Prognostic value of myocardial flow reserve vs corrected myocardial flow reserve in patients without obstructive coronary artery disease.

BACKGROUND: Myocardial flow reserve (MFR) by positron emission tomography (PET) is a validated measure of cardiovascular risk. Elevated resting rate pressure product (RPP = heart rate x systolic blood pressure) can cause high resting myocardial blood flow (MBF), resulting in reduced MFR despite normal/near-normal peak stress MBF. When resting MBF is high, it is not known if RPP-corrected MFR (MFRcorrected) helps reclassify CV risk. We aimed to study this question in patients without obstructive coronary artery disease (CAD). METHODS: We retrospectively studied patients referred for rest/stress cardiac PET at our center from 2006 to 2020. Patients with abnormal perfusion (summed stress score >3) or prior coronary artery bypass grafting (CABG) were excluded. MFRcorrected was defined as stress MBF/corrected rest MBF where corrected rest MBF = rest MBF x 10,000/RPP. The primary outcome was major cardiovascular events (MACE): cardiovascular death or myocardial infarction. Associations of MFR and MFRcorrected with MACE were assessed using unadjusted and adjusted Cox regression. RESULTS: 3276 patients were followed for a median of 7 (IQR 3-12) years. 1685 patients (51%) had MFR <2.0, and of those 366 (22%) had an MFR ≥2.0 after RPP correction. MFR <2.0 was associated with an increased absolute risk of MACE (HR 2.24 [1.79-2.81], P < 0.0001). Among patients with MFR <2.0, the risk of MACE was not statistically different between patients with an MFRcorrected ≥2.0 compared with those with MFRcorrected <2.0 (1.9% vs 2.3% MACE/year, HR 0.84 [0.63-1.13], P = 0.26) even after adjustment for confounders (P = 0.66). CONCLUSIONS: In patients without overt obstructive CAD and MFR< 2.0, there was no significant difference in cardiovascular risk between patients with discordant (≥2.0) and concordant (<2) MFR following RPP correction. This suggests that RPP-corrected MFR may not consistently provide accurate risk stratification in patients with normal perfusion and MFR <2.0. Stress MBF and uncorrected MFR should be reported to more reliably convey cardiovascular risk beyond perfusion results.

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

OBJECTIVES: The 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). BACKGROUND: 15O-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. METHODS: The 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%. CONCLUSIONS: The 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 INFORMATION: Clinical-Trials.gov (#NCT05134012).

99mTc Bone-Avid Tracer Cardiac Scintigraphy: Role in Noninvasive Diagnosis of Transthyretin Cardiac Amyloidosis.

Transthyretin cardiac amyloidosis (ATTR-CA) is an overlooked cause of heart failure, with substantial morbidity and mortality. The emergence of several novel therapies has fueled the interest in early and accurate diagnosis of ATTR-CA so that potentially life-saving pharmacologic therapy can be administered in a timely manner. The most promising imaging modality and biomarker is SPECT imaging with technetium 99m (99mTc)-radiolabeled bone-seeking tracers, which have high specificity in the diagnosis of ATTR-CA, potentially obviating biopsy. In this article, the authors provide a focused review on the use of 99mTc pyrophosphate (PYP), 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), and hydroxymethylene diphosphonate (HMDP) for diagnosis of ATTR-CA, present a systematic approach to interpretation of the scans, and highlight several common pitfalls to illustrate important diagnostic principles for accurate interpretation of these images. The authors indicate when to use endomyocardial biopsy for the diagnosis of cardiac amyloidosis and conclude with a section on quantitation of 99mTc-PYP/DPD/HMDP imaging.

Mitigating bias in deep learning for diagnosis of coronary artery disease from myocardial perfusion SPECT images.

PURPOSE: Artificial intelligence (AI) has high diagnostic accuracy for coronary artery disease (CAD) from myocardial perfusion imaging (MPI). However, when trained using high-risk populations (such as patients with correlating invasive testing), the disease probability can be overestimated due to selection bias. We evaluated different strategies for training AI models to improve the calibration (accurate estimate of disease probability), using external testing. METHODS: Deep learning was trained using 828 patients from 3 sites, with MPI and invasive angiography within 6 months. Perfusion was assessed using upright (U-TPD) and supine total perfusion deficit (S-TPD). AI training without data augmentation (model 1) was compared to training with augmentation (increased sampling) of patients without obstructive CAD (model 2), and patients without CAD and TPD < 2% (model 3). All models were tested in an external population of patients with invasive angiography within 6 months (n = 332) or low likelihood of CAD (n = 179). RESULTS: Model 3 achieved the best calibration (Brier score 0.104 vs 0.121, p < 0.01). Improvement in calibration was particularly evident in women (Brier score 0.084 vs 0.124, p < 0.01). In external testing (n = 511), the area under the receiver operating characteristic curve (AUC) was higher for model 3 (0.930), compared to U-TPD (AUC 0.897) and S-TPD (AUC 0.900, p < 0.01 for both). CONCLUSION: Training AI models with augmentation of low-risk patients can improve calibration of AI models developed to identify patients with CAD, allowing more accurate assignment of disease probability. This is particularly important in lower-risk populations and in women, where overestimation of disease probability could significantly influence down-stream patient management.

Unsupervised learning to characterize patients with known coronary artery disease undergoing myocardial perfusion imaging.

PURPOSE: Patients with known coronary artery disease (CAD) comprise a heterogenous population with varied clinical and imaging characteristics. Unsupervised machine learning can identify new risk phenotypes in an unbiased fashion. We use cluster analysis to risk-stratify patients with known CAD undergoing single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). METHODS: From 37,298 patients in the REFINE SPECT registry, we identified 9221 patients with known coronary artery disease. Unsupervised machine learning was performed using clinical (23), acquisition (17), and image analysis (24) parameters from 4774 patients (internal cohort) and validated with 4447 patients (external cohort). Risk stratification for all-cause mortality was compared to stress total perfusion deficit (< 5%, 5-10%, ≥10%). RESULTS: Three clusters were identified, with patients in Cluster 3 having a higher body mass index, more diabetes mellitus and hypertension, and less likely to be male, have dyslipidemia, or undergo exercise stress imaging (p < 0.001 for all). In the external cohort, during median follow-up of 2.6 [0.14, 3.3] years, all-cause mortality occurred in 312 patients (7%). Cluster analysis provided better risk stratification for all-cause mortality (Cluster 3: hazard ratio (HR) 5.9, 95% confidence interval (CI) 4.0, 8.6, p < 0.001; Cluster 2: HR 3.3, 95% CI 2.5, 4.5, p < 0.001; Cluster 1, reference) compared to stress total perfusion deficit (≥10%: HR 1.9, 95% CI 1.5, 2.5 p < 0.001; < 5%: reference). CONCLUSIONS: Our unsupervised cluster analysis in patients with known CAD undergoing SPECT MPI identified three distinct phenotypic clusters and predicted all-cause mortality better than ischemia alone.

Low coronary flow relative to myocardial mass predicts heart failure in symptomatic hypertensive patients with no obstructive coronary artery disease.

AIMS: The transition from hypertension to heart failure (HF) remains poorly understood. We hypothesized that insufficient perfusion to match global metabolic demand, reflected by a low ratio of myocardial blood flow to global myocardial mass, may be a HF risk marker. METHODS AND RESULTS: A retrospective cohort (n = 346) of patients with hypertension who underwent clinical positron emission tomography (PET) myocardial perfusion imaging for chest pain and/or dyspnoea at Brigham and Women's Hospital (Boston, MA, USA) were studied. Patients without obstructive coronary artery disease by history or PET perfusion (summed stress score <3), HF, cardiomyopathy, or ejection fraction (EF) <40% were followed for HF hospitalization (primary outcome), all-cause death, and their composite. Myocardial blood flow, left ventricular (LV) mass, volumes, and EF were obtained from PET, and a 'flow/mass ratio' was determined as hyperaemic myocardial blood flow over LV mass indexed to body surface area. A lower flow/mass ratio was independently associated with larger end-diastolic (ß = -0.44, P < 0.001) and end-systolic volume (ß = -0.48, P < 0.001) and lower EF (ß = 0.33, P < 0.001). A flow/mass ratio below the median was associated with an adjusted hazard ratio of 2.47 [95% confidence interval (CI) 1.24-4.93; P = 0.01] for HF hospitalization, 1.95 (95% CI 1.12-3.41; P = 0.02) for death, and 2.20 (95% CI 1.39-3.49; P < 0.001) for the composite. CONCLUSION: An integrated physiological measure of insufficient myocardial perfusion to match global metabolic demand identifies subclinical hypertensive heart disease and elevated risk of HF and death in symptomatic patients with hypertension but without flow-limiting coronary artery disease.

Multimodality imaging to distinguish between benign and malignant cardiac masses.

BACKGROUND: To compare the diagnostic accuracy of CMR and FDG-PET/CT and their complementary role to distinguish benign vs malignant cardiac masses. METHODS: Retrospectively assessed patients with cardiac mass who underwent CMR and FDG-PET/CT within a month between 2003 and 2018. RESULTS: 72 patients who had CMR and FDG-PET/CT were included. 25 patients (35%) were diagnosed with benign and 47 (65%) were diagnosed with malignant masses. 56 patients had histological correlation: 9 benign and 47 malignant masses. CMR and FDG-PET/CT had a high accuracy in differentiating benign vs malignant masses, with the presence of CMR features demonstrating a higher sensitivity (98%), while FDG uptake with SUVmax/blood pool ≥ 3.0 demonstrating a high specificity (88%). Combining multiple (> 4) CMR features and FDG uptake (SUVmax/blood pool ratio ≥ 3.0) yielded a sensitivity of 85% and specificity of 88% to diagnose malignant masses. Over a mean follow-up of 2.6 years (IQR 0.3-3.8 years), risk-adjusted mortality were highest among patients with an infiltrative border on CMR (adjusted HR 3.1; 95% CI 1.5-6.5; P = .002) or focal extracardiac FDG uptake (adjusted HR 3.8; 95% CI 1.9-7.7; P < .001). CONCLUSION: Although CMR and FDG-PET/CT can independently diagnose benign and malignant masses, the combination of these modalities provides complementary value in select cases.

Inter-observer reproducibility and intra-observer repeatability in 99mTc-pyrophosphate scan interpretation for diagnosis of transthyretin cardiac amyloidosis.

AIM: The purpose of this study was to determine the inter- and intra-observer variability in 99mtechnetium-pyrophosphate (99mTc-PYP) scan interpretation for diagnosis of transthyretin cardiac amyloidosis (ATTR). METHODS AND RESULTS: Our study cohort comprised 100 consecutive subjects referred for 99mTc-PYP imaging based on clinical suspicion of ATTR cardiac amyloidosis. Myocardial 99mTc-PYP uptake was assessed by both visual (comparison of myocardial to rib uptake) and semi-quantitative (heart-to-contralateral lung uptake ratio, H:CL) methods. Twenty scans were analyzed twice, at least 48 hours apart, by each of two independent observers. Patients with visual scores of ≥ 2 on planar imaging as well as myocardial uptake on SPECT/CT were classified as ATTR positive. Diagnosis of ATTR by visual 99mTc-PYP grade was perfectly reproducible [concordance: positive and negative scans 100% (53/53 and 47/47, respectively). Both inter- and intra-observer correlations for H:CL ratio (r2 = 0.90, 0.99 (Observer 1) and 0.98 (Observer 2), respectively) and repeatability values on Bland-Altman plots were excellent. The coefficient of variation (%) for Observers 1 and 2 was 3.21 (2.14 to 4.29) and 7.49 (4.95 to 10.09), respectively. In addition, there was 100% concordance in positive and negative scan interpretation by visual grading between novice CV imagers (< 3 years' experience) and an experienced CV imager (10 years' experience). CONCLUSIONS: This study showed excellent inter-observer reproducibility and intra-observer repeatability of 99mTc-PYP visual scan interpretation and H:CL ratio for diagnosis of cardiac ATTR amyloidosis. Cardiac ATTR amyloidosis can be diagnosed reliably using 99mTc-PYP SPECT/CT by novice and experienced CV imagers.

Coronary vasomotor dysfunction portends worse outcomes in patients with breast cancer.

BACKGROUND: Impaired MFR in the absence of flow-limiting CAD is associated with adverse events. Cardiovascular disease is an important cause of morbidity and mortality in patients with breast cancer. We sought to test the utility of MFR to predict outcomes in a cohort of patients with breast cancer. METHODS: We retrospectively studied consecutive patients with breast cancer or breast cancer survivors who underwent cardiac stress PET imaging from 2006 to 2017 at Brigham and Women's Hospital. Patients with a history of clinically overt CAD, LVEF < 45%, or abnormal myocardial perfusion were excluded. Subjects were followed from time of PET to the occurrence of a first major adverse cardiovascular event (MACE) and all-cause death. RESULTS: The final cohort included 87 patients (median age 69.0 years, 98.9% female, mean MFR 2.05). Over a median follow-up of 7.6 years after PET, the lowest MFR tertile was associated with higher cumulative incidence of MACE (adjusted subdistribution hazard ratio 4.91; 95% CI 1.68-14.38; p = 0.004) when compared with the highest MFR tertile. CONCLUSIONS: In patients with breast cancer, coronary vasomotor dysfunction was associated with incident cardiovascular events. MFR may have potential as a risk stratification biomarker among patients with/survivors of breast cancer.

Coronary Microvascular Dysfunction, Left Ventricular Remodeling, and Clinical Outcomes in Patients With Chronic Kidney Impairment.

BACKGROUND: Cardiac dysfunction and cardiovascular events are prevalent among patients with chronic kidney disease without overt obstructive coronary artery disease, but the mechanisms remain poorly understood. Coronary microvascular dysfunction has been proposed as a link between abnormal renal function and impairment of cardiac function and cardiovascular events. We aimed to investigate the relations between chronic kidney disease, coronary microvascular dysfunction, cardiac dysfunction, and adverse cardiovascular outcomes. METHODS: Patients undergoing cardiac stress positron emission tomography, echocardiogram, and renal function ascertainment at Brigham and Women's Hospital were studied longitudinally. Patients free of overt coronary (summed stress score <3 and without a history of ischemic heart disease), valvular, and end-organ disease were followed up for the adverse composite outcome of death or hospitalization for myocardial infarction or heart failure. Coronary flow reserve (CFR) was determined from positron emission tomography. Echocardiograms were used to measure cardiac mechanics: diastolic (lateral and septal E/e') and systolic (global longitudinal, radial, and circumferential strain). Image analyses and event adjudication were blinded. The associations between estimated glomerular filtration rate (eGFR), CFR, diastolic and systolic indices, and adverse cardiovascular outcomes were assessed in adjusted models and mediation analyses. RESULTS: Of the 352 patients (median age, 65 years; 63% female; 22% black) studied, 35% had an eGFR <60 mL·min-1·1.73 m-2, a median left ventricular ejection fraction of 62%, and a median CFR of 1.8. eGFR and CFR were associated with diastolic and systolic indices, as well as future cardiovascular events (all P<0.05). In multivariable models, CFR, but not eGFR, was independently associated with cardiac mechanics and cardiovascular events. The associations between eGFR, cardiac mechanics, and cardiovascular events were partly mediated via CFR. CONCLUSIONS: Coronary microvascular dysfunction, but not eGFR, was independently associated with abnormal cardiac mechanics and an increased risk of cardiovascular events. Coronary microvascular dysfunction may mediate the effect of chronic kidney disease on abnormal cardiac function and cardiovascular events in those without overt coronary artery disease.

Reproducibility and Repeatability of Assessment of Myocardial Light Chain Amyloidosis Burden Using 18F-Florbetapir PET/CT.

BACKGROUND: 18F-florbetapir PET is emerging as an excellent quantitative tool to quantify cardiac light chain (AL) amyloidosis burden. The primary aim of this study was to determine interobserver reproducibility and intraobserver repeatability, defined per the recommendations of the Quantitative Imaging Biomarker Alliance technical performance group, of PET 18F-florbetapir retention index (RI) in patients with cardiac AL amyloidosis. METHODS: The study cohort comprised 37 subjects with systemic AL amyloidosis enrolled in the prospective study: Molecular Imaging of Primary Amyloid Cardiomyopathy (clinical trials.gov NCT: 02641145). Using 10 mCi of 18F-florbetapir, a 60-minute dynamic cardiac scan was acquired. Global and segmental left ventricular estimates of retention index (RI) of 18F-florbetapir were calculated (Carimas 2.9 software, Turku, Finland). RI was analyzed twice, at least 24 hours apart, by two independent observers. Intraobserver repeatability and interobserver reproducibility were evaluated using Bland-Altman plots and scatter plots with fitted linear regression curves. RESULTS: All reproducibility (interobserver, r = 0.98) and repeatability (intraobserver, R=0.99 for each observer) measures of 18F-florbetapir RI are excellent. On the Bland-Altman plots, the agreement limits for global 18F-florbetapir RI were high and ranged for reproducibility (interobserver) from - 9.3 to + 9.4% (Fig. 1), and for repeatability (observer 1 from - 10.8 to + 10.7% and from - 9.2 to + 11.4%, for observer 2). CONCLUSIONS: The present study showed excellent interobserver reproducibility and intraobserver repeatability of 18F-florbetapir PET retention index in patients with cardiac AL amyloidosis.

Coronary vasomotor dysfunction in cancer survivors treated with thoracic irradiation.

BACKGROUND: We sought to test the hypothesis that thoracic radiation therapy (RT) is associated with impaired myocardial flow reserve (MFR), a measure of coronary vasomotor dysfunction. METHODS: We retrospectively studied thirty-five consecutive patients (71% female, mean ± standard deviation (SD) age: 66 ± 11 years) referred clinically for positron emission tomography/computed tomography (PET/CT) myocardial perfusion imaging at a median (interquartile range, IQR) interval of 4.3 (2.1, 9.7) years following RT for a variety of malignancies. Radiation dose-volume histograms were generated for the heart and coronary arteries for each patient. RESULTS: The median (IQR) of mean cardiac radiation doses was 12.0 (1.2, 24.2) Gray. There were significant inverse correlations between mean radiation dose and global MFR (MFRGlobal) and MFR in the left anterior descending artery territory (MFRLAD): Pearson's correlation coefficient = - .37 (P = .03) and - .38 (P = .03), respectively. For every one Gray increase in mean cardiac radiation dose, there was a mean ± standard error decrease of .02 ± .01 in MFRGlobal (P = .04) and MFRLAD (P = .03) after adjustment. CONCLUSIONS: In patients with a history of RT clinically referred for cardiac stress PET, we found an inverse correlation between mean cardiac radiation dose and coronary vasomotor function.

Appropriateness of inpatient stress testing: Implications for development of clinical decision support mechanisms and future criteria.

BACKGROUND: An upcoming national mandate will require consultation of appropriate use criteria (AUC) through a clinical decision support mechanism (CDSM) for advanced imaging. We aimed to evaluate our current ability to ascertain test appropriateness. METHODS: We prospectively collected data on 288 consecutive stress tests and coronary computed tomography angiography studies for medical inpatients. Study appropriateness was determined independently by two physicians using the 2013 Multimodality AUC. RESULTS: The median age of the study population was 66 years [interquartile range (IQR) 56, 75], 40.8% were female, and 52.8% had a history of coronary artery disease. Review of the electronic health record (EHR) alone was sufficient to deem appropriateness for 87.2% of cases. The most common reason it was insufficient was inability to determine if the patient could exercise (59.5%). After reviewing the EHR and pilot CDSM data together, appropriateness could be determined for 95.8% of the cases. The most common reason appropriateness could not be determined was that the exam indication was not addressed by an AUC criterion (83.3%). CONCLUSION: In preparing for the mandate, it will be important for future CDSM to obtain information on the patient's ability to exercise and for future AUC to include additional indications that are not currently addressed.

Feasibility of somatostatin receptor-targeted imaging for detection of myocardial inflammation: A pilot study.

BACKGROUND: Gallium-68 Dotatate binds preferentially to somatostatin receptor (sstr) subtype-2 (sstr-2) on inflammatory cells. We aimed at investigating the potential clinical use of sstr-targeted imaging for the detection of myocardial inflammation. METHODS: Thirteen patients, with suspected cardiac sarcoidosis (CS) based on clinical history and myocardial uptake on recent fluorine-18 fluorodeoxyglucose (FDG) PET, were enrolled to undergo Dotatate PET after FDG-PET (median time 37 days [IQR 25-55]). Additionally, we investigated ex-vivo the immunohistochemistry expression of sstr-2 in 3 explanted sarcoid hearts. RESULTS: All FDG scans showed cardiac uptake (focal/multifocal = 6, focal on diffuse/heterogeneous = 7), and 46% (n = 6) extra-cardiac uptake (mediastinal/hilar). In comparison, Dotatate scans showed definite abnormal cardiac uptake (focal/multifocal) in 4 patients, probably abnormal (heterogenous/patchy) in 3, and negative uptake in 6 cases. Similarly, 6 patients had increased mediastinal/hilar Dotatate uptake. Overall concordance of FDG and Dotatate uptake was 54% in the heart and 100% for thoracic nodal activity. Quantitatively, FDG maximum standardized uptake value was 5.0 times [3.8-7.1] higher in the heart, but only 2.25 times [1.7-3.0; P = .019] higher in thoracic nodes relative to Dotatate. Ex-vivo, sstr-2 immunostaining was weakly seen within well-formed granulomas in all 3 examined sarcoid heart specimens with no significant staining of background myocardium or normal myocardium. CONCLUSION: Our preliminary data suggest that, compared to FDG imaging, somatostatin receptor-targeted imaging may be less sensitive for the detection of myocardial inflammation, but comparable for detecting extra-cardiac inflammation.

Women who experience a myocardial infarction at a young age have worse outcomes compared with men: the Mass General Brigham YOUNG-MI registry.

AIMS: There are sex differences in presentation, treatment, and outcomes of myocardial infarction (MI) but less is known about these differences in a younger patient population. The objective of this study was to investigate sex differences among individuals who experience their first MI at a young age. METHODS AND RESULTS: Consecutive patients presenting to two large academic medical centres with a Type 1 MI at ≤50 years of age between 2000 and 2016 were included. Cause of death was adjudicated using electronic health records and death certificates. In total, 2097 individuals (404 female, 19%) had an MI (mean age 44 ± 5.1 years, 73% white). Risk factor profiles were similar between men and women, although women were more likely to have diabetes (23.7% vs. 18.9%, P = 0.028). Women were less likely to undergo invasive coronary angiography (93.5% vs. 96.7%, P = 0.003) and coronary revascularization (82.1% vs. 92.6%, P < 0.001). Women were significantly more likely to have MI with non-obstructive coronary disease on angiography (10.2% vs. 4.2%, P < 0.001). They were less likely to be discharged with aspirin (92.2% vs. 95.0%, P = 0.027), beta-blockers (86.6% vs. 90.3%, P = 0.033), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (53.4% vs. 63.7%, P < 0.001), and statins (82.4% vs. 88.4%, P < 0.001). There was no significant difference in in-hospital mortality; however, women who survived to hospital discharge experienced a higher all-cause mortality rate (adjusted HR = 1.63, P = 0.01; median follow-up 11.2 years) with no significant difference in cardiovascular mortality (adjusted HR = 1.14, P = 0.61). CONCLUSIONS: Women who experienced their first MI under the age of 50 were less likely to undergo coronary revascularization or be treated with guideline-directed medical therapies. Women who survived hospitalization experienced similar cardiovascular mortality with significantly higher all-cause mortality than men. A better understanding of the mechanisms underlying these differences is warranted.

Hypertensive coronary microvascular dysfunction: a subclinical marker of end organ damage and heart failure.

AIMS: Hypertension is a well-established heart failure (HF) risk factor, especially in the context of adverse left ventricular (LV) remodelling. We aimed to use myocardial flow reserve (MFR) and global longitudinal strain (GLS), markers of subclinical microvascular and myocardial dysfunction, to refine hypertensive HF risk assessment. METHODS AND RESULTS: Consecutive patients undergoing symptom-prompted stress cardiac positron emission tomography (PET)-computed tomography and transthoracic echocardiogram within 90 days without reduced left ventricular ejection fraction (<40%) or flow-limiting coronary artery disease (summed stress score ≥ 3) were included. Global MFR was quantified by PET, and echocardiograms were retrospectively analysed for cardiac structure and function. Patients were followed over a median 8.75 (Q1-3 4.56-10.04) years for HF hospitalization and a composite of death, HF hospitalization, MI, or stroke. Of 194 patients, 155 had adaptive LV remodelling while 39 had maladaptive remodelling, which was associated with lower MFR and impaired GLS. Across the remodelling spectrum, diastolic parameters, GLS, and N-terminal pro-B-type natriuretic peptide were independently associated with MFR. Maladaptive LV remodelling was associated with increased adjusted incidence of HF hospitalization and death. Importantly, the combination of abnormal MFR and GLS was associated with a higher rate of HF hospitalization compared to normal MFR and GLS [adjusted hazard ratio (HR) 3.21, 95% confidence interval (CI) 1.09-9.45, P = 0.034), including in the adaptive remodelling subset (adjusted HR 3.93, 95% CI 1.14-13.56, P = 0.030). CONCLUSION: We have demonstrated important associations between coronary microvascular dysfunction and myocardial mechanics that refine disease characterization and HF risk assessment of patients with hypertension based on subclinical target organ injury.

Long-Term Sex- and Genotype-Specific Effects of 56Fe Irradiation on Wild-Type and APPswe/PS1dE9 Transgenic Mice.

Space radiation presents a substantial threat to travel beyond Earth. Relatively low doses of high-energy particle radiation cause physiological and behavioral impairments in rodents and may pose risks to human spaceflight. There is evidence that 56Fe irradiation, a significant component of space radiation, may be more harmful to males than to females and worsen Alzheimer's disease pathology in genetically vulnerable models. Yet, research on the long-term, sex- and genotype-specific effects of 56Fe irradiation is lacking. Here, we irradiated 4-month-old male and female, wild-type and Alzheimer's-like APP/PS1 mice with 0, 0.10, or 0.50 Gy of 56Fe ions (1GeV/u). Mice underwent microPET scans before and 7.5 months after irradiation, a battery of behavioral tests at 11 months of age and were sacrificed for pathological and biochemical analyses at 12 months of age. 56Fe irradiation worsened amyloid-beta (Aß) pathology, gliosis, neuroinflammation and spatial memory, but improved motor coordination, in male transgenic mice and worsened fear memory in wild-type males. Although sham-irradiated female APP/PS1 mice had more cerebral Aß and gliosis than sham-irradiated male transgenics, female mice of both genotypes were relatively spared from radiation effects 8 months later. These results provide evidence for sex-specific, long-term CNS effects of space radiation.

Ischemia and No Obstructive Stenosis (INOCA) at CT Angiography, CT Myocardial Perfusion, Invasive Coronary Angiography, and SPECT: The CORE320 Study.

Background CT allows evaluation of atherosclerosis, coronary stenosis, and myocardial ischemia. Data on the characterization of ischemia and no obstructive stenosis (INOCA) at CT remain limited. Purpose This was an observational study to describe the prevalence of INOCA defined at coronary CT angiography with CT perfusion imaging and associated clinical and atherosclerotic characteristics. The analysis was also performed for the combination of invasive coronary angiography (ICA) and SPECT as a secondary aim. Materials and Methods The prospective CORE320 study (ClinicalTrials.gov: NCT00934037) enrolled participants between November 2009 and July 2011 who were symptomatic and referred for clinically indicated ICA. Participants underwent CT angiography, rest-adenosine stress CT perfusion, and rest-stress SPECT prior to ICA. For this ancillary study, the following three phenotypes were considered, using either CT angiography/CT perfusion or ICA/SPECT data: (a) participants with obstructive (≥50%) stenosis, (b) participants with no obstructive stenosis but ischemia (ie, INOCA) on the basis of abnormal perfusion imaging results, and (c) participants with no obstructive stenosis and normal perfusion imaging results. Clinical characteristics and CT angiography atherosclerotic plaque measures were compared by using the Pearson χ2 or Wilcoxon rank-sum test. Results A total of 381 participants (mean age, 62 years [interquartile range, 56-68 years]; 129 [34%] women) were evaluated. A total of 31 (27%) of 115 participants without obstructive (≥50%) stenosis at CT angiography had abnormal CT perfusion findings. The corresponding value for ICA/SPECT was 45 (30%) of 151. The prevalence of INOCA was 31 (8%) of 381 (95% confidence interval [CI]: 5%, 11%) with CT angiography/CT perfusion and 45 (12%) of 381 (95% CI: 9%, 15%) with ICA/SPECT. Participants with CT-defined INOCA had greater total atheroma volume (118 vs 60 mm3, P = .008), more positive remodeling (13% vs 1%, P = .006), and greater low-attenuation atheroma volume (20 vs 10 mm3, P = .007) than participants with no obstructive stenosis and no ischemia. Comparisons for ICA/SPECT showed similar trends. Conclusion In CORE320, ischemia and no obstructive stenosis (INOCA) prevalence was 8% and 12% at CT angiography/CT perfusion and invasive coronary angiography/SPECT, respectively. Participants with INOCA had greater atherosclerotic burden and more adverse plaque features at CT compared with those with no obstructive stenosis and no ischemia. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by François in this issue.

Quantitative [18F]florbetapir PET/CT may identify lung involvement in patients with systemic AL amyloidosis.

PURPOSE: The clinical diagnosis of pulmonary involvement in individuals with systemic AL amyloidosis remains challenging. [18F]florbetapir imaging has previously identified AL amyloid deposits in the heart and extra-cardiac organs. The aim of this study is to determine quantitative [18F]florbetapir pulmonary kinetics to identify pulmonary involvement in individuals with systemic AL amyloidosis. METHODS: We prospectively enrolled 58 subjects with biopsy-proven AL amyloidosis and 9 control subjects (5 without amyloidosis and 4 with ATTR cardiac amyloidosis). Pulmonary [18F]florbetapir uptake was evaluated visually and quantified as distribution volume of specific binding (Vs) derived from compartmental analysis and simpler semiquantitative metrics of maximum standardized uptake values (SUVmax), retention index (RI), and target-to-blood ratio (TBR). RESULTS: On visual analysis, pulmonary tracer uptake was absent in most AL subjects (40/58, 69%); 12% (7/58) of AL subjects demonstrated intense bilateral homogeneous tracer uptake. In this group, compared to the control group, Vs (median Vs 30-fold higher, 9.79 vs. 0.26, p < 0.001), TBR (median TBR 12.0 vs. 1.71, p < 0.001), and RI (median RI 0.310 vs. 0.033, p < 0.001) were substantially higher. Notably, the AL group without visually apparent pulmonary [18F]florbetapir uptake also demonstrated a > 3-fold higher Vs compared to the control group (median 0.99 vs. 0.26, p < 0.001). Vs was independently related to left ventricular SUVmax, a marker of cardiac AL deposition, but not to ejection fraction, a marker of cardiac dysfunction. Also, intense [18F]florbetapir lung uptake was not related to [11C]acetate lung uptake, suggesting that intense [18F]florbetapir lung uptake represents AL amyloidosis rather than heart failure. CONCLUSIONS: [18F]florbetapir PET/CT offers the potential to noninvasively identify pulmonary AL amyloidosis, and its clinical relevance warrants further study.

SPECT Versus PET Myocardial Perfusion Imaging in Patients with Equivocal CT.

PURPOSE OF REVIEW: The most pertinent clinical question in post-coronary computed tomography angiography (CCTA) patients is the assessment of the physiological significance of an anatomically identified stenosis. The clinical application of radionuclide MPI using single-photon emission computed tomography (SPECT) versus positron emission tomography (PET) in the evaluation and management of patients with an inconclusive CCTA is reviewed using a case-based approach. RECENT FINDINGS: Recent evidence suggests that CCTA is the most sensitive non-invasive test to exclude angiographic CAD and may be an effective first-line test especially among symptomatic low-intermediate risk patients. However, in the presence of angiographic atherosclerosis, its specificity and positive predictive value for identifying flow-limiting stenosis are modest. Radionuclide myocardial perfusion imaging offers accurate quantitative assessment of myocardial ischemia, which helps with risk stratification and patient management especially the potential need for revascularization. Routine accurate quantifications of myocardial blood flow and flow reserve are major advantages of PET MPI, which are especially useful when used in patients at intermediate-high clinical risk.