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

BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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]). CONCLUSIONS: 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.

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

PURPOSE: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Utility of serum ketone levels for assessment of myocardial glucose suppression for 18F-fluorodeoxyglucose PET in patients referred for evaluation of endocarditis.

BACKGROUND: 18F-FDG PET/CT is used to diagnose cardiac sarcoidosis and endocarditis. It requires myocardial glucose utilization (MGU) suppression to avoid false positives, which occur in up to 20% of patients. Serum beta-hydroxybutyrate (BHB) levels may help identify incomplete suppression of MGU. We determined the optimal timing and diagnostic thresholds to identify incomplete suppression of MGU. METHODS AND RESULTS: We retrospectively identified 114 patients referred for 18F-FDG PET/CT for endocarditis, wherein myocardial uptake outside of paravalvular regions is not related to pathology and can be confidently ascribed as being due to inadequate suppression of MGU. Patients followed a high-fat, low-carbohydrate diet and received heparin. Serum BHB, insulin, glucose and hemoglobin A1c were measured. Maximum standardized uptake value (SUVmax) of left ventricle (LV) and mean SUV (SUVmean) in LV blood pool (LVBP) was measured. Logistic regression and area under the receiver-operating characteristic analyses were used to quantify the relationship between biomarkers and MGU suppression. A threshold of BHB ≥ 0.35 mmol·L-1 to detect suppression resulted in sensitivity of 88% and specificity of 61%. A threshold of BHB ≥ 0.95 mmol·L-1 resulted in sensitivity of 45% and specificity of 100%. AUC was 0.87. BHB measured ~ 4 hours prior to 18F-FDG injection performed similarly to or better than later timepoints. CONCLUSIONS: Serum BHB levels are useful for assessing suppression of MGU and could simplify interpretation of 18F-FDG PET/CT inflammation studies.

Impact of residual subtraction on myocardial blood flow and reserve estimates from rapid dynamic PET protocols.

BACKGROUND: 13N-ammonia and 18F-flurpiridaz require longer delays between rest and stress studies to allow for decay, lowering clinical throughput. In this study, we investigated the impact of residual subtraction on MBF and MFR estimates, as well as its effects on diagnostic accuracy. METHODS: We retrospectively analyzed 63 patients who underwent a dynamic ammonia rest/stress study and 231 patients from the flurpiridaz 301 trial. Residual subtraction was performed by subtracting the mean pre-injection activity in each sampled region from that region's time activity curve. Corrected and uncorrected MBF and MFR were analyzed. Diagnostic accuracy was compared to quantitative coronary angiograms (QCA) for the flurpiridaz population. RESULTS: With delays between injections above 3 half-lives, and a doubled stress dose, residual activity did not meaningfully increase ammonia MBF (< 5%). For shorter injection delays, stress MBF was overestimated by 13.6% ± 5.0% (P < .001). Residual activity had a large effect on flurpiridaz stress MBF, overestimating it by 37.9% ± 23.2% (P < .001). Comparison to QCA showed a significant improvement in AUC with residual subtraction (from 0.748 to 0.831, P = .001). MFR yielded similar results. CONCLUSIONS: Accounting for residual activity has a marked impact on stress MBF and MFR and improves diagnostic accuracy relative to QCA.

Added value of myocardial blood flow using 18F-flurpiridaz PET to diagnose coronary artery disease: The flurpiridaz 301 trial.

BACKGROUND: 18F-Flurpiridaz is a promising investigational radiotracer for PET myocardial perfusion imaging with favorable properties for quantification of myocardial blood flow (MBF). We sought to validate the incremental diagnostic value of absolute MBF quantification in a large multicenter trial against quantitative coronary angiography. METHODS: We retrospectively analyzed a subset of patients (N = 231) from the first phase 3 flurpiridaz trial (NCT01347710). Dynamic PET data at rest and pharmacologic stress were fit to a previously validated 2-tissue-compartment model. Absolute MBF and myocardial flow reserve (MFR) were compared with coronary artery disease severity quantified by invasive coronary angiography on a per-patient and per-vessel basis. RESULTS: Stress MBF per-vessel accurately identified obstructive disease (c-index 0.79) and progressively declined with increasing stenosis severity (2.35 ± 0.71 in patients without CAD; 1.92 ± 0.49 in non-obstructed territories of CAD patients; and 1.54 ± 0.50 in diseased territories, P < 0.05). MFR similarly declined with increasing stenosis severity (3.03 ± 0.94; 2.69 ± 0.95; and 2.33 ± 0.86, respectively, P < 0.05). In multivariable logistic regression modeling, stress MBF and MFR provided incremental diagnostic value beyond patient characteristics and relative perfusion analysis. CONCLUSIONS: Clinical myocardial blood flow measurement with 18F-flurpiridaz cardiac PET shows promise for routine application.

Correlating cardiac F-18 FDG PET/CT results with intra-operative findings in infectious endocarditis.

BACKGROUND: Multiple studies have demonstrated that when incorporated with conventional imaging modalities, cardiac F-18 PET/CT can aid in diagnosis of endocarditis and improve the sensitivity of the Duke Criteria. These studies used as their gold standard the opinion of an endocarditis team and were characterized by low percentages of patients who underwent surgery. We reviewed 4 years of surgically managed IE cases where F-18 cardiac PET/CT was used to aid diagnosis. METHODS: Between July 2014 and December 2018, we retrospectively reviewed 68 surgically managed endocarditis cases to identify patients who underwent pre-operative PET scans. RESULTS: Fourteen patients were identified who underwent F-18 cardiac PET/CT prior to surgical intervention. Nine cases were classified as possible endocarditis by Duke Criteria and 8 involved prosthetic valves. Twelve out of fourteen scans were interpreted as suggestive of or consistent with endocarditis based on FDG uptake. Twelve positive PETs were associated with either operative findings of infection and/or positive PCR testing on the excised valve. Two patients with negative scans were found to have non-infectious mobile masses intra-operatively, negative valve cultures and negative pathology. CONCLUSION: In a small cohort, F-18 FDG cardiac PET/CT correlated closely with intra-operative findings in patients with endocarditis and helped guide surgical decision-making. It could be considered for addition to the Duke Criteria in the American Heart Association endocarditis guidelines similar to European protocols.

Initial clinical experience of N13-ammonia myocardial perfusion PET/CT using a compact superconducting production system.

BACKGROUND: Although N13-ammonia has favorable properties among FDA approved radiotracers, complexity of implementation has limited its use. We describe the initial patient experience of N13-ammonia PET imaging using a compact N13-ammonia production system. METHODS: N13 was produced using the ION-12SC, a 12MeV, 10uA superconducting minimally shielded cyclotron, and reduced to N13-ammonia in an automated multi-use purification unit. Patients were power injected with 9.3 ± 1.1 mCi (344.1 ± 40.7 MBq) of N13-ammonia for rest imaging, and 18.8 ± 0.9 mCi (695.6 ± 33.3 MBq) of N13-ammonia was injected at peak hyperemia for stress testing. Images were interpreted for relative perfusion, left ventricular volumes/function, blood flow quantification, and scored for image quality. RESULTS: In total 97 patients underwent 98 N13-ammonia PET scans (32 rest only/65 rest-stress/1 stress only). Image quality was 91.8% good or excellent. None were poor/non-diagnostic. Study durations were acceptable. Tracer related radiation dosimetry to patients was 0.7 ± 0.1 mSv (rest only), and 2.1 ± 0.1 mSv (rest-stress). CONCLUSION: Clinical N13-ammonia production by the Ionetix ION-12SC delivers high quality myocardial PET perfusion images in a rapid protocol.

Spontaneous Coronary Artery Dissection: An Underdiagnosed Clinical Entity-A Primer for Cardiac Imagers.

Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic cause of myocardial infarction in young and middle-aged women that has gained increasing awareness in recent years. Its diagnosis presents a challenge. Invasive coronary angiography is the primary imaging modality for diagnosing SCAD; however, it carries risk in these patients, who have an increased predisposition to complications. Advances in CT technology enable robust noninvasive evaluation of the coronary arteries at low radiation doses and have been increasingly utilized for the diagnosis or resolution of SCAD, in hemodynamically stable patients or when diagnosis of SCAD is uncertain at invasive angiography, particularly in proximal vessels. However, criteria for the diagnosis of SCAD with use of coronary CT angiography (CCTA) have not been currently established, and sensitivity and specificity for diagnosis have not yet been defined. The appearance of SCAD at CCTA can be subtle and can be missed, especially in distal small-caliber coronary arteries; hence utilization of other noninvasive imaging multimodalities may help solve this diagnostic challenge. Accurate and prompt diagnosis is vital, as management of SCAD differs significantly from that of traditional atherosclerotic acute coronary syndromes, with conservative management preferred for the majority of SCAD patients, and invasive treatment reserved for those with ongoing or recurrent ischemia, heart failure, or hemodynamic compromise. The goal of this review is twofold: (a) to discuss the potential role of CCTA in the diagnosis of SCAD, and (b) to discuss the role of multimodality imaging that may improve diagnostic yield, guide management, and enable subsequent surveillance. An invited commentary by Ordovas is available online. Online supplemental material is available for this article. ©RSNA, 2021.

Physician perceptions of a multidisciplinary endocarditis team.

Infectious endocarditis is a highly morbid infection that requires coordination of care across medical and surgical specialties, often through the use of a multidisciplinary team model. Multiple studies have demonstrated that such conferences can improve clinical outcomes. However, little is known about physicians' impressions of these groups. We surveyed 126 (response rate of 30%) internal medicine, infectious diseases, cardiology, and cardiac surgery providers 1 year after the implementation of an endocarditis team at the University of Michigan. Ninety-eight percent of physicians felt that the endocarditis team improved communication between specialties. Additionally, over 85% of respondents agreed that the group influenced diagnostic evaluation, reduced management errors, increased access to surgery, and decreased in-hospital mortality for endocarditis patients. These results suggest that multidisciplinary endocarditis teams are valued by physicians as a tool to improve patient care and serve an important role in increasing communication between providers.

Characterization of a highly effective preparation for suppression of myocardial glucose utilization.

BACKGROUND: With appropriate protocols, F-18 fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) can visualize myocardial inflammation. Optimal protocols and normative myocardial FDG uptake values are not well-established. METHODS: We evaluated 111 patients referred for inflammation cardiac FDG PET/CT. Patients followed a low-carbohydrate, high-fat diet for 36 hours before imaging and received unfractionated heparin. Glucose and fatty acid metabolism biomarkers were obtained. Mean blood pool and maximum myocardial uptake (SUVmean, SUVmax) were measured, avoiding areas of abnormal FDG uptake or spillover. RESULTS: Adequate suppression of myocardial FDG uptake occurred in 95% of patients (n = 106). Myocardial SUVmax was significantly below background blood pool SUVmean: septal myocardial to blood pool ratio 0.75 (95% CI 0.73-0.77; P < 0.001); lateral myocardial to blood pool ratio 0.70 (95% CI 0.68-0.72; P < 0.001). Glucose, insulin, and C-peptide correlated to blood pool SUVmean (Spearman rs = 0.39, P < 0.01; rs = 0.40, P < 0.01; rs = 0.35, P < 0.01) and myocardial SUVmax (Spearman rs = 0.31, P < 0.01; rs = 0.31, P < 0.01; rs = 0.26, P < 0.01). Fatty acid metabolism biomarkers did not correlate to myocardial SUVmax. CONCLUSIONS: Patients following intensive metabolic preparation have myocardial FDG SUVmax below background SUVmean. Biomarkers of glucose metabolism modestly correlate to FDG uptake.

Reducing motion-correction-induced variability in 82rubidium myocardial blood-flow quantification.

BACKGROUND: Clinical use of myocardial blood flow (MBF) and flow reserve (MFR) is increasing. Motion correction is necessary to obtain accurate results but can introduce variability when performed manually. We sought to reduce that variability with an automated motion-correction algorithm. METHODS: A blinded randomized controlled trial of two technologists was performed on the motion correction of 100 dynamic 82Rb patient studies comparing manual motion correction with manual review and adjustment of automated motion correction. Inter-rater variability between technologists for MBF and MFR was the primary outcome with comparison made by analysis of the limits of agreement. Processing time was the secondary outcome. RESULTS: Limits of agreements between the two technologists decreased significantly for both MBF and MFR, going from [- 0.22, 0.22] mL/min/g and [- 0.31, 0.36] to [- 0.12, 0.15] mL/min/g and [- 0.15, 0.18], respectively (both P < .002). In addition, the average time spent on motion correcting decreased by 1 min per study from 5:21 to 4:21 min (P = .001). CONCLUSIONS: In this randomized controlled trial, the use of automated motion correction significantly decreased inter-user variability and reduced processing time.

Automated dynamic motion correction using normalized gradient fields for 82rubidium PET myocardial blood flow quantification.

BACKGROUND: Patient motion can lead to misalignment of left ventricular (LV) volumes-of-interest (VOIs) and subsequently inaccurate quantification of myocardial blood flow (MBF) and flow reserve (MFR) from dynamic PET myocardial perfusion images. We aimed to develop an image-based 3D-automated motion-correction algorithm that corrects the full dynamic sequence for translational motion, especially in the early blood phase frames (~ first minute) where the injected tracer activity is transitioning from the blood pool to the myocardium and where conventional image registration algorithms have had limited success. METHODS: We studied 225 consecutive patients who underwent dynamic rest/stress rubidium-82 chloride (82Rb) PET imaging. Dynamic image series consisting of 30 frames were reconstructed with frame durations ranging from 5 to 80 seconds. An automated algorithm localized the RV and LV blood pools in space and time and then registered each frame to a tissue reference image volume using normalized gradient fields with a modification of a signed distance function. The computed shifts and their global and regional flow estimates were compared to those of reference shifts that were assessed by three physician readers. RESULTS: The automated motion-correction shifts were within 5 mm of the manual motion-correction shifts across the entire sequence. The automated and manual motion-correction global MBF values had excellent linear agreement (R = 0.99, y = 0.97x + 0.06). Uncorrected flows outside of the limits of agreement with the manual motion-corrected flows were brought into agreement in 90% of the cases for global MBF and in 87% of the cases for global MFR. The limits of agreement for stress MBF were also reduced twofold globally and by fourfold in the RCA territory. CONCLUSIONS: An image-based, automated motion-correction algorithm for dynamic PET across the entire dynamic sequence using normalized gradient fields matched the results of manual motion correction in reducing bias and variance in MBF and MFR, particularly in the RCA territory.

Safety of regadenoson positron emission tomography stress testing in orthotopic heart transplant patients.

OBJECTIVES: We sought to determine the safety of regadenoson (REG) stress testing in patients who have undergone orthotopic heart transplantation (OHT). BACKGROUND: Routine screening for cardiac allograft vasculopathy (CAV) is necessary after OHT. Adenosine stress is contraindicated after heart transplantation due to supersensitivity in denervated hearts. Safety of regadenoson stress following OHT has not been well studied. METHODS: We retrospectively reviewed data from OHT patients (N = 123) who were referred to REG stress testing. Medical records were reviewed to determine hemodynamic and ECG response to regadenoson and to identify adverse reactions. RESULTS: No serious adverse events occurred. No life-threatening arrhythmias or hemodynamic changes occurred. Common side-effects related to regadenoson were observed, dyspnea being the most frequent (66.7%). On average the heart rate rose from 82.8 ± 12 to 95.7 ± 13.4 bpm (P < 0.001), systolic blood pressure decreased from 138.7 ± 20.9 to 115.9 ± 23.9 mmHg (P < 0.001) and mean arterial pressure decreased from 103.5 ± 14.1 to 84.72 ± 15.90 mmHg (P < 0.001) during stress protocol. There was no sustained ventricular tachycardia, ventricular fibrillation, or second-or third-degree atrioventricular block. CONCLUSION: Regadenoson stress testing appears to be well tolerated and safe in OHT patients.

Blood pool and tissue phase patient motion effects on 82rubidium PET myocardial blood flow quantification.

BACKGROUND: Patient motion can lead to misalignment of left ventricular volumes of interest and subsequently inaccurate quantification of myocardial blood flow (MBF) and flow reserve (MFR) from dynamic PET myocardial perfusion images. We aimed to identify the prevalence of patient motion in both blood and tissue phases and analyze the effects of this motion on MBF and MFR estimates. METHODS: We selected 225 consecutive patients that underwent dynamic stress/rest rubidium-82 chloride (82Rb) PET imaging. Dynamic image series were iteratively reconstructed with 5- to 10-second frame durations over the first 2 minutes for the blood phase and 10 to 80 seconds for the tissue phase. Motion shifts were assessed by 3 physician readers from the dynamic series and analyzed for frequency, magnitude, time, and direction of motion. The effects of this motion isolated in time, direction, and magnitude on global and regional MBF and MFR estimates were evaluated. Flow estimates derived from the motion corrected images were used as the error references. RESULTS: Mild to moderate motion (5-15 mm) was most prominent in the blood phase in 63% and 44% of the stress and rest studies, respectively. This motion was observed with frequencies of 75% in the septal and inferior directions for stress and 44% in the septal direction for rest. Images with blood phase isolated motion had mean global MBF and MFR errors of 2%-5%. Isolating blood phase motion in the inferior direction resulted in mean MBF and MFR errors of 29%-44% in the RCA territory. Flow errors due to tissue phase isolated motion were within 1%. CONCLUSIONS: Patient motion was most prevalent in the blood phase and MBF and MFR errors increased most substantially with motion in the inferior direction. Motion correction focused on these motions is needed to reduce MBF and MFR errors.

The utility of 82Rb PET for myocardial viability assessment: Comparison with perfusion-metabolism 82Rb-18F-FDG PET.

BACKGROUND: 82Rb kinetics may distinguish scar from viable but dysfunctional (hibernating) myocardium. We sought to define the relationship between 82Rb kinetics and myocardial viability compared with conventional 82Rb and 18F-fluorodeoxyglucose (FDG) perfusion-metabolism PET imaging. METHODS: Consecutive patients (N = 120) referred for evaluation of myocardial viability prior to revascularization and normal volunteers (N = 37) were reviewed. Dynamic 82Rb 3D PET data were acquired at rest. 18F-FDG 3D PET data were acquired after metabolic preparation using a standardized hyperinsulinemic-euglycemic clamp. 82Rb kinetic parameters K1, k2, and partition coefficient (KP) were estimated by compartmental modeling RESULTS: Segmental 82Rb k2 and KP differed significantly between scarred and hibernating segments identified by Rb-FDG perfusion-metabolism (k2, 0.42 ± 0.25 vs. 0.22 ± 0.09 min-1; P < .0001; KP, 1.33 ± 0.62 vs. 2.25 ± 0.98 ml/g; P < .0001). As compared to Rb-FDG analysis, segmental Rb KP had a c-index, sensitivity and specificity of 0.809, 76% and 84%, respectively, for distinguishing hibernating and scarred segments. Segmental k2 performed similarly, but with lower specificity (75%, P < .001) CONCLUSIONS: In this pilot study, 82Rb kinetic parameters k2 and KP, which are readily estimated using a compartmental model commonly used for myocardial blood flow, reliably differentiated hibernating myocardium and scar. Further study is necessary to evaluate their clinical utility for predicting benefit after revascularization.

Relationship of non-invasive quantification of myocardial blood flow to arrhythmic events in patients with implantable cardiac defibrillators.

BACKGROUND: Ischemia contributes to arrhythmogenesis though its role is incompletely understood. Abnormal myocardial perfusion measured by PET imaging may predict ventricular arrhythmias (VAs) in a high-risk population. METHODS: Patients with implantable cardiac defibrillators who had undergone rubidium-82 cardiac PET imaging were identified. Patients were stratified by median MBF and MFR values for analysis. The Cox proportional hazards model was used to assess the impact of myocardial perfusion on survival free of VT independent of critical covariates. RESULTS: A total of 159 patients (124 (78%) males, median age 65.9 years, IQR [56.76-72.63]) were followed for 1.43 years IQR [0.83-2.21]. VA occurred in 29 patients (23.7%). After adjustment for ejection fraction, age, and sex, impaired stress MBF was associated with an increased risk of VA (adjusted HR per ml/min/g 1.52, 95% CI (1.01-2.31), P = 0.04). Summed rest and stress scores were not predictive of VA. Among patients with severe LV dysfunction, stress MBF remained an independent predictor of VA (adjusted HR per 1 ml/min/g HR 1.69, 95% CI (1.03-11.36), P = 0.03), while residual EF, summed rest, and summed stress scores were not (P > 0.05). CONCLUSIONS: Impaired stress myocardial blood flow was associated with less survival free of ventricular arrhythmias.