United States

Background: Excessive fibrosis can alter the electrical conduction in the atrial tissue leading to atrial fibrillation (AFib). However, the underlying mechanisms driving atrial fibrosis and the development of AFib remain incompletely understood. We hypothesized that atrial fibrosis could result due to coronary microvascular vasodilator dysfunction. 

Methods: Right human atrial appendages were collected during cardiac surgeries. Coronary arterioles (~100 µm) were dissected, cannulated, and pressurized (80 mmHg). Using video-microscopy, endothelium-dependent vasodilation was assessed by bradykinin (BK) and smooth muscle-dependent vasodilation was measured using sodium nitroprusside (SNP). Atrial tissue was then paraffin embedded and, via Masson’s Trichrome staining, the collagen content was quantified by ImageJ.

Results: When submitted to cumulative increases of bradykinin, AFib patients showed a significant reduced maximum vasodilation compared to the control patient with sinus rhythm (p=0.021), whereas no significant changes were recorded in SNP-induced vasodilator response. This decrease in BK-induced vasodilatory response was accompanied by a trend in increasing collagen content in the AFib patients, when compared to the control group (p=0.133). 

Conclusion: The collected data shows that patients with AFib have an increased collagen content in association with impaired endothelium-dependent vasodilatory response. Together, these data show that coronary microvascular dysfunction is accompanied by increased fibrosis, which may lead to hypoxia and AFib. 

Relevance for Patient Care: These data show a possible link between coronary microvascular dysfunction and Afib, which allows us to better understand AFib. 

Strengths/limitations: Limitations of this study include small sample size (n=8). The strength of these data is that these are samples taken from patients. 

Ethical Permissions: Ethical Approval was obtained for biological sample use.

AMA Research Challenge 2024 

Coronary Microvascular Dysfunction is Associated with Atrial Fibrosis in Patients with Atrial Fibrillation

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Background: Abdominal aortic aneurysm (AAA) is a potentially lethal vascular disease lacking non-surgical treatments. AAA is associated with decreased expression of estrogen receptor alpha (ERα) in the aorta. The significance of this finding and the mechanisms by which lack of ERα signaling contributes to AAA pathogenesis have not been examined. In this investigation, we test the hypothesis that ERα signaling protects against AAA by decreasing endothelin-1 (ET-1) production and regulating inflammation.

Methods: AAA was induced in endothelial cell-specific ERα knockout (eERαKO) male mice and their littermates (ERαFL2) (n=6-11) by administering β-Aminopropionitrile (BAPN) via drinking water (1 mg/ml, 0.15 g/kg/d) 3 days before angiotensin II (Ang II; 1 µg/kg/day) infusion for 2 weeks. Development of AAA was assessed by in vivo ultrasound measurement of aortic luminal dilation. Relevant molecular mechanisms were examined in abdominal aortic tissues, human aortic endothelial cells (HAECs) and mouse bone marrow-derived macrophages (BMDMs). 

Results: BAPN/Ang II increased abdominal aortic diameter in ERαFL2 and eERαKO mice compared to control. Lack of ERα further augmented the BAPN/Ang II-induced increase in aortic diameter and AAA incidence compared to ERαFL2 mice. Immunohistochemical staining revealed that BAPN/Ang II co-infusion significantly upregulates ET-1 expression and macrophage infiltration of the abdominal aorta in eERαKO mice compared to ERαFL2 mice. In vitro studies in HAECs demonstrated that treatment with ERα agonist, β-estradiol (100 nM, 24 h), decreases TNFα (15 ng/ml)-induced ET-1 production, while treatment with ERα-specific antagonist, methylpiperidinopyrazole (1 µM, 24 h), increases ET-1 production. Additionally, BMDMs obtained from the eERαKO mice exhibited increased production of the pro-inflammatory cytokine monocyte chemoattractant protein-1 compared to macrophages from ERαFL2 mice.

Conclusion: Our findings demonstrate a protective effect of endothelial ERα signaling against AAA in male mice likely through decreased ET-1 production and reduced pro-inflammatory macrophage activation of the aorta. Further studies are needed to delineate the crosstalk between endothelial ET-1 with macrophage phenotype and their impact in AAA pathogenesis.

Role of Estrogen Receptor Alpha and Endothelin-1 in Pathogenesis of Abdominal Aortic Aneurysm in Male Mice

Background: Age and biological sex are well-known cardiovascular risk factors. Advanced age is correlated with vascular stenosis and turbulent flow, and studies suggest females experience increased coronary flow and vascular shear stress compared to males. These conditions increase risks for coronary calcification and luminal surface alterations, and subsequently, hemodynamic changes. Understanding the impact of age and sex on calcification and luminal surface topography in coronary arteries will yield insight not only on the mechanical pathophysiology of hemodynamic changes over time and between sexes, but also on refining risk stratification for cardiovascular diseases. In this study, we aim to detect, quantify, and compare the extent of calcification and luminal surface differences between age groups and sexes in cadaveric left anterior descending arteries (LADs) using a relatively novel approach–surface metrology. We hypothesized that LAD calcification and luminal surface complexity would increase in higher age groups and in the female sex. 

Methods: LADs (n=18) were harvested from cadaveric hearts using a systematic dissection approach. To quantify the extent of calcification, each specimen was scanned using the Bruker Skyscan 1173 microCT scanner and subsequently underwent threshold-based image segmentation on Dragonfly by Object Research Systems. To quantify luminal surface complexity, each specimen was splayed open to expose their luminal surfaces and up to 15 scans were performed at 20X magnification using the Sensofar S Neox optical profiler. Each scan subsequently underwent surface metrologic scale-sensitive fractal analyses in SensoMap 10. 

Results: We established 4 age groups: 60-69, 70-79, 80-89, and 90-99, and categorized our data to the corresponding age and sex groups. Our microCT findings demonstrated statistically significant reductions in LAD calcification in females compared to males, but no differences between age groups. Our surface metrology findings demonstrated statistically significant reductions in fractal complexity (Lsfc) and fractal dimension (Dls) in the highest age group compared to each of the lower age groups, but no differences in smooth rough crossover (SRC) and the scale of maximum complexity (Smfc) between each group. Additionally, no statistically significant differences were observed in SRC, Lsfc, Dls, and Smfc between males and females. 

Conclusions: Our data suggests that males are significantly more prone to LAD calcification than females. Moreover, LAD luminal surfaces may increase in smoothness at a high age (>90) relative to lower ages (>60, but <90). Future studies will involve modeling blood flow across these surfaces using smooth particle hemodynamics (SPH) to evaluate the resulting hemodynamic changes.

The effects of age and sex on calcification and luminal surface complexity in
cadaveric left anterior descending arteries

Intro: Melanoma is the most aggressive and deadly form of skin cancer, especially at later stages. There is currently no excellent diagnostic test established for the diagnosis of melanoma; however, circulating microRNAs (miRNAs) have shown some promise. We seek to conduct a systematic review and meta-analysis to establish the clinical utility of circulating miRNAs in diagnosing melanoma.
Methods: PubMed, Wiley, and Web of Science were searched for studies that determined miRNA sensitivity and specificity in patients with melanoma. The included studies were assessed in Stata, and the sensitivity, specificity, summary receiver operating characteristic (SROC), positive likelihood ratio, negative likelihood ratio, and the area under the SROC curve (AUC) were calculated.
Results: 9 studies with 898 melanoma patients were included in the meta-analysis. The circulating miRNAs showed high diagnostic accuracy with a sensitivity of 0.89 (p < 0.001), specificity of 0.85 (p < 0.001), diagnostic odds ratio of 45, and an area under the curve of 0.93.
Conclusion: Circulating miRNAs have shown a high diagnostic power in detecting melanoma.

Circulating miRNAs as biomarkers for the diagnosis in patients with melanoma: a meta-analysis

Cutaneous Squamous Cell Carcinoma (cSCC) is the second most common form of non-melanoma skin cancer, with both genetic and non-genetic factors influencing its development. Recent evidence suggests that commonly used medications may impact cSCC progression through previously unidentified mechanisms affecting keratinocyte stem cell differentiation and protein synthesis. This study investigates the effects of several widely prescribed drugs - lovastatin, hydrochlorothiazide/amiloride, amiodarone, and PLX-4032 - on these cellular processes, aiming to improve risk assessment and potentially develop new therapeutic strategies for cSCC. Primary keratinocytes and cSCC cells were treated with various medications (lovastatin, hydrochlorothiazide/amiloride, amiodarone, PLX-4032, and Dabrafenib) and analyzed using RT-qPCR, western blotting, immunofluorescence, flow cytometry, and m7-GTP pull-down assays. These techniques were used to assess changes in mRNA levels, protein abundance, protein synthesis activity, and the availability of translation initiation factors. Common medications (lovastatin, hydrochlorothiazide/amiloride, amiodarone, and PLX-4032) significantly reduce KRT10 mRNA levels in keratinocyte stem cells after 24 hours of calcium-induced differentiation. These medications also decrease Keratin 10 protein abundance in differentiating keratinocytes, suggesting a potential impairment of early differentiation processes. Common medications (lovastatin, hydrochlorothiazide/amiloride, amiodarone, and PLX-4032) significantly reduce KRT10 mRNA levels in keratinocyte stem cells after 24 hours of calcium-induced differentiation. These medications also decrease Keratin 10 protein abundance in differentiating keratinocytes, suggesting a potential impairment of early differentiation processes. Common medications (lovastatin, hydrochlorothiazide/amiloride, amiodarone, and PLX-4032) impair keratinocyte stem cell differentiation by reducing both mRNA and protein levels of early differentiation markers. BRAF kinase inhibitors (PLX-4032 and Dabrafenib) decrease global protein synthesis in keratinocyte stem cells by reducing the availability of translation initiation factors, particularly affecting cells entering early differentiation. These findings suggest that commonly prescribed medications may increase cSCC risk by altering keratinocyte stem cell differentiation and protein synthesis, highlighting the need for careful consideration of these drugs in high-risk patients.

Impact of Common Pharmaceuticals on the Development of cutaneous Squamous Cell Carcinoma

Background: Vulvar Lichen Sclerosus (VLS) is a mucocutaneous disorder of chronic inflammation that significantly impacts the biopsychosocial well-being of affected women. VLS is characterized by hypopigmentation, skin atrophy, pruritus, and vulvodynia. The pathophysiology of VLS is primarily linked to the infiltration of activated T-cells stimulating fibroblasts by cytokines, resulting in altered collagen production and fibrosis. Limited research investigates the vulvar microbiome's composition in healthy individuals compared to individuals with VLS. This study aims to address the existing gap by exploring the diverse vulvar microbiome in patients with VLS and examining the potential role of microbiome alterations in the 
disease's pathogenesis.
Methods: A comprehensive review of literature was conducted to explore the relationship between the 
vulvar microbiome and VLS. Studies were selected based on relevance to microbial diversity and VLS pathogenesis.
Results: The vulvar microbiome comprises bacteria from the vulvar skin, vaginal canal, colon, and anus, resulting in a unique and diverse microbial environment that is relatively underexplored. Studies have demonstrated that when healthy skin is transplanted to areas affected by VLS, the transplanted skin can develop characteristics of VLS. This suggests that the microenvironment of the vulvar skin may play a significant role in the pathogenesis of VLS and highlights the importance of preventative measures to maintain vulvar skin health. Common bacteria identified in the vulvar microbiome include Lactobacillus and Prevotella. In healthy individuals, 
Lactobacillus is the dominant bacterium. In contrast, more than 85% of symptomatic VLS patients exhibit an increased presence of Prevotella. Elevated levels of Prevotella have been shown to stimulate epithelial cells to produce cytokines leading to Th17-mediated mucosal inflammation. These findings emphasize the critical role of microbial balance in vulvar health and suggest that targeting specific microbial alterations could offer new avenues for preventing and managing VLS.
Conclusion: There is an observed association between microbiome diversity and VLS. Future research should investigate the role of specific bacteria, such as Prevotella, in the pathogenesis of VLS. The current body of literature on the vulvar microbiome and its connection to chronic inflammatory diseases, including VLS, is limited. To address this significant gap, increased awareness and dedicated research efforts are essential. 


Investigating the Vulvar Microbiome's Role in the Pathogenesis of Vulvar Lichen Sclerosus

Introduction
By 2045 the number of adults living with type I diabetes is projected to increase to 783 million. Current guidelines recommend exogenous insulin replacement therapy, which entails significant adverse effects and inhibiting cost. Surgical transplantation of insulin-producing pancreatic cells has been proposed as a potential lasting curative treatment for diabetes. Current techniques are fraught with post operative complications and life-long immunosuppression. There is a persistent need for a reliable platform that can facilitate pancreatic tissue transplantation without these limitations. Here, we present our novel Arterio-Venous Graft Rx (AVGRx) which sustains both stem-cell derived beta cells (SCDßCs)and human pancreatic tissue viability and function in vivo in a large animal porcine host without immune suppression. 

Methods
The AVGRx contains a treatment zone that is shielded from the host immune cells while facilitating contact with the host arterial blood stream for nutrient and hormone exchange. Adult male Yorkshire pigs were obtained for graft implantation. The common carotid artery and distal external jugular vein were surgically exposed, and an end-to-side anastomosis with both graft ends was performed. The AVGRx treatment zone was then injected with either SCDßCs or human pancreatic islets. No immunosuppression was administered. 1-, 2- and 3-weeks post implantation, the porcine host was injected with a 500mg/kg dextrose injection, and blood was collected to measure human insulin using ELISA. To evaluate cell morphology post-explantation, SCDßCs were evaluated using Nkx (beta cell marker), C-peptide (terminal insulin sequence) immunofluorescence. Following explantation, purified human islets were exposed to 2mM and then 20mM glucose solutions. Their supernatant was collected, and human insulin concentrations were measured. 

Results
Quantification of cellular markers demonstrated unchanged cell count of Nkx (p=0.12) or C-peptide (p=0.13) positive cells between weeks 0, 1 and 2. Compared to baseline insulin secretion, post-explanted human islets demonstrated similar insulin secretion in both low (p=0.68) and high (p=0.31) glucose concentration solutions. Following dextrose bolus, human insulin was detected in vivo each week for three weeks during graft implantation. 
Conclusion

Conclusion
The AVGRx is a novel means to reliably sustain implanted xenograft cells without the need for immunosuppression. SCDßCs and human pancreatic islets were observed to have maintained viability within porcine models for up to 21 days. These findings demonstrate the ability of the AVGRx to interface its payload with a host’s arterial blood supply while also protecting it from a immune response. The AVGRx platform may have a major impact on the future of islet transplant therapy.


Human Pancreatic Cells Survive Porcine Implantation Without Immune Suppression Using Novel Arteriovenous Graft

Kevin Lopez B.S.1, Nizam Karim B.S.1
1The University of Texas Medical Branch (UTMB) John Sealy School of Medicine, Galveston, TX

Background
• Post-operative cognitive dysfunction (POCD) is a detrimental neurocognitive disorder that occurs after surgery with anesthesia where a substantial change in a patient’s baseline cognitive ability leads to difficulty completing activities of daily living, socializing, maintaining a job, and is associated with an increased risk of death.1
• POCD can affect anyone, but patients over 60 years old are at increased risk, lasting from weeks to over a year in some cases.1
• Currently, no treatment exists, and research is very limited. Recently, the Gut-Brain-Axis has been implicated in the pathogenesis of POCD.
• This systematic review aims to summarize recent animal studies and controlled human trials focusing on mechanisms of pathogenesis and/or therapeutic targets for POCD relating to gut microbiome dysbiosis and its role in cognition and neuroinflammation.

Methods
• Systematic review conducted in PubMed database over 5-year period, 2019-2024, using relevant search/MeSH terms.
• Review designed according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. SYRCLE's risk of bias tool and revised Cochrane risk of bias tool (Rob 2) were used. 

Results
• 2 articles demonstrate healthy donor fecal matter transplantation (FMT) to POCD-animals ameliorates POCD-like symptoms. 
• 3 articles demonstrate that POCD-donor FMT to healthy germ-free animals induces dysbiosis and POCD-like symptoms.
• 1 article demonstrated perioperative probiotic administration in humans as effective to reduce incidence of POCD in elderly patients undergoing non-cardiac surgery.

Potential Mechanisms of POCD
Dysregulated Signaling pathways inducing POCD Symptoms:
ERK/Nrf2, ACCS2/HDAC, BTG2/Bax, TLR4/NF-kB, Keap1/Nrf2
“Toxicity”: Increased molecule/compound inducing POCD Symptoms:
Trimethylamine N-oxide (TMAO), NLRP3 inflammasome, Palmitic acid, Valeric acid, IL17A/IL17RA, intestinal exosomes
“Deficiency”: Decreased molecule/compound inducing POCD Symptoms:
C1BR, SIRT1, tight junction protein, methionine sulfoxide reductase (MsrA)
“Protective”: Increased molecule/compound ameliorating POCD Symptoms:
CB1R, SIRT1, and miR-146a (via BTG2/Bax axis)

Novel Therapeutics Ameliorating POCD Symptoms
Short chain fatty acid (SCFA) (via ACCS2/HDAC2 axis), Sodium butyrate (NaB), indole propionic acid, propionic acid, 4 octyl itaconate (via ERK/Nrf2 axis), exogenous dietary restriction (via TLR4/MyD88/NF-kB axis), Sulforaphane (via Keap/Nrf2 axis), and exosome inhibitor GW4869, PLX5622, probiotics, exercise, Cefazolin, Ibuprofen, prebiotic xylooligosaccharides (XOS)

Discussion
Interestingly, it was determined that anesthesia may induce microbiome dysbiosis independently from surgery. This suggests that anesthesia plus surgery may induce dysbiosis in an additive manner in addition to other predisposing factors such as age and anesthesia dose, type, route of administration, and duration of use, comorbidities, pre-existing cognitive dysfunction or other psychiatric conditions.

Future Directions
Further translational research evaluating perioperative administration of novel therapeutic agents, such as those in this search, could provide promising results. Further evaluation of changes in the Gut-Brain-Axis could uncover a deeper understanding of the pathogenesis of POCD.

References
1. Brodier, E., & Cibelli, M. (2020). Postoperative cognitive dysfunction in clinical practice. BJA Education, 21(2), 75–82. https://doi.org/10.1016/j.bjae.2020.10.004


Exploring Mechanisms in the Gut-Brain-Axis for Anesthesia-induced POCD: A Systematic Review

Background
The serotonin transporter (SERT, encoded by SLC6A4) is downregulated in patients with inflammatory bowel disease (IBD) and in pre-clinical IBD models. While serotonin (5-HT) and SERT are known to play crucial roles in gut health and the microbiome, the therapeutic potential of targeting SERT in intestinal inflammation remains unexplored.
Methods
SERT knockout (KO) and wild-type (WT) mice were treated with dextran sulfate sodium (DSS) to induce chronic colitis. Fecal and serum samples were subjected to metabolomic analysis. Bioinformatic tools identified enriched metabolic pathways and microbial-related metabolites. Disease severity was assessed via myeloperoxidase (MPO) activity, RT-PCR, immunoblotting, and immunohistochemistry. Tight junction integrity was evaluated using immunofluorescence, Western blotting, RT-PCR, and serum endotoxin levels. Spearman correlation coefficients were calculated to determine the relationship between metabolite abundance and disease activity.
Results
SERT KO mice with chronic colitis exhibited increased disease severity. Baseline metabolomic profiles of SERT KO mice resembled those of WT mice with chronic colitis, indicating a predisposition to metabolic dysregulation. Metabolomic analysis revealed distinct fecal and serum profiles associated with chronic colitis, mirroring human IBD, including variations in purine and plasmalogen metabolites. SERT deficiency alone led to altered tryptophan metabolism, oxidative metabolism changes, and dysregulation of phosphatidylcholines and plasmalogens. Mechanistically, SERT deficiency in an inflammatory context resulted in reduced ileal tight junction expression and increased serum endotoxin levels, exacerbating disease. Additionally, several microbial metabolites in feces and serum correlated with disease activity. Specifically, indolepropionate levels were reduced in the serum of both chronic colitis and SERT KO mice, with significant negative correlations with histology scores and MPO activity. Conversely, tyrosol excretion was increased in feces of both chronic colitis and SERT KO mice, showing significant positive correlations with histology scores and MPO.
Conclusion
SERT deficiency exacerbates DSS-induced chronic inflammation, disrupts intestinal barrier function, and causes microbially influenced metabolic changes corresponding to disease activity. This study highlights novel changes in host-derived and bacteria-derived metabolites in serum and feces due to SERT loss. Our findings suggest that SERT deficiency leads to a loss of beneficial anti-inflammatory and antioxidant compounds. Future research will explore the therapeutic potential of fecal supernatants containing these beneficial compounds for treating intestinal inflammation. These findings underscore the disruptive role of SERT in metabolic pathways associated with IBD and suggest potential therapeutic targets for intestinal inflammation.

Global serotonin transporter deficiency induces a metabolomic signature resembling chronic intestinal inflammation

Gastrointestinal microbes modulate peristalsis and stimulate the enteric nervous system (ENS), whose development, as in the central nervous system (CNS), continues into the murine postweaning period. Given that adult CNS function depends on stimuli received during critical periods of postnatal development, we hypothesized that adult ENS function, namely motility, depends on microbial stimuli during similar critical periods. We gave fecal microbiota transplantation (FMT) to germ-free mice at weaning or as adults, then measured gastrointestinal transit time either 4 weeks post-FMT or age-matched at 16 weeks. We performed RNAseq of colonic muscularis propria to compare gene expression patterns between mice with or without early life microbiota exposure. We found that only the mice given FMT at weaning recovered normal transit, while those given FMT as adults showed limited improvements. RNAseq of colonic muscularis propria revealed enrichments in neuron developmental pathways in mice exposed to gut microbes earlier in life, while mice exposed later – or not at all – showed exaggerated expression of inflammatory pathways. These findings highlight a microbiota-dependent sensitive period in ENS development, pointing to potential roles of the early life microbiome in later life dysmotility.

Microbiota-dependent early life programming of gastrointestinal motility

Background
Trauma patients with hemorrhagic shock (HS) accounts for 40% of preventable death. Shock-induced endotheliopathy has garnered interest recently and one aspect of this, endothelial glycocalyx shedding (EGX), has shown to promote coagulopathy following hemorrhage. Ferroptosis is an iron dependent, non-apoptotic form of controlled cell death triggered by the oxidation of membrane phospholipids. Liproxstatin-1 is an inhibitor of this process and can protect against oxidative damage to the endothelial cell membrane and subsequent shedding of glycocalyx. Our goal is to determine if administration of Liproxstatin-1, a ferroptosis inhibitor can reduce glycocalyx shedding in hemorrhaged rats providing evidence of its therapeutic value in the setting of hemorrhagic shock. 

Methods
A rat model of hemorrhagic shock and resuscitation was used to assess glycocalyx disruption in the lungs via fluorescent-labeled wheat germ agglutinin staining in frozen tissue and by syndecan-1 ELISA on plasma samples. A control group (n=5) resuscitated only with Lactated Ringer’s solution, following hemorrhage and resuscitation (H/R) was compared against an experimental group (n=1) that received Liproxstatin-1 following hemorrhage and before resuscitation.

Results
Glycocalyx shedding (assessed by an increase in plasma syndecan-1 levels) was significantly lower in the Liproxstatin-1 treated group compared to control group. Additionally, Liproxstatin-1 treated animals were able to sustain a higher mean arterial pressure (MAP), and oxygen saturation throughout the resuscitation period measured at 15- and 30-minutes following Liproxstatin-1 infusion. 

Conclusion
Ferroptosis inhibitor Liproxstatin-1 can reduce morbidity acutely during hemorrhagic shock and protect endothelial cell membrane from oxidative damage due to its ability to slow the generation of reactive oxygen species (ROS) and lipid hydroperoxides. 

Further experiments will be performed to complete the Liproxstatin-1 experimental group (n=5) as well as a control group using Cyrene (n=5), a DMSO-like solvent used to dissolve Liproxstatin-1 for intravenous administration. Additionally, tissue staining of lung vasculature will be performed to evaluate the glycocalyx disruption in the vascular beds of the lungs in the Cyrene, and Liproxstatin-1 groups as well as a group resuscitated with Lactated Ringers solution (H/R) alone. 


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