Serial six year quantitative angiographic follow up in asymptomatic patients following successful coronary angioplasty.

OBJECTIVE: To evaluate long term (six years) lumen changes after balloon angioplasty by using quantitative coronary angiography. METHODS: Complete serial quantitative coronary angiography (before and after angioplasty and at six months, three years, and six years) was performed in 100 patients with successful angioplasty and without subsequent repeated revascularisation. In all, 198 dilated segments were compared with 395 non-dilated segments that were obtained from non-target arteries of study patients. RESULTS: From six months to three years after angioplasty, minimum lumen diameter (MLD) increased significantly by 0.13 (0.28) (mean (SD)) mm in dilated segments and decreased significantly by 0.04 (0.27) mm in non-dilated segments. From three years to six years, MLD remained stable in dilated segments but decreased further (by 0.04 (0.28) mm) in non-dilated segments. Consequently, the DeltaMLD between six months and six years was larger in dilated segments than in non-dilated segments (0.12 (0.32) v -0.08 (0.34); p < 0.001). Further, DeltaMLD from six months to six years correlated positively with the percentage diameter stenosis (DS) at six months in each group (dilated segments r = 0.47, p < 0.0001; non-dilated segments r = 0.49, p < 0.0001). Multivariate analysis showed that the only independent predictor of DeltaMLD over six years for each group was the DS at six months. CONCLUSIONS: Lesion regression occurs within the first three years after angioplasty and reaches a plateau thereafter. Moreover, the stenosis severity at six months predicts the magnitude of late regression after angioplasty.

Final results of the CAPAS trial.

BACKGROUND: The Cutting Balloon (Interventional Technologies Inc) is a new-concept balloon that incorporates 3 to 4 blades to create sharp incisions on the luminal surface of the lesion during dilation without causing severe tearing injury to the vessel wall. It may reduce restenosis and improve clinical outcome. METHODS: Two hundred forty-eight lesions were randomly assigned to Cutting Balloon angioplasty (CBA, 120 lesions) or conventional balloon angioplasty (PTCA, 128 lesions). Inclusion criteria were type B/C lesions (American College of Cardiology/American Heart Association classification) and reference diameter <3.0 mm by visual image on angiogram. Quantitative coronary angiography was performed before and after percutaneous coronary angioplasty and at 3-month follow-up. The primary end point was restenosis, defined as >/=50% diameter stenosis at follow-up. Clinical event rates at 1 year were assessed. RESULTS: Baseline characteristics were similar. Reference diameter was small in both groups (2.16 vs 2.18 mm, CBA vs PTCA). Preprocedural percent diameter stenosis (%DS) was similar (69.8% vs 69.6%). However, postprocedural and follow-up %DS were lower (26.2% vs 28.9%, P =.072; 40.8% vs 47.5%, P =.011) in the CBA group. Restenosis was significantly lower (25.2% vs 41.5%, P =.009) in the CBA group. At 1 year, event-free survival was achieved in 72.8% of the CBA group and in 61.0% of the PTCA group (P =.047). CONCLUSION: These findings suggest that CBA provides superior angiographic and clinical outcomes in comparison with PTCA in small coronary arteries.

Impact of pre-stent plaque debulking for chronic coronary total occlusions on restenosis reduction.

BACKGROUND: While stenting improves the long-term angiographic outcomes of successfully recanalized chronic coronary total occlusions (CTO), the restenosis rate still remains high. The massive plaque burden in CTO is considered to be one of the causes of in-stent restenosis. METHODS: We examined the pre-stent plaque debulking strategy with high-speed rotational atherectomy (RA) for 50 CTO (Thrombolysis in Myocardial Infarction flow grade 0; estimated occlusive duration, 3 months). Angiographic follow-up results were compared to those of 120 consecutive CTO recanalized with primary stenting in which RA could be indicated retrospectively. Angiographic restenosis was defined as diameter stenosis > 50% at 6-month follow-up. RESULTS: RA could be performed safely in all lesions without any major complications. Adjunctive ballooning and stenting could be performed without high-pressure dilatation (8.4 +/- 1.7 atmospheres). Follow-up angiography was performed in 48 lesions 184 +/- 61 days after the procedure. There were no significant differences in baseline characteristics between the two groups; however, the implanted stent type was different. Quantitative coronary angiography revealed that diameter stenosis was smaller at follow-up (36.2 +/- 20.0% versus 52.2 +/- 26.7%; p = 0.0003) as well as post-procedure (7.8 +/- 11.5% versus 17.8 +/- 13.6%; p < 0.0001) compared with the control group. Angiographic restenosis was also significantly reduced (29.2% versus 52.5%; p = 0.0061). CONCLUSIONS: RA is a safe procedure for plaque debulking of CTO in selected cases. Plaque debulking of CTO facilitates subsequent stent expansion and may reduce the restenosis rate.

Identification of the transcriptional regulatory sequences of human calponin promoter and their use in targeting a conditionally replicating herpes vector to malignant human soft tissue and bone tumors.

The calponin (basic or h1) gene, normally expressed in maturated smooth muscle cells, is aberrantly expressed in a variety of human soft tissue and bone tumors. In this study, we show that expression of the calponin gene in human soft tissue and bone tumor cells is regulated at the transcriptional level by the sequence between positions -260 and -219 upstream of the translation initiation site. A novel conditionally replicating herpes simplex virus-1 vector (d12.CALP) in which the calponin promoter drives expression of ICP4, a major trans-activating factor for viral genes was constructed and tested as an experimental treatment for malignant human soft tissue and bone tumors. In cell culture, d12.CALP at low multiplicity of infection (0.001 plaque-forming unit/cell) selectively killed calponin-positive human synovial sarcoma, leiomyosarcoma, and osteosarcoma cells. For in vivo studies, 10 animals harboring SK-LMS-1 human leiomyosarcoma cells were randomly divided and treated twice on days 0 and 9 intraneoplastically with either 1 x 10(7) plaque-forming units of d12.CALP/100 mm(3) of tumor volume or with medium alone. The viral treatment group showed stable and significant inhibition of tumorigenicity with apparent cure in four of five mice by day 35. Replication of viral DNA demonstrated by PCR amplification and expression of the inserted LacZ gene visualized by 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside histochemistry was associated with oncolysis of d12.CALP-treated tumors, while sparing normal vascular smooth muscle cells. In mice harboring two SK-LMS-1 tumors, replication of d12.CALP was detected in a nontreated tumor distant from the site of virus inoculation. These results indicate that replication-competent virus vectors controlled by the calponin transcriptional regulatory sequence may be a new therapeutic strategy for treatment of malignant human soft tissue and bone tumors.

[Role of calponin in the generation and differentiation of blood vessels - increased bone formation in mice lacking smooth muscle calponin -].

Mice lacking smooth muscle calponin (also called basic calponin or calponin h1) expression displayed enhanced entopic bone formation in vivo, induced by recombinant human bone morphogenetic protein-2 (rhBMP-2) and an augmentation of the degree of osteoblastic differentiation of embryonic mesenchymal cells when they were stimulated by rhBMP-2. Calponin messenger RNA was shown to be expressed in developing and healing bone tissues. An examination of the skeletons of mutated mice showed increased postnatal bone formation characterized by an increase in the number of activated periosteal osteoblasts. These data revealed that calponin plays an important role in regulating the osteogenic differentiation of mesenchymal cells.

Regulation of shortening velocity by calponin in intact contracting smooth muscles.

To elucidate the function of calponin in intact contracting smooth muscle cells in vivo, we generated mice with a mutated basic calponin (h1) locus (Yoshikawa et al., Genes Cells 3, 685-695, 1998). Crossbridge cycling rates were estimated in aortic smooth muscle by the force redevelopment following an isometric step shortening as a function of time after K(+) depolarization. Evidence is presented that calponin is involved in the inhibition of shortening velocity in the tonic phase of contraction. The phosphorylation levels of myosin regulatory light chain and cytosolic calcium concentrations were not significantly different in paired comparisons between calponin-deficient (-/-) and wild-type (+/+) muscles at any time point after stimulation. The force-velocity relationships in vas deferens smooth muscle showed that the maximum shortening velocity of -/- muscle was significantly faster than that of +/+ muscle. There was no change in the length-force relationships in both -/- and +/+ muscles of aorta and vas deferens. The results suggest that calponin plays a role in regulation of the crossbridge cycling and that it may be responsible for reduced shortening velocity during a maintained contraction of mammalian smooth muscle.

The Potential of Cilostazol in Interventional Cardiology.

Cilostazol, an antiplatelet agent developed in Japan, has been demonstrated to have the potential to reduce restenosis after percutaneous transluminal coronary angioplasty (PTCA). Unlike conventional antiplatelet agents, cilostazol has several favorable properties in reducing restenosis. Besides the vasodilatory effect, cilostazol directly inhibits smooth muscle proliferation and may enhance reendothelialization after PTCA. Although the magnitude of prevention of restenosis may differ with the PTCA device used, cilostazol appears quite promising as a pharmacologic treatment adjunct to PTCA.

Percutaneous myocardial ablation in double-chamber right ventricle.

Double-chamber right ventricle (DCRV) exhibits intracavitary outflow obstruction. We report the first case of percutaneous myocardial ablation of DCRV in a 73-year-old patient. An alcohol-induced conus branch occlusion provided the reduction of pressure gradient from 81 to 48 mm Hg and clinical improvement. This strategy may be an alternative therapy to surgery in the adult patients with DCRV. Cathet. Cardiovasc. Intervent. 49:97-101, 2000.

Final results of the STent versus directional coronary Atherectomy Randomized Trial (START)

OBJECTIVES: This study was designed to compare primary stenting with optimal directional coronary atherectomy (DCA). BACKGROUND: No previous prospective randomized trial comparing stenting and DCA has been performed. METHODS: One hundred and twenty-two lesions suitable for both Palmaz-Schatz stenting and DCA were randomly assigned to stent (62 lesions) or DCA (60 lesions) arm. Single or multiple stents were implanted with high-pressure dilation in the stent arm. Aggressive debulking using intravascular ultrasound (IVUS) was performed in the DCA arm. Serial quantitative angiography and IVUS were performed preprocedure, postprocedure and at six months. The primary end point was restenosis, defined as > or =50% diameter stenosis at six months. Clinical event rates at one year were also assessed. RESULTS: Baseline characteristics were similar. Procedural success was achieved in all lesions. Although the postprocedural lumen diameter was similar (2.79 vs. 2.90 mm, stent vs. DCA), the follow-up lumen diameter was significantly smaller (1.89 vs. 2.18 mm; p = 0.023) in the stent arm. The IVUS revealed that intimal proliferation was significantly larger in the stent arm than in the DCA arm (3.1 vs. 1.1 mm ; p < 0.0001), which accounted for the significantly smaller follow-up lumen area of the stent arm (5.3 vs. 7.0 mm2; p = 0.030). Restenosis was significantly lower (32.8% vs. 15.8%; p = 0.032), and target vessel failure at one year tended to be lower in the DCA arm (33.9% vs. 18.3%; p = 0.056). CONCLUSIONS: These results suggest that aggressive DCA may provide superior angiographic and clinical outcomes to primary stenting.

Impact of cilostazol on restenosis after percutaneous coronary balloon angioplasty.

BACKGROUND: Restenosis after percutaneous transluminal coronary (balloon) angioplasty (PTCA) remains a major drawback of the procedure. We previously reported that cilostazol, a platelet aggregation inhibitor, inhibited intimal proliferation after directional coronary atherectomy and reduced the restenosis rate in humans. The present study aimed to determine the effect of cilostazol on restenosis after PTCA. METHODS AND RESULTS: Two hundred eleven patients with 273 lesions who underwent successful PTCA were randomly assigned to the cilostazol (200 mg/d) group or the aspirin (250 mg/d) control group. Administration of cilostazol was initiated immediately after PTCA and continued for 3 months of follow-up. Quantitative coronary angiography was performed before PTCA and after PTCA and at follow-up. Reference diameter, minimal lumen diameter, and percent diameter stenosis (DS) were measured by quantitative coronary angiography. Angiographic restenosis was defined as DS at follow-up >50%. Eligible follow-up angiography was performed in 94 patients with 123 lesions in the cilostazol group and in 99 patients with 129 lesions in the control group. The baseline characteristics and results of PTCA showed no significant difference between the 2 groups. However, minimal lumen diameter at follow-up was significantly larger (1.65+/-0.55 vs 1.37+/-0.58 mm; P<0.0001) and DS was significantly lower (34.1+/-17.8% vs 45.6+/-19. 3%; P<0.0001) in the cilostazol group. Restenosis and target lesion revascularization rates were also significantly lower in the cilostazol group (17.9% vs 39.5%; P<0.001 and 11.4% vs 28.7%; P<0. 001). CONCLUSIONS: Cilostazol significantly reduces restenosis and target lesion revascularization rates after successful PTCA.

Simple high-performance liquid chromatography determination of ampicillin in human serum using solid-phase extraction disk cartridges.

A simple and reproducible method for the analysis of ampicillin in human serum was developed. Serum samples were extracted using solid-phase extraction disk cartridges containing a sorbent of styrene divinyl/benzene. Extracts were separated by reversed-phase C18 high-performance liquid chromatography with UV detection at 220 nm. The mobile phase consisted of acetonitrile-10 mM NaH2PO4 (6.5:93.5, v/v). Using this extraction procedure, recovery from serum was 98.4+/-5.6%. The quantitation limit was 0.19 microg/ml using 0.5 ml of serum. The calibration curves from 0.19 to 9.41 microg/ml were linear with correlation coefficients of 0.999. This method is suitable for therapeutic drug monitoring of ampicillin (ABPC) after oral administration of lenampicillin hydrochloride.

Percutaneous revascularization of lesions with saphenous vein graft failure: influence of chronic total occlusion on early outcome.

The purpose of this study was to evaluate a therapeutic strategy of percutaneous transluminal coronary angioplasty (PTCA) in patients with recurrent angina following coronary artery bypass grafting. The study looked at 112 branches associated with graft failure, excluding new lesions in the native coronary artery (NCA). Chronic total occlusion (CTO) was observed in 50% of NCA (56/112) and in 68% of the grafts (76/112). Thirty-three branches (29%) showed CTO in both NCA and the graft. The overall success rate was 86% (96/112). The success rate on NCA was 98% (44/45) in non-CTO, while in CTO it was significantly lower at 62% (18/29). As to grafts, the success rate was 94% (32/34) in non-CTO, while it was 50% (2/4) in CTO. These characteristics, with respect to lesion morphology and the prevalence of CTO, exerted an influence on the selection of the access vessels for revascularization. Early outcome depended on the result of treatment of CTO.

Transluminal percutaneous septal myocardial ablation in a patient with hypertrophic obstructive cardiomyopathy.

Reduction of septal mass by inducing septal infarction using catheter techniques is a new therapy for hypertrophic obstructive cardiomyopathy (HOCM). We report a case of severe HOCM that was dramatically improved by this non-surgical treatment. A 60-year-old woman with HOCM had suffered dyspnea (NYHA class III) with syncopal attack despite medical treatment. Left heart catheterization showed a resting pressure gradient across the left ventricular outflow tract of 156 mmHg. Two proximal septal branches of the anterior descending coronary artery were catheterized with a balloon catheter by the usual percutaneous coronary angioplasty techniques and were completely blocked by injection of absolute alcohol. The pressure gradient decreased to 26 mmHg after the procedure. Symptoms were markedly improved (NYHA class I) without any medical treatment. The reduced pressure gradient was maintained at the 3-month follow-up catheterization (36 mmHg). Further long-term follow-up is needed, but this treatment would seem to to be a promising technique for reducing pressure gradient in symptomatic patients with HOCM.

Comparison of quantitative coronary angiographic results after directional coronary atherectomy and balloon angioplasty of protected left main coronary stenosis.

We compared the angiographic and clinical outcomes after directional coronary atherectomy (DCA, 13 patients) with those after conventional balloon angioplasty (BA, 21 patients) in patients with protected left main coronary artery stenosis. The initial success rate was 100% in the DCA group and 81% (17 of 21) in the BA group. Restenosis was present in 2 of 11 patients in the DCA group and 9 of 16 patients in the BA group (18% vs. 56%, P < 0.05). DCA and BA improved a minimal lumen diameter. The initial gain after DCA was greater than that after BA. At follow-up, the minimal lumen diameter was larger and the percentage diameter stenosis was smaller in the DCA group than in the BA group. The late loss and loss index were equivalent in both groups. Compared with conventional BA, DCA in protected left main coronary artery stenosis is associated with a higher angiographic success rate and provides a wider luminal diameter with reduced incidence of restenosis.

Impact of cilostazol on intimal proliferation after directional coronary atherectomy.

Cilostazol, a novel platelet aggregation inhibitor, inhibits intimal proliferation in animal models. We randomly assigned 41 patients with lesions suitable for directional coronary atherectomy to the cilostazol group (200 mg/day) or the aspirin (250 mg/day) group. Medication was started before directional coronary atherectomy and was continued to a 6-month follow-up. Serial quantitative coronary angiography and intravascular ultrasound study were performed. Baseline characteristics were not different between the two groups. However, the minimal lumen diameter at follow-up was larger (2.33 +/- 0.60 mm vs 1.81 +/- 0.68 mm, p = 0.016) and the percent diameter stenosis (24.5% +/- 16.6% vs 40.9% +/- 21.0%, p = 0.010) was smaller in the cilostazol group. The change in vessel area was not different, but the percent plaque area at follow-up was smaller in the cilostazol group (55.7% +/- 11.2% vs 64.5% +/- 14.5%, p = 0.044). The restenosis rate was significantly lower in the cilostazol group (0% vs 26%, p = 0.020). We conclude that cilostazol appears to have an inhibitory effect on intimal proliferation after directional coronary atherectomy and may reduce restenosis.

Elevated calcium level induces calcium-dependent proteolysis of A-CAM (N-cadherin) in heart--analysis by detergent-treated model.

Calcium overload induces cardiac muscle cell dysfunction in cardiovascular diseases. We investigated the effects of elevated calcium level on adherens-junction-specific cell adhesion molecule (A-CAM). Incubation of Triton X-100-treated canine heart homogenate in the presence of Ca2+ reduced the content of A-CAM. Reduction in A-CAM requires milli-molar Ca2+ and was inhibited by protease inhibitors, leupeptin and calpeptin. Immunohistochemical observation revealed that m-calcium-activated neutral protease (m-CANP) was colocalized with A-CAM in intercalated disks. These data suggested that m-CANP proteolyzes A-CAM in response to calcium overload in cardiac muscle.

Disruption of cell-cell adhesion in an inbred strain of hereditary cardiomyopathic hamster (Bio 14.6).

OBJECTIVE: Disarrangement of cardiomyocytes is a pathological characteristic of dilated cardiomyopathy. Hereditary cardiomyopathic hamster Bio 14.6, a model of dilated cardiomyopathy, displays disorder of cardiomyocyte arrangement. The aim of this study was to analyse the disturbance of cell alignment from the point of view of the cell-cell adhesion system in Bio 14.6. METHOD: Cardiomyopathic hamster Bio 14.6 was used as a model of dilated cardiomyopathy. Histological study was performed by light and electron microscopy. Disorder of the adherens junction-specific cell-adhesion molecule (A-CAM) was analysed by immunofluorescent microscopy and immunoblotting with anti-A-CAM antibody. RESULTS: Hematoxylin-eosin staining revealed that intercalated disks were identifiable less clearly in cardiomyopathy than in a normal cardiac muscle. It was disclosed by electron microscopy that cardiomyocytes adhered to each other with reduction in subsarcolemmal electron density at intercalated disks in Bio 14.6 compared with normal hamsters. We examined the localization of the A-CAM molecule in heart by immunofluorescent microscopy. In contrast to normal cardiac samples, fluorescence was weak in intensity and unclearly demarcated in the Bio 14.6 hamsters. We measured the content of A-CAM in the heart. In Bio 14.6 hamsters, the content of A-CAM was 60 +/- 11% of that measured in normal adult hamsters. A-CAM was reduced to a lesser extent (81 +/- 12%) in the newborn hamsters. CONCLUSIONS: In Bio 14.6 hamster, structural disturbance of the intercalated disks was found on histological examination of the heart. Biochemically, A-CAM, which plays a role in intercellular adhesion in intercalated disk areas, decreased significantly. These results suggest that cardiomyopathy may be accompanied by structural disruption of cell-cell adhesion in intercalated disk regions, which may lead to the pathological feature of disarranged cardiomyocytes.

[Metabolism of lomerizine hydrochloride (KB-2796) in rats].

The metabolism of lomerizine was investigated after the oral administration of [methine-14C] or [benzyl-14C]lomerizine hydrochloride in rats. 1. Urinary, fecal and biliary excretions of the unchanged drug were less than 1% of dose, showing that lomerizine was eliminated by the extensive biotransformation after the oral administration. 2. The main metabolites were 1-(2,3,4-trimethoxybenzyl)piperazine (M7) and 2,3-dimethoxy-4-hydroxybenzylpiperazine in the urine, and 1-[bis(4-fuluorophenyl)methyl]-4-(2,3-dimethoxy-4-hydroxybenzyl)pi perazine in the feces and bile. 3. The radioactive substances in the plasma, liver and brain mainly existed as unconjugated forms, of which the intact drug showed the highest concentration. 4. The main metabolites in the plasma, and in the liver and brain were 1-[bis(4-fuluorophenyl)methyl]-4-(3,4-dimethoxy-2-hydroxybenzyl)pi perazine and bis(4-fluorophenyl)methylpiperazine (M6), respectively. 5. The plasma level of M7 and the biliary excretion of bis(4-fluorophenyl)-methanol in male rats were higher than those in female rats, suggesting the sex difference in the N-dealkylation at the 4-position of piperazine ring of the drug.

Immunoaffinity extraction of 4-hydroxy-2-(4-methylphenyl)benzothiazole and its metabolites for determination by gas chromatography-mass spectrometry.

Immunoaffinity extraction of 4-hydroxy-2-(4-methylphenyl)benzothiazole and its metabolites, together with the corresponding meta-isomers has been achieved by the use of an antibody raised against an immunogen, an O-carboxymethyloxime-bovine serum albumin conjugate of 4-hydroxy-2-(4-formylphenyl)benzothiazole. The antibody produced exhibited a broad spectrum of affinity, not only for metabolites oxidized at the 4-methyl group of the benzene moiety but also for the corresponding meta-isomers. Up to 4 micrograms in total of these benzothiazoles could be extracted on the immunoaffinity adsorbent and recovered almost quantitatively by elution with 90% methanol. The resulting chromatogram was free from any interference. The eluted compounds were derivatized by conversion to their methyl esters and/or trimethylsilyl ethers, and subsequently separated into individual benzothiazoles by means of gas chromatography-mass spectrometry. The derivatized compounds were monitored using a characteristic ion, [M-CH3]+., and the limit of detection was 10 fmole. The peak height ratio of each metabolite to its corresponding meta-isomer internal standard was plotted against the concentration of the former and good linearity was observed over the range 0.2-5 ng/ml.

Novel immunoaffinity extraction for liquid chromatographic determination of major metabolites of 4-acetoxy-2-(4-methylphenyl)benzothiazole in plasma.

Group extraction of the metabolites of 4-acetoxy-2-(4-methylphenyl)benzothiazole has been achieved through the use of an immunoaffinity adsorbent. The antisera elicited from an immunogen, 4-hydroxy-2-(4-formylphenyl)benzothiazole O-carboxymethyloxime-bovine serum albumin conjugate, were characterized to have a broad affinity spectrum for major metabolites oxidized at the 4-methyl group of the benzene moiety. One millilitre of the immunoaffinity adsorbent prepared by immobilization of antibodies (12.5 mg ml-1) was capable of retaining up to 4 micrograms of benzothiazoles. The adsorbates were recovered quantitatively by elution with 90% (v/v) methanol without any interfering peaks on the high-performance liquid chromatogram. The peak-height ratio of each metabolite to an internal standard was plotted against the concentration of the former substance; good linearity was observed in the range of 10-500 ng ml-1.