Variable activation of the DNA damage response pathways in patients undergoing single-photon emission computed tomography myocardial perfusion imaging.
ABSTRACT: BACKGROUND:Although single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) has improved the diagnosis and risk stratification of patients with suspected coronary artery disease, it remains a primary source of low-dose radiation exposure for cardiac patients. To determine the biological effects of low-dose radiation from SPECT MPI, we measured the activation of the DNA damage response pathways using quantitative flow cytometry and single-cell gene expression profiling. METHODS AND RESULTS:Blood samples were collected from patients before and after SPECT MPI (n=63). Overall, analysis of all recruited patients showed no marked differences in the phosphorylation of proteins (H2AX, protein 53, and ataxia telangiectasia mutated) after SPECT. The majority of patients also had either downregulated or unchanged expression in DNA damage response genes at both 24 and 48 hours post-SPECT. Interestingly, a small subset of patients with increased phosphorylation had significant upregulation of genes associated with DNA damage, whereas those with no changes in phosphorylation had significant downregulation or no difference, suggesting that some patients may potentially be more sensitive to low-dose radiation exposure. CONCLUSIONS:Our findings showed that SPECT MPI resulted in a variable activation of the DNA damage response pathways. Although only a small subset of patients had increased protein phosphorylation and elevated gene expression postimaging, continued care should be taken to reduce radiation exposure to both the patients and operators.
Project description:This document from the American Society of Nuclear Cardiology represents an updated consensus statement on the evidence base of stress myocardial perfusion imaging (MPI), emphasizing new developments in single-photon emission tomography (SPECT) and positron emission tomography (PET) in the clinical evaluation of women presenting with symptoms of stable ischemic heart disease (SIHD). The clinical evaluation of symptomatic women is challenging due to their varying clinical presentation, clinical risk factor burden, high degree of comorbidity, and increased risk of major ischemic heart disease events. Evidence is substantial that both SPECT and PET MPI effectively risk stratify women with SIHD. The addition of coronary flow reserve (CFR) with PET improves risk detection, including for women with nonobstructive coronary artery disease and coronary microvascular dysfunction. With the advent of PET with computed tomography (CT), multiparametric imaging approaches may enable integration of MPI and CFR with CT visualization of anatomical atherosclerotic plaque to uniquely identify at-risk women. Radiation dose-reduction strategies, including the use of ultra-low-dose protocols involving stress-only imaging, solid-state detector SPECT, and PET, should be uniformly applied whenever possible to all women undergoing MPI. Appropriate candidate selection for stress MPI and for post-MPI indications for guideline-directed medical therapy and/or invasive coronary angiography are discussed in this statement. The critical need for randomized and comparative trial data in female patients is also emphasized.
Project description:RESCUE is a phase III, randomized, controlled, multicenter, comparative efficacy study, designed to compare two diagnostic imaging/treatment paradigms that use coronary computed tomography angiography (CCTA) or single photon emission computed tomography myocardial perfusion imaging (SPECT MPI) for assisting in the diagnosis of ischemic heart disease in patients with stable angina symptoms, and guiding subsequent treatment. The study is based on the hypothesis that CCTA as a diagnostic tool is associated with no increase in cardiac risk, decreased cost, and reduced radiation exposure compared with SPECT MPI. The RESCUE trial was funded by the Agency for Healthcare Research and Quality (AHRQ) and the American College of Radiology Imaging Network (ACRIN) Fund for Imaging Innovation, began in 2011, and completed in 2014.
Project description:BACKGROUND:Establishing the diagnosis of coronary artery disease (CAD) in symptomatic patients allows appropriately allocating preventative measures. Single-photon emission computed tomography (CT)-acquired myocardial perfusion imaging (SPECT-MPI) is frequently used for the evaluation of CAD, but coronary CT angiography (CTA) has emerged as a valid alternative. METHODS AND RESULTS:We compared the accuracy of SPECT-MPI and CTA for the diagnosis of CAD in 391 symptomatic patients who were prospectively enrolled in a multicenter study after clinical referral for cardiac catheterization. The area under the receiver operating characteristic curve was used to evaluate the diagnostic accuracy of CTA and SPECT-MPI for identifying patients with CAD defined as the presence of ?1 coronary artery with ?50% lumen stenosis by quantitative coronary angiography. Sensitivity to identify patients with CAD was greater for CTA than SPECT-MPI (0.92 versus 0.62, respectively; P<0.001), resulting in greater overall accuracy (area under the receiver operating characteristic curve, 0.91 [95% confidence interval, 0.88-0.94] versus 0.69 [0.64-0.74]; P<0.001). Results were similar in patients without previous history of CAD (area under the receiver operating characteristic curve, 0.92 [0.89-0.96] versus 0.67 [0.61-0.73]; P<0.001) and also for the secondary end points of ?70% stenosis and multivessel disease, as well as subgroups, except for patients with a calcium score of ?400 and those with high-risk anatomy in whom the overall accuracy was similar because CTA's superior sensitivity was offset by lower specificity in these settings. Radiation doses were 3.9 mSv for CTA and 9.8 for SPECT-MPI (P<0.001). CONCLUSIONS:CTA is more accurate than SPECT-MPI for the diagnosis of CAD as defined by conventional angiography and may be underused for this purpose in symptomatic patients. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT00934037.
Project description:OBJECTIVES:This study compared the clinical effectiveness of pharmacologic stress myocardial perfusion imaging (MPI) plus positron emission tomography (PET) with single-photon emission computed tomography (SPECT) in patients with known coronary artery disease (CAD) presenting with symptoms suggestive of ischemia. BACKGROUND:Although PET MPI has been shown to have higher diagnostic accuracy in detecting hemodynamically significant CAD than SPECT MPI, whether this impacts downstream management has not been formally evaluated in randomized trials. METHODS:This study consisted of a single-center trial in which patients with known CAD and suspected ischemia were randomized to undergo PET or attenuation-corrected SPECT MPI between June 2009 and September 2013. Post-test management was at the discretion of the referring physician, and patients were followed for 12 months. The primary endpoint was diagnostic failure, defined as unnecessary angiography (absence of ?50% stenosis in ?1 vessel) or additional noninvasive testing within 60 days of the MPI. Secondary endpoints were post-test escalation of antianginal therapy, referral for angiography, coronary revascularization, and health status at 3, 6, and 12 months. RESULTS:A total of 322 patients with an evaluable MPI were randomized (n = 161 in each group). At baseline, 88.8% of patients were receiving aspirin therapy, 76.7% were taking beta-blockers, and 77.3% were taking statin therapy. Diagnostic failure within 60 days occurred in only 7 patients (2.2%) (3 [1.9%] in the PET group and 4 [2.5%] in the SPECT group; p = 0.70). There were no significant differences between the 2 groups in subsequent rates of coronary angiography, coronary revascularization, or health status at 3, 6, and 12 months of follow-up (all p values ?0.20); however, when subjects were stratified by findings on MPI in a post hoc analysis, those with high-risk MPI on PET testing had higher rates of angiography and revascularization on follow-up than those who had SPECT MPI, whereas those undergoing low-risk PET studies had lower rates of both procedures than those undergoing SPECT (interaction between randomized modality ?high-risk MPI for 12-month catheterization [p = 0.001] and 12-month revascularization [p = 0.09]). CONCLUSIONS:In this contemporary cohort of symptomatic CAD patients who were optimally medically managed, there were no discernible differences in rates of diagnostic failure at 60 days, subsequent coronary angiography, revascularization, or patient health status at 1 year between patients evaluated by pharmacologic PET compared with those evaluated by SPECT MPI. Downstream invasive testing rates with PET MPI were more consistent with high-risk features than those with SPECT MPI. (Effectiveness Study of Single Photon Emission Computed Tomography [SPECT] Versus Positron Emission Tomography [PET] Myocardial Perfusion Imaging; NCT00976053).
Project description:Nuclear cardiology has experienced exponential growth within the past four decades with converging capacity to diagnose and influence management of a variety of cardiovascular diseases. Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) with technetium-99m radiotracers or thallium-201 has dominated the field; however new hardware and software designs that optimize image quality with reduced radiation exposure are fuelling a resurgence of interest at the preclinical and clinical levels to expand beyond MPI. Other imaging modalities including positron emission tomography (PET) and magnetic resonance imaging (MRI) continue to emerge as powerful players with an expanded capacity to diagnose a variety of cardiac conditions. At the forefront of this resurgence is the development of novel target vectors based on an enhanced understanding of the underlying pathophysiological process in the subcellular domain. Molecular imaging with novel radiopharmaceuticals engineered to target a specific subcellular process has the capacity to improve diagnostic accuracy and deliver enhanced prognostic information to alter management. This paper, while not comprehensive, will review the recent advancements in radiotracer development for SPECT and PET MPI, autonomic dysfunction, apoptosis, atherosclerotic plaques, metabolism, and viability. The relevant radiochemistry and preclinical and clinical development in addition to molecular imaging with emerging modalities such as cardiac MRI and PET-MR will be discussed.
Project description:<h4>Aims</h4>To examine whether test utilization and prevalence of ischemia with positron emission tomography (PET) myocardial perfusion imaging (MPI) follow the previously described trends with single photon computed tomography (SPECT).<h4>Methods and results</h4>MPI studies performed between January 2003 and December 2017 were identified. Number of PET and SPECT MPI studies performed per year was determined. Trends in the proportion of studies showing any ischaemia (>0%) with both modalities were compared before and after adjusting for baseline differences in patient characteristics using propensity scores. Interaction between imaging modality and year of testing was examined using modified Poisson regression. A total of 156 244 MPI studies were performed (30% PET and 70% SPECT). Between 2003 and 2017, the number of PET studies increased from 18 to 61 studies/1000 patient encounters, while SPECT volumes declined from 169 to 34/1000 patient encounters (P?<?0.001 for within-group comparisons). The prevalence of any ischaemia in SPECT-tested patients declined from 53.9% to 28.3% between 2003 and 2017, whereas ischaemia prevalence in PET-tested patients declined from 57.2% to 38.2% (P?<?0.001 for within-modality comparisons), with more PET studies showing ischaemia compared to SPECT [relative risk (RR) 1.44, 95% confidence interval (CI) 1.42-1.47; P?<?0.001]. After propensity score matching of 26 066 patients tested with SPECT with 26 066 patients tested with PET, the between-modality difference in ischaemia prevalence was significantly attenuated, with a slightly higher overall likelihood of detecting ischaemia with PET compared to SPECT (RR 1.08, 95% CI 1.05-1.11; P?<?0.001).<h4>Conclusions</h4>Utilization of PET MPI at a large-volume referral centre increased significantly between 2003 and 2017. Despite a significant decrease in the prevalence of ischaemia with SPECT and PET during the same period, the decline was less with PET, perhaps related to baseline risk of tested patients.
Project description:BACKGROUND:In myocardial perfusion imaging (MPI), single-photon emission tomography (SPECT) soft-tissue attenuation by the abdomen, breasts, and lateral chest wall may create artifacts that mimic true perfusion defects. This may cause misdiagnosis of myocardial perfusion. The aim of the present study was to compare the localization, extent, and depth of attenuation artifacts in MPI SPECT for a multi-pinhole cadmium zinc telluride (CZT) camera vs a conventional gamma camera. METHODS:Phantom and patient measurements were performed using a CZT camera (GE NM 530c) and a conventional gamma camera (GE Ventri). All images were attenuation corrected with externally acquired low-dose computed tomography. The localization, extent, and depth of the attenuation artifact were quantified by comparing attenuation-corrected and non-attenuation-corrected images. RESULTS:Attenuation artifacts were shifted from the inferolateral wall to the lateral wall using the CZT camera compared to a conventional camera in both the patient and the phantom. The extent of the attenuation artifact was significantly larger for the CZT camera compared to the conventional camera (23?±?5% vs 15?±?5%, P?<?.001) for patients and the result was similar for the phantom (28% vs 19%). Furthermore, the depth of the attenuation artifact (percent of maximum counts) was less pronounced for the CZT camera than for the conventional camera, both for phantom measurements (73% vs 67%) and patients (72?±?3% vs 68?±?4%, P?<?.001). CONCLUSIONS:Attenuation artifacts are found in different locations to different extents and depths when using a CZT camera vs a conventional gamma camera for MPI SPECT. This should be taken into consideration when evaluating MPI SPECT studies to avoid misinterpretation of myocardial perfusion distribution.
Project description:Acute rest single-photon emission computed tomography-myocardial perfusion imaging (SPECT-MPI) has high predictive value for acute coronary syndrome (ACS) in emergency department patients. Prior studies have shown excellent agreement between rest/stress computed tomography perfusion (CTP) and SPECT-MPI, but the value of resting CTP (rCTP) in acute chest pain triage remains unclear. We sought to determine the diagnostic accuracy of early rCTP, incremental value beyond obstructive coronary artery disease (CAD; ?50% stenosis), and compared early rCTP to late stress SPECT-MPI in patients with CAD presenting with suspicion of ACS to the emergency department.In this prespecified subanalysis of 183 patients (58.1±10.2 years; 33% women), we included patients with any CAD by coronary computed tomography angiography (CCTA) from Rule Out Myocardial Infarction Using Computer-Assisted Tomography I. rCTP was assessed semiquantitatively, blinded to CAD interpretation. Overall, 31 had ACS and 48 had abnormal rCTP. Sensitivity and specificity of rCTP for ACS were 48% (95% confidence interval [CI], 30%-67%) and 78% (95% CI, 71%-85%), respectively. rCTP predicted ACS (adjusted odds ratio, 3.40 [95% CI, 1.37-8.42]; P=0.008) independently of obstructive CAD, and sensitivity for ACS increased from 77% (95% CI, 59%-90%) for obstructive CAD to 90% (95% CI, 74%-98%) with addition of rCTP (P=0.05). In a subgroup undergoing late rest/stress SPECT-MPI (n=81), CCTA/rCTP had noninferior discriminatory value to CCTA/SPECT-MPI (area under the curve, 0.88 versus 0.90; P=0.64) using a noninferiority margin of 10%.Early rCTP provides incremental value beyond obstructive CAD to detect ACS. CCTA/rCTP is noninferior to CCTA/SPECT-MPI to discriminate ACS and presents an attractive alternative to triage patients presenting with acute chest pain.http://www.clinicaltrials.gov. Unique identifier: NCT00990262.
Project description:The purpose of this study was to evaluate whether radiation exposure from cardiac computed tomographic angiography (CTA) is associated with deoxyribonucleic acid (DNA) damage and whether damage leads to programmed cell death and activation of genes involved in apoptosis and DNA repair.Exposure to radiation from medical imaging has become a public health concern, but whether it causes significant cell damage remains unclear.We conducted a prospective cohort study in 67 patients undergoing cardiac CTA between January 2012 and December 2013 in 2 U.S. medical centers. Median blood radiation exposure was estimated using phantom dosimetry. Biomarkers of DNA damage and apoptosis were measured by flow cytometry, whole genome sequencing, and single cell polymerase chain reaction.The median dose length product was 1,535.3 mGy·cm (969.7 to 2,674.0 mGy·cm). The median radiation dose to the blood was 29.8 mSv (18.8 to 48.8 mSv). Median DNA damage increased 3.39% (1.29% to 8.04%, p < 0.0001) and median apoptosis increased 3.1-fold (interquartile range [IQR]: 1.4- to 5.1-fold, p < 0.0001) post-radiation. Whole genome sequencing revealed changes in the expression of 39 transcription factors involved in the regulation of apoptosis, cell cycle, and DNA repair. Genes involved in mediating apoptosis and DNA repair were significantly changed post-radiation, including DDB2 (1.9-fold [IQR: 1.5- to 3.0-fold], p < 0.001), XRCC4 (3.0-fold [IQR: 1.1- to 5.4-fold], p = 0.005), and BAX (1.6-fold [IQR: 0.9- to 2.6-fold], p < 0.001). Exposure to radiation was associated with DNA damage (odds ratio [OR]: 1.8 [1.2 to 2.6], p = 0.003). DNA damage was associated with apoptosis (OR: 1.9 [1.2 to 5.1], p < 0.0001) and gene activation (OR: 2.8 [1.2 to 6.2], p = 0.002).Patients exposed to >7.5 mSv of radiation from cardiac CTA had evidence of DNA damage, which was associated with programmed cell death and activation of genes involved in apoptosis and DNA repair.
Project description:AIMS:To evaluate the diagnostic power of integrating the results of computed tomography angiography (CTA) and CT myocardial perfusion (CTP) to identify coronary artery disease (CAD) defined as a flow limiting coronary artery stenosis causing a perfusion defect by single photon emission computed tomography (SPECT). METHODS AND RESULTS:We conducted a multicentre study to evaluate the accuracy of integrated CTA-CTP for the identification of patients with flow-limiting CAD defined by ?50% stenosis by invasive coronary angiography (ICA) with a corresponding perfusion deficit on stress single photon emission computed tomography (SPECT/MPI). Sixteen centres enroled 381 patients who underwent combined CTA-CTP and SPECT/MPI prior to conventional coronary angiography. All four image modalities were analysed in blinded independent core laboratories. The prevalence of obstructive CAD defined by combined ICA-SPECT/MPI and ICA alone was 38 and 59%, respectively. The patient-based diagnostic accuracy defined by the area under the receiver operating characteristic curve (AUC) of integrated CTA-CTP for detecting or excluding flow-limiting CAD was 0.87 [95% confidence interval (CI): 0.84-0.91]. In patients without prior myocardial infarction, the AUC was 0.90 (95% CI: 0.87-0.94) and in patients without prior CAD the AUC for combined CTA-CTP was 0.93 (95% CI: 0.89-0.97). For the combination of a CTA stenosis ?50% stenosis and a CTP perfusion deficit, the sensitivity, specificity, positive predictive, and negative predicative values (95% CI) were 80% (72-86), 74% (68-80), 65% (58-72), and 86% (80-90), respectively. For flow-limiting disease defined by ICA-SPECT/MPI, the accuracy of CTA was significantly increased by the addition of CTP at both the patient and vessel levels. CONCLUSIONS:The combination of CTA and perfusion correctly identifies patients with flow limiting CAD defined as ?50 stenosis by ICA causing a perfusion defect by SPECT/MPI.