Ute Brehme

Tc-99m-labeled endothelin derivative for imaging of experimentally induced atherosclerosis

OBJECTIVE to characterize the potential of an endothelin derivative labeled with technetium-99m (Tc-99m) for the imaging of experimentally induced atherosclerosis. METHODS neointima of different cellularity and severity of stenosis was induced in 32 rabbits by balloon denudation followed by distinct dietary regimens and drug application. Angiograms and scintigrams after injection of the Tc-99m-labeled endothelin derivative were obtained. The aorta was dissected for autoradiography, sudan-III-staining, morphometry, and immunohistology. RESULTS the lesions induced could be detected in vivo (whole body scintigram) in all the animals 15 min after the injection of the Tc-99m endothelin derivative. Autoradiography revealed a strong relationship between tracer accumulation and sudan-III-staining of lesions. Accumulation of the endothelin derivative correlated with the number of neointimal smooth muscle cells (SMC), but not with the number of medial SMC, neointimal macrophages, and neointimal area. CONCLUSIONS the results indicate that in vivo imaging of atherosclerosis with an endothelin derivative is a feasible method of detecting and characterizing atherosclerotic arterial wall lesions at early stages.

Aortic Plaque Size and Endometrial Response in Cholesterol-Fed Rabbits Treated With Estrogen Plus Continuous or Sequential Progestin

ERT is associated with a reduced incidence of coronary risk and cardiac events in postmenopausal women, but increases the risk of endometrial hyperplasia and carcinoma. Combined estrogen and progestin therapy protects the endometrium; however, its effects on heart disease risk factors are not completely known. In our study, 56 ovariectomized New Zealand White rabbits in 7 groups received a 0.5% cholesterol diet for 12 weeks. Controls were not treated with hormones. All other animals received (per kilogram body weight per week) intramuscular injections of either 0.3 mg estrogen (estradiol valerate) alone, 8.3 mg progestin (hydroxyprogesterone caproate) alone, estrogen and progestin continuously in 3 different dosages (0.3 and 8.3 mg; 1 and 8.3 mg; or 1 and 2.8 mg; estrogen and progestin, respectively), or 1 mg estrogen with 25 mg progestin sequentially in 2-week cycles. Eight non-ovariectomized animals served as further controls for endometrial analysis. Morphometric analysis of plaque size in the aortic arch showed that estrogen monotherapy, and the 3 combined therapies with 1 mg estrogen, significantly reduced intimal thickening (P<0.05). The application of progestin alone had no effect on plaque size. The endometrium was enlarged by 3-fold after estrogen treatment, and was decreased by half after progestin treatment, compared with control uteri (P<0.05). In all groups with combined hormone regimens, endometrial size was not significantly different from control uteri. However, these uteri showed more inflammatory reactions, especially when higher doses of hormones were given. In this animal model, doses of progestin that are able to successfully reduce the proliferative effect of estrogen on endometrium do not diminish the desirable antiatherosclerotic properties of estrogen.

Endothelin A receptor antagonist LU 135252 inhibits hypercholesterolemia-induced, but not deendothelialization-induced, atherosclerosis in rabbit arteries.

Tepe G, Brehme U, Seeger H, et al. Endothelin A receptor antagonist LU 135252 inhibits hypercholesterolemia-induced, but not deendothelialization-induced, atherosclerosis in rabbit arteries. Invest Radiol 2002;37:349–355. rationale and objectives. The purpose of the study was to test the capability of the endothelin A receptor antagonist LU 135252 to reduce neointimal formation in rabbits after balloon denudation with and without the presence of hypercholesterolemia. methods. Twenty-eight male New Zealand White rabbits underwent balloon denudation of the infrarenal aorta. The animals were randomly assigned to 1 of the 4 groups. After balloon denudation, group 1 (n = 6) and 2 (n = 7) received a standard diet, and group 3 (n = 8) and 4 (n = 7) were fed a 0.5% cholesterol diet. All interventional procedures were performed while the rabbits were under general anesthesia. One week prior to intervention treatment with LU 135252 was started in group 2 and 4. After 6 weeks the animals were killed for morphometric and histological analysis. results. Rabbits in all treatment groups developed neointimal hyperplasia. By additional systemic treatment with LU 135252, the mean neointima to media ratio was significantly reduced only in the hypercholesterolemic animals of group 4 (neointimal to media ratio area of group 3 vs group 4: 2.07 ± 0.62 vs 1.41 ± 0.45, P < 0.05). ET receptor blockade in group 2 and 4 did not have an effect on plasma levels of cholesterol, very low-density lipoprotein-, high-density lipoprotein-, and low-density lipoprotein-cholesterol. conclusion. LU 135252 was efficient in reducing lipid induced atherosclerotic changes but was ineffective in inhibiting restenosis induced by balloon denudation.

Local Administration of Ramiprilat is Less Effective than Oral Ramipril in Preventing Restenosis after Balloon Angioplasty in an Animal Model

PURPOSE To test the hypothesis that local administration of angiotensin converting enzyme (ACE) inhibitor via a microporous balloon catheter would be more effective than oral administration of ACE inhibitor in preventing neointima formation after balloon angioplasty. MATERIALS AND METHODS Neointima formation was induced by balloon denudation followed by 0.5% cholesterol diet in 29 New Zealand White rabbits. Directly after denudation, local administration of 1.8 mg of ramiprilat (n = 7) or saline (n = 7) with a microporous balloon catheter at a pressure of 3 atm was performed. Both groups additionally received ramipril orally (1 mg/d). Seven animals were treated exclusively with oral ramipril. The control group was fed a 0.5% cholesterol diet and given no medication (n = 8). Six weeks after intervention, the animals were killed and morphometric and immunohistologic analyses were performed. RESULTS Oral administration of ramipril resulted in a significant reduction of placque area (-66%, P < .05). Oral and local administration of the ACE inhibitor was followed by a nonsignificant reduction of the neointimal area (-17%). Local administration of saline combined with oral ramipril failed to prevent neointimal formation (reduction of 6%, NS). CONCLUSION Oral administration of ramipril resulted in a significant reduction of neointimal proliferation in New Zealand White rabbits. The possible benefit of an additional administration of local ramiprilat was diminished by an excessive neointimal hyperplasia, which was most likely caused by the inherent vessel trauma with use of the microporous balloon catheter.

Local intra-arterial drug delivery for prevention of restenosis: comparison of the efficiency of delivery of different radiopharmaceuticals through a porous catheter.

Tepe G, Duda SH, Kalinowski M, et al. Local intra-arterial drug delivery for prevention of restenosis: Comparison of the efficiency of delivery of different radiopharmaceuticals through a porous catheter. Invest Radiol 2001;36:245–249. rationale and objectives. Several radiopharmaceuticals were administered through a porous balloon catheter to compare the absolute amount deposited and the retention in the vessel wall. The reported efficiency of local drug delivery ranges from 0.001% to 0.1%, with poor retention after 24 hours. methods.An endothelin derivative (n = 6), pertechnetate (n = 6), hexamethylpropylene amineoxime (HMPAO) (n = 5), ethyl cysteinate dimer (ECD) (n = 5), and tin colloid (n = 5) were labeled with 185 MBq/mL 99m-technetium. After balloon denudation of the infrarenal aorta in 27 New Zealand White rabbits, 100 &mgr;L of each agent was administered through a porous balloon at a pressure of 4 bar. Dynamic and static whole-body scintigrams were obtained for 24 hours. The infrarenal aorta was excised and the activity calculated in a gamma counter. results.Apart from their retention in the region of local administration, the radiopharmaceuticals showed different distribution patterns. The highest regional tracer retention was observed with HMPAO. After administration of HMPAO, a significant difference between regional (vessel wall plus surrounding tissue: 14.5% of injected dose [ID]/24 hours) and local (vessel wall: 1.8% ID/24 hours) delivery was found. In contrast, ECD was eliminated quickly (local retention after 24 hours = 0% ID). The retention efficiencies were HMPAO > endothelin derivative > tin colloid > pertechnetate > ECD. conclusions.The different physicochemical and pharmacokinetic properties of radiopharmaceuticals resulted in different delivery efficiencies after local application.

Post-Prandial Lipaemia after a Moderate Fat Challenge in Normolipidaemic Men with and without Coronary Artery Disease

Background The role of triglycerides as a risk factor for coronary artery disease (CAD) is controversial. In prospective studies, which have reported discrepant results, triglycerides have generally been measured with subjects in the fasting state. Taking into account the fact that the average person spends up to 18 h per day in the post-prandial state, fasting triglyceride levels alone are inadequate to describe the actual effective concentrations, metabolism and atherogenicity of triglyceride-rich lipoproteins. Therefore, investigations of the dynamic post-prandial triglyceride metabolism of patients with CAD in comparison with healthy controls are necessary. Methods We studied the post-prandial metabolism of lipids in 99 men: 50 male patients with CAD confirmed by angiography and 49 matched healthy men. After an overnight fast of 12 h, the subjects (aged 40-60 years) ate a standardized oral fat load (3.2 MJ; 49 g fat = 58% of the total energy content). Blood samples for lipid analyses were drawn immediately prior to and hourly during the 6 h period after ingestion of the meal. Results As required by the study design, fasting triglyceride and total cholesterol levels did not differ between patients and controls; however, high-density lipoprotein (HDL), HDL2 and HDL3 cholesterol levels were significantly lower in the CAD patients. The highest post-prandial triglyceride serum concentrations were observed 3 h after ingestion of the oral fat load both in cases and in controls. Generally, CAD patients had slightly higher triglyceride values than did controls and, at the 5 h measurement point, this difference was significant. Conclusion The results suggest that there are differences in triglyceride metabolism between patients with CAD and healthy controls after a challenge with a moderate amount of fat. These differences can best be observed in the degradation phase of post-prandial lipaemia.

Reduction of Intimal Hyperplasia withRe-188-labeled Stents in a Rabbit Model at 7and 26 Weeks: An Experimental Study

The aim of this study was to analyze the feasibility of 188Re-labeled stents to reduce neointimal formation in a rabbit atherosclerosis model and to test the long-term effects at 7 and 26 weeks. Fifty-nine male New Zealand White rabbits were fed a 0.5% cholesterol diet for 4 weeks before balloon angioplasty and insertion of Palmaz stents in the infrarenal aorta. The animals were sacrificed 7 and 26 weeks after stent implantation. Control stents were compared with 188Re stents: (dose 1) 11.3 ± 1.8 MBq; (dose 2) 37.3 ± 4.2 MBq, and (dose 3) 80.1 ± 7.8 MBq. Each activity group consisted of a short-term (7 weeks) and a long-term group (26 weeks), resulting in a total of eight study groups. No thrombotic occlusion was observed. The neointimal formation in the control group was 2.11 [95% confidence interval (CI): 0.68–6.52] mm2 at 7 weeks and 2.10 (0.62–7.11) at 26 weeks. In the treatment groups, neointima reduction was detectable at 7 weeks [dose 1: 0.33 (0.09–1.22) mm2; dose 2: 0.17 (0.05–0.57) mm2; dose 3: 0.03 (0.01–0.13) mm2]. After 26 weeks, a catch-up of neointimal formation in the radioactive groups was most obvious in the low-dose group [dose 1: 0.80 (0.28–2.29) mm2; dose 2: 0.18([0.06–0.52) mm2; dose 3: 0.50 (0.17–1.42) mm2]. Compared to the long-term control group, neointimal reduction was still >60%. No induction of neointimal formation was observed at the edges of the stents. Radiation resulted in delayed re-endothelialization. 188Re stents were capable to reduce intimal hyperplasia and did not cause thrombosis. The edge effect, which was the major limitation of 32P stents, was not observed in 188Re stents.