Management of ischemic nephropathy: dialysis-free survival after surgical repair.

PURPOSE: This retrospective review describes the surgical management of consecutive patients with severe hypertension and ischemic nephropathy due to atherosclerotic renovascular disease. METHODS: From January 1987 through December 1998, a total of 590 patients underwent operative renal artery repair at our center. A subgroup of 232 hypertensive patients (97 women, 135 men; mean age, 66 +/- 8 years) with atherosclerotic renovascular disease and preoperative serum creatinine levels of 1.8 mg/dL or more forms the basis of this report. Change in renal function was determined from glomerular filtration rates estimated from preoperative and postoperative serum creatinine. The influence of selected preoperative parameters and renal function response on time to dialysis and dialysis-free survival was determined by a proportional hazards regression model. RESULTS: In all, 83 patients underwent unilateral renal artery repair and 149 patients underwent bilateral repair, including repair to a solitary kidney in 17 cases. A total of 332 renal arteries were reconstructed, and 32 nephrectomies were performed in these patients. After surgery, there were 17 deaths (7.3%) in the hospital or within 30 days of surgery. Advanced patient age (P =.001; hazard ratio, 1.1; 95% CI [1.1, 1.2]) and congestive heart failure (P =.04; hazard ratio, 2.9 CI [1.0, 8.6]) demonstrated significant and independent associations with perioperative mortality. With a change of 20% or more in EGFR being considered significant, 58% of patients had improved renal function, including 27 patients removed from dialysis dependence; function was unchanged in 35% and worsened in 7%. Follow-up death from all causes or progression to dialysis dependence demonstrated a significant and independent association with early renal function response. Both patients whose function was unchanged (P =.005; hazard ratio, 6.0; CI [2.2, 16.6]) and patients whose function was worsened (P =.03; hazard ratio, 2.2; CI [1.1, 4. 5]) remained at increased risk of death or dialysis dependence. For patients with unchanged renal function after operation, risk of death or dialysis demonstrated a significant interaction with preoperative renal function. In addition to severe preoperative renal dysfunction, diabetes mellitus demonstrated a significant and independent association with follow-up death or dialysis. CONCLUSION: Surgical correction of atherosclerotic renovascular disease can retrieve excretory renal function in selected hypertensive patients with ischemic nephropathy. Patients with improved renal function had a significant and independent increase in dialysis-free survival in comparison with patients whose function was unchanged and patients whose function was worsened after operation. These results add further evidence in support of a prospective, randomized trial designed to define the value of renal artery intervention in patients with ischemic nephropathy.

Aneurysmal degeneration and late rupture of an aortorenal vein graft: case report, review of the literature, and implications for conduit selection.

The saphenous vein is among the most commonly used conduits for renal artery revascularization in adults. Vein grafts are more durable in the renal artery bed than in coronary and peripheral beds, and mechanisms of potential graft failure vary. Coronary vein grafts often fail because of atherosclerotic degeneration, whereas lower extremity grafts fail because of intimal hyperplasia or progression of underlying disease. In contrast, renal vein grafts may dilate over time but seldom fail. This may relate to the distinct hemodynamic environment of the renal bed with low-resistance, high-velocity blood flow. However, frank aneurysmal degeneration of renal vein grafts is rare with only a single report of rupture in the literature. We report an additional case of rupture of a late graft aneurysm and review the literature and our own experience with renal revascularization to underscore the rarity of this serious complication. The saphenous vein for aortorenal bypass grafting continues to be a favorable conduit for renal revascularization. Long-term duplex ultrasound scanning follow-up is recommended to survey the reconstructed artery and perhaps more important, to evaluate progression of subclinical disease in the contralateral renal artery.

Inhibition of early atherogenesis by losartan in monkeys with diet-induced hypercholesterolemia.

BACKGROUND: Angiotensin II may contribute to atherogenesis by facilitating the proliferative and inflammatory response to hypercholesterolemia. This study determined, in a primate model of diet-induced atherosclerosis, the effect of AT(1) blockade on fatty-streak formation, plasma lipids, and surrogate markers of vascular injury. METHODS AND RESULTS: Male cynomolgus monkeys fed a diet containing 0.067 mg cholesterol/kJ for 20 weeks were given losartan (180 mg/d, n=6) or vehicle (n=8) for 6 weeks starting at week 12 of the dietary regimen. Arterial pressure, heart rate, plasma total and lipoprotein cholesterol concentrations, and lipoprotein particle sizes and subclass distributions were unaffected by treatment. Losartan caused significant (P<0.05) increases in plasma angiotensin II and angiotensin-(1-7). Compared with vehicle-treated controls, losartan reduced the extent of fatty streak in the aorta, the coronary arteries, and the carotid arteries by approximately 50% (P<0.05). A significant (P<0.05) reduction in the susceptibility of LDL to in vitro oxidation, serum levels of monocyte chemoattractant protein-1, and circulating monocyte CD11b expression were also associated with losartan treatment. In addition, serum levels of vascular cell adhesion molecule-1 and E-selectin did not change during treatment but increased after discontinuation of losartan. Serum C-reactive protein, platelet aggregability, and white cell counts were not modified by losartan. CONCLUSIONS: This study demonstrates for the first time an antiatherogenic effect of AT(1) receptor blockade in nonhuman primates. Losartan inhibited fatty-streak formation through mechanisms that may include protection of LDL from oxidation and suppression of vascular monocyte activation and recruitment factors.

Angiotensin-converting enzyme expression in human carotid artery atherosclerosis.

Angiotensin-converting enzyme (ACE) inhibitors reduce the progression of atherosclerosis in animal models and reinfarction rates after myocardial infarction in humans. Although expression of components of the renin-angiotensin system has been reported in human coronary arteries, no data regarding their presence in carotid arteries, a frequent site for the occurrence of atherosclerosis plaques, are available. The following study sought to determine whether ACE mRNA and protein can be detected in human carotid atheromatous lesions. Twenty-four intact endarterectomy specimens were obtained from patients with severe carotid occlusive disease (17 males and 7 females, aged 68+/-1 years) and fixed within 30 minutes. Carotid artery specimens contained advanced Stary type V and VI lesions, and human ACE mRNA expression and protein were localized in cross sections by the combination of in situ hybridization and immunohistochemistry. Cell type-specific antibodies were used to colocalize ACE to smooth muscle cells, endothelial cells, macrophages, or lymphocytes. ACE protein was localized in the intima, whereas the overlying media was largely free of ACE staining. In less complicated lesions, ACE staining was modest and could be visualized in scattered clusters of macrophages and on the luminal side of carotid artery vascular endothelium. Smooth muscle cells were largely negative. ACE staining increased as lesions became more complex and was most prominent in macrophage-rich regions. The shoulder regions of plaques contained numerous ACE-positive macrophage foam cells and lymphocytes. In these areas, microvessels were positive for endothelial cell and smooth muscle cell ACE expression. However, microvessels in plaques free of inflammatory cells were stained only faintly for ACE expression. Labeling for ACE mRNA mirrored the pattern of protein expression, localizing ACE mRNA to macrophages and microvessels within the intima. In conclusion, atherosclerosis alters carotid artery ACE production, increasing transcription and translation within regions of plaque inflammation. These data provide another important mechanism by which inflammation associated with increased ACE expression may contribute to the progression of atherosclerosis.

Novel mechanisms linking angiotensin II and early atherogenesis.

We propose that Ang II exerts an as yet uncharacterized immunomodulatory effect on monocyte maturation, differentiation, or extravasation, which may depend on the myelomonocytic phenotype. Since the myelopoietic process originating at stem cells and culminating in release to the blood is at least 6 days, it is conceivable that the observation of reduced monocyte CD11b expression two weeks after completion of losartan treatment indicates a suppression of the CD11b phenotype in newly released CD14(+)/CD45(+) monocytes. Other studies employing suppression of AT(1)-receptors with deoxy-oligonucleotides have reported effects on blood pressure that surpass those predicted by the duration of the treatment.(87) These data would suggest that it is possible to interrupt a stimulatory signal by Ang II through a gene-related mechanism that in our experiments may reside in the mechanisms that regulate myelopoiesis. While our knowledge of the role of Ang II in the regulation of monocyte formation and function is incomplete, we have taken a first step in attempting to synthesize the data described above into a comprehensive hypothesis for further evaluation of the factors that initiate atherogenesis. Such effects may crucially contribute to the clinical benefit of AT(1)-receptor antagonists, independent of depressor effects, and may represent a paradigm for novel, anti-inflammatory actions by this class of drugs.

Surgery after failed percutaneous renal artery angioplasty.

PURPOSE: This retrospective review describes the surgical management of 51 patients after failed percutaneous renal artery angioplasty (F-PTRA). METHODS: From January 1987 through June 1998, 51 consecutive patients underwent surgical repair of either atherosclerotic (32 patients) or fibromuscular dysplastic (FMD; 19 patients) renovascular vascular disease after F-PTRA. These patients form the basis of this report. Surgical repair was performed for hypertension (29 patients with atherosclerosis: mean blood pressure, 205 +/- 34/110 +/- 23 mm Hg; 18 patients with FMD: mean blood pressure, 194 +/- 24/118 +/- 18 mm Hg) or ischemic nephropathy (20 patients with atherosclerosis: mean serum creatinine level, 2.0 +/- 0.8 mg/dL; three patients with FMD: mean serum creatinine level, 2.0 +/- 1.1 mg/dL). Emergency operation was required in four patients for acute renal artery thrombosis (one patient with atherosclerosis, one patient with FMD), renal artery rupture (one patient with atherosclerosis), or infected pseudoaneurysm (one patient with atherosclerosis). Operative management, blood pressure and renal function response to operation, and dialysis-free survival rate were examined and compared with 487 patients (441 patients with atherosclerosis, 46 patients with FMD) treated by operation alone. RESULTS: Among the patients with atherosclerotic renovascular disease, there were three postoperative deaths (9.4%) after repair for F-PTRA. Secondary operative repair was associated with emergent repair or nephrectomy in 16% of cases, while more extensive renal artery exposure and more complex operative management was required in 50% of patients with atherosclerosis and 65% of patients with FMD repaired electively. Among the 28 operative survivors with hypertension and atherosclerotic renovascular disease, blood pressure benefit after F-PTRA was significantly lower when compared with patients with atherosclerosis who underwent treatment with operation only (57% vs 89%; P <.001). However, blood pressure benefit in the 19 patients with FMD did not differ (89% vs 96%). Among the 28 patients with atherosclerosis, preoperative estimated glomerular filtration rate (EGFR) as compared with postoperative EGFR was significantly increased (47.4 +/- 4.2 mL/min/1.73m(2) vs 56. 6 +/- 5.1 mL/min/1.73m(2); P =.002). However, EGFR prior to PTRA was not significantly different from postoperative EGFR (51.6 +/- 3.4 mL/min/1.73m(2) vs 56.6 +/- 4.9 mL/min/1.73m(2); P =.121). As compared with patients with atherosclerosis who underwent treatment with operation alone, there was no difference in the dialysis-free survival rate. CONCLUSION: Operative repair after F-PTRA was altered in 59% of the patients with atherosclerosis and in 68% of patients with FMD. Blood pressure benefit for patients with FMD was unchanged after F-PTRA. However, the blood pressure benefit was significantly decreased among patients with atherosclerosis. Decreased EGFR after F-PTRA was recovered with operative renal artery repair. However, postoperative EGFR as compared with EGFR prior to PTRA was unchanged. Blood pressure and renal function response after F-PTRA for atherosclerotic renovascular disease warrants further study.

Chronic renal artery occlusion: nephrectomy versus revascularization.

PURPOSE: The surgical management of chronic atherosclerotic renal artery occlusion (RA-OCC) was studied. METHODS: From January 1987 through December 1996, 397 consecutive patients were treated for atherosclerotic renal artery disease. Ninety-five hypertensive patients (mean blood pressure, 204 +/- 31/106 +/- 20 mm Hg; mean medications, 3.0 +/- 1.1 drugs) were treated for 100 RA-OCCs. Eighty-four (88%) patients had renal dysfunction, defined by serum creatinine levels >/=1.3 mg/dL (mean serum creatinine level, 2.8 +/- 2.0 mg/dL). Demographic characteristics, operative morbidity and mortality, blood pressure/renal function response, and postoperative decline in renal function were examined and compared with that of 302 patients treated for renal artery stenosis (RAS). RESULTS: After operation, there were 5 perioperative deaths (5.2%), 2 (2.8%) after revascularization and 3 (12%) after nephrectomy (P =.11), compared with 12 (4.0%) perioperative deaths in the RAS group (P =.59). After controlling for important covariates, estimated survival and blood pressure benefits did not differ between RA-OCC patients treated by nephrectomy or revascularization (P =.13; 87% vs 92%, P =.54). Excretory renal function was considered improved in 49% of 79 RA-OCC patients with renal dysfunction, including 9 patients removed from dialysis-dependence. Among patients treated for unilateral disease, revascularization for RA-OCC was associated with significant improvement in renal function (P <.01); however, nephrectomy alone did not increase renal function significantly. Improved renal function after operation was associated with a significant and independent increase in survival (P <.01) and dialysis-free survival (P <.01) among patients treated for RA-OCC. In addition, blood pressure benefit, renal function response, and estimated survival did not differ significantly after reconstruction for RA-OCC or RAS. CONCLUSION: Among hypertensive patients treated for RA-OCC, equivalent beneficial blood pressure response was observed after both revascularization and nephrectomy. In patients who underwent bilateral renal artery revascularization, the change in excretory renal function attributable to repair of RA-OCC cannot be defined. In patients treated for unilateral disease, however, improvement in function was observed only after revascularization. Moreover, improved renal function demonstrated a significant and independent association with improved survival. This experience supports renal revascularization in preference to nephrectomy for RA-OCC in select hypertensive patients when a normal distal artery is demonstrated at operation.

Novel angiotensin peptides regulate blood pressure, endothelial function, and natriuresis.

Accumulating evidence suggests that angiotensin-(1-7) is an important component of the renin-angiotensin system, having actions that are either identical to or opposite that of angiotensin II. Angiotensin I can be directly converted to angiotensin-(1-7), bypassing formation of angiotensin II. This pathway is under the control of three enzymes: neutral endopeptidases 24.11 (neprilysin) and 24.15 and prolyl-endopeptidase 24.26. Two of the three angiotensin-forming enzymes (neprilysin and endopeptidase 24.15) also contribute to the breakdown of bradykinin and the atrial natriuretic peptide. Furthermore, angiotensin-(1-7) is a major substrate for angiotensin-converting enzyme. These observations suggest that the process of biotransformation between the various Ang peptides of the renin-angiotensin system and other vasodepressor peptides are intertwined through this enzymatic pathway. Substantial evidence suggests that angiotensin-(1-7) stimulates the synthesis and release of vasodilator prostaglandins, and nitric oxide, while also augmenting the metabolic actions of bradykinin. In addition, angiotensin-(1-7) alters tubular sodium and bicarbonate reabsorption, decreases Na+-K+-ATPase activity, induces diuresis, and exerts a vasodilator effect. These physiologic effects of angiotensin-(1-7) favor a blood pressure-lowering effect. The majority of the data currently available suggest that angiotensin-(1-7) mediates its effects through a novel non-AT1/AT2 receptor subtype.

Renal artery repair: consequence of operative failures.

OBJECTIVE: This report examines the blood pressure and renal function response in 20 consecutive patients after secondary renal revascularization following failed operative repair. SUMMARY BACKGROUND DATA: Most reports describing operative failure of renal artery (RA) repair emphasize the technical aspects of redo RA reconstruction and the immediate blood-pressure response to secondary operation. This report examines the eventual renal function and estimated survival after secondary intervention. METHODS: Primary methods of RA reconstruction, primary blood pressure and renal function responses, and causes of failed RA repair were defined for 20 patients requiring reoperation for recurrent hypertension or renal insufficiency. These parameters were compared with secondary procedures and eventual blood pressure and renal function response. The eventual outcome for these 20 patients was compared with 514 patients managed by primary renal revascularization during the same period. RESULTS: Failure of primary RA repair correlated with complex fibromuscular dysplasia requiring branch ex vivo reconstruction (p = 0.020). RA thrombosis frequently required nephrectomy (83%), whereas RA stenosis was successfully reconstructed (91 %; p = 0.001). Primary and secondary blood-pressure responses were equivalent (94% vs. 95% cured or improved); however, primary and eventual renal function responses differed significantly (p = 0.015), with seven patients dialysis-dependent on follow-up. Eventual dialysis dependence was associated with preoperative azotemia (p = 0.022), bilateral failure of primary RA repair (p = 0.007), and an increased risk of follow-up death (p = 0.002). Considering all 534 patients, failed RA repair demonstrated a significant and independent association with eventual dialysis dependence and decreased dialysis-free survival. CONCLUSIONS: Contemporary rates of reoperation after surgical RA repair are low. In properly selected patients, beneficial blood-pressure response is reliably observed after both primary and secondary operative procedures. However, secondary procedures are associated with a significant and independent risk of eventual dialysis dependence.

Renovascular disease in blacks: prevalence and result of operative management. Consortium of Southeastern Hypertension Control.

Hypertension in blacks differs in a quantitative sense from hypertension in whites; it occurs in blacks with greater frequency and severity and at a younger age when compared with whites. In addition, elevated blood pressure at any level is associated with increased cardiovascular morbidity and mortality in black patients. Several mechanisms have been suggested to account for this form of hypertension, implying that hypertension in black patients is intrinsically different from that in whites. Although these mechanisms remain unproven, it has generally been accepted that correctable renovascular disease and renovascular hypertension (RVH) occur infrequently in blacks; the authors, however, will review preliminary population-based data which suggest that the presence of renal artery disease is not determined by race or ethnicity. In addition, the prevalence of renovascular disease in a large group of consecutive hypertensive subjects will be presented. Finally, the blood pressure and renal function response after surgical renal artery repair in blacks will be compared with whites treated at the authors' institution. Taken collectively, these data and clinical experience support the search for and treatment of renal artery disease in properly selected hypertensive blacks.

Characterization of angiotensin-(1-7) in the urine of normal and essential hypertensive subjects.

A total of 31 healthy volunteers [39 +/- 7 (SD) years] and 18 untreated essential hypertensive subjects [43 +/- 9 years] collected urine for 24 h after a physical examination and laboratory tests. Radioimmunoassay measurements of angiotensin-(1-7) [Ang-(1-7)] in urine and plasma were done as described previously. Sitting systolic and diastolic blood pressures (+/- SD) averaged 118 +/- 11/74 +/- 7 mm Hg and 146 +/- 16/96 +/- 8 mm Hg in normal and essential hypertensive subjects, respectively (P < .001), whereas 24 h urinary volume was not different in normal and essential hypertensive subjects (P > .05). The concentration of Ang-(1-7) in the urine of normal subjects averaged 62.6 +/- 22.6 pmol/L corresponding to a urinary excretion rate of 98.9 +/- 44.7 pmol/24 h. Concurrent measurements of plasma Ang-(1-7) showed that the content of Ang-(1-7) in urine was 2.5-fold higher than that measured in the plasma. In contrast, untreated essential hypertensive subjects had lower concentrations and 24 h urinary excretion rates of Ang-(1-7) averaging 39.4 +/- 18.0 pmol/L and 60.2 +/- 14.6 pmol/24 h, respectively, (P < .001). Differences in the excretory rate of Ang-(1-7) between normal volunteers and essential hypertensive subjects were not modified by normalization of the data by urinary creatinine excretion rates. Urinary concentrations of Ang-(1-7) correlated inversely with systolic, diastolic and mean arterial pressures (r = -0.48, P < .001). Both urinary Ang-(1-7) [odds ratio of 0.92 (95% CI: 0.88-0.97)] and age were independent predictors of systolic blood pressure. These studies demonstrated the presence of Ang-(1-7) in urine and the existence of reduced levels of the heptapeptide in individuals with untreated essential hypertension. The relatively higher concentrations of Ang-(1-7) in urine compared to plasma agrees with data that showed that Ang-(1-7) may contribute to the regulation of blood pressure. The inverse association between Ang-(1-7) and arterial pressure provides a potential marker for the characterization of forms of essential hypertension associated with reduced production or activity of vasodilator hormones.

Wound healing: a paradigm for lumen narrowing after arterial reconstruction.

PURPOSE: The intimal hyperplasia hypothesis that equates lumen narrowing after arterial injury with intimal mass has recently been challenged. Evidence has emerged to suggest that lumen narrowing is caused in large part by changes in artery wall geometry rather than intimal mass per se. We have begun to explore this hypothesis in a unique nonhuman primate model of atherosclerosis. METHODS: Monkeys who were fed an atherogenic diet for 3 to 5 years underwent experimental angioplasty of the left iliac artery. The contralateral iliac artery served as an intraanimal control. Arteries were removed 2, 4, 7, 14, 28, or 112 days later for analysis (6 or 13 per time point). Angioplasty dilated arteries by fracturing atheroma and stretching or tearing the media. Cross-sections of injured arteries were analyzed for expression of extracellular matrix components and cell surface integrins that are important in wound healing. Antibodies, riboprobes, or histochemical stains specific for fibrin, hyaluronan, versican (chondroitin sulfate-containing proteoglycan), procollagen-I, elastin, and the alpha 2 beta 1 and alpha V beta 3 integrins were used. RESULTS: A thin mural thrombus was seen at sites of denudation and plaque fracture (days 2 to 7). This provisional matrix was invaded by leukocytes (days 2 to 4) and alpha-actin-positive smooth muscle cells (SMCs; days 4 to 7). Thrombus was replaced by SMCs expressing hyaluronan and the associated versican proteoglycans (day 14). Versican was expressed throughout the neointima as it enlarged (day 28), but expression later subsided (day 112). Procollagen-I expression initially increased in the adventitia (day 4) and then in the forming neointima (day 14). Procollagen-I expression was found to persist within the adventitia and in the neointima in SMCs nearest the lumen (days 28 to 112). Elastin staining was prominent within the mature neointima (day 112) but not at earlier time points. Integrin expression also increased within the injured artery wall. alpha v beta 3 staining (fibrin[ogen] receptor) increased in the injured media (days 2 to 7) and was then seen throughout the early neointima (day 7). Low level expression of alpha V beta 3 subsequently persisted within the forming neointima (day 28). alpha 2 beta 1 (collagen receptor) expression increased in the neointima in SMCs nearest the lumen (day 28). CONCLUSIONS: Lumen narrowing after angioplasty in this model of atherosclerosis is caused largely by decreased artery wall diameter. The pattern of matrix and integrin expression within the injured artery wall is in many ways analogous to that of healing wounds. These observations suggest that tissue contraction may play a role in lumen narrowing at sites of arterial reconstruction. Strategies to inhibit wound contraction may prove effective in preventing restenosis.

Structural determinants of lumen narrowing after angioplasty in atherosclerotic nonhuman primates.

PURPOSE: The relationship between lumen narrowing, intimal hyperplasia, and wall remodeling after angioplasty was explored in a nonhuman primate model of atherosclerosis. METHODS: Cynomolgus monkeys (n = 37) used in long-term atherosclerosis studies underwent left iliac artery balloon injury. The uninjured right iliac artery served as a reference segment for intraanimal comparisons. One month later iliac arteries were fixed by perfusion (100 mm Hg) and removed for cross-sectional analysis to determine mean values for lumen area (LA), intimal area (IA), internal elastic lamina area (IELA), plaque burden (IA/IELA), and depth of wall injury. Values for each balloon-injured iliac artery were normalized to the contralateral uninjured iliac artery (percent of control), and linear regression analysis was performed comparing LA with IA, with IELA, and with depth of injury. Comparisons were also made between those arteries that remained dilated 1 month after balloon injury (LA > or = 140%; n = 13) and those that renarrowed (LA < or = 100%; n = 14). RESULTS: For all 37 animals, LA 1 month after balloon injury correlated well with IELA (r = 0.72; p < 0.001) but not with IA (r = 0.10; p = 0.54), suggesting that changes in artery size rather than neointimal mass determined lumen caliber. When comparing arteries that remained dilated (n = 13) with those that renarrowed (n = 14), there were no differences in depth of wall injury (injury depth: 0, no injury; 1, intima; 2, IEL; 3, media; 4, EEL; 2.1 +/- 0.3 vs 1.6 +/- 0.3; p = 0.12), neointimal accumulation (IA, 507% +/- 118% vs. 421% +/- 81% of control; p = 0.55), or plaque burden (IA/IELA, 0.39 +/- 0.04 vs 0.37 +/- 0.06; p = 0.71), respectively. However, wall size defined as IELA was significantly smaller in arteries that renarrowed than in those that remained dilated (IELA, 115% +/- 14% vs 230% +/- 19% of control; p < 0.001). CONCLUSIONS: Restenosis after angioplasty has been attributed to intimal hyperplasia, equating loss of lumen caliber with neointimal mass. The data presented herein suggest that lumen narrowing after arterial wall injury may have little to do with intimal mass per se, but rather that a change in wall caliber or wall narrowing is the cause of restenosis.

Renal artery repair in African-Americans.

PURPOSE: This retrospective review examines the results of atherosclerotic renal artery (RA) repair in consecutive hypertensive African-Americans treated at our center and compares these results with Caucasians treated during the same period. METHODS: From Jan. 1987 through Sep. 1996, a total of 485 patients underwent operative RA repair. Of these, 28 African-Americans and 370 Caucasians were managed for atherosclerotic renovascular disease. These cohorts were compared on the basis of preoperative blood pressure and renal function, extent of renal disease, extrarenal atherosclerosis, response to operation, and estimated survival. RESULTS: The African-American cohort included nine men and 19 women (mean age, 62 years) with hypertension (mean blood pressure, 204 +/- 31/109 +/- 20 mm Hg) for an average of 10.2 +/- 7.5 years. Ischemic nephropathy (serum creatinine level, > 1.3 mg/dl) was present in 82% (n = 23) of the African-American group. RA reconstructions were unilateral in nine patients and bilateral in 19 patients (including repair to two solitary kidneys), for a total of 45 RA reconstructions (30 RA bypass procedures; eight transrenal/transaortic RA endarterectomy procedures; two RA reimplantations; five nephrectomies). Nine patients underwent combined aortic procedures (four abdominal aortic aneurysm; five occlusive disease). There was one perioperative death in the African-American group as a result of sepsis and multiple organ failure. Among surgical survivors, 20 African-American patients (74%) had a beneficial hypertension response (7% cured, 67% improved). Mean estimated glomerular filtration rate improved significantly from 34 to 42 ml/min/1.73 m2 (p < 0.001). In the 23 patients with ischemic nephropathy, 13 (57%) demonstrated greater than 20% decrease in serum creatinine level. In comparison with the 370 Caucasians (191 men, 179 women), the African-American cohort had significantly more preoperative heart disease (congestive heart failure or left ventricular hypertrophy; 68% vs 46%; p = 0.03) and tended toward more severe renal dysfunction (mean serum creatinine level, 2.5 vs 2.1 mg/dl; p = 0.25). However, African-Americans demonstrated a beneficial blood pressure and renal function response after operation, similar to Caucasians. CONCLUSIONS: Our results indicate that the majority of selected African-Americans have a favorable blood pressure and renal function response to operative renal artery repair. This beneficial clinical response appears equivalent to the response observed in Caucasian patients and supports the search for RA disease in hypertensive African-Americans.

Platelet-derived growth factor ligand and receptor expression in response to altered blood flow in vivo.

Blood flow and the tractive force shear stress are important determinants of artery caliber, and reduced shear predisposes arteries to intimal thickening and atherosclerosis. The molecular basis for shear-induced changes in artery wall structure is poorly defined. A number of factors associated with normal and pathological artery wall remodeling are induced by shear stress in endothelial cell cultures. These include platelet-derived growth factor (PDGF), a potent mitogen, chemoattractant, and vasoconstrictor. To determine whether similar changes occur in vivo, we examined the effects of reduced blood flow on endothelial cell PDGF expression and proliferation in the rat carotid artery. Branches of the right internal and external carotid arteries were ligated, reducing common carotid artery blood flow from 8.0+/-0.6 to 0.5+/-0.1 mL/min while increasing flow in the left carotid from 7.1+/-0.6 to 10.8+/-0.7 mL/min. Shear stress following the procedure was 1.4+/-0.2 and 33.4+/-1.1 dyne/cm2 in carotids with reduced blood flow (RF) and increased blood flow (IF), respectively. Arteries were harvested 6, 24, 48, or 72 hours after ligation, perfusion-fixed, and opened longitudinally. Endothelial cell proliferation (bromodeoxyuridine [BrdU] labeling) was assessed en face at 24, 48, and 72 hours; expression of mRNA for PDGF-A and -B chains and PDGF alpha- and beta-receptors (in situ hybridization) was determined at 6, 48, and 72 hours after unilateral flow reduction. RF induced endothelial cell proliferation, which peaked at 48 hours (RF BrdU labeling: 24 hours, 0.4+/-0.2%; 48 hours, 7.2+/-2.0%; and 72 hours, 4.1+/-0.6%; n=5). PDGF-B expression increased in RF compared with IF endothelium within 48 hours and persisted at 72 hours (percent labeling [RF/IFx100]: 6 hours, 76+/-20%; 48 hours, 395+/-179%; and 72 hours, 208+/-44%; n=3). PDGF-A expression was similarly increased in RF endothelium. In contrast, expression of PDGF alpha- and beta-receptors was undetectable in RF and IF endothelium at all times. We conclude that endothelial cell PDGF ligand expression is induced by reduced shear stress in vivo and may play an important role in flow-mediated remodeling and atherogenesis.

Adeno-associated virus vectors for vascular gene delivery.

A variety of delivery systems have been used to genetically modify vascular endothelial cells and smooth muscle cells (SMCs), but currently available systems suffer from either inefficient in vivo gene transfer, transient episomal vector expression, or significant immune responses and inflammation. In the present study, we evaluated an alternate vector system, recombinant adeno-associated virus (rAAV) for transduction of vascular cells in culture and in vivo. Primary cultures of rabbit, monkey, and human SMCs; macaque and human microvascular endothelial cells; and human umbilical vein endothelial cells were efficiently transduced at a dose of 100 to 1000 DNase-resistant particles per cell. rAAV-mediated transduction of the vasculature in vivo was observed after intraluminal gene delivery or after intra-adventitial injection in carotid arteries of atherosclerotic cynomolgus monkeys. Whether vector delivery was intraluminal or adventitial, transduction was observed in the adventitia, particularly within microvessels (vasa vasorum) but not in cells of the intima or media. Transduction of adventitial microvessels was enhanced by balloon injury 4 days before gene transfer. This was particularly true for adventitial delivery. We have previously shown that adventitial cell proliferation increases significantly 4 days after balloon injury (45%) in this animal model. Together, these data suggest that cell proliferation may enhance AAV transduction in vivo in the vasculature. AAV vectors exhibited a tropism in vivo for the microvascular endothelium at the doses used in the present study, which may provide the opportunity for targeting gene delivery. In summary, we have demonstrated the utility of rAAV vectors for ex vivo vascular cell gene delivery and present an initial experience with rAAV for in vivo vascular gene delivery. This alternate vector system may overcome some of the limitations hampering the development of gene therapy for vascular disorders.

Endothelial injury in transgenic (mRen-2)27 hypertensive rats.

Transgenic [(mRen-2)27] rats develop severe hypertension as the result of transfection with the mouse Ren-2 gene. This study tested the hypothesis that hypertensive [(mRen-2)27] rats have increased endothelial dysfunction by examining the extent of vascular endothelial cell injury and turnover within the thoracic aorta of age-matched female transgene positive [Tg(+)] and transgene negative [Tg(-)] littermates. Transgenic hypertensive rats had arterial pressures significantly higher than Tg(-) animals, but no differences in heart rate or body weight. The extent of endothelial cell injury was estimated in Haütchen preparations of thoracic aorta endothelium by counting cells immunostained for the presence of cytoplasmic immunoglobulin G (IgG) at sites with or without intercostal artery branches. Both Tg(+) and Tg(-) littermates had a greater percentage of injured endothelial cells at branch sites than at nonbranch aorta (P < .01). However, the number of vascular endothelial cells staining positively for IgG was significantly higher in hypertensive rats both at sites away from (P < .05) and in the immediate vicinity of (P < .1) the orifices of intercostal arteries. En face preparations of the thoracic aorta were also examined for cells incorporating 5-bromo-2 '-deoxyuridine (BrdU) to estimate the percentage of endothelial cells undergoing replication. There was no difference in endothelial cell replication at either branch or nonbranch sites between hypertensive and normotensive rats. However, the percentage of endothelial cells undergoing replication at branch sites in both Tg(+) and Tg(-) rats was significantly greater than at nonbranch sites (P < .01). These data provide the first demonstration for the effects of high blood pressure on the vascular endothelium of a monogenetic model of hypertension produced by increased activity of the renin-angiotensin system. The divergent effects of this form of hypertension on vascular endothelial injury and endothelial turnover suggest that the decrease in the reparative capacity of the vascular endothelium induced by the combination of hypertension and associated angiotensinemia may contribute to the endothelial dysfunction accompanying vascular remodeling.

Is renal revascularization in diabetic patients worthwhile?

PURPOSE: This retrospective review describes surgical management of atherosclerotic renovascular disease (RVD) in hypertensive adults with diabetes mellitus. METHODS: From July 1987 through July 1995, 54 consecutive hypertensive diabetics (mean 213/103 mm Hg; mean medications three drugs) requiring either insulin (16 patients) or oral hypoglycemic therapy (38 patients) had operative repair of atherosclerotic RVD. Renal dysfunction (serum creatinine [SCr] > or = 1.3 mg/dl) was present in 82% of patients (mean SCr 2.4 mg/dl). Associations between blood pressure and renal function response to operation and preoperative parameters were examined. Clinical characteristics, response to operation, and dialysis-free survival were compared with those of 291 nondiabetic patients. RESULTS: Four (7.4%) operative deaths occurred. Among 50 survivors blood pressure response was considered cured or improved in 72% and unchanged in 28%. Of 42 patients with renal dysfunction 40% had improved function including three patients removed from dialysis. No preoperative parameter examined demonstrated a significant association with blood pressure or renal function response. During follow-up 10 additional patient deaths occurred, and eight patients progressed to dialysis dependence. Time to death or dialysis was associated with preoperative estimates of glomerular filtration (p = 0.03) and the change in estimates of glomerular filtration after operation (p = 0.01). Compared with 291 nondiabetics, the diabetic group had no statistical difference in improved function response (40% vs 51%, p = 0.21); however, diabetics had a significantly lower rate of beneficial blood pressure response (72% vs 89%, p = 0.01) and an increased risk of dialysis or death during follow-up (p = 0.02). By multivariate analysis independent predictors of time to death or dialysis included the presence of diabetes mellitus, patient age, history of congestive heart failure, and increased serum creatinine. CONCLUSIONS: Most of the selected diabetic patients had a beneficial blood pressure response after undergoing operative repair of atherosclerotic RVD, albeit at a lower rate compared with nondiabetics. In diabetics poor renal function before and after operation was associated with progression to dialysis and death. Improved renal function after operation was associated with improved survival; however, function response to renal revascularization was difficult to predict.