Development and evolution of nuclear cardiology and cardiac PET in Canada.

Gated radionuclide angiography and myocardial perfusion imaging were developed in the United States and Europe in the 1970's and soon adopted in Canadian centers. Much of the early development of nuclear cardiology in Canada was in Toronto, Ontario and was quickly followed by new programs across the country. Clinical research in Canada contributed to the further development of nuclear cardiology and cardiac PET. The Canadian Nuclear Cardiology Society (CNCS) was formed in 1995 and became the Canadian Society of Cardiovascular Nuclear and CT Imaging (CNCT) in 2014. The CNCS had a major role in education and advocacy for cardiovascular nuclear medicine testing. The CNCS established the Dr Robert Burns Lecture and CNCT named the Canadian Society of Cardiovascular Nuclear and CT Imaging Annual Achievement Award for Dr Michael Freeman in memoriam of these two outstanding Canadian leaders in nuclear cardiology. The future of nuclear cardiology in Canada is exciting with the expanding use of SPECT imaging to include Tc-99m-pyrophosphate for diagnosis of transthyretin cardiac amyloidosis and the ongoing introduction of cardiac PET imaging.

Radiolabeled Thioflavin-T Derivative PET Imaging for the Assessment of Cardiac Amyloidosis.

PURPOSE OF REVIEW: Cardiac amyloidosis (CA) is an often under-recognized cause of heart failure with preserved ejection fraction. The goal of the current paper was to review imaging modalities available for detecting cardiac amyloidosis. We wished to determine what modalities are available for the diagnosis of cardiac amyloidosis and what modalities could be utilized in the future. RECENT FINDINGS: Early and delayed planar imaging of the chest currently plays a central role in the workup and diagnosis of CA. However, novel positron emission tomography (PET) tracers could play a large role in CA imaging in the future. There is an increasing body of literature supporting the use of targeted amyloid-binding PET radiotracers such as 11C-Pittsburgh compound B (11C-PIB), 18F-florbetapir, -flutemetamol, and -florbetaben for the detection of cardiac amyloid. While planar imaging currently plays a large role in the workup of CA, PET imaging could play an increasing important role in the future. The quantitative abilities of novel PET tracers could theoretically allow for the serial monitoring of patients and detection of response to therapy, and the sensitive nature of the tracers could allow for even earlier disease detection. Further work with large randomized controlled trial data is needed in the development and validation of PET tracers for cardiac amyloid and represents an exciting development within the realm of nuclear cardiology.

A Clinical Tool to Identify Candidates for Stress-First Myocardial Perfusion Imaging.

OBJECTIVES: This study sought to develop a clinical model that identifies a lower-risk population for coronary artery disease that could benefit from stress-first myocardial perfusion imaging (MPI) protocols and that can be used at point of care to risk stratify patients. BACKGROUND: There is an increasing interest in stress-first and stress-only imaging to reduce patient radiation exposure and improve patient workflow and experience. METHODS: A secondary analysis was conducted on a single-center cohort of patients undergoing single-photon emission computed tomography (SPECT) and positron emission tomography (PET) studies. Normal MPI was defined by the absence of perfusion abnormalities and other ischemic markers and the presence of normal left ventricular wall motion and left ventricular ejection fraction. A model was derived using a cohort of 18,389 consecutive patients who underwent SPECT and was validated in a separate cohort of patients who underwent SPECT (n = 5,819), 1 internal cohort of patients who underwent PET (n=4,631), and 1 external PET cohort (n = 7,028). RESULTS: Final models were made for men and women and consisted of 9 variables including age, smoking, hypertension, diabetes, dyslipidemia, typical angina, prior percutaneous coronary intervention, prior coronary artery bypass graft, and prior myocardial infarction. Patients with a score ≤1 were stratified as low risk. The model was robust with areas under the curve of 0.684 (95% confidence interval [CI]: 0.674 to 0.694) and 0.681 (95% CI: 0.666 to 0.696) in the derivation cohort, 0.745 (95% CI: 0.728 to 0.762) and 0.701 (95% CI: 0.673 to 0.728) in the SPECT validation cohort, 0.672 (95% CI: 0.649 to 0.696) and 0.686 (95% CI: 0.663 to 0.710) in the internal PET validation cohort, and 0.756 (95% CI: 0.740 to 0.772) and 0.737 (95% CI: 0.716 to 0.757) in the external PET validation cohort in men and women, respectively. Men and women who scored ≤1 had negative likelihood ratios of 0.48 and 0.52, respectively. CONCLUSIONS: A novel model, based on easily obtained clinical variables, is proposed to identify patients with low probability of having abnormal MPI results. This point-of-care tool may be used to identify a population that might qualify for stress-first MPI protocols.

Comparison of coronary CT angiography versus functional imaging for CABG patients: A resource utilization analysis.

AIMS: The impact of anatomical versus functional testing in patients with prior coronary artery bypass surgery (CABG) is poorly defined. We therefore sought to determine the rates of downstream investigations and the attendant healthcare costs in CABG patients undergoing CCTA versus SPECT. METHODS AND RESULTS: 2754 consecutive CABG patients were imaged by SPECT (2163) or CCTA (591). 425 patients (15.4%) underwent downstream testing which was more common in those imaged with CCTA versus SPECT (23.18% vs 13.31% respectively, p < 0.01). When a propensity score adjustment was made for differences in baseline characteristics, the findings in downstream testing persisted (p < 0.01). When patients who subsequently underwent repeat revascularization (arguably the highest risk patients) were removed from the analysis, downstream testing remained more frequent in CCTA (12.7%) versus SPECT imaged patients (8.8%) (p = 0.01). Costs of downstream tests per patient were two-fold greater in the CCTA group in comparison to the SPECT group ($366.79 ± 29.59 vs $167.35 ± 10.12 respectively, p < 0.01). Conversely, total costs which included the index costs were less in the CCTA group, $764.66 ± 29.59 versus $1396.73 ± 1012 for the SPECT cohort, p < 0.0001). CONCLUSIONS: Index imaging with SPECT versus CCTA in CABG patients was associated with fewer downstream tests, less ICA, less repeat revascularization but greater expense. Cost however is only part of the decision making process that determines an optimal index test. Until CCTA demonstrates improved risk stratification over SPECT in CABG patients it is likely SPECT will remain the preferred first imaging test.

Upper reference limits of transient ischemic dilation ratio for different protocols on new-generation cadmium zinc telluride cameras: A report from REFINE SPECT registry.

BACKGROUND: Upper reference limits for transient ischemic dilation (TID) have not been rigorously established for cadmium-zinc-telluride (CZT) camera systems. We aimed to derive TID limits for common myocardial perfusion imaging protocols utilizing a large, multicenter registry (REFINE SPECT). METHODS: One thousand six hundred and seventy-two patients with low likelihood of coronary artery disease with normal perfusion findings were identified. Images were processed with Quantitative Perfusion SPECT software (Cedars-Sinai Medical Center, Los Angeles, CA). Non-attenuation-corrected, camera-, radiotracer-, and stress protocol-specific TID limits in supine position were derived from 97.5th percentile and mean + 2 standard deviations (SD). Reference limits were compared for different solid-state cameras (D-SPECT vs. Discovery), radiotracers (technetium-99m-sestamibi vs. tetrofosmin), different types of stress (exercise vs. four different vasodilator-based protocols), and different vasodilator-based protocols. RESULTS: TID measurements did not follow Gaussian distribution in six out of eight subgroups. TID limits ranged from 1.18 to 1.52 (97.5th percentile) and 1.18 to 1.39 (mean + 2SD). No difference was noted between D-SPECT and Discovery cameras (P = 0.71) while differences between exercise and vasodilator-based protocols (adenosine, regadenoson, or regadenoson-walk) were noted (all P < 0.05). CONCLUSIONS: We used a multicenter registry to establish camera-, radiotracer-, and protocol-specific upper reference limits of TID for supine position on CZT camera systems. Reference limits did not differ between D-SPECT and Discovery camera.

Comparison of Framingham risk score and chest-CT identified coronary artery calcification in breast cancer patients to predict cardiovascular events.

BACKGROUND: In breast cancer patients, coincidental detection of CAC at chest CT may be important in determining cardiovascular (CV) outcomes and facilitate CV disease primary prevention strategies. METHODS: 408 consecutive breast cancer patients referred to cardiac oncology clinic were included in the study. 256 patients without a prior history of coronary artery disease had undergone a chest CT. CT images were reviewed to detect CAC. Framingham risk score (FRS) was calculated and patient electronic medical records were interrogated to document the incidence of a composite clinical end point of all-cause mortality and cardiac events (coronary revascularization, heart failure hospitalization and de novo atrial fibrillation). Prevalence of statin prescribing was also collected. RESULTS: Patients were followed for a median of 6.5 years. 112 clinical events occurred. Clinical follow up was 98%. CAC was found in 26% of patients. On multivariable analysis, CAC and advance cancer stage, but not FRS predicted the composite clinical end point (OR for CAC 2.59, p < 0.01). CAC but not FRS also predicted the incidence of cardiac events (OR for CAC 4.90, p < 0.01). CAC was present in 7.3% of patients with low FRS; none had been prescribed a statin. In patients with CAC and FRS ≥ 10%, 45% were not on a statin. CONCLUSION: CAC is a common coincidental finding at CT chest in breast cancer patients referred to cardiac oncology. CAC but not FRS was predictive of composite clinical events and cardiac events. Detection of CAC at chest CT could alter the prescribing of primary prevention strategies to help prevent future cardiac events in breast cancer patients.

Development of an inflammation imaging tracer, 111In-DOTA-DAPTA, targeting chemokine receptor CCR5 and preliminary evaluation in an ApoE-/- atherosclerosis mouse model.

BACKGROUND: Chemokine receptor 5 (CCR5) plays an important role in atherosclerosis. Our objective was to develop a SPECT tracer targeting CCR5 for imaging plaque inflammation by radiolabeling D-Ala-peptide T-amide (DAPTA), a CCR5 antagonist, with 111In. METHODS: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugated DAPTA (DOTA-DAPTA) was labeled with 111In. Cell uptake studies were conducted in U87-CD4-CCR5 and U87-MG cells. Biodistribution was determined in C57BL/6 mice. Autoradiography, en face and Oil Red O (ORO) imaging studies were performed in ApoE-/- mice. RESULTS: DOTA-DAPTA was radiolabeled with 111In with high radiochemical purity (> 98%) and specific activity (70 MBq·nmol). 111In-DOTA-DAPTA exhibited fast blood and renal clearance and high spleen uptake. The U87-CD4-CCR5 cells had significantly higher uptake in comparison to the U87-MG cells. The cell uptake was reduced by three times with DAPTA, indicating the receptor specificity of the uptake. Autoradiographic images showed significantly higher lesion uptake of 111In-DOTA-DAPTA in ApoE-/- mice than that in C57BL/6 mice. The tracer uptake in 4 month old ApoE-/- high fat diet (HFD) mice with blocking agent was twofold lower than the same mice without the blocking agent, demonstrating the specificity of the tracer for the CCR5 receptor. CONCLUSION: 111In-DOTA-DAPTA, specifically targeting chemokine receptor CCR5, is a potential SPECT agent for imaging inflammation in atherosclerosis.

Prognostic utility of splenic response ratio in dipyridamole PET myocardial perfusion imaging.

BACKGROUND: Cardiac magnetic resonance perfusion studies with adenosine stress have shown that splenic response can identify patients with inadequate pharmacologic stress. We investigate the incremental prognostic impact of splenic response ratio (SRR) in patients with normal Rubidium (Rb)-82 PET myocardial perfusion imaging (MPI). METHODS: Consecutive patients undergoing dipyridamole Rb-82 PET MPI for the evaluation of coronary artery disease were screened. Spleen and liver Rb-82 activity was measured and the SRR was calculated: SRR = (Spleen stress/Liver stress)/(Spleen rest/Liver rest). Major adverse cardiac events (MACE) were determined at 1 year of follow-up in patients with normal summed stress score and normal summed difference score. RESULTS: Of the 839 patients screened, the spleen was visualized in 703 (84%) of scans. There was significantly higher MACE observed in splenic non-responders vs splenic responders in both the normal SSS (7.8% vs 2.9%, P = .027) and the normal SDS groups (7.4% vs 2.2%, P = .014). In multivariate analysis in patients with normal SDS, splenic response was a significant, independent predictor of MACE (HR 2.97, 95% CI 1.10 to 8.04, P = .033). CONCLUSIONS: SRR is a novel imaging metric to identify patients with sub-maximal vasodilator stress and an incremental prognostic marker in patients with normal SDS and SSS (Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT01128023).

Comparative Effectiveness and Harms of Intraoperative Transesophageal Echocardiography in Noncardiac Surgery: A Systematic Review.

Intraoperative use of transesophageal echocardiography (TEE) has become commonplace in high-risk noncardiac surgeries but the balance of benefits and harms remains unclear. This systematic review investigated the comparative effectiveness and harms of intraoperative TEE in noncardiac surgery. We searched Ovid MEDLINE, PubMed, EMBASE, and the Cochrane Library from 1946 to March 2017. Two reviewers independently screened the literature for eligibility. Studies were assessed for the risk of selection bias, confounding, measurement bias, and reporting bias. Three comparative and 13 noncomparative studies were included. Intraoperative TEE was employed in a total of 1912 of 3837 patients. Studies had important design limitations. Data were not amenable to quantitative synthesis due to clinical and methodological diversity. Reported incidence of TEE complications ranged from 0% to 1.7% in patients undergoing various procedures (5 studies, 540 patients). No serious adverse events were observed for mixed surgeries (2 studies, 197 patients). Changes in surgical or medical management attributable to the use of TEE were noted in 17% to 81% of patients (7 studies, 558 patients). The only randomized trial of intraoperative TEE was grossly underpowered to detect meaningful differences in 30-day postoperative outcomes. There is lack of high-quality evidence of effectiveness and harms of intraoperative TEE in the management of non-cardiac surgeries. Evidence, however, indicates timely evaluation of cardiac function and structure, and hemodynamics. Future studies should be comparative evaluating confounder-adjusted impact on both intraoperative and 30-day postoperative clinical outcomes.

Effects of Hypercapnia on Myocardial Blood Flow in Healthy Human Subjects.

Elevation of the end-tidal partial pressure of CO2 (PETco2) increases cerebral and myocardial blood flow (MBF), suggesting that it may be a suitable alternative to pharmacologic stress or exercise for myocardial perfusion imaging. The purpose of this study was to document the pharmacodynamics of CO2 for MBF using prospective end-tidal targeting to precisely control arterial Pco2 and PET to measure the outcome variable, MBF. Methods: Ten healthy men underwent serial 82Rb PET/CT imaging. Imaging was performed at rest and during 6-min hypercapnic plateaus (baseline; PETco2 at 50, 55, and 60 mm Hg; repeat of PETco2 at 60 mm Hg; and repeat of baseline). MBF was measured using 82Rb injected 3 min after the beginning of hypercapnia and a 1-tissue-compartment model with flow-dependent extraction correction. Results were compared with those obtained during an adenosine stress test (140 µg/kg/min). Results: Baseline PETco2 was 38.9 ± 0.8 (mean ± SD) mm Hg (range, 35-43 mm Hg). All PETco2 targets were sustained, with SDs of less than 1.5 mm Hg. Heart rate, systolic blood pressure, rate × pressure product, and respiratory frequency increased with progressive hypercapnia. MBF increased significantly at each level of hypercapnia to 1.92-fold over baseline (0.86 ± 0.24 vs. 0.45 ± 0.08 mL/min/g; P = 0.002) at a PETco2 of 60 mm Hg. MBF after the administration of adenosine was significantly greater than that with the maximal hypercapnic stimulus (2.00 vs. 0.86 mL/min/g; P < 0.0001). Conclusion: To our knowledge, this study is the first to assess the response of MBF to different levels of hypercapnia in healthy humans with PET. MBF increased with increasing levels of hypercapnia; MBF at a PETco2 of 60 mm Hg was double that at baseline.

Appropriate Use Criteria for Cardiac Computed Tomography: Impact on Diagnostic Utility.

BACKGROUND: Appropriate Use Criteria (AUC) guidelines for cardiac computed tomography (CCT) were developed to limit testing to reasonable clinical settings. However, significant testing is still done for inappropriate indications. This study investigates the impact of AUC on evaluability of CCT to determine if inappropriate tests result in a greater proportion of nondiagnostic results. METHODS: Investigators reviewed the medical records of 2417 consecutive patients who underwent CCT at the University of Ottawa Heart Institute. We applied the 2010 AUC and classified them as appropriate, inappropriate, or uncertain. Unclassifiable tests, as well as those with uncertain appropriateness, were excluded from the final analysis. Cardiac computed tomography results were classified as diagnostic if (1) all coronary segments were visualized, evaluable, and without obstructive stenosis; or (2) obstructive coronary artery disease with greater than 50% diameter stenosis in at least 1 coronary artery. All other test results were considered nondiagnostic. RESULTS: Of the 1984 patients included in the final analysis, 1522 patients (76.7%) had indications that were appropriate, whereas the remaining 462 (23.3%) were inappropriate. Inappropriate tests resulted in a higher rate of nondiagnostic results compared with appropriate CCT (9.0% vs 6.2%, P = 0.034). Inappropriate tests also had significantly more studies with nonevaluable segments than appropriate tests (24.5% vs 16.4%, P < 0.001) and were more likely to reveal obstructive coronary disease than appropriate CCT (50.5% vs 32.7%, P < 0.001). CONCLUSIONS: Cardiac computed tomography done for inappropriate indications may be associated with lower diagnostic yield and could impact future downstream resource utilization and health care costs.

Randomized Trial Comparing the Effects of Ticagrelor Versus Clopidogrel on Myocardial Perfusion in Patients With Coronary Artery Disease.

BACKGROUND: Ticagrelor is a P2Y12 receptor inhibitor used in acute coronary syndromes to reduce platelet activity and to decrease thrombus formation. Ticagrelor is associated with a reduction in mortality incremental to that observed with clopidogrel, potentially related to its non-antiplatelet effects. Evidence from animal models indicates that ticagrelor potentiates adenosine-induced myocardial blood flow (MBF) increases. We investigated MBF at rest and during adenosine-induced hyperemia in patients with stable coronary artery disease treated with ticagrelor versus clopidogrel. METHODS AND RESULTS: This randomized double-blinded crossover study included 22 patients who received therapeutic interventions of ticagrelor 90 mg orally twice a day for 10 days and clopidogrel 75 mg orally once a day for 10 days, with a washout period of at least 10 days between the treatments. Global and regional MBF and myocardial flow reserve were measured using rubidium 82 positron emission tomography/computed tomography at baseline and during intermediate- and high-dose adenosine. Global MBF was significantly greater with ticagrelor versus clopidogrel (1.28±0.55 versus 1.13±0.47 mL/min per gram, P=0.002) at intermediate-dose adenosine and not different at baseline (0.65±0.19 versus 0.60±0.15 mL/min per gram, P=0.084) and at high-dose adenosine (1.64±0.40 versus 1.61±0.19 mL/min per gram, P=0.53). In regions with impaired myocardial flow reserve (<2.5), MBF was greater with ticagrelor compared with clopidogrel during intermediate and high doses of adenosine (P<0.0001), whereas the differences were not significant at baseline. CONCLUSIONS: Ticagrelor potentiates global and regional adenosine-induced MBF increases in patients with stable coronary artery disease. This effect may contribute to the incremental mortality benefit compared with clopidogrel. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01894789.

New solid state cadmium-zinc-telluride technology for cardiac single photon emission computed tomographic myocardial perfusion imaging.

INTRODUCTION: Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is well established as diagnostic test for patients with suspected or known coronary artery disease. New camera systems have been developed with cadmium-zinc-telluride (CZT) detectors, novel collimator designs and reconstruction software. Areas covered: We review the current state of cardiac SPECT, advances in conventional camera technology and the development and clinical validation of solid-state CZT cameras. Expert commentary: The development of CZT systems is timely and addresses current issues for clinical SPECT imaging. These systems have a significant increase in photon sensitivity, permitting much lower radiation patient doses at a time when the lay and medical communities are very concerned about the radiation doses resulting from medical imaging. The increased count sensitivity permits shorter acquisition times and greater patient throughput which may address the ongoing and increasing issue of decreased funding for healthcare and, particularly, diagnostic imaging. The improved image resolution should improve diagnostic accuracy and increase the value of SPECT imaging for management of patients with CAD at a time of significant competition from other imaging modalities.

"Same-patient processing" for multiple cardiac SPECT studies. 2. Improving quantification repeatability.

OBJECTIVES: This paper investigates the ability of grouped quantification (an expression of the same-patient processing approach, or SPP) to improve repeatability of measurements in patients with multiple SPECT studies, and evaluates its performance compared to standard quantification in a population of 100 patients undergoing rest, stress, gated rest, and gated stress SPECT MPI. All acquisitions were performed twice, back-to-back, for a total of 800 image datasets (8 per patient). METHODS: Each dataset was automatically processed (a) independently, using standard quantitative software, and (b) as a group, together with the other 7 datasets belonging to the same patient, using an SPP-modified version of the software that registered the images to one another using a downhill simplex algorithm for the search of optimal translation, rotation, and scaling parameters. RESULTS: Overall, grouped quantification resulted in significantly lower differences between repeated measurements of stress ungated volumes (1.40 ± 2.76 mL vs 3.33 ± 5.06 mL, P < .05), end-diastolic volumes (1.78 ± 2.78 vs 3.49 ± 5.35 mL, P < .05), end-systolic volumes (1.17 ± 1.96 vs 2.44 ± 3.35 mL, P < .05), and LVEFs (-0.45 ± 2.29% vs -1.16 ± 3.30%, P < .05). Additionally, grouped quantification produced better repeatability (lower repeatability coefficients) for stress and rest ungated volumes (5.4 vs 9.9 and 5.2 vs 13.1, respectively), stress TPD (2.6 vs 3.6), stress and rest end-diastolic volumes (5.5 vs 10.5 and 7.2 vs 14.7, respectively), stress and rest end-systolic volumes (3.8 vs 6.6 and 5.3 vs 10.3, respectively), stress and rest LVEFs (4.5 vs 6.5 and 4.7 vs 8.2, respectively), and rest total motion deficit (5.6 vs 9.6). CONCLUSION: It is possible to improve the repeatability of quantitative measurements of parameters of myocardial perfusion and function derived from SPECT MPI studies of a same patient by group processing of image datasets belonging to that patient. This application of the same-patient processing approach is an extension of the "paired processing" technique already described by our group, and can be performed in automated fashion through incorporation in the quantitative algorithm.