Jeffrey D. Pearce

Clinical utility of the resistive index in atherosclerotic renovascular disease

OBJECTIVE This retrospective study examines the relationship between the renal resistive index (RI) and blood pressure and renal function response after open and percutaneous intervention for atherosclerotic renovascular disease (AS-RVD). METHODS From March 1997 to December 2005, 86 patients (46 women, 40 men; mean age, 68 +/- 10 years) underwent renal duplex sonography (RDS), including main renal artery and hilar vessel Doppler interrogation, before treatment of AS-RVD. Of these, 56 patients had open operative repair, and 30 had percutaneous intervention. The RI (1-[EDV/PSV]) was calculated from the kidney with the highest peak systolic velocity (PSV). Hypertension response was graded from preprocedural and postprocedural blood pressure measurements and medication requirements. Renal function response was graded by a >or=20% change in estimated glomerular filtration rate (eGFR) calculated from the serum creatinine concentration. RESULTS Comorbid conditions, baseline blood pressure, and preoperative renal function were not significantly different between open and percutaneous groups. Baseline characteristics that differed between the percutaneous vs open group were higher mean age (71 +/- 11 years vs 67 +/- 9 years; P = .05), kidney length (11.3 +/- 1.3 cm vs 10.7 +/- 1.2 cm; P = .02), proportion of patients with RI >or=0.8 (50% vs 21%; P = .01), and proportion of bilateral AS-RVD (37% vs 80%; P < .01). After controlling for preintervention blood pressure and extent of repair, postoperative eGFR differed significantly for RI <0.8 or >or=0.8 when all patients (P = .003) and percutaneous intervention (P = .008) were considered. Specifically, eGFR declined from preprocedure to postprocedure in the patients with RI >or=0.8 after percutaneous repair and in the group analyzed as a whole. Neither systolic nor diastolic pressure after intervention demonstrated an association with RI. Considering all patients and both groups, multivariable proportional hazards regression models demonstrated that RI was predictive of all-cause mortality. RI was the most powerful predictor of death during follow-up (hazard ratio, 6.7; 95% confidence interval, 2.6-17.2; P < .001). CONCLUSION After intervention for AS-RVD, RI was associated with renal function, but not blood pressure response. A strong, independent relationship between RI and mortality was observed for all patients and both treatment groups.

Restenosis after renal artery angioplasty and stenting: incidence and risk factors.

BACKGROUND Management of renal artery stenosis (RAS) with primary renal artery percutaneous angioplasty and stenting (RA-PTAS) is associated with a low risk of periprocedural death and major complications; however, restenosis develops in a subset of patients and repeat intervention may be required. We examined the incidence of restenosis after RA-PTAS and associations with clinical factors. METHODS Consecutive patients undergoing RA-PTAS for hemodynamically significant atherosclerotic RAS associated with hypertension or ischemic nephropathy, or both, between October 2003 and September 2007 were identified from a registry. Restenosis was defined using duplex ultrasound (DUS) imaging as a renal artery postintervention peak systolic velocity (PSV) >or=180 cm/s. The incidence and temporal distribution of restenosis was analyzed using survival analysis based on treated kidneys. Associations between clinical factors and recurrent stenosis were examined using proportional hazards regression. RESULTS RA-PTAS was performed on 112 kidneys for atherosclerotic RAS during the study period. Initial postintervention renal artery DUS imaging confirming PSV <180 cm/s in 101 kidneys, which formed the basis of this analysis. Estimated restenosis-free survival was 50% at 12 months and 40% at 18 months. Decreased risk of restenosis was associated with preoperative statin use (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.16-0.74; P = .006) and increased preoperative diastolic blood pressure (DBP; HR, 0.70 per 10-mm Hg increase in preoperative DBP; 95% CI, 0.49-0.99; P = .049). No other factors assessed were associated with restenosis. CONCLUSION Restenosis occurs in a substantial number of patients treated with RA-PTAS. Preoperative statin medication use and increased preoperative DBP are associated with reduced risk of restenosis. In the absence of contraindications, statins should be considered standard therapy for patients with atherosclerotic renal artery stenosis.

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.

Endovascular management of atherosclerotic renovascular disease: early results following primary intervention.

OBJECTIVE This retrospective review examines periprocedural morbidity and early functional responses to primary renal artery angioplasty and stenting (RA-PTAS) for patients with atherosclerotic renovascular disease (RVD). METHODS Consecutive patients undergoing primary RA-PTAS for hemodynamically significant atherosclerotic RVD with hypertension and/or ischemic nephropathy were identified from a prospectively maintained registry. Hypertension responses were determined based on pre- and post-intervention blood pressure measurements and medication requirements. Estimated glomerular filtration rate (eGFR) was used to determine renal function responses. Both hypertension and renal function responses were assessed at least three weeks after RA-PTAS. Stepwise multivariable regression analysis was used to examine associations between blood pressure and renal function responses to RA-PTAS and select clinical variables. RESULTS One-hundred ten primary RA-PTAS were performed on 99 patients with atherosclerotic RVD with a mean angiographic diameter-reducing stenosis of 79.2 +/- 12.9%. All patients had hypertension (mean of 3.4 +/- 1.3 antihypertensive agents). Mean pre-intervention eGFR was 49.9 +/- 22.7 mL/min/1.73 m(2), and 74 patients had a pre-intervention eGFR < 60 mL/min/1.73 m(2). The technical success rate for RA-PTAS was 94.5%. The periprocedural complication rate was 5.5%; there were no periprocedural deaths. Statistically significant decreases in mean systolic blood pressure (161.3 +/- 25.2 vs. 148.5 +/- 25.2 post-intervention, P < .0001), diastolic blood pressure (78.6 +/- 13.3 versus 72.5 +/- 13.5 post-intervention, P < .0001), and number of antihypertensive agents (3.3 +/- 1.2 versus 3.1+/- 1.3 post-intervention, P = .009) were observed. Assessed categorically, hypertension response to RA-PTAS was cured in 1.1%, improved in 20.5%, and unchanged in 78.4%. Categorical eGFR response to RA-PTAS was improved in 27.7%, unchanged in 65.1%, and worsened in 7.2%. Multivariable stepwise regression revealed associations between pre- and post-intervention systolic blood pressure (P < .0001), diastolic blood pressure (P < .0001), and eGFR (P < .0001), as well as a trend toward improved diastolic blood pressure response among patients managed with staged bilateral intervention (P = .0589). CONCLUSION Primary RA-PTAS for atherosclerotic RVD was associated with low peri-procedural morbidity and mortality but only modest early improvements in blood pressure and renal function. Results from ongoing prospective trials are needed to assess the long term outcomes associated with RA-PTAS and clarify its role in the management of atherosclerotic RVD.

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).

Atherosclerotic renovascular disease among hypertensive adults.

PURPOSE This report describes the change in atherosclerotic renovascular disease (AS-RVD) among hypertensive adults referred for renal duplex sonography (RDS) scan. METHODS From Oct 1993 through July 2008, 20,994 patients had RDS at our center. A total of 434 hypertensive patients with two or more RDS exams without intervention comprised the study cohort. Patient demographics (blood pressures, medications, serum creatinine levels, and data from RDS) were collected. Analyses of longitudinal changes in Doppler scan parameters, blood pressures, and renal function were performed by fitting linear growth-curve models. After confirming the linearity of change in Doppler scan parameters among patients with variable number of studies, estimates of mean slopes were calculated using maximum likelihood techniques. For changes in renal function, quadratic growth curves were required to describe longitudinal change. RESULTS A total of 434 subjects (212 men [49%] and 222 women [51%]; mean age, 64.6 +/- 12.2 years) provided 1351 studies (mean, 3.2 +/- 2.4; range, 2 to 18) for 863 kidneys over a mean follow-up of 34.4 +/- 25.1 months. At baseline, 20.6% of kidneys demonstrated hemodynamically significant stenosis. On follow-up, 72 kidneys (9.1%) demonstrated anatomic progression of disease. A total of 54 kidneys (6.9%) progressed to significant stenosis and 18 (2.3%) progressed to occlusion. Controlling for progression of disease, baseline renal artery status demonstrated a strong association with baseline kidney length (P = .0006). Significant annualized change in renal length was observed (cm change/year +/- standard error of the mean [SEM]: 0.042 +/- 0.011; P = .0002) among both kidneys with and without critical disease at baseline, however, decline in length was significantly greater among kidneys exhibiting progression of renovascular disease (-0.152 +/- 0.028 cm/year; comparison of slopes between groups P = .0005). In the absence of progression, the presence or absence of critical renal artery stenosis at baseline did not affect the rate of decline in renal length. Fitted models for the natural log transform of serum creatinine demonstrated a significant increase during follow-up (P < .0001). No association was observed between change in serum creatinine and baseline renovascular disease status, or its progression. CONCLUSION A total of 32% of hypertensive adults referred for RDS demonstrated hemodynamically significant renal artery stenosis. Regardless of the presence or absence of baseline disease, a small percentage of patients demonstrated anatomic progression of AS-RVD. A total of 9.1% demonstrated anatomic progression and 2.3% progressed to occlusion. Although anatomic progression of AS-RVD was associated with an increased rate of decline in renal length, progression did not predict a decline in excretory renal function. Intervention for AS-RVD should be selective and reserved for strict indications.

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.