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Clinical decision-making regarding syncope poses challenges, with risk of physician error due to the elusive nature of syncope pathophysiology, diverse presentations, heterogeneity of risk factors, and limited therapeutic options. Artificial intelligence (AI)-based techniques, including machine learning (ML), deep learning (DL), and natural language processing (NLP), can uncover hidden and nonlinear connections among syncope risk factors, disease features, and clinical outcomes. ML, DL, and NLP models can analyze vast amounts of data effectively and assist physicians to help distinguish true syncope from other types of transient loss of consciousness. Additionally, short-term adverse events and length of hospital stay can be predicted by these models. In syncope research, AI-based models shift the focus from causality to correlation analysis between entities. This prompts the search for patterns rather than defining a hypothesis to be tested a priori. Furthermore, education of students, doctors, and health care providers engaged in continuing medical education may benefit from clinical cases of syncope interacting with NLP-based virtual patient simulators. Education may be of benefit to patients. This article explores potential strengths, weaknesses, and proposed solutions associated with utilization of ML and DL in syncope diagnosis and management. Three main topics regarding syncope are addressed: 1) clinical decision-making; 2) clinical research; and 3) education. Within each domain, we question whether "AI will be better than humans," seeking evidence to support our objective inquiry., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Aim: Contrast-enhanced cardiac magnetic resonance (Ce-CMR) and Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) are frequently utilized in clinical practice to assess myocardial viability. However, studies evaluating direct comparison between Ce-CMR and FDG-PET have a smaller sample size, and no clear distinction between the two imaging modalities has been defined. To address this gap, we conducted a meta-analysis of studies comparing Ce-CMR and FDG-PET for the assessment of myocardial viability., Methods: We searched PubMed, EMBASE, Scopus, and Web of Science databases from their inception to 4/20/2022 with search terms "viability" AND "heart diseases" AND "cardiac magnetic resonance imaging" AND "positron-emission tomography." We extracted patient characteristics, segment level viability assessment according to Ce-CMR and FDG-PET, and change in regional wall motion abnormalities (RWMA) at follow-up., Results: We included four studies in the meta-analysis which provided viability assessment with Ce-CMR and FDG-PET in all patients and change in RWMA at follow-up. There were 82 patients among the four included studies, and 585 segments were compared for viability assessment. There were 59 (72%) males, and mean age was 65 years. The sensitivity (95% confidence interval-CI) and specificity (CI) of Ce-CMR for predicting myocardial recovery were 0.88 (0.66-0.96) and 0.64 (0.49-0.77), respectively. The sensitivity (CI) and specificity (CI) of FDG-PET for predicting myocardial recovery were 0.91 (0.63-0.99) and 0.67 (0.49-0.81), respectively., Conclusion: FDG-PET and Ce-CMR have comparable diagnostic parameters in myocardial viability assessment and are consistent with prior research., (© 2023. The Author(s) under exclusive licence to American Society of Nuclear Cardiology.)

Syncope, a form of transient loss of consciousness, remains a complex medical condition for which adverse cardiovascular outcomes, including death, are of major concern but rarely occur. Current risk stratification algorithms have not completely delineated which patients benefit from hospitalization and specific interventions. Patients are often admitted unnecessarily and at high cost. Artificial intelligence (AI) and machine learning may help define the transient loss of consciousness event, diagnose the cause, assess short- and long-term risks, predict recurrence, and determine need for hospitalization and therapeutic intervention; however, several challenges remain, including medicolegal and ethical concerns. This collaborative statement, from a multidisciplinary group of clinicians, investigators, and scientists, focuses on the potential role of AI in syncope management with a goal to inspire creation of AI-derived clinical decision support tools that may improve patient outcomes, streamline diagnostics, and reduce health-care costs., Competing Interests: This research was funded by the Iowa Initiative for Artificial Intelligence (IIAI), Carver College of Medicine Office of Research, University of Iowa. Dr Olshansky is on the Data and Safety Monitoring Board of AstraZeneca. Dr Sonka is an inventor and has patents and patent applications in computer vision and medical image analysis; and is a cofounder of Medical Imaging Applications, LLC, Coralville, Iowa, USA and VIDA Diagnostics, Inc, Coralville, Iowa, USA. Dr Venkatesh Thiruganasambandamoorthy is supported through a Physicians’ Services Incorporated Foundation Mid-Career Clinical Researcher award and University of Ottawa Tier-1 Clinical Research Chair in Cardiovascular Emergencies award. Dr Thiruganasambandamoorthy has received peer-reviewed grant funds for studies from the following governmental or non-profit agencies: the 10.13039/501100000241Physicians’ Services Incorporated Foundation—Ontario, Canada, 10.13039/501100000024Canadian Institutes of Health Research, 10.13039/100004411Heart and Stroke Foundation Canada, and the Cardiac Arrhythmia Network of Canada as part of the Networks of Centres of Excellence (NCE; and is a consultant for the NIH funded Practical Approaches to Care in Emergency Syncope (PACES) study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Background: Syncope, a common problem encountered in the emergency department (ED), has a multitude of causes ranging from benign to life-threatening. Hospitalization may be required, but the management can vary substantially depending on specific clinical characteristics. Models predicting admission and hospitalization length of stay (LoS) are lacking. The purpose of this study was to design an effective, exploratory model using machine learning (ML) technology to predict LoS for patients presenting with syncope. Methods: This was a retrospective analysis using over 4 million patients from the National Emergency Department Sample (NEDS) database presenting to the ED with syncope between 2016−2019. A multilayer perceptron neural network with one hidden layer was trained and validated on this data set. Results: Receiver Operator Characteristics (ROC) were determined for each of the five ANN models with varying cutoffs for LoS. A fair area under the curve (AUC of 0.78) to good (AUC of 0.88) prediction performance was achieved based on sequential analysis at different cutoff points, starting from the same day discharge and ending at the longest analyzed cutoff LoS ≤7 days versus >7 days, accordingly. The ML algorithm showed significant sensitivity and specificity in predicting short (≤48 h) versus long (>48 h) LoS, with an AUC of 0.81. Conclusions: Using variables available to triaging ED clinicians, ML shows promise in predicting hospital LoS with fair to good performance for patients presenting with syncope.

Background: Myocardial infarction can be a trigger of Takotsubo syndrome. We recently characterized imaging features of acute myocardial infarction-induced Takotsubo syndrome ("Takotsubo effect"). In this study, we investigate diagnostic and prognostic implications of Takotsubo effect in patients with anterior wall ST-segment elevation myocardial infarction., Methods: We enrolled 111 consecutive patients who developed anterior wall ST-segment elevation myocardial infarction and received percutaneous coronary intervention, and studied systolic/diastolic function, hemodynamic consequences, adverse cardiac events, as well as 30-day and five-year outcomes in patients with and without Takotsubo effect., Results: Patients with Takotsubo effect showed significantly worse average peak systolic longitudinal strain (-9.5 ± 2.6% vs -11.1 ± 3.6%, p  = 0.038), left ventricular ejection fraction (38.5 ± 6.8% vs 47.7 ± 8.7%, p  = 0.000) and myocardial performance index (0.54 ± 0.17 vs 0.37 ± 0.15, p  = 0.000) within 48 h of myocardial infarction. There was no significant difference between the two groups in diastolic ventricular filling pressures, hemodynamic consequences, and 30-day rehospitalization and mortality (Gehan-Breslow-Wilcoxon test: p =  0.157). However, patients with Takotsubo effect developed more major adverse cardiac events (log-rank test: p =  0.019) when tested at the five-year follow-up. Cox regression analysis revealed that age, hypotension, tricuspid annular plane systolic excursion, and Takotsubo effect were independent prediction factors for five-year major adverse cardiac events. The Doppler/tissue Doppler parameter E/e' correlated with MACE only in patients without Takotsubo effect., Conclusion: Takotsubo effect secondary to anterior ST-segment elevation myocardial infarction predicts a worse long-term prognosis.

Objective: To test the hypothesis that exercise and dobutamine would provide levels of cardiac stress that are comparable to those achieved in a general stress test population, and to one another, in heart transplant recipients., Patients and Methods: From February 10, 2015, to December 31, 2017, 81 patients underwent exercise stress (N=45) or dobutamine stress (N=36) echocardiography at a mean ± SD of 11±14 years (range, 1-29 years) after heart transplant. Hemodynamic and inotropic responses were compared between groups, and to a prior test, longitudinally. The primary outcome was peak heart rate (HR) × systolic blood pressure (SBP)., Results: Peak exercise HR × SBP × 10 -3 was a mean ± SD of 24.9±4.9 mm Hg/min for exercise stress vs 21.2±3.4 mm Hg/min during dobutamine stress ( P <.001). In 35 patients who underwent a dobutamine stress test followed later by another dobutamine stress test, peak HR × SBP changed by 4.2%±16% ( P =.05). In 25 patients who underwent a dobutamine stress test followed later by an exercise stress test, peak HR × SBP increased by 12%±23% ( P =.002 vs serial dobutamine stress tests). Peak exercise HR did not correlate with time since heart transplant, patient age, or graft age. Peak dobutamine HR correlated modestly with patient age ( r 2 =0.28). Inotropic responses were similar in both groups. Overall, patients preferred exercise stress testing to dobutamine stress tests. Dobutamine stress testing was more expensive than exercise stress tests., Conclusion: Exercise induces a level of cardiac stress that is equal to or greater than dobutamine-induced stress, at lower cost, in heart transplant recipients who express preference for exercise stress testing., (© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

The cumulative incidence of systolic heart failure is similar in men and women. However, major prognostic differences exist between genders. We sought to measure gender differences in furosemide prescribing patterns for patients with preexisting heart failure with reduced ejection fraction (HFrEF) admitted with Stage C acute decompensation, regardless of the underlying cause. We conducted a single-center retrospective analysis of patients admitted between 2015 and 2018 for acute on chronic decompensated HFrEF. Primary outcomes were differences in initial furosemide dose, total dose over the first 24 hours of hospitalization, and total dose during the entire hospitalization between women and men. Secondary outcomes included acute kidney injury (AKI), intubation, noninvasive ventilation (NIV), and in-hospital 30-day and 1-year mortality. We studied 434 patients (31% female) with similar baseline characteristics. Females received significantly less furosemide compared to men for the initial dose, over the first 24 hours, and throughout their hospitalization. However, AKI was more prevalent in women versus men ( p =0.008). Females admitted for acute on chronic decompensated HFrEF receive significantly less furosemide when compared to men, but developed more AKI prior to discharge., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Tyler P. Rasmussen et al.)

Objective: We tested the hypothesis that endothelial peroxisome proliferator-activated receptor-γ protects against vascular thrombosis using a transgenic mouse model expressing a peroxisome proliferator-activated receptor-γ mutant (E-V290M) selectively in endothelium., Approach and Results: The time to occlusive thrombosis of the carotid artery was significantly shortened in E-V290M mice compared with nontransgenic littermates after either chemical injury with ferric chloride (5.1 ± 0.2 versus 10.1 ± 3.3 minutes; P=0.01) or photochemical injury with rose bengal (48 ± 9 versus 74 ± 9 minutes; P=0.04). Gene set enrichment analysis demonstrated the upregulation of NF-κB target genes, including P-selectin, in aortic endothelial cells from E-V290M mice (P<0.001). Plasma P-selectin and carotid artery P-selectin mRNA were elevated in E-V290M mice (P<0.05). P-selectin-dependent leukocyte rolling on mesenteric venules was increased in E-V290M mice compared with nontransgenic mice (53 ± 8 versus 25 ± 7 per minute; P=0.02). The shortened time to arterial occlusion in E-V290M mice was reversed by administration of P-selectin-blocking antibodies or neutrophil-depleting antibodies (P=0.04 and P=0.02, respectively) before photochemical injury., Conclusions: Endothelial peroxisome proliferator-activated receptor-γ protects against thrombosis through a mechanism that involves downregulation of P-selectin expression and diminished P-selectin-mediated leukocyte-endothelial interactions., (© 2015 American Heart Association, Inc.)

Aims: It has been well demonstrated that phosphodiesterase-5A (PDE5A) is expressed in smooth muscle cells and plays an important role in regulation of vascular tone. The role of endothelial PDE5A, however, has not been yet characterized. The present study was undertaken to determine the presence, localization, and potential physiologic significance of PDE5A within vascular endothelial cells., Methods and Results: We demonstrate primary location of human, mouse, and bovine endothelial PDE5A at or near caveolae. We found that the spatial localization of PDE5A at the level of caveolin-rich lipid rafts allows for a feedback loop between endothelial PDE5A and nitric oxide synthase (NOS3). Treatment of human endothelium with PDE5A inhibitors resulted in a significant increase in NOS3 activity, whereas overexpression of PDE5A using an adenoviral vector, both in vivo and in cell culture, resulted in decreased NOS3 activity and endothelium-dependent vasodilation. The molecular mechanism responsible for these interactions is primarily regulated by cGMP-dependent second messenger. PDE5A overexpression also resulted in a significant decrease in protein kinase 1 (PKG1) activity. Overexpression of PKG1 rapidly activated NOS3, whereas silencing of the PKG1 gene with siRNA inhibited both NOS3 phosphorylation (S1179) and activity, indicating a novel role for PKG1 in direct regulation of NOS3., Conclusion: Our data collectively suggest another target for PDE5A inhibition in endothelial dysfunction and provide another physiologic significance for PDE5A in the modulation of endothelial-dependent flow-mediated vasodilation. Using both in vitro and in vivo models, as well as human data, we show that inhibition of endothelial PDE5A improves endothelial function.

Purpose: RhoA and rho kinase serve as key regulators of penile vascular homeostasis. The role of RhoA/rho kinase signaling in the penis after cavernous nerve injury has not been fully investigated. We characterized the molecular expression profiles of RhoA/rho kinase signaling that occur in the penis after cavernous nerve injury. We hypothesized that erectile dysfunction after bilateral cavernous nerve injury is accompanied by up-regulation of RhoA/rho kinase activity in the rat penis., Material and Methods: We used 2 groups, including sham operation and bilateral cavernous nerve injury. At 14 days after nerve injury each group underwent cavernous nerve stimulation to determine erectile function at baseline and after intracavernous injection of the rho kinase inhibitor Y-27632 (Tocris Bioscience, Ellisville, Missouri). Penes were assessed at baseline for protein expression of neuronal nitric oxide synthase, RhoA, and rho kinase 1 and 2 by Western blot, immunoreactivity of neuronal nitric oxide synthase, rho kinase 1 and 2, RhoA-guanosine triphosphatase and rho kinase activity., Results: Erectile function was decreased in nerve injured rats. Neuronal nitric oxide synthase protein was significantly decreased while RhoA and rho kinase 2 protein levels were significantly increased in rat penes with nerve injury. Rho kinase 1 protein expression was equivalent. Rho kinase immunoreactivity was qualitatively increased in the corporeal smooth muscle of nerve injured rats. RhoA-guanosine triphosphatase and rho kinase activity was significantly increased in injured rat penes compared to that in sham operated penes. Intracavernous injection of Y-27632 caused a significantly greater increase in intracavernous pressure in nerve injured rats compared to that in sham operated rats, suggesting increased rho kinase activity., Conclusions: Data suggest that RhoA/rho kinase up-regulation in response to cavernous nerve injury contributes to penile vasculature dysfunction after cavernous nerve injury. Thus, the RhoA/rho kinase pathway may be a suitable target for treating post-radical prostatectomy erectile dysfunction., (Copyright © 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Objectives: The Ras homolog gene family, member A (RhoA) and its main downstream effector, Rho-kinase (ROCK) are important in maintaining the penis in the flaccid state. The pathophysiology of sickle cell disease-associated priapism is not well defined. We hypothesized that the RhoA/ROCK vasoconstrictive pathways might be involved in the development of priapism. Therefore, the objective of the present study was to evaluate the molecular changes in RhoA and ROCK in an established transgenic sickle cell mouse model of priapism., Methods: Two groups of mice were used: wild type (WT; C57BL/6) mice and transgenic sickle cell mice. We evaluated RhoA guanosine triphosphatase and total ROCK activities, as well as ROCK1 and ROCK2 protein expression, in WT and sickle mice penises. We also evaluated the in vivo erectile responses to cavernous nerve stimulation and the frequency and duration of spontaneous erections before and after cavernous nerve stimulation., Results: Sickle mice demonstrated significantly (P <.05) enhanced erectile responses to cavernous nerve stimulation and frequency of spontaneous erections both before and after cavernous nerve stimulation compared with the WT mice. The sickle mice penises had a significant decline in RhoA guanosine triphosphatase (P <.01) and total ROCK activities (P <.05) compared with the WT mice. A significant (P <.05) reduction in ROCK2 protein expression in sickle mice penises compared with WT mice protein expression. No change in ROCK1 protein expression was observed in either cohort of mice penises., Conclusions: These data suggest that sickle cell disease associated-priapism might be contributed by a lack of RhoA/ROCK-mediated vasoconstriction and highlight a novel molecular mechanism in the pathophysiology of priapism., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: We determined the effect of passive secondhand cigarette smoke on 1) erectile function in vivo, 2) molecular mechanisms involved in penile vascular function, and 3) erectile function and penile molecular signaling in the presence of phosphodiesterase type 5 inhibitor therapy., Materials and Methods: Four groups of mice were used, including group 1--controls, group 2--mice exposed to 3 weeks of secondhand smoke (5 hours per day for 5 days per week), group 3--control plus sildenafil (100 mg/kg per day) and group 4--smoke exposed plus sildenafil (100 mg/kg per day). Cavernous nerve electrical stimulation and intracavernous injection of acetylcholine were done to assess erectile function. Constitutive and inducible nitric oxide synthase activity, reactive oxygen species generation, nitrotyrosine formation and superoxide anion levels were assessed., Results: Decreased erectile responses to cavernous nerve electrical stimulation and impaired endothelium dependent erectile responses to ACh in mice exposed to secondhand smoke were observed. Superoxide anion was increased in endothelial and corporeal smooth muscle cells of smoking mouse penises. In mice exposed to secondhand smoke constitutive nitric oxide synthase activity was decreased, and inducible nitric oxide synthase activity, reactive oxygen species generation and nitrotyrosine formation increased. Sildenafil therapy restored constitutive nitric oxide synthase activity in the penis of smoking mice, decreased inducible nitric oxide synthase activity, reactive oxygen species generation and nitrotyrosine formation, and improved erectile responses to cavernous nerve electrical stimulation and acetylcholine., Conclusions: Short-term exposure to secondhand smoke impairs erectile function through excessive penile reactive oxygen species signaling and inducible nitric oxide synthase activity. Decreased penile constitutive nitric oxide synthase activity may be attributable to the decreased endothelial nitric oxide synthase activity resulting from increased oxidative stress. Sildenafil therapy restored nitric oxide synthase activity and decreased reactive oxygen species signaling, resulting in improved erectile function.

Objectives: To evaluate the effect of the fibrin sealant, Evicel, on the neuroregulatory control of penile erections in an experimental rat model., Methods: Two groups of rats were used: sham-operated rats with exposure of the bilateral cavernous nerves (CNs) and application of saline vehicle (500 microL), and rats treated with direct application of Evicel (500 microL) bilaterally to the CNs. At 14 and 45 days after application of Evicel to the CNs, the CNs were stimulated to measure the in vivo erectile responses. Additionally, we evaluated the neuronal nitric oxide synthase immunoreactivity in the dorsal CNs of the penis and changes in the smooth muscle and collagen deposition in the penis using a trichrome stain., Results: Evicel application to the CNs did not have any detrimental effect on the neurogenic erectile responses in vivo at 14 or 45 days after application. The neuronal nitric oxide synthase expression in the dorsal CNs of the penis was unchanged after Evicel application at all points studied, and we saw no change in the histomorphometric analysis findings of smooth muscle and collagen deposition in the penis., Conclusion: These data suggest that the hemostatic agent, Evicel, is safe in an experimental rat model of erection physiology, with no detrimental effects on neuroregulatory control of erection.

Erectile dysfunction (ED) is defined as the consistent inability to obtain or maintain an erection for satisfactory sexual relations. The past 20 years of basic science research on erection physiology has been devoted to investigating the pathogenesis of ED and has led to the conclusion that ED is predominately a disease of vascular origin with dramatic changes occurring in the endothelium. Research has also led to an understanding of the biochemical factors and intracellular mechanisms responsible for corporal smooth muscle contraction and relaxation and the influence of endothelium-derived relaxing factors. The development of methods to deliver both stem and endothelial cells to the penis has kindled a keen interest in treating ED with gene- and cell-based therapies. In this paper, erection physiology and stem cell biology is reviewed, and the potential application of novel cell-based therapies for the treatment of ED is discussed.

Erectile dysfunction (ED) commonly results from endothelial dysfunction of the systemic vasculature. Although phosphodiesterase type 5 (PDE-5) inhibitors are effective at treating most cases of ED, they must be taken routinely and are ineffectual for a meaningful number of men. In recent years gene and stem cell-based therapies targeted at the penile endothelium have been gaining momentum in preclinical studies. These early studies reveal that gene and stem cell-based therapies may be both enduring and efficacious, and may eventually lead to a cure for ED. The following review will highlight our current understanding of endothelial-specific gene and stem cell-based therapies performed to date in a number of experimental animal models.

During cell death of human cultured leukocytes (Jurkat, HL-60, THP-1, U937) and freshly prepared leukocytes, we observed a greater than 100-fold increase in the affinity of apoptotic and necrotic cells for fluorescein isothiocyanate (FITC)-heparin in comparison with live cells. Binding of FITC-heparin was reversed in the presence of high ionic strength, unlabeled heparan sulfate, and heparin and pentosan polysulfate, but not in the presence of chondroitin and dermatan sulfates. During the course of cell death, the increase in the percentage of cells positive for annexin V binding correlated with the increase in the population positive for binding FITC-heparin. Confocal microscopy demonstrated that heparin binding to dead cells was restricted to 1 or 2 small domains on the surfaces of apoptotic cells and to larger, but still discrete, areas that did not localize with chromatin on ruptured necrotic cells. The heparin-binding domains originated from the nucleus and may correspond to the ribonucleoprotein-containing structures that have recently been shown to segregate within the nucleus of cells and to move onto the cell membrane. We observed that phagocytosis of dead Jurkat cells by monocyte-derived macrophages was blocked when the heparin-binding capacity of the dead cells was saturated by the addition of pentosan polysulfate. From this we concluded that the ability of dead cells to bind to heparan sulfate proteoglycans on the surfaces of macrophages may assist in phagocytic clearance.

We have observed a striking neutralisation of the anticoagulant activity of unfractionated heparin in the presence of a pancreatic carcinoma cell line (MIA PaCa-2) due to binding of around 9 microg of heparin per 10(7) cells (apparent Kd, 30 nM). The loss of anticoagulant activity was less marked in the presence of low molecular weight forms of heparin. Binding to the cell blocked acceleration of the thrombin:antithrombin interaction by heparin. Neutralisation of heparin activity was also shown to occur in the presence of a number of other tumour cell lines. FACS analysis demonstrated that live cells did not bind heparin and high affinity binding only occurred to dead MIA PaCa-2 cells. Heparin binding proteins accumulating in cell medium were identified as histone and ribosomal proteins that will become exposed during necrosis. The release of these proteins from cells within the necrotic core of a tumour or from cells killed during chemotherapy may abrogate the heparan sulphate/antithrombin system and possibly contribute to the idiopathic thromboembolism often associated with cancer (Trousseau's syndrome). The findings also suggest a reason for the reported advantage of LMWH over UFH in treating venous thromboembolism in cancer patients and in improving patient survival.