Shant M. Vartanian

Ischemic colitis: spectrum of disease and outcome.

BACKGROUND The aim of this study was to identify risk factors, clinical characteristics, and outcome of patients with colon ischemia. METHODS A 10-year (1992-2002) retrospective study was undertaken. Patients were identified from computerized hospital discharge information. Patient variables were entered into a computerized database and analyzed. RESULTS One hundred twenty-nine patients were identified. The mean age was 66 years (range, 29-98 years); 47% were male. Forty-three patients (33%) had chronic renal failure; 73 patients (57%) were receiving vasoactive drugs, and 72 patients (56%) had atherosclerosis. Fifty-four of 129 patients (42%) had ischemic colitis in-hospital. Fifty-six of 129 patients (43%) had melena; 49 of 56 patients (88%) survived. Forty-three of 129 patients (33%) had an acute abdomen; 22 of 43 patients (51%) died. Seventy of 129 patients (54%) were treated nonoperatively initially; the condition of 17 of 70 patients (24%) required surgery. Of 76 patients who were treated operatively, 31 patients (41%) died. Eleven patients at operation had ischemia without colon infarction or perforation; 5 of these patients (45%) died. The overall mortality rate was 29% (37/129 patients). CONCLUSION Ischemic colitis is associated with chronic renal failure and atherosclerosis. Patients commonly have an acute abdomen. The absence of colonic infarction does not ensure a favorable outcome. Patients who are felt to be candidates for nonoperative therapy have significant mortality rates. Mortality rates remain high, despite treatment.

Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice

Brain arteriovenous malformations (BAVMs) can cause devastating stroke in young people and contribute to half of all hemorrhagic stroke in children. Unfortunately, the pathogenesis of BAVMs is unknown. In this article we show that activation of Notch signaling in the endothelium during brain development causes BAVM in mice. We turned on constitutively active Notch4 (int3) expression in endothelial cells from birth by using the tetracycline-regulatable system. All mutants developed hallmarks of BAVMs, including cerebral arteriovenous shunting and vessel enlargement, by 3 weeks of age and died by 5 weeks of age. Twenty-five percent of the mutants showed signs of neurological dysfunction, including ataxia and seizure. Affected mice exhibited hemorrhage and neuronal cell death within the cerebral cortex and cerebellum. Strikingly, int3 repression resolved ataxia and reversed the disease progression, demonstrating that int3 is not only sufficient to induce, but also required to sustain the disease. We show that int3 expression results in widespread enlargement of the microvasculature, which coincided with a reduction in capillary density, linking vessel enlargement to Notchs known function of inhibiting vessel sprouting. Our data suggest that the Notch pathway is a molecular regulator of BAVM pathogenesis in mice, and offer hope that their regression might be possible by targeting the causal molecular lesion.

Surgical Intervention for Peripheral Arterial Disease

The prevalence of peripheral arterial disease (PAD) is increasing worldwide, with recent global estimates exceeding 200 million people. Advanced PAD leads to a decline in ambulatory function and diminished quality of life. In its most severe form, critical limb ischemia, rest pain, and tissue necrosis are associated with high rates of limb loss, morbidity, and mortality. Revascularization of the limb plays a central role in the management of symptomatic PAD. Concomitant with advances in the pathogenesis, genetics, and medical management of PAD during the last 20 years, there has been an ongoing evolution of revascularization options. The increasing application of endovascular techniques has resulted in dramatic changes in practice patterns and has refocused the question of which patients should be offered surgical revascularization. Nonetheless, surgical therapy remains a cornerstone of management for advanced PAD, providing versatile and durable solutions to challenging patterns of disease. Although there is little high-quality comparative effectiveness data to guide patient selection, existing evidence suggests that outcomes are dependent on definable patient factors such as distribution of disease, status of the limb, comorbid conditions, and conduit availability. As it stands, surgical revascularization remains the standard against which emerging percutaneous techniques are compared. This review summarizes the principles of surgical revascularization, patient selection, and expected outcomes, while highlighting areas in need of further research and technological advancement.

Outcomes of Neuroischemic Wounds Treated by a Multidisciplinary Amputation Prevention Service

BACKGROUND Multidisciplinary amputation prevention teams decrease the frequency of major amputations by increasing the use of revascularization procedures and minor amputations. The outcomes of wound healing, wound recurrence, and ambulatory status are assumed to be improved but are not routinely reported. This study investigates the midterm outcomes of neuroischemic wounds treated by our multidisciplinary team. METHODS A retrospective review of patients with neuroischemic wounds treated at a single institution amputation prevention clinic from March 2012 to July 2013. Patient demographics, wound characteristics, procedural details, and clinical and functional outcomes were reviewed. Clinical end points under study included time to wound healing, reulceration rate, and ambulatory status. RESULTS Over 16 months, there were 202 new patients and 1,355 clinic visits. Ninety-one limbs from 89 patients were treated for complex neuroischemic wounds. In 67% (61 of 91) of limbs, wounds were present for >6 weeks before referral. A history of previous revascularization was present in 39% (31 of 91), and 28% (22 of 91) had a previous minor amputation. Forty-one percent of wounds (38 of 91) were limited to the toes or the forefoot whereas 24% (22 of 91) involved the hindfoot or ankle. A total of 151 podiatric and 86 vascular interventions were performed, with an equal distribution of endovascular and open revascularizations. Complete healing was observed for 59% of wounds (54 of 91) over the observation period (median follow up, 207 days; range 56-561 days), and the average time to full healing was 12 weeks. Hindfoot wounds were predictive of failure to heal (odds ratio, 0.21; P < 0.01; 95% confidence interval, 0.06-0.68). Nineteen percent of patients (17 of 91) developed a new wound in the ipsilateral leg during follow-up. Three major amputations were performed (2 below-knee amputation and 1 above-knee amputation) for a major/minor amputation ratio of 0.06. Ambulatory status was preserved or improved in 74% (67 of 91) of patients. The 30-day readmission rate was 11%, which was lower than that observed (21%) in a contemporaneous but all-inclusive population of lower extremity revascularization procedures performed at our institution. CONCLUSIONS Multidisciplinary limb salvage teams effectively heal wounds and maintain ambulatory status in patients with limb-threatening neuroischemic wounds. Patient specific factors, such as hindfoot or ankle wounds, can adversely influence the outcome. Even with aggressive care, healing can be prolonged and a substantial proportion of patients can be expected to have a recurrence, making subsequent surveillance mandatory. Our data also suggest that a coordinated amputation prevention program may help to minimize hospital readmissions in this high-risk population.

Risk factors for clinical failure after stent graft treatment for femoropopliteal occlusive disease.

OBJECTIVE Optimal selection of a revascularization strategy in femoropopliteal occlusive disease (FPOD) remains controversial. Among endovascular treatment options for FPOD, covered stent placement has become increasingly used. We sought to examine the influence of clinical, anatomic, and device-related characteristics on the clinical performance of these devices. METHODS This was a retrospective, single-center study of consecutively treated limbs that underwent Viabahn (W. L. Gore, Flagstaff, Ariz) stent graft placement for FPOD from 2005 to 2010. Clinical, anatomic, and device-related characteristics were obtained from review of medical records and angiograms. End points were occurrence of any reintervention, major adverse limb event (eg, major amputation, thrombolysis/thrombectomy, or open bypass surgery), or thrombolysis/thrombectomy treatment alone. Univariate predictors were calculated and multivariate models constructed for each clinical end point using Cox proportional hazards models. RESULTS The study cohort included 87 limbs in 77 unique patients, with a median follow-up time of 382 days. The indication for intervention was claudication in 56%. In 25 cases (29%), the index procedure was a secondary intervention for FPOD, including treatment of in-stent restenosis in 22 cases (25%). Lesions treated included 45% TransAtlantic Inter-Society Consensus (TASC) II D and 58% chronic total occlusions. The observed Kaplan-Meier 1-year event rates for reintervention, major adverse limb event (MALE), and thrombolysis were 43%, 28%, and 17%, respectively. MALE occurred in 18 patients, nine of whom presented with acute limb ischemia; no patient underwent major amputation. Univariate predictors of negative outcomes included lack of dual-antiplatelet usage, advanced TASC II classification, smaller implant diameter, increased number of devices used, longer total implant length, and coverage of a patent distal collateral vessel. Multivariate analysis demonstrated that the presence of dual-antiplatelet usage was protective against all three outcomes, 5-mm device diameter was a risk factor for both reintervention and MALE, and the use of multiple devices and distal collateral coverage were significant risk factors for thrombolysis events. CONCLUSIONS Reintervention is common in the first year after Viabahn placement for FPOD, with more than half of the events being a MALE. Procedural factors such as antiplatelet therapy, stent graft diameter, implant length/number, and distal collateral coverage are strongly associated with adverse clinical outcomes. These factors should be carefully considered to optimize patient selection and intraoperative decision making for this procedure.

New insights into the heterogeneity of Th17 subsets contributing to HIV-1 persistence during antiretroviral therapy.

BackgroundTh17 cells are permissive to HIV-1 infection and their depletion from the gut of infected individuals leads to microbial translocation, a major cause for non-AIDS co-morbidities. Most recent evidence supports the contribution of long-lived Th17 cells to HIV persistence during antiretroviral therapy (ART). However, the identity of long-lived Th17 cells remains unknown.ResultsHere, we performed an in-depth transcriptional and functional characterization of four distinct Th17 subsets and investigated their contribution to HIV reservoir persistence during ART. In addition to the previously characterized CCR6+CCR4+ (Th17) and CCR6+CXCR3+ (Th1Th17) subsets, we reveal the existence of two novel CCR6+ subsets, lacking (double negative, CCR6+DN) or co-expressing CXCR3 and CCR4 (double positive, CCR6+DP). The four subsets shared multiple Th17-polarization markers, a fraction of cells proliferated in response to C. albicans, and exhibited lineage commitment and plasticity when cultured under Th17 and Th1 conditions, respectively. Of note, fractions of CCR6+DN and Th17 demonstrated stable Th17-lineage commitment under Th1-polarization conditions. Among the four subsets, CCR6+DN expressed a unique transcriptional signature indicative of early Th17 development (IL-17F, STAT3), lymph-node homing (CCR7, CD62L), follicular help (CXCR5, BCL6, ASCL2), and self-renewal (LEFI, MYC, TERC). Cross sectional and longitudinal studies demonstrated that CCR6+DN cells were the most predominant CCR6+ subset in the blood before and after ART initiation; high frequencies of these cells were similarly observed in inguinal lymph nodes of individuals receiving long-term ART. Importantly, replication competent HIV was isolated from CCR6+DN of ART-treated individuals.ConclusionsTogether, these results provide new insights into the functional heterogeneity of Th17-polarized CCR6+CD4+ T-cells and support the major contribution of CCR6+DN cells to HIV persistence during ART.

Risk Factors for 30-Day Hospital Readmission in Patients Undergoing Treatment for Peripheral Artery Disease.

Early hospital readmission among vascular surgery patients is a focus of Medicare’s new reimbursement structure. We aim to identify factors associated with 30-day readmission after lower extremity interventions to treat peripheral artery disease (PAD). Retrospective analysis of 174 consecutive patients discharged from the vascular surgery service between January 1, 2011, and July 31, 2012, after procedures for lower extremity PAD was performed. Of 174 patients, 37 were readmitted within 30 days of discharge. There were no significant differences in baseline characteristics between the readmitted and the nonreadmitted groups. In a multivariate logistic regression model, urgent operation and advanced chronic kidney disease (CKD) were associated with increased risk of 30-day readmission. The most common reasons for readmission were infection of the surgical site or index limb (18 of 37), followed by unresolved limb symptoms (13 of 37). The 30-day readmission is frequent after lower extremity interventions to treat PAD. Urgent operative intervention and advanced CKD appear to be risk factors for early hospital readmission.

Lower extremity weakness after endovascular aneurysm repair with multibranched thoracoabdominal stent grafts.

OBJECTIVE We conducted our study to describe the incidence, presentation, management, risk factors, and outcomes of lower extremity weakness (LEW) after elective endovascular aneurysm repair with multibranched thoracoabdominal stent grafts. METHODS Excluding symptomatic patients and those with aortic dissection, between July 2005 and October 2013, 116 patients with aortic aneurysms were treated in a prospective, single-center trial of multibranched endovascular aneurysm repair. LEW that resolved within 30 days of operation was classified as transient. Persistent LEW was defined as inability to walk or stand 30 days after surgery. Perioperative spinal cord protection measures included bypass as needed to maintain flow to the subclavian and internal iliac arteries, cerebrospinal fluid drainage, and permissive hypertension. RESULTS Postoperative LEW occurred in 24 of 116 patients (20.6%). In 15 (12.9%), LEW was transient with full recovery. Nine patients (7.7%) had persistent LEW, three with paraparesis and six with paraplegia. Five of 24 patients (21%) awoke from anesthesia with LEW. Symptoms of LEW developed within 72 hours of operation in 14 of 24 (58%). Late-onset LEW (≥72 hours postoperatively) always occurred in the presence of a precipitating hypotensive event (5 of 24; 21%). Univariate analysis showed no association between LEW and Crawford type, staged repair, aneurysm extent, or postoperative endoleak. Baseline glomerular filtration rate <30 mL/min/1.73 m(2) (odds ratio [OR], 4.2; 95% confidence interval [CI], 1.2-14.6; P = .03), fluoroscopy time >190 minutes (OR, 3.6; 95% CI, 1.0-12.7; P = .04), and sustained hypotension (OR, 2.9; 95% CI, 1.1-7.7; P = .04) were identified as independent risk factors for LEW in multivariate analysis. CONCLUSIONS Most episodes of LEW after multibranched endovascular aneurysm repair are transient and do not occur in the operating room. Adjunctive strategies to maintain spinal perfusion, including cerebrospinal fluid drainage and permissive hypertension, may help prevent permanent LEW.

Identification and characterization of HIV-specific resident memory CD8+ T cells in human lymphoid tissue

Resident memory T cells in lymphoid tissues help restrain HIV replication in elite controllers. Taking residence to defend In HIV+ individuals receiving antiretroviral therapy, lymphoid tissues (LTs) that CD4+ T cells home to are a key site of HIV persistence. Studying the immune response to HIV in LTs has remained a challenge. By obtaining LTs from HIV+ individuals, Buggert et al. have carried out comprehensive transcriptional and epigenetic analyses on CD8+ T cells in these LTs. They report that CD8+ T cells in LTs of HIV+ individuals have a signature associated with resident memory T cells (TRMs) and that the frequency of these HIV-responsive LT-resident CD8+ T cells was considerably increased in elite controllers. The study brings to the fore the importance of HIV-specific LT-resident TRMs in restraining HIV replication in LTs. Current paradigms of CD8+ T cell–mediated protection in HIV infection center almost exclusively on studies of peripheral blood, which is thought to provide a window into immune activity at the predominant sites of viral replication in lymphoid tissues (LTs). Through extensive comparison of blood, thoracic duct lymph (TDL), and LTs in different species, we show that many LT memory CD8+ T cells bear phenotypic, transcriptional, and epigenetic signatures of resident memory T cells (TRMs). Unlike their circulating counterparts in blood or TDL, most of the total and follicular HIV-specific CD8+ T cells in LTs also resemble TRMs. Moreover, high frequencies of HIV-specific CD8+ TRMs with skewed clonotypic profiles relative to matched blood samples are present in LTs of individuals who spontaneously control HIV replication in the absence of antiretroviral therapy (elite controllers). Single-cell RNA sequencing analysis confirmed that HIV-specific TRMs are enriched for effector-related immune genes and signatures compared with HIV-specific non-TRMs in elite controllers. Together, these data indicate that previous studies in blood have largely failed to capture the major component of HIV-specific CD8+ T cell responses resident within LTs.

Determinants of midterm functional outcomes, wound healing, and resources used in a hospital-based limb preservation program

Objective: The objective of this study was to assess midterm functional status, wound healing, and in‐hospital resource use among a prospective cohort of patients treated in a tertiary hospital, multidisciplinary Center for Limb Preservation. Methods: Data were prospectively gathered on all consecutive admissions to the Center for Limb Preservation from July 2013 to October 2014 with follow‐up data collection through January 2016. Limbs were staged using the Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) threatened limb classification scheme at the time of hospital admission. Patients with nonatherosclerotic vascular disorders, acute limb ischemia, and trauma were excluded. Results: The cohort included 128 patients with 157 threatened limbs; 8 limbs with unstageable disease were excluded. Mean age (±standard deviation [SD]) was 66 (±13) years, and median follow‐up duration (interquartile range) was 395 (80–635) days. Fifty percent (n = 64/128) of patients were readmitted at least once, with a readmission rate of 20% within 30 days of the index admission. Mean total number of admissions per patient (±SD) was 1.9 ± 1.2, with mean (±SD) cumulative length of stay (cLOS) of 17.1 (±17.9) days. During follow‐up, 25% of limbs required a vascular reintervention, and 45% developed recurrent wounds. There was no difference in the rate of readmission, vascular reintervention, or wound recurrence by initial WIfI stage (P > .05). At the end of the study period, 23 (26%) were alive and nonambulatory; in 20%, functional status was missing. On both univariate and multivariate analysis, end‐stage renal disease and prior functional status predicted ability to ambulate independently (P < .05). WIfI stage was associated with major amputation (P = .01) and cLOS (P = .002) but not with time to wound healing. Direct hospital (inpatient) cost per limb saved was significantly higher in stage 4 patients (P < .05 for all time periods). WIfI stage was associated with cumulative in‐hospital costs at 1 year and for the overall follow‐up period. Conclusions: Among a population of patients admitted to a tertiary hospital limb preservation service, WIfI stage was predictive of midterm freedom from amputation, cLOS, and hospital costs but not of ambulatory functional status, time to wound healing, or wound recurrence. Patients presenting with limb‐threatening conditions require significant inpatient care, have a high frequency of repeated hospitalizations, and are at significant risk for recurrent wounds and leg symptoms at later times. Stage 4 patients require the most intensive care and have the highest initial and aggregate hospital costs per limb saved. However, limb salvage can be achieved in these patients with a dedicated multidisciplinary team approach.