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.

Limited health literacy is common among vascular surgery patients.

BACKGROUND: Health literacy is a crucial aspect of informed decision-making, and limited health literacy has been associated with worse health care outcomes. To date, health literacy has not been examined in vascular surgery patients. Therefore, we conducted a prospective observational study to determine the prevalence and factors associated with poor health literacy in vascular surgery patients. METHODS: The Newest Vital Sign (Pfizer, New York, NY), a validated instrument, was used to appraise the health literacy of 150 patients who visited the outpatient vascular clinic at UF Health Shands Hospital between April 2022 and August 2022. Patients who scored a 4 (out of 6) or higher were classified as having adequate health literacy. Each study participant also completed a sociodemographic questionnaire. RESULTS: In total, 82 out of the 150 (54%) patients we screened had limited health literacy. The prevalence of limited health literacy varied and was independently associated with increased age (odds ratio 1.06; 95% [1.02 to 1.10], P = .004), having not attended college (high school diploma versus college+ odds ratio 3.5; 95% [1.26 to 10.1], P = .018), and African American race (odds ratio 5.3; 95% [1.59 to 22.3], P = .012). A total of 83% of African American patients had limited health literacy, compared to 49% of Asian and White patients. CONCLUSION: Most vascular surgery patients have limited health literacy. Increased age, fewer years of education, and African American race were associated with limited health literacy. Physicians caring for patients with lower health literacy should investigate and use communication strategies tailored to patients with limited health literacy.

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.

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.

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.

National Institutes of Health funding among vascular surgeons is rare.

BACKGROUND: The National Institutes of Health (NIH) is an essential source of funding for vascular surgeons conducting research. NIH funding is frequently used to benchmark institutional and individual research productivity, help determine eligibility for academic promotion, and as a measure of scientific quality. We sought to appraise the current scope of NIH funding to vascular surgeons by appraising the characteristics of NIH-funded investigators and projects. In addition, we also sought to determine whether funded grants addressed recent Society for Vascular Surgery (SVS) research priorities. METHODS: In April 2022, we queried the NIH Research Portfolio Online Reporting Tools Expenditures and Results (RePORTER) database for active projects. We only included projects that had a vascular surgeon as a principal investigator. Grant characteristics were extracted from the NIH Research Portfolio Online Reporting Tools Expenditures and Results database. Principal investigator demographics and academic background information were identified by searching institution profiles. RESULTS: There were 55 active NIH awards given to 41 vascular surgeons. Only 1% (41/4037) of all vascular surgeons in the United States receive NIH funding. Funded vascular surgeons are an average of 16.3 years out of training; 37% (n = 15) are women. The majority of awards (58%; n = 32) were R01 grants. Among the active NIH-funded projects, 75% (n = 41) are basic or translational research projects, and 25% (n = 14) are clinical or health services research projects. Abdominal aortic aneurysm and peripheral arterial disease are the most commonly funded disease areas and together accounted for 54% (n = 30) of projects. Three SVS research priorities are not addressed by any of the current NIH-funded projects. CONCLUSIONS: NIH funding of vascular surgeons is rare and predominantly consists of basic or translational science projects focused on abdominal aortic aneurysm and peripheral arterial disease research. Women are well-represented among funded vascular surgeons. Although the majority of SVS research priorities receive NIH funding, three SVS research priorities are yet to be addressed by NIH-funded projects. Future efforts should focus on increasing the number of vascular surgeons receiving NIH grants and ensuring all SVS research priorities receive NIH funding.

Activation of the Aryl Hydrocarbon Receptor in Muscle Exacerbates Ischemic Pathology in Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic solutes, which are ligands for AHR (aryl hydrocarbon receptor), are associated with limb amputation in PAD. Herein, we examined the role of AHR activation in the myopathy of PAD and CKD. METHODS: AHR-related gene expression was evaluated in skeletal muscle obtained from mice and human PAD patients with and without CKD. AHRmKO (skeletal muscle-specific AHR knockout) mice with and without CKD were subjected to femoral artery ligation, and a battery of assessments were performed to evaluate vascular, muscle, and mitochondrial health. Single-nuclei RNA sequencing was performed to explore intercellular communication. Expression of the constitutively active AHR was used to isolate the role of AHR in mice without CKD. RESULTS: PAD patients and mice with CKD displayed significantly higher mRNA expression of classical AHR-dependent genes (Cyp1a1, Cyp1b1, and Aldh3a1) when compared with either muscle from the PAD condition with normal renal function (P<0.05 for all 3 genes) or nonischemic controls. AHRmKO significantly improved limb perfusion recovery and arteriogenesis, preserved vasculogenic paracrine signaling from myofibers, increased muscle mass and strength, as well as enhanced mitochondrial function in an experimental model of PAD/CKD. Moreover, viral-mediated skeletal muscle-specific expression of a constitutively active AHR in mice with normal kidney function exacerbated the ischemic myopathy evidenced by smaller muscle masses, reduced contractile function, histopathology, altered vasculogenic signaling, and lower mitochondrial respiratory function. CONCLUSIONS: These findings establish AHR activation in muscle as a pivotal regulator of the ischemic limb pathology in CKD. Further, the totality of the results provides support for testing of clinical interventions that diminish AHR signaling in these conditions.

Chronic activation of the aryl hydrocarbon receptor in muscle exacerbates ischemic pathology in chronic kidney disease.

Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the cellular and physiological mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic toxins, many of which are ligands for the aryl hydrocarbon receptor (AHR), are associated with adverse limb outcomes in PAD. We hypothesized that chronic AHR activation, driven by the accumulation of tryptophan-derived uremic metabolites, may mediate the myopathic condition in the presence of CKD and PAD. Both PAD patients with CKD and mice with CKD subjected to femoral artery ligation (FAL) displayed significantly higher mRNA expression of classical AHR-dependent genes ( Cyp1a1 , Cyp1b1 , and Aldh3a1 ) when compared to either muscle from the PAD condition with normal renal function ( P <0.05 for all three genes) or non-ischemic controls. Skeletal-muscle-specific AHR deletion in mice (AHR mKO ) significantly improved limb muscle perfusion recovery and arteriogenesis, preserved vasculogenic paracrine signaling from myofibers, increased muscle mass and contractile function, as well as enhanced mitochondrial oxidative phosphorylation and respiratory capacity in an experimental model of PAD/CKD. Moreover, viral-mediated skeletal muscle-specific expression of a constitutively active AHR in mice with normal kidney function exacerbated the ischemic myopathy evidenced by smaller muscle masses, reduced contractile function, histopathology, altered vasculogenic signaling, and lower mitochondrial respiratory function. These findings establish chronic AHR activation in muscle as a pivotal regulator of the ischemic limb pathology in PAD. Further, the totality of the results provide support for testing of clinical interventions that diminish AHR signaling in these conditions.

Photochemically Aided Arteriovenous Fistula Creation to Accelerate Fistula Maturation.

Rates of arteriovenous fistula maturation failure are still high, especially when suboptimal size veins are used. During successful maturation, the vein undergoes lumen dilatation and medial thickening, adapting to the increased hemodynamic forces. The vascular extracellular matrix plays an important role in regulating these adaptive changes and may be a target for promoting fistula maturation. In this study, we tested whether a device-enabled photochemical treatment of the vein prior to fistula creation facilitates maturation. Sheep cephalic veins were treated using a balloon catheter coated by a photoactivatable molecule (10-8-10 Dimer) and carrying an internal light fiber. As a result of the photochemical reaction, new covalent bonds were created during light activation among oxidizable amino acids of the vein wall matrix proteins. The treated vein lumen diameter and media area became significantly larger than the contralateral control fistula vein at 1 week (p = 0.035 and p = 0.034, respectively). There was also a higher percentage of proliferating smooth muscle cells in the treated veins than in the control veins (p = 0.029), without noticeable intimal hyperplasia. To prepare for the clinical testing of this treatment, we performed balloon over-dilatation of isolated human veins and found that veins can tolerate up to 66% overstretch without notable histological damage.

Predicting 1-year in-stent restenosis in superficial femoral arteries through multiscale computational modelling.

In-stent restenosis in superficial femoral arteries (SFAs) is a complex, multi-factorial and multiscale vascular adaptation process whose thorough understanding is still lacking. Multiscale computational agent-based modelling has recently emerged as a promising approach to decipher mechanobiological mechanisms driving the arterial response to the endovascular intervention. However, the long-term arterial response has never been investigated with this approach, although being of fundamental relevance. In this context, this study investigates the 1-year post-operative arterial wall remodelling in three patient-specific stented SFA lesions through a fully coupled multiscale agent-based modelling framework. The framework integrates the effects of local haemodynamics and monocyte gene expression data on cellular dynamics through a bi-directional coupling of computational fluid dynamics simulations with an agent-based model of cellular activities. The framework was calibrated on the follow-up data at 1 month and 6 months of one stented SFA lesion and then applied to the other two lesions. The calibrated framework successfully captured (i) the high lumen area reduction occurring within the first post-operative month and (ii) the stabilization of the median lumen area from 1-month to 1-year follow-ups in all the stented lesions, demonstrating the potentialities of the proposed approach for investigating patient-specific short- and long-term responses to endovascular interventions.

Non-invasive estimation of the parameters of a three-element windkessel model of aortic arch arteries in patients undergoing thoracic endovascular aortic repair.

Background: Image-based computational hemodynamic modeling and simulations are important for personalized diagnosis and treatment of cardiovascular diseases. However, the required patient-specific boundary conditions are often not available and need to be estimated. Methods: We propose a pipeline for estimating the parameters of the popular three-element Windkessel (WK3) models (a proximal resistor in series with a parallel combination of a distal resistor and a capacitor) of the aortic arch arteries in patients receiving thoracic endovascular aortic repair of aneurysms. Pre-operative and post-operative 1-week duplex ultrasound scans were performed to obtain blood flow rates, and intra-operative pressure measurements were also performed invasively using a pressure transducer pre- and post-stent graft deployment in arch arteries. The patient-specific WK3 model parameters were derived from the flow rate and pressure waveforms using an optimization algorithm reducing the error between simulated and measured pressure data. The resistors were normalized by total resistance, and the capacitor was normalized by total resistance and heart rate. The normalized WK3 parameters can be combined with readily available vessel diameter, brachial blood pressure, and heart rate data to estimate WK3 parameters of other patients non-invasively. Results: Ten patients were studied. The medians (interquartile range) of the normalized proximal resistor, distal resistor, and capacitor parameters are 0.10 (0.07-0.15), 0.90 (0.84-0.93), and 0.46 (0.33-0.58), respectively, for common carotid artery; 0.03 (0.02-0.04), 0.97 (0.96-0.98), and 1.91 (1.63-2.26) for subclavian artery; 0.18 (0.08-0.41), 0.82 (0.59-0.92), and 0.47 (0.32-0.85) for vertebral artery. The estimated pressure showed fairly high tolerance to patient-specific inlet flow rate waveforms using the WK3 parameters estimated from the medians of the normalized parameters. Conclusion: When patient-specific outflow boundary conditions are not available, our proposed pipeline can be used to estimate the WK3 parameters of arch arteries.

Assessing the quality of reporting of studies using Vascular Quality Initiative (VQI) data.

OBJECTIVE: The Society for Vascular Surgery Vascular Quality Initiative (VQI) has become an increasingly popular data source for retrospective observational vascular surgery studies. There are published guidelines on the reporting of data in such studies to promote transparency and rigor, but these have not been used to evaluate studies using VQI data. Our objective was to appraise the methodological reporting quality of studies using VQI data by evaluating their adherence to these guidelines. METHODS: The Society for Vascular Surgery VQI publication repository was queried for all articles published in 2020. The REporting of studies Conducted using Observational Routinely-collected Health Data (RECORD) statement and the Journal of American Medical Association-Surgical Section (JAMA-Surgery) checklist were utilized to assess the quality of each article's reporting. Five and three items from the RECORD statement and JAMA-Surgery checklist were excluded, respectively, because they were either inapplicable or nonassessable. Journal impact factor (IF) was queried for each article to elucidate any difference in reporting standards between high and low IF journals. RESULTS: Ninety studies were identified and analyzed. The median score on the RECORD checklist was 6 (of 8). The most commonly missed item was discussing data cleaning methods (93% missed). The median score on the JAMA-Surgery checklist was 3 (of 7). The most commonly missed items were the identification of competing risks (98% missed), the use of a flow chart to clearly define sample exclusion and inclusion criteria (84% missed), and the inclusion of a solid research question and hypothesis (81% missed). There were no differences in JAMA-Surgery checklist or RECORD statement median scores among studies published in low vs high IF journals. CONCLUSIONS: Studies using VQI data demonstrate a poor to moderate adherence to reporting standards. Key areas for improvement in research reporting include articulating a clear hypothesis, using flow charts to clearly define inclusion and exclusion criteria, identifying competing risks, and discussing data cleaning methods. Additionally, future efforts should center on creating tailored instruments to better guide reporting in studies using VQI data.

National Treatment Patterns and Outcomes for Hospitalized Patients with Chronic Limb-Threatening Ischemia and End-Stage Kidney Disease.

BACKGROUND: Chronic limb-threatening ischemia (CLTI) can be associated with dismal outcomes but there are limited real-world data to further define the impact of end-stage kidney disease (ESKD) on outcomes nationally in this subset of patients. We sought to characterize national patterns of inpatient treatment of CLTI and compare outcomes in patients without ESKD. METHODS: The National Inpatient Sample was queried from 2015-2018 for all hospital admissions including treatment for CLTI. Mixed-effects linear and logistic regression models were used to estimate the effect of ESKD on outcomes and treatment choice. RESULTS: We identified 11 652 hospital admissions with CLTI alone and 2705 with CLTI + ESKD. Hospital admissions with CLTI + ESKD patients included patients who were younger (66 vs 69 years, P < .0001), less likely to be white (39% vs 63%, P < .0001), and more likely to reside in lower income large metropolitan areas. Admissions for CLTI + ESKD patients had a lower likelihood of open arterial reconstruction (OR .40, P < .0001) and a higher likelihood of endovascular revascularization or major limb amputation (OR 1.70, P < .0001). Admissions for CLTI + ESKD also had a 4.5- and 1.5-fold higher odds of in-hospital death and complications. These findings were associated with a longer LOS (P < .0001), increased probability of discharge to rehabilitation facility (50% vs 41%, P < .0001), and greater hospital charges (median, $107 K vs $85 K, P < .0001). CONCLUSIONS: Compared to hospital admissions for patients without ESKD, admissions for patients with CLTI + ESKD demonstrated distinctive demographic characteristics, a lower likelihood of open revascularization and a higher likelihood of endovascular revascularization and major limb amputation. Chronic limb-threatening ischemia + ESKD hospital admissions showed worse overall outcomes and greater resource utilization compared to CLTI admissions without ESKD.

Association of Shear Stress with Subsequent Lumen Remodeling in Hemodialysis Arteriovenous Fistulas.

BACKGROUND: Blood flow-induced wall shear stress is a strong local regulator of vascular remodeling, but its effects on arteriovenous fistula (AVF) remodeling are unclear. METHODS: In this prospective cohort study, we used computational fluid dynamics simulations and statistical mixed-effects modeling to investigate the associations between wall shear stress and AVF remodeling in 120 participants undergoing AVF creation surgery. Postoperative magnetic resonance imaging data at 1 day, 6 weeks, and 6 months were used to derive current wall shear stress by computational fluid dynamic simulations and to quantify subsequent changes in AVF lumen cross-sectional area at 1-mm intervals along the proximal artery and AVF vein. RESULTS: Combining artery and vein data, prior mean wall shear stress was significantly associated with lumen area expansion. Mean wall shear stress at day 1 was significantly associated with change in lumen area from day 1 to week 6 (11% larger area per interquartile range [IQR] higher mean wall shear stress, 95% confidence interval [95% CI], 5% to 18%; n =101), and mean wall shear stress at 6 weeks was significantly associated with change in lumen area from 6 weeks to month 6 (14% larger area per IQR higher, 95% CI, 3% to 28%; n =52). The association of mean wall shear stress at day 1 with lumen area expansion from day 1 to week 6 differed significantly by diabetes ( P =0.009): 27% (95% CI, 17% to 37%) larger area per IQR higher mean wall shear stress without diabetes and 9% (95% CI, -1% to 19%) with diabetes. Oscillatory shear index at day 1 was significantly associated with change in lumen area from day 1 to week 6 (5% smaller area per IQR higher oscillatory shear index, 95% CI, 3% to 7%), and oscillatory shear index at 6 weeks was significantly associated with change in lumen from 6 weeks to month 6 (7% smaller area per IQR higher oscillatory shear index, 95% CI, 2% to 11%). Wall shear stress spatial gradient was not significantly associated with subsequent remodeling. In a joint model, wall shear stress and oscillatory shear index statistically significantly interacted in their associations with lumen area expansion in a complex nonlinear fashion. CONCLUSIONS: Higher wall shear stress and lower oscillatory shear index were associated with greater lumen expansion after AVF creation surgery.

Distinct Temporal Pattern of the Prediction of Lumen Remodeling of Lower Extremity Vein Bypass Grafts by Initial Local Hemodynamics.

We predicted human lower extremity vein bypass graft remodeling by hemodynamics. Computed tomography and duplex ultrasound scans of 55 patients were performed at 1 week and 1, 6, and 12 months post-implantation to obtain wall shear stress (WSS) and oscillatory shear index (OSI) at 1-mm intervals via computational fluid dynamics simulations. Graft remodeling was quantified by computed tomography-measured lumen diameter changes in the early (1 week-1 month), intermediate (1-6 months), and late (6-12 months) periods. Linear mixed-effect models were constructed to examine the overall relationship between remodeling and initial hemodynamics using the average data of all cross sections within the same graft. A significant association of graft remodeling with WSS (p < 0.001) and time (p = 0.001) was found; however, the effect size decreased with time (every 2.7 dyne/cm2 increase of WSS was associated with a 0.39, 0.35, 0.002 mm diameter increase in the three periods, respectively). The association of remodeling with OSI was significant only in the intermediate period (every 0.1 increase of OSI was associated with a 0.25 mm lumen diameter decrease, p = 0.004). Therefore, the association of graft lumen remodeling with local hemodynamics has a distinct temporal pattern; WSS and OSI are predictive of remodeling only in certain postoperative periods.

Differential hemodynamics between arteriovenous fistulas with or without intervention before successful use.

A significant number of arteriovenous fistulas (AVFs) fail to maturate for dialysis. Although interventions promote maturation, functional primary patency loss is higher for AVFs with interventions (assisted maturation) than AVFs without interventions (un-assisted maturation). Although blood flow-associated hemodynamics have long been proposed to affect AVF remodeling, the optimal hemodynamic parameters for un-assisted maturation are unclear. Additionally, AVF maturation progress is generally not investigated until 6 weeks after AVF creation, and the examination is focused on the AVF's venous limb. In this exploratory study, patients (n = 6) underwent magnetic resonance imaging (MRI) at 1 day, 6 weeks, and 6 months after AVF creation surgery. Before successful use for hemodialysis, three AVFs required intervention and three did not. MRI of the AVFs were used to calculate lumen cross-sectional area (CSA) and perform computational fluid dynamics (CFD) to analyze hemodynamics, including velocity, wall shear stress (WSS), and vorticity. For the venous limb, the no-intervention group and intervention group had similar pre-surgery vein diameter and 1-day post-surgery venous CSA. However, the no-intervention group had statistically larger 1-day venous velocity (0.97 ± 0.67 m/s; mean ± SD), WSS (333 ± 336 dyne/cm2) and vorticity (1709 ± 1290 1/s) than the intervention group (velocity = 0.23 ± 0.10 m/s; WSS = 49 ± 40 dyne/cm2; vorticity = 493.1 ± 227 1/s) (P < 0.05). At 6 months, the no-intervention group had statistically larger venous CSA (43.5 ± 27.4 mm2) than the intervention group (15.1 ± 6.2 mm2) (P < 0.05). Regarding the arterial limb, no-intervention AVF arteries also had statistically larger 1-day velocity (1.17 ± 1.0 m/s), WSS (340 ± 423 dyne/cm2), vorticity (1787 ± 1694 1/s), and 6-month CSA (22.6 ± 22.7 mm2) than the intervention group (velocity = 0.64 ± 0.36 m/s; WSS = 104 ± 116 dyne/cm2, P < 0.05; vorticity = 867 ± 4551/s; CSA = 10.7 ± 6.0 mm2, P < 0.05). Larger venous velocity, WSS, and vorticity immediately after AVF creation surgery may be important for later lumen enlargement and AVF maturation, with the potential to be used as a tool to help diagnose poor AVF maturation earlier. However, future studies using a larger cohort are needed to validate this finding and determine cut off values, if any.

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.