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Background: Interstitial fibroblasts are central to the inflammatory response during the progression of tubulointerstitial fibrosis. We examined the efficiency of a new gene transfer method that targets interstitial cells by using parenchymal injection of DNA followed by electroporation., Methods: Fluoresceinisothiocyanate-labelled oligodeoxynucleotides (FITC-ODNs) or expression vectors were directly injected into the cortex of the kidney, followed by electroporation., Results: Transfection with FITC-ODNs or the EGFP expression vector resulted in efficient transfection in interstitial fibroblasts, but not in tubular epithelial cells or glomerular cells. Transfection efficiency was optimal after using a total of 150 microg of DNA in 1000 microl of PBS, combined with clamping of the renal vessels prior to electroporation. Gene expression peaked at 4 days after transfection and decreased by two orders of magnitude at 6 weeks post-transfection; however, expression recovered to near peak levels after parenchymal or intraperitoneal injection of FR901228, a histone deacetylase inhibitor., Conclusion: We demonstrated that direct parenchymal injection of DNA combined with electroporation enables gene transfer into interstitial fibroblasts.

Object: Although atypical teratoid/rhabdoid tumor (AT/RT) is known to generate through inactivation of the hSNF5/INI1 gene on chromosome 22q, the downstream molecular mechanism remains unclear. We histologically and molecularly reviewed our pediatric brain tumors for unrecognized AT/RTs and evaluated the role of cyclin D1, a potential molecular target of hSNF5/INI1., Methods: We analyzed 16 tumors under three years of age: seven medulloblastomas, three anaplastic ependymomas (E IIIs), two each of supratentorial primitive neuroectodermal tumors (sPNETs) and choroid plexus carcinomas (CPCs), and one each of neuroblastoma and pineoblastoma. Immunohistochemistry for glial fibrillary acidic protein, vimentin, epithelial membrane antigen, smooth muscle actin and cyclin D1 was performed. Polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis with direct sequencing, differential PCR and microsatellite analysis were conducted for hSNF5/INI1mutation, homozygous deletion and loss of heterozygosity (LOH) on 22q, respectively. Because of the presence of rhabdoid cells and the polyimmunophenotypic features, the diagnosis was revised to AT/RT in five (31%) tumors, namely, two E IIIs and one each of medulloblastoma, CPC and pineoblastoma. Three of them harbored such hSNF5/INI1 aberrations as germline single base deletion (492/6 delC) and missense mutation (C157T) together with LOH 22q or homozygous deletion. Cyclin D1 was overexpressed in those three tumors but not in the two that lacked hSNF5/INI1 inactivation., Conclusion: AT/RT can be misdiagnosed as a variety of tumors, including ependymoma that potentially harbors LOH 22q. Our data indicate that cyclin D1 is a target of hSNF5/INI1in primary tumors.

Background: We developed an electroporation-mediated gene transfer method targeting glomerular mesangial cells. Injecting DNA solution via renal artery followed by electric pulses using tweezers-type electrodes could result in efficient transfection in mesangial cells. Therefore, this gene transfer system opened a feasible strategy to manipulate the function of several cytokines and growth factors in mesangial cells. Recently, a new generation of catalytic nucleic acid composed of DNA, named DNA enzyme (DNAzyme), has been developed., Method: We generated a DNAzyme (TGFDE) targeting transforming growth factor-beta1 (TGF-beta1), and examined the therapeutic effect of TGFDE in vitro and in vivo., Results: In cultured rat mesangial cells, treatment with TGFDE blocked TGF-beta1 mRNA expression, and thereby suppressed type I collagen mRNA expression. Next, we introduced TGFDE or scrambled DNAzyme (TGFSCR) into anti-Thy-1 model of nephritic rats by electroporation 3 days after disease induction. Northern blot analysis and immunohistochemical staining demonstrated that glomerular message and protein expression of TGF-beta1, alpha-smooth muscle actin (alpha-SMA), and type I collagen were suppressed in TGFDE-transfected nephritic rats compared with untreated nephritic rats and TGFSCR-transfected rats on day 7. Consequently, we observed significant reduction in glomerular matrix score in TGFDE-transfected nephritic rats., Conclusion: Inhibition of TGF-beta1 expression by electroporation-mediated DNAzyme transfer might be useful for the therapy of glomerulonephritis.

Background: The clinical utility of cyclosporine A (CsA) has been limited by its nephrotoxicity, which is characterized by tubular atrophy, interstitial fibrosis, and progressive renal impairment. Hepatocyte growth factor (HGF) has been reported to protect and salvage from renal injury as a renotropic and antifibrotic factor. Here, we investigated protective effects of HGF gene therapy on rat CsA-induced nephrotoxicity using electroporation-mediated gene transfer., Method: CsA was subcutaneously administered daily under low sodium diet, and HGF gene was transferred into skeletal muscle by electroporation on days 7 and 14. We also examined the antiapoptotic mechanism of HGF using human proximal tubular epithelial cells., Results: HGF gene transfer rescued CsA-induced initial tubular injury and suppressed interstitial infiltration of ED-1-positive macrophages in CsA-induced nephrotoxicity. In addition, HGF significantly inhibited tubular cell apoptosis, and increased the number of proliferating tubular epithelial cells. In vitro studies suggest that HGF executes the antiapoptotic function by enhancing the phosphorylation of Akt and Bcl-2. Northern blot analysis demonstrated that HGF gene transfer suppressed cortical mRNA levels of transforming growth factor-beta (TGF-beta). Consequently, HGF gene transfer significantly reduced a striped interstitial phenotypic alteration and fibrosis., Conclusion: We demonstrated that HGF gene transfer reduced CsA-induced tubular cell apoptosis and interstitial fibrosis. HGF gene transfer could be a potential strategy for preventing renal fibrosis.

Kidney-targeted gene therapy could be an ideal treatment for renal diseases since the therapeutic molecule is limited in the kidney and the systemic effect may be minimized. The technical development of the gene delivery to kidney and the identification of the responsive gene for a particular disease encourage the challenge to hereditary diseases. Collagen type IV reassembling was reported to be succeeded in Alport syndrome model by introduction of exogenous COL4A5 gene. Many gene therapies are evaluated in various glomerulonephritis models and unilateral ureteral obstruction (UUO) model, and favorable results are accumulated. Transplant kidney is an ideal target for gene therapy, by which ischemia reperfusion, acute rejection and chronic allograft nephropathy can be treated. The importation of the novel technology, for example hybrid stem cell-gene therapy could promote the gene therapy of renal diseases toward clinical application.

Specific treatment of chronic progressive renal disease is very limited. TGF-beta, considered as the major cytokine causing tissue scarring, must be activated extracellularly before it can bind to its receptors. Thrombospondin-1 (TSP1) has been identified as an activator of latent TGF-beta in in vitro systems and in pancreas and lung homeostasis in mouse pups in vivo, but whether this is also true in inflammatory fibrotic disease is unknown. We examined a rat model of mesangial proliferative glomerulonephritis, where TGF-beta has been demonstrated to mediate renal fibrosis. In this study, antisense phosphorothioate oligonucleotides against TSP1 were successfully transferred into almost all glomeruli of perfused diseased kidneys and markedly inhibited de novo synthesis of TSP1. This effect was accompanied by decreased activation but not expression of TGF-beta and by the inhibition of the TGF-beta-dependent smad-signaling pathway, as well as transcription of TGF-beta target genes such as EDA-fibronectin, resulting in a markedly suppressed accumulation of extracellular matrix. In sharp contrast, neither glomerular cell proliferation nor influx of macrophages was affected by this therapy in experimental mesangial proliferative glomerulonephritis. These results demonstrate that TSP1 is the major endogenous activator of TGF-beta in experimental inflammatory kidney disease.

The authors report a case of the rhabdoid predisposition syndrome (RPS) secondary to a germline hSNF5/INI1 mutation, whose brain tumor was originally unclassified but finally diagnosed as an atypical teratoid/rhabdoid tumor (AT/RT) by molecular analysis. A 7-month-old infant presented with hydrocephalus secondary to a huge pineal tumor and subsequently developed a renal rhabdoid tumor. The histology of the brain tumor was initially undetermined; however, an AT/RT was strongly suspected because of her clinical course. Mutational screening of the hSNF5/INI1 gene by heteroduplex and direct sequence analysis detected a missense mutation at codon 53 (CGA --> TGA, arginine --> stop) in both tumors, as well as in normal tissue of the kidney. Polymerase chain reaction (PCR)-based microsatellite analysis showed in both tumors allelic loss on chromosome arm 22q to which the hSNF5/INI1 gene maps. c-myc amplification was examined by differential PCR but not detected. Histologic review of the brain tumor by immunohistochemistry confirmed focal expression of epithelial membrane antigen and smooth muscle actin. These findings suggest that the brain tumor was really an AT/RT as a component of RPS secondary to a germline hSNF5/INI1 mutation. The present mutation has never been reported in the literature.

Sodium ozagrel (ozagrel), a selective thromboxane A2 synthetase inhibitor, has been used for the treatment of various types of acute ischemic stroke, except cardioembolic stroke. Recently, edaravone, a novel free radical scavenger, has been approved for the treatment of acute ischemic stroke within 24 hours after onset. Since these two drugs differ in mode of action, we hypothesized that combination of both drugs would yield further improvement of the outcome of patients with acute ischemic stroke. The clinical efficacy of combination therapy with edaravone and ozagrel for acute ischemic stroke was studied retrospectively, and compared with that of ozagrel alone. A total of 62 patients who suffered acute ischemic stroke within 24 hours after onset during the 10-month period from June 2001 to March 2002, were treated with both edaravone and ozagrel (E-O group), while 76 patients during August 2000 to May 2001, were treated with ozagrel alone (O group). The rate of modified Rankin Scale (MRS) 0 and 1 at discharge in the total ischemic stroke and atherothrombotic stroke, was significantly higher in the E-O group than in the O group. The improvement in MRS also differed between E-O group and O group in total. The difference was significant in patients with atherothrombotic stroke but not in those with lacunar stroke. These results indicate that combination therapy with edaravone and ozagrel is more effective than mono-therapy with ozagrel for the treatment of acute ischemic, especially of atherothrombotic stroke.

Background: Tryptophan (TRP), an essential amino acid, is bound mostly to albumin in plasma. However, it is reported that binding is inhibited by indoles that accumulate in uremic plasma. This may be responsible for the malnutrition observed in uremic patients. AST-120, an oral adsorbent of uremic toxins, can reduce concentrations of indoxyl sulfate (IS), the most abundant indolic metabolite in uremic plasma. We therefore investigated whether AST-120 recovers TRP binding to plasma proteins and improves the nutritional state of uremic patients., Methods: The in vitro binding ratio of TRP to bovine serum albumin (BSA) was measured in the presence of IS by the equilibrium dialysis technique. In addition, five predialysis patients with chronic renal failure (CRF) were administered AST-120 for 2 months. Plasma concentrations of total TRP, IS, and free TRP were measured in five healthy volunteers (normal [N] group) and five patients with CRF before and after 2 weeks of AST-120 therapy (6 g/d). Their nutritional statuses also were compared before and after 2 months of AST-120 administration., Results: IS inhibited in vitro binding of TRP to BSA in a dose-dependent manner. Total TRP concentrations and protein-binding ratios in patients with CRF (0.90 +/- 0.08 mg/dL and 68.7% +/- 6.8%, respectively) were significantly lower than those in the N group (2.45 +/- 0.45 mg/dL and 92.0% +/- 1.4%, respectively). However, a 2-week administration of AST-120 significantly reduced IS levels from 1.79 +/- 1.01 to 1.15 +/- 0.85 mg/dL (N group, 0.06 +/- 0.01 mg/dL), increased total TRP levels (1.16 +/- 0.18 mg/dL), and improved the TRP plasma protein-binding ratio to 83.1% +/- 3.8%, whereas total protein and albumin levels remained unchanged. After 2 months of AST-120 administration, serum albumin and transferrin levels increased significantly., Conclusion: AST-120 improves nutritional state, at least partly through correcting impaired TRP metabolism, in patients with CRF.

Tbx2 and Tbx3 are considered to be cognate genes within a Tbx2/3/4/5 subfamily of T-box genes and are expressed in closely overlapping areas in a variety of tissues, including the eye. Herein, we show that misexpression of Tbx2 and Tbx3 in Xenopus embryos gave rise to defective eye morphogenesis, which was reminiscent of the defect caused by attenuated Sonic hedgehog (Shh) signaling. Indeed, Tbx2/3 misexpression suppressed Gli1, Gli2, Ptc2 and Pax2, mediators or targets of Hedgehog (Hh) signals. From these data, Tbx2/3 may have a shared function in inhibiting Gli-dependent Shh signaling during eye development. Conversely, the expression of Tbx2/3 was severely affected by both Shh and a putative dominant negative form of Hh, as well as by both transactivator and transrepressor forms of Gli-fusion proteins, suggesting that the expression of Tbx2/3 may be regulated by a Gli-dependent Hh signal transduction pathway. Because the Shh signal has been considered to play crucial roles in the formation of the proximal-distal and dorsal-ventral axes in the eyes, these findings about the mutual regulatory mechanism between Tbx2/3 and Gli-dependent Hh signaling provide valuable insight into the cause of the localized expression of Tbx2/3 and their role during the formation of these axes. In addition, our findings also imply the conserved regulation and shared activity between the cognate genes of Tbx2 and Tbx3.

Electroporation has led to new approaches to the analysis of gene regulation of the chick embryonic system. However, application of this method to Xenopus, another model organism of embryology, has left many difficulties to be overcome. The specially devised electrodes, the examination of luciferase activities expressed, and the direct visualization of green fluorescence protein allow us to optimize the conditions of electroporation for Xenopusembryos. The use of mRNA rather than DNA improved the expression efficiency 120 times more than for the case of plasmid DNA, and the effect emerged more immediately after electroporation. The noncontact electroporation adopted here caused less damage to cells and tissues than with the needle type electrode, making it practical for efficient application to early embryos. Furthermore, the mRNA electroporation technique is applicable for other systems in which the DNA electroporation has not had any significant effect because of its low expression efficiency., (Copyright 2002 Wiley-Liss, Inc.)

We have examined the roles of BMP4, Shh, and retinoic acid in establishing the proximal-distal and dorsal-ventral axes in the developing Xenopus eye. Misexpression of BMP4 caused the absence of an optic stalk and the expansion of dorsal and distal markers, tbx2/3/5, and pax6, at the expense of ventral and proximal markers vax2 and pax2. When Shh or Noggin, an antagonist of BMPs, was misexpressed, the reverse expression patterns of these marker genes were observed. These results suggest that BMP4 is involved in the specification of not only dorsal in the optic cup but also distal in the optic vesicle. Because Shh did not suppress bmp4 expression, unlike Noggin, Shh and BMP4 may antagonistically regulate common downstream genes in developing eye. We also found the difference between the effects of Shh and retinoic acid, another possible ventralizing factor, suggesting that Shh could promote ventralization independently of retinoic acid. These findings provide important clues to the coordinate and antagonistic actions of BMP4, Shh, and retinoic acid in axes specifications of Xenopus eyes., (Copyright 2002 Wiley-Liss, Inc.)

Cerebral metastases from papillary carcinoma of the thyroid are a very uncommon condition, but such metastases behave more aggressively and show poor prognosis. These metastases almost always involve concomitant lung or bone metastases which may be the first metastatic sites. Here we report a 53-year-old man with diffuse goiter and cervical lymphadenopathy who developed symptoms of elevated intracranial pressure. Computed tomography demonstrated ring-enhanced lesions showing a severe mass effect in the right cerebrum and a nodule in the right thyroid gland accompanied by swollen lymph nodes. Biopsied specimens of the thyroid nodule demonstrated malignant cells of papillary carcinoma. Surgical excision of the metastatic brain lesions was followed by total thyroidectomy with regional lymphadenectomy. Histological examinations confirmed that the patient had cerebral metastases from papillary carcinoma of the thyroid without other distant metastasis. Neurological abnormality disappeared after surgery and treatment with radioactive iodine (131I) and oral thyroxine were initiated thereafter. This case suggests that the thyroid gland is potentially a primary source of metastatic brain carcinoma. Moreover, early detection of cerebral metastases is crucial because these metastatic lesions can be life threatening, in contrast to the relatively less severe clinical course of this malignancy unless it is associated with any distant metastasis.

We reported three cases of cerebral aneurysms hardly detectable by cerebral angiography, but easily detected by three-dimensional CT angiography (3D-CTA). These cases were ruptured aneurysms with subarachnoid hemorrhage. After detection of subarachnoid hemorrhage on CT scan, cerebral angiography was performed at first, but aneurysms were not detected. Subsequently 3D-CTA was carried out, and aneurysms were detected. In all cases, cerebral angiography was repeated, after the aneurysms had been found by 3D-CTA. This time aneurysms were all detected by cerebral angiography, but each case needed photographs from special direction. The aneurysms were small by usual cerebral angiography and they were almost invisible behind the artery near which they existed. 3D-CTA was very useful for detection of small aneurysms, but small perforating arteries around the aneurysms were invisible by 3D-CTA. To find these perforating arteries, cerebral angiography was needed.

The control mechanism of the anteroposterior axis specification in Xenopus epidermis was studied by comparing the expression of a novel anterior marker, Xepsin, with that of a panepidermal marker, type I keratin. Xepsin mRNA, which encodes a novel Xenopus serine protease, is transcribed zygotically with the expression peak in neurula stages. In normal development, its expression is limited to the anterior and anterior-dorsal portions within epidermis during neurula and tailbud stages, respectively. In UV-irradiated ventralized embryos (dorsoanterior index, DAI 0 and 1), an expression boundary for Xepsin is apparently formed within the epidermis. In contrast, Xepsin expression was observed throughout the epidermis in LiCl-treated dorsalized embryos (DAI 10), as seen from an expression pattern indistinguishable from that of type I keratin. These data suggest that posteriorizing signals which suppress the transcription of Xepsin are present in nonaxial regions and absent in the anterior dorsal mesoderm. That posteriorizing signals were present in nonaxial regions was also supported by a conjugation experiment in which Xepsin expression was suppressed in ectodermal explants conjugated with lateral or ventral marginal zone. Moreover, the partly suppressed expression of Xepsin in the epidermal region of exogastrulae indicates that the signals may travel horizontally within the plane of the epidermis. We also present data showing that both treatment with retinoic acid and the overexpression of a constitutively active form of a retinoic acid receptor caused the suppression of Xepsin mRNA transcription, suggesting that anterior-posterior patterning in the central nervous system and in the epidermis may share common endogenous factors, i.e. , retinoids, in the Xenopus embryo., (Copyright 1999 Academic Press.)

Several T-box genes are considered to play important roles in developing limbs, tails and neural retinae. Five novel T-box genes in the Japanese newt were isolated and their expression was analyzed, together with another T-box gene of brachyury, during embryogenesis and in the developing and regenerating limbs and tail. Four are designated CpTbx2, CpTbx3, CpTbx6R and CpEomesodermin based on molecular phylogenetic analyses, and the other is named CpUbiqT from its ubiquitous expression. While all were expressed during embryogenesis, only four of them (CpTbx2, CpTbx3, CpUbiqT and brachyury) were detected in developing limbs and/or tails. Except for brachyury, they were continuously expressed in normal adult appendages and showed elevated expression levels in regenerating limbs, whereas only CpTbx2 showed significant up-regulation in regenerating tails. Compared with orthologous genes in other species, CpTbx2, CpTbx3 and CpEomesodermin showed several notable differences such as an abundance of maternal transcripts of CpEomesodermin, a unique insertion sequence within the T-box domain of CpTbx2, and a lack of visible expression of CpTbx2and CpTbx3 in the apical ectodermal region of developing limbs. In view of the uniqueness of the newt, these results are discussed with respect to the possibility of their involvement in regeneration.

Objectives: This study evaluated the role of neutrophil adhesion molecules LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18) and p150,95 (CD11c/CD18) in patients undergoing percutaneous transluminal coronary angioplasty (PTCA)., Background: Several recent studies have suggested that cell adhesion molecules on both neutrophils and vascular endothelial cells play an important role in the process of tissue inflammation., Methods: Thirty-eight patients (30 men, 8 women; mean [+/-SE] age 56 +/- 5 years, range 38 to 76) with single-vessel coronary artery disease of the left anterior descending artery underwent coronary angioplasty. Peripheral blood was sampled at baseline before, immediately after and 12, 24, 48 and 144 h after PTCA. The expression of CD18, CD11a, CD11b and CD11c on the surface of polymorphonuclear leukocytes was examined by flow cytometry with monoclonal antibodies., Results: In patients without subsequent restenosis, there was no change in mean channel fluorescence intensity (MFI) of CD18 at each sampling time. However, in the patients with restenosis, the MFI of CD18 significantly increased at 48 h after PTCA (from 57 +/- 6 to 73 +/- 8, p = 0.0008). The MFI of CD11b increased slightly at 48 h after PTCA in patients without restenosis (from 584 +/- 121 to 735 +/- 114, p = 0.037). In patients with restenosis, the MFI of CD11b was slightly increased at 24 h after PTCA (from 586 +/- 122 to 768 +/- 214, p = 0.018) and significantly increased at 48 h after PTCA (to 1,534 +/- 268, p = 0.0006). The expression of CD11a and CD11c did not change at any sampling points after PTCA in either of the two patient groups. Percent change in the expression of CD18 at 48 h after PTCA (from baseline) and that of CD11b were correlated (r = 0.73, p = 0.0008) in patients with restenosis., Conclusions: Inflammatory stimuli within the coronary vessels associated with coronary angioplasty may upregulate Mac-1 expression on the surface of polymorphonuclear leukocytes. This process may be more marked in patients who experience later restenosis. Thus, activation of neutrophil adhesion molecule Mac-1 at 48 h after PTCA may have value as a predictor of subsequent restenosis.

Novel quinoxaline 1,4-dioxide derivatives were synthesized from benzofuroxans and the enolic form of 1,3-diketones or 3-oxoalkanoic esters or 3-oxoalkanamides or butanedioic esters catalyzed by silica gel or molecular sieves and their antibacterial activities were evaluated. As the results of antibacterial screening tests in vitro, quinoxaline 1,4-dioxides revealed strong activities against Bacteroides fragilis.

Background and Hypothesis: To investigate the mechanism of regional left ventricular diastolic filling disturbance in hypertrophic cardiomyopathy (HCM), we assessed the relationship between abnormalities of regional ventricular rapid filling and regional coronary microcirculation using radionuclide ventriculography and exercise 201thallium (201TI) myocardial scintigraphy with sector analysis., Methods: Thirty patients with HCM and 14 patients with atypical chest pain syndrome (controls) were studied. Left ventricular images (left anterior oblique view) were obtained by electrocardiogram-gated 99mtechnetium radionuclide angiography and were divided into three sectors radiating from the geometric center. The time-activity curves and their first derivative curves were analyzed, and the peak filling rate (PFR), the ratio of the time-to-peak filling rate per diastolic interval (TPFR/T) were calculated for the global left ventricle and for the lateral and septal sectors. Exercise stress 201TI myocardial scintigraphy was also performed, and early and delayed images were obtained. The regional washout rate (WR) was then evaluated for the lateral and septal sectors., Results: In HCM patients, the regional PFR in the septal sector (corresponding to the region of hypertrophic myocardium) was 285 +/- 76%/s, and was significantly lower than that in the controls (398 +/- 90%/s, p < 0.01). The regional TPFR/T in the septal sector (32 +/- 10%) was prolonged compared with the value of 21 +/- 5% in the controls (p < 0.05). The regional WR in the septal sector was 21 +/- 9%, and was significantly lower than that in the controls (43 +/- 5%, p < 0.01). Moreover, regional WR correlated positively with regional PFR (r = 0.5, p < 0.05) and showed a weak negative relationship with regional TPFR/T (r = -0.4, p < 0.07) in the septal sector., Conclusions: These results suggest that regional impairment of rapid filling might be related to a disturbance of the coronary microcirculation in HCM.

Manifestation of ischemic preconditioning and its mechanisms during percutaneous transluminal coronary angioplasty (PTCA) was evaluated. Twenty-two patients with angina pectoris, who had one-vessel coronary artery disease of the proximal left anterior descending artery but without visual collateral circulation, underwent elective PTCA performed by balloon inflations of 90 s, repeated three times or more. Changes in standard 12-lead electrocardiogram, hemodynamics and oxygen saturation of the great cardiac vein by a fiber-optic catheter were analyzed. Anginal chest pain occurred in 21 patients (95%) during the first balloon inflation, and in only 9 patients (41%) during the third inflation. In comparison with the first inflation, the third produced less shifts in ST junction (p < 0.01) and peak T (p < 0.01), which were measured and averaged by 4 chest leads from V2 to V5. The heart rate-blood pressure product during the third inflation was equivalent to that during the first. The great cardiac vein oxygen saturation decreased equally during the first and third inflations. However, the ratio of the saturation at reactive hyperemia after balloon deflation to baseline was higher (p < 0.01) in the third than in the first inflation. The adenosine content of the great cardiac vein measured in 11 patients just prior to balloon deflation was also higher (p < 0.05) in the third inflation than the value in the first. Repeated coronary artery occlusion during PTCA could cause ischemic preconditioning, which may be derived from mechanisms common to accelerated reactive hyperemia, for example an increase in intrinsic adenosine levels.

We report the case of a 38-year-old man who developed fatal, systemic amyloidosis following ankylosing spondylitis. He was admitted for symptoms of congestive heart failure. Based on parotid gland biopsy and echocardiography, he was diagnosed as having systemic amyloidosis following active ankylosing spondylitis. However, the clinical course was rapidly progressive and eventually the patient died of acute necrotizing pancreatitis. The association has been reported thus far in a limited number of cases worldwide. The literature has featured localized lesions and a benign clinical course of the amyloidosis. This case, the first report from Japan, indicates that the amyloidosis associated with ankylosing spondylitis might exhibit a rapidly progressive clinical course, thereby suggesting that in such a case, meticulous treatment is required.

Although the pathophysiology of heart failure progression is important to survival it is not fully understood. In 92 patients with acute heart failure due to myocardial infarction or dilated cardiomyopathy, secondary organ dysfunction was evaluated to determine whether this factor contributed to heart failure progression and death. Forty-one patients had renal dysfunction, hepatic disease or loss of consciousness after the onset of the acute heart failure, and 26 of them (63%) died of progressive heart failure during the follow-up period of 20 months on average. The one-year survival rate was 22%. Although 51 other patients showed the same initial clinical features and cardiac function, they did not develop concurrent organ dysfunction during the course and only 11 (22%, p < 0.001) died of progressive heart failure. The one-year survival rate was 67%. The survival rate decreased in the order of renal dysfunction, hepatic disease and loss of consciousness. Transient low cardiac output of less than 2.2 l/min/m2 was more frequent in patients with organ dysfunction. It is suggested that heart failure progresses, in part, due to organ dysfunction secondary to heart failure and careful treatment to prevent organ dysfunction is important to long term survival.

To determine the number of days required to obtain 75% suppression of ventricular premature contractions (VPCs) by antiarrhythmic agents, which was expressed as t1/4, we performed 32 in-hospital continuous all day ECG monitoring trials in four groups of 28 symptomatic patients (ages; 54 +/- 20 years-old) with frequent VPCs. Nine patients had no organic heart disease (group 1, 11 trials), nine had valvular heart disease (group 2, 10 trials), three had dilated cardiomyopathy (group 3, 3 trials) and seven had myocardial infarction within two to four weeks onset (group 4, 8 trials). All patients were monitored by ECG telemetry with an arrhythmia analyzer, which could count hourly and daily VPCs. Class I antiarrhythmic agents were given in 18 trials, class II in two trials and class I+ class II in 12 trials. Plasma concentrations of the antiarrhythmic agents were monitored in 11 trials. In 21 trials, t1/4 could be obtained; ten (91%), six (60%), three (100%) and two trials (25%) in the four groups, respectively (p < 0.05). The value of t1/4 in the four groups was 6 +/- 6, 7 +/- 6, 14 +/- 11 and 13 +/- 2 days, respectively (mean 8 +/- 7 days; N.S.). Immediate response to the initial antiarrhythmic agent administration, expressed as percent VPC count after three hours, correlated significantly with t1/4 (r = 0.696, p = 0.0006), but ejection fraction, patient's age, control VPC counts or plasma antiarrhythmic agent level did not correlate with t1/4. In conclusion, t1/4 is a useful index for the evaluation of VPC suppression, revealing wide inter-individual variations and can be roughly estimated from the immediate response to the initial antiarrhythmic agent administration.

Three ventricular inhibited mode (VVI) pacemaker implanted patients, all above 65 years, female and having sick sinus syndrome suffered from torsades de pointes; one patient after 2.5 years and the other two patients within a day of disopyramide therapy. All had hypopotassemia and plasma disopyramide was below the therapeutic range in two patients. Torsades de pointes was induced following ventricular paced beats and suppressed by cessation of disopyramide in all or by setting a higher pacing rate in one. In our department, permanent VVI pacemakers were implanted in 43 patients with sick sinus syndrome including 26 with bradycardia-tachycardia syndrome, nine of whom were treated by disopyramide. Torsades de pointes was observed only in those disopyramide treated bradycardia-tachycardia patients. Our report stresses the proarrhythmic nature of combined VVI pacing and antiarrhythmic agents in the presence of hypopotassemia.

Both the endothelium-dependent and endothelium-independent vasodilatory responses of coronary resistance vessels were studied in patients with dilated cardiomyopathy (DCM). A 3F coronary Doppler catheter was placed in the proximal left anterior descending artery in 14 patients with DCM and in 10 patients with chest pain syndrome and a normal heart (control subjects). The ratio of maximum mean coronary blood flow velocity after intracoronary administration of the endothelium-independent vasodilator papaverine (10 mg) to resting mean coronary blood flow velocity (Vp/Vo) in patients with DCM was diminished compared with that in control subjects (2.2 +/- 0.6 vs 4.1 +/- 0.9, p < 0.001). The ratio after administration of the endothelium-dependent vasodilator acetylcholine (40 micrograms) (Va/Vo) in 10 DCM patients was also diminished compared with that in seven control subjects (1.3 +/- 0.5 vs 2.4 +/- 0.8, p < 0.01). In DCM patients, Vp/Vo was correlated with left ventricular end-diastolic pressure (r = -0.48, p < 0.05), left ventricular end-diastolic volume index (r = -0.68, p < 0.01), ejection fraction (r = 0.75, p < 0.01), and left ventricular end-diastolic wall stress (r = -0.73, p < 0.01). However, Va/Vo was not correlated with any of these parameters. These results indicate that impairment of the vasodilatory capacity of coronary resistance vessels in DCM may be related to endothelial dysfunction and to an extravascular factor resulting from left ventricular dysfunction.

The incidence of ventricular arrhythmias following the intracoronary injection of papaverine was assessed. A 3F coronary Doppler catheter was placed in the proximal left anterior descending artery and 6-12 mg of papaverine was injected into the left coronary artery in 42 patients. After intracoronary papaverine, the corrected QT interval on the electrocardiogram was prolonged from 0.43 +/- 0.03 to 0.49 +/- 0.07 s (p < 0.001). Occasional premature beats were observed in 2 patients (4.5%) with dilated cardiomyopathy. In 1 patient (2.3%) with 99% stenosis of the left anterior descending artery, polymorphous ventricular tachycardia with marked QT prolongation occurred. This patient also had hypokalemia (2.5 mEq/l) due to primary aldosteronism. In conclusion, careful use of intracoronary papaverine is necessary because of the risk of occasional serious ventricular arrhythmias.

In order to clarify the cellular origin of craniopharyngiomas, the authors examined the distribution of P-glycoprotein (PGP) and human chorionic gonadotropin (HCG) in five normal adenohypophyses and in 23 craniopharyngiomas using peroxidase immunohistochemistry. The correlation between the expression of PGP in craniopharyngiomas and the recurrence of these tumors was also investigated. A number of pars intermedia cyst-lining cells immunostained positively for anti-PGP antibodies. A small number of adenohypophysial cells were also positive for PGP, but squamous epithelial nests were negative in all samples. However, HCG-beta was consistently demonstrated in adenohypophysial cells, pars intermedia cyst-lining cells, and squamous epithelial nests. In 11 craniopharyngiomas, the apical portion of cuboidal cells and some polygonal cells immunostained positively with anti-PGP antibodies. In four HCG-producing craniopharyngiomas, a large number of tumor cells were immunostained with anti-PGP antibodies, three of which showed a recurrence of cystic tumors. By double labeling, the coexpression of HCG-beta and PGP was demonstrated in these recurrent tumors. Accordingly, it is suggested that craniopharyngiomas produce HCG-like peptides and that craniopharyngiomas are unique squamous neoplasms arising in the sellar region from progenitor cells of a neuroendocrine lineage.

To determine the factors of left ventricular aneurysm formation in acute myocardial infarction, the authors studied the distribution of coronary artery lesions and the left ventricular wall motion of 43 patients with anterior myocardial infarction. Of 15 patients with aneurysm, 9 (60%) showed a single-vessel disease with severe stenosis of the proximal left anterior descending artery. Of 9 patients with triple-vessel disease, 8 (89%) had no aneurysm. In patients with the aneurysm, the Gensini score of the culprit lesion was significantly higher (p < 0.05) and the score except for the culprit lesion was less (chi 2 = 5.7, p < 0.05). In 23 patients with single-vessel disease, the collateral score was significantly less (p < 0.05) in patients with the aneurysm. The systolic wall motion on the ventriculogram appeared more impaired in the anterior infarct area but well maintained in the posterior noninfarct area in patients with the aneurysm. In conclusion, the important factors of left ventricular aneurysm formation were as follows: (1) A culprit lesion of the myocardial infarction was severe, but other coronary artery lesions were mild. (2) Collateral vessels were poor. (3) The left ventricular wall motion of the infarct area was impaired, but that of the noninfarct area was relatively good.

To determine the clinical significance of ST-segment depression observed in paroxysmal supraventricular tachycardia (PSVT), we evaluated the 12-lead electrocardiogram (ECG) during spontaneous PSVT in 54 patients (27 men and 27 women: mean age +/- SD; 47 +/- 18 years), who came to our clinic for the treatment of PSVT. Coronary angiography was performed in 16 patients (16 to 74 years; mean = 50 +/- 18) and treadmill exercise testing was performed in 21 patients. A cardiac electrophysiological study was carried out in 24 patients. During PSVT, ST-segment score was calculated as the sum of the ST-segment depression in 12 leads. The correlations between the ST-segment score, PSVT rate and age of the patient were analyzed as follows: The most significant positive correlation was observed between the ST-segment score and the PSVT rate (r = 0.615, p < 0.000001). The next most significant correlation was found between the PSVT rate and the age of the patient (r = -0.500, p = 0.00011). A negative correlation was also observed between the ST-segment score and the age of the patient (r = -0.429, p = 0.0012). In 13 of 16 patients, coronary angiography did not reveal any significant (> or = 75% in area) stenosis. Exercise testing induced significant ST-segment depression in 3 patients, of whom two had significant coronary artery lesions. PSVT was due to atrioventricular reentry via an overt (n = 3) or concealed accessory pathway (n = 15), atrioventricular nodal reentry (n = 5) and sinus node reentry (n = 1). In conclusion, patients with a faster PSVT rate revealed more pronounced ST-segment depression than did those with a slower PSVT rate, possibly reflecting the modified repolarization process instead of coronary artery involvement.

A 53-year-old-man afflicted with combined valvular heart disease and atrial fibrillation was admitted to our department complaining of chest pain. ST elevation on ECG (II, III, aVF) and elevated CPK value were recognized. He was diagnosed as having acute myocardial infarction, and percutaneous transluminal coronary recanalization was performed immediately. The coronary angiogram showed occlusions at the proximal left branch (#12). But these lesions could not be recanalized by 960000 IU urokinase administration. The cineangiogram after one month revealed perfect recanalization of these occlusions. Mitral stenosis with neovascularity to the left atrium and aortic regurgitation were recognized. We supposed this infarction caused by coronary embolism originated from left atrial thrombi. Acute myocardial infarction associated with mitral stenosis has been reported in fifteen cases previously in Japan, but only three cases revealed coronary occlusion in the acute phase with normal coronary artery in the chronic stage. However, there has been no report, except for this case, demonstrating occlusion in two coronary arteries at the same time. So, our case is the first report of the involvement of two coronary artery occlusions.

The venoarterial carbon dioxide tension gradient (P[v-a]CO2) was studied in patients with acute myocardial infarction. Seven patients with congestive heart failure (CHF group) and 10 patients without heart failure (control) were enrolled in this study. In all patients, hemodynamics were continuously monitored. Simultaneously, arterial and mixed venous blood were sampled, and blood gases and lactate concentration were analyzed. At the initial measurement before therapy, arterial and mixed venous pH and bicarbonate values were within the normal range, and there was no significant difference between the CHF group and controls. There was also no difference in arterial oxygen tension under the differential conditions of oxygen inhalation. However, cardiac index and mixed venous oxygen saturation (SvO2) were significantly lower, while the oxygen extraction ratio (OER) and arterial lactate were significantly higher in the CHF group than in the controls. On the other hand, P[v-a]CO2 was significantly higher in the CHF group (7.8 +/- 2.6 vs. 3.5 +/- 2.2 mm Hg, p < 0.01). This finding was due to the elevated mixed venous carbon dioxide tension in the CHF group, since arterial carbon dioxide tension was the same in both groups. Analysis of a total of 42 measurements obtained during the therapeutic course in the CHF group revealed a correlation of P[v-a]CO2 with cardiac index (r = -0.3, p < 0.05), OER (r = 0.57, p < 0.001), SvO2 (r = -0.56, p < 0.001) and lactate (r = 0.62, p < 0.001). The increase in P[v-a]CO2 observed in acute heart failure suggests the evidence of intracellular acidosis despite the absence of acidemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary flow reserve was studied in patients with dilated cardiomyopathy. A 3F coronary Doppler catheter was placed in the proximal left anterior descending artery in each of 10 patients with dilated cardiomyopathy (CDM group), seven patients with coronary artery disease that involved only the left anterior descending artery (CAD group), and seven patients with chest pain syndrome and normal hearts (control group). Coronary flow reserve was calculated as the ratio of the maximum mean coronary blood flow velocity after intracoronary administration of papaverine (10 mg) to resting flow velocity (M/R). The time until maximum flow velocity was reached after papaverine administration (Tmax) was also measured. M/R was lower in the DCM (p < 0.001) and CAD (p < 0.001) groups when compared with the control group. Tmax was not abnormal in the DCM group but was prolonged in the CAD group (p < 0.05). In the DCM group, the M/R ratio correlated with the left ventricular end-diastolic pressure (r = -0.69; p < 0.05), the left ventricular end-diastolic volume index (r = -0.7; p < 0.05), the ejection fraction (r = 0.82; p < 0.01), the left ventricular mass (r = -0.7; p < 0.05), and the left ventricular end-diastolic wall stress (r = -0.84; p < 0.001). These results indicate that coronary flow reserve was decreased in patients with dilated cardiomyopathy and that the mechanism of its reduction may differ from that in patients with coronary artery disease.

Oxygen demand-supply relationships in peripheral tissues were studied in 14 patients who had acute myocardial infarction with advanced pump failure. Seven patients with acute myocardial infarction but without pump failure were studied as a control. In all patients, a Swan-Ganz catheter and a radial arterial cannula were inserted for the purpose of hemodynamic monitoring, and arterial and mixed venous blood were sampled. Initially, oxygen delivery (DO2) (p < 0.01) was lower, and oxygen extraction ratio (OER) (p < 0.001) and oxygen tension at 50% saturation (P50) (p < 0.01) were higher in patients with pump failure than in the controls. During the therapeutic course, with an increase in the cardiac index and DO2, oxygen uptake (VO2) did not change but OER (p < 0.001) and P50 (p < 0.01) significantly decreased in 6 survivors with pump failure. In contrast, an increased VO2 (p < 0.01) and no change of OER and P50 were observed in 8 nonsurvivors with pump failure. These results suggest that reversibility of oxygenokinetics might be an important factor for recovery from critical heart failure.

We investigated the mechanism of the antimitotic effects of calcium channel blockers in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR). VSMC from SHR exhibited rapid proliferation through a quick transition from the G0/G1 to the DNA synthetic (S) phase and from the S to the G2/mitotic (M) phase, whereas the DNA synthetic rate itself was equal to that of Wistar-Kyoto rats (WKY). OPC-13340, a new dihydropyridine calcium channel blocker, dose-dependently decreased incorporation of [3H]thymidine into the DNA fragments in randomly cycling VSMC in SHR. Cell cycle analysis showed that the rapid transition from the S to the G2/M period was restored by OPC-13340 to the control level in WKY, whereas the quick transition from G0/G1 to S was unaffected. This antimitotic effect of OPC-13340 was reflected by attenuation of enhanced cellular protein synthesis during the G2/M period. Protein synthesis in the G0/G1 period was not influenced by OPC-13340. Thus, these data indicate that the calcium channel blocker OPC-13340 mitigates the enhanced proliferation observed in randomly cycling VSMC from SHR and that this effect is primarily due to normalization of the premature mitosis during the G2/M period.

Left ventricular diastolic dysfunction was studied globally and regionally in patients with coronary artery disease, and the effects of coronary revascularization were evaluated. A total of 25 patients with angina pectoris who had a stenotic lesion (greater than or equal to 90%) in only left anterior descending branch underwent coronary revascularization [percutaneous transluminal coronary angioplasty (PTCA) in 13 patients and coronary artery bypass graft (CABG) in 12]. Nine patients with normal coronary artery were studied as controls. Left ventricular volume and radial axes were measured on serial frames of one cardiac cycle by cine left ventriculography. The radial axes were drawn from the left ventricular gravity to left ventricular wall at every 20 degrees. Left ventricular filling fraction and distension rate of radial axes were calculated at the times of 25%, 50%, 75%, and 100% of diastolic period, 100% being end-diastole. Although there were no significant changes of the systolic function by revascularization, the filling fraction increased from 11.2 +/- 2.6 to 14.5 +/- 3.5% (p less than 0.001) at 25% time of diastole, from 29.9 +/- 4.9 to 32.5 +/- 5.0% (p less than 0.05) at 50% time in the PTCA group, and from 11.8 +/- 3.7 to 13.4 +/- 3.8% (p less than 0.01) at 25% time in the CABG group. The distension rate of radial axis to the anterior wall also increased significantly at 25% and 50% time of diastole after revascularization, and the change was marked in the PTCA group. However, these increases did not apply to the control patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Hemofiltration was performed in 15 patients with refractory congestive heart failure. All of these patients had oliguria, although intensive treatment with diuretics, digitalis, vasodilators, and catecholamines was prescribed. Hemofiltration was performed under hemodynamic monitoring in 14 patients. The water removal by hemofiltration decreased pulmonary arterial pressure, pulmonary capillary wedge pressure and right atrial pressure. Despite these hemodynamic improvements, nine patients (60%) died within one month after the start of hemofiltration; the causes were fatal arrhythmia in three, renal failure in two, sepsis in one and irreversible cardiogenic shock in three. Oliguria for over 15 h or a serum creatinine concentration of more than 4.0 mg/dl at the start of hemofiltration related to poor prognosis. In view of these results, hemofiltration for refractory heart failure should be started earlier and performed carefully in order to avoid arrhythmia, cardiogenic shock, and other complications.

Compensation for heart failure can be influenced by cardiac loads due to organ failure. This investigation studied the effect of secondary organ failure on the hemodynamics of acute heart failure. Of 106 patients with acute heart failure due to myocardial infarction or dilated cardiomyopathy, 49 (46%) patients had secondary organ failure, either kidney, liver, brain or blood. Their acute heart failure was sustained for significantly longer than that of 57 patients without organ failure. A transient but severe decompensation induced secondary organ failure, although the left ventricular ejection fraction was not different from that of the control without heart failure. Hypervolemia in cases of renal failure, bradycardia in loss of consciousness, hyperdynamic state in anemia and low blood pressure in liver dysfunction caused the sustained acute heart failure. These results suggested that secondary organ failure might occur in 46% of patients with acute heart failure, and might disrupt compensation by different kinds of hemodynamic loads in low cardiac function.

To investigate the significance of precordial ST-segment depression in acute inferior myocardial infarction, we compared the Gensini score of coronary artery stenosis between 2 groups of patients with and without precordial ST-segment depression. Group I consisted of 28 patients who showed ST-segment depression on admission (greater than or equal to 1 mm in V2-V6) and Group II (n = 16) those without ST-segment depression (less than 1 mm). The Gensini score of the coronary arteries (56 +/- 29 vs. 28 +/- 18; p less than 0.001), the partial score of the infarction-related artery (29 +/- 16 vs. 17 +/- 11; p less than 0.01) and of the infarction-nonrelated artery (27 +/- 24 vs. 11 +/- 12; p less than 0.02) were significantly higher in Group I than in Group II. The Killip score (greater than or equal to II) (34% vs. 6%; p less than 0.05), frequency of arrhythmias (75% vs. 38%; p less than 0.02) and peak CK value (3,676 +/- 2,290 vs. 1,818 +/- 1,153 IU/L; p less than 0.005) were higher in Group I than in Group II. Four patients in Group I died following admission, while no patient died in Group II (N.S.). Autopsy findings from the 4 Group I patients revealed fresh extensive inferior infarction and healed diffuse subendocardial infarction which could not be predicted from electrocardiograms. All patients who survived the acute stage performed treadmill exercise testing and 22 patients underwent exercise thallium-201 single photon emission computer tomography (SPECT). On treadmill exercise test, there was no significant difference between the 2 groups in the frequency of angina pectoris and ST-segment depression. On SPECT, the perfusion defect area under 55% of maximum uptake at the redistribution phase was 45.8 +/- 19.6 cm2 in Group I (n = 14) and 34.7 +/- 21.3 cm2 in Group II (n = 8; N.S.). In conclusion, precordial ST-segment depression in acute inferior myocardial infarction suggested advanced atherosclerosis in both the infarction-related and nonrelated coronary arteries, indicating a larger infarct size.

The expression of a functional P-glycoprotein (P-gp) which pumps drugs out of brain capillary endothelial cells (BCEC) into blood was studied by evaluating the steady-state uptake and efflux of vincristine (VCR) by primary cultured bovine BCEC. The steady-state uptake of VCR was increased in the presence of metabolic inhibitors, and an anti-P-gp monoclonal antibody, MRK16, as well as verapamil and steroid hormones which are known to reverse multidrug resistance in tumor cells. Furthermore, efflux of VCR from BCEC was inhibited by verapamil. By immunohistochemistry, P-gp was localized at the luminal side of the capillary endothelial cells in both gray matter of bovine brain and primary cultured BCEC. These data suggest that P-gp functions as a drug efflux pump at the luminal side of BCEC and regulates the transfer of certain lipophilic drugs from the blood into the brain.

A 50-year-old woman with aortitis syndrome complicated by aortic dissection, is reported. The dissection was observed at the level of the descending thoracic aorta by aortography and at the intimal side of the dilated aorta on CT. An aneurysm of the right subclavian artery and a diffusely thick wall of the abdominal aorta were also observed. This case suggests that the uneven wall of the aorta in aortitis syndrome might be dissected at the intimal side by dilatation.

A thirty-two-year-old man suffered from evolving acute myocardial infarction caused by total occlusion of the left main coronary artery, which was 95% stenosed before the onset. Nevertheless, he had a good clinical course. The myocardium may have been protected by well-developed preexisting collateral vessels as evidenced by serial coronary angiograms.

To see if the lower pacemaker in patients with atrioventricular (AV) block was modulated electrotonically by atrial excitation, we studied R-R intervals in two groups of AV block patients using a phase response curve (PRC). Group I consisted of 20 patients with high degree AV block, including seven patients in whom complete AV block was transiently observed in the course of acute inferior myocardial infarction. Group II consisted of 19 patients with complete AV block. In every patient, PRC was obtained from the continuous electrocardiogram by plotting each R1-R2 interval (response) on the ordinate as a function of the R1-Px interval (phase, x = 1, 2 ...) on the abscissa. In Group I, the R-R interval was prolonged when the P wave fell in the initial half of the R-R interval, and was abbreviated when the P wave fell in the later half of the cycle. In Group II, the fluctuation of the R-R interval was minimum. In ten group I patients, with the improvement of the AV block, PRC became sharper and transition from prolongation to shortening occurred at shorter R-P intervals. We conclude that, in Group I, lower pacemaker was modulated electrotonically by atrial excitations through decreased electrical coupling along the AV node.

Left ventricular diastolic dysfunction at rest was studied in 24 patients with coronary artery disease but no evidence of previous myocardial infarction. Seven patients with normal coronary arteries were studied as control. Diastolic filling was analyzed by the serial left ventricular volume and 14 radial axes from the gravity point of the left ventricle with cine left ventriculography. There were no differences in the systolic function between coronary artery disease and the normal control. Peak filling rate was decreased significantly in the groups with left anterior descending artery disease (LAD, p less than 0.05) and multivessel disease (MVD, p less than 0.05), but not in the group with right coronary artery disease (RCA). Time to peak filling rate was prolonged in each group of LAD (p less than 0.05), RCA (p less than 0.05), and MVD (p less than 0.001), compared with controls. The time-volume curve showed disturbed rapid filling in the LAD and RCA groups, and also both depressed rapid and slow filling in the MVD group. In the LAD group, the filling fraction was decreased significantly at the time of 25% of the diastolic period (p less than 0.001) and radial distension to the anterior wall was decreased at the time of 25%, 50%, and 75% of the diastolic period, compared with controls. In the RCA group, the filling fraction (p less than 0.001) and radial distension to the posterior wall were decreased only at the time of 25% of the diastolic period. In the MVD group, filling fraction and radial distension to the most wall were decreased at 25%, 50%, and 75% of the diastolic period.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitroglycerin induced a paradoxical disappearance of a stenosed coronary artery in a 57-year-old man with non-Q wave myocardial infarction. On the coronary angiogram, the left anterior descending coronary artery (with a 95% stenosis) became completely invisible 2 min after 0.3 mg sublingual nitroglycerin. Three minutes later, the artery was opacified again. This transient occlusion may have resulted from a passive collapse of the distal portion of the artery, due to insufficient access of nitroglycerin across the stenotic region.

Left ventricular diastolic filling was studied by left ventriculography in 17 patients with hypertrophic cardiomyopathy (HCM). In 8 patients this manifested as a spadelike shape (HCM-S type) on the left ventriculogram, and in 9 patients as a banana shape (HCM-B type). Seven patients were studied as controls. Left ventricular end-diastolic pressure was higher in HCM than in controls. In HCM, peak filling rate was decreased from 1.57 +/- 0.28 of the control to 1.28 +/- 0.20 (p less than 0.05), and the time to peak filling rate was prolonged from 27 +/- 6%DT of the control to 37 +/- 7%DT (p less than 0.01). Serial volume analysis in diastole showed filling fraction was also significantly decreased to 8.2 +/- 4.1 (p less than 0.001) at the 25% diastole time and 29.6 +/- 7.2 (p less than 0.01) at half time, compared with 19.8 +/- 6.3 and 32.8 +/- 5.8 for controls, respectively. In HCM-S type, the rate of distention of left ventricular radial axes at the apical area was lower at early and mid-diastole. In HCM-B type, the rate at the basal area was lower at early and mid-diastole. Results suggest that the left ventricular diastolic filling in HCM was impaired not uniformly but regionally in the hypertrophic area at early and mid-diastole.

We designed experiments to investigate the effects of cicletanine, a novel antihypertensive drug, on medial hypertrophy in Dahl rats susceptible to salt-induced hypertension (Dahl S rats). Cicletanine treatment (500 mg of cicletanine/kg of chow) for 6 weeks lowered blood pressure by 19% in Dahl S rats challenged with a high-salt (4%) diet. The blood pressure reduction was associated with a significant decrease in weight of the aortic vessels. Morphological examination revealed that this treatment decreased medial hypertrophy and expansion of intimal tissue, in concert with resolution of the periarteritis in the intrarenal arteries. In fact, the content of actin in the aortic wall, analyzed by SDS-PAGE, was decreased significantly with this treatment and myosin content was reduced to the same extent as well. Moreover, cicletanine per se lowered protein synthesis in randomly cycling cultured vascular smooth muscle cells (VSMCs) from Sprague-Dawley rats. Actin formation by VSMCs was decreased with cicletanine. Thus, these data indicate that chronic cicletanine treatment produces regression of the medial hypertrophy in Dahl S rats. Direct inhibitory effects on cytoskeleton protein synthesis, as well as its antihypertensive action, are partly responsible for this regression in vivo.