Renal denervation for treatment of uncontrolled hypertension in an Asian population: results from the Global SYMPLICITY Registry in South Korea (GSR Korea).

Reports detailing the response of hypertensive patients to renal denervation (RDN) in Asian patients are limited. We evaluated 6- and 12-month outcomes after RDN in an Asian population and compared outcomes to a primarily Caucasian population. The Global SYMPLICITY Registry (GSR) is a prospective, all-comer, worldwide registry that evaluates the safety and effectiveness of RDN and includes the Korean registry substudy (GSR Korea) and a Caucasian subset (GSR Caucasian). Given differences in baseline characteristics among GSR Korea (n=93) as compared with GSR Caucasian (n=169) patients, including lower baseline office systolic blood pressure (SBP), lower body mass index and differences in medications, propensity score adjustment was performed when comparing the change in SBP between subsets. The 6- and 12-month change in SBP in GSR Korea was -19.4±17.2 and -27.2±18.1 mm Hg, respectively (P<0.001 for both vs baseline). GSR Caucasian had a SBP change similar to GSR Korea at 6 months (-20.9±21.4 mm Hg, unadjusted P=0.547, adjusted P=0.998), whereas at 12 months the change was significantly less pronounced (-20.1±23.9 mm Hg, unadjusted P=0.004, adjusted P=0.002). There were no protocol-defined procedure-related adverse events and no chronic adverse events associated with the device in an Asian population. RDN provided a significant reduction in 6- and 12-month office SBP among Asian patients, with a favorable safety profile. The 12-month SBP reduction was larger than that observed in Caucasian patients.

Comparison of inflammatory markers and angiographic outcomes after implantation of sirolimus and paclitaxel-eluting stents.

OBJECTIVE: We compared the degree of systemic inflammation and its relation to the angiographic outcomes after drug-eluting stent (DES) implantations. METHODS: We implanted a single DES in 79 stable angina patients (50 men; 60.4 (9.5) years of age; sirolimus-eluting stent (SES), n = 38; paclitaxel-eluting stent (PES), n = 41). The high-sensitivity C-reactive protein (hs-CRP) and interleukin 6 (IL-6) levels were determined before and at 24 hours, 72 hours, and 4 weeks after the percutaneous coronary intervention (PCI). An angiography and intravascular ultrasound (IVUS) were performed. RESULTS: The hs-CRP and IL-6 levels at baseline did not differ between the two groups. The hs-CRP increased significantly from baseline at 24 hours and 72 hours after the PCI in both groups and there was a significant increase in the IL-6 level at 24 hours after the PCI in both groups. However, there was no significant difference between the two groups in any of the hs-CRP or IL-6 measurements. At follow-up, the late lumen loss was significantly higher in the PES group than in the SES group (0.57 (0.56) mm vs 0.28 (0.58) mm, respectively, p = 0.020). The neointimal hyperplasia (NIH) volume in the PES group was significantly higher than that in the SES group (23.1 (22.7) vs 3.8 (7.1) mm(3), respectively, p = 0.000). The percentage luminal volume reduction was higher in the PES group than in the SES group (18.9 vs 3.9%, p = 0.002). The absolute values or change in the inflammatory markers did not correlate with the NIH or stent volume reduction. CONCLUSIONS: Our study showed that the benefits obtained from the SES, which reduce neointimal proliferation, are not probably mediated by the attenuation of the systemic inflammatory markers hs-CRP or IL-6.

Developmental toxic potential of 1,3-dichloro-2-propanol in Sprague-Dawley rats.

This study investigated the potential adverse effects of 1,3-dichloro-2-propanol (1,3-DCP) on pregnant dams and the embryo-fetal development after maternal exposure on gestational days (GD) 6 through 19 in Sprague-Dawley rats. The test chemical was administered to pregnant rats by gavage at dose levels of 0, 10, 30, and 90mg/kg per day (n=10 for each group). All dams underwent Caesarean sections on GD 20, and their fetuses were examined for morphological abnormalities. Maternal toxicity was noted at 90mg/kg/day. Manifestations of toxicity included clinical signs of illness, lower body weight gain, decreased food intake, and increases in the weight of the adrenal glands and the liver. Developmental toxic effects including decreases in fetal body weight and increases in visceral and skeletal variations also occurred at the highest dose. At 30mg/kg, only a minimal maternal toxicity, including a decrease in maternal food intake and an increase in the liver weight, was observed. No adverse maternal or developmental effects were observed at 10mg/kg/day. These results revealed that a 14-day repeated oral dose of 1,3-DCP was minimally embryotoxic but not teratogenic at a maternal toxic dose (90mg/kg/day), and was not embryotoxic at a minimally maternal toxic dose (30mg/kg/day) in rats. Because the developmental toxicity of 1,3-DCP was observed only in the presence of maternal toxicity, it is concluded that the developmental findings observed in the present study are secondary effects to maternal toxicity. Under these experimental conditions, the no-observed-adverse-effect level of 1,3-DCP is considered to be 10mg/kg/day for dams and 30mg/kg/day for embryo-fetal development.

Evaluation of embryo-fetal development in rats housed in concrete or hwangto cages during pregnancy.

BACKGROUND: Recently, it was reported that the 4-week exposure of rats to a concrete building environment under cool temperatures (11.7-12.1 degrees C) had adverse effects on the general health parameters. This study examined the potential effects of concrete and hwangto building environments on pregnant dams and embryo-fetal development in Sprague-Dawley rats. METHODS: Groups of 10 mated females were exposed to polycarbonate (control), concrete, or hwangto cages from gestational days (GD) 0 to 20 under cool temperatures (11.9-12.5 degrees C). All the females underwent a caesarean section on GD 20, and their fetuses were examined for any morphological abnormalities. RESULTS: The temperatures in the cages were similar in all groups but the relative humidity in the concrete and hwangto groups were higher than in the control group. The concentration of volatile organic compounds in the hwangto group during the study period was lower than in the control group. In the concrete group, maternal effects manifested as an increase in the incidence of clinical signs, a lower body weight, and a decrease in the thymus and ovary weights. Developmental effects included increased post-implantation loss and decreased litter size. In contrast, in the hwangto group, there were no exposure-related adverse effects on the maternal and developmental parameters. CONCLUSIONS: Overall, the exposure of pregnant rats to a concrete building environment under cool temperatures has adverse effects on the clinical signs, body weight, organ weight, and embryo-fetal development. On the other hand, exposure to a hwangto building environment does not have any adverse effects on pregnant dams or on embryo-fetal development in rats.

Effects of tert-butyl acetate on maternal toxicity and embryo-fetal development in Sprague-Dawley rats.

This study investigated the potential adverse effects of tert-butyl acetate (TBAc) on maternal toxicity and embryo-fetal development after maternal exposure of pregnant rats from gestational days 6 through 19. TBAc was administered to pregnant rats by gavage at 0, 400, 800, and 1,600 mg/kg/day. All dams were subjected to a Caesarean section on day 20 of gestation, and their fetuses were examined for any morphological abnormalities. At 1,600 mg/kg, maternal toxicity manifested as increases in the incidence of clinical signs and death, lower body weight gain and food intake, increases in the weights of adrenal glands and liver, and a decrease in thymus weight. Developmental toxicity included a decrease in fetal weight, an increase in the incidence of skeletal variation, and a delay in fetal ossification. At 800 mg/kg, only a minimal developmental toxicity, including an increase in the incidence of skeletal variation and a delay in fetal ossification, were observed. In contrast, no adverse maternal or developmental effects were observed at 400 mg/kg. These results show that a 14-day repeated oral dose of TBAc is embryotoxic at a maternally toxic dose (i.e., 1,600 mg/kg/day) and is minimally embryotoxic at a nonmaternally toxic dose (i.e., 800 mg/kg/day) in rats. However, no evidence for the teratogenicity of TBAc was noted in rats. It is concluded that the developmental findings observed in the present study are secondary effects to maternal toxicity. Under these experimental conditions, the no-observed-adverse-effect level of TBAc is considered to be 800 mg/kg/day for dams and 400 mg/kg/day for embryo-fetal development.

Multiple predictors of coronary restenosis after drug-eluting stent implantation in patients with diabetes.

OBJECTIVES: To identify parameters influencing the likelihood of restenosis after implantation of drug-eluting stents (DES) in patients with diabetes. METHODS: Stented patients (n = 840) with DES were retrospectively reviewed for inclusion in the study from the Multicenter PCI Database Registry. From this database, 211 (25.1%) of 840 patients with six-month angiographic follow up had diabetes. Predictors of coronary restenosis were identified with univariate and multivariate logistic regression analyses. RESULTS: Restenosis occurred in 92 of 629 (14.6%) patients without diabetes and in 44 (20.9%) of 211 patients with diabetes (p < 0.001). Multivariate parameters for predicting restenosis in the diabetic group were current smoking (odds ratio (OR) 1.923, 95% confidence interval (CI) 1.055 to 4.725, p = 0.036), higher C reactive protein concentration (OR 1.031, 95% CI 1.011 to 1.075, p = 0.043), use of the paclitaxel-eluting stent (OR 2.638, 95% CI 1.338 to 5.200, p = 0.005), longer stent length (OR 1.065, 95% CI 1.021 to 1.119, p = 0.033), smaller reference diameter before DES implantation (OR 0.501, 95% CI 0.110 to 0.965, p = 0.040), smaller reference diameter (OR 0.455, 95% CI 0.120 to 0.814, p = 0.026) and minimum lumen diameter (OR 0.447, 95% CI 0.068 to 0.876, p = 0.039) after DES implantation. CONCLUSION: Even with the introduction of DES, diabetes remains a significant predictor of coronary restenosis, especially in cases of a small baseline vessel size, small vessel size after percutaneous coronary intervention, longer stent length, use of the paclitaxel-eluting stent, current smoking and high C reactive protein concentration.

26-Week repeated oral dose toxicity study of the new quinolone antibacterial DW-116 in Sprague-Dawley rats.

The purpose of this study is to investigate the potential subchronic toxicity of DW-116 by a 26-week repeated oral dose in Sprague-Dawley rats. The test article, DW-116, was administered daily by gavage to male and female rats at dose levels of 0, 5, 25 and 125 mg/kg/day. At the end of the treatment period, 12 rats/sex/group were sacrificed, while six extra rats/sex in the vehicle control and highest dose groups were sacrificed after a 4-week recovery. During the test period, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings, organ weights and histopathology were examined. There was no treatment-related mortality. An increase in the incidence of post-dosing salivation was observed in both sexes of the highest dose group. At the scheduled autopsy, an increase in the liver weight was observed in males of the highest dose group in a dose-dependent manner. Hematological investigations revealed a dose-dependent increase in the total white blood cell (WBC) and lymphocyte counts in males treated with the 125 mg/kg dose. Total bilirubin and alanine aminotransferase (ALT) values were also increased in males at the same dose. These effects were completely reversible during the recovery period. There were no adverse effects on body weight, food and water consumption, ophthalmoscopy, urinalysis, necropsy findings and histopathology in any treatment group. Based on these results, it was concluded that the 26-week repeated oral dose of DW-116 caused increases in the liver weight, WBC counts, total bilirubin and ALT values in males at a dose level of 125 mg/kg/day. The target organ was determined to be the liver and WBC in males, but not in females. The no-observed-adverse-effect level (NOAEL) was considered to be 25 mg/kg/day for males and 125 mg/kg/day for females.

Effect of hormone replacement therapy on nitric oxide bioactivity and monocyte chemoattractant protein-1 levels.

BACKGROUND: Vascular inflammation plays an important role in the pathogenesis of atherosclerosis. We investigated the effect of hormone replacement therapy (HRT) on vasomotor function and monocyte chemoattractant protein (MCP)-1 levels, an important serological marker of inflammation. METHODS: We administered micronized progesterone (MP) 200 mg for 10 days with conjugated equine estrogen (CEE) 0.625 mg for 25 days and remaining 5 days off cyclically during 2 months to 20 healthy postmenopausal women (PMW). We measured NO bioactivity and plasma levels of MCP-1 before and after HRT in 20 PMW. And we measured plasma levels of MCP-1 in each 20 subjects of premenopausal women, men <50, and men >50 years, respectively. RESULTS: MP combined with CEE significantly improved the percent flow-mediated dilator response to hyperemia relative to baseline measurements (P<0.001). PMW receiving HRT had lower levels of MCP-1 than those not receiving HRT (121+/-38 versus 146+/-44 pg/ml, P<0.001). In all comparisons, subjects with high estrogen status had significantly lower MCP-1 levels than subjects with low estrogen status (P<0.001 by ANOVA). Premenopausal women had lower levels of MCP-1 than men of a similar age (106+/-14 versus 164+/-40 pg/ml, P<0.001). PMW not receiving HRT had similar levels of MCP-1 compared with men of a similar age (146+/-44 versus 143+/-29 pg/ml, P=0.816). Premenopausal women had markedly lower levels of MCP-1 than PMW not receiving HRT (106+/-14 versus 146+/-44 pg/ml, P=0.001). PMW receiving HRT had similar levels of MCP-1 compared with premenopausal women (121+/-38 versus 106+/-14 pg/ml, P=0.323). CONCLUSION: These findings might provide at least a partial explanation for the protection against cardiovascular disease experienced by premenopausal women, and the loss of that protection following menopause.

Vascular effects of estrogen in type II diabetic postmenopausal women.

OBJECTIVES: We assessed the effects of estrogen on vascular dilatory and other homeostatic functions potentially affected by nitric oxide (NO)-potentiating properties in type II diabetic postmenopausal women. BACKGROUND: There is a higher cardiovascular risk in diabetic women than in nondiabetic women. This would suggest that women with diabetes do not have the cardioprotection associated with estrogen. METHODS: We administered placebo or conjugated equine estrogen, 0.625 mg/day for 8 weeks, to 20 type II diabetic postmenopausal women in a randomized, double-blinded, placebo-controlled, cross-over design. RESULTS: Compared with placebo, estrogen tended to lower low-density lipoprotein (LDL) cholesterol levels by 15 +/- 23% (p = 0.007) and increase high-density lipoprotein (HDL) cholesterol levels by 8 +/- 16% (p = 0.034). Thus, the ratio of LDL to HDL cholesterol levels significantly decreased with estrogen, by 20 +/- 24%, as compared with placebo (p = 0.001). Compared with placebo, estrogen tended to increase triglyceride levels by 16 +/- 48% and lower glycosylated hemoglobin levels by 3 +/- 13% (p = 0.295 and p = 0.199, respectively). However, estrogen did not significantly improve the percent flow-mediated dilatory response to hyperemia (17 +/- 75% vs. placebo; p = 0.501). The statistical power to accept our observation was 81.5%. Compared with placebo, estrogen did not significantly change E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1 or matrix metalloproteinase-9 levels. Compared with placebo, estrogen tended to decrease tissue factor antigen and increase tissue factor activity levels by 7 +/- 46% and 5 +/- 34%, respectively (p = 0.321 and p = 0.117, respectively) and lower plasminogen activator inhibitor-1 levels by 16 +/- 31% (p = 0.043). CONCLUSIONS: The effects of estrogen on endothelial, vascular dilatory and other homeostatic functions were less apparent in type II diabetic postmenopausal women, despite the beneficial effects of estrogen on lipoprotein levels.

Efficacy of heparin-coated stent in early setting of acute myocardial infarction.

Primary stenting has been reported to be superior to balloon percutaneous transluminal coronary angioplasty (PTCA) in acute myocardial infarction (AMI) for recurrent ischemia, target lesion revascularization, and restenosis. However, concerns about early reocclusion or thrombosis after stenting in the very thrombotic environment of acute myocardial infarction still remain. Therefore, postprocedural short-term heparin or GpII(b)/III(a) receptor blockades has been used. The aim of our study was to evaluate the safety, feasibility, and long-term efficacy of heparin-coated stent in the early setting of AMI without postprocedural heparin or GpII(b)/III(a) receptor blockade infusion. We studied 102 consecutive patients presenting to cardiac catheterization laboratory < or = 6 hr from the onset of chest pain. No patients who were implanted with heparin-coated stents received heparin or GpII(b)/III(a) receptor blockade infusion after the procedures, not even patients who showed an angiographically large thrombus burden before stenting. Patients were evaluated for clinical endpoints at 30 days and 6 months. Coronary angiography was required for all patients at 2 weeks and 6 months after the procedure. Angiographic and procedural successes were 100% and 98%, respectively. Two patients (2%) died of heart failure without evidence of reocclusion of stented vessel during the hospitalization and 4 (4%) additional patients died of refractory heart failure within the first 6 months. Major bleeding complication occurred in one patient (1%). Recurrent myocardial infarction developed in one patient at 4 months. Early angiographic follow up at 2 weeks was performed in 88% of all patients, none of whom showed thrombotic stent occlusion. Six-month angiographic follow-up was completed in 71%(64/91) of eligible patients and binary restenosis was present in 17.2% of stented vessels. Eight(8%) patients underwent repeat PTCA. Cardiac event-free survival rate at 6 months was 86.3%. This study demonstrates that heparin-coated stents are safe in the early setting of acute myocardial infarction and no additional heparin infusion after stenting is necessary, which may reduce bleeding complications. Angiographic restenosis rate compares favorably to the binary restenosis rate from other studies with uncoated stents.