How I do it: Pedal access and pedal loop revascularization for patients with chronic limb-threatening ischemia.

An increasing proportion of patients with chronic limb-threatening ischemia are older and have multiple comorbidities, including diabetes and renal failure. For those who are not candidates for a surgical bypass, this set of patients presents a challenge to vascular surgeons and interventionalists owing to the complex below-the-knee and increasingly below-the-ankle disease pattern that can fail traditional approaches for endovascular intervention. Two techniques, the retrograde pedal access and the pedal-plantar loop technique, can be useful in these settings and in skilled hands can be used safely, with a high technical success rate. In patients with chronic limb-threatening ischemia who are not candidates for a single-segment saphenous vein bypass, the retrograde pedal access technique can be used not only in the setting of failed antegrade treatment, but also primarily when faced with a difficult groin or as an adjunct during a planned antegrade-retrograde intervention. The pedal plantar loop technique allows for retrograde access to tibial vessels without retrograde vessel puncture and additionally offers the ability to treat the pedal-plantar arch, which may have added benefit in wound healing. We describe the tips and tricks for these two techniques used in our limb salvage practice.

Advances in non-invasive biosensing measures to monitor wound healing progression.

Impaired wound healing is a significant financial and medical burden. The synthesis and deposition of extracellular matrix (ECM) in a new wound is a dynamic process that is constantly changing and adapting to the biochemical and biomechanical signaling from the extracellular microenvironments of the wound. This drives either a regenerative or fibrotic and scar-forming healing outcome. Disruptions in ECM deposition, structure, and composition lead to impaired healing in diseased states, such as in diabetes. Valid measures of the principal determinants of successful ECM deposition and wound healing include lack of bacterial contamination, good tissue perfusion, and reduced mechanical injury and strain. These measures are used by wound-care providers to intervene upon the healing wound to steer healing toward a more functional phenotype with improved structural integrity and healing outcomes and to prevent adverse wound developments. In this review, we discuss bioengineering advances in 1) non-invasive detection of biologic and physiologic factors of the healing wound, 2) visualizing and modeling the ECM, and 3) computational tools that efficiently evaluate the complex data acquired from the wounds based on basic science, preclinical, translational and clinical studies, that would allow us to prognosticate healing outcomes and intervene effectively. We focus on bioelectronics and biologic interfaces of the sensors and actuators for real time biosensing and actuation of the tissues. We also discuss high-resolution, advanced imaging techniques, which go beyond traditional confocal and fluorescence microscopy to visualize microscopic details of the composition of the wound matrix, linearity of collagen, and live tracking of components within the wound microenvironment. Computational modeling of the wound matrix, including partial differential equation datasets as well as machine learning models that can serve as powerful tools for physicians to guide their decision-making process are discussed.

Preoperative hyponatremia and survival after left ventricular assist device implantation.

BACKGROUND: Hyponatremia is associated with adverse outcomes in heart failure and after cardiac surgery. We hypothesized that hyponatremia is associated with poorer short-term and longer term survival in patients after continuous-flow left ventricular assist device (CF-LVAD) placement. METHODS: We reviewed a single-center database of patients who received a CF-LVAD during 2012-2017. Sodium (Na) values obtained within 14 days before CF-LVAD insertion were averaged; patients (n = 332) were divided into hyponatremia (mean Na <135 mEq/L; n = 160; 48.2%) and normonatremia groups (mean Na 135-145 mEq/L; n = 172; 51.8%). Patients requiring preoperative dialysis or pump exchange were excluded. We compared outcomes between preoperative hyponatremia and normonatremia groups. RESULTS: The two groups' baseline characteristics were similar, although hyponatremia patients more often had preoperative mechanical circulatory support (44.4% vs. 31.4%, p = 0.002). Although hyponatremic and normonatremic patients did not differ in 30-day mortality (7.5% vs. 6.5%, p = 0.7), preoperative hyponatremia was associated with greater 5-year mortality (61% vs. 44%, p = 0.03). On binary logistic regression analysis, the strongest independent predictors of late mortality were hyponatremia (odds ratio [OR] 1.88, 95% CI [1.07-3.31], p = 0.02), older age (OR 1.03, 95% CI [1.01-1.05], p = 0.01), and elevated mean right atrial pressure/pulmonary capillary wedge pressure ratio (OR 4.69, 95% CI [1.76-12.47], p = 0.002). CONCLUSIONS: Hyponatremia was not associated with greater early mortality but was associated with poorer late survival. The optimal timing of LVAD implantation in relation to hyponatremia, and whether correcting hyponatremia perioperatively improves long-term survival, should be investigated.

Hyaluronan, a double-edged sword in kidney diseases.

Over the years, hyaluronic acid (HA) has emerged as an important molecule in nephrological and urological studies involving extracellular matrix (ECM) organization, inflammation, tissue regeneration, and viral sensing. During this time, many have noted the perplexing double-edged nature of the molecule, at times promoting pro-fibrotic events and at other times promoting anti-fibrotic events. Different molecular weights of HA can be attributed to these disparities, though most studies have yet to focus on this subtlety. With regard to the kidney, HA is induced in the initial response phase of injury and is subsequently decreased during disease progression of AKI, CKD, and diabetic nephropathy. These and other kidney diseases force patients, particularly pediatric patients, to face dialysis, surgical procedures, and ultimately, transplant. To summarize the current literature for researchers and pediatric nephrologists, this review aims to expound HA and elucidate its paradoxical effects in multiple kidney diseases using studies that emphasize HA molecular weight when available.

Strategies to Minimize Surgical Scarring: Translation of Lessons Learned from Bedside to Bench and Back.

Significance: An understanding of the physiology of wound healing and scarring is necessary to minimize surgical scar formation. By reducing tension across the healing wound, eliminating excess inflammation and infection, and encouraging perfusion to healing areas, surgeons can support healing and minimize scarring. Recent Advances: Preoperatively, newer techniques focused on incision placement to minimize tension, skin sterilization to minimize infection and inflammation, and control of comorbid factors to promote a healing process with minimal scarring are constantly evolving. Intraoperatively, measures like layered closure, undermining, and tissue expansion can be taken to relieve tension across the healing wound. Appropriate suture technique and selection should be considered, and finally, there are new surgical technologies available to reduce tension across the closure. Postoperatively, the healing process can be supported as proliferation and remodeling take place within the wound. A balance of moisture control, tension reduction, and infection prevention can be achieved with dressings, ointments, and silicone. Vitamins and corticosteroids can also affect the scarring process by modulating the cellular factors involved in healing. Critical Issues: Healing with no or minimal scarring is the ultimate goal of wound healing research. Understanding how mechanical tension, inflammation and infection, and perfusion and hypoxia impact profibrotic pathways allows for the development of therapies that can modulate cytokine response and the wound extracellular microenvironment to reduce fibrosis and scarring. Future Directions: New tension-off loading topical treatments, laser, and dermabrasion devices are under development, and small molecule therapeutics have demonstrated scarless wound healing in animal models, providing a promising new direction for future research aimed to minimize surgical scarring.

Novel antimicrobial ointment for infected wound healing in an in vitro and in vivo porcine model.

Microbial contamination of wounds is a significant problem that delays healing, particularly when bacterial biofilms are present. A novel combination of pectinic acid (PG) + caprylic acid (CAP) was previously found in vitro to be highly effective in eradicating various pathogens in biofilms with minimal cytotoxicity. In this study, a novel wound ointment was formulated with PG + CAP and first assessed in vitro using a well-established biofilm eradication model. In vitro, the PG + CAP ointment was shown to be efficacious in reducing the microbial biofilms. This ointment was then tested in vivo in two pilot porcine wound healing models, with and without Staphylococcus aureus microbial challenge. Ointments were applied to each wound daily, and healing by wound closure area measurement was assessed weekly over 4 weeks. After 4 weeks, pigs were sacrificed and wounds were scored for reepithelialization, inflammation, granulation tissue, and collagen deposition. We compared PG + CAP to hydroxyethylcellulose + glycerol ointment base (control) and MediHoney (comparator). In the porcine microbial challenge model, the novel antimicrobial PG + CAP wound ointment rapidly eradicated bacterial organisms embedded in wounds, was safe and well-tolerated, and was associated with enhanced healing compared to ointment base and MediHoney. Specifically, the cumulative histopathology, reepithelialization of epidermis, and mature granulation tissue in the wound bed was significantly better with PG + CAP than with control and MediHoney treatments. This ointment warrants further study as a non-antibiotic ointment for use in treating a wide array of infected wounds.

Attenuating Fibrotic Markers of Patient-Derived Dermal Fibroblasts by Thiolated Lignin Composites.

We report the use of phenolic functional groups of lignosulfonate to impart antioxidant properties and the cell binding domains of gelatin to enhance cell adhesion for poly(ethylene glycol) (PEG)-based scaffolds. Chemoselective thiol-ene chemistry was utilized to form composites with thiolated lignosulfonate (TLS) and methacrylated fish gelatin (fGelMA). Antioxidant properties of TLS were not altered after thiolation and the levels of antioxidation were comparable to those of L-ascorbic acid. PEG-fGelMA-TLS composites significantly reduced the difference in COL1A1, ACTA2, TGFB1, and HIF1A genes between high-scarring and low-scarring hdFBs, providing the potential utility of TLS to attenuate fibrotic responses.

Skin-specific knockdown of hyaluronan in mice by an optimized topical 4-methylumbelliferone formulation.

Hyaluronan (HA) is abundant in the skin; while HA can be synthesized by the synthases (HAS1-3), HAS2 is the leading contributor. Dysregulation and accumulation of HA is implicated in the pathogenesis of diseases such as keloid scarring, lymphedema and metastatic melanoma. To understand how HA synthesis contributes to skin physiology, and pathologic and fibrotic disorders, we propose the development of skin-specific HA inhibition model, which tests an optimal delivery system of topical 4-methylumbelliferone (4-MU). A design-of-experiments (DOE) approach was employed to develop an optimal 4-MU skin-delivery formulation comprising propylene glycol, ethanol, and water, topically applied to dorsal skin in male and female C57BL/6J wildtype mice to determine the effect on HAS gene expression and HA inhibition. Serum and skin samples were analyzed for HA content along with analysis of expression of HAS1-3, hyaluronidases (HYAL 1-2), and KIAA1199. Using results from DOE and response surface methodology with genetic algorithm optimization, we developed an optimal topical 4-MU formulation to result in ∼70% reduction of HA in dorsal skin, with validation demonstrating ∼50% reduction in HA in dorsal skin. 4-MU topical application resulted in significant decrease in skin HAS2 expression in female mice only. Histology showed thicker dermis in male mice, whereas female mice had thinner dermal layer with more adiposity; and staining for HA-binding protein showed that topical 4-MU resulted in breakdown in HA. Our data suggest a topical 4-MU formulation-based dermal HA inhibition model that would enable elucidating the skin-specific effects of HA in normal and pathologic states.

Impact of the coronavirus disease 2019 pandemic on surgical research and lessons for the future.

BACKGROUND: The current coronavirus disease 2019 pandemic has had an unprecedented impact on all physicians and has resulted in dramatic changes to clinical and research operations. No study has yet looked at the impact of coronavirus disease 2019 on the surgical research community. In this study, we sought to understand the impact of the pandemic and its associated restrictions on academic surgeons. METHODS: We surveyed members of the Association for Academic Surgery and the Society of University Surgeons. Survey questions included demographics, current challenges to basic and clinical research activities, attitudes toward remote work and productivity maintenance, and the solutions implemented to maintain productivity. RESULTS: Of 301 respondents, 70% cited a negative impact on research productivity due to mandatory building shutdowns, minimized personnel as a result of social distancing, and suspensions of animal work and clinical trials, with senior faculty and division chiefs and chairs more likely to report a negative impact (P = .001). Only 11% of respondents are documenting their financial losses, and only 19% indicated they received appropriate guidance regarding why and how to monitor the financial impact of the pandemic. Researchers have attempted to maintain research productivity through a focus on remote work, including manuscript writing, grant writing, and data analysis. Some participants have found silver linings, including more time to dedicate to research and family as a result of fewer clinical duties. CONCLUSION: Productivity strategies developed during the pandemic, including writing, remote work and meetings, and structured scheduling, are lessons that will allow the surgical research community to be resilient in the face of future disruptions.

The Role of an IL-10/Hyaluronan Axis in Dermal Wound Healing.

Scar formation is the typical endpoint of postnatal dermal wound healing, which affects more than 100 million individuals annually. Not only do scars cause a functional burden by reducing the biomechanical strength of skin at the site of injury, but they also significantly increase healthcare costs and impose psychosocial challenges. Though the mechanisms that dictate how dermal wounds heal are still not completely understood, they are regulated by extracellular matrix (ECM) remodeling, neovascularization, and inflammatory responses. The cytokine interleukin (IL)-10 has emerged as a key mediator of the pro- to anti-inflammatory transition that counters collagen deposition in scarring. In parallel, the high molecular weight (HMW) glycosaminoglycan hyaluronan (HA) is present in the ECM and acts in concert with IL-10 to block pro-inflammatory signals and attenuate fibrotic responses. Notably, high concentrations of both IL-10 and HMW HA are produced in early gestational fetal skin, which heals scarlessly. Since fibroblasts are responsible for collagen deposition, it is critical to determine how the concerted actions of IL-10 and HA drive their function to potentially control fibrogenesis. Beyond their independent actions, an auto-regulatory IL-10/HA axis may exist to modulate the magnitude of CD4+ effector T lymphocyte activation and enhance T regulatory cell function in order to reduce scarring. This review underscores the pathophysiological impact of the IL-10/HA axis as a multifaceted molecular mechanism to direct primary cell responders and regulators toward either regenerative dermal tissue repair or scarring.

Chronic Kidney Disease and Acute Kidney Injury Outcomes Post Left Ventricular Assist Device Implant.

Introduction Left ventricular assist devices (LVAD) are used as a bridge to heart transplant or destination therapy for patients with the New York Heart Association (NYHA) class 3 or 4 heart failure. Acute kidney injury (AKI) or need for renal replacement therapy (RRT) post-LVAD implant can lead to poor outcomes. Identifying risk factors of AKI post-LVAD implant can help stratify potential LVAD candidates. Methods This is a retrospective study of all patients who received continuous-flow LVAD at our institution from January 2015 until August 2017. We calculated the incidence of AKI and the need for RRT post-LVAD implant, as well as the rate of renal recovery and survival rates at 30 days and 1-year post-LVAD implant. The presence of chronic kidney disease (CKD) and proteinuria was assessed, and kidney ultrasound results were reviewed on all patients, if available. CKD was present if estimated glomerular filtration rate (eGFR) was <60 mL/min per 1.73m2 for ≥3 months preceding LVAD implant and/or presence of proteinuria ≥ 20 mg/dL on two or more urine samples prior to LVAD implant and/or an abnormal kidney ultrasound with increased echogenicity, small size <9 cm or scarring. AKI was defined as per the current Kidney Disease Initiative Global Outcomes (KDIGO) guidelines. Results A total of 137 patients received LVAD during this time period. There were 112 males and 25 females with a mean age of 59.2 years. Incidence of AKI and the need for RRT post-LVAD implant were 64% and 19.7%, respectively. Sub-group analysis was performed based on the presence of CKD, advanced CKD stage (Stage 1-2 vs 3-5), proteinuria and abnormal kidney ultrasound. The incidence of AKI post-LVAD implant was significantly higher if baseline CKD was present (P = 0.028), and patient had an advanced CKD stage (P = 0.008). The need for RRT post-LVAD implant was significantly higher if baseline CKD was present (P = 0.015), and the patient had an abnormal kidney ultrasound (P = 0.04). Thirty-day and one-year mortality rates post-LVAD implants were 4.3% and 21.1%, respectively for the entire cohort. Out of the 27 patients requiring RRT, nine (33.3%) came off RRT before one year. Compared to the eGFR on the day of LVAD implant, eGFR at 30 days post-LVAD implant was higher in 57% and lower in 42% patients. At one year, this eGFR improvement reversed and eGFR was lower in 67% and higher in 32% patients. Conclusion The incidence of AKI and need for RRT post-LVAD implant are very high. The presence of CKD, advanced CKD stage, and an abnormal kidney ultrasound are statistically significant risk factors of AKI post-LVAD implant and/or need for RRT. Identifying these renal risk factors can help stratify the potential LVAD candidates. Only one out of three patients requiring RRT achieved dialysis independence by one-year post-LVAD implant.

Global cardiovascular care: an overview of high-level political commitment.

BACKGROUND: Six billion people worldwide lack access to safe, timely, and affordable cardiac surgical and interventional care when needed. Cardiovascular diseases are the leading cause of mortality and morbidity around the world, and include a significant surgical backlog of rheumatic and congenital heart diseases. Here, we review the political commitment by the WHO, the UN, and the World Bank to build and strengthen healthcare services for cardiovascular diseases, with a particular focus on cardiac surgical and interventional cardiology services around the world. METHODS: A literature search was performed in the WHO, UN, and World Bank Governing Body databases to identify policy documents mentioning curative cardiovascular disease care. The Governing Body documentation, the Institutional Repository for Information Sharing database of the WHO, and the Official Document System of the UN were used. Documents only discussing prevention of cardiovascular diseases were excluded. RESULTS: Fifty-nine unique documents were identified, including 56 from the WHO, 3 from the World Bank, and none from the UN; 12 (20.4%) documents mentioned cardiac surgery, and 6 (10.2%) contained some actionable language to incorporate cardiac surgical services, but none was explicitly dedicated to cardiac surgical services. CONCLUSION: Although growing, high-level political commitment for curative cardiovascular health services remains minimal. Increased awareness is needed to develop comprehensive cardiovascular care that is necessary to mitigate the increasing burden of premature morbidity and mortality from cardiac disease, and to work towards the Sustainable Development Goals and Universal Health Coverage.

Factor Xa inhibitors in patients with continuous-flow left ventricular assist devices.

OBJECTIVE: Warfarin is standard anticoagulation therapy for patients with a continuous-flow left ventricular assist device (CF-LVAD). However, warfarin requires regular monitoring and dosage adjustments and fails for many patients, causing thromboembolic and bleeding events. Factor Xa inhibitors have been shown to be noninferior to warfarin in preventing strokes and are associated with less intracranial hemorrhage in patients with atrial fibrillation. We evaluated treatment safety and effectiveness in CF-LVAD patients who switched from warfarin to a factor Xa inhibitor (apixaban or rivaroxaban) after warfarin failure. METHODS: This was a retrospective, single-center study of patients treated between 2008 and 2018. We assessed the occurrence of stroke, non-central nervous system (CNS) embolism, pump thrombosis, and major gastrointestinal bleeding and intracranial hemorrhage during therapy. RESULTS: We identified seven patients: five were male, the average body mass index was 30 kg/m2, and average age was 56 years. Preimplantation comorbidities included hypertension (all patients) and diabetes mellitus, ischemic cardiomyopathy, atrial fibrillation, and previous myocardial infarction (four patients each). Overall, patients received warfarin for 3968 days and apixaban/rivaroxaban for 1459 days. The warfarin group was within the therapeutic INR range (2.0-3.0) 30% of the time. Complication rates did not differ between warfarin and apixaban/rivaroxaban: strokes, 0.20 vs none, non-CNS embolism, 0.54 vs none; pump thrombosis, 0.27 vs none; major gastrointestinal bleeding, 0.20 vs 0.50; intracranial hemorrhage, 0.13 vs none. CONCLUSIONS: Factor Xa inhibitors may be viable treatment options for CF-LVAD patients for whom warfarin therapy has failed. Large prospective studies are necessary to confirm these results.