Saphenous vein dilation as an alternative to prosthetic femoral-distal bypass revascularization.

A 63-year-old man with a history of bipolar and schizoaffective disorder was admitted to the psychiatry unit. His comorbidities included active smoking, hypertension, diabetes, hyperlipidemia, coronary artery disease after coronary artery bypass grafting, and peripheral arterial disease. During the admission, the patient began to complain of right foot pain at rest. Angiography revealed occlusion of a previously placed right superficial femoral artery and popliteal stents, severe common femoral and distal popliteal stenosis with only a patent posterior tibial (PT) artery runoff. Serial venoplasty was performed and revealed an inadequately sized, ipsilateral great saphenous vein, followed by a delayed femoral-PT in situ saphenous vein bypass. Angiography at 32 months demonstrated a patent femoral-PT great saphenous vein bypass.

Multiomics assessment of dietary protein titration reveals altered hepatic glucose utilization.

Dietary protein restriction (PR) has rapid effects on metabolism including improved glucose and lipid homeostasis, via multiple mechanisms. Here, we investigate responses of fecal microbiome, hepatic transcriptome, and hepatic metabolome to six diets with protein from 18% to 0% of energy in mice. PR alters fecal microbial composition, but metabolic effects are not transferable via fecal transplantation. Hepatic transcriptome and metabolome are significantly altered in diets with lower than 10% energy from protein. Changes upon PR correlate with calorie restriction but with a larger magnitude and specific changes in amino acid (AA) metabolism. PR increases steady-state aspartate, serine, and glutamate and decreases glucose and gluconeogenic intermediates. 13C6 glucose and glycerol tracing reveal increased fractional enrichment in aspartate, serine, and glutamate. Changes remain intact in hepatic ATF4 knockout mice. Together, this demonstrates an ATF4-independent shift in gluconeogenic substrate utilization toward specific AAs, with compensation from glycerol to promote a protein-sparing response.

A Novel Approach for the Treatment of Nutcracker Syndrome: A Case Report.

We describe a case of nutcracker syndrome in a 35 year-old male that was treated with a left renal vein transposition via an open retroperitoneal approach. Our case highlights some of the advantages of the retroperitoneal approach, which may decrease the risk of postoperative complications when compared to the traditional midline abdominal transperitoneal approach. The patient agreed to publish the case details and images included below.

Nutcracker Phenomenon as a Result of Celiomesenteric Trunk Aneurysm.

A common origin of the celiac trunk and superior mesenteric artery is exceedingly rare, and aneurysms of this common trunk are even rarer. According to our literature search, there are no reported cases of nutcracker syndrome or phenomenon involving this rare aneurysmal anomaly. Repair of such anomalies is standardly via open surgical approach with few reported cases of endovascular repair. We describe a patient with an aneurysm of the celiomesenteric trunk resulting in nutcracker phenomenon of the left renal vein. The celiomesenteric trunk aneurysm was repaired endovascularly, resulting in decreased surrounding inflammation and improvement of the left renal vein compression.

Plasma Hydrogen Sulfide Is Positively Associated With Post-operative Survival in Patients Undergoing Surgical Revascularization.

Objective: Hydrogen sulfide (H2S) is a gaseous signaling molecule and redox factor important for cardiovascular function. Deficiencies in its production or bioavailability are implicated in atherosclerotic disease. However, it is unknown if circulating H2S levels differ between vasculopaths and healthy individuals, and if so, whether H2S measurements can be used to predict surgical outcomes. Here, we examined: (1) Plasma H2S levels in patients undergoing vascular surgery and compared these to healthy controls, and (2) the association between H2S levels and mortality in a cohort of patients undergoing surgical revascularization. Methods: One hundred and fifteen patients undergoing carotid endarterectomy, open lower extremity revascularization or lower leg amputation were enrolled at a single institution. Peripheral blood was also collected from a matched control cohort of 20 patients without peripheral or coronary artery disease. Plasma H2S production capacity and sulfide concentration were measured using the lead acetate and monobromobimane methods, respectively. Results: Plasma H2S production capacity and plasma sulfide concentrations were reduced in patients with PAD (p < 0.001, p = 0.013, respectively). Patients that underwent surgical revascularization were divided into high vs. low H2S production capacity groups by median split. Patients in the low H2S production group had increased probability of mortality (p = 0.003). This association was robust to correction for potentially confounding variables using Cox proportional hazard models. Conclusion: Circulating H2S levels were lower in patients with atherosclerotic disease. Patients undergoing surgical revascularization with lower H2S production capacity, but not sulfide concentrations, had increased probability of mortality within 36 months post-surgery. This work provides insight on the role H2S plays as a diagnostic and potential therapeutic for cardiovascular disease.

Neurovascular dysfunction and neuroinflammation in a Cockayne syndrome mouse model.

Cockayne syndrome (CS) is a rare, autosomal genetic disorder characterized by premature aging-like features, such as cachectic dwarfism, retinal atrophy, and progressive neurodegeneration. The molecular defect in CS lies in genes associated with the transcription-coupled branch of the nucleotide excision DNA repair (NER) pathway, though it is not yet clear how DNA repair deficiency leads to the multiorgan dysfunction symptoms of CS. In this work, we used a mouse model of severe CS with complete loss of NER (Csa-/-/Xpa-/-), which recapitulates several CS-related phenotypes, resulting in premature death of these mice at approximately 20 weeks of age. Although this CS model exhibits a severe progeroid phenotype, we found no evidence of in vitro endothelial cell dysfunction, as assessed by measuring population doubling time, migration capacity, and ICAM-1 expression. Furthermore, aortas from CX mice did not exhibit early senescence nor reduced angiogenesis capacity. Despite these observations, CX mice presented blood brain barrier disruption and increased senescence of brain endothelial cells. This was accompanied by an upregulation of inflammatory markers in the brains of CX mice, such as ICAM-1, TNFα, p-p65, and glial cell activation. Inhibition of neovascularization did not exacerbate neither astro- nor microgliosis, suggesting that the pro-inflammatory phenotype is independent of the neurovascular dysfunction present in CX mice. These findings have implications for the etiology of this disease and could contribute to the study of novel therapeutic targets for treating Cockayne syndrome patients.

Total protein, not amino acid composition, differs in plant-based versus omnivorous dietary patterns and determines metabolic health effects in mice.

Plant-based dietary patterns are associated with improved cardiometabolic health, but causal dietary components are unclear. Protein has been proposed to play a role, but the importance of protein quantity versus quality remains unknown. We investigated the contributions of total protein amount, amino acid (AA) composition, and plant versus animal source. Analysis of total protein and AA composition of food items and dietary patterns revealed differences between individual food items, but few differences between AA profiles of vegan versus omnivorous dietary patterns. Effects of protein quantity, but not quality, on cardiometabolic health markers were observed in mice using semi-purified diets with crystalline AAs in plant versus animal-based ratios and naturally sourced diets with whole-food ingredients. Our data show relatively little difference in protein quality between plant-based and omnivorous dietary patterns and that reduced total protein intake in plant-based dietary patterns may be a contributor to the benefits of plant-based diets.

Periprocedural Hydrogen Sulfide Therapy Improves Vascular Remodeling and Attenuates Vein Graft Disease.

Background Failure rates after revascularization surgery remain high, both in vein grafts (VG) and arterial interventions. One promising approach to improve outcomes is endogenous upregulation of the gaseous transmitter-molecule hydrogen sulfide, via short-term dietary restriction. However, strict patient compliance stands as a potential translational barrier in the vascular surgery patient population. Here we present a new therapeutic approach, via a locally applicable gel containing the hydrogen sulfide releasing prodrug (GYY), to both mitigate graft failure and improve arterial remodeling. Methods and Results All experiments were performed on C57BL/6 (male, 12 weeks old) mice. VG surgery was performed by grafting a donor-mouse cava vein into the right common carotid artery of a recipient via an end-to-end anastomosis. In separate experiments arterial intimal hyperplasia was assayed via a right common carotid artery focal stenosis model. All mice were harvested at postoperative day 28 and artery/graft was processed for histology. Efficacy of hydrogen sulfide was first tested via GYY supplementation of drinking water either 1 week before VG surgery (pre-GYY) or starting immediately postoperatively (post-GYY). Pre-GYY mice had a 36.5% decrease in intimal/media+adventitia area ratio compared with controls. GYY in a 40% Pluronic gel (or vehicle) locally applied to the graft/artery had decreased intimal/media area ratios (right common carotid artery) and improved vessel diameters. GYY-geltreated VG had larger diameters at both postoperative days 14 and 28, and a 56.7% reduction in intimal/media+adventitia area ratios. Intimal vascular smooth muscle cell migration was decreased 30.6% after GYY gel treatment, which was reproduced in vitro. Conclusions Local gel-based treatment with the hydrogen sulfide-donor GYY stands as a translatable therapy to improve VG durability and arterial remodeling after injury.

Short-term preoperative protein restriction attenuates vein graft disease via induction of cystathionine γ-lyase.

AIMS: Therapies to prevent vein graft disease, a major problem in cardiovascular and lower extremity bypass surgeries, are currently lacking. Short-term preoperative protein restriction holds promise as an effective preconditioning method against surgical stress in rodent models, but whether it can improve vein graft patency after bypass surgery is undetermined. Here, we hypothesized that short-term protein restriction would limit vein graft disease via up-regulation of cystathionine γ-lyase and increased endogenous production of the cytoprotective gaseous signalling molecule hydrogen sulfide. METHODS AND RESULTS: Low-density lipoprotein receptor knockout mice were preconditioned for 1 week on a high-fat high-cholesterol (HFHC) diet with or without protein prior to left common carotid interposition vein graft surgery with caval veins from donor mice on corresponding diets. Both groups were returned to a complete HFHC diet post-operatively, and vein grafts analysed 4 or 28 days later. A novel global transgenic cystathionine γ-lyase overexpressing mouse model was also employed to study effects of genetic overexpression on graft patency. Protein restriction decreased vein graft intimal/media+adventitia area and thickness ratios and intimal smooth muscle cell infiltration 28 days post-operatively, and neutrophil transmigration 4 days post-operatively. Protein restriction increased cystathionine γ-lyase protein expression in aortic and caval vein endothelial cells (ECs) and frequency of lung EC producing hydrogen sulfide. The cystathionine γ-lyase inhibitor propargylglycine abrogated protein restriction-mediated protection from graft failure and the increase in hydrogen sulfide-producing ECs, while cystathionine γ-lyase transgenic mice displayed increased hydrogen sulfide production capacity and were protected from vein graft disease independent of diet. CONCLUSION: One week of protein restriction attenuates vein graft disease via increased cystathionine γ-lyase expression and hydrogen sulfide production, and decreased early inflammation. Dietary or pharmacological interventions to increase cystathionine γ-lyase or hydrogen sulfide may thus serve as new and practical strategies to improve vein graft durability.

Insights From a Short-Term Protein-Calorie Restriction Exploratory Trial in Elective Carotid Endarterectomy Patients.

BACKGROUND: Open vascular surgery interventions are not infrequently hampered by complication rates and durability. Preclinical surgical models show promising beneficial effects in modulating the host response to surgical injury via short-term dietary preconditioning. Here, we explore short-term protein-calorie restriction preconditioning in patients undergoing elective carotid endarterectomy to understand patient participation dynamics and practicalities of robust research approaches around nutritional/surgical interventions. METHODS: We designed a pilot prospective, multicenter, randomized controlled study in patients undergoing carotid endarterectomy. After a 3:2 randomization to a 3-day preoperative protein-calorie restriction regimen (30% calorie/70% protein restriction) or ad libitum group, blood, clinical parameters, and stool samples were collected at baseline, pre-op, and post-op days 1 and 30. Subcutaneous and perivascular adipose tissues were harvested periprocedurally. Samples were analyzed for standard chemistries and cell counts, adipokines. Bacterial DNA isolation and 16S rRNA sequencing were performed on stool samples and the relative abundance of bacterial species was measured. RESULTS: Fifty-one patients were screened, 9 patients consented to the study, 5 were randomized, and 4 completed the trial. The main reason for non-consent was a 3-day in-hospital stay. All 4 participants were randomized to the protein-calorie restriction group, underwent successful endarterectomy, reported no compliance difficulties, nor were there adverse events. Stool analysis trended toward increased abundance of the sulfide-producing bacterial species Bilophila wadsworthia after dietary intervention (P = .08). CONCLUSIONS: Although carotid endarterectomy patients held low enthusiasm for a 3-day preoperative inpatient stay, there were no adverse effects in this small cohort. Multidisciplinary longitudinal research processes were successfully executed throughout the nutritional/surgical intervention. Future translational endeavors into dietary preconditioning of vascular surgery patients should focus on outpatient approaches.

Preoperative Protein or Methionine Restriction Preserves Wound Healing and Reduces Hyperglycemia.

BACKGROUND: Dietary restriction (DR), defined as reduced nutrient intake without malnutrition, is associated with longevity extension, improved glucose metabolism, and increased stress resistance, but also poor wound healing. Short-term preoperative DR followed by a return to normal feeding after surgery results in improved surgical outcomes in preclinical models. However, the effect of preoperative DR on wound healing and perioperative glucose homeostasis is currently unknown. Here, we tested the effects of two different preoperative DR regimens-protein restriction (PR) and methionine restriction (MR)-on wound healing and perioperative glucose homeostasis using an established murine model of wound healing in both nondiabetic and diabetic mice. MATERIALS AND METHODS: Surgical outcomes were tested using the McFarlane flap in nondiabetic and streptozotocin-induced diabetic mice. Short-term dietary preconditioning included 1 wk of PR or MR diet (1-2 wk) versus an isocaloric complete diet before surgery; all mice were returned to a complete diet postoperatively. Outcome measures of flap wound recovery included skin viability and laser Doppler imaging of flap perfusion and assessment of CD45+ cell infiltration. Glucose homeostasis was assessed by glucose tolerance testing and by perioperative glucose levels in the diabetic cohort. RESULTS: No significant differences were observed in percentage of viable skin, perfusion, or immune cell infiltration at 7-10 d after surgery in PR or MR mice compared with controls in healthy or diabetic mice. Preoperative glucose tolerance and postoperative glucose levels were however significantly improved by both PR and MR in diabetic mice. CONCLUSIONS: Short-term dietary preconditioning with PR or MR did not impair wound healing in nondiabetic or diabetic mice. However, both regimens reduced preoperative hyperglycemia in diabetic mice. Thus, brief preoperative dietary manipulations stand as strategies to potentially improve perioperative hyperglycemia with no deleterious effects on wound healing in mice.

Dietary protein restriction reduces circulating VLDL triglyceride levels via CREBH-APOA5-dependent and -independent mechanisms.

Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Dietary interventions based on protein restriction (PR) reduce circulating triglycerides (TGs), but underlying mechanisms and clinical relevance remain unclear. Here, we show that 1 week of a protein-free diet without enforced calorie restriction significantly lowered circulating TGs in both lean and diet-induced obese mice. Mechanistically, the TG-lowering effect of PR was due, in part, to changes in very low-density lipoprotein (VLDL) metabolism both in liver and peripheral tissues. In the periphery, PR stimulated VLDL-TG consumption by increasing VLDL-bound APOA5 expression and promoting VLDL-TG hydrolysis and clearance from circulation. The PR-mediated increase in Apoa5 expression was controlled by the transcription factor CREBH, which coordinately regulated hepatic expression of fatty acid oxidation-related genes, including Fgf21 and Ppara. The CREBH-APOA5 axis activation upon PR was intact in mice lacking the GCN2-dependent amino acid-sensing arm of the integrated stress response. However, constitutive hepatic activation of the amino acid-responsive kinase mTORC1 compromised CREBH activation, leading to blunted APOA5 expression and PR-recalcitrant hypertriglyceridemia. PR also contributed to hypotriglyceridemia by reducing the rate of VLDL-TG secretion, independently of activation of the CREBH-APOA5 axis. Finally, a randomized controlled clinical trial revealed that 4-6 weeks of reduced protein intake (7%-9% of calories) decreased VLDL particle number, increased VLDL-bound APOA5 expression, and lowered plasma TGs, consistent with mechanistic conservation of PR-mediated hypotriglyceridemia in humans with translational potential as a nutraceutical intervention for dyslipidemia.

Early animal model evaluation of an implantable contrast agent to enhance magnetic resonance imaging of arterial bypass vein grafts.

Background Non-invasive monitoring of autologous vein graft (VG) bypass grafts is largely limited to detecting late luminal narrowing. Although magnetic resonance imaging (MRI) delineates vein graft intima, media, and adventitia, which may detect early failure, the scan time required to achieve sufficient resolution is at present impractical. Purpose To study VG visualization enhancement in vivo and delineate whether a covalently attached MRI contrast agent would enable quicker longitudinal imaging of the VG wall. Material and Methods Sixteen 12-week-old male C57BL/6J mice underwent carotid interposition vein grafting. The inferior vena cava of nine donor mice was treated with a gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA)-based contrast agent, with control VGs labeled with a vehicle. T1-weighted (T1W) MRI was performed serially at postoperative weeks 1, 4, 12, and 20. A portion of animals was sacrificed for histopathology following each imaging time point. Results MRI signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were significantly higher for treated VGs in the first three time points (1.73 × higher SNR, P = 0.0006, and 5.83 × higher CNR at the first time point, P = 0.0006). However, MRI signal enhancement decreased consistently in the study period, to 1.29 × higher SNR and 2.64 × higher CNR, by the final time point. There were no apparent differences in graft morphometric analyses in Masson's trichrome-stained sections. Conclusion A MRI contrast agent that binds covalently to the VG wall provides significant increase in T1W MRI signal with no observed adverse effects in a mouse model. Further optimization of the contrast agent to enhance its durability is required.