Faculty Bibliography

Tissue injury leads to the well-orchestrated mobilization of systemic and local innate and adaptive immune cells. During aging, immune cell recruitment is dysregulated, resulting in an aberrant inflammatory response that is detrimental for successful healing. Here, we precisely define the systemic and local immune cell response after femur fracture in young and aging mice and identify increased toll-like receptor signaling as a potential culprit for the abnormal immune cell recruitment observed in aging animals. Myd88, an upstream regulator of TLR-signaling lies at the core of this aging phenotype, and local treatment of femur fractures with a Myd88 antagonist in middle-aged mice reverses the aging phenotype of impaired fracture healing, thus offering a promising therapeutic target that could overcome the negative impact of aging on bone regeneration.

OBJECTIVE:Contemporary commercially available endovascular devices for the treatment of abdominal aortic aneurysm (AAA) include standard endovascular aortic repair (sEVAR) or fenestrated EVAR (fEVAR) endografts. However, aortic neck dilatation (AND) can occur in nearly 25% of patients following EVAR, resulting in loss of proximal seal with risk of aortic rupture. AND has not been well characterized in fEVAR, and direct comparisons studying AND between fEVAR and sEVAR have not been performed. This study aims to analyze AND in the infrarenal and suprarenal aortic segments, including seal zone, and quantify sac regression following fEVAR implantation compared to sEVAR. METHOD/METHODS:A retrospective review of prospectively collected data on 20 consecutive fEVAR patients (Cook Zenith® Fenestrated) and 20 sEVAR (Cook Zenith®) patients was performed. Demographic data, anatomic characteristics, procedural details, and clinical outcome were analyzed. Pre-operative, post-operative (1 month), and longest follow-up CT scan at an average of 29.3 months for fEVAR and 29.8 months for sEVAR were analyzed using a dedicated 3D workstation (iNtuition, TeraRecon Inc, Foster City, California). Abdominal aortic aneurysm neck diameter was measured in 5 mm increments, ranging from 20 mm above to 20 mm below the lowest renal artery. Sub-analysis comparing the fEVAR to the sEVAR group at 12 months and at greater than 30 months was performed. Standard statistical analysis was done. RESULTS:Demographic characteristics did not differ significantly between the two cohorts. The fEVAR group had a larger mean aortic diameter at the lowest renal artery, shorter infrarenal aortic neck length, increased prevalence of nonparallel neck shape, and longer AAA length. On follow-up imaging, the suprarenal aortic segment dilated significantly more at all locations in the fEVAR cohort, whereas the infrarenal aortic neck segment dilated significantly less compared to the sEVAR group. Compared to the sEVAR cohort, the fEVAR patients demonstrated significantly greater positive sac remodeling as evident by more sac diameter regression, and elongation of distance measured from the celiac axis to the most cephalad margin of the sac. Device migration, endoleak occurrence, re-intervention rate, and mortalities were similar in both groups. CONCLUSION/CONCLUSIONS:Compared to sEVAR, patients undergoing fEVAR had greater extent of suprarenal AND, consistent with a more diseased native proximal aorta. However, the infrarenal neck, which is shorter and also more diseased in fEVAR patients, appears more stable in the post-operative period as compared to sEVAR. Moreover, the fEVAR cohort had significantly greater sac shrinkage and improved aortic remodeling. The suprarenal seal zone in fEVAR may result in a previously undescribed increased level of protection against infrarenal neck dilatation. We hypothesize that the resultant decreased endotension conferred by better seal zone may be responsible for a more dramatic sac shrinkage in fEVAR.

Methotrexate (MTX) is widely used for the treatment of rheumatoid arthritis due to its well-known anti-inflammatory role in immune cells but its impact on brown and beige adipose tissue biology has not yet been investigated. Here, we present the novel evidence that MTX treatment increases the gene expression of thermogenic genes in brown and beige adipose tissues in a fat cell autonomous manner. Furthermore, we show that treatment of mice with MTX is associated with cold resistance, improved glucose homeostasis, decreased inflammation, and reduced hepatosteatosis in high-fat diet states. Overall, our data provide novel evidence of a role of MTX on thermogenic tissues not previously appreciated.

BACKGROUND:With the exponential increase in the use of endovascular techniques in the treatment of peripheral artery disease, our understanding of factors that affect intervention failures continues to grow. We sought to assess the outcomes of percutaneous transluminal angioplasty for isolated de novo superficial femoral artery (SFA) disease based on balloon diameter. METHODS:The Vascular Quality Initiative database was queried for patients undergoing percutaneous balloon angioplasty for isolated de novo atherosclerotic SFA disease. Based on the diameter of the angioplasty balloon as a surrogate measure of arterial diameter, patients were stratified into two groups: group 1, balloon diameter < 5 mm (354 patients) and group 2, balloon diameter ≥ 5 mm (1,550 patients). The primary patency and major adverse limb event (MALE) were estimated by the Kaplan-Meier method and compared with the log-rank test, based on vessel diameter. multivariable Cox regression analysis was used to determine factors associated with the primary patency. RESULTS:From January 2010 through December 2018, a total of 1,904 patients met criteria for analysis, with a mean follow-up of 13.3 ± 4.5 months. The mean balloon diameters were 3.92 ± 0.26 mm and 5.47 ± 0.55 mm in group 1 and 2, respectively (P<.001). The mean length of treatment and distribution of TASC lesions were not statistically different between the groups. Primary patency at 18 months was significantly lower in group 1, compared with group 2 (55% vs 67%; log-rank P<.001). The MALE rate was higher in group 1 than group 2 (33% vs 26%; log-rank P<.001). Among patients with claudication, there was no significant difference in the primary patency (61% vs 68%; log-rank P=.073) and MALE (27% vs 22%; log-rank P=.176) at 18 months between groups 1 and 2, respectively. However, in patients with CLTI, group 1 had significantly lower 18-month primary patency (47% vs 64%; log-rank P<.014) and higher MALE rates (41% vs 35%; log-rank P=.012) than group 2. Cox proportional hazard analysis confirmed that balloon diameter < 5 mm was independently associated with increased risks of primary patency loss (HR 1.35; 95% CI, 1.04-1.72; P=.021) and MALE (HR 1.29; 95% CI, 1-1.67; P=.048) at 18-months. CONCLUSIONS:In patients undergoing isolated SFA balloon angioplasty for CLTI, smaller SFA (< 5mm) was associated with worse primary patency and MALE. Using balloon size as a surrogate, our findings suggest that patients with a smaller SFA diameter appear to be at increased risk for treatment failure and warrant closer surveillance. Furthermore, these patients may also be considered for alternative approaches, including open revascularization.

Psychological stress (PS) is associated with systemic inflammation and accelerates inflammatory disease progression (e.g., atherosclerosis). The mechanisms underlying stress-mediated inflammation and future health risk are poorly understood. Monocytes are key in sustaining systemic inflammation, and recent studies demonstrate that they maintain the memory of inflammatory insults, leading to a heightened inflammatory response upon rechallenge. We show that PS induces remodeling of the chromatin landscape and transcriptomic reprogramming of monocytes, skewing them to a primed hyperinflammatory phenotype. Monocytes from stressed mice and humans exhibit a characteristic inflammatory transcriptomic signature and are hyperresponsive upon stimulation with Toll-like receptor ligands. RNA and ATAC sequencing reveal that monocytes from stressed mice and humans exhibit activation of metabolic pathways (mTOR and PI3K) and reduced chromatin accessibility at mitochondrial respiration-associated loci. Collectively, our findings suggest that PS primes the reprogramming of myeloid cells to a hyperresponsive inflammatory state, which may explain how PS confers inflammatory disease risk.

Despite a decline in popularity over the last several decades, cigarette smoking remains a leading cause of cardiovascular morbidity and mortality. Yet, the effects of cigarette smoking on vascular structure and function are largely unknown. To evaluate changes in the mechanical properties of the aorta that occur with chronic smoking, we exposed female Apolipoprotein E-deficient mice to mainstream cigarette smoke daily for 24 weeks, with room air as control. By the time of sacrifice, cigarette-exposed mice had lower body mass, but experienced larger systolic/diastolic blood pressure when compared to controls. Smoking was associated with significant wall thickening, reduced axial stretch, and circumferential material softening of the aorta. While this contributed to maintaining intrinsic tissue stiffness at control levels despite larger pressure loads, the structural stiffness became significantly larger. Furthermore, the aorta from cigarette-exposed mice exhibited decreased ability to store elastic energy and augment diastolic blood flow. Histological analysis revealed a region-dependent increase in the cross-sectional area due to smoking. Increased smooth muscle and extracellular matrix content led to medial thickening in the ascending aorta, while collagen deposition increased the thickness of the descending thoracic and abdominal aorta. Atherosclerotic lesions were larger in exposed vessels and featured a necrotic core overlaid by a thinned fibrous cap and macrophage infiltration, consistent with a vulnerable phenotype. Collectively, our data indicate that cigarette smoking decreases the mechanical functionality of the aorta, inflicts morphometric alterations to distinct segments of the aorta, and accelerates the progression of atherosclerosis.

Aortic rupture and dissection are life-threatening complications of ascending thoracic aortic aneurysms (aTAAs), and risk assessment has been largely based on the monitoring of lumen size enlargement. Temporal changes in the extracellular matrix (ECM), which has a critical impact on aortic remodeling, are not routinely evaluated, and cardiovascular biomarkers do not exist to predict aTAA formation. Here, Raman microspectroscopy and Raman imaging are used to identify spectral biomarkers specific for aTAAs in mice and humans by multivariate data analysis (MVA). Multivariate curve resolution-alternating least-squares (MCR-ALS) combined with Lasso regression reveals elastic fiber-derived (Ce1) and collagen fiber-derived (Cc6) components that are significantly increased in aTAA lesions of murine and human aortic tissues. In particular, Cc6 detects changes in amino acid residues, including phenylalanine, tyrosine, tryptophan, cysteine, aspartate, and glutamate. Ce1 and Cc6 may serve as diagnostic Raman biomarkers that detect alterations of amino acids derived from aneurysm lesions.

OBJECTIVE:Endovascular abdominal aortic aneurysm repair (EVAR) is preferred to open surgical repair (OSR) for the treatment of abdominal aortic aneurysm (AAA) in high-risk patients. We sought to compare perioperative and long-term outcomes for EVAR in patients designated as unfit for OSR using a large national dataset. METHODS:The Vascular Quality Initiative database collected from 2013 to 2019 was queried for patients undergoing elective EVARs for AAA > 5cm. The patients were stratified into two cohorts based on the suitability for OSR (FIT vs. UNFIT). Primary outcomes included perioperative (in-hospital) major adverse events, perioperative mortality, and mortality at 1 and 5 years. Patient demographics and postoperative outcomes were analyzed to identify predictors of perioperative and long-term mortality. RESULTS:Of 16,183 EVARs, 1,782 patients were deemed unfit for OSR. The UNFIT cohort was more likely to be older and female, with higher proportions of HTN, CAD, CHF, COPD, and larger aneurysm diameter. Postoperatively, the UNFIT cohort was more likely to have cardiopulmonary complications (6.5% vs. 3%; P<.001), with higher perioperative mortality (1.7% vs. 0.6%; P<.001) and 1 and 5-year mortality (13% and 29% UNFIT vs. 5% and 14% FIT; P<.001). Subgroup analysis within the UNFIT cohort revealed those deemed unfit due to hostile abdomen had significantly lower 1 and 5-year mortality (6% and 20%) compared to those unfit due to cardiopulmonary compromise and frailty (14% and 30%; P=.451). Reintervention-free survival at 1 and 5-years was significantly higher in the FIT cohort (93% and 82%) as compared to the UNFIT cohort (85% and 68%; P<.001). Designation as unfit for OSR was an independent predictor of both perioperative (OR 1.59; 95% CI, 1.03-2.46; P=.038) and long-term mortality (HR 1.92; 95% CI, 1.69-2.17; P<.001). Advanced age (OR 2.91; 95% CI, 1.28-6.66; P=.011) was the strongest determinant of perioperative mortality while ESRD (HR 2.51; 95% CI, 1.78-3.55; P<.001) was the strongest predictor of long-term mortality. Statin (HR 0.77; 95% CI, 0.69-0.87; P<.001) and ACE inhibitor (HR 0.83; 95% CI, 0.75-0.93; P<.001) were protective of long-term mortality. CONCLUSION/CONCLUSIONS:Despite low perioperative mortality, long-term mortality of those designated by the operating surgeons as unfit for OSR was rather high in patients undergoing elective EVARs, likely due to the competing risk of death from their medical frailty. Unfit designation due to hostile abdomen did not confer any additional risks after EVAR. Judicious estimation of the patient's life expectancy is essential when considering treatment options in this subset of patients deemed unfit for OSR.

Obesity is a major public health burden worldwide and is characterized by chronic low-grade inflammation driven by the cooperation of the innate immune system and dysregulated metabolism in adipose tissue and other metabolic organs. Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a central regulator of inflammatory cell function that coordinates inflammation, apoptosis and necroptosis in response to inflammatory stimuli. Here we show that genetic polymorphisms near the human RIPK1 locus associate with increased RIPK1 gene expression and obesity. We show that one of these single nucleotide polymorphisms is within a binding site for E4BP4 and increases RIPK1 promoter activity and RIPK1 gene expression in adipose tissue. Therapeutic silencing of RIPK1 in vivo in a mouse model of diet-induced obesity dramatically reduces fat mass, total body weight and improves insulin sensitivity, while simultaneously reducing macrophage and promoting invariant natural killer T cell accumulation in adipose tissue. These findings demonstrate that RIPK1 is genetically associated with obesity, and reducing RIPK1 expression is a potential therapeutic approach to target obesity and related diseases.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.