Mitochondrial targeted catalase improves muscle strength following arteriovenous fistula creation in mice with chronic kidney disease.

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 < 0.001). In summary, muscle-specific scavenging of mitochondrial hydrogen peroxide significantly improves neuromotor function in mice with CKD following AVF creation.

Short-Term Dietary Restriction Potentiates an Anti-Inflammatory Circulating Mucosal-Associated Invariant T-Cell Response.

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.

Outcomes of Patients with Acute Type B Aortic Dissection and High-Risk Features.

BACKGROUND: Recently the SVS and STS published contemporary guidelines clearly defining complicated vs uncomplicated acute type B aortic dissections (TBADs) with an additional high-risk grouping. Few studies have evaluated outcomes associated with "high-risk" TBADs. The objective of this study was to assess differences in demographics, clinical presentation, symptom onset, and outcomes in high-risk patients that underwent either thoracic endovascular aortic repair (TEVAR) or best medical management for acute TBAD compared to those with complicated and uncomplicated acute TBAD. METHODS: Patients admitted with acute TBADs from a single academic medical center from 10/ 2011 to 3/2020 were analyzed. Per STS/SVS 2020 guidelines, high-risk was defined as refractory pain/hypertension, bloody pleural effusion, aortic diameter >4cm, false lumen diameter >22mm, radiographic malperfusion, early readmission, and complicated was defined as ruptured/malperfusion presentation. Uncomplicated patients were those without malperfusion/rupture and without high-risk features. The primary end-point was inpatient mortality. Secondary end-points included complications, re-intervention and survival. RESULTS: Of 159 patients identified with acute TBAD, 63 (40%) met high-risk criteria. In the high-risk cohort, 38 (60%) underwent TEVAR (HR-TEVAR), with refractory pain as the most common indication, while 25 (40%) were managed medically (HR-Medical). Malperfusion or rupture was present in 63 (40%) patients (C-TBAD), all of whom underwent TEVAR. An additional 33 patients had no high-risk features and were all managed medically (U-TBAD). There were no differences in age, BMI, and race between groups. Among the four groups, there were variable distributions in sex, insurance status, and incidence of several baseline comorbidities including CHF, COPD, and renal dysfunction (p<0.05 for all). C-TBAD had increased length of stay (12, IQR 9-22) compared to HR-TEVAR (11.5, IQR 7-15), HR-Medical (6, IQR 5-8), and U-TBAD (7, IQR 5-10) (p<0.01). C-TBAD had decreased days from admission to repair (0, IQR 0,2) compared to HR-TEVAR (3.5, IQR 1-8) (p<0.01). C-TBAD patients had worse 3-year survival compared to other groups (log-rank p<0.01), although when in-hospital mortality was excluded, survival was similar among groups (p=0.37).Of patients initially managed medically, outpatient TEVAR was performed in 6 (24%) HR-Medical and 4 (12%) uncomplicated patients, with no difference between rate of intervention between groups (p=0.22). CONCLUSIONS: High-risk features, as defined in updated SVS/STS guidelines, are common in patients presenting with acute TBAD. High-risk patients had acceptable outcomes when managed either surgically or medically. High-risk patients that underwent TEVAR had improved perioperative outcomes and mortality compared to those undergoing TEVAR for complicated TBAD, a finding which may help guide preoperative risk stratification and patient counseling.

Comparative outcomes of open mesenteric bypass after a failed endovascular or open mesenteric revascularization for chronic mesenteric ischemia.

INTRODUCTION: Clinical practice guidelines have recommended an endovascular-first approach (ENDO) for the management of patients with chronic mesenteric ischemia (CMI), whereas an open mesenteric bypass (OMB) is proposed for subjects deemed to be poor ENDO candidates. However, the impact of a previous failed endovascular or open mesenteric reconstruction on a subsequent OMB is unknown. Accordingly, this study was designed to examine the results of a remedial OMB (R-OMB) after a failed ENDO or a primary OMB (P-OMB) for patients with recurrent CMI. METHODS: All patients who underwent an OMB from 2002 to 2022 at the University of Florida were reviewed. Outcomes after an R-OMB (ie, history of a failed ENDO or P-OMB) and P-OMB were compared. The primary end point was 30-day mortality, whereas secondary outcomes included complications, reintervention, and survival. The Kaplan-Meier methodology was used to estimate freedom from reintervention and all-cause mortality, whereas multivariable Cox proportional hazards modeling identified predictors of death. RESULTS: A total of 145 OMB procedures (R-OMB, n = 48 [33%]; P-OMB, n = 97 [67%]) were analyzed. A majority of R-OMB operations were performed for a failed stent (prior ENDO, n = 39 [81%]; prior OMB, n = 9 [19%]). R-OMB patients were generally younger (66 ± 9 years vs P-OMB, 69 ± 11 years; P = .09) and had lower incidence of smoking exposure (29% vs P-OMB, 48%; P = .07); however, there were no other differences in demographics or comorbidities. R-OMB was associated with less intraoperative transfusion (0.6 units vs P-OMB, 1.4 units; P = .01), but there were no differences in conduit choice or bypass configuration.The overall 30-day mortality and complication rates were 7% (n = 10/145) and 53% (n = 77/145), respectively, with no difference between the groups. Notably, R-OMB had decreased cardiac (6% vs P-OMB, 21%; P < .01) and bleeding complication rates (2% vs P-OMB, 15%; P = .01). The freedom from reintervention (1 and 5 years: R-OMB: 95% ± 4%, 83% ± 9% vs P-OMB: 97% ± 2%, 93% ± 5%, respectively; log-rank P = .21) and survival (1 and 5 years: R-OMB: 82% ± 6%, 68% ± 9% vs P-OMB: 84% ± 4%, 66% ± 7%; P = .91) were similar. Independent predictors of all-cause mortality included new postoperative hemodialysis requirement (hazard ratio [HR], 7.4, 95% confidence interval [CI], 3.1-17.3; P < .001), pulmonary (HR, 2.7, 95% CI, 1.4-5.3; P = .004) and cardiac (HR, 2.4, 95% CI, 1.1-5.1; P = .04) complications, and female sex (HR, 2.1, 95% CI, 1.03-4.8; P = .04). Notably, R-OMB was not a predictor of death. CONCLUSIONS: The perioperative and longer-term outcomes for a remedial OMB after a failed intraluminal stent or previous open bypass appear to be comparable to a P-OMB. These findings support the recently updated clinical practice guideline recommendations for an endovascular-first approach to treating recurrent CMI due to the significant perioperative complication risk of OMB. However, among the subset of patients deemed ineligible for endoluminal reconstruction after failed mesenteric revascularization, R-OMB results appear to be acceptable and highlight the utility of this strategy in selected patients.

Sarcopenia is a Poor Predictor of Outcomes in Elective Colectomy for Diverticulitis.

BACKGROUND: Sarcopenia is associated with adverse perioperative outcomes in patients undergoing operations for malignancy, but its influence on patients undergoing elective colectomy for diverticulitis is unknown. We hypothesized that sarcopenia is associated with adverse perioperative events in patients undergoing elective colectomy for diverticulitis. METHODS: Comorbidities, operative characteristics, and postoperative complications were extrapolated from our institutional EMR in patients undergoing elective colectomy for diverticulitis from 2016 to 2020. Sarcopenia was calculated using perioperative imaging and defined by standard skeletal muscle index (SMI) and psoas muscle index (PMI) thresholds. Univariate analysis was used to compare sarcopenic and non-sarcopenic patients. RESULTS: 148 patients met inclusion criteria. Using SMI thresholds, 95 patients (64%) were sarcopenic. With SMI criteria, sarcopenic patients were older (67 vs 52 years old; P < .01) and had lower BMIs (26.2 vs 34.0, respectively; P < .001) than non-sarcopenic patients. There were no differences in baseline characteristics, postoperative complications, and non-home discharge between groups (P > .05 for all). Postoperative length of stay was greater in sarcopenic patients (3 IQR 2-5 vs 2 IQR 2-3 days; P < .01). Using PMI thresholds, 68 (46%) met criteria for sarcopenia. Using PMI thresholds, sarcopenic patients were older (68 vs 57.5 years old; P < .01) and had lower BMIs (25.8 vs 32.8; P < .01). There were no differences in comorbidities or measured operative outcomes between groups (P > .05 for all), other than postoperative length of stay which was longer in the sarcopenic group (3.5 IQR 3-5 vs 2 IQR 2-3; P < .01). CONCLUSIONS: Incidence of sarcopenia was high in patients undergoing elective colectomy for diverticulitis in our practice, but sarcopenia was not associated with adverse perioperative outcomes. In select patients, elective colectomy for diverticulitis can be safely performed in the presence of sarcopenia.

Perioperative Cerebrospinal Fluid Drain Placement Does Not Increase Venous Thromboembolism Risk After Thoracic and Fenestrated Endovascular Aortic Repair.

BACKGROUND: Venous thromboembolism (VTE) incidence after thoracic and fenestrated endovascular aortic repair (TEVAR/FEVAR) is high (up to 6-7%) relative to other vascular procedures; however, the etiology for this discrepancy remains unknown. Notably, patients undergoing TEVAR/FEVAR commonly receive cerebrospinal fluid drains (CSFDs) for neuroprotection, requiring interruption of perioperative anticoagulation and prolonged immobility. We hypothesized that CSFDs are a risk factor for VTE after TEVAR/FEVAR. METHODS: Consecutive TEVAR/FEVAR patients at a single center were reviewed (2011-2020). Cerebrospinal fluid drains (CSFDs) were placed based on surgeon preference preoperatively or for spinal cord ischemia (SCI) rescue therapy postoperatively. The primary end-point was VTE occurrence, defined as any new deep venous thrombosis (DVT) or pulmonary embolism (PE) confirmed on imaging within 30 days postoperatively. Routine postoperative VTE screening was not performed. Patients with and without VTE, and subjects with and without CSFDs were compared. Logistic regression was used to explore associations between VTE incidence and CSFD exposure. RESULTS: Eight hundred ninety-seven patients underwent TEVAR/FEVAR and 43% (n = 387) received a CSFD at some point during their care (preoperative: 94% [n = 365/387]; postoperative SCI rescue therapy: 6% [n = 22/387]). CSFD patients were more likely to have previous aortic surgery (44% vs. 37%; P = 0.028) and received more postoperative blood products (780 vs. 405 mL; P = 0.005). The overall VTE incidence was 2.2% (n = 20). 70% (14) patients with VTE had DVT, 50% (10) had PE, and 20% (4) had DVT and PE. Among TEVAR/FEVAR patients with VTE, 65% (n = 13) were symptomatic. Most VTEs (90%, n = 18) were identified inhospital and the median time to diagnosis was 12.5 (interquartile range 7.5-18) days postoperatively. Patients with VTE were more likely to have nonelective surgery (95% vs. 41%; P < 0.001), had higher American Society of Anesthesiologists classification (4.1 vs. 3.7; P < 0.001), required longer intensive care unit admission (24 vs. 12 days; P < 0.001), and received more blood products (1,386 vs. 559 mL; P < 0.001). Venous thromboembolism (VTE) incidence was 1.8% in CSFD patients compared to 3.5% in non-CSFD patients (odds ratio 0.70 [95% confidence interval 0.28-1.78, P = 0.300). However, patients receiving CSFDs postoperatively for SCI rescue therapy had significantly greater VTE incidence (9.1% vs. 1.1%; P = 0.044). CONCLUSIONS: CSFD placement was not associated with an increased risk of VTE in patients undergoing TEVAR/FEVAR. Venous thromboembolism (VTE) risk was greater in patients undergoing nonelective surgery and those with complicated perioperative courses. Venous thromboembolism (VTE) risk was greater in patients receiving therapeutic CSFDs compared to prophylactic CSFDs, highlighting the importance of careful patient selection for prophylactic CSFD placement.

Persistent Acute Kidney Injury is Associated with Poor Outcomes and Increased Hospital Cost in Vascular Surgery.

BACKGROUND: Postoperative acute kidney injury (AKI) is common after major surgery and is associated with increased morbidity, mortality, and cost. Additionally, there are recent studies demonstrating that time to renal recovery may have a substantial impact on clinical outcomes. We hypothesized that patients with delayed renal recovery after major vascular surgery will have increased complications, mortality, and hospital cost. METHODS: A single-center retrospective cohort of patients undergoing nonemergent major vascular surgery between 6/1/2014 and 10/1/2020 was analyzed. Development of postoperative AKI (defined using Kidney Disease Improving Global Outcomes (KDIGO) criteria: >50% or > 0.3 mg/dl absolute increase in serum creatinine relative to reference after surgery and before discharge) was evaluated. Patients were divided into 3 groups: no AKI, rapidly reversed AKI (<48 hours), and persistent AKI (≥48 hours). Multivariable generalized linear models were used to evaluate the association between AKI groups and postoperative complications, 90-day mortality, and hospital cost. RESULTS: A total of 1,881 patients undergoing 1,980 vascular procedures were included. Thirty five percent of patients developed postoperative AKI. Patients with persistent AKI had longer intensive care unit and hospital stays, as well as more mechanical ventilation days. In multivariable logistic regression analysis, persistent AKI was a major predictor of 90-day mortality (odds ratio 4.1, 95% confidence interval 2.4-7.1). Adjusted average cost was higher for patients with any type of AKI. The incremental cost of having any AKI ranged from $3,700 to $9,100, even after adjustment for comorbidities and other postoperative complications. The adjusted average cost for patients stratified by type of AKI was higher among patients with persistent AKI compared to those with no or rapidly reversed AKI. CONCLUSIONS: Persistent AKI after vascular surgery is associated with increased complications, mortality, and cost. Strategies to prevent and aggressively treat AKI, specifically persistent AKI, in the perioperative setting are imperative to optimize care for this population.

Sex differences in outcomes of exercise therapy for patients with intermittent claudication: A scoping review.

Exercise therapy is first-line treatment for intermittent claudication due to peripheral artery disease. We sought to synthesize the literature on sex differences in response to exercise therapy for the treatment of intermittent claudication due to peripheral artery disease. A scoping review was performed (1997 to 2023) using Ovid MEDLINE, CINAHL (Cumulative Index to Nursing and Allied Health Literature), Embase, SPORTDiscus, and Web of Science. Articles were included if they were a scientific report of any measures of health-related quality of life or walking performance after an intervention that included a structured walking program. Of the 13 studies, 11 included measures of walking distance; 7 included measures of walking time, 5 included measures of walking speed, and 4 included quality of life measures. Overall, exercise therapy resulted in significant improvements across most measures of walking performance for both men and females. When comparing magnitudes of outcome improvement by sex, results of walking-based measures were contradictory; some studies noted no difference and others found superior outcomes for men. Results of quality of life-based measures were also contradictory, with some finding no difference and others reporting substantially more improvement for females. Both men and females experienced considerable improvement in walking performance and quality of life with exercise therapy. Evidence regarding the differential effect of exercise therapy on outcomes by sex for intermittent claudication is limited and contradictory. Further efforts should be directed at using standardized interventions and metrics for measuring the outcomes that match the indications for intervention in these patients to better understand the expected benefits and any variance according to sex.

Single-Nuclei RNA-Sequencing of the Gastrocnemius Muscle in Peripheral Artery Disease.

BACKGROUND: Lower extremity peripheral artery disease (PAD) is a growing epidemic with limited effective treatment options. Here, we provide a single-nuclei atlas of PAD limb muscle to facilitate a better understanding of the composition of cells and transcriptional differences that comprise the diseased limb muscle. METHODS: We obtained gastrocnemius muscle specimens from 20 patients with PAD and 12 non-PAD controls. Nuclei were isolated and single-nuclei RNA-sequencing was performed. The composition of nuclei was characterized by iterative clustering via principal component analysis, differential expression analysis, and the use of known marker genes. Bioinformatics analysis was performed to determine differences in gene expression between PAD and non-PAD nuclei, as well as subsequent analysis of intercellular signaling networks. Additional histological analyses of muscle specimens accompany the single-nuclei RNA-sequencing atlas. RESULTS: Single-nuclei RNA-sequencing analysis indicated a fiber type shift with patients with PAD having fewer type I (slow/oxidative) and more type II (fast/glycolytic) myonuclei compared with non-PAD, which was confirmed using immunostaining of muscle specimens. Myonuclei from PAD displayed global upregulation of genes involved in stress response, autophagy, hypoxia, and atrophy. Subclustering of myonuclei also identified populations that were unique to PAD muscle characterized by metabolic dysregulation. PAD muscles also displayed unique transcriptional profiles and increased diversity of transcriptomes in muscle stem cells, regenerating myonuclei, and fibro-adipogenic progenitor cells. Analysis of intercellular communication networks revealed fibro-adipogenic progenitors as a major signaling hub in PAD muscle, as well as deficiencies in angiogenic and bone morphogenetic protein signaling which may contribute to poor limb function in PAD. CONCLUSIONS: This reference single-nuclei RNA-sequencing atlas provides a comprehensive analysis of the cell composition, transcriptional signature, and intercellular communication pathways that are altered in the PAD condition.

Temporal serum metabolomic and lipidomic analyses distinguish patients with access-related hand disability following arteriovenous fistula creation.

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 < 0.0001). Unfortunately, the serum metabolome was indistinguishable between patients with and without weakness following AVF surgery. However, a significant correlation was found between the change in tryptophan levels and the change in grip strength suggesting a possible role of tryptophan-derived uremic metabolites in post-AVF hand-associated weakness. Compared to grip strength, changes in dexterity and sensation were smaller than those observed in grip strength, however, post-operative decreases in phenylalanine, glycine, and alanine were unique to patients that developed signs of motor or sensory disability following AVF creation.

Self-pay insurance status is associated with failure of medical therapy in patients with acute uncomplicated type B aortic dissection.

BACKGROUND: Traditionally, acute uncomplicated type B aortic dissections are managed medically, and acute complicated dissections are managed surgically. Self-pay patients with medically managed acute uncomplicated type B aortic dissections may fare worse than their insured counterparts. METHODS: In this single-center, retrospective cohort study, demographics, follow-up, and outcomes of patients with acute type B aortic dissections from 2011 to 2020 were analyzed. RESULTS: In total, 159 patients presented with acute type B aortic dissections; 102 were complicated and managed with thoracic endovascular aortic repair, and 57 were uncomplicated and managed medically. A total of 32% (n = 51) were self-pay. Self-pay patients were from areas with worse area deprivation indices (71% vs 63%, P = .024). They more often reported alcohol abuse (28% vs 7%, P < .001), cocaine/methamphetamine use (16% vs 5%, P = .028), and nonadherence to home antihypertensives (35% vs 11%, P < .001). Self-pay patients less often had a primary care physician (65% vs 7%, P < .001) or took antihypertensives before admission (31% vs 58%, P = .003). Self-pay patients frequently required financial assistance at discharge (63%), most often using charity funds (46%). Few patients (7%) qualified for our hospital's financial assistance program, and most (78%) remained uninsured at the first follow-up. Self-pay acute uncomplicated type B aortic dissections patients had the lowest rate of follow-up (31% vs 66%, P < .001) and were more likely to represent emergently (75% vs 0%, P = .033) compared to insured acute uncomplicated type B aortic dissections patients. Self-pay patients were more likely to follow up after thoracic endovascular aortic repair for acute complicated type B aortic dissections (82% vs 31%, P < .001). CONCLUSION: Self-pay patients have multiple, interconnected, complex socioeconomic factors that likely influence preadmission risk for dissection and post-discharge adherence to optimal medical management. Further research is needed to clarify treatment strategies in this high-risk group.

Presentation and Outcomes of Elective and Nonelective Complex Endovascular Repair for Thoracoabdominal and Juxtarenal Aortic Aneurysms.

BACKGROUND: Endovascular repair of thoracoabdominal aortic aneurysms (TAAA) and juxtarenal aortic aneurysms (JAA) with fenestrated and/or branched endografts (B/FEVAR) has become common. Physician modified endografts for patients presenting with symptomatic or contained ruptures has made B/FEVAR a feasible option in nonelective settings. The purpose of this study was to describe our 10-year institutional experience with endovascular interventions for TAAA in elective and nonelective cases to evaluate differences in outcomes and the clinical risk factors associated with nonelective presentation. METHODS: A prospectively maintained database was retrospectively queried for patients undergoing B/FEVAR for TAAA and JAA at a single tertiary care academic institution between 1/2011 and 12/2020. Data collected included demographics, comorbidities, presenting symptoms, aneurysm characteristics, and clinical outcomes. Nonelective repair was defined as any patient that presented through the Emergency Department, as a hospital transfer, or as a direct admission from clinic and had aortic repair performed during the same admission. Univariate analyses were used to compare patients. The primary outcomes were 30-day and 1-year mortality. Secondary outcomes included perioperative complications and nonhome discharge. RESULTS: Between 1/201 and 12/2020, a total of 208 patients underwent B/FEVAR for TAAA (173) and JAA (35). Nonelective repair was performed in 44 (21%) patients with 39 for TAAA (23%) and 5 for JAA (14%). Nonelective patients were younger (71 ± 11 vs. 74 ± 7 years, P = 0.03), more likely to be self-pay or have Medicaid (11% vs. 2%, P = 0.02) and had a different race distribution compared to the elective cohort (P < 0.01). Thirty-day mortality was 4% (n = 6) in elective repairs and 7% (n = 3) in nonelective repairs. One-year mortality was 13% (n = 22) in elective repairs and 18% (n = 8) in nonelective repairs. There were no differences between patients receiving elective versus nonelective repair in 30-day (P = 0.40) or 1-year mortality (P = 0.47). Nonelective patients had longer median duration of stay (11 interquartile range (IQR) 6-15 vs. 5 IQR 4-8, P < 0.01), postoperative length of stay (7 IQR 5-12 vs. 4 IQR 3-7, P < 0.01), and more intensive care unit days (6 IQR 3-8 vs. 3 IQR 2-5, P < 0.01). There were no differences in other secondary outcomes between elective and nonelective patients including inpatient and access-related complications, re-interventions, and nonhome discharge (P > 0.05 for all comparisons). A composite "any complication" occurred more frequently in patients with nonelective repair (50% vs. 35%, P = 0.03). CONCLUSIONS: Endovascular repair for TAAA or JAA is a good option in patients undergoing nonelective surgical intervention, with comparable 30-day mortality, 1-year mortality, and perioperative morbidity to that of patients undergoing elective B/FEVAR.

N-acetylcysteine treatment attenuates hemodialysis access-related limb pathophysiology in mice with chronic kidney disease.

The objective of the present study was to determine if treatment with N-acetylcysteine (NAC) could reduce access-related limb dysfunction in mice. Male and female C57BL6J mice were fed an adenine-supplemented diet to induce chronic kidney disease (CKD) prior to the surgical creation of an arteriovenous fistula (AVF) in the iliac vascular bundle. AVF creation significantly increased peak aortic and infrarenal vena cava blood flow velocities, but NAC treatment had no significant impact, indicating that fistula maturation was not impacted by NAC treatment. Hindlimb muscle and paw perfusion recovery and muscle capillary density in the AVF limb were unaffected by NAC treatment. However, NAC treatment significantly increased the mass of the tibialis anterior (P = 0.0120) and soleus (P = 0.0452) muscles post-AVF. There was a significant main effect of NAC treatment on hindlimb grip strength at postoperative day 12 (POD 12) (P = 0.0003), driven by significantly higher grip strength in both male (P = 0.0273) and female (P = 0.0031) mice treated with NAC. There was also a significant main effect of NAC treatment on the walking speed at postoperative day 12 (P = 0.0447), and post hoc testing revealed an improvement in NAC-treated male mice (P = 0.0091). The area of postsynaptic acetylcholine receptors (P = 0.0263) and motor endplates (P = 0.0240) was also increased by NAC treatment. Interestingly, hindlimb skeletal muscle mitochondrial oxidative phosphorylation trended higher in NAC-treated female mice but was not statistically significant (P = 0.0973). Muscle glutathione levels and redox status were not significantly impacted by NAC treatment in either sex. In summary, NAC treatment attenuated some aspects of neuromotor pathology in mice with chronic kidney disease following AVF creation.NEW & NOTEWORTHY Hemodialysis via autogenous arteriovenous fistula (AVF) is the preferred first-line modality for renal replacement therapy in patients with end-stage kidney disease. However, patients undergoing AVF surgery frequently experience a spectrum of hand disability symptoms postsurgery including weakness and neuromotor dysfunction. Unfortunately, no treatment is currently available to prevent or mitigate these symptoms. Here, we provide evidence that daily N-acetylcysteine supplementation can attenuate some aspects of limb neuromotor function in a preclinical mouse model of AVF.

Influences of renal insufficiency and ischemia on mitochondrial bioenergetics and limb dysfunction in a novel murine iliac arteriovenous fistula model.

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.

Psoas Muscle Area as a Prognostic Factor for Survival in Patients Undergoing Endovascular Aneurysm Repair Conversion.

BACKGROUND: Endovascular aneurysm repair conversion (EVAR-c) is increasingly reported and known to be technically complex and physiologically demanding. It has been proposed that pragmatic anthropomorphic measures such as psoas muscle area (PMA) may reliably quantify levels of preoperative frailty and be used to inform point of care clinical decision-making and patient discussions for a variety of complex operations. To date, there is mixed data supporting use of PMA as a prognostic factor in fenestrated endovascular and open abdominal aortic aneurysms (AAA) repairs; however, no literature exists evaluating the impact of preoperative PMA on EVAR-c results. Therefore, the purpose of this study was to review our EVAR-c experience and evaluate the association of PMA with perioperative and long-term mortality outcomes. METHODS: A retrospective single-center review of all AAA repairs was performed (2002-2019) and EVAR-c procedures were subsequently analyzed (n = 153). Cross-sectional PMA at the mid-body of the L3 vertebrae was measured. The lowest PMA tertile was used as a threshold value to designate patients as having "low" PMA (n = 51) and this cohort was subsequently compared to subjects with "normal" PMA (n = 102). Cox proportional hazards modeling was used to estimate covariate association with all-cause mortality. RESULTS: Patients with low PMA were older (77 vs. 72 years; P = 0.002), more likely to be female (27% vs. 5%; P < 0.001), and had reduced body mass index (26 vs. 29 kg/m2; P = 0.002). Time to conversion, total number of endovascular aneurysm repair (EVAR) reinterventions prior to conversion and elective EVAR-c presentation incidence were similar; however, patients with low PMA had larger aneurysms (8.3 vs. 7.5 cm; P = 0.01) and increased post-EVAR sac growth (2.3 vs. 1 cm; P = 0.005). Unadjusted inpatient mortality was significantly greater for low PMA patients (16% vs. normal PMA, 5%, P = 0.02). Similarly, the total number of complications was higher among low PMA subjects (1.5 ± 1.9 vs. normal PMA, 0.9 ± 1.5; P = 0.02). Although frequency of major adverse cardiovascular events and new onset inpatient hemodialysis were similar, low PMA patients had a more than four-fold increased likelihood of having persistent requirement of hemodialysis at discharge (18% vs. 4%,P = 0.01). The low PMA group had decreased survival at 1 and 5 years, respectively (77 ± 5%, 65 ± 6% vs. normal PMA, 86 ± 3%, 82% ± 5%; log-rank P = 0.03). Low PMA was an independent predictor of mortality with every 100 mm2 increase in PMA being associated with a 15% reduction in mortality (hazard ratio: 0.85,95% confidence interval:, 0.74-0.97; P = 0.02). CONCLUSIONS: Among EVAR-c patients, subjects with low preoperative PMA had higher rates of postoperative complications and worse overall survival. PMA assessments may be a useful adjunct to supplement traditional risk-stratification strategies when patients are being considered for EVAR-c.

Metabolomic profiling reveals muscle metabolic changes following iliac arteriovenous fistula creation in mice.

End-stage kidney disease, the most advanced stage of chronic kidney disease (CKD), requires renal replacement therapy or kidney transplant to sustain life. To accomplish durable dialysis access, the creation of an arteriovenous fistula (AVF) has emerged as a preferred approach. Unfortunately, a significant proportion of patients that receive an AVF experience some form of hand dysfunction; however, the mechanisms underlying these side effects are not understood. In this study, we used nuclear magnetic resonance spectroscopy to investigate the muscle metabolome following iliac AVF placement in mice with CKD. To induce CKD, C57BL6J mice were fed an adenine-supplemented diet for 3 wk and then randomized to receive AVF or sham surgery. Two weeks following surgery, the quadriceps muscles were rapidly dissected and snap frozen for metabolite extraction and subsequent nuclear magnetic resonance analysis. Principal component analysis demonstrated clear separation between groups, confirming a unique metabolome in mice that received an AVF. AVF creation resulted in reduced levels of creatine, ATP, and AMP as well as increased levels of IMP and several tricarboxylic acid cycle metabolites suggesting profound energetic stress. Pearson correlation and multiple linear regression analyses identified several metabolites that were strongly linked to measures of limb function (grip strength, gait speed, and mitochondrial respiration). In summary, AVF creation generates a unique metabolome profile in the distal skeletal muscle indicative of an energetic crisis and myosteatosis.NEW & NOTEWORTHY Creation of an arteriovenous fistula (AVF) is the preferred approach for dialysis access, but some patients experience hand dysfunction after AVF creation. In this study, we provide a detailed metabolomic analysis of the limb muscle in a murine model of AVF. AVF creation resulted in metabolite changes associated with an energetic crisis and myosteatosis that associated with limb function.

Phenotype clustering in health care: A narrative review for clinicians.

Human pathophysiology is occasionally too complex for unaided hypothetical-deductive reasoning and the isolated application of additive or linear statistical methods. Clustering algorithms use input data patterns and distributions to form groups of similar patients or diseases that share distinct properties. Although clinicians frequently perform tasks that may be enhanced by clustering, few receive formal training and clinician-centered literature in clustering is sparse. To add value to clinical care and research, optimal clustering practices require a thorough understanding of how to process and optimize data, select features, weigh strengths and weaknesses of different clustering methods, select the optimal clustering method, and apply clustering methods to solve problems. These concepts and our suggestions for implementing them are described in this narrative review of published literature. All clustering methods share the weakness of finding potential clusters even when natural clusters do not exist, underscoring the importance of applying data-driven techniques as well as clinical and statistical expertise to clustering analyses. When applied properly, patient and disease phenotype clustering can reveal obscured associations that can help clinicians understand disease pathophysiology, predict treatment response, and identify patients for clinical trial enrollment.

Temporal Dynamics of the Intestinal Microbiome Following Short-Term Dietary Restriction.

Short-term dietary restriction has been proposed as an intriguing pre-operative conditioning strategy designed to attenuate the surgical stress response and improve outcomes. However, it is unclear how this nutritional intervention influences the microbiome, which is known to modulate the systemic condition. Healthy individuals were recruited to participate in a four-day, 70% protein-restricted, 30% calorie-restricted diet, and stool samples were collected at baseline, after the restricted diet, and after resuming normal food intake. Taxonomy and functional pathway analysis was performed via shotgun metagenomic sequencing, prevalence filtering, and differential abundance analysis. High prevalence species were altered by the dietary intervention but quickly returned to baseline after restarting a regular diet. Composition and functional changes after the restricted diet included the decreased relative abundance of commensal bacteria and a catabolic phenotype. Notable species changes included Faecalibacterium prausnitzii and Roseburia intestinalis, which are major butyrate producers within the colon and are characteristically decreased in many disease states. The macronutrient components of the diet might have influenced these changes. We conclude that short-term dietary restriction modulates the ecology of the gut microbiome, with this modulation being characterized by a relative dysbiosis.

A Murine Model of Hemodialysis Access-related Hand Dysfunction.

Chronic kidney disease is a major public health problem, and the prevalence of end-stage renal disease (ESRD) requiring chronic renal replacement therapies such as hemodialysis continues to increase. Autogenous arteriovenous fistula (AVF) placement remains a primary vascular access option for ESRD patients. Unfortunately, approximately half of the hemodialysis patients experience dialysis access-related hand dysfunction (ARHD), ranging from subtle paresthesia to digital gangrene. Notably, the underlying biologic drivers responsible for ARHD are poorly understood, and no adequate animal model exists to elucidate the mechanisms and/or develop novel therapeutics for the prevention/treatment of ARHD. Herein, we describe a new mouse model in which an AVF is created between the left common iliac artery and vein, thereby facilitating the assessment of limb pathophysiology. The microsurgery includes vessel isolation, longitudinal venotomy, creation of arteriovenous anastomosis, and venous reconstruction. Sham surgeries include all the critical steps except for AVF creation. Iliac AVF placement results in clinically relevant alterations in central hemodynamics, peripheral ischemia, and impairments in hindlimb neuromotor performance. This novel preclinical AVF model provides a useful platform that recapitulates common neuromotor perturbations reported by hemodialysis patients, allowing researchers to investigate the mechanisms of ARHD pathophysiology and test potential therapeutics.