Positron Emission Tomography Myocardial Perfusion Research Articles

Duration of adenosine-induced myocardial hyperemia - Insights from quantitative 13N-ammonia positron emission tomography myocardial perfusion imaging.

To assess the impact of adenosine on quantitative myocardial blood flow (MBF) in a rapid stress-rest protocol compared to a rest-stress protocol using 13N-ammonia positron emission tomography (PET) myocardial perfusion imaging (MPI) and to gain insights into the time dependency of such effects. Quantitative MBF at rest (rMBF), during adenosine-induced stress (sMBF) and myocardial flow reserve (MFR) were obtained from 331 retrospectively identified patients who underwent 13N-ammonia PET-MPI for suspected chronic coronary syndrome and who all exhibited no perfusion defects. Of these, 146 (44.1%) underwent a rapid stress-rest protocol with a time interval (Δtstress-rest) of 20 ± 4 minutes between adenosine infusion offset and rest-imaging, as per clinical routine. The remaining 185 (55.9%) patients underwent a rest-stress protocol and served as the reference. Groups did not differ regarding demographics, risk factors, medication, left ventricular function, and calcium scores. rMBF was significantly higher in the stress-rest vs. the rest-stress group (0.80 [IQR 0.66-1.00] vs. 0.70 [0.58-0.83] ml·min-1·g-1, p < 0.001) and, as sMBF was identical between groups (2.52 [2.20-2.96] vs. 2.50 [1.96-3.11], p = 0.347), MFR was significantly lower in the stress-rest group (3.07 [2.43-3.88] vs. 3.50 [2.63-4.10], p < 0.001). There was a weak correlation between Δtstress-rest and rMBF (r = -0.259, p = 0.002) and between Δtstress-rest and MFR (r = 0.163, p = 0.049), and the proportion of patients with abnormally high rMBF was significantly decreasing with increasing Δtstress-rest. Intravenously applied adenosine induces a long-lasting hyperemic effect on the myocardium. Consequently, rapid stress-rest protocols could lead to an overestimation of rMBF and an underestimation of MFR.

Guiding early revascularization using [15O]H2O PET myocardial perfusion imaging - Impact of atrial fibrillation.

Myocardial perfusion imaging (MPI) using [15O]H2O positron emission tomography (PET) is used to guide the selection of patients with angina for invasive angiography and possible revascularization. Our study evaluated whether atrial fibrillation (AF): 1) reduces global hyperemic myocardial blood flow (MBF) and 2) whether [15O]H2O PET MPI effectively guides revascularization procedures for patients with ongoing AF. We prospectively recruited 346 patients with angina and persistent or paroxysmal AF referred for baseline/hyperemic [15O]H2O PET MPI. The primary outcome was revascularization within 3 months of MPI. In the analyses, patients were divided into four groups based on whether they had ongoing AF or sinus rhythm (SR) and whether they had previously documented coronary artery disease (CAD) or not. Thus, four groups were compared: SR-noCAD, AF-noCAD, SR-CAD and AF-CAD. Hyperemic MBF was affected by both ongoing AF and prior CAD [MBF (mL/min/g): 2.82 (SR-noCAD) vs. 2.12 (AF-noCAD) vs. 2.22 (SR-CAD) vs. 1.80 (AF-CAD), two-way ANOVA p<0.0001]. In multiple linear regression ongoing AF was independently associated with reduced hyperemic MBF. Every 0.1 mL/min/g decrease in hyperemic MBF was associated with a 23% increase in odds of early revascularization. ROC-analysis of vessel specific hyperemic MBF to predict early revascularization yielded the following areas under the ROC curve (AUC): SR-noCAD: 0.95 (p<0.0001); AF-noCAD: 0.79 (p<0.0001); SR-CAD: 0.78 (p<0.0001); AF-CAD: 0.88 (p<0.0001). Ongoing AF is associated with 19-25 % reduced global hyperemic MBF as measured by [15O]H2O MPI PET. Regardless, vessel specific hyperemic MBF still predicts early revascularization in patients with AF.

Validation of resting full-cycle ratio and diastolic pressure ratio with [15O]H2O positron emission tomography myocardial perfusion

Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are invasive techniques used to evaluate the hemodynamic significance of coronary artery stenosis. These methods have been validated through perfusion imaging and clinical trials. New invasive pressure ratios that do not require hyperemia have recently emerged, and it is essential to confirm their diagnostic efficacy. The aim of this study was to validate the resting full-cycle ratio (RFR) and the diastolic pressure ratio (dPR), against [15O]H2O positron emission tomography (PET) imaging. A total of 129 symptomatic patients with an intermediate risk of coronary artery disease (CAD) were included. All patients underwent cardiac [15O]H2O PET with quantitative assessment of resting and hyperemic myocardial perfusion. Within a 2 week period, coronary angiography was performed. Intracoronary pressure measurements were obtained in 320 vessels and RFR, dPR, and FFR were computed. PET derived regional hyperemic myocardial blood flow (hMBF) and myocardial perfusion reserve (MPR) served as reference standards. In coronary arteries with stenoses (43%, 136 of 320), the overall diagnostic accuracies of RFR, dPR, and FFR did not differ when PET hyperemic MBF < 2.3 ml min−1 (69.9%, 70.6%, and 77.1%, respectively) and PET MPR < 2.5 (70.6%, 71.3%, and 66.9%, respectively) were considered as the reference for myocardial ischemia. Non-significant differences between the areas under the receiver operating characteristic (ROC) curve were found between the different indices. Furthermore, the integration of FFR with RFR (or dPR) does not enhance the diagnostic information already achieved by FFR in the characterization of ischemia via PET perfusion. In conclusion, the novel non-hyperemic pressure ratios, RFR and dPR, have a diagnostic performance comparable to FFR in assessing regional myocardial ischemia. These findings suggest that RFR and dPR may be considered as an FFR alternative for invasively guiding revascularization treatment in symptomatic patients with CAD.

Phase I, first-in-human study of XTR004, a novel 18F-labeled tracer for myocardial perfusion PET: Biodistribution, radiation dosimetry, pharmacokinetics, and safety after a single injection at rest

ObjectivesThis study assessed the imaging characteristics, pharmacokinetics and safety of XTR004, a novel 18F-labeled Positron Emission Tomography (PET) myocardial perfusion imaging tracer, after a single injection at rest in humans. MethodsEleven healthy subjects (eight men and three women) received intravenous XTR004 (239–290 megabecquerel [MBq]). Safety profiles were monitored on the dosing day and three follow-up visits. Multiple whole-body PET scans were conducted over 4.7 h to evaluate biodistribution and radiation dosimetry. Blood and urine samples collected for 7.25 h were metabolically corrected to characterize pharmacokinetics. ResultsIn the first 0–12 min PET images of ten subjects, liver (26.81 ± 4.01), kidney (11.43 ± 2.49), lung (6.75 ± 1.76), myocardium (4.72 ± 0.67) and spleen (3.1 ± 0.84) exhibited the highest percentage of the injected dose (%ID). Myocardial uptake of XTR004 in the myocardium initially reached 4.72 %ID and 7.06 g/mL, and negligibly changed within an hour (Δ: 7.20%, 5.95%). The metabolically corrected plasma peaked at 2.5 min (0.0013896 %ID/g) and halved at 45.2 min. Whole-body effective dose was 0.0165 millisievert (mSv)/MBq. Cumulative urine excretion was 8.18%. Treatment-related adverse events occurred in seven out of eleven subjects (63.6%), but no severe adverse event was reported. ConclusionsXTR004 demonstrated a favorable safety profile, rapid, high, and stable myocardial uptake and excellent potential for PET myocardial perfusion imaging (MPI). Further exploration of XTR004 PET MPI for detecting myocardial ischemia is warranted.

PET-determined myocardial perfusion and flow in coronary artery disease characterization

Positron emission tomography (PET) myocardial perfusion imaging in conjunction with tracer-kinetic modeling enables the concurrent assessment of myocardial perfusion and regional myocardial blood flow (MBF) of the left ventricle in absolute terms in milliliters per gram per minute (mL/g/min). The non-invasive quantification of MBF during pharmacologically induced hyperemia, at rest, and corresponding myocardial flow reserve (MFR) opens a new avenue for the identification and characterization of classical or endogen type of coronary microvascular dysfunction (CMD) as functional substrate for microvascular angina in patients with non-obstructive coronary artery disease (CAD) and/or no CAD at all. Further, PET-MBF quantification expands the scope of conventional myocardial perfusion imaging from the identification of advanced, and flow-limiting, epicardial CAD to early stages of atherosclerosis and/or CMD. Adding MBF assessment to myocardial perfusion may also reliably unravel diffuse ischemia owing to significant left main stenosis and/or multivessel CAD, confirmed by peak stress transient ischemic cavity dilation of the left ventricle during maximal vasomotor stress on gated PET images. Owing to high spatial and contrast resolution in conjunction with photon-attenuation free myocardial perfusion PET images, PET is preferentially used for CAD in advanced obesity and women with pronounced breast habitus. With increasing clinical use of cardiac PET perfusion and MBF assessment, individualized, and image-guided cardiovascular treatment decisions in CAD patients is likely to ensue, while its translation into improved cardiovascular outcome remains to be investigated.

Rationale and design of the RAPID-WATER-FLOW trial: Radiolabeled perfusion to identify coronary artery disease using water to evaluate responses of myocardial FLOW

ObjectivesThe objective of this study was to determine the diagnostic performance of 15O-water positron emission tomography (PET) myocardial perfusion imaging to detect coronary artery disease (CAD) using the truth-standard of invasive coronary angiography (ICA) with fractional flow reserve (FFR) or instantaneous wave-Free Ratio (iFR) or coronary computed tomography angiogram (CCTA). Background15O-water has a very high first-pass extraction that allows accurate quantification of myocardial blood flow and detection of flow-limiting CAD. However, the need for an on-site cyclotron and lack of automated production at the point of care and relatively complex image analysis protocol has limited its clinical use to date. MethodsThe RAPID WATER FLOW study is an open-label, multicenter, prospective investigation of the accuracy of 15O-water PET to detect obstructive angiographic and physiologically significant stenosis in patients with suspected CAD. The study will include the use of an automated system for producing, dosing, and injecting 15O-water and enrolling approximately 215 individuals with suspected CAD at approximately 10 study sites in North America and Europe. The primary endpoint of the study is the diagnostic sensitivity and specificity of the 15O-water PET study using the truth-standard of ICA with FFR or iFR to determine flow-limiting stenosis, or CCTA to rule out CAD and incorporating a quantitative analytic platform developed for the 15O-water PET acquisitions. Sensitivity and specificity are to be considered positive if the lower bound of the 95% confidence interval is superior to the threshold of 60% for both, consistent with prior registration studies.Subgroup analyses include assessments of diagnostic sensitivity, specificity, and accuracy in female, obese, and diabetic individuals, as well as in those with multivessel disease. All enrolled individuals will be followed for adverse and serious adverse events for up to 32 hours after the index PET scan.The study will have >90% power (one-sided test, α = 0.025) to test the hypothesis that sensitivity and specificity of 15O-water PET are both >60%. ConclusionsThe RAPID WATER FLOW study is a prospective, multicenter study to determine the diagnostic sensitivity and specificity of 15O-water PET as compared to ICA with FFR/iFR or CCTA. This study will introduce several novel aspects to imaging registration studies, including a more relevant truth standard incorporating invasive physiologic indexes, coronary CTA to qualify normal individuals for eligibility, and a more quantitative approach to image analysis than has been done in prior pivotal studies. Clinical trial registration informationClinical-Trials.gov (#NCT05134012).

Coronary microvascular function in male physicians with burnout and job stress: an observational study

BackgroundAs a professional group, physicians are at increased risk of burnout and job stress, both of which are associated with an increased risk of coronary heart disease that is at least as high as that of other professionals. This study aimed to examine the association of burnout and job stress with coronary microvascular function, a predictor of major adverse cardiovascular events.MethodsThirty male physicians with clinical burnout and 30 controls without burnout were included. Burnout was assessed with the Maslach Burnout Inventory and job stress with the effort-reward imbalance and overcommitment questionnaire. All participants underwent myocardial perfusion positron emission tomography to quantify endothelium-dependent (cold pressor test) and endothelium-independent (adenosine challenge) coronary microvascular function. Burnout and job stress were regressed on coronary flow reserve (primary outcome) and two additional measures of coronary microvascular function in the same model while adjusting for age and body mass index.ResultsBurnout and job stress were significantly and independently associated with endothelium-dependent microvascular function. Burnout was positively associated with coronary flow reserve, myocardial blood flow response, and hyperemic myocardial blood flow (r partial = 0.28 to 0.35; p-value = 0.008 to 0.035). Effort-reward ratio (r partial =  − 0.32 to − 0.38; p-value = 0.004 to 0.015) and overcommitment (r partial =  − 0.30 to − 0.37; p-value = 0.005 to 0.022) showed inverse associations with these measures.ConclusionsIn male physicians, burnout and high job stress showed opposite associations with coronary microvascular endothelial function. Longitudinal studies are needed to show potential clinical implications and temporal relationships between work-related variables and coronary microvascular function. Future studies should include burnout and job stress for a more nuanced understanding of their potential role in cardiovascular health.

Association between global sleep quality and coronary microvascular function in male physicians with occupational burnout.

Occupational burnout has been associated with an increased risk of coronary heart disease, although the mechanisms involved are elusive. We investigated whether poor global sleep quality is associated with impaired coronary microvascular function in male physicians, a professional group at increased risk for burnout. Study participants were 30 male physicians with clinical burnout and 30 controls without burnout defined by the Maslach Burnout Inventory. Global sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI). Endothelium-dependent (cold pressor test) and endothelium-independent (adenosine challenge) coronary microvascular function were quantified with myocardial perfusion positron emission tomography. In multivariable analyses, the interaction between burnout and the PSQI global score was regressed on measures of coronary microvascular function, adjusting for age, body mass index, physical activity, alcohol consumption, and main effects of burnout and PSQI score. The prevalence of poor sleepers (PSQI score > 5) was 40% in the burnout group and 10% in the control group. Adjusting for covariates, burnout-by-global PSQI score interactions were observed for myocardial blood flow (MBF) at rest (r partial = -.30, p = .025), endothelium-dependent coronary flow reserve (r partial = -.26, p = .062), MBF response (r partial = -.30, p = .028), and hyperemic MBF (r partial = -.34, p = -.012). The global PSQI score was inversely associated with these MBF measures in the burnout group relative to the control group. No significant interactions emerged for endothelium-independent MBF. In male physicians with occupational burnout, poor global sleep quality was associated with reduced endothelium-dependent coronary microvascular function, suggesting a mechanism by which burnout may affect cardiovascular health.

Coronary Microcirculatory Dysfunction in People With HIV and Its Association With Antiretroviral Therapy.

HIV infection and abacavir-containing antiretroviral regimens are associated with vascular endothelial dysfunction and increased cardiovascular risk. Positron emission tomography (PET)-derived myocardial blood flow reserve (MBFR), the ratio of vasodilator stress to rest myocardial blood flow, is a well-validated measure of coronary microvascular health and marker of cardiovascular risk. Our objective was to compare MBFR among people with HIV (PWH) with matched non-HIV controls and to assess whether switching from dolutegravir/lamivudine/abacavir to the non-abacavir regimen bictegravir/emtricitabine/tenofovir alafenamide (TAF) would improve MBFR. Thirty-seven PWH were 1:2 matched on cardiovascular risk factors to 75 people without HIV, and MBFR corrected for differences in resting hemodynamics was compared in a cross-sectional design. PWH were majority men (68%) with a mean age of 56 years. Mean stress myocardial blood flow (1.83 mL/min per g [95% CI, 1.68-1.98] versus 2.40 mL/min per g [95% CI, 2.25-2.54]; P<0.001) and MBFR (2.18 [95% CI, 1.96-2.40] versus 2.68 [95% CI, 2.47-2.89]; P=0.002) was significantly lower in PWH than in people without HIV. In a single-arm, multicenter trial, a subset of 25 PWH who were virologically suppressed on dolutegravir/lamivudine/abacavir underwent positron emission tomography myocardial perfusion imaging at baseline and after switching to bictegravir/emtricitabine/TAF. MBFR was unchanged after switching to bictegravir/emtricitabine/TAF for a mean of 27 weeks (MBFR, 2.34 to 2.29; P=0.61), except in PWH with impaired MBFR at baseline (<2.00; N=6) in whom MBFR increased from 1.58 to 2.02 (P=0.02). PWH had reduced coronary microvascular function compared with controls without HIV. Coronary microvascular function did not improve after switching from dolutegravir/lamivudine/abacavir to bictegravir/emtricitabine/TAF. URL: https://www.clinicaltrials.gov; unique identifier: NCT03656783.

Validation of the resting full-cycle ratio and diastolic pressure ratio through myocardial perfusion imaging with [15O]H2O positron emission tomography

Abstract Background Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are invasive techniques used to evaluate the hemodynamic significance of coronary artery stenosis. These methods have been validated through perfusion imaging techniques and clinical trials. However, new invasive pressure indices that do not require hyperemia have recently emerged, and it is essential to confirm their diagnostic efficacy. Purpose To validate the resting full-cycle ratio (RFR) and the diastolic pressure ratio (dPR), against [15O]H2O positron emission tomography (PET) imaging. Methods A total of 129 symptomatic patients with an intermediate risk of coronary artery disease (CAD) were included. All patients underwent cardiac [15O]H2O PET with quantitative assessment of myocardial perfusion, and within 2 weeks coronary angiography was performed. Intracoronary pressure measurements were obtained in 320 vessels and RFR, dPR, and FFR were computed. In the case of RFR and dPR, values ≤ 0.89, and for FFR, values ≤ 0.8 were classified as abnormal. PET myocardial blood flow (MBF) and myocardial perfusion reserve (MPR) served as reference standards. The index tests and gold standard results were evaluated by blinded researchers. Results Figure 1 shows the diagnostic performance of each ratio in coronary arteries with stenoses (136 of 320 vessels, 38%). The overall diagnostic accuracies of RFR, dPR and FFR did not differ when PET MBF &amp;lt; 2.3 ml · min-1 and PET MPR &amp;lt; 2.5 were considered as the reference standard. No significant differences were observed in the areas under the receiver-operating-characteristic (ROC) curve among the indices (Figure 2). In addition, the indices demonstrated comparable performance when the analysis included all of the vessels. Conclusion The novel non-hyperemic pressure ratios, RFR and dPR, have a diagnostic performance that is comparable to FFR when using [15O]H2O PET to assess myocardial perfusion abnormalities. These findings suggest that RFR and dPR may be considered for clinical use in symptomatic patients with CAD.Figure 1Diagnostic performance;StenosisFigure 2ROC curve analysis;Stenosis

Abstract 17343: Coronary Microvascular Function in Physician Burnout and Job Stress

Background: As a professional group, physicians are at increased risk of burnout and job stress, both of which are associated with an increased risk of coronary heart disease that seems more prevalent among male than female physicians. Aim: This study aimed to examine the association of burnout and job stress with coronary microvascular function, a predictor of major adverse cardiovascular events. Methods: Thirty male physicians with clinical burnout and 30 controls without burnout were included. Burnout was assessed with the Maslach Burnout Inventory and job stress with the effort-reward imbalance and overcommitment questionnaire. All participants underwent myocardial perfusion positron emission tomography to quantify endothelium-dependent (cold pressor test) and endothelium-independent (adenosine challenge) coronary microvascular function. Burnout and job stress were regressed on measures of coronary microvascular function in the same model while adjusting for age and body mass index. Results: Burnout and job stress had significant and independent effects on endothelium-dependent microvascular function. Burnout was positively associated with coronary flow reserve, myocardial blood flow (MBF) response, and hyperemic MBF (r partial: 0.29 to 0.35; p-value: 0.008 to 0.027). Effort-reward ratio (r partial: -0.32 to -0.34; p-value: 0.009 to 0.017) and overcommitment (r partial: -0.29 to -0.35; p-value: 0.008 to 0.027) showed inverse associations with these measures. Conclusions: In male physicians, burnout and high job stress showed opposite effects on coronary microvascular endothelial function. Longitudinal studies are needed to show potential clinical implications. Future studies should include burnout and job stress for a more nuanced understanding of their potential impact on cardiovascular health.

Abstract 16514: Head-to-Head Comparison of Quantitative Image Quality on Rubidium-82 Myocardial Perfusion Positron Emission Tomography Between a Digital Silicon Photomultiplierand Conventional Scanner

Introduction: The purpose of this study was to compare rubidium-82 positron emission tomography ( 82 Rb PET) myocardial perfusion imaging (MPI) findings and quantitative image quality measures between the digital silicone photomultipliers (SiPM) scanner and a conventional scanner. Methods: We studied 24 consecutive patients (mean age 71.2±2.2 years) who underwent two clinically indicated rest/stress 82 Rb PET MPI examinations on two scanners, one using a SiPM-based PET scanner (Biograph Vision, Siemens Healthineers) and the other using a conventional photomultiplier tube (PMT)-based PET scanner (Discovery 710, GE Healthcare). Inclusion criteria were: 1) interval between the scans &lt;2 yr (median 1.1 yr, 95% CI: 0.9-1.4), 2) no interval revascularization, and 3) no interval symptom changes. Stress and imaging protocols were the same. 82 Rb doses were 925 MBq at rest and stress. Image quality was assessed using blood background coefficient-of-variation (COV), myocardium to blood signal to noise ratio (SNR) and contrast to noise ratio (CNR) calculated from the 82 Rb images. Results: Between two scanners, there were no significant differences in perfusion and functional measures, including summed stress score (SiPM: 1.6 ± 0.7 vs. PMT: 1.8 ± 0.8, p=0.21), summed rest score (SiPM: 2.7 ± 1.0 vs. PMT: 3.1 ± 1.2, p=0.34), LV function (LVEF, SiPM: 62.6 ± 2.8 vs. PMT: 61.4 ± 2.8, p=0.82) and volumes (LVEDV, SiPM: 62.6 ± 2.8 vs. PMT: 61.4 ± 2.8, p=0.51). Image quality measures significantly improved (Figure), with lower COV (SiPM: 15.3 ± 0.8 vs. PMT: 19.3 ± 1.1, p=0.006), higher SNR (SiPM; 26.4 ± 1.8 vs. PMT; 20.5 ± 1.5, p&lt;0.001) and CNR (SiPM; 14.2 ± 1.2 vs. PMT; 11.4 ± 1.1, p=0.02). Conclusions: 82 Rb PET MPI performed with SiPM-based a PET scanner showed significantly better image contrast and less noise compared to a PMT-based PET scanner. These findings suggest that the SiPM based PET scanner provides more previse evaluations for patients undergoing 82 Rb PET MPI.

Abstract 17801: Age-Specific Normal Values for Myocardial Blood Flow on 82rb Positron Emission Tomography

Introduction: Positron emission tomography (PET) myocardial perfusion imaging (MPI) is utilized to evaluate ischemia along with myocardial blood flow (MBF). The ability to adequately augment blood flow, measured by myocardial blood flow reserve (MBFR), is a measure of overall health of the coronary circulation and associated with lower major adverse cardiovascular events (MACE) and all-cause mortality. The age-specific ranges of MBFR in patients without demonstrable coronary artery disease (CAD) has not been well established. Hypothesis/Aim: To determine the effect of age on MBF and MBFR in a cohort of patients without demonstrable CAD. Methods: Patients who underwent PET MPI studies from 2012-2022 on Siemens PET/CT cameras were included if Summed Stress Score=0, coronary calcium score=0, and left ventricular ejection fraction ≥50%. Those with prior history of MI or coronary intervention, heart/kidney/liver transplant, cirrhosis, or CKD stage IV+ were excluded. MBF was calculated using a net retention model (ImagenQ, Cardiovascular Imaging Technologies, Kansas City, MO) and multivariable linear regression models were developed to predict MBF. Results: Among 3,235 patients (age 59.5+/-12.6 years, 24.2% male) with median rest MBF 0.74 [0.61-0.92] and stress MBF 1.71 [1.41-2.10], MBFR was 2.28 [1.93-2.72]. With increasing age, rest MBF remained fairly stable while stress MBF and MBFR decreased, such that for every 10 years of age, stress MBF decreased by 0.07 [95% CI 0.05-0.08] mL/min/g and MBFR decreased by 0.12 [95% CI 0.11-0.14] after multivariable adjustment. Age-specific predicted MBFR values are documented in the Table. Conclusions: In patients without demonstrable CAD, the MBFR decreases with age. Abnormal MBFR values under 2.0 may be seen in a significant number of older patients.

Abstract 15719: Prognostic Interplay Between Myocardial Flow Reserve and Left Ventricular Ejection Fraction

Introduction: Myocardial flow reserve (MFR), measured using positron emission tomography (PET), has been shown to add incremental prognostic value in multiple patient populations. Whether this association is modified by left ventricular ejection fraction (LVEF) is not well studied. The aim of this analysis is to determine whether there is a prognostic interplay between myocardial flow reserve and LVEF. Methods: The study population included patients who had clinically indicated PET myocardial perfusion imaging and were prospectively followed for incident events. MFR was calculated as the ratio of stress to rest myocardial blood flow (MBF) (ml/min/g). Rest LVEF was calculated from end systolic and end diastolic LV volumes on gated images. Cox proportional hazards were used to study the association between MFR (&lt;2 vs ≥2) and incident cardiovascular events stratified by LVEF (&lt;50% vs ≥50%). Results: The study population included 5,523 patients (mean±SD age 67±12 years, 53% male), 16% of LVEF&lt;50% and 47% MFR &lt;2. Rest MBF was similar among patients with normal or reduced LVEF while stress MFR was lower with lower EF. In adjusted analysis, patients with impaired MFR had a higher incident event rate regardless of LVEF (Figure 1). Patients with MFR&lt;2 had a higher risk of incident outcomes in both LVEF ≥50% (HR=2.58, 95% CI:1.93 - 3.46, p&lt;0.001) and LVEF &lt;50% (HR=2.76, 95% CI: 1.62 - 4.70, p&lt;0.001); p-value for interaction= 0.045. Conclusions: Impaired MFR is associated with a higher risk of cardiovascular outcomes and death in patients with high or low LVEF.

Reproducibility of Left Ventricular Function Derived From Cardiac Magnetic Resonance and Gated 13N-Ammonia Positron Emission Tomography Myocardial Perfusion Imaging: A Head-to-Head Comparison Using Hybrid Positron Emission Tomography/Magnetic Resonance

Cardiac magnetic resonance (CMR) and gated 13N-ammonia positron emission tomography myocardial perfusion imaging (PET-MPI) offer accurate and highly comparable global left ventricular ejection fraction (LVEF) measurements. In addition to accuracy, however, reproducibility is crucial to avoid variations in LVEF assessment potentially negatively impacting treatment decisions. We performed a head-to-head comparison of the reproducibility of LVEF measurements derived from simultaneously acquired CMR and PET-MPI using different state-of-the-art commercially available software. 93 patients undergoing hybrid PET/MR were retrospectively included. LVEF was derived from CMR and PET-MPI at two separate core labs, using two state-of-the-art software packages for CMR (cvi42 and Medis Suite MR) and PET (QPET and CardIQ Physio). Intra- and inter-reader agreement was assessed using correlation and Bland-Altman (BA) analyses. While intra- and inter-reader reproducibility of LVEF was high among both modalities and all software packages (r≥0.87 and ICC≥0.91, all significant at p<0.0001), LVEF derived from PET-MPI and analyzed with QPET outperformed all other analyses (intra-reader reproducibility: r=0.99, ICC=0.99; inter-reader reproducibility: r=0.98, ICC=1.00; Pearson correlations significantly higher than all others at p≤0.0001). BA analyses showed smaller biases for LVEF derived from PET-MPI (-0.1% and +0.9% for intra-reader, -0.4% and -0.8% for inter-reader agreement) than those derived from CMR (+0.7% and +2.8% for intra-reader, -0.9% and -2.2% for inter-reader agreement) with similar results for BA limits of agreement. Gated 13N-ammonia PET-MPI provides equivalent reproducibility of LVEF compared to CMR. It may offer a valid alternative to CMR for patients requiring LV functional assessment.

Integrated myocardial flow reserve (iMFR) assessment: optimized PET blood flow quantification for diagnosis of coronary artery disease.

Distinguishing obstructive epicardial coronary artery disease (CAD) from microvascular dysfunction and diffuse atherosclerosis would be of immense benefit clinically. However, quantitative measures of absolute myocardial blood flow (MBF) integrate the effects of focal epicardial stenosis, diffuse atherosclerosis, and microvascular dysfunction. In this study, MFR and relative perfusion quantification were combined to create integrated MFR (iMFR) which was evaluated using data from a large clinical registry and an international multi-center trial and validated against invasive coronary angiography (ICA). This study included 1,044 clinical patients referred for 82Rb rest/stress positron emission tomography myocardial perfusion imaging and ICA, along with 231 patients from the Flurpiridaz 301 trial (clinicaltrials.gov NCT01347710). MFR and relative perfusion quantification were combined to create an iMFR map. The incremental value of iMFR was evaluated for diagnosis of obstructive stenosis, adjusted for patient demographics and pre-test probability of CAD. Models for high-risk anatomy (left main or three-vessel disease) were also constructed. iMFR parameters of focally impaired perfusion resulted in best fitting diagnostic models. Receiver-operating characteristic analysis showed a slight improvement compared to standard quantitative perfusion approaches (AUC 0.824 vs. 0.809). Focally impaired perfusion was also associated with high-risk CAD anatomy (OR 1.40 for extent, and OR 2.40 for decreasing mean MFR). Diffusely impaired perfusion was associated with lower likelihood of obstructive CAD, and, in the absence of transient ischemic dilation (TID), with lower likelihood of high-risk CAD anatomy. Focally impaired perfusion extent derived from iMFR assessment is a powerful incremental predictor of obstructive CAD while diffusely impaired perfusion extent can help rule out obstructive and high-risk CAD in the absence of TID.

Integrated myocardial flow reserve (iMFR) assessment: diffuse atherosclerosis and microvascular dysfunction are more strongly associated with mortality than focally impaired perfusion.

Although treatment of ischemia-causing epicardial stenoses may improve symptoms of ischemia, current evidence does not suggest that revascularization improves survival. Conventional myocardial ischemia imaging does not uniquely identify diffuse atherosclerosis, microvascular dysfunction, or nonobstructive epicardial stenoses. We sought to evaluate the prognostic value of integrated myocardial flow reserve (iMFR), a novel noninvasive approach to distinguish the perfusion impact of focal atherosclerosis from diffuse coronary disease. This study analyzed a large single-center registry of consecutive patients clinically referred for rest-stress myocardial perfusion positron emission tomography. Cox proportional hazards modeling was used to assess the association of two previously reported and two novel perfusion measures with mortality risk: global stress myocardial blood flow (MBF); global myocardial flow reserve (MFR); and two metrics derived from iMFR analysis: the extents of focal and diffusely impaired perfusion. In total, 6867 patients were included with a median follow-up of 3.4 years [1st-3rd quartiles, 1.9-5.0] and 1444 deaths (21%). Although all evaluated perfusion measures were independently associated with death, diffusely impaired perfusion extent (hazard ratio 2.65, 95%C.I. [2.37-2.97]) and global MFR (HR 2.29, 95%C.I. [2.08-2.52]) were consistently stronger predictors than stress MBF (HR 1.62, 95%C.I. [1.46-1.79]). Focally impaired perfusion extent (HR 1.09, 95%C.I. [1.03-1.16]) was only moderately related to mortality. Diffusely impaired perfusion extent remained a significant independent predictor of death when combined with global MFR (p < 0.0001), providing improved risk stratification (overall net reclassification improvement 0.246, 95%C.I. [0.183-0.310]). The extent of diffusely impaired perfusion is a strong independent and additive marker of mortality risk beyond traditional risk factors, standard perfusion imaging, and global MFR, while focally impaired perfusion is only moderately related to mortality.

Prevalence and Prognostic Importance of Abnormal Positron Emission Tomography Among Asymptomatic Patients With Diabetes Mellitus

BackgroundIschemia and reduced global myocardial blood flow reserve (MBFR) are associated with high cardiovascular risk among symptomatic patients with diabetes mellitus (DM). ObjectivesThis study aimed to assess the prevalence and prognostic importance of silent ischemia and reduced MBFR among asymptomatic patients with DM. MethodsThis study included 2,730 consecutive patients with DM, without known coronary artery disease (CAD) or cardiomyopathy, who underwent rubidium-82 rest/stress positron emission tomography (PET) myocardial perfusion imaging (MPI) from 2010 to 2016. These patients were followed up for all-cause mortality (n = 461) for a median follow-up of 3 years. Patients were considered asymptomatic if neither chest pain nor dyspnea was elicited. Rates of ischemia, reduced MBFR, and coronary microvascular dysfunction on PET were assessed in both groups. Cox regression was used to define the independent association of abnormal MPI markers with mortality. ResultsOne-quarter of patients with DM (23.7%; n = 647) were asymptomatic; ischemia was present in 30.5% (n = 197), reduced MBFR in 62.3% (n = 361), and coronary microvascular dysfunction in 32.7% (n = 200). In adjusted analyses, reduced MBFR (HR per 0.1 unit decrease in MBFR: 1.08 [95% CI: 1.03-1.12]; P = 0.001) and reduced ejection fraction (HR per 5% decrease: 1.10 [95% CI: 1.01-1.18]; P = 0.02) were independently prognostic of mortality among asymptomatic patients, but ischemia was not. This was comparable to DM patients with symptoms. Insulin use and older age were significant predictors of reduced MBFR among asymptomatic patients with DM. ConclusionsIn both symptomatic and asymptomatic patients with DM, impairment in MBFR is common and associated with greater mortality risk.

Flurpiridaz F-18 PET Myocardial Perfusion Imaging in Patients With Suspected Coronary Artery Disease

BackgroundFlurpiridaz F-18 (flurpiridaz) is a novel positron emission tomography (PET) myocardial perfusion imaging tracer. ObjectivesThe purpose of this study was to further assess the diagnostic efficacy and safety of flurpiridaz for the detection and evaluation of coronary artery disease (CAD) defined as ≥50% stenosis by quantitative invasive coronary angiography (ICA). MethodsIn this second phase 3 prospective multicenter clinical study, 730 patients with suspected CAD from 48 clinical sites in the United States, Canada, and Europe were enrolled. Patients underwent 1-day rest/stress flurpiridaz PET and 1- or 2-day rest-stress Tc-99m–labeled single photon emission computed tomography (SPECT) before ICA. PET and SPECT images were read by 3 experts blinded to clinical and ICA data. ResultsA total of 578 patients (age 63.7 ± 9.5 years) were evaluable; 32.5% were women, 52.3% had body mass index ≥30 kg/m2, and 33.6% had diabetes. Flurpiridaz PET met the efficacy endpoints of the study; its sensitivity and specificity were significantly higher than the prespecified threshold value by 2 of the 3 readers. The sensitivity of flurpiridaz PET was higher than SPECT (80.3% vs 68.7%; P = 0.0003) and its specificity was noninferior to SPECT (63.8% vs 61.7%; P = 0.0004). PET area under the receiver-operating characteristic curves were higher than SPECT in the overall population (0.80 vs 0.68; P < 0.001), women, and obese patients (P < 0.001 for both). Flurpiridaz PET was superior to SPECT (P < 0.001) for perfusion defect size/severity evaluation, image quality, diagnostic certainty, and radiation exposure. Flurpiridaz PET was safe and well tolerated. ConclusionsThis second flurpiridaz PET myocardial perfusion imaging trial shows that flurpiridaz has utility as a new tracer for CAD detection, specifically in women and obese patients. (An International Study to Evaluate Diagnostic Efficacy of Flurpiridaz [18F] Injection PET MPI in the Detection of Coronary Artery Disease [CAD]; NCT03354273)

Interaction of impaired myocardial flow reserve and extent of myocardial ischemia assessed using 13N-ammonia positron emission tomography imaging on adverse cardiovascular outcomes

BackgroundMyocardial flow reserve (MFR) and the extent of myocardial ischemia identify patients at high risk of major adverse cardiovascular events (MACEs). Associations between positron emission tomography (PET)-assessed extent of ischemia, MFR, and MACEs is unclear. MethodOverall, 640 consecutive patients with suspected or known coronary artery disease undergoing 13N-ammonia myocardial perfusion PET were followed-up for MACEs. Patients were categorized into three groups based on myocardial ischemia severity: Group I (n = 335), minimal (myocardial ischemia < 5%); Group II (n = 150), mild (5–10%); and Group III (n = 155), moderate-to-severe (> 10%). ResultsCardiovascular death and MACEs occurred in 17 (3%) and 93 (15%) patients, respectively. Following statistical adjustment for confounding factors, impaired MFR (global MFR < 2.0) was revealed as an independent predictor of MACEs in Groups I (hazard ratio [HR], 2.89; 95% confidence interval [CI], 1.48–5.64; P = 0.002) and II (HR, 3.40; 95% CI 1.37–8.41; P = 0.008) but was not significant in Group III (HR, 1.15; 95% CI 0.59–2.26; P = 0.67), with a significant interaction (P < 0.0001) between the extent of myocardial ischemia and MFR. ConclusionImpaired MFR was significantly associated with increased risk of MACEs in patients with ≤ 10% myocardial ischemia but not with those having > 10% ischemia, allowing a clinically effective risk stratification.