Autoantibodies: new upstream targets of paroxysmal atrial fibrillation in patients with congestive heart failure

OBJECTIVES: The clinical implications of autoantibodies (Abs) were investigated as upstream indicators of paroxysmal atrial fibrillation in patients with congestive heart failure. METHODS: Circulating Abs against myosin (M-Abs) detected by immunofluorescence, Abs against beta 1-adrenergic receptors (Beta 1-Abs) detected by enzyme-linked immunosorbent assay (ELISA), and Abs against NA-K-ATPase (NKA-Abs) detected by ELISA were screened in 95 congestive heart failure patients with < or = 45% left ventricular ejection fraction (coronary artery disease, n = 48; dilated cardiomyopathy, n = 47) and 48 age-matched control patients with hypertension. No patient received antiarrhythmic therapy. All patients were enrolled with angiotensin converting enzyme inhibitors in the chronic stable state. Relationship of the presence of paroxysmal atrial fibrillation to other clinical variables were assessed by 48-hour Holter monitoring. RESULTS: No control patient had Abs. However, M-Abs, Beta 1-Abs, and NKA-Abs were detected in 22%, 26% and 16% of patients with congestive heart failure (coronary artery disease; 8%, 10%, and 4%, dilated cardiomyopathy; 36%, 43%, and 28%, respectively). Paroxysmal atrial fibrillation was more frequent in patients with dilated cardiomyopathy than in those with coronary artery disease (47% vs 15%, p < 0.01). Multivariate analysis suggested that NKA-Abs was an independent risk factor for the occurrence of paroxysmal atrial fibrillation (p < 0.01), although there were no differences in other clinical factors: age, sex, New York Heart Association functional class, concomitant medication, left ventricular ejection fraction, left atrial diameter, severity of mitral regurgitation, serum potassium, plasma norepinephrine, and atrial natriuretic peptide concentration. CONCLUSIONS: Autoantibodies against sarcolemmal Na-K-ATPase were closely related to the occurrence of paroxysmal atrial fibrillation in patients with congestive heart failure, so an autoimmune process may be an upstream factor in atrial fibrillation.     

Synergistic action in platelet activation induced by an antiplatelet autoantibody in ITP

Summary. We detected an autoantibody which activated normal platelets in a patient with immune thrombocytopenic purpura and investigated the mechanism by which this autoantibody mediated platelet activation. The patient's IgG induced platelet aggregation and ATP secretion in normal platelet-rich plasma (PRP). IgG-induced aggregation was inhibited by aspirin (ASA), apyrase, a protein kinase C (PKC) inhibitor and two anti-platelet glycoprotein (GP) IIb/IIIa monoclonal antibodies. The increase of aequorin-detected intraplatelet Ca²⁺ induced by the patient's IgG was extremely slight. Phosphorylation of a 40 kDa protein was induced by the patient's IgG without any obvious phosphorylation of a 20 kDa protein, and was inhibited by a PKC inhibitor but not by ASA. With ASA-treated normal PRP, the patient's IgG failed to induce aggregation itself, but enhanced ADP- or STA₂-induced aggregation. Western blotting and immuno-precipitation experiments showed that the patient's IgG reacted to a protein of 36 kDa. These results suggest that the platelet activation induced by this autoantibody depended on both the selective activation of PKC and the slight Ca²⁺ mobilization induced by thromboxane A₂ synthesis, while the aggregation depended on secretion induced by the synergistic action of the above two mechanisms and was mediated through GP IIb/IIIa.     

Portable-type signal-averaged electrocardiography with dipyridamole to detect patients with coronary artery disease.

BACKGROUND: In a retrospective study portable-type signal-averaged electrocardiography (SAECG) with dipyridamole stress was found to identify patients with coronary artery disease (CAD) at their bedside with high sensitivity and specificity, so the utility of this method was prospectively investigated in the present study. METHODS AND RESULTS: Standard 12-lead QRS wave SAECG was performed before and after dipyridamole stress at the bedside in 71 patients with chest pain (43 males, mean age 63 +/-9 years). The filtered QRS duration (fQRSd) before and after dipyridamole stress was determined by multiphasic oscillation method for each of the standard 12 leads, and the maximal value of changes in fQRSd (MAX DeltafQRSd) among the 12 leads was determined. The positive test was defined as MAX DeltafQRSd >or=5 ms, and negative as MAX DeltafQRSd <5 ms based on the previous study. Selective coronary arteriography was performed next. In the positive group (n=31), 25 patients had significant stenosis of the coronary artery and 6 did not. In the negative group (n=40), 5 patients had significant stenosis and 35 did not. The sensitivity, specificity, positive predictive accuracy and negative predictive accuracy for CAD detection by SAECG was 83%, 85%, 81% and 88%, respectively. CONCLUSIONS: Dipyridamole-stress portable SAECG is useful for detecting CAD at the patient's bedside with high sensitivity and specificity.     

Effects of Chronic Administration with Nilvadipine Against Immunohistochemical Changes Related to Aging in the Mouse Hippocampus

We investigated the effect of Ca²⁺ antagonist nilvadipine on age-related immunohistochemical alterations in ubiquitin and S100 protein of the hippocampal CA1 sector in mice using 8-, 18-, 40-, and 59-week-old mice. No significant changes in the number of neuronal cells were observed in the hippocampal CA1 sector up to 59 weeks after birth. The administration of nilvadipine did not affect the number of the hippocampal CA1 cells of 40-week-old mice. Age-dependent increases in ubiquitin immunoreactivity were observed in the hippocampal CA1 neurons up to 59 weeks after birth. The administration of nilvadipine prevented dose-dependently the increases in the number of ubiquitin-immunoreactive neurons in the hippocampal CA1 sector of 40-week-old mice. S100 immunoreactivity was unchanged in the hippocampal CA1 sector up to 40 weeks after birth. In 59-week-old mice, the level of staining of S100-immunoreactive cells increased significantly in the hippocampal CA1 sector. The administration of nilvadipine decreased dose-dependently the number of S100-immunoreactive cells in the hippocampal CA1 sector of 40-week-old mice. The present study demonstrates that age-related increases in ubiquitin system may play a pivotal role in protecting neuronal cell damage during aging. In contrast, our results suggest that expression of S100 protein in the hippocampal CA1 sector may play an exacerbating factor in some neuronal cells damaged by aging. Our results also demonstrate that nilvadipine, a dihydropyridine-type calcium channel blocker, can prevent dose-dependently the increases in the ubiquitin immunoreactive neurons and decrease the number of S100 immunoreactive cells in the hippocampal CA1 neurons of aged mice. These results suggest that nilvadipine may offer a new approach for the treatment of neuronal dysfunction in aged humans.     

Effect of recombinant human erythropoietin on anticancer drug-induced anaemia

Anaemia was induced in rats with fluorouracil (5-FU) or cisplatin (CDDP) and the mechanisms of anaemia induction were analysed. Furthermore, the therapeutic effects of recombinant human erythropoietin (rHu Epo) on these anticancer drug-induced anaemias were investigated. In 5-FU-induced anaemia, marked serum erythropoietin (Epo) elevation was observed in inverse correlation to blood Hb concentration and Hb concentration rapidly recovered to normal levels. On the other hand, in CDDP-induced anaemia, serum Epo elevation was modest and the lowered Hb concentration persisted longer. Treatment with rHu Epo significantly improved both anticancer drug-induced anaemias but rHu Epo was more effective on CDDP-induced anaemia. These results suggest that rHu Epo might be useful for the therapy of anaemia associated with anticancer chemotherapy.     

Small non-functioning endocrine tumor of pancreas: Comparison with solid cystic tumor

A small non-functioning islet-cell tumor of the pancreas in a 79-year-old man is reported. Ultrasonography showed a solid small mass in the body of the pancreas. All laboratory data, including serum hormones and tumor markers, were within normal limits. A distal pancreatectomy was performed. Cut sections of the specimen revealed a small, hard, solid mass measuring 2.8 × 2.2 × 2.0 cm. Histologically, the tumor consisted of large acidophilic cells with round nuclei, and these cells were similar to those normally found in solid and cystic tumors (SCT) of the pancreas. However, the tumor cells were slightly positive for somatostatin and neuron-specific enolase. Ultrastructural studies revealed clear nuclei with no zymogen but immature neurosecretory granules in the cytoplasm of the tumor cells. These findings were consistent with those of non-functioning islet-cell tumors. We describe the clinical and histological differences between non-functioning islet-cell tumors and SCT based on an analysis of the literature. Received Feb. 14, 1997; accepted June 27, 1997     

Prognostic significance of serum uric acid in patients with chronic obstructive pulmonary disease receiving home oxygen therapy]

Home oxygen therapy (HOT) not only prolongs life expectancy but also improves quality of life. Serum uric acid (UA), the final product of purine catabolism, has been shown to be increased in the hypoxic state. To elucidate the prognostic significance of serum UA in patients with chronic obstructive pulmonary disease (COPD) receiving HOT, we assessed the ratio between the serum concentration of UA and creatinine (Cr) in 91 outpatients with COPD. During a mean follow-up period of 31 months, 24 patients died of acute exacerbation of COPD. The delta UA/Cr ratio was calculated as the percent changes in serum UA/Cr during HOT. delta UA/Cr was increased in non-survivors, but not in survivors, and was negatively correlated with the nadir of oxyhemoglobin saturation (r = -0.32, p < 0.01). Of the clinical and laboratory variables, only the delta UA/Cr ratio was found to be independently related to mortality by a multivariate Cox proportional-hazards analysis. The Kaplan-Meier survival curves divided into values below and above the median value (9.7%) of this ratio demonstrated that mortality was significantly higher among patients with high values than among those with low values (log-rank test: p < 0.05). We conclude that the delta UA/Cr ratio appears to be a reliable marker of prognosis, and may be useful for the long-term follow-up of outpatients with COPD receiving HOT.