Shang A. Loh

Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis

Hypertrophic scars occur following cutaneous wounding and result in severe functional and esthetic defects. The pathophysiology of this process remains unknown. Here, we demonstrate for the first time that mechanical stress applied to a healing wound is sufficient to produce hypertrophic scars in mice. The resulting scars are histopathologically identical to human hypertrophic scars and persist for more than six months following a brief (one‐week) period of augmented mechanical stress during the proliferative phase of wound healing. Resulting scars are structurally identical to human hypertrophic scars and showed dramatic increases in volume (20‐fold) and cellular density (20‐fold). The increased cellularity is accompanied by a four‐fold decrease in cellular apoptosis and increased activation of the prosurvival marker Akt. To clarify the importance of apoptosis in hypertrophic scar formation, we examine the effects of mechanical loading on cutaneous wounds of animals with altered pathways of cellular apoptosis. In p53‐null mice, with down‐regulated cellular apoptosis, we observe significantly greater scar hypertrophy and cellular density. Conversely, scar hypertrophy and cellular density are significantly reduced in proapoptotic BclII‐null mice. We conclude that mechanical loading early in the prolifer‐ative phase of wound healing produces hypertrophic scars by inhibiting cellular apoptosis through an Akt‐dependent mechanism.—Aarabi S., Bhatt, K. A., Shi, Y., Paterno, J., Chang, E. I., Loh, S. A., Holmes, J. W., Longaker, M. T., Yee, H., Gurtner G. C. Mechanical load initiates hypertrophic scar formation through decreased cellular apoptosis. FASEB J. 21, 3250–3261 (2007)

Age Decreases Endothelial Progenitor Cell Recruitment Through Decreases in Hypoxia-Inducible Factor 1α Stabilization During Ischemia

Background— Advanced age is known to impair neovascularization. Because endothelial progenitor cells (EPCs) participate in this process, we examined the effects of aging on EPC recruitment and vascular incorporation. Methods and Results— Murine neovascularization was examined by use of an ischemic flap model, which demonstrated aged mice (19 to 24 months) had decreased EPC mobilization (percent mobilized 1.4±0.2% versus 0.4±0.1%, P<0.005) that resulted in impaired gross tissue survival compared with young mice (2 to 6 months). This decrease correlated with diminished tissue perfusion (P<0.005) and decreased CD31+ vascular density (P<0.005). Gender-mismatched bone marrow transplantation demonstrated significantly fewer chimeric vessels in aged mice (P<0.05), which confirmed a deficit in bone marrow–mediated vasculogenesis. Age had no effect on total EPC number in mice or humans. Reciprocal bone marrow transplantations confirmed that impaired neovascularization resulted from defects in the response of aged tissue to hypoxia and not from intrinsic defects in EPC function. We demonstrate that aging decreased hypoxia-inducible factor 1α stabilization in ischemic tissues because of increased prolyl hydroxylase–mediated hydroxylation (P<0.05) and proteasomal degradation. This resulted in a diminished hypoxia response, including decreased stromal cell–derived factor 1 (P<0.005) and vascular endothelial growth factor (P<0.0004). This effect can be reversed with the iron chelator deferoxamine, which results in hypoxia-inducible factor 1α stabilization and increased tissue survival. Conclusions— Aging impairs EPC trafficking to sites of ischemia through a failure of aged tissues to normally activate the hypoxia-inducible factor 1α–mediated hypoxia response.

SDF-1α expression during wound healing in the aged is HIF dependent

Background: Age-related impairments in wound healing are associated with decreased neovascularization, a process that is regulated by hypoxia-responsive cytokines, including stromal cell–derived factor (SDF)-1&agr;. Interleukin-1&bgr; is an important inflammatory cytokine involved in wound healing and is believed to regulate SDF-1&agr; expression independent of hypoxia signaling. Thus, the authors examined the relative importance of interleukin (IL)-1&bgr; and hypoxia-inducible factor (HIF)-1&agr; on SDF-1&agr; expression in aged wound healing. Methods: Young and aged mice (n = 4 per group) were examined for wound healing using a murine excisional wound model. Wounds were harvested at days 0, 1, 3, 5, and 7 for histologic analysis, immunohistochemistry, enzyme-linked immunosorbent assay, and Western blot. An engineered wild-type and mutated SDF luciferase reporter construct were used to determine HIF transactivation. Results: Aged mice demonstrated significantly impaired wound healing, reduced granulation tissue, and increased epithelial gap compared with young controls. Real-time polymerase chain reaction demonstrated reduced SDF-1&agr; levels in aged wounds that correlated with reduced CD31+ neovessels. Western blots revealed decreased HIF-1&agr; protein in aged wounds. However, both IL-1&bgr; and macrophage infiltrate were unchanged between young and aged animals. Using the wild-type and mutated SDF luciferase reporter construct in which the hypoxia response element was deleted, only young fibroblasts were able to respond to IL-1&bgr; stimulation, and this response was abrogated by mutating the HIF-binding sites. This suggests that HIF binding is essential for SDF-1 transactivation in response to both inflammatory and hypoxic stimuli. Conclusions: SDF-1&agr; deficiency observed during aged wound healing is attributable predominantly to decreased HIF-1&agr; levels rather than impaired IL-1&bgr; expression.

Comparative healing of surgical incisions created by the PEAK PlasmaBlade, conventional electrosurgery, and a scalpel.

Background: The PEAK PlasmaBlade is a new electrosurgical device that uses pulsed radiofrequency to generate a plasma-mediated discharge along the exposed rim of an insulated blade, creating an effective cutting edge while the blade stays near body temperature. Methods: Full-thickness incisions were made on the dorsums of pigs with the PlasmaBlade, a conventional electrosurgical device, and a scalpel, and blood loss was quantified. Wounds were harvested at designated time points, tested for wound tensile strength, and examined histologically for scar formation and tissue damage. Results: Bleeding was reduced significantly (59 percent) in PlasmaBlade incisions compared with scalpel incisions, and acute thermal damage from the PlasmaBlade (66 ± 5 &mgr;m) was significantly less than both cut and coagulation mode electrosurgical incisions (456 ± 35 &mgr;m and 615 ± 22 &mgr;m, respectively). Histologic scoring for injury and wound strength was equivalent between the PlasmaBlade and scalpel incisions. By 6 weeks, the healed PlasmaBlade and scalpel incisions were approximately three times stronger, and scar cosmetic appearance was significantly better compared with electrosurgical incisions. Conclusions: The PlasmaBlade is a promising new surgical instrument that provides atraumatic, scalpel-like cutting precision and electrosurgical-like hemostasis, resulting in minimal bleeding, tissue injury, and scar formation.

Endovascular solutions to arterial injury due to posterior spine surgery

Iatrogenic arterial injury is an uncommon but recognized complication of posterior spinal surgery. The spectrum of injuries includes vessel perforation leading to hemorrhage, delayed pseudoaneurysm formation, and threatened perforation by screw impingement on arterial vessels. Repair of these injuries traditionally involved open direct vessel repair or graft placement, which can be associated with significant morbidity. We identified five patients with iatrogenic arterial injury during or after posterior spinal surgery between July 2004 and August 2009 and describe their endovascular treatment. Intraoperative arterial bleeding was encountered in two patients during posterior spinal surgery. The posterior wounds were packed, temporarily closed, and the patient was placed supine. In both patients, angiography demonstrated arterial injury necessitating repair. Covered stent grafts were deployed through femoral cutdowns to exclude the areas of injury. In three additional patients, postoperative computed tomography imaging demonstrated pedicle screws abutting/penetrating the thoracic or abdominal aorta. Angiography or intravascular ultrasound imaging, or both, confirmed indention/perforation of the aorta by the screw. Aortic stent graft cuffs were deployed through femoral cutdowns to cover the area of aortic contact before hardware removal. All five patients did well and were discharged home in good condition. Endovascular repair of arterial injuries occurring during posterior spinal procedures is feasible and can offer a safe and less invasive alternative to open repair.

Existing trauma and critical care scoring systems underestimate mortality among vascular trauma patients

BACKGROUND The impact of vascular injuries on patient mortality has not been well evaluated in multi-trauma patients. This study seeks to determine (1) whether the presence of vascular trauma negatively affects outcome compared with nonvascular trauma (NVT) and (2) the utility of existing severity scoring systems in predicting mortality among vascular trauma (VT) patients. METHODS A retrospective review of our trauma database from January 2005 to December 2007 was conducted. Demographics, Injury Severity Scores (ISS), Revised Trauma Scores (RTS), Trauma Score-Injury Severity Scores (TRISS), Acute Physiology and Chronic Health Evaluation II (APACHE II) scores, and mortality rates were compared. Control patients were selected from a matching cohort based on ISS. Comparisons were made between groups based on the above scoring systems. Statistical analysis used χ(2) analysis and Student t-tests. RESULTS Fifty VT and 50 NVT patients were identified with no significant differences in age, gender, mechanism of injury, ISS, RTS, or TRISS. The mean APACHE II score was higher in VT compared with NVT (12.3 vs 8.8, P < .05). Overall mortality was higher in VT compared with NVT but did not reach statistical significance (24% vs 11.8%, P = .108). VT patients with RTS score >5 had a higher mortality rate (26% vs 2.2%, P = .007). VT patients with an ISS score >24 had a higher mortality compared with NVT patients (61% vs 28.6%, P = .04). VT patients with an APACHE II score <14 also had a higher mortality rate (18.2% vs 0%, P = .007). Finally, VT patients with a TRISS probability of survival of >80% had a higher mortality rate (13.9% vs 0%, P = .05). CONCLUSIONS In multi-trauma patients, the presence of vascular injury was associated with increased mortality in less severely injured patients based on the RTS, TRISS, and APACHE II scores. These scoring systems underestimated mortality in patients with vascular trauma. Level of care and future trauma algorithms should be adjusted in the presence of vascular trauma.

Carotid endarterectomy: still the standard of care for carotid bifurcation disease.

Current treatment guidelines of symptomatic and asymptomatic carotid stenosis are based on studies performed over a decade ago. Since that time, significant advances have been made in medical management, namely high dose statin therapy and improved antiplatelet agents, and in carotid interventions, namely the advent of carotid artery stenting. Especially with carotid stenting, the technology has grown by leaps and bounds and continues to advance at a rapid pace. These advances have necessitated new studies to compare these treatments with the gold standard of carotid endarterectomy. In asymptomatic patients, the current data does not justify medical management alone for severe (>80%) carotid stenosis. Furthermore, in both asymptomatic and symptomatic patients current studies have failed to demonstrate equivalence of CAS to CEA for significant carotid stenosis. Clearly additional studies comparing CAS, CEA, and medical management are needed to further clarify this issue. In the future, advances in CAS technology and techniques may greatly expand the role of CAS beyond its current role in certain high-risk patient subsets. However, for the time being CEA still remains the gold standard for carotid intervention.

Coil Embolization of an Aortic Pseudoaneurysm after Open Repair of Type A Aortic Dissection

Anastomotic pseudoaneurysms represent an uncommon and challenging complication of open aortic repair with prosthetic graft. First characterized by Clayton et al. in 1956, they affect approximately 1.4-4% of arterial anastomoses. These pseudoaneurysms are the result of many factors, foremost of which are infection, integrity of the host tissue, surgical technique, and location of the anastomosis. Pseudoaneurysms were traditionally treated with open resection of the pseudoaneurysm and revision of the anastomosis. This case presents a novel approach to the treatment of pseudoaneurysms in a difficult location. The patient was a 77-year-old man status after repair of a type A aortic dissection with a Dacron tube graft. Follow-up imaging 18 months postoperatively showed a 1.6 cm×1.7 cm pseudoaneurysm off of the posteromedial proximal suture line. Through a right brachial artery approach, a diagnostic angiogram was performed demonstrating a bilobed pseudoaneurysm. A Judkins left 3.5 catheter and 0.035″-angled Glidewire was used to engage the orifice of the pseudoaneurysm. Two 4 mm×6 cm Boston Scientific Interlock coils were then deployed into the pseudoaneurysm sac. Completion angiogram demonstrated complete exclusion of the pseudoaneurysm. The patient did well and was discharged the following day. Follow-up computed tomography scan at 3 months showed regression and complete thrombosis of the pseudoaneurysm. Traditional operative repair of anastomotic pseudoaneurysms can lead to long operations, high blood loss, and increased morbidity and mortality as a result of their reoperative nature. Coil embolization is a safe and effective approach for the treatment of anastomotic pseudoaneurysms in difficult locations.

Incidence and Outcome of Filter Occlusion during Carotid Artery Stent Procedure

Recent reviews of device-specific complications using neuroprotection have addressed technical difficulties during delivery as well as adverse outcomes, intraoperative and 30-day. Little has been written, however, regarding the relevance of filter occlusion during the carotid stent procedure. A retrospective review was conducted of patients undergoing carotid artery stent procedures using a variety of neuroprotection devices from 2003 to 2007. Prospective databases from two institutions were examined for incidence and management of filter occlusions during procedures as well as adverse neurological events (intraoperative and 30-day) associated with filter occlusion. There were 283 carotid artery stent procedures performed on 256 patients (163 male, 93 female): 177 (62.5%) arteries were asymptomatic and 106 were symptomatic. Neurological adverse events occurred in six patients (2.1%); three of these resolved completely at 72 hr. Neuroprotection was used in 95% of all patients, and filters were used in 221 stent procedures: Boston Scientific Filter Wire (n = 81), Guidant Accunet (n = 100), Angioguard (n = 17), and Abbot Emboshield (n = 23). Filter occlusion occurred in 11 patients (4.9%) in whom this form of neuroprotection was employed: Angioguard (n = 5), Accunet (n = 2), Emboshield (n = 2), and EPI Filter wire (n = 2). Two of the 11 patients with filter occlusions suffered a neurological event. There was no correlation between filter occlusion and gender, symptoms, stent, or filter type (p > 0.05). Filter occlusion was managed with export catheter-directed aspiration in seven patients and with prompt filter retrieval in five patients. Filter occlusion is an infrequent event that does not appear to be filter-specific and can be managed successfully by catheter-directed aspiration or filter retrieval. The majority of patients with filter occlusion do not suffer from atheroemboli as a result of this occlusion.

Fluoroscopy time is not accurate as a surrogate for radiation exposure

Objective The Food and Drug Administration and the Vascular Quality Initiative still utilize fluoroscopy time as a surrogate marker for procedural radiation exposure. This study demonstrates that fluoroscopy time does not accurately represent radiation exposure and that dose area product and air kerma are more appropriate measures. Methods Lower extremity endovascular interventions (N = 145) between 2013 and 2015 performed at an academic medical center on a Siemens Artis-Zee floor mounted c-arm were identified. Data was collected from the summary sheet after every case. Scatter plots with Pearson correlation coefficients were created. A strong correlation was indicated by an r value approaching 1. Results Overall mean AK and DAP was 380.27 mGy and 4919.2 µGym2. There was a poor correlation between fluoroscopy time and total AK or DAP (r = 0.27 and 0.32). Total DAP was strongly correlated to cine DAP and fluoroscopy DAP (r = 0.92 vs. 0.84). The number of DSA runs and average frame rate did not affect AK or DAP levels. Mean magnification level was significantly correlated with total AK (r = 0.53). Conclusions Fluoroscopy time shows minimal correlation with radiation delivered and therefore is a poor surrogate for radiation exposure during fluoroscopy procedures. DAP and AK are more suitable markers to accurately gauge radiation exposure.