Endovascular Aneurysm Repair-First Strategy for Ruptured Abdominal Aortic Aneurysm Might Not Be Applicable To All Cases.

OBJECTIVE: We evaluate the relationship between the hospital case volume (HCV) and mortality outcomes after open aortic repair (OAR) and endovascular aortic repair (EVAR) of intact (i) and ruptured (r) abdominal aortic aneurysm using a contemporary administrative database. METHODS: The Healthcare Cost and Utilization Project Database for New York (2016) and New Jersey/Maryland/Florida (2016-2017) were queried using International Classification of Disease-10th edition to identify patients who had undergone OAR and EVAR. The hospitals were categorized into quartiles (Q) per overall (EVAR+OAR) volume, OAR-alone volume and EVAR- alone volume. Cox regression adjusted for confounding factors was used to estimate hazard ratios (HR) for mortality. RESULTS: A total of 8825 patients (mean age, 73.5±9.5 years; 6861 male [77.7%]) had undergone 1355 OARs and 7470 EVARs. Overall HCV had no impact on in-hospital mortality across quartiles after iEVAR (range, 0.7%-1.4%, p=.15), rEVAR (range, 20.5%-29.6%, p=.63) and iOAR (range, 4.9%-8.8%, p=0.63). However, the rOAR mortality rates in highest-volume (Q4) hospitals were significantly lower than those in the three lower quartile hospitals (23.1% vs 44.7%, p<.001). When analyzed per OAR-alone volume, the same findings were observed (22.0% for Q4 vs 41.6% for Q1-3, p<.001). Furthermore, in Q4 hospitals per the OAR-alone volume analysis, the mortality hazard was greater for rEVAR (39.0%) than for rOAR (22.0%) (HR=2.3, 95% confidence interval, 1.02-5.34, p<.05). CONCLUSION: The mortality rates for iEVAR, rEVAR and iOAR were independent of HCV. However, after rOAR, mortality rates in high OAR volume hospitals were lower than those in the lower quartile hospitals, and, at least comparable to those of rEVAR. EVAR-first strategy for ruptured AAA might not be applicable to all cases. Patent-specific, individualized treatment should be the gold standard, For patients requiring rOAR, transfer to a regional center of excellene, when clinical safe, should be encouraged. deferred to high-volume aortic OAR centers whenever feasible.

Impact of Care Fragmentation after Major Lower Extremity Amputation.

BACKGROUND: Care fragmentation (CF) is a known risk factor for unplanned readmission, morbidity, and mortality after surgery. The goal of this study was to evaluate the impact of CF on outcomes of major lower extremity amputation for peripheral vascular disease. METHODS: Health-care Cost and Utilization Project Database for NY (2016) and MD/FL (2016-2017) were queried using International Classification of Diseases 10thedition to identify patients who underwent above the knee-, through the knee-, and below the knee-amputation for peripheral vascular disease. Patients with CF were identified as those with admissions to ≥2 hospitals during the study period. We compared the postamputation outcomes of mortality, readmission rate, length of stay (LOS) and hospital charges. RESULTS: We identified a total of 13,749 encounters of 2,742 patients who underwent major lower extremity amputations. There were 1,624 (59.2%) patients with CF. Patients with CF were younger (68.4 years old vs. 69.7 years old, P = 0.005), with higher Charlson Comorbidity Indices (4.4 vs. 4.1, P < 0.001), and required more hospital resources on index admission ($113,699 vs. $91,854, P < 0.001). These patients were prevalent for higher 30-, and 90-day readmission rates (34.7% vs. 24.5%, P < 0.001 and 54.7% vs. 42.0%, P < 0.001, respectively). On their first postamputation readmission, LOS (16.3 days vs. 14.7 days, P = 0.004) and hospital charge ($48,964 vs. $44,388, P = 0.002) were significantly higher. Multivariate regression analysis demonstrated that the CF was an independent predictor for 30-day (hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.39-1.96, P < 0.001) and 90-day (HR 1.66, 95% CI 1.42-1.95, P < 0.001) readmission after the major lower extremity amputation, but not for mortality (HR 0.83, 95% CI 0.56-1.23, P = 0.36). CONCLUSIONS: CF after major lower extremity amputation is associated with higher readmission rate, LOS, and hospital charge. Collaboration of care providers to maintain continuity of care for peripheral vascular disease patients may enhance quality of care and reduce health care cost.

External carotid artery pseudoaneurysm rupture in a patient with polycystic kidney disease: Case report and review of literature.

BACKGROUND: Vascular abnormalities, including dissections and aneurysms, can be found in patients with autosomal dominant kidney disease (ADPKD). While intracranial aneurysms have been reported in 10%-25% of ADPCKD, occurrences at other locations are exceedingly rare. METHOD: This is a first case report of a patient with ADPCKD who presented with a rupture of the left external carotid artery pseudoaneurysm. CONCLUSION: Rupture of a carotid artery aneurysm is rare with potentially high morbidity. An endovascular and surgical approach are effective strategies for successful management that depends on etiology, location, and surgeon experience.

The development of peripheral microvasculopathy with chronic metabolic disease in obese Zucker rats: a retrograde emergence?

The study of peripheral vasculopathy with chronic metabolic disease is challenged by divergent contributions from spatial (the level of resolution or specific tissue being studied) and temporal origins (evolution of the developing impairments in time). Over many years of studying the development of skeletal muscle vasculopathy and its functional implications, we may be at the point of presenting an integrated conceptual model that addresses these challenges within the obese Zucker rat (OZR) model. At the early stages of metabolic disease, where systemic markers of elevated cardiovascular disease risk are present, the only evidence of vascular dysfunction is at postcapillary and collecting venules, where leukocyte adhesion/rolling is elevated with impaired venular endothelial function. As metabolic disease severity and duration increases, reduced microvessel density becomes evident as well as increased variability in microvascular hematocrit. Subsequently, hemodynamic impairments to distal arteriolar networks emerge, manifesting as increasing perfusion heterogeneity and impaired arteriolar reactivity. This retrograde "wave of dysfunction" continues, creating a condition wherein deficiencies to the distal arteriolar, capillary, and venular microcirculation stabilize and impairments to proximal arteriolar reactivity, wall mechanics, and perfusion distribution evolve. This proximal arteriolar dysfunction parallels increasing failure in fatigue resistance, hyperemic responses, and O2 uptake within self-perfused skeletal muscle. Taken together, these results present a conceptual model for the retrograde development of peripheral vasculopathy with chronic metabolic disease and provide insight into the timing and targeting of interventional strategies to improve health outcomes.NEW & NOTEWORTHY Working from an established database spanning multiple scales and times, we studied progression of peripheral microvascular dysfunction in chronic metabolic disease. The data implicate the postcapillary venular endothelium as the initiating site for vasculopathy. Indicators of dysfunction, spanning network structures, hemodynamics, vascular reactivity, and perfusion progress in an insidious retrograde manner to present as functional impairments to muscle blood flow and performance much later. The silent vasculopathy progression may provide insight into clinical treatment challenges.

Impact of interfacility transfer of ruptured abdominal aortic aneurysm patients.

OBJECTIVE: The interfacility transfer (IT) of patients with a ruptured abdominal aortic aneurysm (rAAA) occurs not infrequently to allow for a higher level of care. In the present study, we evaluated, using a contemporary administrative database, the effects of IT on mortality after rAAA repair. METHODS: The Healthcare Cost and Utilization Project Database for New York (2016) and New Jersey, Maryland, and Florida (2016-2017) was queried using the International Classification of Diseases, 10th edition, to identify patients who had undergone open or endovascular repair of AAAs. The hospitals were categorized into quartiles (Qs) per overall volume. The mortality rates for IT vs nontransferred (NT) rAAA patients stratified by treatment modality (open aneurysm repair of an rAAA [rOAR] vs endovascular aneurysm repair of an rAAA [rEVAR]) were compared. A Cox proportional hazard model was used to estimate the hazard ratios (HRs) for mortality. RESULTS: A total of 1476 patients had presented with a rAAA, of whom 673 (45.7%) were not treated. Of the remaining 803 patients, 226 (28.1%) were transferred, of whom 50 (22.1%) had died without repair after IT. The remaining 753 patients (IT, n = 176; NT, n = 576) had undergone rEVAR (n = 492) or rOAR (n = 261). The baseline characteristics were similar between the IT and NT patients, except for a greater proportion of black patients (P = .03), lower income families (P = .049), and rOAR (45.5% vs 31.4%; P = .001) for the IT patients. The overall mortality rates were similar between the NT (30.2%) and IT (27.3%) groups (P = .46). The subgroup analysis revealed that the operative mortality rates after rEVAR were similar between the NT and IT patients, without significant differences among the hospital quartiles. After rOAR, however, the operative mortality rates were lower for the IT patients, largely owing to improved outcomes in the Q4 hospitals (Q4 vs Q1-Q3, P = .001). Cox regression analysis demonstrated that age (HR, 1.03; 95% confidence interval, 1.00-1.06; P = .02) and treatment at a low-volume hospital (Q1-Q3; HR, 1.89; 95% confidence interval, 1.02-3.51; P = .04) were predictors of mortality. The total charges were similar (IT, $286,727; vs NT, $265,717; P = .38). CONCLUSIONS: The results from the present study have shown that <30% of rAAA patients deemed a candidate for repair will be transferred. We found that IT did not affect the mortality rates after rEVAR, irrespective of the hospital volume. For rOAR candidates, however, regionalization of care with prompt transfer to a high-volume center could improve the survival benefits without increased healthcare costs.

Feasibility of Cryopreserved Conduits for Complex Vascular Reconstruction in the Pediatric Population: The Case of a 3-Year-Old With Femoral Vessels Transections.

This report presents an unusual case of traumatic iliofemoral vessel transection in a 3-year-old patient successfully reconstructed using a cryopreserved greater saphenous conduit. Five years after injury, the patient continues to do well with normal ambulation. An arterial duplex demonstrated graft patency free of aneurysmal dilatation. These encouraging results suggest that the natural history of cryopreserved conduits may differ in the pediatric population and cryopreserved conduits could be used for complex vascular reconstructions.

Feasibility of Bioengineered Tracheal and Bronchial Reconstruction Using Stented Aortic Matrices.

Importance: Airway transplantation could be an option for patients with proximal lung tumor or with end-stage tracheobronchial disease. New methods for airway transplantation remain highly controversial. Objective: To establish the feasibility of airway bioengineering using a technique based on the implantation of stented aortic matrices. Design, Setting, and Participants: Uncontrolled single-center cohort study including 20 patients with end-stage tracheal lesions or with proximal lung tumors requiring a pneumonectomy. The study was conducted in Paris, France, from October 2009 through February 2017; final follow-up for all patients occurred on November 2, 2017. Exposures: Radical resection of the lesions was performed using standard surgical techniques. After resection, airway reconstruction was performed using a human cryopreserved (-80°C) aortic allograft, which was not matched by the ABO and leukocyte antigen systems. To prevent airway collapse, a custom-made stent was inserted into the allograft. In patients with proximal lung tumors, the lung-sparing intervention of bronchial transplantation was used. Main Outcomes and Measures: The primary outcome was 90-day mortality. The secondary outcome was 90-day morbidity. Results: Twenty patients were included in the study (mean age, 54.9 years; age range, 24-79 years; 13 men [65%]). Thirteen patients underwent tracheal (n = 5), bronchial (n = 7), or carinal (n = 1) transplantation. Airway transplantation was not performed in 7 patients for the following reasons: medical contraindication (n = 1), unavoidable pneumonectomy (n = 1), exploratory thoracotomy only (n = 2), and a lobectomy or bilobectomy was possible (n = 3). Among the 20 patients initially included, the overall 90-day mortality rate was 5% (1 patient underwent a carinal transplantation and died). No mortality at 90 days was observed among patients who underwent tracheal or bronchial reconstruction. Among the 13 patients who underwent airway transplantation, major 90-day morbidity events occurred in 4 (30.8%) and included laryngeal edema, acute lung edema, acute respiratory distress syndrome, and atrial fibrillation. There was no adverse event directly related to the surgical technique. Stent removal was performed at a postoperative mean of 18.2 months. At a median follow-up of 3 years 11 months, 10 of the 13 patients (76.9%) were alive. Of these 10 patients, 8 (80%) breathed normally through newly formed airways after stent removal. Regeneration of epithelium and de novo generation of cartilage were observed within aortic matrices from recipient cells. Conclusions and Relevance: In this uncontrolled study, airway bioengineering using stented aortic matrices demonstrated feasibility for complex tracheal and bronchial reconstruction. Further research is needed to assess efficacy and safety. Trial Registration: clinicaltrials.gov Identifier: NCT01331863.

Thoracic stent graft placement for repair of iatrogenic aortic injury secondary to sheath placement during pacemaker insertion.

We describe the inadvertent cannulation of the proximal descending thoracic aortic stent with a five French sheath during attempted pacemaker placement in an 88- year-old male. The injury was managed successfully by the percutaneous placement of a thoracic aortic stent graft with good outcome. Our case highlights the feasibility of managing this uncommon injury with this technique.

Primary Endovascular Repair of Ilio-Caval Injury Encountered during Anterior Exposure Spine Surgery: Evolution of the Paradigm.

BACKGROUND: Rates of major venous injury are now being reported at between 1% and 15%. Risk factors for injury include the previous spine surgery, level of exposure, and number of retractors used. To review and describe the evolution of our use of stent grafts for repair of life-threatening ilio-caval injuries encountered during anterior exposure lumbosacral (L-S) spine surgery from rescue utilization after failed direct repair to preferred modality using occlusion balloons and covered stents akin to the modern management of the ruptured abdominal aortic aneurysm (AAA) with endovascular aneurysm repair. METHODS: Five-year retrospective review of all anterior and retroperitoneal spine procedures was performed at our institution. RESULTS: One hundred two procedures were done. Major ilio-caval injury occurred in 3/102 (2.9%) cases. Average blood loss per case decreased as our approach evolved from unsuccessful direct open repair with percutaneous endovascular rescue to primary percutaneous endovascular repair. All treated patients had patent venous repair in short-term follow-up with computed tomography angiography. CONCLUSIONS: Identification and rapid direct repair of major ilio-caval injuries during anterior approach spine surgery can be extremely challenging. When control of these potentially fatal injuries is required, our choice is primary endovascular repair using the modern techniques for endovascular management of ruptured AAA with endovascular aneurysm repair.

Increased peripheral vascular disease risk progressively constrains perfusion adaptability in the skeletal muscle microcirculation.

To determine the impact of progressive elevations in peripheral vascular disease (PVD) risk on microvascular function, we utilized eight rat models spanning "healthy" to "high PVD risk" and used a multiscale approach to interrogate microvascular function and outcomes: healthy: Sprague-Dawley rats (SDR) and lean Zucker rats (LZR); mild risk: SDR on high-salt diet (HSD) and SDR on high-fructose diet (HFD); moderate risk: reduced renal mass-hypertensive rats (RRM) and spontaneously hypertensive rats (SHR); high risk: obese Zucker rats (OZR) and Dahl salt-sensitive rats (DSS). Vascular reactivity and biochemical analyses demonstrated that even mild elevations in PVD risk severely attenuated nitric oxide (NO) bioavailability and caused progressive shifts in arachidonic acid metabolism, increasing thromboxane A2 levels. With the introduction of hypertension, arteriolar myogenic activation and adrenergic constriction were increased. However, while functional hyperemia and fatigue resistance of in situ skeletal muscle were not impacted with mild or moderate PVD risk, blood oxygen handling suggested an increasingly heterogeneous perfusion within resting and contracting skeletal muscle. Analysis of in situ networks demonstrated an increasingly stable and heterogeneous distribution of perfusion at arteriolar bifurcations with elevated PVD risk, a phenomenon that was manifested first in the distal microcirculation and evolved proximally with increasing risk. The increased perfusion distribution heterogeneity and loss of flexibility throughout the microvascular network, the result of the combined effects on NO bioavailability, arachidonic acid metabolism, myogenic activation, and adrenergic constriction, may represent the most accurate predictor of the skeletal muscle microvasculopathy and poor health outcomes associated with chronic elevations in PVD risk.

An Unpredictable Chronic Mild Stress Protocol for Instigating Depressive Symptoms, Behavioral Changes and Negative Health Outcomes in Rodents.

Chronic, unresolved stress is a major risk factor for the development of clinical depression. While many preclinical models of stress-induced depression have been reported, the unpredictable chronic mild stress (UCMS) protocol is an established translationally-relevant model for inducing behavioral symptoms commonly associated with clinical depression, such as anhedonia, altered grooming behavior, and learned helplessness in rodents. The UCMS protocol also induces physiological (e.g., hypercortisolemia, hypertension) and neurological (e.g., anhedonia, learned helplessness) changes that are clinically associated with depression. Importantly, UCMS-induced depressive symptoms can be ameliorated through chronic, but not acute, treatment with common SSRIs. As such, the UCMS protocol offers many advantages over acute stress protocols or protocols that utilize more extreme stressors. Our protocol involves randomized, daily exposures to 7 distinct stressors: damp bedding, removal of bedding, cage tilt, alteration of light/dark cycles, social stresses, shallow water bath, and predator sounds/smells. By subjecting rodents 3-4 hr daily to these mild stressors for 8 weeks, we demonstrate both significant behavioral changes and poor health outcomes to the cardiovascular system. This approach allows for in-depth interrogation of the neurological, behavioral, and physiological alterations associated with chronic stress-induced depression, as well as for testing of new potential therapeutic agents or intervention strategies.

Metabolic syndrome impairs reactivity and wall mechanics of cerebral resistance arteries in obese Zucker rats.

The metabolic syndrome (MetS) is highly prevalent in the North American population and is associated with increased risk for development of cerebrovascular disease. This study determined the structural and functional changes in the middle cerebral arteries (MCA) during the progression of MetS and the effects of chronic pharmacological interventions on mitigating vascular alterations in obese Zucker rats (OZR), a translationally relevant model of MetS. The reactivity and wall mechanics of ex vivo pressurized MCA from lean Zucker rats (LZR) and OZR were determined at 7-8, 12-13, and 16-17 wk of age under control conditions and following chronic treatment with pharmacological agents targeting specific systemic pathologies. With increasing age, control OZR demonstrated reduced nitric oxide bioavailability, impaired dilator (acetylcholine) reactivity, elevated myogenic properties, structural narrowing, and wall stiffening compared with LZR. Antihypertensive therapy (e.g., captopril or hydralazine) starting at 7-8 wk of age blunted the progression of arterial stiffening compared with OZR controls, while treatments that reduced inflammation and oxidative stress (e.g., atorvastatin, rosiglitazone, and captopril) improved NO bioavailability and vascular reactivity compared with OZR controls and had mixed effects on structural remodeling. These data identify specific functional and structural cerebral adaptations that limit cerebrovascular blood flow in MetS patients, contributing to increased risk of cognitive decline, cerebral hypoperfusion, and ischemic stroke; however, these pathological adaptations could potentially be blunted if treated early in the progression of MetS.

Cerebral Cortical Microvascular Rarefaction in Metabolic Syndrome is Dependent on Insulin Resistance and Loss of Nitric Oxide Bioavailability.

OBJECTIVE: Chronic presentation of the MS is associated with an increased likelihood for stroke and poor stroke outcomes following occlusive cerebrovascular events. However, the physiological mechanisms contributing to compromised outcomes remain unclear, and the degree of cerebral cortical MVD may represent a central determinant of stroke outcomes. METHODS: This study used the OZR model of MS and clinically relevant, chronic interventions to determine the impact on cerebral cortical microvascular rarefaction via immunohistochemistry with a parallel determination of cerebrovascular function to identify putative mechanistic contributors. RESULTS: OZR exhibited a progressive rarefaction (to ~80% control MVD) of the cortical microvascular networks vs. lean Zucker rats. Chronic treatment with antihypertensive agents (captopril/hydralazine) had limited effectiveness in blunting rarefaction, although treatments improving glycemic control (metformin/rosiglitazone) were superior, maintaining ~94% control MVD. Chronic treatment with the antioxidant TEMPOL severely blunted rarefaction in OZR, although this ameliorative effect was prevented by concurrent NOS inhibition. CONCLUSIONS: Further analyses revealed that the maintenance of glycemic control and vascular NO bioavailability were stronger predictors of cerebral cortical MVD in OZR than was prevention of hypertension, and this may have implications for chronic treatment of CVD risk under stroke-prone conditions.

Protective effect of sex on chronic stress- and depressive behavior-induced vascular dysfunction in BALB/cJ mice.

The presence of chronic, unresolvable stresses leads to negative health outcomes, including development of clinical depression/depressive disorders, with outcome severity being correlated with depressive symptom severity. One of the major outcomes associated with chronic stress and depression is the development of cardiovascular disease (CVD) and an elevated CVD risk profile. However, in epidemiological research, sex disparities are evident, with premenopausal women suffering from depressive symptoms more acutely than men, but also demonstrating a relative protection from the onset of CVD. Given this, we investigated the differential effect of sex on conduit artery and resistance arteriolar function in male and female mice following 8 wk of an unpredictable chronic mild stress (UCMS) protocol. In males, plasma cortisol and depressive symptom severity (e.g., coat status, anhedonia, delayed grooming) were elevated by UCMS. Endothelium-dependent dilation to methacholine/acetylcholine was impaired in conduit arteries and skeletal muscle arterioles, suggesting a severe loss of nitric oxide bioavailability and increased production of thromboxane A2 vs. prostaglandin I2 associated with elevated reactive oxygen species (ROS) and an increased level of systemic inflammation. Endothelium-independent dilation was intact. In females, depressive symptoms and plasma cortisol increases were more severe than in males, although alterations to vascular reactivity were blunted, including the effects of elevated ROS and inflammation on dilator responses. These results suggest that compared with males, female rats are more susceptible to chronic stress in terms of the severity of depressive behaviors, but that the subsequent development of vasculopathy is blunted owing to an improved ability to tolerate elevated ROS and systemic inflammatory stress.

Altered aortic vascular reactivity in the unpredictable chronic mild stress model of depression in mice: UCMS causes relaxation impairment to ACh.

Major depression is an independent risk factor for the development of cardiovascular disease. This impact of depression on vascular function seems to be mediated by the endothelial dysfunction, defined as an impairment of endothelium-dependent vasorelaxation, which represents a reliable predictor of atherosclerosis and has been regularly found to be associated with depression. This study aimed at investigating aortic vascular reactivity in mice submitted to the unpredictable chronic mild stress (UCMS) procedure, a reliable model of depression. The results confirm the effectiveness of the UCMS procedure to induce neuroendocrine, physical and behavioral depression-like alterations as well as a significant decrease of acetylcholine-induced vasorelaxation without any effect on phenylephrine-induced vasoconstriction. In this study, we reveal an altered vascular reactivity in an animal model of depression, demonstrating an endothelial dysfunction reminiscent to the one found in depressed patients.

Early and late-onset effect of chronic stress on vascular function in mice: a possible model of the impact of depression on vascular disease in aging.

Depression is recognized as a predictor of increased cardiac morbidity and mortality. In addition, depressed patients exhibit an increase in the serum markers of endothelial dysfunction and platelet activation involved in the cascade of events leading to atherosclerosis. The purpose of this study was to determine the early and late-onset expression of various vascular markers in a rodent model of depression. Male DBA (an inbred strain of mice)/2J mice were exposed to either 7 weeks of controlled living conditions or unpredictable chronic mild stress (UCMS), and subsequently given daily fluoxetine (10 mg/kg) or NaCl (9%) during the last 5 weeks of the experiment. Depressive-like behavior was evaluated by using motivational and self-care behavior, including the assessment of the animal's coat state and grooming behavior. Enzyme-linked immunoassay was used to quantify matrix metalloproteinase-9 (MMP-9), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and plasminogen activator inhibitor-1 (PAI-1) expression either immediately after the end of the UCMS procedure (short term condition) or 10 months later (long-term condition). Results indicate that 1) UCMS procedure induces a short-term depressive-like behavior in mice, defined as coat state deterioration, an effect that is prevented by fluoxetine treatment; 2) UCMS procedure has no effect on the short-term expression of the studied markers; however, UCMS increases expression of plasminogen activator inhibitor-1 only in the long-term group; 3) fluoxetine treatment is unable to counteract this UCMS-induced change; 4) aging induces behavioral perturbation, defined as a decrease in grooming motivation, and an increase of all the vascular markers in both control and UCMS groups and 5) pretreatment with fluoxetine has no protective effects on aging-induced behavioral and vascular alterations. Thus, in this model of depression-like behavior, UCMS appears to induce late-onset physiological changes, which are consistent with human studies indicating that depression is a risk factor for the development of heart disease.

Aspirin resistance with genetic dyslipidemia: contribution of vascular thromboxane generation.

One clinical intervention against the negative outcomes associated with atherothrombotic vascular disease (AVD) is low-dose, chronic aspirin therapy. However, epidemiological studies suggest that recurrence of adverse vascular events with aspirin therapy is growing and associated with therapy duration. The contributors to this outcome are unclear and include poor patient compliance and aspirin-resistant platelet thromboxane A(2) (TxA(2)) production. Based on previous results in hypercholesterolemic mice, we hypothesized that elevated aspirin-insensitive arachidonic acid (AA)-induced TxA(2) production by the vascular endothelium contributes to aspirin resistance in AVD independent of platelet behavior. AA-induced dilation was blunted in aortic rings and in arterioles from apolipoprotein E (ApoE) and low-density lipoprotein receptor (LDLR) gene deletion mice (vs. C57/Bl6/J), partially due to elevated TxA(2) production. Acute inhibition of cyclooxygenases or TxA(2) synthase attenuated the increased TxA(2) production in ApoE and LDLR and improved AA-induced dilation, responses that were mirrored by chronic treatment with low-dose aspirin of 16 wk duration. However, this effect was not temporally stable, and, with longer-duration therapy, the beneficial impact of aspirin on outcomes diminished. A similar, though less robust, pattern to the impact of chronic aspirin therapy on vascular outcomes was identified with chronic antioxidant treatment (TEMPOL). These results suggest that in dyslipidemic mice, the beneficial impact of chronic aspirin therapy on improving vascular outcomes decay with time and that a contributing element to subsequent negative vascular events may be the development of aspirin-resistant TxA(2) production by the vasculature itself.

Differential impact of familial hypercholesterolemia and combined hyperlipidemia on vascular wall and network remodeling in mice.

Genetic familial hypercholesterolemia (FH) and combined hyperlipidemia (FCH) are characterized by elevated plasma low-density lipoprotein (LDL) (FH) and LDL/triglycerides (FCH), with mouse models represented by LDL receptor (LDLR) and apolipoprotein E (ApoE) gene deletion mice, respectively. Given the impact of FH and FCH on health outcomes, we determined the impact of FH/FCH on vascular structure in LDLR and ApoE mice. LDLR, ApoE and control mice were utilized at 12-13 and 22-23 weeks when gracilis arteries were studied for wall mechanics and gastrocnemius muscles were harvested for microvessel density measurements. Conduit arteries and plasma samples were harvested for biochemical analyses. Arteries from ApoE and LDLR exhibited blunted expansion versus control, reduced distensibility and left-shifted stress versus strain relation (LDLR > ApoE). Microvessel density was reduced in ApoE and LDLR (ApoE > LDLR). Secondary analyses suggested that wall remodeling in LDLR was associated with cholesterol and MCP-1, while rarefaction in ApoE was associated with tumor necrosis factors-alpha, triglycerides and vascular production of TxA(2). Remodeling in ApoE and LDLR appears distinct; as that in LDLR is preferential for vascular walls, while that for ApoE is stronger for rarefaction. Remodeling in LDLR may be associated with cellular adhesion, while that in ApoE may be associated with pro-apoptotsis and constrictor prostanoid generation.

Depressive behavior and vascular dysfunction: a link between clinical depression and vascular disease?

As chronic stress and depression have become recognized as significant risk factors for peripheral vascular disease in patients with no prior history of vasculopathy, we interrogated this relationship utilizing an established mouse model of chronic stress/depressive symptoms from behavioral research. Male mice were exposed to 8 wk of unpredictable chronic mild stress (UCMS; e.g., wet bedding, predator sound/smell, random disruption of light/dark cycle), with indexes of depressive behavior (coat status, grooming, and mobility) becoming exacerbated vs. controls. In vascular rings, constrictor (phenylephrine) and endothelium-independent dilator (sodium nitroprusside) responses were not different between groups, although endothelium-dependent dilation (methacholine) was attenuated with UCMS. Nitric oxide synthase (NOS) inhibition was without effect in UCMS but nearly abolished reactivity in controls, while cyclooxygenase inhibition blunted dilation in both. Combined blockade abolished reactivity in controls, although a significant dilation remained in UCMS that was abolished by catalase. Arterial NO production was attenuated by UCMS, although H2O2 production was increased. UCMS mice demonstrated an increased, although variable, insulin resistance and inflammation. However, while UCMS-induced vascular impairments were consistent, the predictive power of aggregate plasma levels of insulin, TNF-alpha, IL-1beta, and C-reactive peptide were limited. However, when separated into tertiles with regard to vascular outcomes, insulin resistance and hypertension were predictive of the most severe vascular impairments. Taken together, these data suggest that aggregate insulin resistance, inflammation, and hypertension in UCMS mice are not robust predictors of vascular dysfunction, suggesting that unidentified mechanisms may be superior predictors of poor vascular outcomes in this model.