The glucagon-like peptide-1 receptor agonist liraglutide improves hypoxia-induced pulmonary hypertension in mice partly via normalization of reduced ET(B) receptor expression.

The glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide is an incretin hormone mimetic used in the treatment of diabetes. However, the effects of liraglutide on pulmonary hypertension (PH) and pulmonary endothelin (ET) system are unknown. Eight-week-old C57BL6/J mice were injected liraglutide or vehicle for 5 weeks. One week after injection, the mice were exposed to either room air (normoxia) or chronic hypoxia (10 % O(2)) for 4 weeks. The right ventricular systolic pressure (RVSP) was significantly higher in hypoxia + vehicle group than in normoxia + vehicle group. ET-1 mRNA expression in the lungs was comparable among all the groups. ET(B) mRNA and protein expression in the lungs was significantly lower in hypoxia + vehicle group than in normoxia + vehicle group. The above changes were normalized by liraglutide treatment. The expression of phospho-eNOS and phospho-AMPK proteins in the lungs was significantly higher in hypoxia + liraglutide group than in normoxia + vehicle group. We demonstrated for the first time that liraglutide effectively improved RVSP and RV hypertrophy in hypoxia-induced PH mice by activating eNOS through normalization of impaired ET(B) pathway and augmentation of AMPK pathway. Therefore, GLP-1R agonists can be promising therapeutic agents for PH.

Differential localization of atrial natriuretic peptide and skeletal alpha-actin messenger RNAs in left ventricular myocytes of patients with dilated cardiomyopathy.

OBJECTIVES: This study was designed to determine whether atrial natriuretic peptide and skeletal alpha-actin messenger RNAs (mRNAs) are co-localized in ventricular myocytes of patients with dilated cardiomyopathy. BACKGROUND: Atrial natriuretic peptide and skeletal alpha-actin are known as augmented genes with cardiac hypertrophy. However, the expression and localization of both genes in chronic failing heart remain unclear. METHODS: Left ventricular biopsy specimens were obtained from 14 patients with dilated cardiomyopathy. Atrial natriuretic peptide and skeletal alpha-actin mRNAs were detected by in situ hybridization with specific sulfur-35 uridine triphosphate-labeled RNA probes in the serial sections. RESULTS: Atrial natriuretic peptide mRNA was detected in 10 patients, and intense signals were localized in the myocytes located in the subendocardium and around the interstitial fibrous area. By contrast, skeletal alpha-actin mRNA was homogeneously detected in all myocytes in seven patients. By left ventriculography, patients with skeletal alpha-actin-positive findings had a lower ejection fraction (37.1 +/- 6.0%) than those with negative findings (46.3 +/- 5.8%, p < 0.05), but atrial natriuretic peptide mRNA expression was not related to left ventricular function. CONCLUSIONS: These results indicate that the expression of atrial natriuretic peptide and skeletal alpha-actin mRNAs are not always co-localized in the left ventricle of patients with dilated cardiomyopathy and suggest that the mechanisms of the regulation of these two genes in the chronic failing heart are different.

Lymphocytic myocarditis presenting as unexplained ventricular arrhythmias: diagnosis with endomyocardial biopsy and response to immunosuppression.

During a period of 18 months beginning in January 1982, a total of 65 patients were referred to the Miami Heart Institute for evaluation of either aborted out of hospital sudden death, ventricular tachycardia resistant to standard clinically directed antiarrhythmic medication programs or high grade ventricular arrhythmia (Lown class greater than or equal to IV B) with or without syncope. After complete evaluation including cardiac catheterization in all but 1 patient, 17 patients were identified in whom no obvious cardiac disease could be found. Twelve of the 17 underwent right ventricular endomyocardial biopsy. Six of the 12 biopsies demonstrated clinically unsuspected lymphocytic myocarditis (Group A). Findings in three of the remaining six biopsies were consistent with an early cardiomyopathy and in three were completely normal (Group B). Retrospective review of the clinical, laboratory, electrophysiologic, hemodynamic and angiographic data failed to identify a marker that reliably separated Group A from Group B patients. In addition to antiarrhythmic therapy guided by laboratory electrophysiologic study, all Group A patients were treated with prednisone and azathioprine. After 6 months of immunosuppression, all patients with myocarditis were reevaluated in the hospital without antiarrhythmic medication. Ventricular tachycardia/fibrillation could not be provoked in the laboratory during repeat electrophysiologic testing in five of the six patients. Repeat myocardial biopsy after all immunosuppressive therapy had been discontinued revealed absence of inflammation associated with varying degrees of residual interstitial fibrosis. There were no deaths. It was concluded that a patient with an otherwise clinically silent lymphocytic myocarditis can present with potentially life-threatening ventricular arrhythmias.(ABSTRACT TRUNCATED AT 250 WORDS)

Demonstration of diastolic and presystolic Purkinje potentials as critical potentials in a macroreentry circuit of verapamil-sensitive idiopathic left ventricular tachycardia.

OBJECTIVES: The purpose of this study was to determine the relation of diastolic and presystolic potentials recorded during verapamil-sensitive idiopathic left ventricular tachycardia (ILVT) to reentry circuit. BACKGROUND: Successful ablation of verapamil-sensitive ILVT at the zone of slow conduction from which the diastolic potential is recorded has been reported. However, the relationship between the diastolic potential and the reentrant circuit remains a matter of debate. METHODS: Radiofrequency (RF) ablation was performed in 20 patients with verapamil-sensitive ILVT. After identifying the ventricular tachycardia (VT) exit site, we searched for the mid-diastolic potential (P1) during VT. Entrainment followed by RF current application was performed. If the mid-diastolic potential could not be detected, RF current was applied at the VT exit site showing the earliest ventricular activation with a single fused presystolic Purkinje potential (P2). RESULTS: In 15 of 20 patients, both P1 and P2 were recorded during VT from midseptal region. Entrainment pacing captured P1 orthodromically and reset the VT. The interval from stimulus to P1 was prolonged as the pacing rate was increased. Radiofrequency ablation was successfully performed at this site in all 15 patients. After successful ablation, P1 appeared after the QRS complex during sinus rhythm with the identical sequence to that during VT. In the remaining five patients, the diastolic potential could not be detected, and a single fused P2 was recorded only at the VT exit site. Successful ablation was performed at this site in all five patients. CONCLUSIONS: This study demonstrates that P1 and P2 are critical potentials in a circuit of verapamil-sensitive ILVT and suggests the presence of a macroreentry circuit involving the normal Purkinje system and the abnormal Purkinje tissue with decremental property and verapamil-sensitivity.

Prognostic significance of sustained monomorphic ventricular tachycardia induced by programmed ventricular stimulation using up to triple extrastimuli in survivors of acute myocardial infarction.

The prognostic significance of sustained monomorphic ventricular tachycardia (VT) induced by programmed ventricular stimulation using up to 3 extrastimuli was evaluated in 133 consecutive survivors of acute myocardial infarction (AMI) at a mean interval of 1.8 +/- 1.1 months after onset. This was compared with hemodynamic and angiographic abnormalities shown by cardiac catheterization and ventricular ectopic activity detected by Holter monitoring. Sustained monomorphic VT was induced in 25 (19%) patients, sustained polymorphic VT in 11 (8%) patients, nonsustained monomorphic VT (greater than or equal to 10 beats) in 12 patients (9%) and nonsustained polymorphic VT in 9 patients (7%). Multivariate logistic regression analysis of clinical, angiographic, hemodynamic and electrocardiographic variables showed that the presence of a left ventricular aneurysm (p = 0.005) and Lown grade 4B ventricular ectopic activity (p less than 0.001) were independent predictors of inducibility of sustained monomorphic VT. During a mean follow-up of 21 +/- 13 months, there were 8 (6%) sudden cardiac deaths and 3 (2.3%) spontaneous occurrences of life-threatening sustained VT. The 2-year probability of freedom from sudden cardiac death or sustained ventricular tachyarrhythmias was 53 +/- 13% for patients with inducible sustained monomorphic VT, 70 +/- 10% for those with a left ventricular ejection fraction less than 40% and 58 +/- 13% for those with Lown grade 4B ventricular ectopic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Usefulness of early versus late programmed ventricular stimulation in acute myocardial infarction.

To determine the influence of timing on the prognostic value of programmed ventricular stimulation after acute myocardial infarction (AMI), 32 patients were studied on day 19 (early study) and again on day 36 (late study) after AMI using up to 3 extrastimuli. At the early study, sustained monomorphic ventricular tachycardia (VT) was induced in 12 patients (38%), sustained polymorphic VT in 8 (25%), nonsustained monomorphic VT in 1 (3%), nonsustained polymorphic VT in 1 (3%) and no inducible arrhythmia in 10 (31%). At the late study, sustained monomorphic VT, nonsustained monomorphic VT and nonsustained polymorphic VT were induced in 8 patients (25%) each, and no inducible arrhythmia in 8 (25%). Of the 12 patients who had inducible sustained monomorphic VT at the early study, 7 had noninducibility of sustained monomorphic VT at the late study. Of the 20 patients who had noninducibility of sustained monomorphic VT at the early study, 3 had inducible sustained monomorphic VT at the late study. During the follow-up period (mean +/- standard deviation 21 +/- 8 months), there were 2 sudden cardiac deaths and 3 occurrences of sustained VT. Univariate analysis revealed both inducibilities of sustained monomorphic VT at the early study (p = 0.045) and at the late study (p less than 0.001) to be predictive of sudden cardiac death or clinical occurrence of sustained VT. However, inducibility of sustained monomorphic VT at the late study had a higher sensitivity (100%), specificity (89%), positive predictive value (63%) and negative predictive value (100%) than at the early study (80, 70, 33 and 95%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Colloidal gold uptake as a marker for monocyte differentiation and maturation in normal and leukemic cells.

The uptake of colloidal gold particles by human monocytes was studied by electron microscopy, with special emphasis on changes in this uptake during the differentiation and maturation of these cells. The way in which leukemic cells of childhood acute non-lymphocytic leukemia (ANLL) can function in this gold uptake was also examined. In monocytes, microendocytosis was temperature-dependent; colloidal gold uptake increased as temperatures rose from 4 degrees C to 37 degrees C. It appeared that gold particles first adhered to the cell surface membrane, were then incorporated into the cytoplasmic vesicles, and then were transported into the granules. Original HL-60 cells and retinoic acid (RA)-treated HL-60 cells, which were differentiating and maturing along the granulocyte lineage, did not ingest colloidal gold particles, but 1,25(OH)2D3-treated HL-60 cells showed colloidal gold uptake during their differentiation and maturation along the monocyte lineage: 68.6% of the cells contained gold particles. Gold uptake was demonstrated in 27.3% of original U937 cells; the percentage increased to 70.3% when they were induced to mature by RA. In 15 specimens of childhood ANLL, none of the M1, M2 or M3 cells showed colloidal gold uptake, whereas 76-97% of M4 and M5 cells showed this uptake. These findings indicate that colloidal gold uptake is a marker of monocyte differentiation and maturation and can provide additional information for ANLL cytology.

[Experimental studies on the gastroduodenojejunal motility and gastric emptying after duodenectomy with preservation of the total stomach and pylorus].

It is of interest to know whether or not the removal of the pyloric branch of the vagus nerve (subsequently referred to as vagotomy) is associated with the early stagnation of gastric contents supervening upon duodenectomy with preservation of the total stomach and pylorus (innervation of pylorus group 5, denervation of pylorus group 5). In the present study preservative duodenectomy was performed on dogs to determine the effects of vagotomy on gastroduodenojejunal motility and gastric emptying. The group of typical strong preprandial contraction waves (subsequently referred to as phase III) did not appear after vagotomy. The appearance of phase III was delayed and its duration was reduced. The duration of pyloric phase III significantly reduced, at 2 and 4 weeks post-surgery, in the denervation of pylorus group, compared to the innervation of pylorus group, and at 4 weeks, the area of phase III was significantly decreased in the denervation group. Post-vagotomy gastric emptying was poor throughout the course of observation. The results of this study suggest that the vagotomy-induced change in gastroduodenal motility in fasting conditions is one of the factors responsible for the stagnation of gastric contents.

Time-domain and spectral turbulence analyses of the signal-averaged electrocardiogram have different predictive values for sustained ventricular tachycardia in patients with myocardial infarction.

We performed signal-averaged ECG and programmed stimulation in 15 patients after myocardial infarction with ventricular tachycardia and 49 patients after myocardial infarction without ventricular tachycardia to compare the spectral turbulence analysis and time-domain analysis of signal-averaged ECG for prediction of clinical and induced ventricular tachycardia. Sustained monomorphic ventricular tachycardia was inducible in all 15 patients with clinical sustained monomorphic ventricular tachycardia (group 1) and in 9 patients without clinical sustained monomorphic ventricular tachycardia (group 2). Sustained monomorphic ventricular tachycardia was not inducible in 40 patients without clinical sustained monomorphic ventricular tachycardia (group 3). While there was no difference in time-domain variables between groups 1 and 2, there were significant differences between groups 2 and 3. Values obtained by spectral turbulence analysis differed significantly between groups 1 and 2, but not between groups 2 and 3. Time-domain analysis showed abnormal values in 87% of group 1 patients, 78% of group 2, and 35% of group 3. Spectral turbulence analysis showed abnormal values in 93% of group 1, 11% of group 2, and 30% of group 3. In conclusion, frequency-domain spectral turbulence analysis of signal-averaged ECG is more useful than the time-domain analysis in predicting the spontaneous occurrence of sustained monomorphic ventricular tachycardia in patients after myocardial infarction.

[Hereditary spherocytosis first diagnosed upon the development of aplastic crisis; a case report].

We report a Childhood case of hereditary spherocytosis (HS) first diagnosed upon the development of aplastic crisis. A 6-year-old boy presented with fever and anemia. Although there was neither icterus nor splenomegaly at first, mild icterus and splenomegaly gradually developed with improvement of anemia. The diagnosis of HS was made on the basis of the presence of numerous spherocytes on the peripheral smear, increased osmotic fragility and the auto-hemolysis test result. The severe anemia in the early course with a marked decrease in the bone marrow erythroid cells and the absence of icterus and splenomegaly indicate that it was due to aplastic crisis. In the virological study, anti-human parvovirus (HPV) antibody titers were increased: the values of anti-HPV IgM were high and those of anti-HPV IgG were suddenly elevated. We thus considered that this HS case developed aplastic crisis by HPV infection.

[Prediction of inducible ventricular tachycardia by signal averaged electrocardiogram in patients with healed myocardial infarction].

Induction of ventricular tachycardia by programmed ventricular stimulation (PVS) is believed to be the most reliable clinical test which predicts high risk group of clinical ventricular tachycardia (VT) and sudden cardiac death (SCD) after acute myocardial infarction (MI). On the other hand, late potential (LP) detected by signal averaged electrocardiogram (SAECG) may also predict high risk group of clinical VT in MI. We compared the usefulness of these two tests. LP in SAECG could roughly predict patient group with induced sustained monomorphic VT. Moreover, PVS clearly identified non-high risk group of clinical VT or SCD which have no inducible sustained monomorphic VT with high negative predictive value. It was concluded that SAECG should be used as a screening test for life-threatening arrhythmia, and those patients who have LP should undergo PVS study to clarify the actual risk of VT and/or SCD.

Which are the most reliable predictors of recurrence of atrial fibrillation after transcatheter ablation?: a meta-analysis.

CONTEXT: Transcatheter ablation of atrial fibrillation (AF) has undergone important development, with acceptable midterm results in terms of the safety and recurrence. A meta-analysis was performed to identify the periprocedural complications, midterm success rates and predictors of recurrence after AF ablation. METHODS AND RESULTS: 4357 patients with paroxysmal AF, 1083 with persistent AF and 1777 with long standing AF were included. The pooled analysis showed that there was an in-hospital complication rate of tamponade requiring drainage of 0.99% (0.44-1.54; CI 99%), stroke with neurological persistent impairment of 0.22% (0.04-0.47; CI 99%), and stroke without of 0.36% (0.03-0.70; CI 99%) After a follow up of 22 (13-28) months and 1.23 (1.19-1.5; CI 99%) procedures per patient, the AF recurrence rate was 31.20% (24.87-34.81; CI 99%). The persistent AF patients exhibited a greater risk of recurrence after the first ablation (OR 1.78 [1.14, 2.77] CI 99%), but a trend towards non significance was present in the patients with more than one procedure (OR 1.69 [0.95, 3.00] CI 99%). The most powerful predictors of an AF ablation failure in the overall population were a recurrence within 30-days (OR 4.30; 2.00-10.80), valvular AF (OR 5.20; 2.22-9.50) and a left atrium diameter of more than 50mm (OR 5.10 2.00-12.90; all CI 95%). CONCLUSIONS: Persistent AF remains burdened from higher recurrence rates, however not so following redo-procedures. Three predictors, valvular AF, a left atrium diameter longer than 50mm and recurrence within 30 days, could be appraised to drive selection of patients and therapeutic strategy.

Impact of serum flecainide level on control of atrial fibrillation in a case treated with cardiac resynchronization therapy.

A 72-year-old male patient with dilated cardiomyopathy was treated with oral flecainide (100 mg/day) for persistent atrial fibrillation (AF) that could not be converted to sinus rhythm by electrical cardioversion. Initiation of flecainide treatment provided sinus rhythm without prolongation of QRS and QTc, bradycardia and first-degree atrioventricular block at a serum flecainide level of 438 ng/mL. Then, he received cardiac resynchronization therapy (CRT). Dose reduction to 50 mg/day because of stabilization of heart rate after CRT produced AF at a serum flecainide level of 270 ng/mL. Electrical cardioversion did not restore the AF to a sinus or pacing rhythm. Dose escalation of flecainide (to 100 mg/day) restored the pacing rhythm at a serum flecainide level of 401 ng/mL. This case suggests that in the Japanese population, serum flecainide level should be maintained at >300 ng/mL to control AF even after effective CRT.

Tissue factor expression as a possible determinant of thromboembolism in ovarian cancer.

Ovarian cancer, and clear cell carcinoma in particular, reportedly increases the risk of venous thromboembolism (VTE). However, the mechanisms remain unclear. Tissue factor (TF) supposedly represents a major factor in the procoagulant activities of cancer cells. The present study examined the involvement of TF expression in VTE for patients with ovarian cancer. Subjects comprised 32 consecutive patients (mean age 49.8 years) with histologically confirmed ovarian cancer. Presence of VTE was examined using a combination of clinical features, D-dimer levels and venous ultrasonography. Immunohistochemical analysis was used to evaluate TF expression into 4 degrees. Venous thromboembolism was identified in 10 of the 32 patients (31%), including five of the 11 patients with clear cell carcinoma. Tissue factor expression was detected in cancer tissues from 24 patients and displayed significant correlations with VTE development (P=0.0003), D-dimer concentration (P=0.003) and clear cell carcinoma (P<0.05). Multivariate analysis identified TF expression as an independent predictive factor of VTE development (P<0.05). Tissue factor (TF) expression is a possible determinant of VTE development in ovarian cancer. In particular, clear cell carcinoma may produce excessive levels of TF and is more likely to develop VTE.

Pseudo-Chediak-Higashi anomaly in acute myeloid leukemia (M2) of childhood.

The frequency and clinical significance of the pseudo-Chediak-Higashi (PCH) anomaly were studied in 20 children with acute myeloid leukemia (AML) M2 in the FAB nomenclature. PCH granules were recognized as giant eosinophilic granules, measuring up to 5 microns, in the cytoplasm of leukemic cells on smears. At the electron microscope level, most PCH granules were round to oval and outlined by a limiting membrane, and contained homogeneous, granular, crystalloid, rod-like or myelin-like materials. The PCH anomaly was demonstrable in five (25.0%) of the 20 patients, which indicates that the anomaly is not rare in childhood AML M2. There were no differences between PCH anomaly-positive and PCH anomaly-negative groups with regard to hepatosplenomegaly, hemoglobin levels, white blood cell counts, bone marrow cellularity, t(8q-, 21q+) chromosome abnormalities or prognoses. Circulating leukemic cells were observed less frequently in the PCH anomaly-positive group than in the PCH anomaly-negative group (p less than 0.05); the leukemic cells were not demonstrable in three of the five patients in the former group, although they were detected in all 15 patients in the latter group. The existence of PCH granules and/or a defect of the cytoskeleton responsible for the PCH anomaly in leukemic cells may impede their movement from the bone marrow to the peripheral blood.

Effects of procainamide and lidocaine on electrically inducible ventricular tachycardia studied with programmed ventricular stimulation in post myocardial infarction.

The effects of procainamide and lidocaine, representative of class IA and IB antiarrhythmic agents, on electrically inducible ventricular tachycardia (VT) were studied using programmed ventricular stimulation in 47 post myocardial infarction patients at an average of 1.5 months after the onset. The mean doses of administered procainamide and lidocaine were 1050 mg and 161 mg, and their mean plasma concentrations were 7.5 micrograms/ml and 3.1 micrograms/ml respectively. The induction of sustained VT was suppressed in 15 of 29 patients (52%) by procainamide, but in none by lidocaine. The induction of nonsustained VT was suppressed in 6 of 18 patients (33%) by procainamide, and in 1 of 8 patients (13%) by lidocaine. The efficacy rate of procainamide was significantly higher than that of lidocaine in suppression of VT induction (21/47 vs 1/14 p less than 0.01). Procainamide significantly prolonged the effective refractory period of the right ventricle as well as the HV and QRS interval, however lidocaine did not affect them significantly. On the other hand, the worsening effect which changed nonsustained VT inducible in the baseline into sustained VT inducible post drug administration was demonstrated in 8 of 18 procainamide cases (44%), and in 3 of 8 lidocaine cases (38%). Between the procainamide effective and ineffective or worsening patients, there were no differences found in the electrophysiologic variables either in the baseline or post procainamide administration. We concluded that procainamide was more effective than lidocaine for the prevention of potential life-threatening VT induction in post myocardial infarction patients, although its efficacy was considerably limited, and to confirm the effectiveness and exclude the worsening effects of the class IA and IB antiarrhythmic agents, drug testing using programmed ventricular stimulation appeared to be valuable.