Perfusion Deficits Research Articles

Targeting post-stroke neuroinflammation with Salvianolic acid A: molecular mechanisms and preclinical evidence.

Salvianolic acid A (SalA), a bioactive compound extracted from Salvia miltiorrhiza, has garnered considerable interest for its potential in ameliorating the post-stroke neuroinflammation. This review delineates the possible molecular underpinnings of anti-inflammatory and neuroprotective roles of SalA, offering a comprehensive analysis of its therapeutic efficacy in preclinical studies of ischemic stroke. We explore the intricate interplay between post-stroke neuroinflammation and the modulatory effects of SalA on pro-inflammatory cytokines, inflammatory signaling pathways, the peripheral immune cell infiltration through blood-brain barrier disruption, and endothelial cell function. The pharmacokinetic profiles of SalA in the context of stroke, characterized by enhanced cerebral penetration post-ischemia, makes it particularly suitable as a therapeutic agent. Preliminary clinical findings have demonstrated that salvianolic acids (SA) has a positive impact on cerebral perfusion and neurological deficits in stroke patients, warranting further investigation. This review emphasizes SalA as a potential anti-inflammatory agent for the advancement of innovative therapeutic approaches in the treatment of ischemic stroke.

Compromised Cerebral Arterial Perfusion, Altered Brain Tissue Integrity, and Cognitive Impairment in Adolescents with Complex Congenital Heart Disease.

(1) Introduction: Adolescents with complex congenital heart disease (CCHD) show brain tissue injuries in regions associated with cognitive deficits. Alteration in cerebral arterial perfusion (CAP), as measured by arterial transit time (ATT), may lead to perfusion deficits and potential injury. Our study aims to compare ATT values between CCHD patients and controls and assess the associations between ATT values, MD values, and cognitive scores in adolescents with CCHD. (2) Methods: 37 CCHD subjects, 14-18 years of age, who had undergone surgical palliation and 30 healthy controls completed cognitive testing and brain MRI assessments using a 3.0-Tesla scanner. ATT values and regional brain mean diffusivity [MD] were assessed for the whole brain using diffusion tensor imaging. (3) Results: The mean MoCA values [23.1 ± 4.1 vs. 28.1 ± 2.3; p < 0.001] and General Memory Index, with a subscore of WRAML2 [86.8 ± 15.4 vs. 110.3 ± 14.5; p < 0.001], showed significant cognitive deficits in CCHD patients compared to controls. The mean global ATT was significantly higher in CCHD patients versus controls (mean ± SD, s, 1.26 ± 0.11 vs. 1.19 ± 0.11, p = 0.03), respectively. The partial correlations between ATT values, MD values, and cognitive scores (p < 0.005) showed significant associations in areas including the hippocampus, prefrontal cortices, cerebellum, caudate, anterior and mid cingulate, insula, thalamus, and lingual gyrus. (4) Conclusions: Adolescents with CCHD had prolonged ATTs and showed correlation with clinical measurements of cognitive impairment and MRI measurements of brain tissue integrity. This suggests that altered CAP may play a role in brain tissue injury and cognitive impairment after surgical palliation.

External Validation of a Model for Persistent Perfusion Deficit in Patients With Incomplete Reperfusion After Thrombectomy: EXTEND-PROCEED.

We recently developed a model (PROCEED) that predicts the occurrence of persistent perfusion deficit (PPD) at 24 hours in patients with incomplete angiographic reperfusion after thrombectomy. This study aims to externally validate the PROCEED model using prospectively acquired multicenter data. Individual patient data for external validation were obtained from the Endovascular Therapy for Ischemic Stroke with Perfusion-Imaging Selection, Tenecteplase versus Alteplase Before Endovascular Therapy for Ischemic Stroke part 1 and 2 trials, and a prospective cohort of the Medical University of Graz. The model's primary outcome was the occurrence of PPD, defined as a focal, wedge-shaped perfusion delay on 24-hour follow-up perfusion imaging that corresponds to the capillary phase deficit on last angiographic series in patients with <Thrombolysis in Cerebral Infarction 3 reperfusion after thrombectomy. The model's performance was evaluated with discrimination, calibration accuracy, and clinical decision curves. We included 371 patients (38% with PPD). The externally validated model had good discrimination (C-statistic 0.81, 95% CI 0.77-0.86) and adequate calibration (intercept 0.25, 95% CI 0.21-0.29 and slope 0.98, 95% CI 0.90-1.12). Across a wide range of probability thresholds (i.e., depending on the physicians' preferences on how the model should be used), the model shows net benefit on clinical decision curves, informing physicians on the likelihood of PPD. If a physician's attitude toward false-positive and false-negative ratings is equal, the model would reduce 13 in 100 unnecessary interventions by correctly predicting complete delayed reperfusion, without missing a patient with PPD. The externally validated model had adequate predictive accuracy and discrimination. Depending on the acceptable threshold probability, the model accurately predicts persistent incomplete reperfusion and may advise physicians whether additional reperfusion attempts should be performed.

Comparative effectiveness of positron emission tomography and single-photon emission computed tomography myocardial perfusion imaging for predicting risk in patients with cardiometabolic disease

BackgroundThe epidemiology of coronary artery disease (CAD) has shifted, with increasing prevalence of cardiometabolic disease and decreasing findings of obstructive CAD on myocardial perfusion imaging (MPI). Coronary microvascular dysfunction (CMD), defined as impaired myocardial flow reserve (MFR) by positron emission tomography (PET), has emerged as a key mediator of risk. We aimed to assess whether PET MFR provides additive value for risk stratification of cardiometabolic disease patients compared with single-photon emission computed tomography (SPECT) MPI. MethodsWe retrospectively followed patients referred for PET, exercise SPECT, or pharmacologic SPECT MPI with cardiometabolic disease (obesity, diabetes, or chronic kidney disease) and without known CAD. We compared rates and hazards of composite major adverse cardiovascular events (MACEs) (annualized cardiac mortality or acute myocardial infarction) among propensity-matched PET and SPECT patients using Poisson and Cox regression. Normal SPECT was defined as a total perfusion deficit (TPD) of <5%, reflecting the absence of obstructive CAD. Normal PET was defined as a TPD of <5% plus an MFR of ≥2.0. ResultsAmong 21,544 patients referred from 2006 to 2020, cardiometabolic disease was highly prevalent (PET: 2308 [67%], SPECT: 9984 [55%]) and higher among patients referred to PET (P < 0.001). Obstructive CAD findings (TPD > 5%) were uncommon (PET: 21% and SPECT: 11%). Conversely, impaired MFR on PET (<2.0) was common (62%). In a propensity-matched analysis over a median 6.4-year follow-up, normal PET identified low-risk (0.9%/year MACE) patients, and abnormal PET identified high-risk (4.2%/year MACE) patients with cardiometabolic disease; conversely, those with normal pharmacologic SPECT remained moderate-risk (1.6%/year, P < 0.001 compared to normal PET). ConclusionsCardiometabolic disease is common among patients referred for MPI and is associated with a heterogenous level of risk. Compared with pharmacologic SPECT, PET with MFR can detect nonobstructive CAD including CMD and can more accurately discriminate low-risk from higher-risk individuals.

Applications of SPECT and PET Imaging for the Physiological Evaluation of Lower Extremity Peripheral Artery Disease.

Peripheral artery disease (PAD) is classified as the narrowing or complete occlusion of the lower extremity arteries due to atherosclerosis. The risk of developing PAD increases with increased age and risk factors such as smoking, diabetes, hypertension, and hypercholesterolemia. Current treatment for PAD involves lifestyle and symptom management, statin and antiplatelet therapy, and/or surgical interventions to improve quality of life with varying efficacy. PAD affects approximately 5 to 6 percent of the global population, with this global burden continuing to increase. Despite the increase in disease prevalence, no gold standard functional diagnostic tool has been established for enabling early detection of the disease, appropriate medical management, and prediction of adverse outcomes for PAD patients. The visualization and quantification of the physiological consequences of PAD are possible by way of nuclear imaging: specifically, via scintigraphy, single-photon emission computed tomography (SPECT), and positron emission tomography (PET) imaging. These non-invasive modalities, when combined with targeted radionuclides, possess utility for detecting functional perfusion deficits and provide unique insight into muscle tissue- and vascular-level characteristics of PAD patients. This review discusses the past, present, and emerging applications of hybrid nuclear imaging modalities in the evaluation and monitoring of patients with PAD.

Effect of Beta-Blocker Consumption on the Severity and Extension of Perfusion Defects in Dipyridamole Myocardial Perfusion Single-Photon Emission Computed Tomography.

Background Regarding the less-known effects of beta-blocker consumption on the diagnostic value of the myocardial perfusion scan with dipyridamole stress in coronary artery disease (CAD), we aimed to compare the findings of the scans done on the beta-blocker consumption course and after discontinuation of this medications. Materials and Methods Thirty patients with probably CAD and abnormal myocardial perfusion scans (presence of reversible defect), who had been treated with beta-blockers for at least 3 months, were studied. Dipyridamole stress phase of myocardial perfusion single-photon emission computed tomography (SPECT) was performed two times with an interval of about 1 week, once after discontinuation of all antianginal and anti-ischemic medications, statins, and beta-blockers for 72 hours prior to the study, and again after discontinuation of all these medications except for beta-blockers. Imaging was done with the same protocol, radiopharmaceutical dose, and imaging parameters. Summed stress score (SSS), summed stress rest, and summed difference scores (SDS), total perfusion deficit (TPD), severity, and extension of myocardial perfusion defects in three coronary artery territories were analyzed, using quantitative perfusion SPECT software. Results Most variables such as SSS, SDS, TPD, severity, and extension of defects showed a significant difference between the two conditions including beta-blocker consumption and after discontinuing beta-blocker consumption before stress imaging ( p < 0.05). Moreover, in patients on treatment with metoprolol, all studied factors including SSS, SDS, TPD, severity, and extension of perfusion defects were significantly reduced when patients consumed beta-blockers before SPECT evaluation ( p < 0.05). Conclusion Beta-blocker consumption can lead to a decrease in the severity and extent of myocardial perfusion defects and therefore probably a decrease in the sensitivity of myocardial scans. Discontinuation of beta-blocker prior to the dipyridamole myocardial perfusion scan can improve diagnostic accuracy.

SUVmean ratios of liver/muscle and lung/muscle from 13N-NH3 PET perfusion outperformed traditional myocardial viability parameters in predicting survival after CABG.

Myocardial viability evaluation in predicting survival after coronary arterybypass graft (CABG) remains debatable. Thus, this study aimed to investigate the role of 13N-NH3/18F-FDG PET myocardial viability scan in predicting treatment outcomes and survival. 90 patients with CABG and pre-surgical PET-based myocardial viability scan were retrospectively reviewed. Perfusion-metabolism features, myocardium motion parameters, and patient characteristics were recorded. Additionally, the SUVmean of blood pool, lung, liver, spleen, and muscle were measured and the SUVmean ratios were calculated. Factors associated with treatment outcomes and survival were analyzed by Logistic and Cox regressions. Nomogram models were subsequently established to predict ejection fraction (EF) improvement and survival outcomes. The mean EF of these 90 patients was 38.1 ± 9.5% and 46.0 ± 9.2% before and after CABG surgery, and 35 patients (38.9%) achieved EF improvement ≥ 10%. EF measurements by PET and echocardiogram showed a reasonable linear correlation (R = 0.752). Sex, pre-surgical EF, mismatch of the left ventricle, total perfusion deficit (TPD), and peak ejection rate (PER) were independent predictive factors of EF improvements. Surgery waiting time, valve damage, and SUVmean ratio of Liver/Muscle were independently predictive of event-free survival (EFS), while valve damage, together with SUVmean ratio of either Liver/Muscle or Lung/Muscle, were independently predictive of overall survival (OS). Although traditional cardiac parameters from PET-based myocardial viability can effectively predict EF improvements after CABG, SUVmean ratios of liver/muscle and lung/muscle from 13N-NH3 PET perfusion outperformed these parameters in predicting survival.

A Novel Interhemispheric Dural Inversion Technique for Indirect Parafalcine Cerebral Revascularization: Case Report

BACKGROUND AND IMPORTANCE: Variety of revascularization strategies have been deployed to treat the deterioration of cerebral blood flow. Blood flow restoration can be achieved by direct or indirect procedures. The indirect reconstructive procedure to augment blood flow involves encephalomyosynangiosis, encephaloduroarteriosynangiosis, or encephalodurosynangiosis, and has been used effectively in ischemic Moyamoya disease. However, the preferred procedure must be evaluated on a case-by-case basis and remains controversial in other cerebral arterial diseases. Here, we report the “interhemispheric dural inversion (IDI)” as a novel technique for indirect parafalcine cortical revascularization. CLINICAL PRESENTATION: A 54-year-old white man with a complex history of neck radiation secondary to childhood Hodgkin's lymphoma presented with focal perfusion deficit in the right mesial occipital lobe near the primary visual cortex. A large c-shaped dural flap with a paramedian base is harvested and, after an interhemispheric dissection, placed in contact with the ischemic parafalcine cortical tissue (IDI). CONCLUSION: The IDI was used successfully for indirect revascularization of a focal right paramedian occipital lobe deficit in a 54-year-old man with complex cerebro-occlusive disease from childhood radiation and multiple previous bypass surgeries. The IDI is a simple approach for targeted indirect parafalcine cortical revascularization to facilitate an increased blood supply and prompt new vessels to sprout from preexisting dural arteries. It can be used as a standalone technique or combined with other revascularization strategies, as warranted.

Radiomics Nomogram Derived from Gated Myocardial Perfusion SPECT for Identifying Ischemic Cardiomyopathy.

Personalized management involving heart failure (HF) etiology is crucial for better prognoses. We aim to evaluate the utility of a radiomics nomogram based on gated myocardial perfusion imaging (GMPI) in distinguishing ischemic from non-ischemic origins of HF. A total of 172 heart failure patients with reduced left ventricular ejection fraction (HFrEF) who underwent GMPI scan were divided into training (n = 122) and validation sets (n = 50) based on chronological order of scans. Radiomics features were extracted from the resting GMPI. Four machine learning algorithms were used to construct radiomics models, and the model with the best performances were selected to calculate the Radscore. A radiomics nomogram was constructed based on the Radscore and independent clinical factors. Finally, the model performance was validated using operating characteristic curves, calibration curve, decision curve analysis, integrated discrimination improvement values (IDI), and the net reclassification index (NRI). Three optimal radiomics features were used to build a radiomics model. Total perfusion deficit (TPD) was identified as the independent factors of conventional GMPI metrics for building the GMPI model. In the validation set, the radiomics nomogram integrating the Radscore, age, systolic blood pressure, and TPD significantly outperformed the GMPI model in distinguishing ischemic cardiomyopathy (ICM) from non-ischemic cardiomyopathy (NICM) (AUC 0.853 vs. 0.707, p = 0.038). IDI analysis indicated that the nomogram improved diagnostic accuracy by 28.3% compared to the GMPI model in the validation set. By combining radiomics signatures with clinical indicators, we developed a GMPI-based radiomics nomogram that helps to identify the ischemic etiology of HFrEF.

Imaging Assessments and Clinical Significance of Brain Frailty in Moyamoya Disease.

Imaging assessment of brain frailty in ischemic stroke has been extensively studied, while the correlation between brain frailty and Moyamoya disease remains obscure. This study aimed to investigate the imaging characteristics of brain frailty and its clinical applications in Moyamoya disease. This study included 60 patients with Moyamoya disease (107 hemispheres). All patients were divided into stroke and nonstroke groups based on clinical symptoms and imaging findings. The modified brain frailty score was adapted to consider 4 imaging signs: white matter hyperintensity, enlargement of perivascular space, old vascular lesions, and cerebral microbleed. The relative CBF of the MCA territory was quantified using pseudocontinuous arterial-spin labeling. Surgical outcome after revascularization surgery was defined by the Matsushima grade. The relative CBF of the MCA territory decreased as the modified brain frailty score and periventricular white matter hyperintensity grades increased (ρ = -0.22, P = .02; ρ = -0.27, P = .005). Clinically, the modified brain frailty score could identify patients with Moyamoya disease with stroke (OR = 2.00, P = .02). Although the modified brain frailty score showed no predictive value for surgical outcome, basal ganglia enlargement of the perivascular space had a significant correlation with the postoperative Matsushima grade (OR = 1.29, P = .03). The modified brain frailty score could reflect a cerebral perfusion deficit and clinical symptoms of Moyamoya disease, and its component basal ganglia enlargement of perivascular space may be a promising marker to predict surgical outcome and thus aid future clinical decision-making.

Early localization of tissue at risk for delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage: blood distribution on initial imaging vs early CT perfusion.

Delayed cerebral ischemia (DCI) is a potentially reversible adverse event after aneurysmal subarachnoid hemorrhage (aSAH), when early detected and treated. Computer tomography perfusion (CTP) is used to identify the tissue at risk for DCI. In this study, the predictive power of early CTP was compared with that of blood distribution on initial CT for localization of tissue at risk for DCI. A consecutive patient cohort with aSAH treated between 2012 and 2020 was retrospectively analyzed. Blood distribution on CT was semi-quantitatively assessed with the Hijdra-score. The vessel territory with the most surrounding blood and the one with perfusion deficits on CTP performed on day 3 after ictus were considered to be at risk for DCI, respectively. A total of 324 patients were included. Delayed infarction occurred in 17% (56/324) of patients. Early perfusion deficits were detected in 82% (46/56) of patients, 85% (39/46) of them developed infarction within the predicted vessel territory at risk. In 46% (25/56) a vessel territory at risk was reliably determined by the blood distribution. For the prediction of DCI, blood amount/distribution was inferior to CTP. Concerning the identification of "tissue at risk" for DCI, a combination of both methods resulted in an increase of sensitivity to 64%, positive predictive value to 58%, and negative predictive value to 92%. Regarding the DCI-prediction, early CTP was superior to blood amount/distribution, while a consideration of subarachnoid blood distribution may help identify the vessel territories at risk for DCI in patients without early perfusion deficits.

A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke with Proven Occlusion (TEMPO-2): Rational and design of a multicenter, randomized open-label clinical trial.

Almost half of acute ischemic stroke patients present with mild symptoms and there are large practice variations in their treatment globally. Individuals with an intracranial occlusion who present with minor stroke are at an increased risk of early neurological deterioration and poor outcomes. Individual patient data meta-analysis in the subgroup of patients with minor deficits showed benefit of alteplase in improving outcomes; however, this benefit has not been seen with intravenous alteplase in published randomized trials. TEMPO-2 (A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion) is a prospective, open label with blinded outcome assessment, randomized controlled trial, designed to test the superiority of intravenous tenecteplase (0.25 mg/kg) over nonthrombolytic standard of care, with an estimated sample size of 1274 patients. Adult patients presenting with acute ischemic stroke with the National Institutes of Health Stroke Scale (NIHSS) ⩽ 5 and visible arterial occlusion or perfusion deficit within 12 h of onset are randomized to receive either tenecteplase (0.25 mg/kg) or standard of care. The primary outcome is return to baseline neurological functioning, measured by the modified Rankin scale (mRS) at 90 days. Safety outcomes include death and symptomatic hemorrhage (intra or extra-cranial). Other secondary outcomes include mRS 0-1, mRS 0-2, ordinal shift analysis of the mRS, partial, and full recanalization on follow-up computed tomography angiogram. Results of this trial will aid in determining whether there is benefit of using tenecteplase (0.25 mg/kg) in treating patients presenting with minor stroke who are at high risk of developing poor outcomes due to presence of an intracranial occlusion. Data will be available upon reasonable request.

Alginate-Encapsulated Mesenchymal Stromal Cells Improve Hind Limb Ischemia in a Translational Swine Model.

Cellular therapies have been investigated to improve blood flow and prevent amputation in peripheral artery disease with limited efficacy in clinical trials. Alginate-encapsulated mesenchymal stromal cells (eMSCs) demonstrated improved retention and survival and promoted vascular generation in murine hind limb ischemia through their secretome, but large animal evaluation is necessary for human applicability. We sought to determine the efficacy of eMSCs for peripheral artery disease-induced limb ischemia through assessment in our durable swine hind limb ischemia model. Autologous bone marrow eMSCs or empty alginate capsules were intramuscularly injected 2 weeks post-hind limb ischemia establishment (N=4/group). Improvements were quantified for 4 weeks through walkway gait analysis, contrast angiography, blood pressures, fluorescent microsphere perfusion, and muscle morphology and histology. Capsules remained intact with mesenchymal stromal cells retained for 4 weeks. Adenosine-induced perfusion deficits and muscle atrophy in ischemic limbs were significantly improved by eMSCs versus empty capsules (mean±SD, 1.07±0.19 versus 0.41±0.16, P=0.002 for perfusion ratios and 2.79±0.12 versus 1.90±0.62 g/kg, P=0.029 for ischemic muscle mass). Force- and temporal-associated walkway parameters normalized (ratio, 0.63±0.35 at week 3 versus 1.02±0.19 preligation; P=0.17), and compensatory footfall patterning was diminished in eMSC-administered swine (12.58±8.46% versus 34.85±15.26%; P=0.043). Delivery of eMSCs was associated with trending benefits in collateralization, local neovascularization, and muscle fibrosis. Hypoxia-cultured porcine mesenchymal stromal cells secreted vascular endothelial growth factor and tissue inhibitor of metalloproteinase 2. This study demonstrates the promise of the mesenchymal stromal cell secretome at improving peripheral artery disease outcomes and the potential for this novel swine model to serve as a component of the preclinical pipeline for advanced therapies.

Optimal cerebral perfusion pressure in aneurysmal subarachnoid hemorrhage and its relation to perfusion deficits on CT-perfusion.

Preservation of optimal cerebral perfusion is a crucial part of the acute management after aneurysmal subarachnoid hemorrhage (aSAH). A few studies indicated possible benefits of maintaining a cerebral perfusion pressure (CPP) near the calculated optimal CPP (CPPopt), representing an individually optimal condition at which cerebral autoregulation functions at its best. This retrospective observational monocenter study was conducted to investigate, whether "suboptimal" perfusion with actual CPP deviating from CPPopt correlates with perfusion deficits detected by CT-perfusion (CTP). A consecutive cohort of aSAH-patients was reviewed and patients with available parameters for CPPopt-calculation, who simultaneously received CTP, were analyzed. By plotting the pressure reactivity index (PRx) versus CPP, CPP correlating the lowest PRx value was identified as CPPopt. Perfusion deficits on CTP were documented. In 86 out of 324 patients, the inclusion criteria were met. Perfusion deficits were detected in 47% (40/86) of patients. In 43% of patients, CPP was lower than CPPopt, which correlated with detected perfusion deficits (r = 0.23, p = 0.03). Perfusion deficits were found in 62% of patients with CPP<CPPopt compared to 34% in patients without deviation or CPP>CPPopt (OR 3, p = 0.01). These findings support the hypothesis, that a deviation of CPP from CPPopt is an indicator of suboptimal cerebral perfusion.

[15O]H2O myocardial perfusion positron emission tomography: Added value of relative stress perfusion deficit in the prediction of significant coronary artery stenosis in a mixedpopulation

BackgroundIt remains unknown whether estimation of the relative stress perfusion deficit offers added value in the prediction of significant coronary artery stenosis in myocardial perfusion imaging with [15O]H2O positron emission tomography (PET) in a population with high prevalence of established cardiac disease. MethodsDuring eight months, we consecutively included all patients undergoing [15O]H2O PET and subsequent invasive coronary angiography (ICA). Significant stenosis was defined from ICA as fractional flow reserve ≤.8 or coronary artery narrowing of ≥70%. We calculated absolute and relative total perfusion deficits (aTPD and rTPD, respectively) as semiquantitative measures of the extent and severity of reduced stress perfusion. A multivariate logistic regression analysis was performed to test the adjusted associations (odds ratio (OR) with 95% CI) with significant coronary artery stenosis. ResultsOf 800 patients undergoing [15O]H2O PET, 144 underwent ICA, where 142 patients had aTPD of ≥3% and 79 (55%) of these had at least one significant stenosis. In an adjusted analysis, rTPD (OR10% increase = 2.12 (1.44-3.12), P < .001), previous coronary artery bypass grafting (CABG) (OR = .11 (.03-.36), P < .001) and reduced left ventricular ejection fraction (LVEF) (OR = .25 (.08-.84), P = .02) were independently associated with significant stenosis, whereas the association with aTPD (OR10% increase = 1.14 (.98-1.32), P = .08) was modest. ConclusionsIn the presence of an absolute perfusion deficit (aTPD of ≥3%), rTPD may improve the prediction of significant stenosis in a heterogeneous population of patients examined with [15O]H2O PET. Furthermore, previous CABG and reduced LVEF are associated with nonstenotic perfusion deficiencies, suggesting caution when interpreting myocardial perfusion imaging in such patients.

Abstract 120: Neutrophilic Mice Are Protected Against Staphylococcus Aureus Sepsis And Immunothrombosis Through Peptidylarginine Deiminase 4-mediated Neutrophil Extracellular Trap Formation

Background: Neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) have been proposed as key drivers of immunothrombosis and thromboinflammation in Staphylococcus aureus sepsis. Peptidylarginine deiminase 4 (PAD4) contributes to NET formation and citrullinates coagulation proteins. NETs interact with VWF and platelets, thus providing a scaffold for the formation of microthrombi that cause microvascular perfusion deficits. Aims: To study the relationship between PAD4, NETs, and VWF in murine S. aureus sepsis. Methods: Murine sepsis was induced by injecting methicillin-resistant S. aureus (MRSA, USA300 strain) intravenously in C57BL/6J, MRP8Cre + PAD4 flfl (NET-defective) or PAD4 fl/fl littermates. In separate experiments, granulocyte colony stimulating factor (G-CSF) was used to induce neutrophilia prior to administration of USA300. Mice were followed for up to 8 days for clinical scoring and reaching humane endpoints as a surrogate readout for survival. Cell counts and plasma levels of citrullinated histone H3-DNA (H3Cit-DNA) complexes, VWF antigen, and PAD4 were measured at days 1, 4, and 8. Results: WT mice injected with USA300 developed thrombocytopenia and had higher plasma levels of NETs, VWF, and PAD4 as compared to vehicle (saline)-injected mice. MRP8Cre + PAD4 flfl mice had significantly reduced H3Cit-DNA and lower levels of VWF antigen 1d after USA300 injection as compared to littermate controls, with comparable VWF levels in the later disease phase. There was no difference in levels of cell-free PAD4 in plasma indicating a non-neutrophil source of PAD4, but the substantial reduction of plasma NET levels supporting that neutrophil PAD4 was essential for NET release. Neutrophilic mice (prior to sepsis induction) had lower sepsis disease scores and significantly improved survival rates as compared to mice receiving saline control. This protection was absent in the NET-defective mice, who surprisingly retained higher VWF levels. Conclusion: Individually eliminating NETs or VWF had little impact in MRSA sepsis in mice, and circulating PAD4 likely does not originate from neutrophils. Inducing neutrophilia protected mice against S. aureus sepsis, an effect which was abrogated in the absence of NET formation.

Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial.

XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina. In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery. There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months. XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732.

Sex Alters the Effect of Perfusion Deficits on Functional Outcome in Patients with Acute Ischemic Stroke Undergoing Mechanical Thrombectomy

Introduction: The discourse surrounding differences in cerebral hemodynamics and clinical outcomes among male and female patients treated with mechanical thrombectomy (MT) for acute ischemic stroke (AIS) remains unresolved. We aimed to elucidate these differences by employing computed tomography perfusion (CTP) imaging before MT and examining the influence of perfusion deficits on the 90-day functional outcome. Methods: This single-center retrospective analysis involved patients with anterior circulation AIS treated with MT at the Comprehensive Stroke Center, University Hospital, Krakow, from January 2019 to July 2023. We compared male and female patients in terms of baseline characteristics, CTP deficits, hypoperfusion intensity ratio (HIR, defined as T10max/T6max), and complications. The endpoints included the 90-day excellent functional outcome, defined as modified Rankin Score <2, and the 90-day mortality rate. Results: We included 794 patients, of whom 408 were female (51.4%). Female patients had a smaller early infarct volume (median [interquartile range]: 7 mL [0–24.8] vs. 10 mL [0–33], p = 0.004), smaller penumbra volume (77.5 mL [46–117] vs. 99.5 mL [59.8–140], p < 0.001), lower HIR (0.34 [0.16–0.5] vs. 0.37 [0.2–9.53], p = 0.043) and were less likely to achieve an excellent functional outcome (55.6% vs. 66.1%, p = 0.003). For every 10 mL increase in early infarct volume, the odds for achieving an excellent outcome were lower in females (odds ratio [OR]: 0.82 [95% confidence interval: 0.73–0.92]) compared to males (OR: 0.96 [0.88–1.04]), whereas the risk of death was higher for females (OR: 1.25 [1.13–1.39] than for males (OR: 1.05 [0.98–1.14]). Discussion: Despite more favorable cerebral hemodynamic profile, female AIS patients have worse outcomes than their male counterparts. This effect seems to be independently mediated by the more pronounced impact of early infarct volume on the prognosis in female patients. These findings underscore the possible explanatory power arising from sex-specific interpretation of early infarct volume in clinical practice.

Radiation dose reduction of 50% in dynamic myocardial CT perfusion with skipped beat acquisition: a retrospective study.

Dynamic myocardial computed tomography perfusion (CTP) is a novel imaging technique that increases the applicability of CT for cardiac imaging; however, the scanning requires a substantial radiation dose. To investigate the feasibility of dose reduction in dynamic CTP by comparing all-heartbeat acquisitions to periodic skipping of heartbeats. We retrieved imaging data of 38 dynamic CTP patients and created new datasets with every fourth, third or second beat (Skip1:4, Skip1:3, Skip1:2, respectively) removed. Seven observers evaluated the resulting images and perfusion maps for perfusion deficits. The mean blood flow (MBF) in each of the 16 myocardial segments was compared per skipped-beat level, normalized by the respective MBF for the full dose, and averaged across patients. The number of segments/cases whose MBF was <1.0 mL/g/min were counted. Out of 608 segments in 38 cases, the total additional number of false-negative (FN) segments over those present in the full-dose acquisitions and the number of additional false-positive cases were shown as acquisition (segment [%], case): Skip1:4: 7 (1.2%, 1); Skip1:3: 12 (2%, 3), and Skip1:2: 5 (0.8%, 2). The variability in quantitative MBF analysis in the repeated analysis for the reference condition resulted in 8 (1.3%) additional FN segments. The normalized results show a comparable MBF across all segments and patients, with relative mean MBFs as 1.02 ± 0.16, 1.03 ± 0.25, and 1.06 ± 0.30 for the Skip1:4, Skip1:3, and Skip1:2 protocols, respectively. Skipping every second beat acquisition during dynamic myocardial CTP appears feasible and may result in a radiation dose reduction of 50%. Diagnostic performance does not decrease after removing 50% of time points in dynamic sequence.

Severity of Disorganization of Retinal Layers and Visual Function Impairment in Diabetic Retinopathy

To evaluate best-corrected visual acuity (BCVA), retina sensitivity (RS), and fixation impairment by microperimetry (MP) due to the presence and severity of disorganization of retinal inner and outer layers (DRIL/DROL) and ischemia in OCT/OCT angiography (OCTA) in diabetic retinopathy (DR). Retrospective case-control study. Seventy-six eyes (65 patients) with DR were analyzed. Major exclusion criteria were: center-involving diabetic macular edema (DME), significant media opacity, nondiabetic macular pathology, and active proliferative DR. Patients with DRIL and DROL within central 3 mm were enrolled as cases. Patients with DR and no retina disorganization were considered as controls. A detailed grading of MP and OCT/OCTA images using Image J software, and specific Image Manipulation Program was applied to colocalize the presence of retina disorganization and RS. Best-corrected visual acuity and RS were correlated with the disorganization of retina layers' characteristics and grading (grade 1-DRIL; grade 2-DROL; grade 3-DROL plus, with involvement of the ellipsoid zone). The same procedure of colocalization was applied to the vascular layers on OCTA using MATLAB. Correlation between BCVA and MP parameters with disorganization of retina layers grading and OCTA parameters. Best-corrected visual acuity, mean RS within 1 mm and central 3 mm (overall RS [oRS]), perfusion density, vessel density, and geometric perfusion deficit in intermediate and deep capillary plexuses were lower in cases versus controls (P < 0.001). Mean RS within 1 mm (21.4 decibels [dB] ± 2.4 vs. 13.8 dB ± 5.4, P= 0.002), oRS (22.0 dB ± 2.1 vs. 14.4 dB ± 4.6, P < 0.001), and BCVA (76.1 ± 7.4 vs. 61.2 ± 20.4 ETDRS letters; P= 0.02), had a significant decrease from grade 1 to grade 3 retina disorganization. Choriocapillaris flow voids (CC-FVs) increased from grade 1 to grade 3 (DROL plus) (P= 0.004). Overall retina sensitivity and CC-FV were identified as significant predictors of retina disorganization grade with an adjusted coefficient of determination, R2= 0.45. Cases had more dense scotomas (P= 0.03) than controls with a positive correlation between the worsening of fixation stability and the severity of DRIL/DROL (P= 0.04). Microperimetry and BCVA documented a reduction in visual function in patients with DR and disorganization of retina layers at different grades, with greater functional impairment when outer retina layers and photoreceptors are involved. The severity of retina disorganization and the presence of ischemia could serve as a potential biomarker of functional impairment. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.