Biomedical subjects

Peter K Henke

Publications and source records attributed to Peter K Henke.

At least 19 recordsLinked to original sources

PubMed2006

Differential regulation of the superoxide dismutase family in experimental aortic aneurysms and rat aortic explants.

OBJECTIVE: Oxidative stress has been implicated in abdominal aortic aneurysm pathogenesis. This study sought to characterize the relevance of superoxide dismutases (SOD), a family of reactive oxygen catalyzing metalloenzymes, including manganese SOD (MnSOD), copper-zinc SOD (CuZnSOD), and extracellular SOD (EcSOD), in a rodent aortic aneurysm model. METHODS: Male rat infrarenal abdominal aortas were perfused with either saline (control) or porcine pancreatic elastase (6 U/mL). Aortic diameter was measured and aortas harvested on post-operation days 1, 2, and 7 (N=5-6 per treatment group per day). MnSOD, CuZnSOD, EcSOD, catalase, MMP-2, MMP-9, and beta-actin expression in aortic tissue was determined by quantitative real-time PCR. MnSOD protein levels were measured using western immunoblotting and immunohistochemistry. In subsequent experiments, aimed at understanding the mechanism by which SOD is involved in AAA pathogenesis, rat aortic explants (RAEs) were incubated in media for 24 h in the presence of interleukin-1beta (IL-1beta, 2 ng/mL) and TEMPOL (SOD mimetic), catalase, or a combined SOD and catalase mimetic. Media MMP-2 and MMP-9 activity was determined by zymography. Data were analyzed by Student's t-tests and ANOVA. RESULTS: Elastase-perfused aortic diameters were significantly increased compared to control aortas by post-perfusion day 7 (P=0.016). MnSOD mRNA levels in elastase perfused aortas were 6.0 (P=0.05) and 7.5 times (P<0.01) greater than control aortas at post-perfusion days 1 and 2, respectively. EcSOD, CuZnSOD, catalase, and MMP-2 mRNA expression did not statistically vary between the two groups. MMP-9 expression was 3.5-fold higher in the elastase group on post-perfusion day 2 (P=0.04). Western immunoblotting confirmed MnSOD protein was up-regulated on day 4 in the elastase-perfused group compared to controls (P=0.02). Immunohistrochemistry demonstrated increased MnSOD staining in the elastase group on day 4. In RAE experiments, TEMPOL increased both MMP-9 and MMP-2 activity 2 (P=0.09) and 3-fold (P=0.05), respectively, whereas catalase and the combined SOD/catalase mimetic failed to increase MMP-2 or MMP-9 activity. CONCLUSION: Experimental abdominal aortic aneurysm formation is associated with early increases in MnSOD expression and an increase in MMP-9 activity. Strategies aimed at inhibiting oxidative stress during AAA formation should focus on MnSOD.

Animals↗

PubMed2006

Pediatric renovascular hypertension: 132 primary and 30 secondary operations in 97 children.

PURPOSE: This study was undertaken to characterize the contemporary surgical treatment of pediatric renovascular hypertension. METHODS: A retrospective analysis was conducted of the clinical data of 97 consecutive pediatric patients (39 girls, 58 boys), aged from 3 months to 17 years, who underwent operation at the University of Michigan from 1963 to 2006. All but one patient had refractory hypertension not responsive to contemporary medical therapy. Developmental renal artery stenoses accounted for 80% of the renal artery disease, with inflammatory and other ill-defined stenoses encountered less frequently. Splanchnic arterial occlusive lesions affected 24% and abdominal aortic coarctations, 33%. RESULTS: Primary renal artery operations were undertaken 132 times. Procedures included resection beyond the stenosis and implantation into the aorta in 49, renal artery in 7, or superior mesenteric artery in 3; aortorenal and iliorenal bypasses with vein or iliac artery grafts in 40; focal arterioplasty in 10; resection with reanastomosis in 4; operative dilation in 4; splenorenal bypass in 2; and primary nephrectomy in 13 when arterial reconstructions proved impossible. Bilateral renal operations were done in 34 children, and 17 underwent celiac or superior mesenteric arterial reconstructions, including 15 at the time of the renal operation. Thirty patients underwent abdominal aortic reconstructions with patch aortoplasty (n = 19) or thoracoabdominal bypass (n = 11). Twenty-five of the aortic procedures were performed coincidently with the renal operations. Thirty secondary renal artery procedures were done in 19 patients, including nine nephrectomies. Hypertension was cured in 68 children (70%), improved in 26 (27%), and was unchanged in three (3%). Follow-up averaged 4.2 years. No patients required dialysis, and there were no operative deaths. CONCLUSION: Contemporary surgical treatment of pediatric renovascular hypertension emphasizes direct aortic implantation of the normal renal artery beyond its stenosis and single-staged concomitant splanchnic and aortic reconstructions when necessary. Benefits accompany carefully executed operative procedures in 97% of these children.

Adolescent↗

PubMed2006

Acute limb ischemia associated with type B aortic dissection: clinical relevance and therapy.

BACKGROUND: The goal of the current study is to characterize the presentation, therapy, and outcomes of acute limb ischemia (ALI) associated with type B aortic dissection (AoD). METHODS: The prospective/retrospective International Registry for Acute Aortic Dissection (IRAD) database and a single institutional database were queried for all patients with type B AoD from 1996 to 2002. Univariate and multivariate statistics were used to delineate factors associated with morbidity and mortality outcomes. RESULTS: According to the IRAD data (n = 458), the mean age of patients was 64 years, and 70% were men. The overall mortality was 12%; of these, 6% had ALI. Pulse (3-fold) and neurologic deficits (5-fold) were more common in those with ALI (P < .001). Endovascular, but not surgical therapy, was more commonly performed in patients with ALI compared with those without ALI (31% vs 10%, P = .004). No difference in age, race, gender, or origin of dissection was observed. ALI was associated with acute renal failure (odds ratio [OR] = 2.7; 95% confidence interval [CI] 1.1-7.1; P = .048) and acute mesenteric ischemia/infarction (OR = 6.9; 95% CI 2.5-20; P < .001). Adjusting for patient characteristics, ALI was associated with death (3.5; 95% CI 1.1-10; P = .02). The single institution analysis revealed similar patient demographics and mortality in 93 AoD patients, of whom 28 had ALI. Aortic fenestration or aorto-iliac stenting was the primary therapy in 93%; surgical bypass was used in 7%. Limb salvage was 93% in those with ALI at a mean of 18 months follow-up. The number of organ systems with malperfusion was 2-fold higher at aortography than suspected preprocedure (P = .002). By stepwise regression modeling, mortality was greater in those not taking a beta-blocker (OR = 19; 95% CI 3.1-111; P = .001). CONCLUSIONS: ALI secondary to AoD is predictive of death and visceral ischemia. Endovascular therapy confers excellent limb salvage and allows diagnosis of unsuspected visceral ischemia.

Acute Disease↗

PubMed2006

Targeted deletion of CCR2 impairs deep vein thombosis resolution in a mouse model.

CCR2 is required for monocyte recruitment in many inflammatory processes, as well as conferring Th1 lymphokine responses. Deep vein thrombosis (DVT) resolution represents a specific inflammatory response whereby the thrombus must be dissolved for restoration of blood flow. Using a stasis model of DVT in the mouse, we investigated the role of CCR2 on DVT resolution. Genetic deletion of CCR2 (CCR2-/-) was associated with larger thrombi at early and later time points, increased thrombus collagen, fewer thrombus monocytes (F4/80), and significantly impaired neovascularization. IL-2 and IFN-gamma were significantly reduced in early CCR2-/- thrombi, whereas MCP-1 was significantly increased, and Th2 lymphokines were unaffected. Supplementation of CCR2-/- mice with IFN-gamma normalized early thrombus resolution without increasing monocyte influx. Neither Ab depletion of IFN-gamma nor genetic deletion of IFN-gamma impaired early DVT resolution. Early fibrinolysis was not impaired in CCR2-/- mice, but a significant reduction in both matrix metalloproteinase (MMP)-2 and MMP-9 activity was observed. However, only MMP-9 activity was restored with administration of IFN-gamma. We conclude that an early CCR2-dependent Th1 lymphokine response predominates in normal DVT resolution, mediates this in part by MMP-9 activation, but is not solely dependent on IFN-gamma.

Animals↗

PubMed2006

The nitric oxide donor DETA-NONOate decreases matrix metalloproteinase-9 expression and activity in rat aortic smooth muscle and abdominal aortic explants.

Our objective was to examine the role of an exogenous nitric oxide (NO) donor, DETA-NONOate (DETA), on matrix metalloproteinase (MMP)-9, MMP-2, and tissue inhibitor of matrix metalloproteinases (TIMP)-1 expression and activity in interleukin (IL)-1beta-induced rat aortic smooth muscle cells (RA-SMCs) and rat aortic explants (RAEs). RA-SMCs were incubated with IL-1beta (2 ng/ml), an inflammatory cytokine known to induce MMP-9 expression, and increasing concentrations of DETA (0, 1.0, 10, 100 microM; n = 3/group) for 48 hr. RAEs were incubated with IL-1beta (2 ng/mL) and increasing concentrations of DETA (0, 5.0, 50, 100, and 500 microM; n = 3/group) for 48 hr. Media were collected and assayed for NO(x) by the Griess reaction and MMP-9 activity by zymography. Messenger RNA (mRNA) was extracted from cells and analyzed for MMP-9, MMP-2, and TIMP-1 expression levels by quantitative real-time reverse-transcriptase polymerase chain reaction. All statistical analyses were performed by analysis of variance. In RA-SMCs and RAEs, DETA administration resulted in a dose-dependent increase in media NOx concentration (RA-SCM p < 0.01, RAE p < 0.01) and a concurrent decrease in both MMP-9 expression (RASMC p = 0.01, RAE p = 0.01) and activity (RASMC p = 0.04, RAE p = 0.006). There were no significant differences seen in MMP-2 and TIMP-1 expression or activity in response to DETA exposure. DETA decreased IL-1beta-induced MMP-9 expression and activity in both RA-SMCs and RAEs in a dose-dependent fashion. In addition, DETA administration had no effect on MMP-2 or TIMP-1 expression or activity in vitro. These data suggest that NO donors may be beneficial in decreasing MMP-9 levels and might serve to inhibit MMP-9-dependent vessel wall remodeling seen during abdominal aortic aneurysm formation.

Animals↗

PubMed2006

A biologic basis for asymmetric growth in descending thoracic aortic aneurysms: a role for matrix metalloproteinase 9 and 2.

OBJECTIVE: This study was undertaken to define matrix metalloproteinase (MMP) expression in the anterior and posterior wall of descending thoracic aortic aneurysms (TAAs) and correlate it with specific computed tomography (CT) image sites within the descending thoracic aorta. METHODS: Serial CT images of patients with TAAs were compared with age- and gender-matched normal descending thoracic aortas at levels T4-T12. The mean circumference of the TAAs was 153 mm (n = 12) and 148 mm (n = 11) at T8 and T10, respectively, compared with 75 mm (n = 12) and 75 mm (n = 10) in controls (P < .001). Aortic tissue was collected from a separate set of eight patients undergoing descending TAA resection (processed < or =12 hours of excision) and six cadavers (processed < or =24 hours of death). Tissue collected between the intercostals arteries was defined as posterior wall, and directly opposite was the anterior wall. MMP-9 and MMP-2 messenger RNA (mRNA) extracted from aortic tissue was analyzed by quantitative real time polymerase chain reaction (PCR) and normalized to beta-actin. Immunohistochemistry was performed for MMP-9 and MMP-2. CT aortic measurements and MMP expression were compared by t tests and analysis of variance, respectively. RESULTS: The ratio of arc distance between the intercostals on the posterior wall to total aortic circumference was 0.14 in healthy controls compared with 0.08 in TAAs at vertebral level T8 (P = .001). At T10, the ratio was 0.15 in healthy controls compared with 0.11 in TAAs (P = .001). MMP-9 expression in TAAs was 4.3-fold higher in the anterior wall compared with the posterior wall (P = .03). Conversely, MMP-2 expression in TAAs was 3.2-fold higher in the posterior wall compared with the anterior wall (P = .008). MMP expression was not detected in control cadaver aortas. CONCLUSION: Anterior walls of expanding TAAs grow at a greater rate than the posterior wall, as determined from the lower ratio of intercostal arc distance to total circumference in TAAs. Differential MMP expression appears to be a biologic marker for asymmetric growth in the TAA wall. CLINICAL RELEVANCE: The pathogenesis of thoracic aortic aneurysms (TAAs) is poorly understood. Multiple lines of evidence suggest that matrix metalloproteinases (MMPs), a family of enzymes, are important in aneurysm development. Earlier experiments documented a regional variation of MMP-9 in stimulated rodent aortas, with production greater in the abdominal aorta compared with the thoracic aorta. The present study extends that observation and documents asymmetric aneurysm development in the TAA wall, with increased anterior wall growth in correlation to increased MMP-9 production. An improved understanding of the mechanisms by which MMP production is regulated is critical.

Aortic Aneurysm, Thoracic↗

PubMed2006

Experimental pulmonary embolism: effects of the thrombus and attenuation of pulmonary artery injury by low-molecular-weight heparin.

BACKGROUND: Pulmonary embolism (PE) is a life-threatening condition that is associated with the long-term sequelae of chronic pulmonary hypertension. Prior experimental work has suggested that post-PE inflammation is accompanied by pulmonary artery intimal hyperplasia. This study evaluated the effect of the thrombus and tested the hypothesis that thrombolytic, antiplatelet, and anticoagulant agents would decrease pulmonary injury. METHODS: Male Sprague-Dawley rats (n = 267) underwent laparotomy and temporary clip occlusion of the infrarenal inferior vena cava for the formation of endogenous thrombus or placement of an inert silicone "thrombus." Two days later, repeat laparotomy was performed, the clip removed, and the thrombus or silicone plug was embolized to the lungs. The endogenous thrombus group received normal saline, low-molecular-weight heparin (LMWH), tissue plasminogen activator (tPA), or a gIIB/IIIA antagonist (abciximab). Lung tissue was harvested at various times over 21 days and assayed for total collagen, monocyte chemoattractant protein-1 (MCP-1), interleukin-13 (IL-13), and transforming growth factor-beta (TGF-beta). Fixed sections were stained with trichrome for intimal hyperplasia determination and ED-1 monocytes and alpha-actin-positive staining. RESULTS: The overall survival for rats undergoing PE was 90%, was not affected by treatment, and 84% of all PE localized to the right pulmonary artery. The PE significantly reduced Pa(O2) in all groups. Compared with controls, the silicone emboli group had an increased level of IL-13 on day 1, an increased level of MCP-1 on day 4, and an increase in the levels of all inflammatory mediators on day 14 (P < .05). Accompanying these differences were greater pulmonary artery intimal hyperplasia at days 4 and 21 in the silicone group compared with controls (P < .05). LMWH treatment in the thrombus of PE rats significantly decreased IL-13 levels at all time points, whereas treatment with abciximab or tPA significantly increased IL-13 levels compared with controls. TGF-beta levels were significantly increased by LMWH at day 4 and 14, and abciximab was associated with lower TGF-beta at day 14. Only LMWH was associated with less pulmonary artery intimal hyperplasia at day 14 compared with controls and the other treatment groups. CONCLUSIONS: Persistent pulmonary artery distention by an inert material is sufficient to invoke significant inflammation and intimal hyperplasia independent of the thrombus itself. Compared with nontreated PE, LMWH is the only therapy associated with a significant reduction in late intimal hyperplasia and, with the exception of TGF-beta, lower profibrotic growth-factor production.

Angiography↗

PubMed2006

Treatment with an oral small molecule inhibitor of P selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis.

BACKGROUND: Vein wall injury after thrombosis is multifactorial but seems dependent on thrombus and local thrombotic and inflammatory mechanisms. We hypothesized that inhibition of vein wall injury through reduction of thrombotic and inflammatory events with P-selectin inhibition and/or low-molecular-weight heparin (LMWH) occurs independently of thrombus resolution in a rat model of venous thrombosis. METHODS: Male rats underwent inferior vena cava (IVC) stenosis (94.4% +/- 0.5% reduction in IVC diameter) to induce thrombosis. Rats were treated from 2 days after thrombosis until they were killed 7 days later. Groups consisted of (1) PSI-697, a P-selectin inhibitor (30 mg/kg; oral gavage daily); (2) LMWH-Lovenox (LOV; enoxaparin) 3 mg/kg subcutaneously daily; (3) PSI-697 (30 mg/kg; oral gavage daily) plus LOV 3 mg/kg subcutaneously daily (PSI + LOV); (4) and untreated controls. Evaluations included thrombus mass, vein wall tensiometry (stiffness [inverse of compliance]), intimal thickness scoring by light microscopy, vein wall inflammatory mediators by enzyme-linked immunosorbent assay, and vein wall inflammatory cells by histologic evaluation. RESULTS: Thrombus mass was not reduced by any treatment. Animals treated with PSI-697 alone, LOV alone, or PSI + LOV demonstrated significant decreases in vein wall stiffness when compared with controls. The vein wall stiffness of the PSI-697-treated groups was also significantly lower than in the LOV-only group. Animals treated with PSI-697 showed a significantly decreased intimal thickness score when compared with vehicle control IVCs. Vein wall intimal thickening was also significantly decreased in animals treated with PSI-697 vs LOV. The PSI-697 and PSI + LOV groups manifested significant decreases in the immunoregulatory and inflammatory cytokine interleukin 13 as compared with controls and LOV. Vein wall monocyte chemotactic protein 1 levels were also significantly reduced in the PSI-697 and PSI + LOV groups vs control. Only PSI-697 significantly decreased vein wall levels of platelet-derived growth factor betabeta. Both the LOV and PSI + LOV groups had significant increases in vein wall monocytes and total inflammatory cells vs controls. CONCLUSIONS: These data suggest that both LMWH and PSI-697 inhibit vein wall injury independently of thrombus mass. P-selectin inhibition seemed superior to LMWH in measured parameters of injury and mediator inhibition.

Animals↗

PubMed2006

Risk factors associated with venous thromboembolic events in patients with malignancy.

Malignancy is a major risk factor for venous thromboembolic events, but not all patients with malignancy develop such events. This study attempts to identify risk factors in patients with malignancy who develop venous thromboembolic events. In the current study, 566 consecutive patients without venous thromboembolic events and 416 patients with, admitted to University of Michigan with malignancy between 1992 and 2000, were identified using International Classification of Diseases-9 Clinical Modification codes. Data on potential risk factors was obtained from the University of Michigan Cancer Registry and the medical record. Univariate and multivariate analysis was used to identify factors associated with venous thromboembolic events and mortality. The mean patient age was 45.6 years with a mean survival of 7.8 years from cancer diagnosis. Venous thromboembolic events were associated with solid tumors (odds ratio 5.0; 95% confidence interval 1.7-14.9; P = 0.004), infection (4.9; 1.2-19.8; P = 0.03), and increasing age (1.05; 1.03-1.08; P < 0.001). While leukopenia (4.2; 1.2-14.6; P = 0.02) was associated with an increased incidence of venous thromboembolic events, neutropenia was not. Sex, type of therapy, and cancer stage were not independently associated with venous thromboembolic events. Survival was decreased in patients with venous thromboembolic events (5.9 versus 9.2 years, P < 0.0001). Solid tumors (3.9; 1.8-8.4; P = 0.001), infection (3.3; 1.1-9.9; P = 0.03), advanced stage (1.6; 1.2-2.1; P = 0.001), and increasing age (1.02; 1.0-1.04; P = 0.01) were associated with decreased survival. Patients with malignancy who have solid tumors, advanced age, infection, and leukopenia have a significantly increased risk of venous thromboembolic events.

Adolescent↗

PubMed2006

Neutrophils modulate post-thrombotic vein wall remodeling but not thrombus neovascularization.

Early deep venous thrombosis (DVT) resolution is associated with neutrophil (PMN) influx. This study examined the role of PMNs in thrombus neovascularization and vein wall injury after DVT. A rat model of DVT by inferior vena cava (IVC) ligation was performed with control serum or rabbit anti-rat PMN serum administered perioperatively with sacrifice at 2 and 7 days. At 2 days, neutropenic rats had 1.6-fold larger thrombi (P = .04) and 1.4-fold higher femoral venous pressures by water manometry (P = .008) but no difference in thrombus neovascularization was observed. By 7 days, DVT sizes were similar, but vein wall injury persisted in the neutropenic rats with a 2.0-fold increase in vein wall stiffness by microtensiometry (P < .05), as well as a 1.2-fold increased thickness (P = .04). Collagen and profibrotic growth factors were significantly increased in neutropenic IVC at 7 days (all P < .05). Vein wall and intrathrombus uPA byWestern immunoblotting, and intrathrombus MMP-9 gelatinase activity were significantly less in neutropenic rats than controls (P < .001). Conversely, MMP-2 was significantly elevated in neutropenic IVC at 2 days after DVT. However, neutropenia induced 24 hours after DVT formation resulted in no significant increase in vein wall stiffness or collagen levels at 7 days, despite 1.4-fold larger thrombi (P < .05). These data suggest a critical early role for PMN in post DVT vein wall remodeling.

Animals↗

PubMed2006

Diffusion of Alexa Fluor 488-conjugated dendrimers in rat aortic tissue.

In this study, the distribution of labeled dendrimers in native and aneurysmal rat aortic tissue was examined. Adult male rats underwent infrarenal aorta perfusion with generation 5 (G5) acetylated Alexa Fluor 488-conjugated dendrimers for varying lengths of time. In a second set of experiments, rats underwent aortic elastase perfusion followed by aortic dendrimer perfusion 7 days later. Aortic diameters were measured prior to and postelastase perfusion, and again on the day of harvest. Aortas were harvested 0, 12, or 24 h postperfusion, fixed, and mounted. Native aortas were harvested and viewed as negative controls. Aortic cross-sections were viewed and imaged using confocal microscopy. Dendrimers were quantified (counts/high-powered field). Results were evaluated by repeated measures ANOVA and Student's t-test. We found that in native aortas, dendrimers penetrated the aortic wall in all groups. For all perfusion times, fewer dendrimers were present as time between dendrimer perfusion and aortic harvest increased. Longer perfusion times resulted in increased diffusion of dendrimers throughout the aortic wall. By 24 h, the majority of the dendrimers were through the wall. Dendrimers in aneurysmal aortas, on day 0 postdendrimer perfusion, diffused farther into the aortic wall than controls. In conclusion, this study documents labeled dendrimers delivered intra-arterially to native rat aortas in vivo, and the temporal diffusion of these molecules within the aortic wall. Increasing perfusion time and length of time prior to harvest resulted in continued dendrimer diffusion into the aortic wall. These preliminary data provide a novel mechanism whereby local inhibitory therapy may be delivered locally to aortic tissue.

Aneurysm↗

PubMed2006

Attenuation of experimental aortic aneurysm formation in P-selectin knockout mice.

The aim of this study was to determine the role of P-selectin, an adhesion molecule found on the surface of activated platelets and endothelial cells during experimental aortic aneurysm formation. Infrarenal abdominal aortas of C57 black wild-type (WT) mice and P-selectin knockout (PKO) mice were measured in situ and then perfused with porcine pancreatic elastase (0.332 U/mL). Whole blood was drawn from the tail artery on day 2 pre-perfusion to determine total and differential white blood cell (WBC) counts. On day 14 postperfusion, aortic diameters (AD) of WT mice (N = 19) and PKO mice (N = 9) were measured. An aortic aneurysm was defined as a 100% or greater increase in AD from pre-perfusion measurement. Immunohistochemistry, including H&E, trichrome and von Gieson staining, was performed on harvested aortic tissue. Statistical analysis was performed by t-test and Fisher's exact test. There were no significant differences in peripheral leukocyte counts at baseline between the two groups. WT mice had significantly larger AD compared to PKO mice at day 14 postperfusion (116 % vs. 38 %, P < 0.001). Aortic aneurysm penetrance was 52% in WT mice, while 0% (P = 0.01) of PKO mice formed aneurysms. On histologic examination, WT mouse aortas were associated with a significant inflammatory response and degradation of elastin and collagen fibers, while PKO mouse aortas lacked signs of inflammation or vessel wall injury. P-selectin deficiency attenuates aneurysm formation in the elastase aortic perfusion model. This was associated with a blunting of the inflammatory response and preserved vessel wall intergrity following elastase perfusion in the P-selectin knockout mice. Further investigation to elucidate the independent contributions of endothelial cell and platelet P-selectin in experimental aortic aneurysm formation is required.

Animals↗

PubMed2006

Female gender attenuates cytokine and chemokine expression and leukocyte recruitment in experimental rodent abdominal aortic aneurysms.

Female gender appears to be protective in the development of abdominal aortic aneurysms (AAAs). This study sought to identify gender differences in cytokine and chemokine expression in an experimental rodent AAA model. Male and female rodent aortas were perfused with either saline (control) or elastase to induce AAA formation. Aortic diameter was determined and aortic tissue was harvested on postperfusion days 4 and 7. Cytokine and chemokine gene expression was examined using focused gene arrays. Immunohistochemistry was used to quantify aortic leukocyte infiltration. Data were analyzed by Student's t-tests and ANOVA. Elastase-perfused female rodents developed significantly smaller aneurysms compared to males by day 7 (93 +/- 10% vs. 201 +/- 25%, P = 0.003). Elastase-perfused female aortas exhibited a fivefold decrease in expression of the BMP family and ligands of the TNF superfamily compared to males. In addition, the expression of members of the TGF beta and VEGF families were three to fourfold lower in female elastase-perfused aortas compared to males. Multiple members of the interleukin, CC chemokine receptor, and CC ligand families were detectable in only the male elastase-perfused aortas. Female elastase-perfused aortas demonstrated a corollary twofold lower neutrophil count (females: 17.5 +/- 1.1 PMN/HPF; males: 41 +/- 5.2 neutrophils/HPF, P = 0.01) and a 1.5-fold lower macrophage count (females: 12 +/- 1.1 macrophages/HPF; males: 17.5 +/- 1.1 macrophages/HPF, P = 0.003) compared to male elastase-perfused aortas. This study documents decreased expression of multiple cytokines and chemokines and diminished leukocyte trafficking in female rat aortas compared to male aortas following elastase perfusion. These genes may contribute to the gender disparity seen in AAA formation.

Animals↗

PubMed2006

Epidemiology of aortic aneurysm repair in the United States from 1993 to 2003.

The epidemiology of abdominal aortic aneurysm (AAA) disease has been well described over the preceding 50 years. This disease primarily affects elderly males with smoking, hypertension, and a positive family history contributing to an increased risk of aneurysm formation. The aging population as well as increased screening in high-risk populations has led some to suggest that the incidence of AAAs is increasing. The National Inpatient Sample (1993-2003), a national representative database, was used in this study to determine trends in mortality following AAA repair in the United States. In addition, the impact of the introduction of less invasive endovascular AAA repair was assessed. Overall rates of treated unruptured and ruptured AAAs remained stable (unruptured 12 to 15/100,000; ruptured 1 to 3/100,000). In 2003, 42.7% of unruptured and 8.8% of ruptured AAAs were repaired through an endovascular approach. Inhospital mortality following unruptured AAA repair continues to decline for open repair (5.3% to 4.7%, P = 0.007). Mortality after elective endovascular AAA repair also has statistically decreased (2.1% to 1.0%, P = 0.024) and remains lower than open repair. Mortality rates for ruptured AAAs following repair remain high (open: 46.5% to 40.7%, P = 0.01; endovascular: 40.0% to 35.3%, P = 0.823). These data suggest that the numbers of patients undergoing elective AAA repair have remained relatively stable despite the introduction of less invasive technology. A shift in the treatment paradigm is occurring with a higher percentage of patients subjected to elective endovascular AAA repair compared to open repair. This shift, at least in the short term, appears justified as the mortality in patients undergoing elective endovascular AAA repair is significantly reduced compared to patients undergoing open AAA repair.

Aged↗

PubMed2005

A negative carotid plaque area test is superior to other noninvasive atherosclerosis studies for reducing the likelihood of having underlying significant coronary artery disease.

OBJECTIVE: Coronary calcium score (CCS), carotid plaque area (CPA), intima-media thickness (IMT), and C-reactive protein (CRP) are independent predictors of cardiovascular prognosis. Although each test may enhance risk stratification, their comparative abilities to screen for underlying coronary stenoses in individual patients is less established. METHODS AND RESULTS: Forty-two patients who had a 16-slice coronary computed tomography angiogram (CTA) performed were invited to have CPA, IMT, and CRP measured. CPA was defined as the sum of all the cross-sectional areas of each plaque >1 mm in diameter found in all carotid vessels bilaterally. CCS and the number plus degree of stenotic coronary arteries were determined by CTA. The presence of clinically significant coronary artery disease (CAD) was defined as the existence of any stenosis > or =50%. CTA identified clinically significant CAD in 43% of the patients. CPA >0 was more sensitive (72%) and specific (58%) than a CCS >0 (58% and 55%) for identifying CAD. A "clean" carotid artery (CPA=0) provides a superior negative predictive value (74%) and likelihood ratio of a negative test (0.48) than all other studies, in particular versus a CCS=0 (65% and 0.72). The areas under the receiver-operator curves for CPA and CCS in relation to any CAD were similar (0.640 versus 0.675). Carotid IMT and CRP performed poorly compared with CPA and CCS. For detecting CAD in only the left main or left anterior descending artery, the negative predictive value and likelihood ratio of a negative test remained superior for CPA (87% and 0.33) compared with CCS (80% and 0.56). In our population with a prevalence of these coronary lesions of 30%, the post-test probability in any patient with a negative CPA result is reduced to 10%. CONCLUSIONS: CPA determination is superior to CCS, IMT, and CRP in its ability to reduce the likelihood of clinically significant underlying CAD in patients of varying cardiac risk.

Aged↗

PubMed2005

Neutrophil depletion inhibits experimental abdominal aortic aneurysm formation.

BACKGROUND: Neutrophils may be an important source of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), two matrix-degrading enzymes thought to be critical in the formation of an abdominal aortic aneurysm (AAA). The purpose of this investigation was to test the hypothesis that neutrophil depletion would limit experimental AAA formation by altering one or both of these enzymes. METHODS AND RESULTS: Control, rabbit serum-treated (RS; n=27) or anti-neutrophil-antibody-treated (anti-PMN; n=25) C57BL/6 mice underwent aortic elastase perfusion to induce experimental aneurysms. Anti-PMN-treated mice became neutropenic (mean, 349 cells/microL), experiencing an 84% decrease in the circulating absolute neutrophil count (P<0.001) before elastase perfusion. Fourteen days after elastase perfusion, control mice exhibited a mean aortic diameter (AD) increase of 104+/-14% (P<0.0001), and 67% developed AAAs, whereas anti-PMN-treated mice exhibited a mean AD increase of 42+/-33%, with 8% developing AAAs. The control group also had increased tissue neutrophils (20.3 versus 8.6 cells per 5 high-powered fields [HPFs]; P=0.02) and macrophages (6.1 versus 2.1 cells per 5 HPFs, P=0.005) as compared with anti-PMN-treated mice. There were no differences in monocyte chemotactic protein-1 or macrophage inflammatory protein-1alpha chemokine levels between groups by enzyme-linked immunosorbent assay. Neutrophil collagenase (MMP-8) expression was detected only in the 14-day control mice, with increased MMP-8 protein levels by Western blotting (P=0.017), and MMP-8-positive neutrophils were seen almost exclusively in this group. Conversely, there were no statistical differences in MMP-2 or MMP-9 mRNA expression, protein levels, enzyme activity, or immunostaining patterns between groups. When C57BL/6 wild-type (n=15) and MMP-8-deficient mice (n=17) were subjected to elastase perfusion, however, ADs at 14 days were no different in size (134+/-7.9% versus 154+/-9.9%; P=0.603), which suggests that MMP-8 serves only as a marker for the presence of neutrophils and is not critical for AAA formation. CONCLUSIONS: Circulating neutrophils are an important initial component of experimental AAA formation. Neutrophil depletion inhibits AAA development through a non-MMP-2/9-mediated mechanism associated with attenuated inflammatory cell recruitment.

Animals↗

PubMed2005

L-selectin-mediated neutrophil recruitment in experimental rodent aneurysm formation.

BACKGROUND: This investigation tested the hypothesis that L-selectin is important in experimental abdominal aortic aneurysm (AAA) formation in rodents. METHODS AND RESULTS: Rat abdominal aortas were perfused with saline (control) or porcine pancreatic elastase and studied on postperfusion days 1, 2, 4, 7, and 14 (n=5 per treatment group per day). Neutrophil (polymorphonucleur leukocyte, PMN) and macrophage counts per high-powered field (HPF) were performed on fixed sections. L-selectin expression and protein levels in aortic tissue were determined by polymerase chain reaction and Western blot, respectively. Elastase-perfused aortic diameters were significantly increased compared with control aortas at all time points except day 1 (P<0.05). PMN counts significantly increased in elastase-perfused aortas compared with control aortas at days 1, 2, and 4, reaching maximum levels at day 7 (40.8 versus 0.3 PMNs/HPF, P=0.001). L-selectin mRNA expression in elastase-perfused aortas was 18 (P=0.018), 17 (P<0.001), and 8 times (P=0.02) times greater than control aortas at days 1, 2, and 4, respectively. Western blot demonstrated a significant 69% increase in L-selectin protein at day 7 in elastase- as compared with saline-perfused aortas (P=0.005). Subsequent experiments involved similar studies on postperfusion days 4, 7, and 14 of aortas from C57BL/6 wild-type (WT) mice (n=21) and L-selectin-knockout (LKO) mice (n=19). LKO mice had significantly smaller aortic diameters at day 14 as compared with WT mice (88% versus 123%, P=0.02). PMN counts were significantly greater in elastase-perfused WT mouse aortas as compared with LKO mouse aortas at day 4 after perfusion (12.8 versus 4.8 PMNs/HPF, P=0.02). Macrophage counts were significantly greater at all time points after perfusion in elastase-perfused WT mouse aortas compared with elastase-perfused LKO mouse aortas, with a maximum difference at day 7 after perfusion (13.3 versus 0.5 macrophages/HPF, P<0.001). CONCLUSIONS: L-selectin-mediated neutrophil recruitment may be a critical early step in AAA formation.

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PubMed2005

Severe chronic venous insufficiency: magnitude of the problem and consequences.

The aim of this study was to characterize patients requiring hospitalization for severe chronic venous insufficiency (CVI) at the local and national levels and to analyze factors related to primary amputation. An administrative database (Nationwide Inpatient Sample, 1988-2000) and a single institution (1992-2000) were reviewed using the International Classification of Diseases, 9th ed., Clinical Modification, codes for CVI, excluding phlegmasia and concomitant peripheral vascular occlusive disease codes. Demographics, clinical course, and outcomes were assessed. Descriptive, univariate, and multivariate statistical analyses were used; p < 0.05 was considered significant. Nationally, CVI occurred with a mean incidence of 92/100,000 admissions, of which 55% were women, having a mean age of 65 years and a median length of stay of 7 days. Mean hospital charges were $13,900 and did not change significantly over time. Acute deep vein thrombosis affected 1.3%, amputation was performed in 1.2%, and in-hospital mortality was 1.6% The local cohort included 67 patients with a mean age of 51 years; a majority were men (60%), and 85% were C6 (of Clinical-Etiologic-Anatomic-Pathophysiology [CEAP]). Patients averaged 23 clinic visits and a median of one hospitalization for CVI care over a 44-month follow-up. Twelve patients (18%) underwent a CVI-related amputation (one transmetatarsal amputation, nine below-knee amputations, and two above-knee amputations). They had fourfold more CVI-related hospitalizations, greater preoperative chronic narcotic use than nonamputee patients (85% vs. 58%), but less ongoing wound care needs (25% vs. 89%) (all p values < 0.05). However, no significant difference in long-term mortality, number of clinic visits, duration of symptoms, antibiotic courses, or prior venous-related surgeries was found. In those with amputation, ambulatory status was maintained in 75% at 15-month follow-up. The physiological and economic costs of severe CVI are significant and have not decreased over more than a decade. Amputation for CVI-related nonhealing wounds has a reasonable outcome. Future therapy must focus on prevention of CVI sequelae.

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