Quantitative 99mTc-pyrophosphate myocardial uptake: Changes on transthyretin stabilization therapy.

BACKGROUND: Quantitative technetium-99m-pyrophosphate cardiac single-photon emission computed tomography (99mTc-PYP SPECT/CT) is an emerging method for estimating myocardial burden of transthyretin cardiac amyloidosis (ATTR-CA), but its efficacy in monitoring longitudinal changes remains uncertain. We aimed to investigate longitudinal changes in cardiac ATTR amyloid burden following transthyretin stabilization therapy using visual and quantitative 99mTc-PYP SPECT/CT and to relate these with changes in cardiac biomarkers and function. METHODS: This prospective longitudinal cohort study investigated changes in 99mTc-PYP SPECT/CT in 23 participants with ATTR-CA on transthyretin stabilization therapy (median: 2.6 years). Quantitative analysis included left ventricular (LV) standardized uptake values (SUVs) (SUVmax, SUVmean), cardiac amyloid activity (CAA; SUVmean∗LV activity volume), and percent injected dose (%ID) (mean activity concentration∗LV activity volume/injected activity), calculated using a threshold of >1.5 times left atrial blood pool activity concentration on SPECT/CT. Longitudinal changes of paired continuous and ordinal variables were analyzed using Wilcoxon signed-rank test. RESULTS: Following therapy, visual grade decreased significantly (P = 0.003). Several quantitative 99mTc-PYP metrics also decreased significantly: SUVmax (median -0.75, P = 0.011), CAA (median: -406.6, P < 0.001), and %ID (median: -0.45, P < 0.001). Serum transthyretin levels improved (median: +6.5 mg/dL, P = 0.008). Echocardiographic parameters (global longitudinal strain, LV mass index, and LV wall thickness), N-terminal pro-B-type natriuretic peptide, and estimated glomerular filtration rate remained stable. CONCLUSIONS: Favorable changes in 99mTc-PYP myocardial uptake were observed in participants on transthyretin stabilization therapy, whereas echocardiographic parameters and biomarkers remained stable. These results likely signify myocardial ATTR amyloid stabilization rather than amyloid burden regression. Further investigation is needed to understand the implications of these findings.

Potential clinical utility of 68Ga-DOTATATE PET/CT for detection and response assessment in cardiac sarcoidosis.

BACKGROUND: Somatostatin receptor is expressed in sarcoid granulomas, and preliminary clinical studies have shown that myocardial sarcoidosis can be identified on somatostatin receptor-targeted PET. We examined the potential clinical use of 68Ga-DOTATATE PET/CT for diagnosis and response assessment in cardiac sarcoidosis compared to 18F-FDG PET/CT. METHODS: Eleven cardiac sarcoidosis patients with 18F-FDG PET/CT were prospectively enrolled for cardiac 68Ga-DOTATATE PET/CT. The two PET/CT studies were interpreted independently and were compared for patient-level and segment-level concordance, as well as for the degree of radiotracer uptake. Follow-up 68Ga-DOTATATE PET/CT was performed in eight patients. RESULTS: Patient-level concordance was 91%: ten patients had multifocal DOTATATE uptake (active cardiac sarcoidosis) and one patient showed diffuse DOTATATE uptake. Segment-level agreement was 77.1% (Kappa 0.53 ± 0.07). The SUVmax-to-blood pool ratio was lower on 68Ga-DOTATATE PET/CT (3.2 ± 0.6 vs. 4.9 ± 1.5, P = 0.006 on paired t test). Follow-up 68Ga-DOTATATE PET/CT showed one case of complete response and one case of partial response, while 18F-FDG PET/CT showed four cases of response, including three with complete response. CONCLUSION: Compared to 18F-FDG PET/CT, 68Ga-DOTATATE PET/CT can identify active cardiac sarcoidosis with high patient-level concordance, but with moderate segment-level concordance, low signal-to-background ratio, and underestimation of treatment response.

Frequency, compliance, and yield of cardiac testing after high-sensitivity troponin accelerated diagnostic protocol implementation.

BACKGROUND: Among persons presenting to the emergency department with suspected acute myocardial infarction (MI), cardiac troponin (cTn) testing is commonly used to detect acute myocardial injury. Accelerated diagnostic protocols (ADPs) guide clinicians to integrate cTn results with other clinical information to decide whether to order further diagnostic testing. OBJECTIVE: To determine the change in the rate and yield of stress test or coronary CT angiogram following cTn measurement in patients with chest pain presenting to the emergency department pre- and post-transition to a high-sensitivity (hs-cTn) assay in an updated ADP. METHODS: Using electronic health records, we examined visits for chest pain at five emergency departments affiliated with an integrated academic health system 1-year pre- and post-hs-cTn assay transition. Outcomes included stress test or coronary imaging frequency, ADP compliance among those with additional testing, and diagnostic yield (ratio of positive tests to total tests). RESULTS: There were 7564 patient-visits for chest pain, including 3665 in the pre- and 3899 in the post-period. Following the updated ADP using hs-cTn, 862 (23.5 per 100 patient visits) visits led to subsequent testing versus 1085 (27.8 per 100 patient visits) in the pre-hs-cTn period, (P < 0.001). Among those who were tested, the protocol-compliant rate fell from 80.9% to 46.5% (P < 0.001), but the yield of those tests rose from 24.5% to 29.2% (P = 0.07). Among tests that were noncompliant with ADP guidance, yield was similar pre- and post-updated hs-cTn ADP implementation (pre 13.0%, post 15.4% (P = 0.43). CONCLUSION: Implementation of hs-cTn supported by an updated ADP was associated with a lower rate of stress testing and coronary CT angiogram.

Reducing radiation dose from myocardial perfusion imaging in subjects with complex congenital heart disease.

INTRODUCTION: The prevalence of defects and effective radiation dose from various myocardial perfusion imaging (MPI) strategies in congenital heart disease (CHD) is unknown. METHODS: We studied 75 subjects with complex CHD (ages 5 to 80 years) referred for MPI between 2002 and 2015. A rest and exercise or pharmacologic stress MPI was performed using 99mTechnetium sestamibi, 82rubidium or 13N-ammonia, and Sodium iodide SPECT (single-photon emission computed tomography), SPECT/CT or Cadmium zinc telluride (CZT) SPECT or PET (positron emission tomography)/CT scanners. Deidentified images were interpreted semi-quantitatively in three batches: stress only MPI, stress/rest MPI, and stress/rest MPI with taking into account a history of ventricular septal defect repair. Effective radiation dose was estimated for stress/rest MPI and predicted for 1-day stress-first (normal stress scans), and for 2-day stress/rest MPI (abnormal stress scans). RESULTS: The median age was 18.6 years. The most common type of CHD was transposition of the great arteries (63%). Rest/stress MPI was abnormal in 43% of subjects and 25% of the abnormal scans demonstrated reversible defects. Of the subjects with abnormal MPI, 33% had significant underlying anatomic coronary artery obstruction. Estimated mean effective radiation dose ranged from 2.1 ± 0.6 mSv for 13N-ammonia PET/CT to 12.5 ± 0.9 mSv for SPECT/CT. Predicted effective radiation dose was significantly lower for stress-first MPI and for 2-day stress/rest protocols. CONCLUSIONS: Due to the relatively high prevalence of abnormal stress MPI, tailored protocols with a stress-first MPI as well as the use of 2-day protocols and advanced imaging technologies including CZT SPECT, novel image reconstruction software, and PET MPI could substantially reduce radiation dose in complex CHD.

Patient preparation for cardiac fluorine-18 fluorodeoxyglucose positron emission tomography imaging of inflammation.

Although the number of clinical applications for fluorine-18 fluorodeoxyglucose (18F-FDG) cardiac positron emission tomography (PET) has continued to grow, there remains a lack of consensus regarding the ideal method of suppressing normal myocardial glucose utilization for image optimization. This review describes various patient preparation protocols that have been used as well as the success rates achieved in different studies. Collectively, the available literature supports using a high-fat, no-carbohydrate diet for at least two meals with a fast of 4-12 hours prior to 18F-FDG PET imaging and suggests that isolated fasting for less than 12 hours and supplementation with food or drink just prior to imaging should be avoided. Each institution should adopt a protocol and continuously monitor its effectiveness with a goal to achieve adequate myocardial suppression in greater than 80% of patients.

Dose reduction in half-time myocardial perfusion SPECT-CT with multifocal collimation.

BACKGROUND: Recent technological advances in myocardial perfusion imaging may warrant the use of lower injected activity. We evaluated whether quantitative measures of stress myocardial perfusion defects using Tc-99m sestamibi and low-energy high-resolution (LEHR) collimators are equivalent to lower dose SPECT-CT with cardiac multifocal collimators and software (IQ·SPECT). METHODS: 93 patients underwent one-day rest-stress gated SPECT-CT. Following conventional rest imaging, 925-1100 MBq (25-30 mCi) of Tc-99m sestamibi was injected during stress testing. Stress SPECT-CT images were acquired two ways: with LEHR (13 minutes) and IQ·SPECT (7 minutes). Low-dose IQ·SPECT stress was simulated by subsampling the full-dose data to half-, quarter-, and eighth-count levels. Abnormalities were quantified using the total perfusion deficit (TPD) score and dose-specific databases. RESULTS: The mean ± SD of the differences between LEHR and IQ·SPECT TPD scores were -1.01 ± 5.36%, -0.10 ± 5.81%, 1.78 ± 4.81%, and 1.75 ± 6.05% at full, half, quarter, and eighth doses, respectively. Differences were statistically significant for quarter and eighth doses. Correlation between LEHR and IQ·SPECT was excellent at all doses (R ≥ 0.93). Bland-Altman plots demonstrated minimal bias. CONCLUSIONS: With IQ·SPECT, quantitative stress SPECT-CT imaging is possible with half of the standard injected activity in half the time.

Comprehensive assessment of radiation dose estimates for the CORE320 study.

OBJECTIVE. The purpose of this study was to comprehensively study estimated radiation doses for subjects included in the main analysis of the Combined Non-invasive Coronary Angiography and Myocardial Perfusion Imaging Using 320 Detector Computed Tomography (CORE320) study ( ClinicalTrials.gov identifier NCT00934037), a clinical trial comparing combined CT angiography (CTA) and perfusion CT with the reference standard catheter angiography plus myocardial perfusion SPECT. SUBJECTS AND METHODS. Prospectively acquired data on 381 CORE320 subjects were analyzed in four groups of testing related to radiation exposure. Radiation dose estimates were compared between modalities for combined CTA and perfusion CT with respect to covariates known to influence radiation exposure and for the main clinical outcomes defined by the trial. The final analysis assessed variations in radiation dose with respect to several factors inherent to the trial. RESULTS. The mean radiation dose estimate for the combined CTA and perfusion CT protocol (8.63 mSv) was significantly (p < 0.0001 for both) less than the average dose delivered from SPECT (10.48 mSv) and the average dose from diagnostic catheter angiography (11.63 mSv). There was no significant difference in estimated CTA-perfusion CT radiation dose for subjects who had false-positive or false-negative results in the CORE320 main analyses in a comparison with subjects for whom the CTA-perfusion CT findings were in accordance with the reference standard SPECT plus catheter angiographic findings. CONCLUSION. Radiation dose estimates from CORE320 support clinical implementation of a combined CT protocol for assessing coronary anatomy and myocardial perfusion.

Coronary Microvascular Dysfunction Is Present Among Well-Treated Asymptomatic Persons With HIV and Similar to Those With Diabetes.

Background: Coronary microvascular dysfunction (CMD) could be a potential underlying mechanism for myocardial disease in HIV. Methods: Comparisons of coronary flow reserve corrected for heart rate-blood pressure product (CFRCOR) were made among people with HIV (PWH) with no known history of cardiovascular disease (CVD) or diabetes mellitus, persons without HIV (PWOH), and persons with diabetes (PWDM) and no known history of CVD or HIV. Results: PWH (n = 39, 74% male, age 55 [7] years, body mass index [BMI] 32.3 (26.8-34.9) kg/m2, duration of antiretroviral therapy 13 [5] years, CD4+ count 754 [598-961] cells/µL) were similar to PWOH (n = 69, 74% male, age 55 [8] years, BMI 32.2[25.6-36.5] kg/m2) and PWDM (n = 63, 63% male, age 55 [8] years, BMI 31.5 [28.6-35.6] kg/m2). CFRCOR was different among groups: PWOH 2.76 (2.37-3.36), PWH 2.47 (1.92-2.93), and PWDM 2.31 (1.98-2.84); overall P = .003. CFRCOR was reduced comparing PWH to PWOH (P = .04) and PWDM to PWOH (P = .007) but did not differ when comparing PWH to PWDM (P = .98). A total 31% of PWH had CFRCOR < 2.0, a critical cutoff for CMD, compared to 14% of PWOH and 27% with PWDM. A total 40% of women with HIV had a CFRCOR < 2.0 compared to 6% of women without HIV (P = .02). Conclusions: Subclinical CMD is present among chronically infected and well-treated, asymptomatic PWH who are immunologically controlled. This study demonstrates CFR is reduced in PWH compared to PWOH and comparable to PWDM, further highlighting that well-treated HIV infection is a CVD-risk enhancing factor for CMD similar to diabetes. Clinical Trials Registration: NCT02740179.

Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial.

BACKGROUND: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina. METHODS: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery. RESULTS: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months. CONCLUSIONS: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732.

Initial multicentre experience of high-speed myocardial perfusion imaging: comparison between high-speed and conventional single-photon emission computed tomography with angiographic validation.

PURPOSE: High-speed (HS) single-photon emission computed tomography (SPECT) with a recently developed solid-state camera shows comparable myocardial perfusion abnormalities to those seen in conventional SPECT. We aimed to compare HS and conventional SPECT images from multiple centres with coronary angiographic findings. METHODS: The study included 50 patients who had sequential conventional SPECT and HS SPECT myocardial perfusion studies and coronary angiography within 3 months. Stress and rest perfusion images were visually analysed and scored semiquantitatively using a 17-segment model by two experienced blinded readers. Global and coronary territorial summed stress scores (SSS) and summed rest scores (SRS) were calculated. Global SSS ≥3 or coronary territorial SSS ≥2 was considered abnormal. In addition the total perfusion deficit (TPD) was automatically derived. TPD >5% and coronary territorial TPD ≥3% were defined as abnormal. Coronary angiograms were analysed for site and severity of coronary stenosis; ≥50% was considered significant. RESULTS: Of the 50 patients, 13 (26%) had no stenosis, 22 (44%) had single-vessel disease, 6 (12%) had double-vessel disease and 9 (18%) had triple-vessel disease. There was a good linear correlation between the visual global SSS and SRS (Spearman's ρ 0.897 and 0.866, respectively; p < 0.001). In relation to coronary angiography, the sensitivities, specificities and accuracies of HS SPECT and conventional SPECT by visual assessment were 92% (35/38), 83% (10/12) and 90% (45/50) vs. 84% (32/38), 50% (6/12) and 76% (38/50), respectively (p < 0.001). The sensitivities, specificities and accuracies of HS SPECT and conventional SPECT in relation to automated TPD assessment were 89% (31/35), 57% (8/14) and 80% (39/49) vs. 86% (31/36), 77% (10/13) and 84% (41/49), respectively. CONCLUSION: HS SPECT allows fast acquisition of myocardial perfusion images that correlate well with angiographic findings with overall accuracy by visual assessment better than conventional SPECT. Further assessment in a larger patient population may be needed to confirm this observation.

Association Between Inflammation, Incident Heart Failure, and Heart Failure Subtypes in Patients With Rheumatoid Arthritis.

OBJECTIVE: In rheumatoid arthritis (RA), there are limited data on risk factors for the clinical heart failure (HF) subtypes of HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). This study examined the association between inflammation and incident HF subtypes in RA. Because inflammation changes over time with disease activity, we hypothesized that the effect of inflammation may be stronger at the 5-year follow-up than at the standard 10-year follow-up from general population studies of cardiovascular risk. METHODS: We studied an electronic health record (EHR)-based RA cohort with data pre- and post-RA incidence. We applied a validated approach to identify HF and extract ejection fraction to classify HFrEF and HFpEF. Follow-up started from the RA incidence date (index date) to the earliest occurrence of incident HF, death, last EHR encounter, or 10 years. Baseline inflammation was assessed using erythrocyte sedimentation rate or C-reactive protein values. Covariates included demographic characteristics, established HF risk factors, and RA-related factors. We tested the association between baseline inflammation with incident HF and its subtypes using Cox proportional hazards models. RESULTS: We studied 9,087 patients with RA; 8.2% developed HF during 10 years of follow-up. Elevated inflammation was associated with increased risk for HF at both 5- and 10-year follow-ups (hazard ratio [HR] 1.66, 95% confidence interval [95% CI] 1.12-2.46 and HR 1.46, 95% CI 1.13-1.90, respectively), which is also seen for HFpEF at 5 years (HR 1.72, 95% CI 1.09-2.70) and 10 years (HR 1.45, 95% CI 1.07-1.94). HFrEF was not associated with inflammation for either follow-up time. CONCLUSION: Elevated inflammation early in RA diagnosis was associated with HF; this association was driven by HFpEF and not HFrEF, suggesting a window of opportunity for prevention of HFpEF in RA.

EXACT Trial: Results of the Phase 1 Dose-Escalation Study.

BACKGROUND: New therapies are needed for patients with refractory angina. Encoberminogene rezmadenovec (XC001), a novel adenoviral-5 vector coding for all 3 major isoforms of VEGF (vascular endothelial growth factor), demonstrated enhanced local angiogenesis in preclinical models; however, the maximal tolerated dose and safety of direct epicardial administration remain unknown. METHODS: In the phase 1 portion of this multicenter, open-label, single-arm, dose-escalation study, patients with refractory angina received increasing doses of encoberminogene rezmadenovec (1×109, 1×1010, 4×1010, and 1×1011 viral particles) to evaluate its safety, tolerability, and preliminary efficacy. Patients had class II to IV angina on maximally tolerated medical therapy, demonstrable ischemia on stress testing, and were angina-limited on exercise treadmill testing. Patients underwent minithoracotomy with epicardial delivery of 15 0.1-mL injections of encoberminogene rezmadenovec. The primary outcome was safety via adverse event monitoring over 6 months. Efficacy assessments included difference from baseline to months 3, 6 (primary), and 12 in total exercise duration, myocardial perfusion deficit using positron emission tomography, angina class, angina frequency, and quality of life. RESULTS: From June 2, 2020 to June 25, 2021, 12 patients were enrolled into 4 dosing cohorts with 1×1011 viral particle as the highest planned dose. Seventeen serious adverse events were reported in 7 patients; none were related to study drug. Six serious adverse events in 4 patients were related to the thoracotomy, 3 non-serious adverse events were possibly related to study drug. The 2 lowest doses did not demonstrate improvements in total exercise duration, myocardial perfusion deficit, or angina frequency; however, there appeared to be improvements in all parameters with the 2 higher doses. CONCLUSIONS: Epicardial delivery of encoberminogene rezmadenovec via minithoracotomy is feasible, and up to 1×1011 viral particle appears well tolerated. A dose response was observed across 4 dosing cohorts in total exercise duration, myocardial perfusion deficit, and angina class. The highest dose (1×1011 viral particle) was carried forward into phase 2. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04125732.

Effector function of anti-pyroglutamate-3 Aß antibodies affects cognitive benefit, glial activation and amyloid clearance in Alzheimer's-like mice.

BACKGROUND: Pyroglutamate-3 Aß (pGlu-3 Aß) is an N-terminally truncated and post-translationally modified Aß species found in Alzheimer's disease (AD) brain. Its increased peptide aggregation propensity and toxicity make it an attractive emerging treatment strategy for AD. We address the question of how the effector function of an anti-pGlu-3 Aß antibody influences the efficacy of immunotherapy in mouse models with AD-like pathology. METHODS: We compared two different immunoglobulin (Ig) isotypes of the same murine anti-pGlu-3 Aß mAb (07/1 IgG1 and 07/2a IgG2a) and a general N-terminal Aß mAb (3A1 IgG1) for their ability to clear Aß and protect cognition in a therapeutic passive immunotherapy study in aged, plaque-rich APPSWE/PS1ΔE9 transgenic (Tg) mice. We also compared the ability of these antibodies and a CDC-mutant form of 07/2a (07/2a-k), engineered to avoid complement activation, to clear Aß in an ex vivo phagocytosis assay and following treatment in APPSLxhQC double Tg mice, and to activate microglia using longitudinal microPET imaging with TSPO-specific 18F-GE180 tracer following a single bolus antibody injection in young and old Tg mice. RESULTS: We demonstrated significant cognitive improvement, better plaque clearance, and more plaque-associated microglia in the absence of microhemorrhage in aged APPSWE/PS1ΔE9 Tg mice treated with 07/2a, but not 07/1 or 3A1, compared to PBS in our first in vivo study. All mAbs cleared plaques in an ex vivo assay, although 07/2a promoted the highest phagocytic activity. Compared with 07/2a, 07/2a-k showed slightly reduced affinity to Fcγ receptors CD32 and CD64, although the two antibodies had similar binding affinities to pGlu-3 Aß. Treatment of APPSLxhQC mice with 07/2a and 07/2a-k mAbs in our second in vivo study showed significant plaque-lowering with both mAbs. Longitudinal 18F-GE180 microPET imaging revealed different temporal patterns of microglial activation for 3A1, 07/1, and 07/2a mAbs and no difference between 07/2a-k and PBS-treated Tg mice. CONCLUSION: Our results suggest that attenuation of behavioral deficits and clearance of amyloid is associated with strong effector function of the anti-pGlu-3 Aß mAb in a therapeutic treatment paradigm. We present evidence that antibody engineering to reduce CDC-mediated complement binding facilitates phagocytosis of plaques without inducing neuroinflammation in vivo. Hence, the results provide implications for tailoring effector function of humanized antibodies for clinical development.

18F-PBR06 Versus 11C-PBR28 PET for Assessing White Matter Translocator Protein Binding in Multiple Sclerosis.

BACKGROUND AND PURPOSE: F-PBR06 and C-PBR28 are second-generation PET radioligands targeting the 18-kd translocator protein to assess microglial activation. We directly compared F-PBR06 and C-PBR28 for detecting brain translocator protein binding in multiple sclerosis (MS). METHODS: Six patients with MS (4 women; mean age ± SD, 32.1 ± 4.9 [range, 23.5-37.4 years]; Expanded Disability Status Scale score 2.3 ± 1.2 [range, 1.0-4.0]) underwent brain PET with both ligands, along with 3-T MRI. MRI was coregistered to the summed 60- to 90-minute PET images. SUV ratios (SUVRs), derived by normalization to global brain radioactivity, were obtained for whole-brain white matter (WM), supratentorial WM, normal-appearing WM (NAWM), and T2 (fluid-attenuated inversion recovery) hyperintense and T1 hypointense MS WM lesions. The highest mean SUVR for the fluid-attenuated inversion-recovery lesional slices was defined as SUVRmax. RESULTS: F-PBR06 and C-PBR28 were moderately intercorrelated for whole-brain WM SUVR (r = 0.83, P = 0.04) and supratentorial WM SUVR (r = 0.81, P = 0.05) but not for SUVRs of NAWM, T1 lesions, T2 lesions, or SUVRmax. Both tracers demonstrated that SUVR was higher in NAWM than in T1 and T2 lesions (all P < 0.05). F-PBR06 (but not C-PBR28) demonstrated a higher SUVR in T1 versus T2 lesions (0.85 ± 0.07 vs 0.78 ± 0.03, P = 0.03). F-PBR06-derived (but not C-PBR28) SUVRmax correlated with both Expanded Disability Status Scale score (r = 0.82, P = 0.04) and timed 25-ft walking speed (r = 0.89, P = 0.01). CONCLUSIONS: Our preliminary results suggest an association between microglial activation and physical disability in MS. Microglial detection in lesions was not interchangeable between the tracers, with a higher clinical relevance suggested for F-PBR06.

Diagnostic accuracy of semi-automatic quantitative metrics as an alternative to expert reading of CT myocardial perfusion in the CORE320 study.

AIMS: To determine the diagnostic accuracy of semi-automatic quantitative metrics compared to expert reading for interpretation of computed tomography perfusion (CTP) imaging. METHODS: The CORE320 multicenter diagnostic accuracy clinical study enrolled patients between 45 and 85 years of age who were clinically referred for invasive coronary angiography (ICA). Computed tomography angiography (CTA), CTP, single photon emission computed tomography (SPECT), and ICA images were interpreted manually in blinded core laboratories by two experienced readers. Additionally, eight quantitative CTP metrics as continuous values were computed semi-automatically from myocardial and blood attenuation and were combined using logistic regression to derive a final quantitative CTP metric score. For the reference standard, hemodynamically significant coronary artery disease (CAD) was defined as a quantitative ICA stenosis of 50% or greater and a corresponding perfusion defect by SPECT. Diagnostic accuracy was determined by area under the receiver operating characteristic curve (AUC). RESULTS: Of the total 377 included patients, 66% were male, median age was 62 (IQR: 56, 68) years, and 27% had prior myocardial infarction. In patient based analysis, the AUC (95% CI) for combined CTA-CTP expert reading and combined CTA-CTP semi-automatic quantitative metrics was 0.87(0.84-0.91) and 0.86 (0.83-0.9), respectively. In vessel based analyses the AUC's were 0.85 (0.82-0.88) and 0.84 (0.81-0.87), respectively. No significant difference in AUC was found between combined CTA-CTP expert reading and CTA-CTP semi-automatic quantitative metrics in patient based or vessel based analyses(p > 0.05 for all). CONCLUSION: Combined CTA-CTP semi-automatic quantitative metrics is as accurate as CTA-CTP expert reading to detect hemodynamically significant CAD.

Nuclear cardiac imaging for the assessment of coronary artery disease in the elderly.

Stress single photon emission computed tomography (SPECT) and positron emission tomography (PET), the standard clinical methods for measuring myocardial perfusion, have been extensively validated for diagnostic and prognostic purposes in general populations. Published data in the elderly are limited. The available data suggest that in elderly patients, SPECT is as accurate for diagnostic purposes as in younger patients and that stress SPECT is considerably more accurate for prognostic purposes when compared with standard treadmill testing. Pharmacologic stress testing can be performed in conjunction with SPECT and PET, representing another advantage of these techniques because many elderly patients cannot exercise to a high enough workload to provoke ischemia during testing.

Effect of a peroxisome proliferator-activated receptor-gamma agonist on myocardial blood flow in type 2 diabetes.

OBJECTIVE: The relationship between coronary endothelial function and insulin resistance remains speculative. We sought to determine whether pioglitazone, an insulin-sensitizing peroxisome proliferator-activated receptor (PPAR)-gamma agonist, improves cardiac endothelial function in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: Sixteen subjects with insulin-treated type 2 diabetes and without overt cardiovascular disease were randomly assigned to receive either 45 mg of pioglitazone or matching placebo for 3 months. Rest and adenosine-stimulated myocardial blood flow (MBF) were quantified with [(13)N]ammonia and positron emission tomography at baseline and study conclusion. RESULTS: After 3 months, HbA(1c) levels dropped by 0.68% in the pioglitazone group and increased by 0.17% in the placebo group (P = 0.009 for difference between groups). Triglyceride (-93 vs. -39 mg/dl, P = 0.026) and HDL concentrations (+4.8 vs. -6.0 mg/dl, P = 0.014) improved significantly in the pioglitazone group compared with placebo. Despite these favorable changes, there was no demonstrable change in baseline MBF (-0.05 +/- 0.24 vs. -0.09 +/- 0.24 ml . min(-1) . g(-1), P = 0.45), adenosine-stimulated MBF (0.10 +/- 0.75 vs. 0.14 +/- 0.31 ml . min(-1) . g(-1), P = 0.25), or coronary flow reserve (0.45 +/- 1.22 vs. 0.35 +/- 0.72 ml . min(-1) . g(-1), P = 0.64) after 12 weeks of exposure to pioglitazone or placebo, respectively. Regression analysis revealed that lower glucose concentration at the time of the study was associated with higher coronary flow reserve (P = 0.012). CONCLUSIONS: Pioglitazone treatment for 12 weeks in subjects with insulin-requiring type 2 diabetes had no demonstrable effect on coronary flow reserve despite metabolic improvements. Higher ambient glucose levels contribute to impaired vascular reactivity in individuals with diabetes.

Economic outcomes in the Study of Myocardial Perfusion and Coronary Anatomy Imaging Roles in Coronary Artery Disease registry: the SPARC Study.

OBJECTIVES: The goal of this study was to compare the economic outcomes of patients undergoing different noninvasive tests to evaluate suspected coronary artery disease (CAD). BACKGROUND: Evaluation of noninvasive tests is shifting to an assessment of their effect on clinical outcomes rather than on their diagnostic accuracy. Economic outcomes of testing are particularly important in light of rising medical care costs. METHODS: We used an observational registry of 1,703 patients who underwent coronary computed tomography angiography (CTA) (n = 590), positron emission tomography (PET) (n = 548), or single-photon emission computed tomography (SPECT) (n = 565) for diagnosis of suspected CAD at 1 of 41 centers. We followed patients for 2 years, and documented resource use, medical costs for CAD, and clinical outcomes. We used multivariable analysis and propensity score matching to control for differences in baseline characteristics. RESULTS: Two-year costs were highest after PET ($6,647, 95% confidence interval [CI]: $5,896 to $7,397), intermediate after CTA ($4,909, 95% CI: $4,378 to $5,440), and lowest after SPECT ($3,965, 95% CI: $3,520 to $4,411). After multivariable adjustment, CTA costs were 15% higher than SPECT (p < 0.01), and PET costs were 22% higher than SPECT (p < 0.0001). Two-year mortality was 0.7% after CTA, 1.6% after SPECT, and 5.5% after PET. The incremental cost-effectiveness ratio for CTA compared with SPECT was $11,700 per life-year added, but was uncertain, with higher costs and higher mortality in 13% of bootstrap replications. Patients undergoing PET had higher costs and higher mortality than patients undergoing SPECT in 98% of bootstrap replications. CONCLUSIONS: Costs were significantly lower after using SPECT rather than CTA or PET in the evaluation of suspected coronary disease. SPECT was economically attractive compared with PET, whereas CTA was associated with higher costs and no significant difference in mortality compared with SPECT.