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We present a case of cardiogenic shock secondary to refractory polymorphic ventricular tachycardia associated with coronary ischemia resulting in cardiac arrest. Following the return of spontaneous circulation, the patient was cannulated for peripheral venoarterial extracorporeal membrane oxygenation (V-A ECMO) in anticipation of high-risk “protected” percutaneous coronary intervention (PCI). Under full V-A ECMO support, inotropes and vasopressors were weaned off, and the patient underwent uneventful PCI of left circumflex and obtuse marginal lesions. After 48 hours, the patient was decannulated and could be discharged home alive 16 days after his initial cardiac arrest.

Abstract Hand dysfunction is a common observation after arteriovenous fistula (AVF) creation for hemodialysis access and has a variable clinical phenotype; however, the underlying mechanism responsible is unclear. Grip strength changes are a common metric used to assess AVF-associated hand disability but has previously been found to poorly correlate with the hemodynamic perturbations post-AVF placement implicating other tissue-level factors as drivers of hand outcomes. In this study, we sought to test if expression of a mitochondrial targeted catalase (mCAT) in skeletal muscle could reduce AVF-related limb dysfunction in mice with chronic kidney disease (CKD). Male and female C57BL/6J mice were fed an adenine-supplemented diet to induce CKD prior to placement of an AVF in the iliac vascular bundle. Adeno-associated virus was used to drive expression of either a green fluorescent protein (control) or mCAT using the muscle-specific human skeletal actin (HSA) gene promoter prior to AVF creation. As expected, the muscle-specific AAV-HSA-mCAT treatment did not impact blood urea nitrogen levels (P = 0.72), body weight (P = 0.84), or central hemodynamics including infrarenal aorta and inferior vena cava diameters (P > 0.18) or velocities (P > 0.38). Hindlimb perfusion recovery and muscle capillary densities were also unaffected by AAV-HSA-mCAT treatment. In contrast to muscle mass and myofiber size which were not different between groups, both absolute and specific muscle contractile forces measured via a nerve-mediated in-situ preparation were significantly greater in AAV-HSA-mCAT treated mice (P = 0.0012 and P = 0.0002). Morphological analysis of the post-synaptic neuromuscular junction uncovered greater acetylcholine receptor cluster areas (P = 0.0094) and lower fragmentation (P = 0.0010) in AAV-HSA-mCAT treated mice. Muscle mitochondrial oxidative phosphorylation was not different between groups, but AAV-HSA-mCAT treated mice had lower succinate-fueled mitochondrial hydrogen peroxide emission compared to AAV-HSA-GFP mice (P

Raffaele Galiero,1,* Alfredo Caturano,1,* Erica Vetrano,1 Marcellino Monda,2 Raffaele Marfella,1 Celestino Sardu,1 Teresa Salvatore,3 Luca Rinaldi,1 Ferdinando Carlo Sasso1 1Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy; 2Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy; 3Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Naples, Italy*These authors contributed equally to this workCorrespondence: Ferdinando Carlo Sasso, Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, Naples, Italy, Tel/Fax +39 0815665010, Email ferdinandocarlo.sasso@unicampania.itAbstract: Type 2 diabetes mellitus (T2DM) is one of the most widespread diseases in Western countries, and its incidence is constantly increasing. Epidemiological studies have shown that in the next 20 years. The number of subjects affected by T2DM will double. In recent years, owing to the development and improvement in methods for studying the genome, several authors have evaluated the association between monogenic or polygenic genetic alterations and the development of metabolic diseases and complications. In addition, sedentary lifestyle and socio-economic and pandemic factors have a great impact on the habits of the population and have significantly contributed to the increase in the incidence of metabolic disorders, obesity, T2DM, metabolic syndrome, and liver steatosis. Moreover, patients with type 2 diabetes appear to respond to antihyperglycemic drugs. Only a minority of patients could be considered true non-responders. Thus, it appears clear that the main aim of precision medicine in T2DM is to identify patients who can benefit most from a specific drug class more than from the others. Precision medicine is a discipline that evaluates the applicability of genetic, lifestyle, and environmental factors to disease development. In particular, it evaluated whether these factors could affect the development of diseases and their complications, response to diet, lifestyle, and use of drugs. Thus, the objective is to find prevention models aimed at reducing the incidence of pathology and mortality and therapeutic personalized approaches, to obtain a greater probability of response and efficacy. This review aims to evaluate the applicability of precision medicine for T2DM, a healthcare burden in many countries.Keywords: type 2 diabetes mellitus, precision medicine, risk factors, genomic, environmental factors, drugs

Abstract For end-stage kidney disease (ESKD) patients, hemodialysis requires durable vascular access which is often surgically created using an arteriovenous fistula (AVF). However, some ESKD patients that undergo AVF placement develop access-related hand dysfunction (ARHD) through unknown mechanisms. In this study, we sought to determine if changes in the serum metabolome could distinguish ESKD patients that develop ARHD from those that have normal hand function following AVF creation. Forty-five ESKD patients that underwent first-time AVF creation were included in this study. Blood samples were obtained pre-operatively and 6-weeks post-operatively and metabolites were extracted and analyzed using nuclear magnetic resonance spectroscopy. Patients underwent thorough examination of hand function at both timepoints using the following assessments: grip strength manometry, dexterity, sensation, motor and sensory nerve conduction testing, hemodynamics, and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. Nineteen of the forty-five patients displayed overt weakness using grip strength manometry (P

Background Major depressive disorder (MDD) has been identified as a causal risk factor for multiple forms of cardiovascular disease. Although observational evidence has linked MDD to peripheral artery disease (PAD), causal evidence of this relationship is lacking. Methods and Results Inverse variance weighted 2‐sample Mendelian randomization was used to test the association the between genetic liability for MDD and genetic liability for PAD. Genetic liability for MDD was associated with increased genetic liability for PAD (odds ratio [OR], 1.17 [95% CI, 1.06–1.29]; P=2.6×10−3). Genetic liability for MDD was also associated with increased genetically determined lifetime smoking (β=0.11 [95% CI, 0.078–0.14]; P=1.2×10−12), decreased alcohol intake (β=−0.078 [95% CI, −0.15 to 0]; P=0.043), and increased body mass index (β=0.10 [95% CI, 0.02–0.19]; P=1.8×10−2), which in turn were associated with genetic liability for PAD (smoking: OR, 2.81 [95% CI, 2.28–3.47], P=9.8×10−22; alcohol: OR, 0.77 [95% CI, 0.66–0.88]; P=1.8×10−4; body mass index: OR, 1.61 [95% CI, 1.52–1.7]; P=1.3×10−57). Controlling for lifetime smoking index, alcohol intake, and body mass index with multivariable Mendelian randomization completely attenuated the association between genetic liability for MDD with genetic liability for PAD. Conclusions This work provides evidence for a possible causal association between MDD and PAD that is dependent on intermediate risk factors, adding to the growing body of evidence suggesting that effective management and treatment of cardiovascular diseases may require a composite of physical and mental health interventions.

Ruptured abdominal aortic aneurysms (rAAA) remain one of the most clinically challenging and technically complex emergencies in contemporary vascular surgery practice. Over the past 30 years, a variety of changes surrounding the treatment of rAAA have evolved including improvements in diagnosis, development of coordinated referral networks to transfer patients more efficiently to higher volume centers, deliberate de-escalation of pre-hospital resuscitation, modification of patient and procedure selection, implementation of clinical pathways, as well as enhanced awareness of certain high-impact postoperative complications. Despite these advances, current postoperative outcomes remain sobering since morbidity and mortality rates ranging from 25%-50% persist among modern published series. Some of the most impactful variation in rAAA management has been fostered by the rapid proliferation of endovascular repair (EVAR) along with service alignment at selected centers to improve timely revascularization. Indeed, clinical care pathways and emergency response networks are now increasingly utilized which has led to improved outcomes contemporaneously. Moreover, evolution in pre- and post-operative physiologic resuscitation has also contributed to observed improvements in rAAA outcomes. Due to different developments in care provision over time, the purpose of this review is to describe the modern management of rAAA, while providing historical perspectives on patient, procedure and systems-based practice elements that have evolved care delivery paradigms in this complex group of patients.

Short-term protein-calorie dietary restriction (StDR) is a promising preoperative strategy for modulating postoperative inflammation. We have previously shown marked gut microbial activity during StDR, but relationships between StDR, the gut microbiome, and systemic immunity remain poorly understood. Mucosal-associated invariant T-cells (MAITs) are enriched on mucosal surfaces and in circulation, bridge innate and adaptive immunity, are sensitive to gut microbial changes, and may mediate systemic responses to StDR. Herein, we characterized the MAIT transcriptomic response to StDR using single-cell RNA sequencing of human PBMCs and evaluated gut microbial species-level changes through sequencing of stool samples. Healthy volunteers underwent 4 days of DR during which blood and stool samples were collected before, during, and after DR. MAITs composed 2.4% of PBMCs. More MAIT genes were differentially downregulated during DR, particularly genes associated with MAIT activation (CD69), regulation of pro-inflammatory signaling (IL1, IL6, IL10, TNFα), and T-cell co-stimulation (CD40/CD40L, CD28), whereas genes associated with anti-inflammatory IL10 signaling were upregulated. Stool analysis showed a decreased abundance of multiple MAIT-stimulating Bacteroides species during DR. The analyses suggest that StDR potentiates an anti-inflammatory MAIT immunophenotype through modulation of TCR-dependent signaling, potentially secondary to gut microbial species-level changes.

Background: There is wide variation in stress test utilization before major vascular surgery and adherence to practice guidelines is unclear. We defined rates of stress test compliance at our institution and led a quality improvement initiative to improve compliance with American Heart Association (ACC/AHA) guidelines. Methods: We implemented a stress testing order set in the electronic medical record at one tertiary hospital. We reviewed all patients who underwent elective, major vascular surgery in the 6 months before (Jan 1, 2022 – Jul 1, 2022) and 6 months after (Aug 1, 2022 – Jan 31, 2023) implementation. We studied stress test guideline compliance, changes in medical or surgical management, and major adverse cardiac events (MACE). Results: Before order set implementation, 37/122 patients (30%) underwent stress testing within the past year (29 specifically ordered preoperatively) with 66% (19/29) guideline compliance. After order set implementation, 50/173 patients (29%) underwent stress testing within the past year (41 specifically ordered preoperatively) with 80% (33/41) guideline compliance. In the pre- and postimplementation cohorts, stress testing led to a cardiovascular medication change or preoperative coronary revascularization in 24% (7/29) and 27% (11/41) of patients, and a staged surgery or less invasive anesthetic strategy in 14% (4/29) and 4.9% (2/41) of patients, respectively. All unindicated stress tests were surgeon-ordered and none led to a change in management. There was no change in MACE after order set implementation. Conclusions: Electronic medical record-based guidance of perioperative stress testing led to a slight decrease in overall stress testing and an increase in guideline-compliant testing. Our study highlights a need for improved preoperative cardiovascular risk assessment prior to major vascular surgery, which may eliminate unnecessary testing and more effectively guide perioperative decision-making. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the association of surgeon self-reported gender on clinical outcomes in contemporary US surgical practice. Background: Previous research has suggested that there are potentially improved surgical outcomes for female surgeons, yet the underlying causal path for this association remains unclear. Methods: Using the Vizient Clinical Database(2016-2021), 39 operations categorized by the CDC's National Healthcare Safety Network were analyzed. The surgeon self-reported gender as the primary exposure. The primary outcome was a composite of inhospital death, complications, and/or 30-day readmission. Multivariable logistic regression and propensity score matching were used for risk adjustment. Results: The analysis included 4,882,784 patients operated on by 11,955 female surgeons (33% of surgeons performing 21% of procedures) and 23,799 male surgeons (67% of surgeons performing 79% of procedures). Female surgeons were younger (45±9 vs males-53±11 y; P<0.0001) and had lower operative volumes. Unadjusted incidence of the primary outcome was 13.6%(10.7%-female surgeons, 14.3%-male surgeons; P<0.0001). After propensity matching, the primary outcome occurred in 13.0% of patients [12.9%-female, 13.0%-male; OR (M vs. F)=1.02, 95% CI: 1.01-1.03; P= 0.001), with female surgeons having small statistical associations with lower mortality and complication rates but not readmissions. Procedure-specific analyses revealed inconsistent or no surgeon-gender associations. Conclusions: In the largest analysis to date, surgeon self-reported gender had a small statistical, clinically marginal correlation with postoperative outcomes. The variation across surgical specialties and procedures suggests that the association with surgeon gender is unlikely causal for the observed differences in outcomes. Patients should be reassured that surgeon gender alone does not have a clinically meaningful impact on their outcome. [ABSTRACT FROM AUTHOR]

Objective: Hand disability after hemodialysis access surgery has been common yet has remained poorly understood. Arteriovenous fistula (AVF) hemodynamic perturbations have not reliably correlated with the observed measures of hand function. Chronic kidney disease (CKD) is known to precipitate myopathy; however, the interactive influences of renal insufficiency and ischemia on limb outcomes have remained unknown. We hypothesized that CKD would contribute to access-related hand dysfunction via altered mitochondrial bioenergetics. Using a novel murine AVF model, we sought to characterize the skeletal muscle outcomes in mice with and without renal insufficiency. Methods: Male, 8-week-old C57BL/6J mice were fed either an adenine-supplemented diet to induce renal insufficiency (CKD) or a casein-based control chow (CON). After 2 weeks of dietary intervention, the mice were randomly assigned to undergo iliac AVF surgery (n = 12/group) or a sham operation (n = 5/group). Measurements of aortoiliac hemodynamics, hindlimb perfusion, and hindlimb motor function were collected for 2 weeks. The mice were sacrificed on postoperative day 14 to assess skeletal muscle histopathologic features and mitochondrial function. To assess the late outcome trends, 20 additional mice had undergone CKD induction and sham (n = 5) or AVF (n = 15) surgery and followed up for 6 weeks postoperatively before sacrifice. Results: The adenine-fed mice had had a significantly reduced glomerular filtration rate and elevated blood urea nitrogen, confirming the presence of CKD. The sham mice had a 100% survival rate and AVF cohorts an 82.1% survival rate with an 84.4% AVF patency rate. The aorta and inferior vena cava velocity measurements and the vessel diameter had increased after AVF creation (P < .0001 vs sham). The AVF groups had had a 78.4% deficit in paw perfusion compared with the contralateral limb after surgery (P < .0001 vs sham). Mitochondrial function was influenced by the presence of CKD. The respiratory capacity of the CKD-sham mice (8443 ± 1509 pmol/s/mg at maximal energy demand) was impaired compared with that of the CON-sham mice (12,870 ± 1203 pmol/s/mg; P = .0001). However, this difference was muted after AVF creation (CKD-AVF, 4478 ± 3685 pmol/s/mg; CON-AVF, 5407 ± 3582 pmol/s/mg; P = .198). The AVF cohorts had had impairments in grip strength (vs sham; P < .0001) and gait (vs sham; P = .012). However, the presence of CKD did not significantly alter the measurements of gross muscle function. The paw perfusion deficits had persisted 6 weeks postoperatively for the AVF mice (P < .0001 vs sham); however, the myopathy had resolved (grip strength, P = .092 vs sham; mitochondrial respiration, P = .108 vs sham). Conclusions: CKD and AVF-induced distal limb ischemia both impaired skeletal muscle mitochondrial function. Renal insufficiency was associated with a baseline myopathy that was exacerbated by the acute ischemic injury resulting from AVF creation. However, ischemia was the primary driver of the observed phenotype of gross motor impairment. This model reliably reproduced the local and systemic influences that contribute to access-related hand dysfunction and provides a platform for further mechanistic and therapeutic investigation. : Clinical Relevance: Access-related hand dysfunction (ARHD) has remained a common hemodialysis access surgery complication. Because of the poor mechanistic insight, the currently available therapies have been limited to surgical remediation of the hemodynamic changes in the limb for only the most severe clinical manifestations. Furthermore, expectant management or access revision will not be ideal options, especially for patients with mild to moderate ARHD, owing to the perioperative risk and implications for long-term access durability. Therefore, skeletal muscle mitochondrial-based therapy represents an intriguing treatment strategy. However, the characteristics of mitochondrial function after arteriovenous fistula placement are unknown. In the present study, we have characterized the ischemic and uremic influences on skeletal muscle physiology to identify the pathogenic drivers of ARHD.

Objective: The objective of the present study was to determine whether elevated levels of S100A8 and S100A9 (S100A8/A9) alarmins contribute to ischemic limb pathology. Methods: Gastrocnemius muscle was collected from control patients without peripheral arterial disease (PAD; n = 14) and patients with chronic limb threatening limb ischemia (CLTI; n = 14). Mitochondrial function was assessed in permeabilized muscle fibers, and RNA and protein analyses were used to quantify the S100A8/A9 levels. Additionally, a mouse model of hindlimb ischemia with and without exogenous delivery of S100A8/A9 was used. Results: Compared with the non-PAD control muscles, CLTI muscles displayed significant increases in the abundance of S100A8 and S100A9 at both mRNA and protein levels (P < .01). The CLTI muscles also displayed significant impairment in mitochondrial oxidative phosphorylation and increased mitochondrial hydrogen peroxide production compared with the non-PAD controls. The S100A8/A9 levels correlated significantly with the degree of muscle mitochondrial dysfunction (P < .05 for all). C57BL6J mice treated with recombinant S100A8/A9 displayed impaired perfusion recovery and muscle mitochondrial impairment compared with the placebo-treated mice after hindlimb ischemia surgery. These mitochondrial deficits observed after S100A8/A9 treatment were confirmed in the muscle cell culture system under normoxic conditions. Conclusions: The S100A8/A9 levels were increased in CLTI limb muscle specimens compared with the non-PAD control muscle specimens, and the level of accumulation was associated with muscle mitochondrial impairment. Elevated S100A8/A9 levels in mice subjected to hindlimb ischemia impaired perfusion recovery and mitochondrial function. Together, these findings suggest that the inflammatory mediators S100A8/A9 might be directly involved in ischemic limb pathology. : Clinical Relevance: Despite improvements in the surgical management of chronic limb threatening limb ischemia (CLTI), the rates of major adverse limb events have remained high. Skeletal muscle has emerged as a strong predictor of outcomes in peripheral arterial disease (PAD)/CLTI; however, a complete understanding of muscle pathology in CLTI is lacking. This study identified elevated S100A8 and S100A9 alarmin proteins as a characteristic of CLTI muscle specimens and that the S100A8/A9 levels are associated with the degree of mitochondrial impairment in patient limb muscle specimens. Using a mouse model of PAD, treatment with S100A8/A9 exacerbated ischemic limb pathology, including impaired limb perfusion recovery and muscle mitochondrial impairment. Taken together, these findings connect the inflammatory milieu in the CLTI limb to exacerbated limb muscle outcomes via mitochondrial alterations.