Sabahat Bokhari

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.

Patient management after noninvasive cardiac imaging: Results from SPARC (Study of myocardial perfusion and coronary anatomy imaging roles in coronary artery disease)

OBJECTIVES This study examined short-term cardiac catheterization rates and medication changes after cardiac imaging. BACKGROUND Noninvasive cardiac imaging is widely used in coronary artery disease, but its effects on subsequent patient management are unclear. METHODS We assessed the 90-day post-test rates of catheterization and medication changes in a prospective registry of 1,703 patients without a documented history of coronary artery disease and an intermediate to high likelihood of coronary artery disease undergoing cardiac single-photon emission computed tomography, positron emission tomography, or 64-slice coronary computed tomography angiography. RESULTS Baseline medication use was relatively infrequent. At 90 days, 9.6% of patients underwent catheterization. The rates of catheterization and medication changes increased in proportion to test abnormality findings. Among patients with the most severe test result findings, 38% to 61% were not referred to catheterization, 20% to 30% were not receiving aspirin, 35% to 44% were not receiving a beta-blocker, and 20% to 25% were not receiving a lipid-lowering agent at 90 days after the index test. Risk-adjusted analyses revealed that compared with stress single-photon emission computed tomography or positron emission tomography, changes in aspirin and lipid-lowering agent use was greater after computed tomography angiography, as was the 90-day catheterization referral rate in the setting of normal/nonobstructive and mildly abnormal test results. CONCLUSIONS Overall, noninvasive testing had only a modest impact on clinical management of patients referred for clinical testing. Although post-imaging use of cardiac catheterization and medical therapy increased in proportion to the degree of abnormality findings, the frequency of catheterization and medication change suggests possible undertreatment of higher risk patients. Patients were more likely to undergo cardiac catheterization after computed tomography angiography than after single-photon emission computed tomography or positron emission tomography after normal/nonobstructive and mildly abnormal study findings. (Study of Perfusion and Anatomys Role in Coronary Artery [CAD] [SPARC]; NCT00321399).

Multiple testing, cumulative radiation dose, and clinical indications in patients undergoing myocardial perfusion imaging.

CONTEXT Myocardial perfusion imaging (MPI) is the single medical test with the highest radiation burden to the US population. Although many patients undergoing MPI receive repeat MPI testing, or additional procedures involving ionizing radiation, no data are available characterizing their total longitudinal radiation burden and relating radiation burden with reasons for testing. OBJECTIVES To characterize procedure counts, cumulative estimated effective doses of radiation, and clinical indications for patients undergoing MPI. DESIGN, SETTING, AND PATIENTS A retrospective cohort study of 1097 consecutive patients undergoing index MPI during the first 100 days of 2006 (January 1-April 10) at Columbia University Medical Center, New York, New York, that evaluated all preceding medical imaging procedures involving ionizing radiation undergone beginning October 1988, and all subsequent procedures through June 2008, at the center. MAIN OUTCOME MEASURES Cumulative estimated effective dose of radiation, number of procedures involving radiation, and indications for testing. RESULTS Patients underwent a median of 15 (interquartile range [IQR], 6-32; mean, 23.9) procedures involving radiation exposure; of which 4 (IQR, 2-8; mean, 6.5) were high-dose procedures (≥3 mSv; ie, 1 years background radiation), including 1 (IQR, 1-2; mean, 1.8) MPI study per patient. A total of 344 patients (31.4%) received cumulative estimated effective dose from all medical sources of more than 100 mSv. Multiple MPIs were performed in 424 patients (38.6%), for whom cumulative estimated effective dose was 121 mSv (IQR, 81-189; mean, 149 mSv). Men and white patients had higher cumulative estimated effective doses. More than 80% of initial and 90% of repeat MPI examinations were performed in patients with known cardiac disease or symptoms consistent with it. CONCLUSION In this institution, multiple testing with MPI was common and in many patients associated with high cumulative estimated doses of radiation.

99mTc-Pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses

Background— Differentiating amyloid light-chain (AL) from transthyretin-related cardiac amyloidoses (ATTR) is imperative given implications for prognosis, therapy, and genetic counseling. We validated the discriminatory ability of 99mTc-pyrophosphate (99mTc-PYP) scintigraphy in AL versus ATTR. Methods and Results— Forty-five subjects (12 AL, 16 ATTR wild type, and 17 ATTR mutants) underwent 99mTc-PYP planar and single-photon positive emission computed tomography cardiac imaging. Scans were performed by experienced nuclear cardiologists blinded to the subjects’ cohort assignment. Cardiac retention was assessed with both a semiquantitative visual score (range, 0; no uptake to 3, diffuse uptake) and by quantitative analysis by drawing a region of interest over the heart corrected for contralateral counts and calculating a heart-to-contralateral ratio. Subjects with ATTR cardiac amyloid had a significantly higher semiquantitative cardiac visual score than the AL cohort (2.9±0.06 versus 0.8±0.27; P<0.0001) as well as a higher quantitative score (1.80±0.04 versus 1.21±0.04; P<0.0001). Using a heart-to-contralateral ratio >1.5 consistent with intensely diffuse myocardial tracer retention had a 97% sensitivity and 100% specificity with area under the curve 0.992, P<0.0001 for identifying ATTR cardiac amyloidosis. Conclusions— 99mTc-PYP cardiac imaging distinguishes AL from ATTR cardiac amyloidosis and may be a simple, widely available method for identifying subjects with ATTR cardiac amyloidosis, which should be studied in a larger prospective manner.

Agreement of visual estimation of coronary artery calcium from low-dose CT attenuation correction scans in hybrid PET/CT and SPECT/CT with standard Agatston score.

OBJECTIVES We sought to evaluate the accuracy and reproducibility of visual estimation of coronary artery calcium (CAC) from computed tomography attenuation correction (CTAC) scans performed for hybrid positron emission tomography (PET)/computed tomography (CT) and single-photon emission computed tomography (SPECT)/CT myocardial perfusion imaging (MPI). BACKGROUND At the time of MPI, hybrid systems obtain a low-dose, non-electrocardiogram (ECG)-gated CT scan that is used to perform attenuation correction. Utility of this CTAC scan in estimating actual CAC as measured by Agatston score (AS) on standard ECG-gated scans has not been previously studied. METHODS A total of 492 patients, from 3 centers, receiving both MPI with CTAC and a standard CAC scan were studied. At each site, experienced readers blinded to AS reviewed CTAC images, visually estimating CAC on a 6-level scale: classifying patients as estimated AS of 0, 1 to 9, 10 to 99, 100 to 300, 400 to 999, or ≥1,000. Agreement between visually estimated coronary artery calcium (VECAC) on CTAC and AS, measured standardly and converted to the same scale, was evaluated, as was inter-reader agreement. RESULTS Although CTAC images are low dose and nongated, a high degree of association was observed between VECAC and AS, with 63% of VECACs in the same category as the AS category and 93% within 1 category. Weighted kappa was 0.89 (95% confidence interval: 0.88 to 0.91, p < 0.0001). High weighted kappa statistics were observed for each site, scanner type, and sex. Readers reported identical scores in 65% of cases and scores within 1 category in 93%. CONCLUSIONS CAC can be visually assessed from low-dose CTAC scans with high agreement with AS. CTAC scans should be routinely assessed for VECAC.

(99m)Tc-pyrophosphate scintigraphy for differentiating light-chain cardiac amyloidosis from the transthyretin-related familial and senile cardiac amyloidoses.

Background— Differentiating amyloid light-chain (AL) from transthyretin-related cardiac amyloidoses (ATTR) is imperative given implications for prognosis, therapy, and genetic counseling. We validated the discriminatory ability of 99mTc-pyrophosphate (99mTc-PYP) scintigraphy in AL versus ATTR. Methods and Results— Forty-five subjects (12 AL, 16 ATTR wild type, and 17 ATTR mutants) underwent 99mTc-PYP planar and single-photon positive emission computed tomography cardiac imaging. Scans were performed by experienced nuclear cardiologists blinded to the subjects’ cohort assignment. Cardiac retention was assessed with both a semiquantitative visual score (range, 0; no uptake to 3, diffuse uptake) and by quantitative analysis by drawing a region of interest over the heart corrected for contralateral counts and calculating a heart-to-contralateral ratio. Subjects with ATTR cardiac amyloid had a significantly higher semiquantitative cardiac visual score than the AL cohort (2.9±0.06 versus 0.8±0.27; P<0.0001) as well as a higher quantitative score (1.80±0.04 versus 1.21±0.04; P<0.0001). Using a heart-to-contralateral ratio >1.5 consistent with intensely diffuse myocardial tracer retention had a 97% sensitivity and 100% specificity with area under the curve 0.992, P<0.0001 for identifying ATTR cardiac amyloidosis. Conclusions— 99mTc-PYP cardiac imaging distinguishes AL from ATTR cardiac amyloidosis and may be a simple, widely available method for identifying subjects with ATTR cardiac amyloidosis, which should be studied in a larger prospective manner.

Comparison of Image Quality, Myocardial Perfusion, and Left Ventricular Function Between Standard Imaging and Single-Injection Ultra-Low-Dose Imaging Using a High-Efficiency SPECT Camera: The MILLISIEVERT Study

SPECT myocardial perfusion imaging plays a central role in coronary artery disease diagnosis, but concerns exist regarding its radiation burden. Compared with standard Anger SPECT (A-SPECT) cameras, new high-efficiency (HE) cameras with specialized collimators and solid-state cadmium-zinc-telluride detectors offer potential to maintain image quality (IQ), while reducing administered activity and thus radiation dose to patients. No previous study has compared IQ, interpretation, total perfusion deficit (TPD), or ejection fraction (EF) in patients receiving both ultra-low-dose (ULD) imaging on an HE SPECT camera and standard low-dose (SLD) A-SPECT imaging. Methods: We compared ULD HE SPECT with SLD A-SPECT imaging by dividing the rest dose in 101 patients at 3 sites scheduled to undergo clinical A-SPECT myocardial perfusion imaging using a same day rest–stress 99mTc protocol. Patients underwent HE SPECT imaging after an initial approximately 130-MBq (3.5 mCi) dose and SLD-A-SPECT imaging after the remainder of the planned dose. Images were scored visually by 2 masked readers for IQ and summed rest score. TPD and EF were assessed quantitatively. Results: Mean activity was 134 MBq (3.62 mCi) for ULD HE SPECT (effective dose, 1.15 mSv) and 278 MBq (7.50 mCi, 2.39 mSv) for SLD A-SPECT. Overall IQ was superior for ULD HE SPECT (P < 0.0001), with twice as many studies graded excellent quality. Extracardiac activity and overall perfusion assessment were similar. Between-method correlations were high for summed rest score (r = 0.87), TPD (r = 0.91), and EF (r = 0.88). Conclusion: ULD HE SPECT rest imaging correlates highly with SLD A-SPECT. It has improved image quality, comparable extracardiac activity, and achieves radiation dose reduction to 1 mSv for a single injection.

PET Imaging May Provide a Novel Biomarker and Understanding of Right Ventricular Dysfunction in Patients With Idiopathic Pulmonary Arterial Hypertension

Background— The clinical course in pulmonary arterial hypertension (PAH) is variable, and there is limited information on the determinants and progression of right ventricular (RV) dysfunction. The objective is to develop PET metabolic imaging of the RV as a noninvasive tool in patients with PAH. Methods and Results— We performed PET scanning in 16 patients with idiopathic PAH (age, 41±14 years, 82% women) using 13N-NH3 for perfusion imaging and 18F-fluorodeoxyglucose for metabolic imaging. The myocardium was divided into 6 regions of interest (3 left ventricular [LV], 3 RV), and time-activity curves were generated. A 2- compartment model was used to calculate myocardial blood flow (MBF), and Patlak analysis was used to calculate the rate of myocardial glucose uptake (MGU). All patients underwent cardiac catheterization, cardiac MRI, and cardiopulmonary exercise testing with gas exchange. MBF, MGU, and the ratio of RV/LV MGU were correlated to clinical parameters. Pulmonary artery (PA) pressure was 79±19/30±8 mm Hg (mean, 48±10 mm Hg). MBF was 0.84±0.33 mL/g per minute for the LV and 0.45±0.14 mL/g per minute for the RV. Mean MGU was 136±72 nmol/g per minute for the LV and 96±69 nmol/g per minute for the RV. The ratio of RV/LV MGU correlated significantly with PA systolic (r=0.75, P=0.0085) and mean (r=0.87, P=0.001) pressure and marginally with maximum oxygen consumption (r=−0.59, P=0.05). RV free wall MGU also correlated well with mean PA pressure (r=0.66, P=0.03). Conclusions— PET scanning with 13N-NH3 and 18F-fluorodeoxyglucose is a feasible modality for quantifying RV blood flow and metabolism in patients with idiopathic PAH.

Positron Emission Tomography Imaging May Provide a Novel Biomarker and Understanding of Right Ventricular Dysfunction in Patients with Idiopathic Pulmonary Arterial Hypertension

Background— The clinical course in pulmonary arterial hypertension (PAH) is variable, and there is limited information on the determinants and progression of right ventricular (RV) dysfunction. The objective is to develop PET metabolic imaging of the RV as a noninvasive tool in patients with PAH. Methods and Results— We performed PET scanning in 16 patients with idiopathic PAH (age, 41±14 years, 82% women) using 13N-NH3 for perfusion imaging and 18F-fluorodeoxyglucose for metabolic imaging. The myocardium was divided into 6 regions of interest (3 left ventricular [LV], 3 RV), and time-activity curves were generated. A 2- compartment model was used to calculate myocardial blood flow (MBF), and Patlak analysis was used to calculate the rate of myocardial glucose uptake (MGU). All patients underwent cardiac catheterization, cardiac MRI, and cardiopulmonary exercise testing with gas exchange. MBF, MGU, and the ratio of RV/LV MGU were correlated to clinical parameters. Pulmonary artery (PA) pressure was 79±19/30±8 mm Hg (mean, 48±10 mm Hg). MBF was 0.84±0.33 mL/g per minute for the LV and 0.45±0.14 mL/g per minute for the RV. Mean MGU was 136±72 nmol/g per minute for the LV and 96±69 nmol/g per minute for the RV. The ratio of RV/LV MGU correlated significantly with PA systolic (r=0.75, P=0.0085) and mean (r=0.87, P=0.001) pressure and marginally with maximum oxygen consumption (r=−0.59, P=0.05). RV free wall MGU also correlated well with mean PA pressure (r=0.66, P=0.03). Conclusions— PET scanning with 13N-NH3 and 18F-fluorodeoxyglucose is a feasible modality for quantifying RV blood flow and metabolism in patients with idiopathic PAH.

Multicenter Study of Planar Technetium 99m Pyrophosphate Cardiac Imaging: Predicting Survival for Patients With ATTR Cardiac Amyloidosis.

Importance Transthyretin cardiac amyloidosis (also known as ATTR cardiac amyloidosis) is an increasingly recognized cause of heart failure with preserved ejection fraction. In single-center studies, technetium 99m pyrophosphate (Tc 99m PYP) cardiac imaging noninvasively detects ATTR cardiac amyloidosis, but the accuracy of this technique in a multicenter study and the association of Tc 99m PYP myocardial uptake with survival are unknown. Objective To assess Tc 99m PYP cardiac imaging as a diagnostic tool for ATTR cardiac amyloidosis and its association with survival in a multicenter study. Design, Setting, and Participants Retrospective cohort study performed at 3 academic specialty centers for cardiac amyloidosis in the United States in which 229 participants were evaluated for cardiac amyloidosis and also underwent Tc 99m PYP cardiac imaging. The date of analysis and final confirmation from the statistician was May 4, 2016. Exposure Tc 99m PYP cardiac imaging for detection of ATTR cardiac amyloidosis. Main Outcomes and Measures Retention of Tc 99m PYP in the heart was assessed using both a semiquantitative visual score (range, 0 [no uptake] to 3 [uptake greater than bone]) and a quantitative heart to contralateral (H/CL) ratio. The H/CL ratio was calculated as total counts in a region of interest over the heart divided by background counts in an identical size region of interest over the contralateral chest. The outcome measured was time to death after Tc 99m PYP imaging. Results Tc 99m PYP imaging of 171 participants (121 with ATTR cardiac amyloidosis and 50 with non-ATTR cardiac amyloidosis [34 with AL amyloidosis and 16 with nonamyloid heart failure with preserved ejection fraction]; 86% male; median [IQR] age, 73 years [65-79 years]) demonstrated 91% sensitivity and 92% specificity for detecting ATTR cardiac amyloidosis with an area under the curve of 0.960 (95% CI, 0.930-0.981). Univariable and multivariable Cox proportional hazards regression analyses among participants with ATTR cardiac amyloidosis showed that an H/CL ratio of 1.6 or greater predicted worse survival (hazard ratio, 3.911 [95% CI, 1.155-13.247]; P = .03 for univariable analysis and 7.913 [95% CI, 1.679-37.296]; P = .01 for multivariable analysis). In Kaplan-Meier analysis over a 5-year follow-up period, survival was significantly worse if the H/CL ratio was 1.6 or greater rather than less than 1.6 (log-rank P = .02). Conclusions and Relevance In this multicenter study, Tc 99m PYP cardiac imaging conferred a high level of sensitivity and specificity for differentiation of patients with ATTR cardiac amyloidosis (irrespective of genotype) from patients with AL cardiac amyloidosis and patients with nonamyloid heart failure with preserved ejection fraction. An H/CL ratio of 1.6 or greater was associated with worse survival among patients with ATTR cardiac amyloidosis. Among patients for whom there is a high clinical suspicion of cardiac amyloidosis, Tc 99m PYP may be of diagnostic and prognostic importance.