Pannexin-1 Deficient Mice Have an Increased Susceptibility for Atrial Fibrillation and Show a QT-Prolongation Phenotype.

BACKGROUND/AIMS: Pannexin-1 (Panx1) is an ATP release channel that is ubiquitously expressed and coupled to several ligand-gated receptors. In isolated cardiac myocytes, Panx1 forms large conductance channels that can be activated by Ca2+ release from the sarcoplasmic reticulum. Here we characterized the electrophysiological function of these channels in the heart in vivo, taking recourse to mice with Panx1 ablation. METHODS: Cardiac phenotyping of Panx1 knock-out mice (Panx1(-/-)) was performed by employing a molecular, cellular and functional approach, including echocardiography, surface and telemetric ECG recordings with QT analysis, physical stress testing and quantification of heart rate variability. In addition, an in vivo electrophysiological study entailed programmed electrical stimulation using an intracardiac octapolar catheter. RESULTS: Panx1 deficiency results in a higher incidence of AV-block, delayed ventricular depolarisation, significant prolongation of QT- and rate corrected QT-interval and a higher incidence of atrial fibrillation after intraatrial burst stimulation. CONCLUSION: Panx1 seems to play an important role in murine cardiac electrophysiology and warrants further consideration in the context of hereditary forms of atrial fibrillation.

In vivo electrophysiological characterization of TASK-1 deficient mice.

BACKGROUND/AIMS: TASK-1 is a potassium channel predominantly expressed in heart and brain. We have previously shown that anesthetized TASK-1(-/-)mice have prolonged QT intervals in surface electrocardiograms (ECGs). In addition, heart rate variability quantified by time and frequency domain parameters was significantly altered in TASK-1(-/-) mice with a sympathetic preponderance. Aims of the present study were the analysis of QT intervals by telemetric ECGs, to determine potential influences of anesthesia and ß-adrenergic stimulation on repolarization in surface ECGs, to investigate in vivo electrophysiological parameters by intracardiac electrical stimulation and to quantify heart rate turbulence after ischemia/reperfusion or ventricular pacing in TASK-1(+/+) and TASK-1(-/-) mice. METHODS: Rate corrected QT intervals (QTc) were recorded in conscious mice by telemetry and in surface ECGs following administration of various anesthetics (tribromoethanol (Avertin(®)), pentobarbital and isoflurane). TASK-1(+/+) and TASK-1(-/-) mice were characterized by programmed electrical stimulation using an intracardiac octapolar catheter. The baroreceptor reflex was analyzed by heart rate turbulence (turbulence onset and slope) after ischemia/reperfusion and by stimulated premature ventricular contractions. RESULTS: Telemetric and surface ECGs in mice sedated with Avertin(®) and pentobarbital, showed a significantly lengthened rate corrected QT interval in TASK-1(-/-) mice (telemetry: TASK-1(+/+) 43±3ms vs. TASK-1(-/-) 49±5ms, n=6, p<0.05; Avertin(®): TASK-1(+/+) 36±8ms vs. TASK-1(-/-) 48±4ms, n=13/16, p<0.0001). The prolongation of the QT interval was most pronounced at lower heart rates. Isoflurane, known for its stimulatory effects on the TASK channel family, attenuated the rate corrected QT interval prolongation in TASK-1(-/-)mice. Intracardiac electrical stimulation revealed normal values for electrical conduction and refractoriness. No significant arrhythmias after atrial and ventricular burst stimulation were induced before and after adrenergic challenge in both genotypes. Turbulence onset after premature ventricular contraction was significantly altered in TASK-1(-/-) mice. CONCLUSION: TASK-1(-/-) mice exhibit a phenotype of QT prolongation, which distinct relation to heart rate. TASK-1 deficiency does neither alter key electrophysiological parameters nor increases atrial/ventricular vulnerability after electrical stimulation. The heart rate response after premature ventricular contractions is significantly abolished indicating a diminished baroreceptor reflex in TASK-1(-/-) mice.

A presumably benign human ether-a-go-go-related gene mutation (R176W) with a malignant primary manifestation of long QT syndrome.

A 12-year-old girl presented with a first prolonged syncope. She was successfully resuscitated by external defibrillation after recording torsade de pointes tachycardia. Repeated electrocardiograms and a 12-channel Holter monitoring showed an intermittent prolongation of the QT interval. Genetic analysis identified a heterozygous point mutation in the KCNH2 gene, which is thought to be associated with a rather mild clinical phenotype of the long QT syndrome.

Functional role of TASK-1 in the heart: studies in TASK-1-deficient mice show prolonged cardiac repolarization and reduced heart rate variability.

TASK-1, a member of the recently identified K2P channel family, is mainly expressed in the heart and the nervous system. TASK-1 is regulated by several physiological and pathological conditions and functions as a background potassium channel. However, there are limited data concerning the significance of TASK-1 in cardiac physiology. We studied the functional role of TASK-1 in the heart by cardiac phenotyping the TASK-1-deficient mouse (TASK-1(-/-)). TASK-1 was predominantly expressed in the ventricles of control animals. Real-time PCR and immunoblot demonstrated that the expression of seven other K2P channels was unchanged in TASK-1(-/-) mice. No structural or functional abnormalities were found by histology and echocardiography. Electrophysiological studies recording monophasic action potentials (MAPs) showed a significant prolongation of action potential duration in spontaneously beating and atrially paced hearts, respectively. Surface ECGs of TASK-1(-/-) mice revealed a significant prolongation of the rate corrected QT interval. Telemetric ECG recordings for 24 h, during physical and pharmacological stress testing and after ischemia/reperfusion injury did not result in a higher incidence of arrhythmias. Infarct size was comparable in both genotypes. However, TASK-1(-/-) mice had a higher mean heart rate and significantly reduced heart rate variability (HRV). Time and frequency domain measurements as well as baroreceptor reflex testing revealed a sympathovagal imbalance with a shift to an increase in sympathetic influence in TASK-1(-/-) mice. In conclusion, TASK-1 plays a functional role in the repolarization of the cardiac action potential in vivo and contributes to the maintenance of HRV.

Beta-blockers for congestive heart failure in children.

BACKGROUND: Beta-blockers are an essential part of standard therapy in adult congestive heart failure and are therefore also expected to be beneficial in children. However, congestive heart failure in children differs strongly from that in adults in terms of characteristics and aetiology; also, an increased drug clearance has been reported. Paediatric needs have therefore to be specifically investigated. OBJECTIVES: To assess the effect of beta-adrenoceptor-blockers in children with congestive heart failure. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library (Issue 4 2007), MEDLINE (1966 to January 2008), EMBASE (1980 to January 2008), and LILACS (1980 to January 2008). Bibliographies of identified studies were checked. No language restrictions were applied. SELECTION CRITERIA: Randomised, controlled clinical trials investigating the effect of beta-blocker therapy on paediatric congestive heart failure. DATA COLLECTION AND ANALYSIS: Two authors independently extracted and assessed data from the included trials. MAIN RESULTS: Three studies with an overall number of 203 participants were identified. Two small studies, with 20 and 22 children respectively, showed an improvement of congestive heart failure, while a larger study with 161 participants showed no evidence of benefit over placebo in the composite measure of heart failure outcomes which was the main outcome measure of the trial (56% improvement in both the placebo and the treatment group, p=0.74). However, study populations showed vast differences with regard to treatment (choice of beta-blocker, dosing, duration of treatment), age and age range of the participants and in particular with regard to condition (aetiology and severity of heart failure; homogeneity of condition in the study population). In addition methods and outcome measures differed strongly and were not standardised. The results can therefore not be compared against each other. AUTHORS' CONCLUSIONS: There are not enough data to recommend or discourage the use of beta-blockers in children with congestive heart failure. Further investigations in clearly defined populations with standardised methodology are required to establish guidelines for therapy. Pharmacokinetic investigations of beta-blockers in children are required to provide effective dosing in future trials.

[Drug interactions of tacrolimus]. / Arzneimittelinteraktionen von Tacrolimus.

Allogeneic hematopoetic stem cell transplantations can be complicated by a graft-versus-host disease (GvHD), i.e., immunocompetent cells from the transplanted bone marrow act against solid organs of the recipient. A GvHD is treated with immunosuppressants. Consequently, further drugs are required, for example in order to prevent infections and result in in polymedication of those patients with a risk of drug interactions. In this case report, drug interactions between tacrolimus and concomitant therapy in a stem-cell-transplanted patient are discussed.

Pearson marrow-pancreas syndrome with worsening cardiac function caused by pleiotropic rearrangement of mitochondrial DNA.

Pearson marrow-pancreas syndrome is a usually fatal disorder that involves the hematopoietic system, exocrine pancreas, liver, kidneys, and often presents clinically with failure to thrive. We report a 5-year-old patient who developed, in addition to the typical features of Pearson syndrome, worsening cardiac function, mainly affecting the left ventricle. The latter finding is particularly interesting because cardiac involvement has not yet been regarded as a major feature of Pearson syndrome. The diagnosis was proved by the finding of so far undescribed pleioplasmatic rearrangement of mitochondrial (mt)DNA (loss of 5,630 bp, 70% deleted and duplicated mtDNA) in blood cells. Our report demonstrates that patients with Pearson syndrome may also have impaired cardiac function. Thus, Pearson syndrome should be considered in the differential diagnosis of patients with left ventricular dysfunction of unknown origin and other clinical findings suggestive of a mitochondrial disease.

Fibrin- and collagen-based matrices attenuate inflammatory and procoagulant responses in human endothelial cell cultures exposed to Staphylococcus aureus.

Infective endocarditis (IE) remains a serious complication after heart valve replacement. Autologous valves constructed by matrix-based tissue engineering are under investigation to increase biocompatibility. The impact of the underlying matrix on the risk to develop IE is not known. The IE is characterized by bacterial adhesion and subsequent interactions of disseminating bacteria with endothelial cells (ECs) and monocytes, evoking endothelial proinflammatory and procoagulant activity, leading to heart valve destruction. In the current study, we, therefore, have seeded human ECs on a fibrin versus collagen gel matrix and, at confluence, infected them with Staphylococcus aureus, Streptococcus sanguis, and Staphylococcus epidermidis. Especially Sta. aureus infected ECs grown on fibrin (4.2% of the inoculum) and collagen (3.7%) matrices, more than on ECs grown on noncoated plates (1.2%; p<0.01). This was associated with higher monocyte adhesion (61%; p<0.01 on fibrin and 43%; p<0.05 on collagen) versus control cultures (30%), even at comparable EC surface expression of intercellular adhesion molecule-1 and vascular adhesion molecule-1. The collagen matrix attenuated the Sta. aureus-induced monocyte chemoattractant protein 1 expression 2.0-fold, compared with the noncoated control ECs. This reduction coincided with a 4.2-5.0-fold reduction of the procoagulant activity, triggered in ECs grown on noncoated wells, as a consequence of tissue factor (TF) expression by ECs, further stimulated by EC-bound monocytes. Overall, moderate responses were seen on infection with Str. sanguis and Sta. epidermidis for both gel matrices. Thus, even when fibrin and collagen gel matrices equally increase bacterial adhesion, and subsequent monocyte adhesion to infected ECs, these matrices modulate EC responses to these stimuli, thus resulting in attenuated cytokine production and attenuated adherent monocyte-dependent TF production by the ECs. Further investigations will need to confirm whether also in vivo, EC-matrix interactions can attenuate EC responses to bacteria and inflammatory cells to reduce IE at infected endovascular sites.

Techniques for assessing cardiac output and fetal cardiac function.

Fetal echocardiography was initially used to diagnose structural heart disease, but recent interest has focused on functional assessment. Effects of extracardiac conditions on the cardiac function such as volume overload (in the recipient in twin-twin transfusion syndrome), a hyperdynamic circulation (arterio-venous malformation), cardiac compression (diaphragmatic hernia, lung tumours) and increased placental resistance (intrauterine growth restriction and placental insufficiency) can be studied by ultrasound and may guide decisions for intervention or delivery. A variety of functional tests can be used, but there is no single clinical standard. For some specific conditions, however, certain tests have shown diagnostic value.

Off-label drug use among hospitalised children: identifying areas with the highest need for research.

OBJECTIVE OF THE STUDY: To analyse the off-label use of drugs on a paediatric ward in Germany, and to identify domains of pharmacotherapy with the highest need for research concerning off-label use in children. SETTING: A prospective observational study was conducted on a paediatric ward in Duesseldorf in Germany between January and June 2006. METHOD: Data about patients, diagnoses and prescribed drugs were collected from the prescription records and the discharge letters. Diagnoses were classified in groups by means of the International Classification of Diseases. Drugs were grouped according to the Anatomical Therapeutic Chemical Classification system. We compared the off-label prescriptions with those on the list of paediatric needs and priority list established by the European Medicines Agency (EMEA). MAIN OUTCOME MEASURE: Off-label use was defined due to age, indication, route of application and dose. RESULTS: The study included 417 patients. We analysed 1,812 prescriptions representing 211 different drugs. In total, 253 patients (61%) received at least one off-label prescription. Of all analysed prescriptions, 553 (31%) were off-label. The percentage of off-label prescriptions among the five most frequently prescribed drug groups were as follows: 60% cardiovascular drugs (CV: 129/216), 42% anti-infectives (AI: 190/449), 30% drugs for respiratory system (RS: 100/335), 25% drugs for alimentary tract and metabolism (AM: 67/269) and 3% analgesics and antipyretics (AA: 8/264); with 17 drugs, the cardiovascular drugs also showed the highest number of different off-label prescribed drugs due to age: AI: 14; AM: 11; RS: 5; AA: 1. In addition, there was a nearly complete overlap between the identified off-label prescriptions in cardiovascular drugs and those listed by the EMEA to be prioritized for urgent research in Europe. CONCLUSION: Cardiovascular drugs are a domain of pharmacotherapy, with a large need for research in paediatrics. The results of our study can guide the researcher to future trials on off-label prescriptions such as cardiovascular drugs, especially due to the fact that the identified off-label prescribed drugs in this group are also mentioned by the EMEA to be prioritized for paediatric research.

Case report: severe gastrointestinal inflammation and persistent HHV-6B infection in a paediatric cancer patient.

Lymphotropic herpesviruses such as human herpesvirus type 6 (HHV-6) have enhanced pathogenicity in some immunocompromised hosts, such as transplant recipients and HIV-infected patients. The clinical relevance of HHV-6 infections in cancer patients undergoing conventional cytotoxic therapy is undetermined, however. Here we report on a 10-month-old boy with an anaplastic astrocytoma, who acquired an HHV-6 variant B infection during chemotherapy. HHV-6B infection caused or triggered severe gastrointestinal inflammation with intractable diarrhoea and failure to thrive over several months. The clinical symptoms were associated with pronounced (CD4) lymphopenia and a marked increase in serum immunoglobulin A levels. After unsuccessful therapy with ganciclovir and foscarnet, combined antiviral and anti-inflammatory treatment with cidofovir and prednisolone controlled the HHV-6 infection and enabled resolution of clinical symptoms.

Painful rash and swelling of the limbs after recurrent infections in a teenager: polyarteritis nodosa.

UNLABELLED: Polyarteritis nodosa is a rare disease in childhood and adolescence that is difficult to diagnose clinically. We report on a 17-y-old girl presenting with a history of recurrent infections of the upper respiratory tract and conjunctivitis followed by a painful rash on the upper and lower extremities resembling erythema nodosum. The diagnosis of polyarteritis nodosa was proven by skin biopsy. Therapy with intravenous immunoglobulins failed, but with systemic steroids she responded promptly. CONCLUSION: Polyarteritis nodosa is a differential diagnosis in adolescents presenting with fever and an erythema nodosum-like rash.

Persistent right umbilical vein associated with complex congenital cardiac malformation.

Umbilical venous catheterization is frequently used for vascular access during neonatal resuscitation. The differentiation between umbilical artery and vein, specifically during the resuscitation procedure, is clinically neither always easy nor unambiguous. A preterm infant of 35 weeks of gestational age was born after an uneventful course of his mother's pregnancy. Severe postnatal cyanosis led to the placement of presumed arterial and venous umbilical catheters. Chest x-ray was suggestive of the presence of a persistent right umbilical vein (PRUV). Echocardiography showed a double outlet right ventricle with mitral atresia and a levo-atrial cardinal vein draining the left atrium into the azygos vein. The foramen ovale was firmly closed and conventional balloon atrioseptostomy failed. Several attempts of transseptal puncture and subsequent creation of an atrial septal defect were unsuccessful and the infant eventually died. There is an association of PRUV and congenital cardiac malformation. PRUV can be diagnosed prenatally if specifically looked for. The presence of PRUV can be the only clue prenatally alerting to the presence of congenital heart disease. Postnatal diagnosis of PRUV may justify echocardiography and cardiologic assessment even in the absence of clinical cyanosis.

Tuberculous pericarditis in an infant evolving during triple chemotherapy.

UNLABELLED: A 36-month-old girl was treated for pulmonary tuberculosis (Mycobacterium tuberculosis) with isoniazid, rifampin and pyrazinamide. Four weeks after starting chemotherapy, she developed high fever and clinical signs of acute pericardial tamponade. Pericardial effusion was shown by echocardiography and subsequently removed by pericardiocentesis. M. tuberculosis was demonstrated in the pericardial fluid by microscopy, polymerase chain reaction and specific culture. After pericardial drainage, the actual therapy was extended to include streptomycin and prednisone. Follow-up examinations demonstrated complete recovery without signs of constrictive pericarditis. CONCLUSION: infants treated for tuberculosis should be followed closely in order to monitor not only side-effects of antituberculous drugs but also to detect early extrapulmonary spread that may occur even with adequate chemotherapy. Rapid intervention and treatment adjustment in infants with tuberculous pericarditis may prevent pericardial constriction and may lead to full recovery.

Recurrent atrial ectopic tachycardia following chemotherapy with ifosfamide.

In most pediatric tumors, particularly sarcomas, cyclophosphamide or ifosfamide represent essential first-line chemotherapeutic agents. Whereas cyclophosphamide is known to be associated with a well-defined cardiomyopathy, only a few cardiac complications following ifosfamide chemotherapy have been observed to date. Here we report a patient treated for Ewing sarcoma with multiple pulmonary and osseous metastases who repeatedly developed a supraventricular tachyarrhythmia following administration of ifosfamide as part of a polychemotherapy regimen.