In vivo effects of interleukin-11 and stem cell factor in combination with erythropoietin in the regulation of erythropoiesis

Summary. In this study we evaluated the in vivo effects of interleukin-11 (IL-11) and stem cell factor (SCF), in combination with erythropoietin (EPO) on murine erythropoiesis. Mice were treated for 7d with IL-11, SCF and EPO, each at three dose levels. In total, 27 different dose combinations were tested. IL-11 as well as SCF could only marginally stimulate erythroid progenitor cell numbers, but IL-11 in combination with SCF was able to increase BFU-E and CFU-E numbers 4-fold, in the absence of exogenous EPO. This resulted in an increased reticulocyte count. In contrast with the stimulatory effect on immature erythroid cell stages, IL-11 treatment induced a mild anaemia, which probably resulted from a plasma volume expansion. The additional treatment with EPO resulted in strong synergistic effects on CFU-E numbers. The combination of high-dose IL-11 and high-dose SCF was able to increase the overall efficiency of EPO-induced erythroid amplification, which was reflected by a left-shift of the in vivo EPO dose-response curve. The stimulating effects of IL-11 and SCF were further demonstrated when the effects on the reticulocyte count of a single high-dose EPO injection were assessed in normal and SCF + IL-11 treated mice. Whereas a single EPO dose increased the reticulocyte count by a factor of 3, IL-11 + SCF pretreatment increased this to a factor of 7. This study shows that in vivo SCF and IL-11 are important modulators of red blood cell production. First, these factors probably increase the input from the stem cell compartment into the erythroid lineage, where subsequently EPO is required for further amplification. Additionally, however, IL-11 and SCF increase the overall efficiency of EPO-induced amplification, probably due to a stimulatory effect on late-stage erythroid cells and to a redistribution of cells from marrow to spleen.     

Diagnosis and treatment of latent infection with Mycobacterium tuberculosis

In clinical practice, latent infection with Mycobacterium tuberculosis is defined by the presence of an M. tuberculosis‐specific immune response in the absence of active tuberculosis. Targeted testing of individuals from risk groups with the tuberculin skin test or an interferon‐γ release assay is currently the best method to identify those with the highest risk for progression to tuberculosis. Positive predictive values of the immunodiagnostic tests are substantially influenced by the type of test, the age of the person who is tested, the prevalence of tuberculosis in the society and the risk group to which the person belongs. As a general rule, testing should only be offered when preventive chemotherapy will be accepted in the case of a positive test result. Preventive chemotherapy can effectively protect individuals at risk from the development of tuberculosis, although at least 3 months of combination therapy or up to 9 months of monotherapy are required, and overall acceptance rate is low. Improvements of the current generation of immunodiagnostic tests could substantially lower the number of individuals that need to be treated to prevent a case of tuberculosis. If shorter treatment regimens were equally effective than those currently recommended, acceptance of preventive chemotherapy could be much improved.     

Is Antiarrhythmia Device Implantation Safe Under Dual Antiplatelet Therapy?

Background: Device implantations in patients on dual antiplatelet‐therapy (DA‐therapy) continue to rise. The aim of our study was to compile and analyze data on complications of antiarrhythmia device implantation under DA‐therapy. Methods: We prospectively collected data on all device implantations in our department from January 2008 until February 2009. The control group was comprised of patients on acetylsalicylic acid alone or no antiplatelet medication at all (318 subjects). The DA‐therapy group consisted of 109 patients of whom 71 were analyzed retrospectively (implantations from 2002 to 2007). Results: Procedure times were significantly longer in DA‐therapy patients receiving a pacemaker for the first time. In contrast, procedure times did not differ significantly between the two study groups for implantable cardioverter defibrillator (ICD) implantations and for pacemaker replacements. Fluid losses via drainage systems and drainage times were significantly increased in the DA‐therapy group as compared with the control group after pacemaker but not after ICD implantations. Importantly, there were no significant differences in complication rates, particularly the hematoma rate, between the DA‐therapy and the control group. Conclusions: When drainage systems are used, antiarrhythmia device implantation is safe and can be performed without significantly increased risk of clinically relevant hematoma in patients on continued DA‐therapy. (PACE 2010; 394–399)     

Incidence of T Wave Alternation After Acute Myocardial Infarction and Correlation with Other Prognostic Parameters: Results of a Prospective Study

Tachycardia induced alternation of the T wave (TWA) has been associated with arrhythmia morbidity in mixed patient populations. However, less is known concerning the general incidence of TWA and its usefulness in risk stratification early after acute myocardial infarction (MI). TWA was prospectively and systematically assessed in 140 consecutive patients 15 +/- 6 days after acute MI and prior to discharge. Results of TWA measurements were compared to other noninvasive risk markers, LV function, and coronary angiography. Sustained TWA was present at rest or inducible during exercise in 27% of patients. The patient-specific heart rate for the onset of TWA was 98 +/- 9 beats/min. After multivariate analysis, TWA correlated with age (P = 0.02) and LV function (P = 0.002) and occurred more often in patients after nonanterior MI (P = 0.03). Acute results of Holter monitoring, late potentials by signal-averaged ECG, and heart rate variability were unrelated to the TWA status. During follow-up (451 +/- 210 days) two major arrhythmic events occurred. The incidence of TWA early after MI is about 25%. TWA is related to age and LV function but not to other common arrhythmia markers. Although TWA does not appear to be related to excessive cardiac morbidity, evaluation of the prognostic significance of TWA requires further study.     

Enhanced psychophysiological signs of attention after angiotensin-converting enzyme inhibition by captopril

Complementary to its essential role in the central nervous control of cardiovascular activity, the neuropeptide angiotensin 11 may regulate attentional processes. The present study evaluated central nervous, cardiovascular, and sympathetic indicators of attention after inhibition of angiotensin II synthesis by captopril (50 mg vs. placebo) in 14 men. Event-related potentials (ERPs) and stimulus-related electroencephalographic (EEG) activity were recorded while the subject performed an auditory oddball task. Captopril increased both the N1-P2 component of the ERP (p < .05) and – following the first tone of the task – the EEG desynchronization in the lower alpha frequency band (p < .05). Although blood pressure remained unchanged, heart rate was lowered (p < .05) and plasma norepinephrine concentrations increased (p < .01) after captpril. The effects suggest that inhibition of angiotensin II synthesis enhances an attentional state typically present during sensory intake.     

An Increase in Sinus Rate Following Radiofrequency Energy Application in the Posteroseptal Space

An increase in sinus rate has been previously described in patients with AV node reentry (AVNRT) following successful A V node modification. This increase could either be a specific sign of elimination of slow pathway conduction or it could be a consequence of energy application in the posteroseptal area. Thus, we compared the changes in sinus cycle length following successful slow pathway ablation (defined as complete elimination of dual AV node physiology) in patients having AVNRT with those in patients undergoing successful ablation of a posteroseptal atriovetriricular accessory connection. Twenty five patients (16 women and 9 men, mean age 41 ± 4 years) with typical AVNRT (cycle length 378 ± 12 ms and 29 patients (16 women and 13 men, age 34 ± 5 years) with an accessory connection (17 manifest and 12 concealed) were studied. The electrophysiology study was performed during sedation with Fentanyl and Midazolam. The mean number of energy applications was 3 ± 1 for successful slow pathway ablation and 4 ± 1 for successful ablation of the accessory connection (p:NS). Following the successful energy application, the sinus cycle length decreased significantly 776 ms at baseline to 691 ms in patients with AVNRT. Following successful ablation of the posteroseptal AC, sinus cycle length decreased from 755 ms at baseline to 664 ms (p < 0.05 in both groups [difference between groups not significant]). The decrease in sinus cycle length did not correlate with the number ofRF energy applications required for successful ablation or the total energy delivered. In conclusion, ablation of the AV node slow pathway and a posteroseptal accessory connection results in similar increases in the sinus rate. Thus, the increase in sinus rate is probably due to energy application in the posteroseptal space, possibly due to concomitant destruction of vagal inputs, and it is not specific for elimination of slow pathway conduction.     

Benign Prognosis of Early Sinus Node Dysfunction After Orthotopic Cardiac Transplantation

Previous reports raised concern about the prognosis of patients with sinus node (SN) dysfunction after cardiac transplantation and led to a low threshold for permanent pacemaker (PM) placement at most institutions. The present study addresses the survival in patients with normal and impaired post operative SN function and the effect of permanent pacing with respect to overall and cardiac mortality. There were 120 patients with normal (corrected SN recovery time < 520 ms, group I) and 47 patients with impaired SN function (corrected SN recovery time < 520 ms and/or sinus arrest ± escape rhythms). Pacing support was deemed unnecessary in 23 of 47 patients with SN dysfunction (group II; asymptomatic SN bradycardia and corrected SN recovery time 3,812 ± 5,800 ms) while a total of 24 patients had PM placement a mean of 29 ± 44 days after transplantation (symptomatic bradycardia or absence of sinus rhythm at discharge, group III). Patients were followed for a mean of 46.7 months. Thirty-five deaths occurred during the study period. Sixteen deaths were cardiac but none were causally related to the SN dysfunction (graft failure due to rejection or atheropathy n =14; myocardial infarction n = 2). Four of these cardiac deaths were sudden and all occurred in the presence of widespread structural abnormalities (rejection/vasculopathy/myocardial infarction). SN dysfunction was not related to overall (P = 0.25) or cardiac mortality (P = 0.33). Regarding either endpoint, patients who had permanent PM placement did no belter than their unpaced counterparts in group II (P = 0.53 and P = 0.33, overall and cardine mortality, respectively). Likewise, survival did not differ between groups 1 and III for either endpoint (P = 0.77, P = 0.65, respectively). These data suggest that patients with mild SN abnormality, who are in sinus rhythm at the time of discharge, can be followed by observation without specific therapy.     

Morphology Discrimination: A Beat-to-Beat Algorithm for the Discrimination of Ventricular from Supraventricular Tachycardia by Implantable Cardioverter Defibrillators

Inappropriate therapy of SVTs by ICDs remains a major clinical problem despite enhanced detection criteria like "sudden onset" and "rate stability" in third-generation devices. Electrogram morphology discrimination offers an additional approach to improve discrimination of supraventricular tachycardia (SVT) from ventricular tachycardia (VT). In a prospective, multicenter study, patients received an ICD with a beat-to-beat algorithm for morphological analysis of the intracardiac electrogram (Morphology Discrimination, MD). A nominal programmingfor standard enhancement criteria and morphology discrimination was required at implant. Electrogram storage of tachycardia episodes irrespective of delivery of therapy was used to assess sensitivity and specificity of the morphology algorithm alone and in combination with established detection criteria. During a 126 6-month follow-up, 886 episodes of device stored electrograms from 82 of 256patients were evaluated. Atnominal settings, the MD algorithm correctly identified 423 of 551 episodes as VT resulting in sensitivity of 77%. The classification of SVT was met in 239 of 335 episodes resulting in specificity of 71%. In combination with sudden onset, sensitivityincreased to 99.5% at the expense of specificity (48%). In conclusion, SVT-VT discrimination based on morphological analysis alone results in limited sensitivity and specificity. Programming the monitor mode allows individual assessment of the performance of this detection enhancement feature during clinical follow-up without compromising device safety. Only in patients with documented efficacy of morphology discrimination should this feature be subsequently activated.