Loss of Secreted Frizzled-Related Protein-1 expression is associated with poor prognosis in intrahepatic cholangiocarcinoma.

AIMS: Secreted Frizzled-Related Protein-1 (SFRP1) is a well-known negative regulator of the wingless type (Wnt)-ß-catenin pathway and its inactivation plays an important role in the development and progression of many cancers. In this study, we aimed to determine the clinical significance of SFRP1 expression in intrahepatic cholangiocarcinoma (IHCC) and to define the relationship to Wnt-ß-catenin pathway. METHODS: Fifty IHCC patients who had liver resection were enrolled in this study. SFRP1 protein expression was examined by immunohistochemistry in tumor tissues. The patients were divided into two groups: SFRP1 positive (n = 30) and negative (n = 20). Clinicopathological characteristics were analyzed. RESULTS: SFRP1 significantly correlated with curability (Cur A, B vs. C, p = 0.029); and recurrent pattern (intrahepatic vs. extrahepatic, p = 0.010). The negative SFRP1 group had significantly poorer prognosis, and 5-year survival rates were 8.1% of the negative SFRP1 group and 44.6% of the positive SFRP1 group, respectively. Moreover, the disease-free survival rate in the negative SFRP1 group was significantly poorer (p < 0.001). Multivariate analysis revealed that loss of SFRP1served as an independent prognostic factor in IHCC for both overall (HR, 2.923; 95% CI, 1.30-6.56; p = 0.009) and disease-free (HR, 2.631; 95% CI, 1.31-5.27; p = 0.006) survival. In addition, SFRP1 expression negatively correlated to ß-catenin expression (p = 0.005). CONCLUSIONS: Those results suggested that the loss of SFRP1 could be a poor prognostic factor for IHCC, through the Wnt-ß-catenin pathway.

Long-term effects of LDL apheresis on carotid arterial atherosclerosis in familial hypercholesterolaemic patients.

OBJECTIVES: To assess the long-term effect of LDL apheresis on carotid arterial atherosclerosis in severe familial hypercholesterolaemic (FH) patients. DESIGN: Changes in existing plaque, new plaque formation and annual progression rate of carotid early plaque were evaluated by B-mode ultrasonography. SUBJECTS: LDL apheresis group: two homozygous FH and nine heterozygous FH patients received a combination of LDL apheresis and cholesterol-lowering drug therapy for a mean of 7.8 years. CONTROL GROUP: 10 heterozygous FH patients were maintained by medication only for a mean of 5.5 years. RESULTS: As a result of LDL apheresis treatment, LDL cholesterol levels reduced from 16.0+/-3.60 to 6.43+/-0.07 mmol L(-1) in homozygous FH patients and from 11.5+/-2.46 to 4.32+/-1.2 mmol L(-1) in heterozygous FH patients. During the long-term treatment period, the existing plaque tended to progress and new plaque formation in carotid arteries was also observed in both groups. The annual progression rate of mean maximum intima-media thickness in the common carotid artery was a mean of -0.0023+/-0.0246 mm year(-1) in heterozygous FH patients in the LDL apheresis group, suggesting regression. This was significantly lower when compared with the control group, which had a mean of 0.0251+/-0.0265 mm year(-1) CONCLUSION: The results suggest that the long-term treatment with combined LDL apheresis and drugs may delay the progression of the atherosclerotic process and prompt the stabilization of atheromatous plaque in severe FH patients.

Hyperinsulinemia in patients with spastic angina pectoris.

We evaluated the association between coronary spasm and hyperinsulinemia (high immunoreactive insulin, IRI) in patients with angina pectoris. The study cohort comprised 30 patients with spastic angina pectoris, 30 patients with angina pectoris showing fixed-obstructive coronary sclerosis and 30 control subjects who were matched for body mass index, age and sex. A 75-gram oral glucose test was performed, and blood sugar and IRI were serially measured concomitant with serum total cholesterol, triglyceride and HDL cholesterol. The IRI level at 60 min, the peak IRI during the test, sigma IRI and sigma IRI/sigma blood sugar were significantly higher in the patients than in the controls. Total cholesterol and LDL cholesterol levels were significantly increased in patients showing fixed-obstructive coronary sclerosis compared to controls.

Effects of an angiotensin II antagonist on reperfusion arrhythmias in dogs.

Losartan, an angiotensin II receptor antagonist with no bradykinin potentiating property, provides the opportunity to study the consequences of blocking angiotensin II. The objective of this study was to evaluate the antiarrhythmic responses of reperfusion arrhythmia to losartan in dogs. The effects of losartan on ventricular tachyarrhythmias induced during occlusion and reperfusion of the left anterior descending coronary artery were investigated in 30 dogs. The animals were randomized to receive either losartan (n = 15) or saline (n = 15). The VF inducing threshold was measured before occlusion and after reperfusion. Losartan (50 micrograms/kg per min) or saline was intravenously administered 5 minutes before occlusion and continued throughout the entire study period. The incidence of ventricular tachyarrhythmias during reperfusion was lower in the losartan group than in the control group (4/15 vs 6/15). There was no significant change in VF inducing threshold between the period before occlusion and during reperfusion in the losartan group [10.9 +/- 5.7 vs 11.1 +/- 5.7 mA, P = NS), whereas there was a significant decrease in the control group (15.5 +/- 4.4 vs 7.7 +/- 3.9 mA, P < 0.01). Blockade of the angiotensin II receptor has beneficial effects on reperfusion arrhythmias.

Structure of the rat methionine adenosyltransferase 2A gene and its promoter.

In this study, to understand the regulation of methionine adenosyltransferase (MAT) gene expression, we isolated the rat MAT2A gene encoding MAT alpha2, the catalytic subunit of non-hepatic-type enzyme MAT II and characterized its structural organization and 5'-flanking region. The gene spans approximately 7 kbp and consists of nine exons interrupted by eight introns. The transcription initiation site, as demonstrated by primer extension analysis, is located 123 bp upstream of the translation start codon. Comparison of the structural organization of the rat MAT2A gene to that of the mouse MAT1A gene encoding MAT alpha1, the subunit of liver-type enzymes MAT I and III, shows that the exon structure of two genes is very similar and the insertion sites of all corresponding introns are identical. A canonical TATA box and a GC box, the potential Sp1-binding site, are found 32 bp and 70 bp upstream of the transcription initiation site, respectively. The 5'-flanking region also contains potential recognition sites for various transcription factors including AP-1, AP-2 and NF-IL6 (C/EBPbeta), and a large G+C-rich domain with the characteristics of a CpG island. The 5'-flanking sequence of the rat MAT2A gene has no significant similarity with those of the MAT1A genes. Transient transfection experiments using a luciferase reporter gene showed that the first 820-bp sequence of the 5'-flanking region directed high levels of luciferase activity in cultured rat kidney fibroblast (NRK-49F) and hepatocellular carcinoma (FAA-HTC1) cells, but not in primary rat hepatocytes. Deletion analysis suggested that the first 343 bp of the 5'-flanking region contained cell-type-specific promoter elements of this gene.

Evaluation of abnormal signal-averaged electrocardiograms in young athletes.

Our objectives in this study were to determine the incidence of abnormal signal-averaged ECG (SAECG) and its relation to the extent and type of exercise in young healthy athletes, and to evaluate the association, if any, between the development of abnormal SAECGs and vigorous exercise. The presence of abnormal SAECG was evaluated in 796 athletes (mean age 19 years), and its relation to findings on 12-lead electrocardiogram, echocardiogram, and the presence arrhythmias was studied using Holter monitoring. An SAECG was considered abnormal when any one of the three following criteria was met: filtered QRS duration of more than 114 msec, root-mean-square voltage in the terminal 40 msec of less than 20 muV, or a voltage of less than 40 muV for more than 38 msec. Abnormal SAECGs were present in 68 (8.5%) of the athletes and were associated with a smaller left ventricular mass. Athletes who performed anaerobic exercise tended to exhibit a high incidence of abnormal SAECGs, which was associated with a smaller left ventricular mass. No serious ventricular arrhythmias were observed on 24 h Holter monitoring or during the follow-up period of 20 +/- months. There were no sudden cardiac deaths. Continuous anaerobic exercise may induce abnormal SAECGs through the development of delayed myocardial conduction or electrical inhomogeneity in cardiac tissue. Te presence of an abnormal SAECG was unrelated to the development of arrhythmias in young athletes.

[Signal-averaged electrocardiograms in young athletes--sudden death during exercise].

Our objective was to evaluate the incidence of abnormal SAECG in young athletes, and to evaluate the relationship between abnormal SAECG and electrocardiographic and echocardiographic parameters. The presence of an abnormal SAECG was evaluated in 796 athletes (mean age 19 years), and its relation to findings on 12-lead electro-cardiograms, echocardiograms, and arrhythmias was studied, as recorded by the Holter monitor. An abnormal SAECG was defined as two of the three following criteria: filtered QRS duration > or = 114 msec, root mean squared voltage in the terminal 40 msec < or = 20 microV, or duration < 40 microV > or = 38 msec. Abnormal SAECGs were present in 68 (8.5%) of the athletes and were associated with a smaller left ventricular mass. Athletes who performed anaerobic exercise tended to exhibit a high incidence of abnormal SAECG, which was associated with smaller left ventricular mass. No serious ventricular arrhythmias were observed on Holter monitoring for 24h and during a follow-up period of 20 +/- 10 months in 796 subjects. Continuous anaerobic exercise may induce abnormal SAECG due to the development of delayed myocardial conduction or to electrical inhomogeneity in the cardiac tissue. The presence of an abnormal SAECG was unrelated to the development of arrhythmias in young athletes.

Wavelength index: a predictor of the response to disopyramide in paroxysmal lone atrial fibrillation.

We investigated whether the new parameter wavelength index could predict the response to chronic disopyramide therapy in patients with paroxysmal atrial fibrillation (AF). Twenty-seven patients with AF underwent electrophysiologic studies and the wavelength index was determined before and after intravenous administration of disopyramide. Then all patients were treated with oral disopyramide for 6 months. In 17 patients, AF was eliminated (group A), while it persisted in another 10 patients (group B). The ratio of the wavelength index before and after intravenous disopyramide was higher in group A than in group B. Thus, the wavelength index proved useful for predicting the response of AF to disopyramide.

[Early diagnosis and management of acute pulmonary embolism: clinical evaluation those of 225 cases].

To contribute for making early diagnosis and treatment of acute pulmonary embolism (APE), we investigated on clinical pictures of 225 patients with APE. Common underlying factors were heart disease, prolonged bed rest, post-surgical state, thrombophlebitis, malignant tumor and post-catheterization state in this order. Dyspnea, chest pain, tachycardia and shock were frequently seen as initial symptoms and signs. Blood screening showed leukocytosis, hypoxemia, hypocapnia and elevated serum LDH. Electrocardiographic findings highly demonstrated were ST.T abnormalities, such as T inversion with ST elevation in V1-3, ST depression in V4-6 and sinus tachycardia. Chest X-rays showed diminished pulmonary vascular marking and pulmonary artery dilation. Right ventricular dilatation were frequently seen on 2-dimensional echocardiograms. Pulmonary artery pressure were elevated up to 49/20 (30) mmHg. Twenty-five percent of the patients died, and the recurrence was seen in 4%. Thus, as soon as APE is suspected by above clinical findings, definitive diagnosis should be obtained by the lung perfusion scan and pulmonary arteriography, then oxygen and thrombolytic agents should be given immediately to prevent the fatal outcome.

Pathological extent of interventricular septal infarction in patients with acute anteroseptal myocardial infarction with and without right bundle branch block.

The purpose of the present study is to elucidate the difference in extent of myocardial infarction (MI) between those cases with and those without right bundle branch block (RBBB) occurring during the course of acute MI. We examined postmortem hearts from 20 patients with acute anteroseptal MI; 10 with (group A) and 10 without RBBB (group B). The extent of MI was studied pathologically in the interventricular septum (IVS) and reconstructed. The longitudinal extent of MI did not distinctly differ between groups A and B. In 5 hearts of group B, the anterior limit of the MI extended as high, or as close to the cardiac base, as in group A hearts. Transmural MI was relatively common and seen more frequently in group A than in group B. However, the MI did not always extend evenly to the left and right ventricular sides in the IVS. Left-sided predominance in extent of the MI was more frequently observed in group B than in group A. Right-sided predominance in the extent of septal MI was relatively rare and was seen in 5 cases at the portion where the right bundle branch came down. Four of these were group A patients. Thus, involvement of the right bundle branch might partly depend on the unevenness of the mural extent of the MI as well as the height of extension of the MI in the IVS.

Use of monophasic action potentials to evaluate postpacing T wave changes.

We examined the relationship between postpacing T wave changes and monophasic action potentials recorded from the ventricle in dogs. MAPs were recorded from the right and left ventricle before and after cessation of pacing. The duration of the MAP was calculated as the time in milliseconds from the upstroke to 90% repolarization (MAPD90). T waves in limb leads were flat or had a biphasic pattern, eventually becoming negative after pacing. The Q-T interval of the escape beat after pacing was prolonged compared with the control. After right ventricular pacing, the average duration of MAPD90 in the right ventricle, but not in the left ventricle, was prolonged. (right MAPD: control 275 +/- 10 ms; after pacing: 311 +/- 17 ms, p < 0.05; left MAPD: control: 266 +/- 23 ms, after pacing: 284 +/- 26 ms, NS). After left ventricular pacing, the average duration of MAPD90 in the left ventricle, but not in the right ventricle, was prolonged (right MAPD: control: 247 +/- 75 ms, after pacing: 287 +/- 39 ms, NS; left MAPD: control: 257 +/- 23 ms, after pacing: 303 +/- 25 ms, p < 0.05). Furthermore, the average duration of MAPD90 at the pacing site became progressively prolonged over time. These results suggest that myocardial cells retain the memory of abnormal repolarization associated with pacing.

A fast Fourier transform analysis of coronary reperfusion-induced ventricular fibrillation and the modification by dibutyryl cyclic AMP in a cat model.

To investigate the effect of dibutyryl cyclic AMP (dbcAMP) on ventricular fibrillation after coronary reperfusion, the proximal portion of the anterior descending branch of left coronary artery was reperfused 20 min after ligation in 24 cats. McFee X Y Z electrocardiograms were recorded and ventricular fibrillation was analyzed using a fast Fourier transform analysis (FFT). Ventricular fibrillation occurred in 20 of 24 cases. Sixty seconds after the occurrence of ventricular fibrillation, an intracardiac infusion of dbcAMP was administered. Nine of the 20 were defibrillated and converted to sinus rhythm or junctional rhythm after the administration of dbcAMP. The amplitude and frequency of the main power spectrum of the ventricular fibrillation waves were analyzed by FFT before and after the infusion of saline or dbcAMP. In the saline group there was no significant change in FFT. However, in the dbcAMP group, the amplitude increased significantly from 0.036 +/- 0.015 (MV--2) to 0.054 +/- 0.013 (MV--2) (p < 0.01) and the frequency decreased significantly from 4.22 +/- 1.37 (Hz) to 1.33 +/- 0.91 (Hz) (p < 0.01). Those results indicate that dbcAMP increased the amplitude and decreased the frequency of the main power spectrum of ventricular fibrillation analyzed by FFT. These distinctive changes in FFT analysis were associated with defibrillation in 9 of 20 cases.

Transesophageal low-energy synchronous cardioversion of atrial flutter/fibrillation in the dog.

The purpose of this study was to determine the feasibility and efficacy of terminating atrial flutter/fibrillation using low-energy synchronous shocks delivered through a transesophageal catheter in dogs with talc-induced pericarditis. Atrial flutter/fibrillation was induced by employing the pulse train method. The minimum effective cardioversion energy level was compared for three different methods--method A, delivery between a distal esophageal electrode and a proximal esophageal electrode; method B, delivery of shocks through a distal esophageal electrode and a plate placed on the chest; method C, transthoracic cardioversion. The minimum effective cardioversion energy level did not differ significantly between methods A and B (1.30 +/- 0.46 joules versus 1.29 +/- 0.35 joules). Transesophageal cardioversion decreased the defibrillation threshold three- to fourfold from that of conventional transthoracic cardioversion. There were no complications of heart block, ventricular fibrillation, or any pathologic evidence of esophageal injury. Thus transesophageal low-energy synchronous cardioversion is considered a feasible and effective method for the treatment of atrial flutter/fibrillation.

Lymphocytic active myocarditis characterized by numerous clusters of lymphocytes: a chronic variant of myocarditis?

We report three patients with a particular form of myocarditis characterized by numerous clusters of lymphocytes. Their common clinical manifestation was progressive and fatal heart failure with a 3- to 6-year duration. Atrioventricular and intraventricular conduction disturbances were observed in two patients. At necropsy, the hearts weighed 480, 530, and 430 gm, respectively, and showed marked dilatation of the bilateral ventricles and atria, with frequent mural thrombi. Histologic examination revealed numerous lymphocytic clusters and scattered foci of acute myocardial cell damage on a background of extensive fibrosis. We propose the term "chronic active myocarditis" to denote clinicopathologic characteristics of the present cases.

Effects of transcatheter cardioversion on chronic lone atrial fibrillation.

The effectiveness and safety of internal transcatheter cardioversion on chronic lone atrial fibrillation were examined in ten patients resistant to external electrical (400 joules) and pharmacological cardioversion. Transcatheter cardioversion was performed by pulling back the atrioventricular junction catheter just inferior to the site of the His-bundle recording and delivering the shock between a proximal electrode (cathode) and backplate (anode). Transcatheter cardioversion restored sinus rhythm in all of the ten patients. The only complication observed was transient atrioventricular block after the shock and this was treated by temporary pacing. However, atrial fibrillation recurred in five patients at 30, 27, 52, 1, and 6 days, respectively. A second attempt at transcatheter cardioversion was performed in those patients an was successful in three patients. During a follow-up period ranging from 12 to 22 months, eight patients continued in sinus rhythm. Thus, transcatheter cardioversion is considered effective and safe in selected patients with chronic lone atrial fibrillation in whom external cardioversion was unsuccessful.

Alcohol intake and nonfatal acute myocardial infarction in Japan.

The relation between alcohol and nonfatal acute myocardial infarction (AMI) was examined in a case-control study of 89 male patients and 271 control subjects in Fukuoka, Japan. Patients admitted for the first AMI at 2 hospitals in Fukuoka City were aged 40 to 69 years, and control subjects were recruited based on the telephone directory of the city. Information on alcohol drinking and potential coronary risk factors was obtained by using a self-administered questionnaire, and past drinkers were separated from lifelong abstainers in the analysis. After adjustment for age, occupation, cigarette smoking, strenuous exercise, body mass index, hypertension, diabetes mellitus and parental heart disease, the risk of AMI was progressively less with increasing levels of alcohol consumption. With those who never drank as a referent, adjusted odds ratios for current drinkers consuming less than 30, 30 to 59, and greater than or equal to 60 ml/day of alcohol were 1.11 (95% confidence interval 0.51 to 2.42), 0.31 (0.11 to 0.83), and 0.13 (0.05 to 0.36), respectively. These findings add to the body of data showing that alcohol drinkers are less likely to have AMI.

Electrophysiological properties in chronic lone atrial fibrillation.

BACKGROUND: Although the electrophysiological mechanisms underlying self-sustaining atrial fibrillation (AF) are unclear, recent studies suggest that one requirement for reentry, slow conduction, is frequently present in patients with AF. However, these observations limited to paroxysmal AF may not necessarily apply to chronic AF. Therefore, electrophysiological properties of the atrium and sinus nodal function in chronic lone AF were evaluated. METHODS AND RESULTS: Electrophysiological studies were performed after electrocardioversion in 12 patients with chronic lone AF. Atrial enlargement was absent in the patients with AF. Twelve patients without atrial arrhythmias served as the control group. The patients with AF had a higher incidence of sinus nodal dysfunction, a shorter atrial effective refractory period (215 +/- 19 msec versus 238 +/- 23 msec, p less than 0.02), and a longer P wave duration than control patients (115 +/- 16 msec versus 86 +/- 16 msec, p less than 0.01). The conduction delay zone was significantly greater in patients with AF (60 +/- 12 msec) than that in the control patients (8 +/- 13 msec, p less than 0.01), and the maximal conduction delay was also greater in the study patients than those in the control group, both to the His bundle region (31 +/- 12 msec versus 10 +/- 15 msec, p less than 0.01) and to the coronary sinus (41 +/- 15 msec versus 15 +/- 11 msec, p less than 0.01). The fragmented atrial activity zone was wider in the study group (23 +/- 25 msec) than in control subjects (1.7 +/- 4 msec, p less than 0.02). Repetitive atrial firing was observed in four patients with AF but it was not seen in the control group. CONCLUSIONS: These electrophysiological features, which are manifestations of the abnormal atrial electrophysiology, would favor production of atrial reentry in chronic lone AF.

Effects of atrioventricular block on ventricular fibrillation threshold in dog.

The effects of complete atrioventricular block (CAVB) on ventricular vulnerability were studied 1 week after a transcatheter electrical ablation of the AV junction in 18 closed-chest dogs. All dogs exhibited CAVB and a stable ventricular escape rhythm with a mean cycle length of 1795 +/- 600 ms. Although QT interval during CAVB was significantly prolonged compared with that during the sinus rhythm, QTc interval was significantly shortened. The ventricular fibrillation threshold was significantly elevated after creation of the block (from 9.35 +/- 2.28 to 12.3 +/- 3.69 mA, p less than 0.01). Thus, CAVB which is not associated with QTc prolongation would be even less likely to play an important role in producing ventricular fibrillation presumably including torsades de pointes or polymorphous ventricular tachycardia.

A quantitative histopathological study of right bundle branch block complicating acute anteroseptal myocardial infarction.

The aim of the present study was to evaluate whether necrosis of the right bundle branch is responsible for development of right bundle branch block in acute myocardial infarction. Twenty patients with acute anteroseptal myocardial infarction were studied--10 with right bundle branch block (group A) and 10 without (group B)--to evaluate by serial sectioning the pathological extent of myocardial infarction surrounding the right bundle branch and also that of right bundle branch necrosis. Myocardial infarction reached the right bundle branch more than 8 mm above the moderator band in all of group A, whereas myocardial infarction reached the right bundle branch less than 3 mm above the moderator band in only three patients in group B. Nine hearts in group A showed significant necrosis of the right bundle branch. In group B and in one case with transient right bundle branch block no necrosis was found. The occurrence of right bundle branch block was almost entirely explained by necrosis of the right bundle branch, but transient right bundle branch block did develop without necrosis of the right bundle branch.

Antiarrhythmic and proarrhythmic properties of diazepam demonstrated by electrophysiological study in humans.

We evaluated the electrophysiological parameters before and after the intravenous infusion of diazepam (0.2 mg/kg) in 20 cardiac patients to investigate the drug's antiarrhythmic effect. Diazepam did not significantly change the arterial pressure. After the intravenous infusion of diazepam, the sinus cycle length significantly shortened from 847 +/- 132 to 747 +/- 155 ms (p less than 0.01). No significant change in the maximal sinus node recovery time was noted. The AH interval at the atrial pacing length of 600 ms shortened significantly from 140 +/- 40 to 127 +/- 39 ms (p less than 0.05). However, there was no significant change after the administration of diazepam in the longest atrial pacing rate associated with Wenckebach conduction in the atrioventricular (AV) node, effective and functional refractory periods of the AV node, HV interval, and QRS width during ventricular pacing at the cycle length of 600 ms. The atrial and ventricular effective refractory periods remained unchanged after the administration of diazepam. Six of the eight patients who showed dual AV nodal refractory period curves in the control study did not demonstrate them after diazepam administration by increasing the atrial or AV node effective refractory period. Thus, diazepam showed significant electrophysiological effects of the heart including shortening of the sinus cycle length, improvement in AV node conduction, and no significant effect on the His-Purkinje or intraventricular conduction and refractoriness of the atrium, AV node and ventricle. On the other hand, diazepam may influence the inducibility of supraventricular reentrant tachycardia incorporating the AV node.