Intracoronary radiation with gamma wire inhibits recurrent in-stent restenosis

To study the safety and efficacy of intracoronary gamma radiation delivered via a new high-activity (192)Ir source wire for the treatment of in-stent restenosis. In-stent restenosis results from neointimal tissue proliferation especially in its diffused form and presents a therapeutic challenge. Gamma radiation has been shown to decrease neointima formation within stents in animal models and in initial clinical trials. A total of 26 patients with in-stent restenosis underwent successful intervention and was treated with open-label (192)Ir using a high-activity line source. The specific activity of the source wire was 372+/-51 mCi, and the dwell time was 10.8+/-1.9 min. Primary endpoints were freedom from death, myocardial infraction (MI), and repeat target lesion revascularization (TLR) at 6 months. Secondary endpoints included angiographic restenosis and intravascular ultrasound (IVUS) neointimal hyperplasia. Procedural success was high (96.2%), and in-hospital and 30-day complications were low with no deaths, MI, or requirement for repeat revascularization. At 6 months, event-free survival was 85%: one patient required repeat PTCA, one underwent bypass surgery, and two had an MI. Baseline lesion length measured 15.77 mm. Follow-up angiography was available in 21/25 (84%) patients. The binary restenosis rates were 19.0% (4/21) in-stent and 23.8% (5/21) in-lesion. Follow-up IVUS was available in 20/25 patients. There was no increase in intimal hyperplasia from postintervention to follow-up (3.11.8 vs. 3.41.8 mm(2); P=.32). Eight patients had a reduction of neointimal intimal tissue at follow-up. These results indicate that intracoronary gamma radiation with the Angiorad source wire is safe and effective in preventing in-stent restenosis.     

Inhibition of interleukin-1β convertase is associated with decrease of neointimal hyperplasia after coronary artery stenting in pigs

Inhibition of IL-1 convertase has been shown to decrease inflammation and apoptosis, which are features of the neointimal development after vascular interventions. The aim of our study was to reduce neointimal proliferation after stenting of the porcine coronary artery, using the irreversible IL-1 convertase and caspase-1 inhibitor acetyl-tyrosinyl-valyl-alanyl-aspartyl-chloromethyl-ketone (Ac-YVAD-cmk). Before coronary stent implantation, 8 pigs received an intracoronary infusion of 50 mg Ac-YVAD-cmk into the left coronary artery (group 1, n - 8), while 8 animals served as untreated controls (group 2). After 4 weeks, coronary angiography and intracoronary ultrasound (IVUS) with 3D measurements were performed. IVUS revealed a smaller in-stent intimal volume (27.3 ± 11.6 vs. 75.8 ± 18.4 mm³, p < 0.005) and a decreased maximal percentage area stenosis (36.1 ± 8.5 vs. 69.0 ± 8.2%, p < 0.001) in group 1 vs. group 2. A smaller maximal neointimal thickness (0.63 ± 0.28 vs. 1.75 ± 0.94 mm, p < 0.005) and a decreased maximal neointimal area (2.14 ± 1.29 vs. 5.03 ± 1.92 mm², p < 0.005), assessed by computerized planimetry, were found in group 1 vs. group 2. Lower apoptotic indices of the neointimal cells were observed in the treated animals (3.0 vs. 13.4% of total intimal cells, p < 0.05). The coronary arterial tissue IL-1 level was significantly decreased in the animals treated with Ac-YVAD-cmk (0.254 ± 0.162 vs. 0.463 ± 0.307 pg/mg protein, p < 0.05), and exhibited a positive linear correlation (r = 0.581, p = 0.013) with the in-stent plaque volume. In conclusion, intracoronary administration of Ac-YVAD-cmk before coronary artery stenting results in significantly decreased neointimal hyperplasia due to the inhibition of local IL-1 production and decreased neointimal apoptosis.     

Shear stress,vascular remodeling and neointimal formation

The role of shear stress in atherosclerosis has been well documented. However, its role in restenosis was underexposed. In this paper a novel in vivo measuring technique and several of its applications related to restenosis will be described. The technique consists of a combination of 3D reconstruction of blood vessels and computational fluid dynamics (CFD). The 3D imaging techniques use either of 3D intravascular ultrasound (IVUS) as a stand-alone technique or a fusion of biplane angiography and IVUS (ANGUS). CFD is applied in order to relate local shear stress distribution to the morphology of the vessel wall. In the applications of these techniques it will be demonstrated that shear stress plays a role in the prediction of neointimal formation in in-stent restenosis and in vascular remodeling after balloon angioplasty. Attempts to locally increase shear stress by a newly developed flow divider indicate that shear stress reduce in-stent neointimal formation by 50%.     

Tetrahydrobiopterin deficiency exaggerates intimal hyperplasia after vascular injury

Decreased levels of tetrahydrobiopterin (BH4), an absolute cofactor for nitric oxide synthase (NOS), lead to uncoupling of NOS into a superoxide v. nitric oxide producing enzyme, and it is this uncoupling that links it to the development of vascular disease. However, the effects of in vivo deficiency of BH4 on neointimal formation after vascular injury have not been previously investigated. Hph-1 mice, which display 90% deficiency in guanine triphosphate cyclohydrolase I, the rate limiting enzyme in BH4 synthesis, were used. Hph-1 and wild-type mice, treated with either vehicle or BH4 (n = 15 per group), were subjected to wire-induced femoral artery injury, and NOS expression and activity, inflammation, cell proliferation, superoxide production, and neointimal formation were assessed. The major form of NOS expressed over vessel wall after vascular injury was endothelial NOS. Hph-1 mice exhibited lower NOS activity (2.8 +/- 0.3 vs. 4.5 +/- 0.4 pmol/min/mg protein, P < 0.01), and higher aortic superoxide content (5.2 +/- 2.0 x 10(5) cpm vs. 1.6 +/- 0.7 x 10(5) cpm, P < 0.01) compared with wild-type controls, indicating uncoupling of NOS. Treatment of hph-1 mice with BH4 significantly increased NOS activity (from 2.8 +/- 0.3 to 4.1 +/- 0.4 pmol.min(-1).mg protein(-1), P < 0.05), and attenuated superoxide production (from 5.2 +/- 2.0 x 10(5) cpm to 0.8 +/- 0.7 x 10(5) cpm, P < 0.05). Hph-1 mice also had higher inflammatory reactions and more cell proliferation after vascular injury. Furthermore, hph-1 mice responded by a marked increase in neointimal formation at 4 wk after vascular injury, compared with wild-type controls (intima:media ratio: 4.5 +/- 0.5 vs. wild-type 0.7 +/- 0.1, P < 0.001). Treatment of hph-1 mice with BH4 prevented vascular injury-induced increase in neointimal formation (intima:media ratio: 1.4 +/- 0.1 vs. hph-1, P < 0.001). Treatment had no effect on wild-type controls. In summary, we describe, for the first time, that in vivo BH4 deficiency facilitates neointimal formation after vascular injury. Modulation of BH4 bioavailability is an important therapeutic target for restenosis.     

Local methylprednisolone delivery using a BiodivYsio phosphorylcholine-coated drug-delivery stent reduces inflammation and neointimal hyperplasia in a porcine coronary stent model

Phosphorylcholine (PC)-coated stents have shown excellent blood and tissue biocompatibility in porcine coronary arteries. The purpose of this study was to determine the efficacy of local methylprednisolone (MP) delivery using PC-coated stents to inhibit inflammatory response and in-stent neointimal hyperplasia in an overstretched porcine coronary model. BiodivYsio (Biocompatibles, Farnham, Surrey, UK) PC-coated drug delivery (DD) stents and DD stents loaded with a high dose of MP (269 microg) were implanted in the coronary arteries of 20 pigs with a balloon/artery ratio of 1.2 : 1. At five days the peri-strut inflammatory response score and thrombus score of the MP-loaded DD stents were lower than in the control stents. The neointimal hyperplasia of MP-loaded DD stents was significantly reduced (0.80 +/- 0.10 versus 0.48 +/- 0.10 mm(2), p < 0.01). At four-week follow-up, the inflammatory response of MP-loaded stents was lower than the control stents, but without significant difference. The MP-loaded stents showed decreased peri-strut arterial injury and in-stent neointimal hyperplasia (2.42 +/- 0.87 versus 1.62 +/- 0.71 mm(2), p < 0.05). It is concluded that local vascular delivery of a high dose of MP from PC-coated DD stents could effectively decrease inflammatory response and thrombus formation after oversized stent deployment and result in a significant reduction of neointimal hyperplasia.     

Chronic hypoxia induces nonreversible right ventricle dysfunction and dysplasia in rats

The purpose of this study was to evaluate the reversibility of right ventricular (RV) remodelling after pulmonary artery hypertension (PAHT) secondary to 3 wk of hypobaric hypoxia. A group of 10 adult male Wistar rats were studied and were the following: control normoxic (C), after 3 wk of chronic hypoxia (CH), and after 3 wk of exposure to hypoxia followed by 3 wk of normoxia recovery (N-RE). Mean pulmonary artery pressure was 11 +/- 2 mmHg in the C group, 35 +/- 2 mmHg in the CH group, and 14 +/- 3 mmHg in the N-RE group. RV function was assessed by echocardiography. In the CH group, the pulmonary flow measured in Doppler mode depicted a midsystolic notch and a decrease of the pulmonary acceleration time compared with control [17 +/- 1 vs. 34 +/- 1 ms (n = 10), respectively; P < 0.05]. RV thickening measured in M-mode was apparent in the CH group compared with the control group [2.84 +/- 0.40 vs. 1.73 +/- 0.26 mm (n = 10), P < 0.05]. In the N-RE group, the RV wall was significantly thinner compared with the CH group [1.56 +/- 0.08 vs. 1.73 +/- 0.26 mm (n = 10), P < 0.05]. The calculated RV diameter shortness fraction was not different between the CH group and C group (34 +/- 4.2% vs. 36 +/- 2.8%) but decreased in the N-RE group [20 +/- 2.4% (n = 10), P < 0.01]. The E-to-A wave ratio on the tricuspid Doppler inflow was significantly lower in the CH group and N-RE group compared with the C group [0.70 +/- 0.8 and 0.72 +/- 0.1 vs. 0.88 +/- 0.2 (n = 10), respectively; P < 0.05]. In the isolated perfused heart using the Langendorff method, RV compliance was increased in the CH group and decreased in the N-RE group. In the N-RE group, fibrous bands with metaplasia were observed on histological sections of the RV free wall. We conclude that PAHT induces nonreversible RV dysfunction with dysplasia.     

Coronary stent implantation changes 3-D vessel geometry and 3-D shear stress distribution

Mechanisms of in-stent restenosis are not fully understood. Shear stress is known to play a role in plaque and thrombus formation and is sensitive to changes in regional vessel geometry. Hence, we evaluated the regional changes in 3-D geometry and shear stress induced by stent placement in coronary arteries of pigs.Methods. 3-D reconstruction was performed, applying a combined angiographic and IVUS technique (ANGUS), from seven Wallstents (diameter 3.5 (n=3) and 5mm (n=4)), which were implanted in seven coronary arteries of five pigs. This 3-D geometry was used to calculate locally the curvature, while the shear stress distribution was obtained by computational fluid dynamics. Local changes in shear stress were obtained at the entrance and exit of the stent for baseline (0. 65+/-0.22 ml/s) and hyperemic flow (2.60+/-0.86 ml/s) conditions. Results. After stent implantation, the curvature increased by 121% at the entrance and by 100% at the exit of the stent, resulting in local changes in shear stress. In general, at the entrance of the stent local maxima in shear stress were generated, while at the exit both local maxima and minima in shear stress were observed (p<0.05). Additionally, the shear stress at the entrance and exit of the stent were correlated with the local curvature (r: 0.30-0.84).Conclusion. Stent implantation changes 3-D vessel geometry in such a way that regions with decreased and increased shear stress occur close to the stent edges. These changes might be related to the asymmetric patterns of in-stent restenosis.     

Persistent alterations in heart rate variability, baroreflex sensitivity, and anxiety-like behaviors during development of heart failure in the rat

Depressed heart rate variability and mood are associated with increased mortality in patients with congestive heart failure (CHF). Here autonomic indexes were assessed 3 and 7 wk after left coronary artery ligation in telemetered rats, after which anxiety-like behaviors were assessed in an elevated plus maze. Low frequency (LF) and high frequency (HF) heart rate variability were reduced in CHF rats 3 wk after infarction (LF, 1.60 +/- 0.52 vs. 6.97 +/- 0.79 ms(2); and HF, 1.53 +/- 0.39 vs. 6.20 +/- 1.01 ms(2); P < 0.01). The number of sequences of interbeat intervals that correlated with arterial pressure was decreased in CHF rats at 3 and 7 wk (week 3, 26.60 +/- 10.85 vs. 59.75 +/- 11.4 sequences, P < 0.05; and week 7, 20.80 +/- 8.97 vs. 65.38 +/- 5.89 sequences, P < 0.01). Sequence gain was attenuated in CHF rats by 7 wk (1.34 +/- 0.06 vs. 2.70 +/- 0.29 ms/mmHg, P < 0.01). Coherence between interbeat interval and mean arterial blood pressure variability in the LF domain was reduced in CHF rats at 3 (0.12 +/- 0.03 vs. 0.26 +/- 0.05 k(2), P < 0.05) and 7 (0.16 +/- 0.02 vs. 0.31 +/- 0.05 k(2), P < 0.05) wk. CHF rats invariably entered the open arm of the elevated plus maze first and spent more time in the open arms (36.0 +/- 15% vs. 4.6 +/- 1.9%, P < 0.05). CHF rats also showed a tendency to jump head first off the apparatus, whereas controls did not. Together the data indicate that severe autonomic dysfunction is accompanied by escape-seeking behaviors in rats with verified CHF.     

Exercise training improves left ventricular contractile response to beta-adrenergic agonist.

To determine whether endurance exercise training can improve left ventricular function in response to beta-adrenergic stimulation, young healthy sedentary subjects (10 women and 6 men) were studied before and after 12 wk of endurance exercise training. Training consisted of 3 days/wk of interval training (running and cycling) and 3 days/wk of continuous running for 40 min. The training resulted in an increase in maximal O2 uptake from 41.0 +/- 2 to 49.3 +/- 2 ml.kg-1.min-1 (P less than 0.01). Left ventricular function was evaluated by two-dimensional echocardiography under basal conditions and during beta-adrenergic stimulation induced by isoproterenol infusion. Fractional shortening (FS) under basal conditions was unchanged after training (36 +/- 1 vs. 36 +/- 2%). During the highest dose of isoproterenol, FS was 52 +/- 1% before and 56 +/- 1% after training (P less than 0.05). At comparable changes in end-systolic wall stress (sigma es), the increase in FS induced by isoproterenol was significantly larger after training (13 +/- 1 vs. 17 +/- 2%, P less than 0.01). Furthermore there was a greater decrease in end-systolic dimension at similar changes in sigma es in the trained state during isoproterenol infusion (-4.6 +/- 0.1 mm before vs. -7.0 +/- 0.1 mm after training, P less than 0.01). There were no concurrent changes in end-diastolic dimension between the trained and untrained states during isoproterenol infusion, suggesting no significant changes in preload at comparable levels of sigma es.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gender differentiation of the chemoreflex during growth at high altitude: functional and neurochemical studies

The effect of chronic hypoxia on gender differences in physiology and neurochemistry of chemosensory pathways was studied in prepubertal and adult rats living at sea level (SL; Lyon, France) or at high altitude (HA; La Paz, Bolivia, 3,600 m). HA adult rats had higher hematocrit (Ht%), Hb concentration, resting ventilatory rate (Ve(100)), and higher tyrosine hydroxylase (TH) activity in carotid bodies (CB) than SL animals. At HA and SL, adult females had lower Ht% (46.0 +/- 0.8 vs. 50.4 +/- 0.6% at HA, P < 0.05 and 43.8 +/- 0.9 vs. 47.1 +/- 0.8% at SL, P < 0.05) and Hb (16.1 +/- 0.3 vs. 17.7 +/- 0.2 g/dl at HA, P < 0.05 and 14.5 +/- 0.3 vs. 15.6 +/- 0.1 g/dl at SL, P < 0.05) than males. Females had higher Ve(100) [170 +/- 19 vs. 109 +/- 7 ml. min(-1). 100 g(-1) at HA, P < 0.05 and 50 +/- 3 vs. 40 +/- 2 ml. min(-1). 100 g(-1) at SL, not significant (NS)] and lower CB-TH activity (1.40 +/- 0.2 vs. 3.87 +/- 0.6 pmol/20 min at HA, P < 0.05 and 0.52 +/- 0.1 vs. 0.68 +/- 0.1 pmol/20 min at SL; NS) than males at HA only. The onset of hypoxic ventilatory response during development was delayed at HA. Prepubertal HA females had higher Ve(100) than males (2 wk old, +47%) and higher CB-TH activity (3 wk old, +51%). Medullary noradrenergic groups were sex dimorphic during development at SL. Rats raised at HA had a drop of TH activity between the second and the third postnatal week in all medullary groups. In conclusion, our data support the hypothesis that the CB is the major site for sexual differentiation of the ventilatory control. Ventilatory differences appeared before puberty, and the animals bred at HA had profound alterations in the developmental process of the chemoreflex and its neural pathways. Some of these alterations are under dependence of the sex of the animal, and there is an important interaction between gender and the hypoxic environmental condition during the developmental period.     

Progressive resistance training reduces myosin heavy chain coexpression in single muscle fibers from older men.

The purpose of this study was to examine myosin heavy chain (MHC) and myosin light chain (MLC) isoforms following 12 wk of progressive resistance training (PRT). A needle biopsy was taken from the vastus lateralis to determine fiber-type expression [ATPase (pH 4.54) and MHC/MLC] in seven healthy men (age = 74.0 +/- 1.8 yr). Subjects were also tested for 1-repetition maximum (1-RM), pre- and posttraining. The progressive knee extensor protocol consisted of three sets at 80% of 1-RM 3 days/wk for 12 wk. Freeze-dried, single muscle fibers were dissected for MHC and MLC analysis and then subjected to SDS-PAGE and silver staining, pre- and posttraining. MHC expression increased in the I (10.4%; P < 0.05) and decreased in I/IIa (9.0%; P < 0.05), I/IIa/x (0.9%; P < 0.05), and IIa/x (8.9%; P < 0.05) isoforms, with no change in the IIa and IIx isoforms, pre- vs. posttraining (total fibers = 3,059). The MLC(3f)-to-MLC(2) ratio did not change with the PRT in either the MHC I or MHC IIa isoforms (total fibers = 902), pre- to posttraining. ATPase fiber distribution did not significantly differ following training (I: 50. 4 +/- 6.7 vs. 51.9 +/- 7.9, IIa: 36.8 +/- 5.3 vs. 41.1 +/- 7.0, IIb: 12.8 +/- 5.6 vs. 7.0 +/- 4.0%; pre- vs. posttraining, respectively). 1-RM increased (51.9%; P < 0.05) from pre- to posttraining. The PRT provide a stimulus for alterations in MHC isoforms, which demonstrated a decrease in all hybrid isoforms and an increase in MHC I expression (not found in the ATPase results), unlike the MLC ratio (3:2), which was not altered with training.     

Modulation of macrophage activation and resistance by suppressor T lymphocytes in chronic murine Schistosoma mansoni infection

Activated macrophages (M phi) appear responsible for at least part of the concomitant resistance in mice infected with Schistosoma mansoni. We found that as murine S. mansoni progressed from acute (8 to 12 wk of infection) to chronic (16 to 24 wk) stages, acquired resistance decreased (57% resistance to challenge with cercariae at 8 wk vs 28% by 24 wk, p less than 0.05), as did macrophage activation (21% +/- 2 killing of schistosomula by 8 wk M phi vs 8% +/- 2 for 24 wk M phi, p less than 0.01). T cells from the spleens of 8 wk-infected mice were capable of activating M phi from naive animals when stimulated with worm antigens (24% +/- 2 killing vs 8% +/- 2 induced by normal T cells, p less than 0.01); T cells obtained from 24 wk-infected mice did not activate M phi (13% +/- 2 killing). Furthermore, T cells from 24 wk-infected animals suppressed activation of M phi by 8 wk T cells. The addition of 10(5) 24 wk T cells to 3 X 10(5) antigen-stimulated 8 wk T cells reduced subsequent M phi killing from 27% +/- 4 to 13% +/- 2 (p less than 0.05). Week 24 T cells (3 X 10(5] reduced this additionally to 9% +/- 1 (p less than 0.01), a value no greater than that of unstimulated M phi. The subpopulation of T cells responsible for suppression of M phi activation was Lyt-2+1- nonadherent T cells. Cyclophosphamide treatment of chronically infected mice resulted in enhanced resistance (41%), M phi activation (18% +/- 1 killing), and T cell activation of naive M phi (10% +/- 1 killing). Thus, during chronic S. mansoni infection, resistance to reinfection wanes in parallel to and perhaps because of development of suppressor T cells that interfere with T-dependent M phi activation.     

Effect of frequency of follicle aspiration on oocyte yield and subsequent superovulatory response in cattle

The effect of frequency of transvaginal follicular aspiration on oocyte yield and subsequent superovulatory response was studied in 2 experiments. In Experiment 1, 32 primiparous Hereford x Friesian cows were assigned to 4 treatments (n = 8 per treatment). Oocyte recovery was carried out once a week for 12, 8, 4 or 0 (control) wk. Embryo recovery for all animals was 7 wk after the completion of the aspiration schedules. In Experiment 2, the effects of oocyte recovery once or twice a week (n = 8 per treatment; control n = 18) for 12 wk and response to superovulation 4 wk after the last aspiration were compared using nulliparous purebred Simmental heifers. Increasing the period of once weekly aspirations from 4 to 12 wk (Experiment 1) did not affect the number of follicles observed per session (mean +/- SEM; 10.0 +/- 0.82) or aspirated (7.8 +/- 0.71), but the recovery rate of oocytes from follicles aspirated was greater for donors aspirated for either 4 or 8 wk than for 12 wk (32.3 +/- 3.73 vs 28.4 +/- 2.61 vs 20.1 +/- 2.13 %; P < 0.05). Following the last aspiration and prior to commencing superovulatory procedures, estrus or estrous activity was observed in 7 8 , 8 8 , 7 8 and 6 8 of the animals aspirated over 12, 8, 4 or 0 wk, respectively. Subsequent superovulatory responses and in vivo embryo recoveries were similar for all aspiration treatments and for control animals. Changing the frequency of oocyte recovery from once to twice weekly (Experiment 2) did not affect the numbers of follicles observed (9.1 +/- 0.63 vs 8.3 +/- 0.85), follicles aspirated (5.9 +/- 0.56 vs 6.2 +/- 0.69), oocytes recovered (1.7 +/- 0.27 vs 1.9 +/- 2.0) per session or the oocyte recovery rate (29.4 +/- 2.4 vs 30.4 +/- 2.4 %); nor was there any effect of frequency of aspiration on subsequent superovulatory response and embryo recovery. In conclusion, increasing the period of aspiration from 4 to 12 wk and the frequency from once to twice a week over 12 wk did not reduce the number of follicles observed or aspirated, or number of oocytes recovered per donor per session. Subsequent estrous cyclicity and responses to superovulation were unaffected by the periods or frequencies of oocyte recovery examined here.     

Exendin-4, but not dipeptidyl peptidase IV inhibition, increases small intestinal mass in GK rats

Long-term treatment with dipeptidyl peptidase IV inhibitors (DPPIV-I) or glucagon-like peptide (GLP)-1 analogs may potentially affect intestinal growth by down- or upregulating the intestinotrophic hormone GLP-2. This study compared the intestinotrophic effects of 12-wk administration of vehicle, exendin-4 (Ex-4; 5 nmol/kg bid sc), or DPPIV-I (NN-7201, 10 mg/kg qd orally) in GK rats. Some animals were observed additionally for 9 wk after the end of treatment. Both treatments lowered glycated hemoglobin A1c at wk 12 vs. control (Ex-4, -0.8%; DPPIV-I, -0.4%). Body weight was reduced by Ex-4 compared with control (361 +/- 4 vs. 399 +/- 5 g; P < 0.001) because of reduced food intake, whereas neither parameter was affected by DPPIV-I. Linear bone growth was unaffected by either treatment. After treatment end, food intake in Ex-4 animals increased, and, by wk 21, body weight was identical in all groups. The small intestine of Ex-4-treated animals was larger at wk 12 compared with control (length, 135.6 +/- 1.6 vs. 124.5 +/- 2.3 cm, P < 0.001; absolute weight, 8.4 +/- 0.2 vs. 6.4 +/- 0.4 g, P < 0.001), being most pronounced proximally, where the absolute cross-sectional area related to body weight increased by 24% because of increased mucosal thickness. These effects were reversible, and 9 wk after the end of treatment, no differences between Ex-4 and control were apparent. Plasma GLP-2 concentrations were unaltered by either treatment, and Ex-4 had no agonistic or antagonistic effects on the transfected GLP-2 receptor. DPPIV-I had no intestinal effects. In conclusion, the continued presence of Ex-4 is necessary to maintain weight loss in GK rats. Effective antihyperglycemic treatment with Ex-4 increases intestinal mass reversibly, whereas DPPIV-I lacks intestinal effects.     

Intravascular Ultrasound and Angiographic Predictors of In-Stent Restenosis of Chronic Total Occlusion Lesions

Despite the benefits of successful percutaneous coronary interventions (PCIs) for chronic total occlusion (CTO) lesions, PCIs of CTO lesions still carry a high rate of adverse events, including in-stent restenosis (ISR). Because previous reports have not specifically investigated the intravascular ultrasound (IVUS) predictors of ISR in CTO lesions, we focused on these predictors. We included 126 patients who underwent successful PCIs, using drug-eluting stents, and post-PCI IVUS of CTO lesions. Patient and lesion characteristics were analyzed to elucidate the ISR predictors. In each lesion, an average of 1.7 ± 0.7 (mean length, 46.4 ± 20.3 mm) stents were used. At 9 months follow-up, 14 (11%) patients demonstrated ISR, and 8 (6.3%) underwent target lesion revascularization. Multivariate logistic regression analysis showed that the independent predictors of ISR were the post-PCI minimal luminal diameter (MLD) and the stent expansion ratio (SER; minimal stent cross-sectional area (CSA) over the nominal CSA of the implanted stent), measured using quantitative coronary angiography (QCA) and IVUS, respectively. A receiver operating characteristic analysis indicated that the best post-PCI MLD and SER cut-off values for predicting ISR were 2.4 mm (area under the curve [AUC], 0.762; 95% confidence interval (CI), 0.639–0.885) and 70% (AUC, 0.714; 95% CI, 0.577–0.852), respectively. Lesions with post-PCI MLD and SER values less than these threshold values were at a higher risk of ISR, with an odds ratio of 23.3 (95% CI, 2.74–198.08), compared with lesions having larger MLD and SER values. Thus, the potential predictors of ISR, after PCI of CTO lesions, are the post-PCI MLD and SER values. The ISR rate was highest in lesions with a post-PCI MLD ≤2.4 mm and an SER ≤70%.     

Cardiac-specific overexpression of diacylglycerol kinase zeta attenuates left ventricular remodeling and improves survival after myocardial infarction

Left ventricular (LV) remodeling, including cardiomyocyte necrosis, scar formation, LV geometric changes, and cardiomyocyte hypertrophy, contributes to cardiac dysfunction and mortality after myocardial infarction (MI). Although precise cellular signaling mechanisms for LV remodeling are not fully elucidated, G(q) protein-coupled receptor signaling pathway, including diacylglycerol (DAG) and PKC, are involved in this process. DAG kinase (DGK) phosphorylates DAG and controls cellular DAG levels, thus acting as a negative regulator of PKC and subsequent cellular signaling. We previously reported that DGK inhibited angiotensin II and phenylephrine-induced activation of the DAG-PKC signaling and subsequent cardiac hypertrophy. The purpose of this study was to examine whether DGK modifies LV remodeling after MI. Left anterior descending coronary artery was ligated in transgenic mice with cardiac-specific overexpression of DGKzeta (DGKzeta-TG) and wild-type (WT) mice. LV chamber dilatation (4.12 +/- 0.10 vs. 4.53 +/- 0.32 mm, P < 0.01), reduction of LV systolic function (34.8 +/- 8.3% vs. 28.3 +/- 4.8%, P < 0.01), and increases in LV weight (95 +/- 3.6 vs. 111 +/- 4.1 mg, P < 0.05) and lung weight (160 +/- 15 vs. 221 +/- 25 mg, P < 0.05) at 4 wk after MI were attenuated in DGKzeta-TG mice compared with WT mice. In the noninfarct area, fibrosis fraction (0.51 +/- 0.04, P < 0.01) and upregulation of profibrotic genes, such as transforming growth factor-beta1 (P < 0.01), collagen type I (P < 0.05), and collagen type III (P < 0.01), were blocked in DGKzeta-TG mice. The survival rate at 4 wk after MI was higher in DGKzeta-TG mice than in WT mice (61% vs. 37%, P < 0.01). In conclusion, these results demonstrate the first evidence that DGKzeta suppresses LV structural remodeling and fibrosis and improves survival after MI. DGKzeta may be a potential novel therapeutic target to prevent LV remodeling after MI.     

Salvia miltiorrhiza inhibits intimal hyperplasia and monocyte chemotactic protein-1 expression after balloon injury in cholesterol-fed rabbits

Antioxidants that prevent low density lipoproteins (LDL) from oxidation may inhibit atherosclerosis and post-angioplasty restenosis. Salvia miltiorrhiza (SM) has been shown to inhibit LDL oxidation and reduce atherosclerosis in cholesterol-fed rabbits. The effects of SM on neointimal hyperplasia and monocyte chemotactic protein-1 (MCP-1) expression after balloon injury were studied. Male New Zealand white rabbits were fed a 2% cholesterol diet together with daily SM (4.8 gm/kg body wt.) treatment (SM; n=10) or without SM as a control (C; n=9) for 6 weeks. Probucol-treated (0.6 gm/kg body wt.) rabbits (P; n=9) were used as a positive control group. A balloon injury of the abdominal aorta was performed at the end of the third week. Aortas were harvested at the end of 6 weeks. The plasma cholesterol levels were lowered in SM group. The neointimal hyperplasia in abdominal aortas was significantly inhibited in SM group [neointima/media area ratio: 0.63+/-0.05 (SM) versus 0.78+/-0.05 (C); P < 0.05] and in P group [0.45+/-0.02 (P) versus 0.78+/-0.05 (C); P < 0.05] when compared with C group. SM treatment significantly reduced MCP-1 mRNA and protein expression in balloon-injured abdominal aorta. These inhibitory effects on intimal response after balloon injury might be attributed to antioxidant capacity and cholesterol lowering effect of SM. SM treatment may offer some protection against post-angioplasty restenosis.     

The role of acute wall recoil and late restenosis: results of the OCBAS trial (Optimal Coronary Balloon Angioplasty with Provisional Stenting versus Primary Stent)

Early deterioration of minimal luminal diameter immediately after PTCA, has been associated with an increase of late restenosis. Lesions with no early loss after PTCA have a low restenosis rate. Coronary stents reduce restenosis in lesions exhibiting early wall recoil. The purpose of the OCBAS study was to compare two strategies during coronary interventions; provision vs. elective stenting. 116 patients with good PTCA results were randomized to stent (n = 57) or to optimal PTCA (n = 59). After randomization in PTCA group, 13.5% of the patients crossed over to stent due to early loss (provisional stenting). Baseline demographic and angiographic characteristics were similar in both groups of patients. At 7.6 months, 96.6% of the entire population had a follow-up angiographic study; 98.2% in the stent and 94.9% in the PTCA group. Immediate and follow-up angiographic data showed that acute gain was significantly higher in the stent than in the PTCA group (1.95 vs. 1.5 mm; P < 0.03). However, late loss was significantly higher in the stent than the PTCA groups (0.63 +/- 0.59 vs. 0.26 +/- 0.44, respectively; P = 0.01). Hence, net gain with both techniques was similar (1.32 +/- 0.3 vs. 1.24 +/- 0.29 mm for the stent and PTCA groups respectively; P = NS). Angiographic restenosis rate at follow-up (19.2% in stent vs. 16.4% in PTCA; P = NS) and TVR (17.5 in stent vs. 13.5% in PTCA; P = NS) were also similar. Furthermore, event-free survival was 80.8% in the stent versus 83.1% in the PTCA group (P = NS). Overall costs (hospital and follow-up) were US$591,740 in the stent versus US$398,480 in the PTCA group (P < 0.02). The strategy of the PTCA with delay angiogram and provisional stent if early loss occurs, had similar restenosis rate and TVR than universal use of bare stents.     

Effect of prolonged renal dysfunction on intravascular and extravascular pulmonary fluid volumes during left atrial hypertension

To examine the development of pulmonary edema during experimental renal dysfunction, left atrial pressure was altered in 14 mongrel dogs divided into two groups. Group 1 was composed of seven control animals, and Group 2 was composed of seven animals with surgically induced renal failure (1 week of bilateral ureteral ligation). Data were obtained at two levels of matched transmural pulmonary vascular pressure (defined as mean left atrial pressure less serum protein osmotic pressure). In the animals with renal dysfunction, extravascular lung water (EVLW) (thermal-green dye technique) was higher at moderately (-1 to -2 mm Hg) and severely elevated (11 to 12 mm Hg) vascular driving pressures (11.5 +/- 1.2 cc/kg vs 10.6 +/- 0.8 cc/kg and 14.8 +/- 1.3 cc/kg vs 13.0 +/- 1.9 cc/kg, respectively, both P less than 0.05 vs control). Because protein osmotic pressure was lower in the renal failure group (15.0 +/- 1.8 mm Hg vs 18.4 +/- 1.4 mm Hg, P less than 0.05), greater accumulations of extravascular lung water occurred at lower levels of left atrial pressure (14.2 +/- 1.4 mm Hg vs 17.1 +/- 1.2 mm Hg, P less than 0.05; 26.8 +/- 2.6 mm Hg vs 29.5 +/- 2.3 mm Hg, P less than 0.01). In addition, when the ratio of EVLW/PBV (pulmonary blood volume) was examined in both groups at each stage of the experiment, the ratio was greater in the Group 2 animals at each elevated pressure, suggesting increased permeability with renal dysfunction. In conclusion, pulmonary edema formation occurs at lower left atrial pressures in the setting of sustained renal dysfunction, this phenomenon can be partially explained by lower protein osmotic pressure though altered pulmonary microvascular permeability may contribute to edema formation.