Electrophysiological effects of flecainide and sotalol in the human atrium during persistent atrial fibrillation

Aims Atrial fibrillation (AF) shortens the atrial action potential and the atrial refractory period. These changes promote persistence of AF. Pharmacological prolongation of atrial action potential duration (APD) may therefore help to prevent recurrent AF. In addition to prolonging APD, sodium channel blockers may prevent AF by inducing post–repolarization refractoriness (PRR). We studied whether two antiarrhythmic drugs (sotalol, flecainide) prolong APD or induce PRR in the fibrillating human atrium. Methods In 12 patients with persistent AF (11 male, 58 ± 5 yrs, 27 ± 7 months duration of AF), we recorded monophasic action potentials from the right atrial appendage and inferior right atrium at baseline and 15 minutes after intravenous administration of sotalol (1.5 mg/kg) or flecainide (2 mg/kg). APD and effective refractory periods (ERP) were determined. Results Both drugs prolonged APD90 during AF (flecainide from 109 ± 7 ms to 137 ± 10 ms, sotalol from 108 ± 6 ms to 131 ± 8 ms, both p < 0.05 vs. baseline). Sotalol prolonged ERP in parallel to APD (from 119 ± 8 ms to 139 ± 8 ms, p < 0.05). Flecainide induced PRR by prolonging ERP more than APD90 (from 134 ± 9 ms to 197 ± 28 ms, p < 0.05 vs. baseline and vs. sotalol). Conclusions Flecainide and sotalol prolong the atrial action potential during atrial fibrillation in humans. In addition, flecainide induces atrial PRR. These electrophysiological effects may reduce AF recurrences and prevent their persistence.Drs. Kirchhof, Engelen and Breithardt are Members of the Kompetenznetz Vorhofflimmern     

Dialysate concentration and pharmacokinetics of 2F-Ara-A in a patient with acute renal failure

Fludarabine is frequently used for treatment of B-cell chronic lymphocytic leukemia and in conditioning regimes for hematopoietic cell transplantations. The total body clearance of the principal metabolite 2-fluoro-ara-A (2F-Ara-A) correlates with the creatinine clearance. We report data on total dialysate concentration as well as pharmacokinetics of 2F-Ara-A in a patient with anuric acute renal failure. On three consecutive days the patient received a daily dose of 80 mg (40 mg/m(2)) fludarabine and underwent three consecutive extended (daily) dialysis (ED) sessions. ED removed a considerable amount of the drug. The average dialysis clearance was 33.85 ml/min which is about 25% of the clearance in patients without renal failure. No toxic side effects of the treatment were observed. This case suggests that fludarabine treatment can be considered in patients requiring dialysis if dose reduction and adequate removal of the drug by hemodialysis is provided.     

Oxidized LDL induces ventricular myocyte damage and abnormal electrical activity--role of lipid hydroperoxides

OBJECTIVE: It was our aim to investigate effects of human LDL, copper-, or AAPH-oxidized over different periods of time to different degrees (ox-LDL), on viability and electrophysiological parameters of isolated ventricular myocytes of guinea pigs. METHODS: Guinea pig ventricular myocytes were incubated with ox-LDL or native LDL (at 0.5 mg/ml) for 12 h, and afterwards myocyte damage, action potentials, and transmembrane ion currents were studied (at 37 degrees C). RESULTS: Ox-LDL was found to induce severe myocyte damage, whereas native LDL had no effect. Myocyte damage was dependent on the content of total lipid hydroperoxides in both copper-oxidized and AAPH-oxidized LDL. Incubation with ox-LDL led to intense contractile and electrophysiological effects including prolongation of action potential duration, depolarization of resting membrane potential, spontaneous activity, generation of afterdepolarizations, and modification of transmembrane ion currents (e.g. inward rectifier, calcium, and background currents). CONCLUSIONS: Ox-LDL induced cell damage and irregular electrical activity in ventricular myocytes. These effects were dependent on the lipid hydroperoxide content of ox-LDL and were similar to oxidative stress (OS) induced by various OS-generating systems. The observed effects may play a role for functional cardiac abnormalities in patients with increased ox-LDL levels.     

Hepatitis C-associated autoimmunity in patients coinfected with HIV.

Background: Hepatitis C virus (HCV) infection is associated with multiple extrahepatic manifestations. It is unclear to what extent extrahepatic manifestations occur in HIV/HCV coinfection. Methods: We prospectively assessed cross-sectional frequencies of autoimmune manifestations in HIV/HCV-coinfected patients (n=98), HIV-mono-infected (n=45) and HCV-mono-infected patients (n=78). Diagnostic vasculitis scores, HCV and HIV loads, CD4 cell counts, thyroid-, cardiolipin-, non-organ-specific tissue antibodies (nuclear, smooth muscle, anti-liver-kidney-microsome, neutrophil-cytoplasmic) and cryoglobulins were determined. Results: Synergistic effects of HCV and HIV infection were observed with respect to the prevalence of antibodies against thyroglobulin (HCV infection 15.4%, HIV infection 8.8%, HIV/HCV coinfection 30.6%; P<0.001) and cardiolipin antibodies (HCV infection 9.0%, HIV infection 31%, HIV/HCV coinfection 46%; P<0.001). Cryoglobulinemia type III, was significantly associated with HCV infection (HCV, 25.6%; HIV/HCV, 20.4%) but not with HIV infection (4.4%, P<0.05). Rheumatoid factor was commonly detected in patients with HCV infection (48%), but occurred considerably less frequently in patients with HIV infection (4.4%) or HIV/HCV coinfection (9.5%, P<0.01). Conclusion: HIV coinfection appears to differentially modulate the frequency of HCV-related autoimmunity. However, autoimmunity is rarely accompanied by clinical manifestations.     

Increased distribution of collagen type III and reduced expression of matrix metalloproteinase 1 in patients with diverticular disease

Diverticular disease is an increasingly common clinical problem especially in Western industrialized countries, but the mechanism by which the disease develops remains unclear. Based on studies showing a structural change in the colonic wall in these patients, we examined whether there are any disorders concerning the collagen metabolism in patients with diverticular disease. Samples of colonic tissue from 13 patients with diverticulitis were compared to 14 controls. We performed a Sirius red test for the overall collagen content and immunohistochemical studies facing differentiation between collagen type I and type III and the expression of matrix metalloproteinases 1 and 13. In the bowel sections of patients with diverticulitis there were decreased levels of mature collagen type I (1.37+/- 0.32 vs. 1.59 +/- 0.31) and increased levels of collagen type III (1.61+/- 0.32 vs. 1.42 +/- 0.42), with a resulting lower collagen ratio I/III. The expression of MMP-I was reduced significantly in the diverticulitis group (4.83 +/- 0.92 vs. 6.02 +/- 1.98) while expression of MMP-13 did not differ significantly between the two groups (1.03 +/- 0.11 vs. 1.04 +/- 0.12). Our findings support the theory of structural changes in the colonic wall as one of the major pathogenic factors in the development of diverticular disease. Further studies must focus on the complex interactions of several extracellular matrix components.     

Inflammatory pseudotumor of the lung following invasive aspergillosis in a patient with chronic graft-vs.-host disease

Inflammatory myofibroblastic tumor (IMT) is an uncommon cause of solitary or multifocal lung nodules and can also be rarely found in various other extrapulmonary sites. Although this pseudotumor is benign, it can be locally very aggressive. The pathogenesis of IMT remains unclear; autoimmune or infectious origins have been hypothesized, so far. Here, we report a case of inflammatory pseudotumor of the lung secondary to invasive pulmonary aspergillosis in a patient with chronic graft-vs.-host disease. The 42-year-old patient presented with coughing and hemoptysis as major clinical signs 1 yr after successful HLA-identical stem cell transplantation. Aspergillus fumigatus was cultured from the bronchoscopic lavage, but intensive antifungal treatment could only initially improve the clinical situation. Diagnostic re-evaluation by open-chest biopsy surprisingly revealed an inflammatory pseudotumor responsible for clinical and radiographical deterioration. Both clinical and radiographical signs resolved under long-term steroids and secondary antifungal prophylaxis.     

Anticoagulation treatment for the reduction of stroke in atrial fibrillation: a cohort study to examine the gap between guidelines and routine medical practice

Background Atrial fibrillation (AF) is the most common heart arrhythmia, affecting 6% of people over 65 years, and carries a 4.5% average annual stroke risk, which can be reduced by appropriate anticoagulation. A multi-centre observational study, Management and Outcomes in the Care of Atrial fibrillation in Germany (MOCA) was conducted to evaluate the current anticoagulation treatment pattern in patients with AF in Germany. Methods Patients with AF were recruited from December 2003 to June 2004 in physician practices. Clinical data including International Normalised Ratio (INR) values and anticoagulation strategy were obtained from the physician chart and the patient follow-up, documenting hospitalisations, medications, and complications, was conducted at three and six months. Main outcome measures included anticoagulation methods, practice guidelines adherence and time within recommended anticoagulation range. Results 361 patients with AF (mean age 71±9, 61% male) were recruited in 45 physician practices. 90% of all patients had been treated with Vitamin K-Antagonists (VKA) at some time since AF-diagnosis, 88% were still treated. 10% of patients received aspirin as their anticoagulation therapy. Monitoring occurred at least once a month in over 70% of patients. Monitored INR values were 56% of the time within, 14% below and 30% over the recommended target range. A gap of 40% existed between the guideline recommendations and actual practice. Younger patients (<60 years of age) with no documented risk factors for stroke were over-treated with VKAs and patients older than 75 years without contraindications for anticoagulation were under-treated. Conclusions This study presents ‘real-life’ data in treating patients with AF in Germany and identifies the potential to advance the quality of care with respect to anticoagulation.     

Expression and Activity Patterns of Nitric Oxide Synthases and Antioxidant Enzymes Reveal a Substantial Heterogeneity Between Cardiac and Vascular Aging in the Rat

We investigated the effects of aging and ischemia–reperfusion (I/R) injury on the expression and activity of nitric oxide (^•NO) synthases and superoxide dismutase (SOD) isoforms. To this end we perfused excised hearts from young (6 months old) and old (31–34 months old) rats according to the Langendorff technique. The isolated hearts were, after baseline perfusion for 30 min, either subjected to 20 min of global no-flow ischemia followed by 40 min of reperfusion or were control-perfused (60 min normoxic perfusion). Both MnSOD and Cu,ZnSOD expression remained unchanged with increasing age and remained unaltered by I/R. However, SOD activity decreased from 7.55 ± 0.1 U/mg protein in young hearts to 5.94 ± 0.44 in old hearts (P<0.05). Furthermore, I/R led to a further decrease in enzyme activity (to 6.35 ± 0.41 U/mg protein; P<0.05) in myocardium of young, but not in that of old animals. No changes in myocardial protein-bound 3-nitrotyrosine levels could be detected. Endothelial NOS (eNOS) expression and activity remained unchanged in aged left ventricles, irrespective of I/R injury. This was in steep contrast to peripheral (renal and femoral) arteries obtained from the same animals where a marked age-associated increase of eNOS protein expression could be demonstrated. Inducible NOS expression was undetectable either in the peripheral arteries or in the left ventricle, irrespective of age. In particular when associated with an acute pathology, which is furthermore limited to a certain time frame, changes in the aged myocardium with respect to enzymes crucially involved in maintaining the redox homeostasis, seem to be much less pronounced or even absent compared to the vascular aging process. This may point to heterogeneity in the molecular regulation of the cardiovascular aging process.     

The Myc-evoked DNA damage response accounts for treatment resistance in primary lymphomas in vivo

In addition to the ARF/p53 pathway, the DNA damage response (DDR) has been recognized as another oncogene-provoked anticancer barrier in early human tumorigenesis leading to apoptosis or cellular senescence. DDR mutations may promote tumor formation, but their impact on treatment outcome remains unclear. In this study, we generated ataxia telangiectasia mutated (Atm)-proficient and -deficient B-cell lymphomas in Emu-myc transgenic mice to examine the role of DDR defects in lymphomagenesis and treatment sensitivity. Atm inactivation accelerated development of lymphomas, and their DNA damage checkpoint defects were virtually indistinguishable from those observed in Atm+/+-derived lymphomas that spontaneously inactivated the proapoptotic Atm/p53 cascade in response to Myc-evoked reactive oxygen species (ROS). Importantly, acquisition of DDR defects, but not selection against the ARF pathway, could be prevented by lifelong exposure to the ROS scavenger N-acetylcysteine (NAC) in vivo. Following anticancer therapy, DDR-compromised lymphomas displayed apoptotic but, surprisingly, no senescence defects and achieved a much poorer long-term outcome when compared with DDR-competent lymphomas treated in vivo. Hence, Atm eliminates preneoplastic lesions by converting oncogenic signaling into apoptosis, and selection against an Atm-dependent response promotes formation of lymphomas with predetermined treatment insensitivity.     

Comparison between pulsed and continuous radiofrequency delivery

INTRODUCTION: Potentials arising in the pulmonary veins (PV) have been proposed to be a trigger of atrial fibrillation. Percutaneously, the best results for curative treatment of atrial fibrillation have been achieved by segmental or circumferential isolation of the PV. The purpose of our study was to determine the feasibility of ostial pulmonary vein isolation and to compare continuous radiofrequency (RF) with pulsed RF concerning homogeneity and transmurality of produced lesions. MATERIALS AND METHODS: In vivo tests were performed in seven anesthetized and ventilated pigs. Under fluoroscopy and guided by intracardiac electrograms each of the 28 pulmonary veins was targeted for circumferential isolation near its ostium. After the continuous energy application in one PV-ostium the catheter was placed into the next PV-ostium and the same procedure was repeated using pulsed energy. The ablations were performed with an octapolar circumferential ablation catheter, with either continuous RF energy delivery to each electrode for 120 s or pulsed energy delivery to four electrodes simultaneously with a 5 ms duty cycle. Lesion diameter was measured with a microcaliper and homogeneity classified from 1 (highest) to 4 (least). RESULTS: More homogeneous lesions were produced in significantly less time with pulsed rather than with continuous energy delivery. There were no significant differences in impedance or temperature of the electrodes. We did not observe tissue carbonization or "popping," pulmonary vein stenosis, pericardial effusion/perforation at any time. CONCLUSION: Ostial ablation of the PV with pulsed energy delivery proved feasible. It was the faster and more reliable method of creating linear circumferential lesions with a maximum amount of homogeneity and transmurality. We observed no elevated risk of PV stenosis during our experiments.