosis (ATTR) is a rare, but underdiagnosed, cardiomyopathy. Traditionally diagnosed invasively, ATTR can be diagnosed with non-invasive 99mTechnetium pyrophosphate (99mTc-PYP) planar scintigraphy. Non-planar imaging has not been validated for ATTR diagnosis. Here, we develop and validate a Cadmium Zinc Telluride (CZT) protocol for diagnosing ATTR. METHODS: Forty-three subjects (24 ATTR, 19 non-ATTR) were imaged with Philips Dual-Head Anger (planar) and General Electric CZT cameras. Myocardial uptake was quantified by heart-to-contralateral (H/CL) ratios. CZT scans were quantified by two readers blinded to planar H/CL, with one repeating blinded quantification. Using the previously validated diagnostic threshold (H/CL ≥ 1.5), sensitivity and specificity of CZT scintigraphy was measured. McNemar's test and Pearson's correlation coefficient were calculated. RESULTS: Among subjects (76.7% male, age 77 ± 9), there was no significant difference in proportion of ATTR-positive identification between modalities. There was high correlation between CZT and planar H/CL ratios (r = 0.92, P < 0.0001), with low intra- [ICC = 0.89 (0.80-0.94)] and inter-observer [ICC = 0.80 (0.65-0.89)] variability. CZT scintigraphy had 100% sensitivity and specificity for diagnosing ATTR. CONCLUSION: 99mTc-PYP CZT imaging is as highly sensitive and specific diagnosing ATTR as planar imaging. These findings are clinically salient given the emergence of disease-modifying ATTR therapies, as it could expand diagnostic capability.

Estimating cancer risk from 99mTc pyrophosphate imaging for transthyretin cardiac amyloidosis.

BACKGROUND: Increasing recognition that transthyretin cardiac amyloidosis (ATTR-CA) is much more common than previously appreciated and the emergence of novel disease-modifying therapeutic agents have led to a paradigm shift in which ATTR-CA screening is considered in high-risk populations, such as patients with heart failure with preserved ejection fraction (HFpEF) or aortic stenosis. Radiation risk from 99mTc-pyrophosphate (99mTc-PYP) scintigraphy, a test with very high sensitivity and specificity for ATTR-CA, has not been previously determined. METHODS AND RESULTS: Radiation doses to individual organs from 99mTc-PYP were estimated using models developed by the Medical Internal Radiation Dose Committee and the International Commission on Radiological Protection. Excess future cancer risks were estimated from organ doses, using risk projection models developed by the National Academies and extended by the National Cancer Institute. Excess future risks were estimated for men and women aged 40-80 and compared to total (excess plus baseline) future risks. All-organ excess cancer risks (90% uncertainty intervals) ranged from 5.88 (2.45,11.4) to 12.2 (4.11,26.0) cases per 100,000 patients undergoing 99mTc-PYP testing, were similar for men and women, and decreased with increasing age at testing. Cancer risks were highest to the urinary bladder, and bladder risk varied nearly twofold depending on which model was used. Excess 99mTc-PYP-related cancers constituted < 1% of total future cancers to the critical organs. CONCLUSION: Very low cancer risks associated with 99mTc-PYP testing suggest a favorable benefit-risk profile for 99mTc-PYP as a screening test for ATTR-CA in high-risk populations, such as such as patients with HFpEF or aortic stenosis.

ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI expert consensus recommendations for multimodality imaging in cardiac amyloidosis: Part 2 of 2-Diagnostic criteria and appropriate utilization.

Cardiac amyloidosis is emerging as an underdiagnosed cause of heart failure and mortality. Growing literature suggests that a noninvasive diagnosis of cardiac amyloidosis is now feasible. However, the diagnostic criteria and utilization of imaging in cardiac amyloidosis are not standardized. In this paper, Part 2 of a series, a panel of international experts from multiple societies define the diagnostic criteria for cardiac amyloidosis and appropriate utilization of echocardiography, cardiovascular magnetic resonance imaging, and radionuclide imaging in the evaluation of patients with known or suspected cardiac amyloidosis.

Avoiding misdiagnosis: expert consensus recommendations for the suspicion and diagnosis of transthyretin amyloidosis for the general practitioner.

BACKGROUND: Transthyretin amyloidosis (also known as ATTR amyloidosis) is a systemic, life-threatening disease characterized by transthyretin (TTR) fibril deposition in organs and tissue. A definitive diagnosis of ATTR amyloidosis is often a challenge, in large part because of its heterogeneous presentation. Although ATTR amyloidosis was previously considered untreatable, disease-modifying therapies for the treatment of this disease have recently become available. This article aims to raise awareness of the initial symptoms of ATTR amyloidosis among general practitioners to facilitate identification of a patient with suspicious signs and symptoms. METHODS: These consensus recommendations for the suspicion and diagnosis of ATTR amyloidosis were developed through a series of development and review cycles by an international working group comprising key amyloidosis specialists. This working group met to discuss the barriers to early and accurate diagnosis of ATTR amyloidosis and develop a consensus recommendation through a thorough search of the literature performed using PubMed Central. RESULTS: The cardiac and peripheral nervous systems are most frequently involved in ATTR amyloidosis; however, many patients often also experience gastrointestinal and other systemic manifestations. Given the multisystemic nature of symptoms, ATTR amyloidosis is often misdiagnosed as a more common disorder, leading to significant delays in the initiation of treatment. Although histologic evaluation has been the gold standard to confirm ATTR amyloidosis, a range of tools are available that can facilitate early and accurate diagnosis. Of importance, genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy. CONCLUSIONS: A diagnostic algorithm based on initial red flag symptoms and manifestations of cardiac or neurologic involvement will facilitate identification by the general practitioner of a patient with clinically suspicious symptoms, enabling subsequent referral of the patient to a multidisciplinary specialized medical center.

ASNC/AHA/ASE/EANM/HFSA/ISA/SCMR/SNMMI Expert Consensus Recommendations for Multimodality Imaging in Cardiac Amyloidosis: Part 2 of 2-Diagnostic Criteria and Appropriate Utilization.

Cardiac amyloidosis is emerging as an underdiagnosed cause of heart failure and mortality. Growing literature suggests that a noninvasive diagnosis of cardiac amyloidosis is now feasible. However, the diagnostic criteria and utilization of imaging in cardiac amyloidosis are not standardized. In this paper, Part 2 of a series, a panel of international experts from multiple societies define the diagnostic criteria for cardiac amyloidosis and appropriate utilization of echocardiography, cardiovascular magnetic resonance imaging, and radionuclide imaging in the evaluation of patients with known or suspected cardiac amyloidosis.

18Fluorine sodium fluoride positron emission tomography, a potential biomarker of transthyretin cardiac amyloidosis.

BACKGROUND: Non-invasive imaging to diagnose and quantify amyloid load, progression, and response to treatment are central for the care of patients with cardiac amyloidosis. 18Fluorine-labeled sodium fluoride (18F-NaF) is a widely available radioisotope and PET imaging allows for absolute quantification of tracer uptake. METHODS: Patients with biopsy-proven transthyretin (ATTR-CA) and light-chain cardiac amyloidosis (AL) (3 ATTRwt, 2 ATTRV122I, 2 AL) and controls (n = 5), underwent 18F-NaF PET imaging. Scans were assessed visually for radiotracer uptake and analyzed using standard uptake values in the entire myocardium (SUVm) and in a 17-segment cardiac model. Wilcoxon rank-sum tests were used for statistical analyses. RESULTS: Qualitative 18F-NaF uptake was absent in controls and AL patients. There was qualitative 18F-NaF uptake in ATTR-CA patients, with slightly increased uptake in wild-type patients. SUVm for controls and AL patients overlapped at 0.8(0.4-0.9) and 0.95(0.9-1.0), respectively (P = 0.434). At 1.5(1.4-1.7), SUVm for ATTR-CA patients was ≈1.5*SUVm of controls (P = 0.012) and AL patients (P = 0.078). While there was diffuse 18F-NaF myocardial in ATTR-CA patients, the degree of uptake varied according to cardiac segment. CONCLUSION: 18F-NaF PET effectively imaged and differentiated ATTR-CA patients. Semi-automatic software enabled quantification of radiotracer uptake and regional distribution. 18F-NaF PET may be useful for disease monitoring and localizing amyloid deposition in ATTR-CA patients.

Standardization of 99mTechnetium pyrophosphate imaging methodology to diagnose TTR cardiac amyloidosis.

BACKGROUND: Technetium pyrophosphate (99mTc-PYP) imaging to diagnose transthyretin cardiac amyloidosis (ATTR-CA) has been increasingly utilized. The objective of this study is to provide a standardized 99mTc-PYP imaging protocol to diagnose ATTR-CA. METHODS: 104 scans from 45 subjects with biopsy-proven ATTR-CA or light-chain cardiac amyloidosis (AL) were assessed. Multiple scans were obtained using different counts (750 vs 2000 K), times to acquisition (1 vs 2 to 4 hours), processing matrix (256 vs 128), and 99mTc-PYP dose. Image quality and extracardiac activity was assessed. Quantitative methods using heart-to-contralateral ratios (H/CL) and a visual semiquantitative scale were used to diagnose ATTR-CA.19 The correlation between H/CL ratios and reproducibility of semiquantitative visual scores, acquired using various imaging parameters, were evaluated. RESULTS: All imaging parameters had good to excellent image quality. 750 vs 2000 K counts, 1 hour acquisition and 256 matrix, had lower extracardiac activity (P = .00018). 10 mCi of 99mTc-PYP v. higher doses showed excellent image quality and less extracardiac activity (P = .0015). Correlation of H/CL ratios was strong (r ≥ 0.92) and reproducibility of semiquantitative visual scores was high (Kappa = 95%). CONCLUSION: An imaging protocol using 750 K counts, 10 mCi of 99mTc-PYP, and a 256 matrix was chosen as the standardized imaging protocol since it provided the shortest overall study time (1 vs 2 to 4 hours) and lowest radiation exposure (3 vs 8 to 10 mSv).

Unveiling transthyretin cardiac amyloidosis and its predictors among elderly patients with severe aortic stenosis undergoing transcatheter aortic valve replacement.

AIMS: Transthyretin cardiac amyloidosis (ATTR-CA) has been reported in patients with aortic stenosis (AS) but its prevalence and phenotype are not known. We examine elderly patients with severe symptomatic AS undergoing transcatheter aortic valve replacement (TAVR) and determine the prevalence and phenotype of ATTR-CA non-invasively. METHODS AND RESULTS: We performed technetium-99m pyrophosphate (99mTc-PYP) cardiac scintigraphy prospectively on patients who underwent TAVR, to screen for ATTR-CA. Transthoracic echocardiography and speckle-strain imaging were performed. We assessed the association of several parameters with ATTR-CA using multivariable logistic regression and constructed receiver operating curves to evaluate the best predictors of ATTR-CA. Among 151 patients (mean age 84 ± 6 years, 68% men), 16% (n = 24) screened positive for ATTR-CA with 99mTc-PYP scintigraphy. Compared with patients without ATTR-CA, ATTR-CA patients had a thicker interventricular septum (1.3 vs. 1.1 cm, P = 0.007), higher left ventricular (LV) mass index (130 vs. 98 g/m2, P = 0.002), and lower stroke volume index (30 vs. 36 mL/m2, P = 0.009). ATTR-CA patients had advanced diastolic dysfunction with higher E/A ratio (2.3 vs. 0.9, P = 0.001) and lower deceleration time (176 vs. 257 ms, P < 0.0001); impairment in systolic function with lower ejection fraction (48% vs. 56%, P = 0.011), myocardial contraction fraction (26 vs. 41, P < 0.0001), and average of lateral and septal mitral annular tissue Doppler S' (4.0 vs. 6.6 cm/s, P < 0.0001). While ATTR-CA patients had more impaired global longitudinal strain (-12 vs. -16%, P = 0.007), relative apical longitudinal strain was the same regardless of ATTR-CA diagnosis (0.98 vs. 0.98, P = 0.991). Average S' best predicted ATTR-CA in multivariable logistic regression (odds ratio 16.67 per 1 cm/s decrease with AUC 0.96, 95% confidence interval 0.90-0.99, P = 0.002) with a value ≤6 conferring 100% sensitivity for predicting a positive 99mTc-PYP amyloid scan. CONCLUSIONS: Transthyretin cardiac amyloidosis is prevalent in 16% of patients with severe calcific AS undergoing TAVR and is associated with a severe AS phenotype of low-flow low-gradient with mildly reduced ejection fraction. Average tissue Doppler mitral annular S' of < 6 cm/s may be a sensitive measure that should prompt a confirmatory 99mTc-PYP scan and subsequent testing for ATTR-CA. Prospective assessment of outcomes after TAVR is needed in patients with and without ATTR-CA.

Nonbiopsy Diagnosis of Cardiac Transthyretin Amyloidosis.

BACKGROUND: Cardiac transthyretin (ATTR) amyloidosis is a progressive and fatal cardiomyopathy for which several promising therapies are in development. The diagnosis is frequently delayed or missed because of the limited specificity of echocardiography and the traditional requirement for histological confirmation. It has long been recognized that technetium-labeled bone scintigraphy tracers can localize to myocardial amyloid deposits, and use of this imaging modality for the diagnosis of cardiac ATTR amyloidosis has lately been revisited. We conducted a multicenter study to ascertain the diagnostic value of bone scintigraphy in this disease. METHODS AND RESULTS: Results of bone scintigraphy and biochemical investigations were analyzed from 1217 patients with suspected cardiac amyloidosis referred for evaluation in specialist centers. Of 857 patients with histologically proven amyloid (374 with endomyocardial biopsies) and 360 patients subsequently confirmed to have nonamyloid cardiomyopathies, myocardial radiotracer uptake on bone scintigraphy was >99% sensitive and 86% specific for cardiac ATTR amyloid, with false positives almost exclusively from uptake in patients with cardiac AL amyloidosis. Importantly, the combined findings of grade 2 or 3 myocardial radiotracer uptake on bone scintigraphy and the absence of a monoclonal protein in serum or urine had a specificity and positive predictive value for cardiac ATTR amyloidosis of 100% (positive predictive value confidence interval, 98.0-100). CONCLUSIONS: Bone scintigraphy enables the diagnosis of cardiac ATTR amyloidosis to be made reliably without the need for histology in patients who do not have a monoclonal gammopathy. We propose noninvasive diagnostic criteria for cardiac ATTR amyloidosis that are applicable to the majority of patients with this disease.

F-18 sodium fluoride PET/CT does not effectively image myocardial inflammation due to suspected cardiac sarcoidosis.

BACKGROUND: Sarcoidosis is an inflammatory disorder of unknown etiology that can involve the heart. While effective in imaging cardiac sarcoidosis, F-18 fluorodeoxyglucose (FDG) PET/CT often shows non-specific myocardial uptake. F-18 sodium fluoride (NaF) has been used to image inflammation in coronary artery plaques and has low background myocardial uptake. Here, we evaluated whether F-18 NaF can image myocardial inflammation due to clinically suspected cardiac sarcoidosis. PATIENTS AND METHODS: We performed a single institution pilot study testing if F-18 NaF PET/CT can detect myocardial inflammation in patients with suspected cardiac sarcoidosis. Patients underwent cardiac PET/CT with F-18 FDG as part of their routine care and subsequently received an F-18 NaF PET/CT scan. RESULTS: Three patients underwent F-18 FDG and F-18 NaF imaging. In all patients, there was F-18 FDG uptake consistent with cardiac sarcoidosis. The F-18 NaF PET/CT scans showed no myocardial uptake. CONCLUSIONS: In this small preliminary study, PET/CT scan using F-18 NaF does not appear to detect myocardial inflammation caused by suspected cardiac sarcoidosis.

Serial scanning with technetium pyrophosphate (99mTc-PYP) in advanced ATTR cardiac amyloidosis.

BACKGROUND: Development of noninvasive imaging modalities to quantify amyloid burden over time is an unmet clinical need. Technetium pyrophosphate (99mTc-PYP) scintigraphy is a simple and widely available radiotracer useful to differentiate transthyretin from light-chain amyloidosis in patients with advanced cardiac amyloidosis. We examined the utility of serial 99mTc-PYP scanning to quantify amyloid burden over time in TTR cardiac amyloidosis (ATTR-CA). METHODS AND RESULTS: Twenty subjects with ATTR-CA (10 wild type, 10 mutant) underwent serial 99mTc-PYP planar cardiac imaging. Cardiac retention was assessed both semiquantitatively (visual score 0, no uptake to 3, uptake greater than bone) and quantitatively (region of interest drawn over the heart, copied, and mirrored over the contralateral chest) to calculate a heart-to-contralateral (H/CL) ratio. Index scan mean visual score and H/CL were 3.0 ± 0.2 and 1.79 ± 0.2, respectively, and after an average 1.5 ± 0.5 years follow-up, did not differ, 3.0 ± 0.2, P = .33 and 1.76 ± 0.2, P = .44. H/CL change was minimal, 0.03 ± 0.17, did not correlate with time between scans, r = 0.19, P = .43, and was observed despite obvious clinical progression (increase in troponin ≥ 0.1 ng/mL, BNP ≥ 400 pg/mL, NYHA class, and/or death). CONCLUSIONS: Serial 99mTc-PYP scanning in subjects with advanced ATTR-CA does not show significant changes over an average 1.5 years of follow-up despite obvious clinical progression.