Aortic Healing Appears to Occur Rapidly after Successful Endovascular Sealing of Blunt Thoracic Aortic Injury.

BACKGROUND: The traumatic nature of blunt thoracic aortic injury (BTAI) would suggest that healing of the aorta would occur once the injured area is shielded from aortic pressure. This would be in contrast to degenerative aortic diseases which often continue to degenerate despite coverage. We hypothesize that after successful thoracic aortic endografting (TEVAR) that the aorta rapidly heals itself leaving minimal to no trace of the residual injury. METHODS: BTAI that were successfully covered with TEVAR from 2006 to 2019 were collected. Those with failed sealing or a lack of follow-up scans were excluded. Centerline aortic diameters were measured at healthy aorta 1 cm above (D1) and below the injury (D3) and at the widest point of injury (D2) on preoperative and initial postoperative computed tomography (CT) scans. Postoperative CTs were examined for residual signs of aortic injury including residual periaortic hematoma, persistent thrombosed pseudoaneurysm, or thickened aortic wall. Diameter changes in the healthy and injured aortic segments were compared pre and post TEVAR. Aortic diameter changes were analyzed with the Student's t-test. RESULTS: Twenty four patients were identified with sealed BTAI. The mean graft diameter was 24.2 ± 3.2 mm with oversizing of 10.74 ± 6.1 % at D1 and 19.52 ± 10.22 % at D3. Postoperative CTs occurred at 61.25 ± 123.6 days with one outlier at 602 days. Injured aortic segments (D2) had significantly larger diameters compared to D1 (28.94 ± 5.08 mm vs. 22.14 ± 3.08 mm, P < 0.001). After TEVAR, 23/24 (95.8%) had no residual radiographic evidence of aortic injury by 2 months. One patient had a persistent thrombosed pseudoaneurysm likely due to more than 50% disruption of the aortic wall. Post TEVAR, there was a significant diameter reduction at D2 by 13.8% (29.10 ± 5.27 mm vs. 24.8 ± 4.2 mm, P < 0.001) which was within 2.45% of the mean stent graft diameter. The healthy aorta dilated to accommodate the graft by 9% at D1 (21.9 ± 3.0 vs. 23.7 ± 2.5 mm, P < 0.001) and 17% at D3 (20.6 ± 3.4 mm vs. 23.6 ± 3.2 mm, P < 0.001). CONCLUSIONS: TEVAR promotes rapid aortic healing in BTAI with no evidence of residual aortic injury suggesting that a long-term seal is not necessary. The healthy aorta dilates to the stent graft size, as expected, whereas the injured aortic segment heals around the stent graft and assumes its diameter as well. Massive disruption of the aortic wall may preclude early healing.

Use of three-dimensional-three-dimensional digital subtraction angiography spin fusion protocol for complex aortoiliac endovascular interventions.

Complex endovascular aortic interventions in patients with excessive tortuosity or difficult gantry angles can be challenging. Although fusion imaging can help navigate these issues, it is based on preoperative imaging studies, which becomes skewed after introduction of stiff wires and large devices into the aorta. The subtraction spin protocol performs two cone-beam computed tomography scans to create a subtracted image of the contrast-filled vessels after wire and device placement to accommodate vessel distortion. We have reported a complex fenestrated endovascular aneurysm repair case with a highly angulated neck to highlight the advantages of the subtraction spin protocol in anatomically hostile endovascular repairs.

Mid-Term Outcomes of Thrombolysis for Acute Lower Extremity Ischemia at a Tertiary Care Center.

BACKGROUND: Acute limb ischemia (ALI) is challenging to treat because of high morbidity and mortality. Endovascular-first options beginning with thrombolysis are technically feasible with similar results to open surgery. We examined our experience with thrombolysis to identify patients and target conduits that are predictive of improved outcomes. METHODS: We performed a retrospective review of our institutional database of thrombolysis cases for arterial lower extremity disease. Thrombolysis was the index procedure, and any subsequent treatment was a reintervention. Conversion to open surgery perioperatively such as thromboembolectomy or bypass was considered a technical failure. Primary outcomes included primary patency, secondary patency, amputation-free survival (AFS), and survival. Secondary outcomes included conversion to open, reintervention <30 days, and amputation <30 days. Descriptive statistics and analysis of variance were performed for preoperative and intraoperative risk factors. Kaplan-Meier estimation and Cox proportional hazard models were used for primary and secondary outcomes. RESULTS: Ninety-nine patients with ALI were treated with thrombolysis from 2007 to 2017. Thrombolysis was attempted on native artery (40%), vein bypass (7%), prosthetic bypass (33%), and stent (19%). Rutherford class distribution was 50% class 1, 41% class 2a, 5% class 2b, and 3% class 3. Technical success was 70%, characterized by an all-endovascular approach, patency at 30 days, and AFS for 30 days. Primary patency at 1- and 2-years was 31% and 22%, respectively. Secondary patency at 1- and 2-years was 39% and 27%, respectively. Overall, 30% required conversion to open surgery at the time of the index procedure, 7% reintervention <30 days, 5% mortality <30 days, and 5% major amputation <30 days. Prosthetic grafts and vein bypasses had the worst primary and secondary patency (P < 0.05). Five out of 7 vein bypasses required open conversion. Thrombolysis of native arteries was most successful maintaining primary patency (P < 0.05), secondary patency (P < 0.05), and AFS (P < 0.05). Patients who had adjunctive procedures at the time of thrombolysis had a significantly greater primary patency (P < 0.05) and secondary patency (P < 0.05) but not greater AFS. CONCLUSION: Outcomes in thrombolysis for ALI have not significantly improved 20 years after the STILE trial. Technical success and mid-term patency rates are modest at best. Thrombolysis of vein bypasses and prosthetic grafts have poor technical success and primary patency compared with native arteries. However, aggressive adjunctive interventions during thrombolysis appear to improve primary and secondary patency.

Endovascular Repair of the Ascending Aorta for an Anastomotic Saphenous Vein Graft Aneurysm.

The ascending aorta is the final segment of the aorta to be explored with endovascular stent grafts. With a patient population of increasingly advanced age and disease, there are situations where traditional open repair for ascending aneurysms or dissections may be prohibitive. However, the ascending aorta has multiple hostile characteristics that make endovascular treatment challenging. There is also a lack of approved specialized devices in the United States for this aortic territory. We demonstrate the feasibility of adapting an abdominal aortic graft to the ascending aorta for the treatment of a saphenous vein graft aneurysm with a discussion of the technical considerations for the operation.

Parallel Stent Graft Technique for Hypogastric Aneurysm Repair With Flow Preservation of Distal Pelvic Circulation.

Hypogastric artery aneurysms (HAA) necessitate repair due to significant morbidity and potential mortality associated with rupture. Coverage or coiling of HAA are not always possible, as the risk of pelvic and spinal cord ischemia become especially significant in bilateral hypogastric disease as well as with prior extensive aortic coverage. We report 2 cases of endovascular HAA exclusion using parallel stent grafts for preservation of flow through the distal hypogastric artery branches and external iliac artery in patients with prior thoracic and abdominal aortic repairs, contralateral hypogastric disease, and significant anatomic constraints.

Short-term results of left subclavian artery salvage in blunt thoracic aortic injury with short proximal landing zones.

OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) is the standard treatment of blunt thoracic aortic injury (BTAI). The concept of seal was derived from the treatment of aneurysms and has been adopted for BTAI. Given the location of injury in BTAI, left subclavian artery (LSA) coverage is sometimes necessary. In these often healthier aortas, a shorter proximal landing zone may be acceptable and beneficial in avoiding some complications. Current practice patterns vary, and long-term effects of LSA coverage remain unknown. METHODS: A single-institution experience with BTAI for TEVAR was examined from 2006 to 2017. The primary outcome was failure of sealing, endoleak, or persistent aortic injury on follow-up imaging. A centerline was used to measure the length of the landing zone, aortic diameter, and other parameters. Post-TEVAR computed tomography scans were examined for evidence of residual aortic injury. RESULTS: A total of 30 TEVARs were performed for BTAI. The mean age of the patients was 38.7 years (standard deviation [SD], 19.8 years), and 70% were male. The mean injury severity score was 36.75 (SD, 13.1). Treated patients had grade 2 (36.7%) or grade 3 (63.3%) BTAI. The LSA was salvaged in 23 cases and covered in seven cases. The mean landing zone in LSA uncovered cases was 16 mm (SD, 10.4 mm). There were 15 patients (65%) who had a landing zone <20 mm, and eight (35%) patients had a landing zone >20 mm. The mean landing zone in the seven covered cases was 1.8 mm (SD, 2.4 mm). Procedural success was 96% for the uncovered group and 100% for the covered group. On follow-up imaging, there was only one residual endoleak in all surviving patients (n = 25). Five patients did not have postoperative imaging, two (7%) of whom died of nonaorta-related issues. CONCLUSIONS: TEVAR for BTAI in patients with short proximal landing zones of 10 to 20 mm as well as in select patients with landing zones of 5 to 10 mm appears to be safe and efficacious. The aorta demonstrates no residual injury after TEVAR, with the graft acting potentially more as a bridge to allow healing. Long-term issues regarding LSA coverage have been difficult to ascertain and to evaluate because of historically poor follow-up in this population of patients. However, potential issues with LSA coverage and revascularization may be avoided by preserving the subclavian artery even with shorter proximal landing zones.

A rare case of idiopathic bilateral ovarian vein thrombosis.

Ovarian vein thrombosis (OVT) is a rare medical disorder most often diagnosed in the peripartum period and maybe associated with other risk factors for thrombosis. Rarely, OVT is considered idiopathic. It occurs in the right ovarian vein alone in two-thirds of patients. In this report, we present a case of idiopathic and bilateral OVT in a 35-year-old woman who presented with 2-day history of left flank pain. Duplex ultrasound imaging and computed tomography confirmed the diagnosis. Oral anticoagulation achieved a favorable outcome.

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.

Inguinal pain and fullness due to an intravascular leiomyoma in the external iliac vein.

Intravascular leiomyomatosis (IVL) is a benign smooth muscle tumor that evolves from the pelvic veins and can spread to the central veins and heart. Cardiac involvement is the most commonly reported presentation. Initial diagnosis is difficult, and IVL is commonly misdiagnosed as thrombus or atrial myxoma. Appropriate imaging and a high clinical suspicion are required for accurate diagnosis. We report a rare case of IVL in the external iliac vein that recurred 4 years after hysterectomy. Only four cases have been reported in the literature to involve the external iliac vein as it has no direct connection to pelvic venous drainage.

Delayed migration of a thrombosed aortic endograft within a thrombosed aneurysm sac resulting in continued sac expansion and rupture.

We present the case of delayed migration of a thrombosed aortic endograft within a thrombosed aneurysm sac that expanded and ruptured. Dilation of the aortic neck likely led to endograft migration and exposure of the occluded endograft and aneurysm sac to systemic pressure. Although no endoleak was identified, a key finding on ultrasound showed mobility of the sac thrombus. This may be an indicator of flow within the sac that may predict potential for rupture. Despite thrombosis of the aortic sac and endograft, the risk of rupture still lingers, and thus continued surveillance of occluded endografts may be prudent.

Tibioperoneal Trunk Aneurysm Resulting in Compartment Syndrome with Associated Aneurysms of the Popliteal and Dorsalis Pedis Arteries.

True aneurysms of the tibioperoneal trunk are rare. Given the scarcity of reports, the clinical presentation and treatment is not well defined. This is a case report of a 50-year-old male patient presenting with severe lower extremity swelling and compartment syndrome with neurological compromise secondary to a tibioperoneal trunk aneurysm. He was also noted to have discrete ipsilateral popliteal and dorsalis pedis artery aneurysms. Given the location and size of the aneurysm, the severe leg swelling, and venous hypertension, aneurysmorrhaphy or aneurysm sac excision with arterial reconstruction was prohibitively dangerous. Thus, following fasciotomies, a hybrid repair utilizing a saphenous vein superficial femoral to anterior tibial artery bypass along with coil embolization of the aneurysm sac was performed. The patient recovered full function of his leg and follow-up computed tomography angiogram demonstrated thrombosis and regression of the aneurysm sac with a patent bypass.

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.

Mid- and long-term results of the treatment of infrainguinal arterial occlusive disease with precuffed expanded polytetrafluoroethylene grafts compared with vein grafts.

BACKGROUND: Prosthetic grafts for lower-extremity bypass have limited patency compared with autologous vein grafts. Precuffed expanded polytetrafluoroethylene (ePTFE) grafts alter the geometry of the distal hood to improve patency. This study reports the authors' long-term results on the use of precuffed ePTFE grafts for infrainguinal bypasses in patients with arterial occlusive disease and compares these with results of reversed great saphenous vein grafts (rSVG). METHODS: A retrospective review of billing codes identified 101 polytetrafluoroethylene (PTFE) and 47 rSVG bypasses performed over a 6-year period. Femoral to below-knee popliteal and femoral to tibial bypasses were analyzed. Data collected consisted of risk factors, Rutherford classification, bypass inflow and outflow, runoff vessels, patency, amputation, and death. Primary end points consisted of primary, assisted-primary, and secondary patency along with limb salvage. RESULTS: Mean age of the patients was 76 years in the PTFE group and 69.8 years in the rSVG group. For femoral to below-knee popliteal bypasses, primary patency at 1, 3, and 5 years in the PTFE group was 76.9%, 48.7%, and 43.3%, respectively, compared with 77.1%, 77.1%, and 77.1%, respectively, in the rSVG group (P = 0.225). Secondary patency was 89.2%, 70.9%, and 50.6% in the PTFE group compared with 84.4%, 84.4%, and 84.4% in the rSVG group (P = 0.269). Limb salvage was similar in the PTFE compared with the rSVG group (97.7%, 90.5%, and 79.4% vs. 83.3%, 83.3%, and 83.3%; P = 0.653). For femoral to tibial bypasses, primary patency in the PTFE group at 1, 3, and 5 years was 57.1%, 40.4%, and 22.1%, respectively, compared with 67.4%, 67.4%, and 50.6%, respectively, for the rSVG group (P = 0.246). Secondary patency was 75.5%, 44.9%, and 22.7% in the PTFE group compared with 91.8%, 91.8%, and 52.5% in the rSVG group (P = 0.022). Limb salvage at 1, 3, and 5 years was 79.2%, 55.7%, and 55.7%, respectively, in the PTFE group compared with 96.4%, 96.4%, and 64.3%, respectively, in the rSVG group (P = 0.046). CONCLUSIONS: Precuffed ePTFE grafts demonstrate similar 1-year patency to that of rSVG. However, mid- and long-term patency is reduced compared with saphenous vein grafts (SVG), especially to tibial targets. PTFE grafts to the popliteal demonstrate limb salvage rates similar to those of SVG. In the tibial vessels, limb salvage rates for PTFE grafts are significantly worse compared with SVG.

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.

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 microm) was significantly less than both cut and coagulation mode electrosurgical incisions (456 +/- 35 microm and 615 +/- 22 microm, 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.

SDF-1 alpha 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 alpha. Interleukin-1 beta is an important inflammatory cytokine involved in wound healing and is believed to regulate SDF-1 alpha expression independent of hypoxia signaling. Thus, the authors examined the relative importance of interleukin (IL)-1 beta and hypoxia-inducible factor (HIF)-1 alpha on SDF-1 alpha 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 alpha levels in aged wounds that correlated with reduced CD31+ neovessels. Western blots revealed decreased HIF-1 alpha protein in aged wounds. However, both IL-1 beta 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 beta 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 alpha deficiency observed during aged wound healing is attributable predominantly to decreased HIF-1 alpha levels rather than impaired IL-1 beta expression.

Age decreases endothelial progenitor cell recruitment through decreases in hypoxia-inducible factor 1alpha 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 1alpha 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 1alpha 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 1alpha-mediated hypoxia response.

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 proliferative phase of wound healing produces hypertrophic scars by inhibiting cellular apoptosis through an Akt-dependent mechanism.