Cystathionine-γ-lyase overexpression modulates oxidized nicotinamide adenine dinucleotide biosynthesis and enhances neovascularization.

Objective: Hydrogen sulfide is a proangiogenic gas produced primarily by the transsulfuration enzyme cystathionine-γ-lyase (CGL). CGL-dependent hydrogen sulfide production is required for neovascularization in models of peripheral arterial disease. However, the benefits of increasing endogenous CGL and its mechanism of action have not yet been elucidated. Methods: Male whole body CGL-overexpressing transgenic (CGLTg) mice and wild-type (WT) littermates (C57BL/6J) were subjected to the hindlimb ischemia model (age, 10-12 weeks). Functional recovery was assessed via the treadmill exercise endurance test. Leg perfusion was measured by laser Doppler imaging and vascular endothelial-cadherin immunostaining. To examine the angiogenic potential, aortic ring sprouting assay and postnatal mouse retinal vasculature development studies were performed. Finally, comparative metabolomics analysis, oxidized/reduced nicotinamide adenine dinucleotide (NAD+/NADH) analysis, and quantitative real-time polymerase chain reaction were performed on CGLWT and CGLTg gastrocnemius muscle. Results: The restoration of blood flow occurred more rapidly in CGLTg mice. Compared with the CGLWT mice, the median ± standard deviation running distance and time were increased for the CGLTg mice after femoral artery ligation (159 ± 53 m vs 291 ± 74 m [P < .005] and 17 ± 4 minutes vs 27 ± 5 minutes [P < .05], respectively). Consistently, in the CGLTg ischemic gastrocnemius muscle, the capillary density was increased fourfold (0.05 ± 0.02 vs 0.20 ± 0.12; P < .005). Ex vivo, the endothelial cell (EC) sprouting length was increased in aorta isolated from CGLTg mice, especially when cultured in VEGFA (vascular endothelial growth factor A)-only media (63 ± 2 pixels vs 146 ± 52 pixels; P < .05). Metabolomics analysis demonstrated a higher level of niacinamide, a precursor of NAD+/NADH in the muscle of CGLTg mice (61.4 × 106 ± 5.9 × 106 vs 72.4 ± 7.7 × 106 area under the curve; P < .05). Similarly, the NAD+ salvage pathway gene expression was increased in CGLTg gastrocnemius muscle. Finally, CGL overexpression or supplementation with the NAD+ precursor nicotinamide mononucleotide improved EC migration in vitro (wound closure: control, 35% ± 9%; CGL, 55% ± 11%; nicotinamide mononucleotide, 42% ± 13%; P < .05). Conclusions: Our results have demonstrated that CGL overexpression improves the neovascularization of skeletal muscle on hindlimb ischemia. These effects correlated with changes in the NAD pathway, which improved EC migration.

Saturday multidisciplinary hemodialysis access clinics to enhance patient care.

Fragmentation of outpatient care is a substantial barrier to creation and maintenance of hemodialysis access. To improve patient accessibility, satisfaction, and multidisciplinary provider communication, we created a monthly Saturday multidisciplinary vascular surgery and interventional nephrology access clinic at a tertiary care hospital in a major urban area for the complicated hemodialysis patient population. The study included patients presenting for new access creation as well as those who had previously undergone access surgery. Staffing included two to three interventional nephrologists, two to three vascular surgeons, one medical assistant, one research assistant, and one practice assistant. Patient satisfaction and perception of the clinic was measured using surveys during six of the monthly Saturday hemodialysis clinics. A total of 675 patient encounters were completed (18.2 average/clinic ±6.3 standard deviation) from August 2016 to August 2019. All patients were seen by both disciplines. The average no-show rate was 19.9% throughout the study period. Patient satisfaction in all measures was consistently high with the Saturday clinic. Providers were also assayed, and they generally valued the real-time, multidisciplinary care plan generation, and its subsequent efficient execution. Saturday multidisciplinary hemodialysis access clinics offer high provider and patient satisfaction and streamlined patient care. However, no-show rates remain relatively high for this challenging patient population.

Systematic identification and management of barriers to vascular surgery patient discharge time of day.

OBJECTIVE: Length of stay fails to completely capture the clinical and economic effects of patient progression through the phases of inpatient care, such as admission, room placement, procedures, and discharge. Delayed hospital throughput has been linked to increased time spent in the emergency department and postanesthesia care unit, delayed time to treatment, increased in-hospital mortality, decreased patient satisfaction, and lost hospital revenue. We identified barriers to vascular surgery inpatient care progression and instituted defined measures to positively impact standardized metrics. METHODS: The study was divided into three periods: preintervention, "wash-in," and postintervention. During the preintervention phase, barriers to patient flow were quantified by an interdisciplinary team. Suboptimal provider communication emerged as the key barrier. An enhanced communication intervention consisting of face-to-face and mobile application-based education on key patient flow metrics, explicit discussion of individual patient barriers to progression at rounds and interdisciplinary huddles, and communication of projected discharge and potential barriers via e-mail was developed with input from all stakeholders. Following a 4-week wash-in implementation phase, data collection was repeated. RESULTS: The pre- and postintervention patient cohorts accounted for 244.3 and 238.1 inpatient days, respectively. Both groups had similar baseline demographic, clinical characteristics, and procedures performed during hospitalization. The postintervention group was discharged 78 minutes earlier (14:00:32 vs 15:18:37; P = .03) with a trend toward increased discharge by noon (94% vs 88%; P = .09). Readmission rates did not differ (P = .44). CONCLUSIONS: Implementation of a focused, interdisciplinary, frontline provider-driven, enhanced communication program can be feasibly incorporated into existing specialty surgical workflow. The program resulted in improved timeliness of discharge and projected cost savings, without increasing readmission rates.

Endogenous hydrogen sulfide production is essential for dietary restriction benefits.

Dietary restriction (DR) without malnutrition encompasses numerous regimens with overlapping benefits including longevity and stress resistance, but unifying nutritional and molecular mechanisms remain elusive. In a mouse model of DR-mediated stress resistance, we found that sulfur amino acid (SAA) restriction increased expression of the transsulfuration pathway (TSP) enzyme cystathionine γ-lyase (CGL), resulting in increased hydrogen sulfide (H2S) production and protection from hepatic ischemia reperfusion injury. SAA supplementation, mTORC1 activation, or chemical/genetic CGL inhibition reduced H2S production and blocked DR-mediated stress resistance. In vitro, the mitochondrial protein SQR was required for H2S-mediated protection during nutrient/oxygen deprivation. Finally, TSP-dependent H2S production was observed in yeast, worm, fruit fly, and rodent models of DR-mediated longevity. Together, these data are consistent with evolutionary conservation of TSP-mediated H2S as a mediator of DR benefits with broad implications for clinical translation. PAPERFLICK: