OBJECTIVE:To evaluate the incremental prognostic value of a blunted heart rate response (HRR) to regadenoson beyond PET-derived myocardial flow parameters. BACKGROUND:A blunted HRR during pharmacologic stress with regadenoson, an adenosine A2A receptor agonist, may reflect autonomic dysfunction and heightened cardiovascular (CV) risk. Whether HRR provides prognostic information beyond stress myocardial blood flow (sMBF) and myocardial flow reserve (MFR) remains uncertain. METHODS:We retrospectively analyzed consecutive rest-stress 82Rb PET/CT studies performed between 2016 and 2022. Abnormal sMBF and MFR were defined as less than 1.8 mL/min/g and <2.0, respectively. HRR was calculated as (peak HR - rest HR)/rest HR and considered blunted if less than 20%. We compared differences in major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, or heart failure hospitalization) between patients with blunted and normal HRR using multivariable Cox regression, stratified by sMBF and MFR. Nonlinear associations between HRR and MACE were evaluated using restricted cubic splines. Incremental prognostic value was assessed by changes in the area under the receiver-operating characteristic curve (AUC) and net reclassification index (NRI). RESULTS:Among 4611 patients (63 ± 11 years; 54% female), 1263 (27%) had blunted HRR. These patients had a higher prevalence of abnormal sMBF (49% vs 27%) and MFR (66% vs 30%). Over a median follow-up of 3.3 years (IQR 1.8-5.1), MACE rates were higher among patients with blunted HRR (16.2 vs 5.5 events/100 patient-years; adjusted HR 1.70 [95% CI: 1.50-1.94]; P < .001), irrespective of sMBF or MFR status. Risk increased progressively with lower HRR. Adding HRR to a model with key clinical characteristics and MBF improved prognostic discrimination and reclassification (ΔAUC +0.017; NRI 0.12; all P < .001). CONCLUSIONS:Blunted HRR to regadenoson is independently associated with higher CV risk and provides incremental prognostic value beyond PET myocardial flow.

BACKGROUND:Limited prospective data exist on the utility of serial cardiovascular magnetic resonance (CMR) imaging in immune checkpoint inhibitor (ICI) myocarditis. OBJECTIVES:To evaluate serial changes in CMR parameters and outcomes in patients with ICI myocarditis. METHODS:Patients were enrolled into two arms as follows: 1) ICI myocarditis (ICI exposure with development of cardiac symptoms and abnormal cardiac biomarkers) or 2) pre-ICI control (patients planned to receive ICI therapy). Both cohorts received CMR imaging at the time of enrollment and upon follow-up at 8-12 weeks. CMR parameters were associated with adverse cardiovascular events (ACE). RESULTS:Sixty-two patients were enrolled (N=52 in ICI myocarditis cohort; N=10 in pre-ICI control cohort). In those with ICI myocarditis, upon presentation, 38% of patients had a reduced LVEF (defined as < 57%) with a mean LVEF of 58% (SD ±12). LV global longitudinal strain (GLS) by feature tracking (FT) CMR was abnormal in 81% of patients (defined as > -18%) with a mean GLS -10% (SD ± 5). Eighty-five percent met at least one Lake Louise Criteria (LLC). Decreased LVEF at enrollment was associated with ACE (r= -0.437, p=0.002), as was increased CMR FT GLS and global circumferential strain (r=0.387, p=0.008 and r=0.439, p=0.002, respectively). Worse left atrial (LA) ejection fraction by CMR correlated with arrhythmia (r= -0.467, p=0.051), and presence of LA LGE correlated with heart failure (r=0.866, p=0.012). Abnormal LA strain parameters, including contraction strain (r=0.611, p=0.007) and reservoir strain (r=0.543, p=0.005) on follow-up, CMR were associated with death in those with ICI myocarditis. CONCLUSIONS:Baseline and serial CMR parameters are associated with incident ACE. Serial CMR evaluation may further risk-stratify ICI myocarditis patients.

OBJECTIVE:To investigate the long-term prognosis of coronary microvascular dysfunction (CMD) in emergency department (ED) patients with chest pain for major adverse cardiac events (MACE) due to all-cause mortality, myocardial infarction (MI), heart failure (HF), or stroke. METHODS:A prospective cohort of ED patients evaluated by hybrid cardiac positron emission tomography with attenuation computed tomography within 24 h of arrival. Patients were classified as: (1) Controls - coronary flow reserve (CFR) ≥2 without perfusion defect or coronary calcification; (2) CMD: CFR <2 without defect or calcification; or (3) CAD/CALC - established or new coronary artery disease (CAD) or calcification (CALC). We conducted annual follow-ups for MACE and all-cause healthcare utilization (hospitalizations and ED visits). We adjusted incidence rates (aIR) and hazard ratio (aHR) for demographics, comorbidities, and medications. RESULTS:Between 2014 and 2020, 189 patients were enrolled: 95 (50 %) Controls, 34 (18 %) with CMD, and 60 (32 %) with CAD/CALC. Median follow-up time was 50 months (38-92), and a total of 187 unique MACE were recorded in 44 patients. CMD patients had 4× higher MACE risk than controls (aIR 3.8; 95 % CI: 2.1-6.6). CAD/CALC patients had similarly higher risk than controls (aIR: 4.5; 95 % CI: 2.6-7.8). CMD patients had 4× higher risk for time to first MACE than controls (aHR: 3.6; 95 % CI: 1.2-10.7) and higher healthcare utilization per 100 person-months (aIR: 124; 95 % CI: 119-130). Using Seattle Angina Questionnaire, CMD patients showed worse angina frequency than controls (difference: -16.4, 95 % CI: -29.5 to -3.4). CONCLUSIONS:Patients with contemporary phenotypes of ischemia (CMD and CAD/CALC) had higher adverse events than controls, positing ED encounters as an opportunity for early identification and treatment.

We previously demonstrated that a deep learning (DL) model of myocardial perfusion SPECT imaging improved accuracy for detection of obstructive coronary artery disease (CAD). We aimed to improve the clinical translatability of this artificial intelligence (AI) approach using the results to derive enhanced total perfusion deficit (TPD) and 17-segment summed scores. Methods: We used a cohort of patients undergoing myocardial perfusion imaging within 180 d of invasive coronary angiography. Obstructive CAD was defined as any stenosis of at least 70% or at least 50% in the left main coronary artery. We used per-vessel DL predictions to modulate polar map pixel scores. These transformed polar maps were then used to derive TPD-DL and summed stress score-DL. We compared diagnostic performance using area under the receiver operating characteristic curve (AUC). Results: In the 555 patients held out for testing, the median age was 65 y (interquartile range, 57-73 y), and 381 (69%) were male. Obstructive CAD was present in 329 (59%) patients. The prediction performance for obstructive CAD of stress TPD-DL (AUC, 0.837; 95% CI, 0.804-0.870) was higher than AI prediction alone (AUC, 0.795; 95% CI, 0.758-0.831; P = 0.005) and traditional stress TPD (AUC, 0.737; 95% CI, 0.696-0.778; P < 0.001). Summed stress score-DL had the second highest prediction performance (AUC, 0.822; 95% CI, 0.788-0.857) and higher AUC than traditional quantitative summed stress score (AUC, 0.728; 95% CI, 0.686-0.769; P < 0.001). At a threshold of 5%, the sensitivity and specificity of TPD rose from 72% to 79% and from 62% to 70%, respectively. Conclusion: Integrating AI predictions with traditional quantitative approaches leads to a simplified AI approach, presenting clinicians with familiar measures but operating with higher accuracy than traditional quantitative scoring. This approach may facilitate integration of new AI methods into clinical practice.

Myocardial perfusion imaging (MPI) is frequently used to improve cardiac risk prediction in patients undergoing non-cardiac surgery. However, the data supporting this practice is derived from single center studies and predates current therapy for coronary artery disease (CAD). We evaluated the association between pre-operative testing indication and outcomes as well as predictors of death or myocardial infarction (MI) in these patients. We include patients from the international, multicenter REFINE-SPECT registry (13 sites). Based on referral indication, patients were classified as pre-operative testing indications and non-pre-operative testing. We evaluated the associations between pre-operative testing and incidence of death or MI. We then evaluated associations with death or MI in patients referred for pre-operative testing compared to other patients. In total, 32,711 patients were included with pre-operative testing as the indication in 2,173(6.6

This review summarizes the role of the novel 18F-labeled positron emission tomography (PET) sympathetic radiotracers for risk stratification in patients with ischemic heart disease. PET tracers have demonstrated prognostic value by characterizing myocardial sympathetic nerve density and by extension the extent of myocardial sympathetic denervation. The unique features of these PET radiotracers are discussed in relation to clinical application. Absolute quantification of sympathetic denervation has been possible with 18F-labeled PET tracers which outperform low ejection fraction (<35

With an increasing number of elderly individuals, the demand for advanced technologies to treat cardiac diseases has become more critical than ever. Additionally, there is a pressing need to reduce the learning curve for cardiac interventionalists to keep pace with the rapid development of new types of procedures and devices and to expand the adoption of established procedures in more hospitals. This comprehensive review aims to shed light on recent advancements in novel robotic systems for cardiac interventions. To do so, this review provides a brief overview of the history of previously developed robotic systems and describes the necessity for advanced technologies for cardiac interventions to address the technological limitations of current systems. Moreover, this review explores the potential of cutting-edge technologies and methods in developing the next generation of intra-procedure autonomous navigation. Each highlighted topic undergoes a critical analysis to evaluate its technical limitations and the challenges that must be addressed for successful clinical implementation.

Background: Observational data have suggested that patients with moderate to severe ischemia benefit from revascularization. However, this was not confirmed in a large, randomized trial. Objectives: Using a contemporary, multicenter registry, the authors evaluated differences in the association between quantitative ischemia, revascularization, and outcomes across important subgroups. Methods: Patients who underwent myocardial perfusion imaging in 12 centers were included in this retrospective analysis. The population was divided into original (2009-2014) and recent (2014-2021) registry sites. Early revascularization was defined as any revascularization within 90 days of myocardial perfusion imaging. A propensity score was developed to adjust for nonrandomization. Propensity score-adjusted survival analyses were used to evaluate the associations between quantitative ischemia, early revascularization, and death or myocardial infarction (MI) to identify at what severity of ischemia the HR for early revascularization crosses 1 (threshold for potential benefit). Results: Overall, 40,449 patients were included with a median follow-up of 3.5 (IQR: 2.4-4.6) years, during which death or MI occurred in 2,797 (6.9%). Early revascularization was associated with reduced death or MI in patients with >9.0% myocardial ischemia (95% upper CI: 11.2%, interaction P < 0.001). The threshold for ischemia, above which patients may benefit from revascularization, was higher in more recent patients (14.0% vs 6.5%), but similar in female (>10.0%) and male patients (>8.6%). Conclusions: Early revascularization was associated with reduced risk in patients with a higher burden of quantitative ischemia in more recent populations. These findings suggest that methods integrating more factors than just ischemia are needed to improve patient selection for revascularization.

Cardiac image segmentation is an important step in many cardiac image analysis and modeling tasks such as motion tracking or simulations of cardiac mechanics. While deep learning has greatly advanced segmentation in clinical settings, there is limited work on pre-clinical imaging, notably in porcine models, which are often used due to their anatomical and physiological similarity to humans. However, differences between species create a domain shift that complicates direct model transfer from human to pig data. Recently, foundation models trained on large human datasets have shown promise for robust medical image segmentation; yet their applicability to porcine data remains largely unexplored. In this work, we investigate whether foundation models can generate sufficiently accurate pseudo-labels for pig cardiac CT and propose a simple self-training approach to iteratively refine these labels. Our method requires no manually annotated pig data, relying instead on iterative updates to improve segmentation quality. We demonstrate that this self-training process not only enhances segmentation accuracy but also smooths out temporal inconsistencies across consecutive frames. Although our results are encouraging, there remains room for improvement, for example by incorporating more sophisticated self-training strategies and by exploring additional foundation models and other cardiac imaging technologies.

With FDA-approved devices, left atrial appendage (LAA) occlusion has emerged as a well-established and rapidly growing approach to stroke prevention in patients with non-valvular atrial fibrillation. These devices are indicated for use in patients who are at increased risk of stroke and systemic embolism, as determined by CHA2DS2-VASc scores, and are suitable for anticoagulation therapy, with an appropriate rationale for seeking a non-pharmacologic alternative. This includes patients who may be unsuitable for long-term anticoagulation due to contra-indications. These devices, generally consisting of a nitinol-framed structure with a circular cross-section, are positioned within the LAA to obstruct the ostium, effectively preventing the thrombus from embolizing the brain. The initial clinical data from pivotal trials and observational registries indicated no strong correlation between peri-device leaks (PDLs) and adverse events. However, recent studies have shown that PDLs are associated with a higher risk of thrombo-embolic events, leading to renewed interest in managing PDLs. This paper reviews the occurrence of PDLs after percutaneous LAA occlusion using current FDA-approved devices, highlighting the need for non-circular occluders to better-accommodate the inherent variability in LAA anatomy. It also compares the benefits and limitations of emerging approaches still under investigation, focusing on addressing PDLs.

While the volume of epicardial adipose tissue (EAT) has been linked to various conditions and showed a prognostic value of cardiovascular events, an insufficient effort was put into proposing clear, race- and sex-specific thresholds of high-risk and low-risk EAT amounts. Also, previous works focused on the absolute volume of EAT in milliliters, adjusted to the body size of the patients, and none has proposed a relative measure of what is the amount of EAT for a given patient also in reference to the size of the patient's heart. In this retrospective study, computed tomography attenuation correction (CTAC) scans from 20,587 patients (58% male; 84% White, 13% Black, 3% Asian) from 6 sites were used. With the previously described deep learning (DL)-based method, EAT values per patient were calculated, and subsequently normalized using either the DL-obtained cardiac volume mask, body size, or both. The association between the percent of EAT in reference to the heart size and incident mortality or nonfatal myocardial infarction (MI) was evaluated with Cox models adjusted for age, sex, body mass index, race, cigarette smoking status, hypertension, diabetes, family history of coronary artery disease, dyslipidemia, and left ventricle size. In total, 4,133 events were observed over a period of 6-year follow-up. Our analysis showed that when the amount of EAT was normalized jointly for body surface area and heart size, the predictive effect of EAT was diminished (p=0.85). Patients with higher EAT density, however, were more likely to experience death or MI during follow-up (p<0.001). These results were also confirmed in an analysis with race- and sex-specific thresholds. Additionally, per-race analysis showed that the density was predictive only for White patients (both when using global, as well as race- and sex-specific thresholds). To conclude, we showed that the previously observed effect of the EAT indexed for body size predicting cardiovascular risk was associated with patients' cardiac sizes. Nevertheless, in our analysis EAT density was still associated with a 6-year risk of death or nonfatal myocardial infarction, and this effect was significant only for a single race.

BACKGROUND:CT attenuation correction (CTAC) scans are routinely obtained during cardiac perfusion imaging, but currently only used for attenuation correction and visual calcium estimation. We aimed to develop a novel artificial intelligence (AI)-based approach to obtain volumetric measurements of chest body composition from CTAC scans and to evaluate these measures for all-cause mortality risk stratification. METHODS:We applied AI-based segmentation and image-processing techniques on CTAC scans from a large international image-based registry at four sites (Yale University, University of Calgary, Columbia University, and University of Ottawa), to define the chest rib cage and multiple tissues. Volumetric measures of bone, skeletal muscle, subcutaneous adipose tissue, intramuscular adipose tissue (IMAT), visceral adipose tissue (VAT), and epicardial adipose tissue (EAT) were quantified between automatically identified T5 and T11 vertebrae. The independent prognostic value of volumetric attenuation and indexed volumes were evaluated for predicting all-cause mortality, adjusting for established risk factors and 18 other body composition measures via Cox regression models and Kaplan-Meier curves. FINDINGS:The end-to-end processing time was less than 2 min per scan with no user interaction. Between 2009 and 2021, we included 11 305 participants from four sites participating in the REFINE SPECT registry, who underwent single-photon emission computed tomography cardiac scans. After excluding patients who had incomplete T5-T11 scan coverage, missing clinical data, or who had been used for EAT model training, the final study group comprised 9918 patients. 5451 (55%) of 9918 participants were male and 4467 (45%) of 9918 participants were female. Median follow-up time was 2·48 years (IQR 1·46-3·65), during which 610 (6%) patients died. High VAT, EAT, and IMAT attenuation were associated with an increased all-cause mortality risk (adjusted hazard ratio 2·39, 95% CI 1·92-2·96; p<0·0001, 1·55, 1·26-1·90; p<0·0001, and 1·30, 1·06-1·60; p=0·012, respectively). Patients with high bone attenuation were at reduced risk of death (0·77, 0·62-0·95; p=0·016). Likewise, high skeletal muscle volume index was associated with a reduced risk of death (0·56, 0·44-0·71; p<0·0001). INTERPRETATION:CTAC scans obtained routinely during cardiac perfusion imaging contain important volumetric body composition biomarkers that can be automatically measured and offer important additional prognostic value. FUNDING:The National Heart, Lung, and Blood Institute, National Institutes of Health.

Myocardial perfusion imaging using SPECT is widely utilized to diagnose coronary artery diseases, but image quality can be negatively affected in low-dose and few-view acquisition settings. Although various deep learning methods have been introduced to improve image quality from low-dose or few-view SPECT data, previous approaches often fail to generalize across different acquisition settings, limiting realistic applicability. This work introduced DiffSPECT-3D, a diffusion framework for 3D cardiac SPECT imaging that effectively adapts to different acquisition settings without requiring further network re-training or fine-tuning. Using both image and projection data, a consistency strategy is proposed to ensure that diffusion sampling at each step aligns with the low-dose/few-view projection measurements, the image data, and the scanner geometry, thus enabling generalization to different low-dose/few-view settings. Incorporating anatomical spatial information from CT and total variation constraint, we proposed a 2.5D conditional strategy to allow DiffSPECT-3D to observe 3D contextual information from the entire image volume, addressing the 3D memory/computational issues in diffusion model. We extensively evaluated the proposed method on 1,325 clinical 99mTc tetrofosmin stress/rest studies from 795 patients. Each study was reconstructed into 5 different low-count levels and 5 different projection few-view levels for model evaluations, ranging from 1% to 50% and from 1 view to 9 view, respectively. Validated against cardiac catheterization results and diagnostic review from nuclear cardiologists, the presented results show the potential to achieve low-dose and few-view SPECT imaging without compromising clinical performance. Additionally, DiffSPECT-3D could be directly applied to full-dose SPECT images to further improve image quality, especially in a low-dose stress-first cardiac SPECT imaging protocol.

Background: Peripheral artery disease (PAD) portends significant morbidity (immobility, limb amputation, life-threatening infections, etc) and an up to 10-fold greater mortality, yet remains a largely ill-defined and poorly characterized disease. Lower extremity ischemia in PAD patients may lead to heightened sympathetic activity, stress, which may be imageable with novel high-resolution sympathetic radiotracers like 18 F-labeled fluorobenguanane ( 18 F-FBBG), a norepinephrine analogue. The ability to image ischemic stress may have diagnostic/prognostic implications for PAD patients. Methods/Approach: Sympathetic activity was evaluated in calf muscles in a rabbit model of hindlimb ischemia using 18 F-FBBG. New Zealand rabbits (n=6) underwent 2D angiography, contrast CT angiography, and 18 F-FBBG PET/CT 50-60 minutes post-injection on a high-resolution PET scanner (NX, United Imaging) with 18 F-FBBG PET uptake expressed as mean SUVs ( Figures 1 and 2 ). The animals were then euthanized at 5, 14, or 28 days post right femoral artery ligation. Calf muscles were then gamma well-counted for 18 F-FBBG activity ( Table 1 ). 18 F-FBBG uptake in ischemic (I) and non-ischemic (NI) muscles was related to relative percentage of type I or slow twitch oxidative fibers. Results: In the calf the ischemic soleus (a muscle with up to 90% type I fiber content compared to all other calf muscles being ≤20%) demonstrated significant uptake of 18 F-FBBG (I/NI median: 1.089, IQR: 0.137, p =0.031) an observation which trended with 18 F-FBBG uptake on PET-imaging (R=0.98, p =0.003, Table 1 and Figures 1 and 2 ). Further, 18 F-FBBG uptake trended with type I fiber content especially in the most acute, 5 day, timepoint in the calf (R=-0.62, p =0.022) with the greatest average I/NI uptake of all calf muscles, excluding the outlier, being the 5-day soleus. Conclusions: The most oxygen-dependent muscle, the soleus, demonstrates a significant and imageable uptake of the novel sympathetic tracer 18 F-FBBG under acute and chronic ischemic conditions ( Table 1, Figures 1 and 2 ). This suggests, that the ischemic stress response of skeletal muscle may relate to extent of type I fiber content and potentially the reliance on oxygen during acute ischemia, although less evident at chronic timepoints.

Background: Reactive oxygen species (ROS) plays a major role in the pathogenesis of myocardial ischemia-reperfusion injury (IRI). However, molecular imaging probes enabling the in vivo detection of ROS are limited. Aim: To evaluate and validate the myocardial uptake of a novel 67 Ga-labeled SPECT tracer, 67 Ga-Galuminox, for the in vivo quantitative assessment of myocardial IRI in relation to myocardial perfusion. Methods: Three anesthetized Yorkshire pigs were subjected to myocardial IRI by 90 min balloon occlusion in the left anterior descending artery and reperfusion. In vivo SPECT/CT images of the heart were acquired on the day of injury or 3 days post injury with hybrid 360° CZT SPECT 64-slice CT (Veriton-CT 400, Spectrum Dynamics) with 67 Ga-Galuminox (93 keV) in evaluation of ROS and 99m Tc-Tetrofosmin (140.5 keV) to define myocardial perfusion. Quantitative segmental image analysis was performed and compared with tissue gamma well counting for the corresponding epicardial (EP) and endocardial (EN) segments. Results: Myocardial uptake of 67 Ga-Galuminox was increased in the area at risk as defined by 99m Tc-Tetrofosmin (Figure 1). 67 Ga-Galuminox uptake assessed by in vivo SPECT correlated positively with the tissue well counting in corresponding EP (r=0.57, p<0.005) and EN (r=0.43, p=0.002) segments. Uptake of 67 Ga-Galuminox was significantly higher in the infarcted segments compared to remote area by both in vivo SPECT and gamma well counting. Regional myocardial 99m Tc-Tetrofosmin and 67 Ga-Galuminox uptake were negatively correlated in EP (r=-0.78, p<0.001) and EN (r=-0.8, p<0.001). Conclusions: Myocardial 67 Ga-Galuminox SPECT/CT imaging provides excellent image quality, enabling accurate non-invasive quantification of EN and EP activation of ROS in our porcine model of myocardial IRI.

BACKGROUND:Coronary artery disease (CAD) and peripheral artery disease (PAD) are often regarded as analogous risk factors for major adverse cardiovascular events (MACE), given their shared pathophysiology. We aimed to investigate whether the elevated MACE risk in PAD is driven by myocardial perfusion abnormalities or through other PAD-specific mediators. METHODS:We analyzed 45,252 patients from an international, multicentre registry who underwent SPECT myocardial perfusion imaging, excluding those with early coronary revascularization (< 90 days). Myocardial perfusion abnormalities were quantified using total perfusion deficit (TPD). MACE was defined as all-cause mortality, unstable angina admission, myocardial infarction, or late coronary revascularization. PAD was defined using questionnaires or review of electronic medical records. Propensity-score matching was used to select balanced groups of patients with and without PAD. RESULTS:During a median follow-up of 3.6 years (interquartile range [IQR]: 2.6-4.8 years), 5932 patients (13.7%) experienced at least 1 MACE. Compared with patients with neither disease, isolated history of CAD (adjusted hazard ratio [aHR], 1.92; 95% confidence interval [CI], 1.80-2.05) conferred a similar MACE risk as concomitant history of CAD and PAD (aHR, 1.57; 95% CI, 1.44-1.71) and greater risk than isolated history of PAD (aHR, 1.20; 95% CI, 1.09-1.32; P < 0.001). After propensity-score matching, history of PAD alone was not independently associated with increased MACE risk (P = 0.064). CONCLUSIONS:Although patients with PAD often have concomitant CAD and greater myocardial perfusion abnormalities, PAD itself was not linked to higher risk of MACE after adjusting for these factors. These findings highlight the importance of assessing myocardial ischemic burden in PAD for risk stratification and prompt initiation of disease-modifying therapies.