Nicholas D. Andersen

Inflammation and neuropeptides: the connection in diabetic wound healing.

Abnormal wound healing is a major complication of both type 1 and type 2 diabetes, with nonhealing foot ulcerations leading in the worst cases to lower-limb amputation. Wound healing requires the integration of complex cellular and molecular events in successive phases of inflammation, cell proliferation, cell migration, angiogenesis and re-epithelialisation. A link between wound healing and the nervous system is clinically apparent as peripheral neuropathy is reported in 30-50% of diabetic patients and is the most common and sensitive predictor of foot ulceration. Indeed, a bidirectional connection between the nervous and the immune systems and its role in wound repair has emerged as one of the focal features of the wound-healing dogma. This review provides a broad overview of the mediators of this connection, which include neuropeptides and cytokines released from nerve fibres, immune cells and cutaneous cells. In-depth understanding of the signalling pathways in the neuroimmune axis in diabetic wound healing is vital to the development of successful wound-healing therapies.

Retrograde ascending aortic dissection as an early complication of thoracic endovascular aortic repair

OBJECTIVE Retrograde ascending aortic dissection (rAAD) is a potential complication of thoracic endovascular aortic repair (TEVAR), yet little data exist regarding its occurrence. This study examines the incidence, etiology, and outcome of this event. METHODS A prospective institutional database was used to identify cases of acute rAAD following TEVAR from a cohort of 309 consecutive procedures from March 2005 (date of initial Food and Drug Administration approval) to September 2010. The database was analyzed for the complication of rAAD as well as relevant patient and operative variables. RESULTS The incidence of rAAD was 1.9% (6/309); all cases occurred with proximal landing zone in the ascending aorta and/or arch (zones 0-2). All were identified in the perioperative period (range, 0-6 days) with 33% (2/6) 30-day/in-hospital mortality. Eighty-three percent (5/6) underwent emergent repair; one patient died without repair. rAAD patients were similar to the non-rAAD group (n = 303) across pertinent variables, including age, gender, race, and device size (all P > .1). rAAD incidence by aortic pathology was 1.0% (2/200) for aneurysm, 4.4% (4/91) for dissection, and 0% (0/18) for transection; P = .08. rAAD incidence by device was TAG (Gore) 1.0% (2/205), Talent (Medtronic) 4.7% (2/43), and Zenith TX2 (Cook) 3.6% (2/55). rAAD incidence was observed to be higher among patients with an ascending aortic diameter ≥ 4.0 cm (4.8% vs 0.9% for ascending diameter <4.0 cm); P = .047. Incidence was also higher with proximal landing zone in the native ascending aorta (zone 0) 6.9% (2/29) versus 1.4% for all others (4/280); P = .101. For patients with dissection pathology and an ascending aortic diameter ≥ 4.0 cm, 11% (3/28) suffered rAAD; with the combination of native ascending aorta (zone 0) landing zone measuring ≥ 4.0 cm, the incidence was 25% (2/8). Definitive diagnosis was by computed tomography angiography (n = 1), intraoperative transesophageal echocardiography (n = 3), intraoperative arteriography (n = 1), or postmortem autopsy (n = 1). CONCLUSIONS rAAD is a lethal early complication of TEVAR, which may be more common when treating dissection, with devices utilizing proximal bare springs or barbs for fixation, with native zone 0 proximal landing zone and with ascending aortic diameter ≥ 4 cm. Combinations of these risk factors may be particularly high risk. Intraoperative imaging assessment of the ascending aorta should be conducted following TEVAR to avoid under-recognition. National database reporting of this complication is needed to ensure safety and proper application of emerging TEVAR technology.

Contemporary results for proximal aortic replacement in North America.

OBJECTIVES The purpose of this study was to characterize operative outcomes for ascending aorta and arch replacement on a national scale and to develop risk models for mortality and major morbidity. BACKGROUND Contemporary outcomes for ascending aorta and arch replacement in North America are unknown. METHODS We queried the Society of Thoracic Surgeons Database for patients undergoing ascending aorta (with or without root) with or without arch replacement from 2004 to 2009. The database captured 45,894 cases, including 12,702 root, 22,048 supracoronary ascending alone, 6,786 ascending plus arch, and 4,358 root plus arch. Baseline characteristics and clinical outcomes were analyzed. A parsimonious multivariable logistic regression model was constructed to predict risks of mortality and major morbidity. RESULTS Operative mortality was 3.4% for elective cases and 15.4% for nonelective cases. A risk model for operative mortality (c-index 0.81) revealed a risk-adjusted odds ratio for death after emergent versus elective operation of 5.9 (95% confidence interval: 5.3 to 6.6). Among elective patients, end-stage renal disease and reoperative status were the strongest predictors of mortality (adjusted odds ratios: 4.0 [95% confidence interval: 2.6 to 6.4] and 2.3 (95% confidence interval: 1.9 to 2.7], respectively; p < 0.0001). CONCLUSIONS Current outcomes for ascending aorta and arch replacement in North America are excellent for elective repair; however, results deteriorate for nonelective status, suggesting that increased screening and/or lowering thresholds for elective intervention could potentially improve outcomes. The predictive models presented may serve clinicians in counseling patients.

Results with an algorithmic approach to hybrid repair of the aortic arch

OBJECTIVE Hybrid repair of the transverse aortic arch may allow for aortic arch repair with reduced morbidity in patients who are suboptimal candidates for conventional open surgery. We present our results with an algorithmic approach to hybrid arch repair, based on the extent of aortic disease and patient comorbidities. METHODS Between August 2005 and January 2012, 87 patients underwent hybrid arch repair by three principal procedures: zone 1 endograft coverage with extra-anatomic left carotid revascularization (zone 1; n = 19), zone 0 endograft coverage with aortic arch debranching (zone 0; n = 48), or total arch replacement with staged stented elephant trunk completion (stented elephant trunk; n = 20). RESULTS The mean patient age was 64 years, and the mean expected in-hospital mortality rate was 16.3% as calculated by the EuroSCORE II. Of operations, 22% (n = 19) were nonelective. Sternotomy, cardiopulmonary bypass, and deep hypothermic circulatory arrest were required in 78% (n = 68), 45% (n = 39), and 31% (n = 27) of patients to allow for total arch replacement, arch debranching, or other concomitant cardiac procedures, including ascending with or without hemiarch replacement in 17% (n = 8) of patients undergoing zone 0 repair. All stented elephant trunk procedures (n = 20) and 19% (n = 9) of zone 0 procedures were staged, with 41% (n = 12) of patients undergoing staged repair during a single hospitalization. The 30-day/in-hospital rates of stroke and permanent paraplegia or paraparesis were 4.6% (n = 4) and 1.2% (n = 1). Of 27 patients with native ascending aorta zone 0 proximal landing zone, three (11.1%) experienced retrograde type A dissection after endograft placement. The overall in-hospital mortality rate was 5.7% (n = 5); however, 30-day/in-hospital mortality increased to 14.9% (n = 13) owing to eight 30-day out-of-hospital deaths. Native ascending aorta zone 0 endograft placement was found to be the only univariate predictor of 30-day in-hospital mortality (odds ratio, 4.63; 95% confidence interval, 1.35-15.89; P = .02). Over a mean follow-up period of 28.5 ± 22.2 months, 13% (n = 11) of patients required reintervention for type 1A (n = 4), type 2 (n = 6), or type 3 (n = 1) endoleak. Kaplan-Meier estimates of survival at 1 year, 3 years, and 5 years were 73%, 60%, and 51%. CONCLUSIONS Hybrid aortic arch repair can be tailored to patient anatomy and comorbid status to allow complete repair of aortic pathology, frequently in a single stage, with acceptable outcomes. However, endograft placement in the native ascending aorta is associated with high rates of retrograde type A dissection and 30-day/in-hospital mortality and should be approached with caution.

Five-year results for endovascular repair of acute complicated type B aortic dissection

INTRODUCTION Despite a current lack of U.S. Food and Drug Administration approval for the indication, thoracic endovascular aortic repair (TEVAR) has replaced open surgical management for acute complicated type B aortic dissection due to promising short- and midterm data. However, long-term results, with a view toward durability and need for secondary procedures, are limited. As such, the objective of the present study is to report long-term outcomes of TEVAR for acute (≤ 2 weeks from symptom onset) complicated type B dissection. METHODS Between July 2005 and September 2012, 50 consecutive patients underwent TEVAR for management of acute complicated type B dissection at a single referral institution. Patient records were retrospectively reviewed from a prospectively maintained clinical database. RESULTS Indications for intervention included rupture in 10 (20%), malperfusion in 24 (48%), and/or refractory pain/impending rupture in 17 (34%). One patient (2%) had both rupture and malperfusion indications. Ten (20%) patients required one or more adjunctive procedures, in addition to TEVAR, to treat malperfusion syndromes. In-hospital and 30-day rates of death were both 0%; 30-day/in-hospital rates of stroke, permanent paraplegia/paraparesis, and new-onset dialysis were 2% (n = 1), 2% (n = 1), and 4% (n = 2), respectively. Median follow-up was 33.8 months [interquartile range, 12.3-56.6 months]. Overall survival at 5 and 7 years was 84%, with no deaths attributable to aortic pathology. Thirteen (26%) patients required a total of 17 reinterventions over the study period for type I endoleak (n = 5), metachronous aortic pathology (n = 5), persistent false lumen pressurization via distal fenestrations (n = 4), type II endoleak (n = 2), or retrograde acute type A aortic dissection (n = 1). Median time to first reintervention was 4.5 months (range, 0 days-40.3 months). Of the 17 total reinterventions, six (35%) were performed using open techniques and 11 (65%) with endovascular or hybrid methods; there was no difference in survival between patients who did or did not require reintervention. CONCLUSIONS This study confirms the excellent short-term outcomes of TEVAR for acute complicated type B dissection and demonstrates the results to be durable and sustained over long-term follow-up. Although aortic reinterventions were required in one-quarter of patients, no aortic-related deaths were observed. These data support the use of TEVAR for acute complicated type B aortic dissection but also highlight the importance of life-long aortic surveillance by an experienced aortic referral center in order to identify and treat complications of the underlying disease process and treatment, as well as new aortic pathologies, as they arise.

Gene Expression of Pro-Inflammatory Cytokines and Neuropeptides in Diabetic Wound Healing

The interaction between neuropeptides and cytokines and its role in cutaneous wound healing is becoming evident. The goal of the present study is to investigate the impact of diabetes on peripheral cytokine and neuropeptide expression and its role in diabetic wound healing. To achieve this goal, the effect of diabetes on wound healing, along with the role of inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-8 (IL-8) secreted in the wound microenvironment, and neuropeptides such as substance P (SP) and neuropeptide Y (NPY), secreted from peripheral nerves is monitored in non-diabetic and diabetic rabbits. Rabbits in the diabetic group received alloxan monohydrate (100mg/kg i.v.). Ten days after diabetic induction, four full thickness circular wounds were created in both ears using a 6mm punch biopsy. Wound healing was monitored over 10 d and gene expression of cytokines and neuropeptides was assessed in the wounds. Compared with the non-diabetic rabbits, wounds of diabetic rabbits heal significantly slower. Diabetic rabbits show significantly increased baseline gene expression of IL-6 and IL-8, their receptors, CXCR1, CXCR2, GP-130, and a decrease of prepro tachykinin-A (PP-TA), the precursor of SP, whereas the expression of prepro-NPY (PP-NPY), the precursor of NPY is not different. Similarly, baseline protein expression of CXCR1 is higher in diabetic rabbit skin. Post-injury, the increase over baseline gene expression of IL-6, IL-8, CXCR1, CXCR2, and GP-130 is significantly less in diabetic wounds compared with non-diabetic wounds. Although there is no difference in PP-TA gene expression between non-diabetic and diabetic rabbits post-injury, the gene expression of PP-NPY is reduced in diabetic rabbits. In conclusion, diabetes causes dysregulation in the neuropeptide expression in the skin along with a suppressed focused inflammatory response to injury. This suggests that the chronic inflammation in the skin of diabetic rabbits inhibits the acute inflammation much needed for wound healing.

Staged total abdominal debranching and thoracic endovascular aortic repair for thoracoabdominal aneurysm

OBJECTIVE Thoracoabdominal aortic aneurysms (TAAAs) occur most commonly in elderly individuals, who are often suboptimal candidates for open repair because of significant comorbidities. The availability of a hybrid option, including open visceral debranching with endovascular aneurysm exclusion, may have advantages in these patients who are at high-risk for conventional repair. This report details the evolution of our technique and results with complete visceral debranching and endovascular aneurysm exclusion for TAAA repair in high-risk patients. METHODS Between March 2005 and June 2011, 47 patients (51% women) underwent extra-anatomic debranching of all visceral vessels, followed by aneurysm exclusion by endovascular means at a single institution. A median of four visceral vessels were bypassed. The debranching procedure was initially performed through a partial right medial visceral rotation approach, leaving the left kidney posterior in the first 22 patients, and in the last 25 by a direct anterior approach to the visceral vessels. The debranching and endovascular portions of the procedure were performed in a single operation in the initial 33 patients and as a staged procedure during a single hospital stay in the most recent 14. RESULTS Median patient age was 71.0 ± 9.8 years. All had significant comorbidity and were considered suboptimal candidates for conventional repair: 55% had undergone previous aortic surgery, 40% were American Society of Anesthesiologists (ASA) class 4, and baseline serum creatinine was 1.5 ± 1.3 mg/dL. The 30-day/in-hospital rates of death, stroke, and permanent paraparesis/plegia were 8.5%, 0%, and 4.3%, respectively, but 0% in the most recent 14 patients undergoing staged repair. These patients had significantly shorter combined operative times (314 vs 373 minutes), decreased intraoperative red blood cell transfusions (350 vs 1400 mL), and were more likely to be extubated in the operating room (50% vs 12%) compared with patients undergoing simultaneous repair. Over a median follow-up of 19.3 ± 18.5 months, visceral graft patency was 97%; all occluded limbs were to renal vessels and clinically silent. There have been no type I or III endoleaks or reinterventions. Kaplan-Meier overall survival is 70.7% at 2 years and 57.9% at 5 years. CONCLUSIONS Hybrid TAAA repair through complete visceral debranching and endovascular aneurysm exclusion is a good option for elderly high-risk patients less suited to conventional repair in centers with the requisite surgical expertise with visceral revascularization. A staged approach to debranching and endovascular aneurysm exclusion during a single hospitalization appears to yield optimal results.

Outcomes of Acute Type A Dissection Repair Before and After Implementation of a Multidisciplinary Thoracic Aortic Surgery Program

OBJECTIVES The purpose of this study was to compare the results of acute type A aortic dissection (ATAAD) repair before and after implementation of a multidisciplinary thoracic aortic surgery program (TASP) at our institution, with dedicated high-volume thoracic aortic surgeons, a multidisciplinary approach to thoracic aortic disease management, and a standardized protocol for ATAAD repair. BACKGROUND Outcomes of ATAAD repair may be improved when operations are performed at specialized high-volume thoracic aortic surgical centers. METHODS Between 1999 and 2011, 128 patients underwent ATAAD repair at our institution. Records of patients who underwent ATAAD repair 6 years before (n = 56) and 6 years after (n = 72) implementation of the TASP were retrospectively compared. Expected operative mortality rates were calculated using the International Registry of Acute Aortic Dissection pre-operative prediction model. RESULTS Baseline risk profiles and expected operative mortality rates were comparable between patients who underwent surgery before and after implementation of the TASP. Operative mortality before TASP implementation was 33.9% and was statistically equivalent to the expected operative mortality rate of 26.0% (observed-to-expected mortality ratio 1.30; p = 0.54). Operative mortality after TASP implementation fell to 2.8% and was statistically improved compared with the expected operative mortality rate of 18.2% (observed-to-expected mortality ratio 0.15; p = 0.005). Differences in survival persisted over long-term follow-up, with 5-year survival rates of 85% observed for TASP patients compared with 55% for pre-TASP patients (p = 0.002). CONCLUSIONS ATAAD repair can be performed with results approximating those of elective proximal aortic surgery when operations are performed by a high-volume multidisciplinary thoracic aortic surgery team. Efforts to standardize or centralize care of patients undergoing ATAAD are warranted.

Management of acute type B aortic dissection

Acute type B aortic dissection (identified within 2 weeks of symptom onset), as described using the Stanford classification, involves the aorta distal to the left subclavian artery and accounts for 25%-40% of all aortic dissections. The traditional treatment paradigm of medical management for uncomplicated acute type B dissection and open surgical intervention for early or late complications of type B dissection is currently undergoing a period of evolution as a result of the influence of minimally invasive thoracic endovascular aortic repair options. Thoracic endovascular repair has replaced open surgical repair as the preferred treatment for complicated acute type B dissection, and may also prove beneficial for prophylactic repair of uncomplicated acute type B dissection for high-risk patients. This review discusses the management of acute type B aortic dissection and long-term treatment considerations.

Results With a Selective Revascularization Strategy for Left Subclavian Artery Coverage During Thoracic Endovascular Aortic Repair

BACKGROUND The need for routine left subclavian artery (LSCA) revascularization when this vessel is covered during thoracic endovascular aortic repair remains controversial. We report our results with a selective LSCA revascularization strategy during thoracic endovascular aortic repair. METHODS Between May 2002 and March 2010, 287 thoracic endovascular aortic repair procedures were performed at our institution. LSCA coverage occurred in 145 (51%), which form the basis of this report. RESULTS Left subclavian artery revascularization was performed in 32 patients (22%) through a left common carotid-LSCA bypass. Indications for selective LSCA revascularization included spinal cord protection in 10, patent pedicled left internal mammary artery graft in 9, left arm ischemia after LSCA coverage in 5, origin of the left vertebral artery from the arch in 4, dialysis access in the left arm in 2, and vertebrobasilar insufficiency in 2. There were no instances of dominant left vertebral artery. The revascularized and non-revascularized groups had similar rates of death (6.3% vs 1.8%; p=0.21), stroke (3.1% vs 3.5%; p>0.99), permanent paraplegia or paraparesis (3.1% vs 0%; p=0.22), and type II endoleak (4.3% vs 6.5%; p>0.99). There were no instances of ischemic stroke related to left posterior circulation hypoperfusion. Four complications of carotid-subclavian bypass occurred in 3 patients (9.4%). CONCLUSIONS Selective LSCA revascularization is safe and does not appear to increase the risk of neurologic events. Further, subclavian revascularization is not without complications, which should be considered with regards to a nonselective revascularization strategy.