Diagnostic performance characteristics of planar quantitative and semi-quantitative parameters of Tc99m pyrophosphate (PYP) imaging for diagnosis of transthyretin (ATTR) cardiac amyloidosis: the SCAN-MP study.

BACKGROUND: The optimal heart-to-contralateral chest (H/CL) ratio threshold for non-invasive diagnosis of transthyretin cardiac amyloidosis (ATTR-CA) using Tc99m pyrophosphate (PYP) imaging in a population with low pretest probability is not known. METHODS: Using myocardial PYP retention by SPECT as the reference standard, we evaluated the diagnostic performance of different semi-quantitative and quantitative (H/CL chest ratio) planar parameters obtained from 3-hour PYP imaging in a prospectively recruited cohort of minority older adults with heart failure and increased LV wall thickness. RESULTS: Of 229 patients, 14 were found to have ATTR-CA (6.1%). No PYP uptake (grade 0) was observed in 77% of scans, all grade 3 scans were ATTR-CA, and only 4 of 11 (36%) grade 2 scans were ATTR-CA. An H/CL threshold of ≥ 1.4 maximized specificity (99%) and positive predictive value (93%) but resulted in decreased sensitivity (93%), compared to the ≥ 1.3 threshold which had 100% sensitivity. CONCLUSION: Among patients with a low pretest likelihood of ATTR-CA, planar interpretation, while useful to exclude disease, must be interpreted with caution. H/CL ratio threshold of ≥ 1.3 resulted in clinically important misclassifications. These data suggest that quantitative planar imaging thresholds may not be appropriate to apply in low pretest likelihood populations being evaluated for ATTR-CA.

Prevalence and significance of extracardiac uptake on pyrophosphate imaging in the SCAN-MP study: the first 379 cases.

INTRODUCTION: Technetium-labeled bone-avid radiotracers can be used to diagnose transthyretin cardiac amyloidosis (ATTR-CA). Extracardiac uptake of technetium pyrophosphate (Tc-99m PYP) in this context has not been extensively explored and its significance is not well characterized. We assessed extracardiac Tc-99m PYP uptake in individuals undergoing nuclear scintigraphy and the extent of clinically actionable findings. METHODS: The Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations (SCAN-MP) study utilizes Tc-99m PYP imaging to identify ATTR-CA in self-identified Black and Caribbean Hispanic participants ≥ 60 years old with heart failure. We characterized the distribution of extracardiac uptake, including stratification of findings by timing of scan (1 hour vs 3 hours after Tc-99m PYP administration) and noted any additional testing in these subjects. RESULTS: Of 379 participants, 195 (51%) were male, 306 (81%) Black race, and 120 (32%) Hispanic ethnicity; mean age was 73 years. Extracardiac Tc-99m PYP uptake was found in 42 subjects (11.1%): 21 with renal uptake only, 14 with bone uptake only, 4 with both renal and bone uptake, 2 with breast uptake, and 1 with thyroid uptake. Extracardiac uptake was more common in subjects with Tc-99m PYP scans at 1 hour (23.8%) than at 3 hours (6.2%). Overall, four individuals (1.1%) had clinically actionable findings. CONCLUSION: Extracardiac Tc-99m PYP uptake manifested in about 1 in 9 SCAN-MP subjects but was clinically actionable in only 1.1% of cases.

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.

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.

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.

Diagnosing Transthyretin Cardiac Amyloidosis by Technetium Tc 99m Pyrophosphate: A Test in Evolution.

OBJECTIVES: This study aimed to characterize trends in technetium Tc 99m pyrophosphate (99mTc-PYP) scanning for amyloid transthyretin cardiac amyloidosis (ATTR-CA) diagnosis, to determine whether patients underwent appropriate assessment with monoclonal protein and genetic testing, to evaluate use of single-photon emission computed tomography (SPECT) in addition to planar imaging, and to identify predictive factors for ATTR-CA. BACKGROUND: 99mTc-PYP scintigraphy has been repurposed for noninvasive diagnosis of ATTR-CA. Increasing use of 99mTc-PYP can facilitate identification of ATTR-CA, but appropriate use is critical for accurate diagnosis in an era of high-cost targeted therapeutics. METHODS: Patients undergoing 99mTc-PYP scanning 1 h after injection at a quaternary care center from 2010 to 2019 were analyzed; clinical information was abstracted; and SPECT results were analyzed. RESULTS: Over the decade, endomyocardial biopsy rates remained stable with scanning rates peaking at 132 in 2019 (p < 0.001). Among 753 patients (516 men, mean age 77 years), 307 (41%) had a visual score of 0, 177 (23%) of 1, and 269 (36%) of 2 or 3. Of 751 patients with analyzable heart to contralateral chest ratios, 249 (33%) had a ratio ≥1.5. Monoclonal protein testing status was assessed in 550 patients, of these, 174 (32%) did not undergo both serum immunofixation and serum free light chain analysis tests, and 331 (60%) did not undergo all 3 tests-serum immunofixation, serum free light chain analysis, and urine protein electrophoresis. Of 196 patients with confirmed ATTR-CA, 143 (73%) had genetic testing for transthyretin mutations. In 103 patients undergoing cardiac biopsy, grades 2 and 3 99mTc-PYP had sensitivity of 94% and specificity of 89% for ATTR-CA with 100% specificity for grade 3 scans. With respect to SPECT as a reference standard, planar imaging had false positive results in 16 of 25 (64%) grade 2 scans. CONCLUSIONS: Use of noninvasive testing with 99mTc-PYP scanning for evaluation of ATTR-CA is increasing, and the inclusion of monoclonal protein testing and SPECT imaging is crucial to rule out amyloid light chain amyloidosis and distinguish myocardial retention from blood pooling.

Comparison of sensitivity, specificity, positive predictive value, and negative predictive value of stress testing versus 64-multislice coronary computed tomography angiography in predicting obstructive coronary artery disease diagnosed by coronary angiography.

Sixty-four-multislice coronary computed tomographic angiography (CTA) and coronary angiography were performed in 145 patients (mean age 67 +/- 10 years), and stress testing was performed in 47 of these patients to determine the sensitivity, specificity, positive predictive value, and negative predictive value of coronary CTA and of stress testing in diagnosing obstructive coronary artery disease (CAD) in patients with suspected CAD. In 145 patients, coronary CTA had 98% sensitivity, 74% specificity, 90% positive predictive value, and 94% negative predictive value in diagnosing obstructive CAD. In 47 patients, stress testing had 69% sensitivity, 36% specificity, 78% positive predictive value, and 27% negative predictive value for diagnosing obstructive CAD, whereas coronary CTA had 100% sensitivity, 73% specificity, 92% positive predictive value, and 100% negative predictive value for diagnosing obstructive CAD. In conclusion, coronary CTA has better sensitivity, specificity, positive predictive value, and negative predictive value than stress testing in diagnosing obstructive CAD.

Prevalence of an increased ascending thoracic aorta diameter diagnosed by two-dimensional echocardiography versus 64-multislice cardiac computed tomography.

The prevalence of an enlarged ascending thoracic aortic diameter (AAD) diagnosed by 2-dimensional echocardiography compared with 64-slice cardiac computed tomography (MSCT) was investigated in 97 women and 117 men (mean age 65 +/- 12 years). Enlarged AADs were diagnosed in 42 of 214 patients (20%) by echocardiography and in 45 of 214 patients (21%) by MSCT (p = NS). The sensitivity, specificity, positive predictive value, and negative predictive value of echocardiography in diagnosing an enlarged AAD using MSCT were 69%, 93%, 74%, and 92%, respectively. A Bland-Altman plot showed that the agreement for AAD measured by echocardiography and MSCT was 95% inside the 2-SD limits. In conclusion, the sensitivity, specificity, positive predictive value, and negative predictive value of 2-dimensional echocardiography in diagnosing enlarged AAD using MSCT were 69%, 93%, 74%, and 92%, respectively.

Prevalence of an increased ascending and descending thoracic aorta diameter diagnosed by multislice cardiac computed tomography in men versus women and in persons aged 23 to 50 years, 51 to 65 years, 66 to 80 years, and 81 to 88 years.

The prevalence of increased ascending thoracic aortic diameter (AAD) and increased descending thoracic aortic diameter (DAD) diagnosed using multislice cardiac computed tomography was investigated in 624 consecutive patients at an academic cardiology practice in 2006. Increased AAD (>3.7 cm) was present in 71 of 361 men (20%) and in 23 of 263 women (9%) (p <0.001). Increased DAD (>3.0 cm) was present in 26 of 339 men (8%) and in 8 of 258 women (3%) (p <0.02). Increased AAD was present in (1) 7 of 96 patients (7%) aged 23 to 50 years, (2) 22 of 234 patients (9%) aged 51 to 65 years, (3) 53 of 263 patients (20%) aged 66 to 80 years, and (4) 12 of 31 patients (39%) aged 81 to 88 years (p <0.005 comparing groups 3 and 1; p <0.001 comparing groups 4 and 1, groups 4 and 2, and groups 3 and 2; p <0.02 comparing groups 4 and 3). Increased DAD was present in (1) 0 of 96 patients (0%) aged 23 to 50 years, (2) 5 of 227 patients (2%) aged 51 to 65 years, (3) 21 of 244 patients (9%) aged 66 to 80 years, and (4) 8 of 30 patients (27%) aged 81 to 88 years (p <0.005 comparing groups 3 and 1, groups 3 and 2, and groups 4 and 3; p <0.001 comparing groups 4 and 1 and groups 4 and 2). In conclusion, men have a higher prevalence of increased AAD and DAD than women, and increasing age increases the prevalence of increased AAD and DAD.

Comparison of prevalence of unrecognized myocardial infarction and of silent myocardial ischemia detected by a treadmill exercise sestamibi stress test in patients with versus without diabetes mellitus.

We investigated, in 287 patients with diabetes (71% men; mean age 63 +/- 8 years) and 292 age- and gender-matched patients with diabetes, the prevalence of unrecognized myocardial infarction (MI) and silent myocardial ischemia (SMI) detected by a treadmill exercise sestamibi stress test. In the patients without a history of MI, MI was diagnosed by treadmill exercise sestamibi stress test in 40 of 217 patients (18%) with diabetes and 16 of 224 patients (7%) without diabetes (p <0.001). In patients with a history of angina, SMI was diagnosed in 35 of 98 patients (36%) with diabetes and 30 of 101 patients (30%) without diabetes (p = NS). In patients without a history of angina, SMI was diagnosed in 62 of 189 patients (33%) with diabetes and 35 of 191 patients (15%) without diabetes (p <0.001). In patients with 2 or 3 risk factors, SMI was diagnosed in 58 of 144 patients (40%) with diabetes and 41 of 142 patients (29%) without diabetes (p <0.005). In patients with 0 or 1 risk factor, SMI was diagnosed in 39 of 143 patients (27%) with diabetes and 24 of 150 patients (16%) without diabetes (p <0.02). In conclusion, patients with diabetes have a higher prevalence of unrecognized MI and a higher prevalence of SMI without a history of angina than patients without diabetes.

Prevalence of silent myocardial ischemia in persons with diabetes mellitus or impaired glucose tolerance and association of hemoglobin A1c with prevalence of silent myocardial ischemia.

Silent myocardial ischemia detected by exercise treadmill or pharmacologic sestamibi stress testing was present in 67 of 196 patients (34%) who had diabetes mellitus or impaired glucose tolerance and in 89 of 640 patients (14%) who had normal glucose tolerance (p <0.001). Among those who had diabetes mellitus or impaired glucose tolerance, silent myocardial ischemia was present in 27 of 54 patients (50%) who had a hemoglobin A1c level > or =7.6% and in 39 of 137 patients (28%) with a hemoglobin A1c level <7.6% (p <0.005).

Anomalous origin of the left main coronary artery from the right sinus of Valsalva with an intramural course identified by transesophageal echocardiography in a 14 year old with acute myocardial infarction.

Coronary artery anomalies have an incidence of 0.6% to 1.3% in angiographic studies and 0.3% in an autopsy series. Anomalous origin of the left main coronary artery (LMCA) from the right sinus of Valsalva (RSOV) represents a small fraction (1.3%) of these anomalies, with an overall prevalence of 0.017% to 0.03% in angiographic studies. The high incidence of sudden cardiac death associated with this specific anomaly during or immediately after vigorous physical exercise makes identification and appropriate surgical intervention critical. We present a case report of a 14-year-old patient with an LMCA arising from the RSOV with an initial intramural course, presenting with acute myocardial infarction (AMI) as the first indication of the anomaly. Transthoracic echocardiogram suggested this anomaly, which was confirmed by cardiac catheterization and transesophageal echocardiogram.

Radiation dose and prognosis of ultra-low-dose stress-first myocardial perfusion SPECT in patients with chest pain using a high-efficiency camera.

UNLABELLED: Although SPECT myocardial perfusion imaging (MPI) provides valuable information about patients with chest pain, there is growing concern regarding its radiation burden and lengthy duration. New high-efficiency (HE) cameras and stress-first protocols both offer the potential to markedly reduce radiation. No previous study has assessed outcomes and radiation doses of patients undergoing MPI on an HE-SPECT camera using an ultra-low-dose stress-first protocol. METHODS: One hundred patients presenting to the emergency department with chest pain who were candidates for stress-first MPI underwent injection of approximately 185 MBq (5 mCi) of (99m)Tc-tetrofosmin at peak stress, followed by supine and prone imaging on an HE-SPECT camera. Same-day rest imaging was performed on patients with any abnormality on imaging after stress. Radiation effective dose was calculated from administered and residual activities. Patients were contacted 3 mo after discharge, and electronic records were accessed to evaluate the need for reevaluation for chest pain, additional imaging, or cardiac events. RESULTS: Stress-only imaging was performed in 69 patients, for whom radiation effective dose averaged 0.99 mSv and study duration, 117 min. Radiation dose averaged 2.22 mSv over all patients. At 3 mo, 96 patients were free of major adverse cardiac events, repeat hospital chest pain evaluation, and repeat imaging or stress testing. One year after MPI and hospital discharge, all patients were living and without acute coronary syndrome. CONCLUSION: HE-SPECT stress-only imaging can be performed in more than two thirds of chest pain patients without a high pretest probability of a stress perfusion defect, with excellent prognosis, a radiation dose averaging 1 mSv, and a test duration of less than 2 h.

Sensitivity, specificity, positive predictive value, and negative predictive value of the dipyridamole sestamibi stress test in predicting graft occlusion or > or = 50% new native coronary artery disease in men versus women and in patients aged > or = 65 years versus < 65 years who had prior coronary artery bypass grafting.

The sensitivity, specificity, positive predictive value, and negative predictive value of the dipyridamole sestamibi stress test (DSST) in predicting graft obstruction or > or = 50% new native coronary artery disease (CAD) in 88 men compared with 56 women with prior coronary artery bypass surgery were 96% and 94% (p = NS), 30% and 67% (p = NS), 91% and 96 % (p = NS), 50% and 57% (p = NS), respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of the DSST in predicting graft obstruction or > or = 50% new native CAD in 92 patients aged < 65 years were 95% and 95% (p = NS), 50% and 40% (p = NS), 96% and 87% (p = NS), and 43% and 67% (p = NS), respectively.

Comparison of two-dimensional echocardiographic tissue harmonic imaging and gated sestamibi single-photon emission computed tomographic left ventricular ejection fraction measurements.

There was good correlation between left ventricular ejection fraction (EF) measurements employing 2-dimensional echocardiography with tissue harmonic imaging and single-photon emission computed tomography using quantitative gated scintigraphy, although in most patients, echocardiographic EF was lower. There was a high degree of agreement between these 2 techniques in assignment of EF to the categories of normal, mildly, moderately, or severely decreased. However, when EF categories did differ, echocardiography always resulted in assignment to a lower category.