Loss of the hyaluronan receptor RHAMM prevents constrictive artery wall remodeling.

OBJECTIVE: Constrictive extracellular matrix (ECM) remodeling contributes significantly to restenosis after arterial reconstruction, but its molecular regulation is poorly defined. Hyaluronan (HA) accumulates within ECM at sites of injury where it is thought to facilitate smooth muscle cell (SMC) trafficking and collagen remodeling analogous to its role in cutaneous wound healing. SMC receptors for HA include receptor for hyaluronan-mediated motility (RHAMM), which mediates HA-induced migration. We hypothesized RHAMM would also mediate SMC-matrix interactions to alter the extent of constrictive remodeling. METHODS: We studied the role of RHAMM in SMC attachment to collagen, migration, and contraction of collagen gels using blocking antibodies and SMC from RHAMM -/- knockout mice. We then determined the role of RHAMM in constrictive artery wall remodeling by comparing changes in wall geometry in RHAMM -/- vs wild-type (WT) RHAMM +/+ controls 1 month after carotid ligation. RESULTS: HA increased SMC attachment to collagen-coated plates, but blocking RHAMM reduced adhesion (P = .025). RHAMM -/- SMC also demonstrated reduced adhesion (% adherent: 36.1 ± 2.2 vs 76.3 ± 1.9; P < .05). SMC contraction of collagen gels was enhanced by HA and further increased by RHAMM blockade (P < .01) or knockout (gel diameter, mm: RHAMM -/-, 6.7 ± 0.1 vs WT 9.8 ± 0.1; P < .01). RHAMM promoted constrictive remodeling in vivo as carotid artery size was significantly larger in knockout mice 1 month after ligation. Neointimal thickening, however, was not affected in RHAMM -/- (P = NS vs WT), but lumen size was significantly larger (lumen area, µm(2): 52.4 ± 1.4 × 10(3) vs 10.4 ± 1.8 × 10(3); P = .01) because artery size constricted less (external elastic lamina area, µm(2): RHAMM -/-, 92.4 ± 4.7 × 10(3) vs WT, 51.3 ± 5.9 × 10(3); P = .015). Adventitial thickening and collagen deposition were also more extensive in ligated RHAMM -/- carotids (adventitial thickness, µm: 218 ± 12.2 vs 109 ± 7.9; P = .01). CONCLUSIONS: HA activation of RHAMM significantly impacts SMC-ECM adhesive interactions and contributes to constrictive artery wall remodeling in mice. Strategies to block RHAMM at sites of vessel injury may prove useful in the prevention of clinical restenosis.

Renal duplex parameters, blood pressure, and renal function in elderly people.

BACKGROUND: Changes in renal artery and renal parenchyma perfusion are believed to correlate with severity of hypertension and worsened renal function, but population-based studies of these associations are not available. This study examines relationships between parameters derived from renal duplex sonography (RDS), blood pressure (BP), and excretory renal function in a population-based cohort of elderly Americans. METHODS: Through an ancillary study to the Cardiovascular Health Study, 758 participants (37% men; mean age, 77 years) underwent RDS in which flow velocities and frequency shifts were determined from spectral analysis of Doppler-shifted signals obtained from the renal artery and parenchyma. Associations of these duplex parameters with BP and inverse serum creatinine were examined by using multivariate regression techniques. RESULTS: Main renal artery peak systolic flow velocity (PSV) showed independent associations with BP, with an SD increase in PSV (0.53 m/s) associated with a 3.3-mm Hg increase in systolic BP (SBP) and a 2.4-mm Hg decrease in diastolic BP (DBP). An SD decrease in end-diastolic frequency shift (EDF; 131 kHz) was associated with a 6.0-mm Hg increase in SBP, a 4.2-mm Hg decrease in DBP, and a significant 3.7% decrease in inverse serum creatinine. CONCLUSION: Increases in renal artery PSV and decreases in parenchymal EDF are associated with increased SBP and decreased DBP. Moreover, decreased parenchymal EDF showed significant associations with impaired excretory renal function. These results suggest that renal duplex parameters are associated with renal parenchymal changes caused by hypertension and progressive renal dysfunction in elderly people.

Chronic visceral ischemia: symptom-free survival after open surgical repair.

A retrospective review of patients treated with a history of chronic visceral ischemia (CVI) was made to determine primary patency of open surgical repair and estimated symptom-free survival. Patients with CVI between 1990 and 2003 were reviewed. Included were those with chronic symptoms alone (C-CVI) and acute-on-chronic symptoms (A-CVI). Data were obtained from a vascular database. Symptom-free survival and graft patency were estimated by using product limit estimates. Fifty-eight patients (13 men, 45 women; mean age: 63 years) were treated surgically for C-CVI (34 patients) and A-CVI (24 patients). All patients had postprandial abdominal pain and weight loss (mean: 17 kg). One fourth reported food fear. Preoperative imaging demonstrated disease of the superior mesenteric artery (SMA) (100%; 64% occluded), celiac axis (89%; 37% occluded), and inferior mesenteric artery (IMA) (54%; 60% occluded). Multiple vessels were involved in 95% of patients (mean: 2.3 vessels/patient). Operative management included antegrade revascularization of 80 vessels. Combined aortic and/or renal procedures were performed in 7 patients. Patient demographics and visceral disease did not differ for C-CVI and A-CVI; however, perioperative mortality differed significantly (10% for C-CVI vs 54% for A-CVI [p < 0.001]). Intestinal gangrene at presentation was associated with perioperative (hazard ratio [HR]: 7.6; 95% CI: 2.7-21.6; p=0.0002) and follow-up death (HR: 7.8; CI 2.8-21.9; p <0.0001). Follow-up (mean: 34 months) was complete for 54/68 vessels (79%). Estimated primary and primary assisted patency at 5 years were 81% and 89% respectively. Estimated symptom-free survival for hospital survivors was 57% at 70 months. Open antegrade methods of visceral artery repair for CVI were durable and associated with 57% symptom-free survival at 70 months. Patient demographics and distribution of visceral artery anatomy were similar; however, perioperative mortality for C-CVI and A-CVI differed dramatically. Improved outcomes for A-CVI require recognition and treatment of CVI before onset of intestinal gangrene.

Mesenteric artery disease in the elderly.

PURPOSE: The purpose of this study was to estimate the population-based prevalence of mesenteric artery stenosis (MAS) and occlusion among independent elderly Americans. METHOD: As part of an ancillary investigation to the Cardiovascular Health Study (CHS), participants in the Forsyth County, NC cohort had visceral duplex sonography of the celiac arteries and superior mesenteric arteries (SMAs). Critical MAS was defined by celiac peak systolic velocity >or=2.0 m/s and/or SMA peak systolic velocity >or=2.7 m/s. Occlusion of either vessel was defined by lack of a Doppler-shifted signal within the imaged artery. Demographic data, blood pressures, and blood lipid levels were collected as part of the baseline CHS examination. Participants' weights were measured at baseline and before the duplex exam. Univariate tests of association were performed with two-way contingency tables, Student t tests, and Fisher exact tests. Multivariate associations were examined with logistic regression analysis. RESULTS: A total of 553 CHS participants had visceral duplex sonography technically adequate to define the presence or absence of MAS. The study group had a mean age of 77.2 +/- 4.9 years and comprised 63% women and 37% men. Participant race was 76% white and 23% African-American. Ninety-seven participants (17.5%) had MAS. There was no significant difference in age, race, gender, body mass index, blood pressure, cholesterol, or low-density lipoproteins for participants with or without MAS. Forward stepwise variable selection found renal artery stenosis (P =.008; odds ratio [OR], 2.85; 95% confidence interval [CI], 1.31, 6.21) and high-density lipoprotein >40 (P =.02; OR, 3.03; 95% CI, 1.17, 7.81) significantly associated with MAS in a multivariate logistic regression model. Eighty-three of the 97 participants with MAS (15.0% of the cohort) had isolated celiac stenosis. Seven participants (1.3% of the cohort) had combined celiac and SMA stenosis. Five participants (0.9% of the cohort) had isolated SMA stenosis. Two participants (0.4% of the cohort) had celiac occlusion. Considering all participants with MAS, there was no association with weight change. However, SMA stenosis and celiac occlusion demonstrated an independent association with annualized weight loss (P =.028; OR, 1.54; 95% CI, 1.05, 2.26) and with renal artery stenosis (P =.001; OR, 9.48; 95% CI, 2.62, 34.47). CONCLUSION: This investigation provides the first population-based estimate of the prevalence of MAS among independent elderly Americans. MAS existed in 17.5% of the study cohort. The majority had isolated celiac disease. SMA stenosis and celiac artery occlusion demonstrated a significant and independent association with weight loss and concurrent renal artery disease.

Surgical management of renal artery aneurysms.

PURPOSE: This retrospective review describes the surgical management and clinical outcome for renal artery aneurysms (RAAs) in 62 consecutive patients. METHODS: From January 1987 through July 2003, 804 patients had operative renal artery (RA) repair involving 1206 kidneys at our center. A subgroup of 62 patients (42 women, 20 men; mean age 46 +/- 18 years) received repair of 72 RAAs. Demographic data, comorbidity, and surgical technique were examined. Blood pressure and renal function response were determined. Patency of repair was evaluated by renal duplex sonography. Primary patency and patient survival were estimated by life-table methods. Tests of association were performed using chi(2) and the Student t tests. RESULTS: Seventy-two RAs were repaired for RAA with a mean diameter of 2.6 cm (range, 1.3 to 5.5 cm). Bilateral RAAs were present in 21 patients. Associated conditions included fibromuscular dysplasia, atherosclerosis, and arteritis in 54%, 35%, and 7%, respectively. Hypertension was present in 89% (mean blood pressure, 171 +/- 35/95 +/- 19 mm Hg; mean medications, 2.2 +/- 1.2 drugs) and renal insufficiency was present in 8% (mean serum creatinine, 1.9 +/- 0.6 mg/dL). RAA repair included bypass (67%), aneurysmorrhaphy (15%), or a combination (17%). One planned nephrectomy (1%) was performed for un-reconstructable disease. Branch RA reconstruction in 78% used ex vivo cold perfusion in 50%, in situ cold perfusion in 29%, and warm in situ repair in 21%. Of 9 bilateral RAA repairs, 7 (78%) were staged and 2 (22%) were simultaneous. Combined aortic reconstruction was required in 6 (10%) patients. Perioperative death occurred in 1 patient (1.6%), and significant morbidity was observed in 8 patients (12%). Hypertension was considered improved in 54%, cured in 21%, and unchanged in 25% at mean follow-up of 48 months (range, 1-156 months). Among patients with renal insufficiency, renal function was improved in 3 (60%), unchanged in 1 (20%), and declined in 1 (20%). Follow-up patency (mean, 33 months; range, 1-118 months) was determined for 64 (91%) RA reconstructions. Product-limit estimate of primary patency at 48 months was 96%. Product-limit estimate of survival was 91% at 120 months. CONCLUSION: RAAs were repaired with low morbidity and mortality. Complex branch RAA repair using cold perfusion preservation and ex vivo techniques resulted in no unplanned nephrectomy, with an estimated primary patency of 96% at 48 months. Beneficial blood pressure response was observed in the majority of hypertensive patients. These results support selective surgical management of RAA.

Differential effects of Rho-kinase inhibition on artery wall mass and remodeling.

PURPOSE: Constrictive remodeling and new artery wall mass contribute to lumen narrowing in atherosclerosis and following injury. Rho-kinase, an important regulator of myosin phosphorylation and cytoskeletal reorganization, is critical to smooth muscle cell (SMC) growth and vasoconstriction, but its role in artery wall remodeling is poorly defined. We hypothesized that constrictive artery wall remodeling is dependent on Rho signaling so that blocking Rho-kinase would promote outward artery wall remodeling in response to intimal hyperplasia and thus limit lumen narrowing. METHODS: To test this hypothesis, we first studied the effects of the Rho-kinase inhibitor fasudil on SMC remodeling of collagen matrix in vitro. Mouse aortic SMCs were seeded into three-dimensional collagen gels with and without fasudil, and extent of contraction was measured at 24 hours. We then used the mouse carotid ligation model to study the effects of Rho-kinase inhibition on remodeling and intimal hyperplasia in vivo. C57B6/J mice were randomly assigned to fasudil (100 mg/kg per day) or vehicle and underwent unilateral carotid artery ligation or sham ligation. Remodeling and wall mass were measured after 28 days. RESULTS: Fasudil blocked SMC contraction of collagen gels in a dose-dependent manner. Complete inhibition of collagen gel remodeling was achieved between 10 and 30 micromol/L fasudil. In control mice, carotid ligation caused significant thickening of the adventitia, media, and intima (P <.01) and outward remodeling of the carotid wall. The external elastic lamina (EEL) area increased by 14% versus sham (P <.05), but this increase was insufficient to prevent lumen narrowing (-42% vs sham, P <.05). Fasudil treatment had favorable effects on wall mass, inhibiting neointimal (P =.04), medial (P =.03), and adventitial thickening (P =.07) versus controls. Opposite our hypothesis, however, fasudil did not enhance outward artery wall remodeling or improve lumen caliber. Rather, inhibiting Rho-kinase blocked outward remodeling in response to ligation. EEL area was significantly smaller in treated versus control animals (P =.04) and slightly smaller versus shams (P = NS). These data suggest that Rho activation contributes significantly to both hyperplasia and outward remodeling of the injured artery wall. Rho-kinase may prove an important target to limit intimal hyperplasia and prevent restenosis when remodeling is improved by other means (eg, stents).

Multiple aneurysms in childhood.

Arterial aneurysms in children are rare. When present, they are often associated with connective tissue disorders or arteritidies. Idiopathic aneurysms occurring at multiple sites throughout the arterial tree are rare, with only ten cases reported. This report describes a case of multiple arterial aneurysms of uncertain origin involving upper-extremity, extracranial cerebrovascular, aortoiliac, and renal arteries in a 14-year-old boy. The clinical presentation, vascular reconstruction, pathologic findings, and a brief review of the literature are described.

There is no difference in survival between African-American and white women with breast cancer.

A difference in survival by race in women with breast cancer has been reported. We examined survival of African-American (AA) and white (W) women diagnosed with breast cancer and evaluated variables that may affect survival at a university teaching hospital. A retrospective review of tumor registry data for breast cancer was performed in all AA and W female breast cancer patients diagnosed between the years 1990 and 1999 at a university hospital. Survival between AA and W women diagnosed with breast cancer during that period was compared using Kaplan-Meier analysis. Variables including age and stage of disease at diagnosis, receptor status, treatment, and tobacco exposure were evaluated utilizing Chi-square testing. A P value <0.05 was considered statistically significant. A total of 585 AA and W women were diagnosed with breast cancers between the years 1990 and 1999. Mean ages were 51.8 years for AA and 56.9 years for W (P = 0.001). Overall survival (7.8 years AA and 7.6 years W) and survival by stage were not statistically different between the groups. AA patients were younger (P = 0.001), presented with higher-stage tumors (P = 0.017), more often had positive axillary lymph nodes (P = 0.012), more often were estrogen and progesterone receptor negative (P = 0.004), and more often were premenopausal (P = 0.048). AA women were more likely treated with chemotherapy while W women tended to receive hormone therapy (P = 0.01). Statistical significance was not reached for differences in tumor histology or tobacco exposure. We conclude that despite presenting with worse prognostic indicators AA women experience survival equivalent to their W counterparts.