The enhanced pre- and postnatal study for nonhuman primates: update and perspectives.

The enhanced pre- and postnatal (ePPND) study design has been developed in response to new scientific knowledge and subsequent guideline changes, that is, ICH M3(R2) and ICH S6(R1). The design changes were basically driven by the experiences obtained during preclinical development of biopharmaceuticals. The ePPND concept typically does not apply to pharmaceuticals. In essence, the ePPND design is a PPND study in which key elements of an embryofetal development (EFD) study are being investigated in newborns and infants rather than in the fetus. The current relevant nonhuman primate model is the cynomolgus monkey. The ICH S6(R1) has reached step 4 during June 2011 and provides detailed recommendations on various parameters and the conduct of an ePPND study. By the time this article is written, it appears that for monoclonal antibodies, the ePPND study is the preferred approach although ICH S6(R1) also leaves options for modified EFD and PPND study concepts. Our data also demonstrate that social housing is feasible for developmental toxicity studies in the cynomolgus monkey model.

Transplanted human cord blood-derived unrestricted somatic stem cells preserve high-energy reserves at the site of acute myocardial infarction.

BACKGROUND AIMS: It has been demonstrated that transplantation of human cord blood-derived unrestricted somatic stem cells (USSC) in a porcine model of acute myocardial infarction (MI) significantly improved left ventricular (LV) function and prevented scar formation as well as LV dilation. Differentiation, apoptosis and macrophage mobilization at the infarct site could be excluded as the underlying mechanisms. The paracrine effect of the cells is most likely to be observed as the cause for the USSC treatment. The aim of our study was to examine the cardiomyocyte metabolism and the role of high-energy phosphates at the marginal infarct. Methods. USSC were transplanted into the myocardium of the LV, which was supplied by a ligated circumflex artery. Forty-eight hours later, the hearts were harvested and biopsies were performed from the marginal infarct zone surrounding the site of the cell injection. The concentrations of creatinine phosphate (CP), adenosine monophosphate (AMP), adenosine diphosphate (ADP) and adenosine triphosphate (ATP) were determined by chromatography. RESULTS: The concentration of ADP, ATP and CP in the marginal zone of the infarction was significantly higher in the USSC group. The mean global left ventricular ejection fraction (LVEF) (SD) was 64% (8%) before MI; post-MI, LVEF decreased to 35% (9%). CONCLUSIONS: Preservation of high-energy phosphates in the marginal infarct zone suggests that the preservation of energy reserves of surviving cardiomyocytes is a possible mechanism of action of transplanted stem cells in acutely ischemic myocardium.

Echocardiographic detection of cardiac ectopy: a possible alternative to electrophysiological mapping?

PURPOSE: Three-dimensional (3-D) visualization of ventricular activation sequence is imperative for the diagnosis and treatment of malignant cardiac arrhythmias. Modern mapping systems that serve as the gold standard for detection and localization of the focus are costly and require an invasive approach into the cavity of the ventricles. The aim of our study was the development of a noninvasive and 3-D mapping system based upon echocardiography. METHODS: In a porcine model, animals underwent ablation of the atrioventricular node (AV-node). 3-D electrophysiological cardiac mapping was performed using the ENSITE™ electro-anatomical system (St. Jude Medical, Minneapolis, MN, USA). Simultaneously, transesophageal echocardiography (TEE) including pulse wave (Pw) tissue Doppler was performed, and time to peak early diastolic velocity (PEDV) was measured. Both ENSITE-mapping and tissue Pw-Doppler were compared as to their ability to pinpoint the origin of ventricular ectopic focus. RESULTS: PEDV corresponded well with the results as determined by noncontact mapping with ENSITE. CONCLUSIONS: Tissue Doppler is a reliable method to deliver information about the topography of first onset of myocardial excitation. Further development of this method with a higher regional resolution and integration of color Doppler as well as 3-D echocardiography may eventually lead to the development of a completely noninvasive and echo-based electromechanical mapping system.

Effects of mobile phone electromagnetic fields at nonthermal SAR values on melatonin and body weight of Djungarian hamsters (Phodopus sungorus).

In three experiments, adult male Djungarian hamsters (Phodopus sungorus) were exposed 24 hr/day for 60 days to radio frequency electromagnetic fields (RF-EMF) at 383, 900, and 1800 MHz, modulated according to the TETRA (383 MHz) and GSM standards (900 and 1800 MHz), respectively. A radial waveguide system ensured a well defined and uniform exposure at whole-body averaged specific absorption rates of 80 mW/kg, which is equal to the upper limit of whole-body exposure of the general population in Germany and other countries. For each experiment, using two identical waveguides, hamsters were exposed (n = 120) and sham-exposed (n = 120) in a blind fashion. In all experiments, pineal and serum melatonin levels as well as the weights of testes, brain, kidneys, and liver were not affected. At 383 MHz, exposure resulted in a significant transient increase in body weight up to 4%, while at 900 MHz this body weight increase was more pronounced (up to 6%) and not transient. At 1800 MHz, no effect on body weight was seen. The results corroborate earlier findings which have shown no effects of RF-EMF on melatonin levels in vivo and in vitro. The data are in accordance with the hypothesis that absorbed RF energy may result in metabolic changes which eventually cause body weight increases in exposed animals. The data support the notion that metabolic effects of RF-EMFs need to be investigated in more detail in future studies.

High prevalence of asymptomatic bacterial colonization of rhythm management devices.

AIMS: Recent work has been focused on causes of and risk factors for rhythm management device infections. The aim of this study was to elucidate whether patients may be asymptomatic carriers of bacteria on their rhythm management device, possibly allowing later manifestation of infection. METHODS AND RESULTS: A total of 108 devices were changed for battery depletion between April 2005 and February 2006 in asymptomatic patients who were examined for evidence of bacterial DNA on the device and in the surrounding tissue using single strand conformation polymorphism analysis (SSCP). Follow-up was for 23.4 months. In 47.2% of the patients, bacterial DNA was demonstrated on the device, which had been in place for 64.1 months. The sequences identified bacterial strains that are untypical for clinical device infections. Staphylococci were demonstrated in only 3.7% of the patients and they became symptomatic within the observation interval; all others remained asymptomatic. The known risk factors for device infections did not correlate with the demonstration of bacterial DNA in this population. Common cohabitation was identified among the strains found. CONCLUSION: A large proportion of patients carry bacteria on their pacemaker or implantable cardioverter defibrillator asymptomatically. The strains found differ from those commonly seen in clinically evident device infections. Common risk factors for device infection did not correlate with the presence of DNA.

Physiology and Endocrinology of the Ovarian Cycle in Macaques.

Macaques provide excellent models for preclinical testing and safety assessment of female reproductive toxicants. Currently, cynomolgus monkeys are the predominant species for (reproductive) toxicity testing. Marmosets and rhesus monkeys are being used occasionally. The authors provide a brief review on physiology and endocrinology of the cynomolgus monkey ovarian cycle, practical guidance on assessment and monitoring of ovarian cyclicity, and new data on effects of social housing on ovarian cyclicity in toxicological studies. In macaques, cycle monitoring is achieved using daily vaginal smears for menstruation combined with cycle-timed frequent sampling for steroid and peptide hormone analysis. Owing to requirements of frequent and timed blood sampling, it is not recommended to incorporate these special evaluations into a general toxicity study design. Marmosets lack external signs of ovarian cyclicity, and cycle monitoring is done by regular determinations of progesterone. Cynomolgus and marmoset monkeys do not exhibit seasonal variations in ovarian activity, whereas such annual rhythm is pronounced in rhesus monkeys. Studies on pair- and group-housed cynomolgus monkeys revealed transient alterations in the duration and endocrinology of the ovarian cycle followed by return to normal cyclicity after approximately six months. This effect is avoided if the animals had contact with each other prior to mingling. These experiments also demonstrated that synchronization of ovarian cycles did not occur.

Four-chamber pacing in patients with poor ejection fraction but normal QRS durations undergoing open heart surgery.

BACKGROUND: Poor ejection fraction (EF) comprises a critical risk factor in cardiac bypass surgery (CABG). It has been unclear, whether biventricular or four-chamber pacing confers benefit upon patients with intact atrioventricular and interventricular conduction especially following surgery. METHODS: Twenty-one consecutive patients with an EF

Incidence and clinical relevance of supraventricular tachyarrhythmias in pulmonary hypertension.

BACKGROUND: In patients with severe pulmonary hypertension (PH), right ventricular function is a main determinant of clinical stability and outcome. Supraventricular tachyarrhythmias (SVTs) may compromise cardiac function and threaten prognosis in patients with PH, but the incidence and clinical relevance of SVTs in PH and chronic right ventricular failure have not been evaluated. METHODS: In a 6-year retrospective single-center analysis, 231 consecutive patients followed for pulmonary arterial hypertension, or inoperable chronic thromboembolic PH were studied for SVTs. Analysis included incidence, clinical consequences, treatment, and outcome. RESULTS: Thirty-one episodes of SVT were observed in 27 of 231 patients (cumulative incidence 11.7%, annual risk 2.8% per patient), including atrial flutter (n = 15), atrial fibrillation (n = 13), and AV nodal reentry tachycardia (n = 3). Supraventricular tachyarrhythmia onset was almost invariably associated with marked clinical deterioration and right ventricular failure (84% of SVT episodes). Outcome was strongly associated with the type of SVT and restoration of sinus rhythm. During follow-up, cumulative mortality was low (6.3%, follow-up 26 +/- 23 months) when sinus rhythm was restored (all cases of AV nodal reentry tachycardia and atrial flutter). In contrast, 9 of 11 patients with sustained atrial fibrillation died from right ventricular failure (cumulative mortality 82%, follow-up 11 +/- 8 months). CONCLUSIONS: In patients with PH, SVTs constitute a relevant problem, often resulting in clinical deterioration. Sustained atrial fibrillation may be associated with a high risk of death from right ventricular failure.

Reduced delayed rectifier K+ current, altered electrophysiology, and increased ventricular vulnerability in MLP-deficient mice.

BACKGROUND: Mice with a knockout (KO) of muscle LIM protein (MLP) exhibit many morphologic and clinical features of human cardiomyopathy. In humans, MLP-expression is downregulated both in ischemic and dilative cardiomyopathy. In this study, we investigated the effects of MLP on the electrophysiologic phenotype in vivo and on outward potassium currents. METHODS AND RESULTS: MLP-deficient (MLPKO) and wild-type (MLPWT) mice were subjected to long-term electrocardiogram (ECG) recording and in vivo electrophysiologic study. The whole-cell, patch-clamp technique was applied to measure voltage dependent outward K+ currents in isolated cardiomyocytes. Long-term ECG revealed a significant prolongation of RR mean (108 +/- 9 versus 99 +/- 5 ms), P (16 +/- 3 versus 14 +/- 1 ms), QRS (17 +/- 3 versus 13 +/- 1 ms), QT (68 +/- 8 versus 46 +/- 7 ms), QTc (66 +/- 6 versus 46 +/- 7 ms), JT (51 +/- 7 versus 34 +/- 7 ms), and JTc (49 +/- 5 versus 33 +/- 7 ms) in MLPKO versus MLPWT mice (P < .05). During EP study, QT (80 +/- 8 versus 58 +/- 7 ms), QTc (61 +/- 6 versus 45 +/- 5 ms), JT (62 +/- 9 versus 43 +/- 6 ms), and JTc (47 +/- 5 versus 34 +/- 5 ms) were also significantly prolonged in MLPKO mice (P < .05). Nonsustained VT was inducible in 9/16 MLPKO versus 2/15 MLPWT mice (P < .05). Analysis of outward K+ currents in revealed a significantly reduced density of the slowly inactivating outward K+ current IK, slow in MLPKO mice (11 +/- 5 pA/pF versus 18 +/- 7 pA/pF; P < .05). CONCLUSION: Mice with KO of MLP exhibit significant prolongation of atrial and ventricular conduction and an increased ventricular vulnerability. A reduction in repolarizing outward K+ currents may be responsible for these alterations.

Enrichment of cardiac pacemaker-like cells: neuregulin-1 and cyclic AMP increase I(f)-current density and connexin 40 mRNA levels in fetal cardiomyocytes.

Generation of a large number of cells belonging to the cardiac pacemaker system would constitute an important step towards their utilization as a biological cardiac pacemaker system. The aim of the present study was to identify factors, which might induce transformation of a heterogenous population of fetal cardiomyocytes into cells with a pacemaker-like phenotype. Neuregulin-1 (alpha- and beta-isoform) or the cAMP was added to fresh cell cultures of murine embryonic cardiomyocytes. Quantitative northern blot analysis and flowcytometry were performed to detect the expression of connexins 40, 43 and 45. Patch clamp recordings in the whole cell configuration were performed to determine current density of I (f), a characteristic ion current of pacemaker cells. Fetal cardiomyocytes without supplement of neuregulin or cAMP served as control group. Neuregulin and cAMP significantly increased mRNA levels of connexin 40 (Cx-40), a marker of the early differentiating conduction system in mice. On the protein level, flowcytometry revealed no significant differences between treated and untreated groups with regard to the expression of connexins 40, 43 and 45. Treatment with cAMP (11.2 +/- 2.24 pA/pF; P < 0.001) and neuregulin-1-beta (6.23 +/- 1.07 pA/pF; P < 0.001) significantly increased the pacemaker current density compared to control cardiomyocytes (1.76 +/- 0.49 pA/pF). Our results indicate that neuregulin-1 and cAMP possess the capacity to cause significant transformation of a mixed population of fetal cardiomyocytes into cardiac pacemaker-like cells as shown by electrophysiology and increase of Cx-40 mRNA. This method may allow the development of a biological cardiac pacemaker system when applied to adult or embryonic stem cells.

Female mice lacking estrogen receptor beta display prolonged ventricular repolarization and reduced ventricular automaticity after myocardial infarction.

BACKGROUND: Major gender-based differences in the incidence of ventricular tachyarrhythmia after myocardial infarction have been shown in humans. Although the underlying mechanisms are unclear, earlier studies suggest that estrogen receptor-mediated effects play a major role in this process. METHODS AND RESULTS: We examined the effect of estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) on the electrophysiological phenotype in female mice with and without chronic anterior myocardial infarction. There was no significant difference in overall mortality, infarct size, and parameters of left ventricular remodeling when we compared infarcted ERalpha-deficient and ERbeta-deficient mice with infarcted wild-type animals. In the 12-hour telemetric ECG recording 6 weeks after myocardial infarction, surface ECG parameters did not show significant differences in comparisons of ERalpha-deficient mice versus wild-type controls, infarcted versus noninfarcted ERalpha-deficient mice, and infarcted ERalpha-deficient versus infarcted wild-type mice. However, infarcted ERbeta-deficient versus noninfarcted ERbeta-deficient mice showed a significant prolongation of the QT (61+/-6 versus 48+/-8 ms; P<0.05) and QTc intervals (61+/-7 versus 51+/-9 ms; P<0.05) and the JT (42+/-6 versus 31+/-4 ms; P<0.05) and JTc intervals (42+/-7 versus 33+/-4 ms; P<0.05). Furthermore, infarcted ERbeta-deficient versus infarcted wild-type mice showed a significant prolongation of the QT (61+/-6 versus 53+/-8 ms; P<0.05) and QTc intervals (61+/-7 versus 53+/-7 ms; P<0.05) and the JT (42+/-6 versus 31+/-5 ms; P<0.05) and JTc intervals (42+/-7 versus 31+/-5 ms; P<0.05), accompanied by a significant decrease of ventricular premature beats (7+/-21/h versus 71+/-110/h; P<0.05). Finally, real-time polymerase chain reaction-based quantitative analysis of mRNA levels showed a significantly lower expression of Kv4.3 (coding for I(to)) in ERbeta-deficient mice (P<0.05). CONCLUSIONS: Estrogen receptor beta deficiency results in prolonged ventricular repolarization and decreased ventricular automaticity in female mice with chronic myocardial infarction.

Interference between cellular telephones and implantable rhythm devices: a review on recent papers.

BACKGROUND: Cardiac pacemakers and implantable defibrillators are potentially susceptible to electromagnetic interferences as they have complex circuitry for sensing and communication purposes. Cellular telephones being an important source of electromagnetic waves are likely to cause interference in the function of these devices. METHODS: A systematic analysis of studies on interaction between cellular telephones and implantable devices was done using professional databases for literature. Related articles and references of relevant articles were also searched for suitable studies. RESULTS: Fourteen studies on pacemakers and eight studies on implantable defibrillators were identified. No dangerous malfunction was found in any of the analyzed studies, but most of the studies noted interference with device function when the phone was operated very close to the device. Interference was minimally in those devices with built in feed-through filters for eliminating electromagnetic interference. Device programming and interrogation were the most susceptible phases of operation. SUMMARY: Cellular phones are likely to interfere with implantable rhythm devices if operated in close proximity or during programming of the device. Patients with implanted devices can safely use cellular phones if they are not carried close to the implanted devices or operated near them. Carrying the cellular phones in the belt position, receiving calls in the ear opposite to the side of the implanted device and keeping the phone as far away as possible while dialing can be considered a safe practice. Interrogation of the devices should take place exclusively in areas where utilization of cellular phones is strictly prohibited. Studies on pacemakers published in the current decade have shown much lesser rates of interference, possibly due to improvement in device technology.

Quality of life in patients with implantable cardioverter defibrillators.

BACKGROUND: The implantable cardioverter defibrillator (ICD) is a life saving device for individuals with life threatening ventricular arrhythmias. There is no doubt that it is a cost effective therapy in various congenital and acquired arrhythmogenic disorders. Nevertheless, shock delivery may be painful and frightening which causes psychological distress and deterioration of perceived quality of life. METHODS: A systematic meta-analysis on studies reporting quality of life in patients implanted with ICDs was done using professional databases. Related articles and references of the relevant articles were also searched for suitable studies. RESULTS: Thirty studies with a total of 3412 patients on implantable defibrillators were identified. Five of them were large randomised studies with a total of 1680 patients, while 25 were non-randomised studies. Medical Outcome Study 36-item Short Form health survey (SF -94 36) was the most common instrument used for assessment of quality of life. Only one of the 5 major randomised trial reported worsening of quality of life after implantation of a defibrillator. In the subgroup of patients receiving shocks, three out of the five trials reported worsening of quality of life. SUMMARY: Most of the randomised studies showed either neutral or better quality of life in patients on implantable defibrillators. In the subset of patients receiving shocks, worsening of quality of life was found in most randomised studies. Therefore, activation of antitachycardia pacing should be performed in every ICD-patient in order to miminze painful shocks and consequent deterioration of quality of life.

Significant prolongation of atrial monophasic action potential duration: short-term reverse electrophysiological changes after internal cardioversion of atrial fibrillation.

OBJECTIVE: Since short action potentials and short refractory periods facilitate the induction of atrial reentry, this maladaptation has been proposed as the pathophysiological basis of the frequent immediate recurrences of atrial fibrillation (IRAF) after internal cardioversion. However, short-term reverse electrophysiological changes of the atria after cardioversion have not been studied in humans. METHODS: Thirty-seven patients with chronic atrial fibrillation of 16+/-19 months and ten patients with an atrial fibrillation duration < or =48 h underwent internal cardioversion. Antiarrhythmic medication was only continued in 10 patients (21%), who were on amiodarone before cardioversion. Atrial monophasic action potential duration at 90% repolarization (APD(90)), sinus rate, P wave duration and interatrial conduction times between high right atrium and coronary sinus were recorded at min 0, 1, 3, 5, 10, 15 and 20 after cardioversion. RESULTS: Internal cardioversion was successful in all patients, but twelve of the patients with chronic AF (32%) and three of the patients with intermittent AF (30%) had one to four episodes of IRAF after 16+/-28 s. There was a significant 52+/-30 ms APD(90) prolongation, 83% of which occurred in min 0-3 (P<0.0001) and 17% in min 3-20 (P<0.05) after internal cardioversion. There was no significant temporal change in sinus rate, P-wave and interatrial conduction time during the time studied. APD(90) prolongation and its time dependence did not show a detectable difference in subgroups with chronic AF, IRAF, left atrial size >40 mm and treatment with amiodarone. CONCLUSIONS: There is a significant prolongation of action potential duration in min 0-3 after internal cardioversion of atrial fibrillation, whereas sinus rate and intra- and interatrial conduction time remain unchanged. APD(90) prolongation in min 0-3 shows a temporal relationship to the high rate of immediate recurrences of atrial fibrillation during this time interval. The data imply that there is a transient recovery of atrial refractoriness after cardioversion and suggest a mechanism of the high rate of early recurrences of atrial fibrillation.

Transplanted fetal cardiomyocytes as cardiac pacemaker.

BACKGROUND: While morphologic integration of transplanted fetal cardiomyocytes into the ventricular myocardium is a well-known fact, no studies have yet shown transplanted cells to coherently contribute to contraction and electrical excitation of the host myocardium. The aim of this study was to prove the hypothesis that by transplanting cardiomyocytes with a higher intrinsic rhythmic rate into the myocardium of the left ventricle, these cells could act as an ectopic pacemaker by functional coupling with host cardiomyocytes. METHODS AND RESULTS: Dissociated fetal canine atrial cardiomyocytes including sinus nodal cells were delivered into the free wall of the left ventricle of adult canine X-linked muscular dystrophy dogs (n=2). These dogs fail to express Dystrophin in both cardiac and skeletal muscle. In the control group (n=2) fetal skin fibroblasts were used for grafting. A total of 3-4 weeks after transplantation the dogs underwent catheter ablation of the atrioventricular node (AV-node) and subsequent electrophysiological mapping studies. Transplanted cells were identified by Dystrophin immunoreactivity, indicating survival and morphological integration in the recipient heart. The expression of Connexin 43 between donor and recipient cells suggested formation of gap junctions between injected and host cardiomyocytes. After catheter ablation of the AV-node, a ventricular escape rhythm emerged driving the pace of the heart and originating from the labeled transplantation site. This effect could not be observed in the control group (n=2). CONCLUSIONS: The results constitute the first observation of phenomena indicating electrical and mechanical coupling between allogeneic donor cardiomyocytes and recipient myocardium in-vivo. Further experiments are necessary to evaluate the technique as a potential therapy for atrioventricular block.

Feasibility of atrial sensing via a free-floating single-pass defibrillation lead for dual-chamber defibrillators.

BACKGROUND: Detection and misclassification of rapidly conducted atrial fibrillation (AF) and marked sinus tachycardia by implantable cardioverter defibrillators (ICD) can result in the delivery of inappropriate therapies. Continuous atrial sensing may improve the differentiation between supraventricular and ventricular tachycardia. The present approach is to implant a separate atrial pacing lead connected to a dual-chamber defibrillator. We hypothesized that a free-floating single-pass defibrillation lead reliably senses the atrial electrical activity. The aim of the study was to assess during implantation the efficacy of a custom-built free-floating single-pass defibrillation lead and to record sinus rhythm (SR), induced AF, and atrial flutter (Afl). METHODS: The free-floating single-pass defibrillation lead (Biotronik, Berlin, Germany) had an atrial bipole with 10 mm spacing and a distance between the atrial bipole and the electrode tip of 13.5, 15 or 17-cm. The lead was temporarily implanted in 15 patients during an ICD implantation. Fifteen seconds recordings were made during SR and after the induction of AF and Afl as well as during induced ventricular fibrillation. The amplitude and the time that the amplitude was less than 0.3 mV were assessed. RESULTS: The amplitude during SR (2.1 +/- 1.4 mV) was significantly higher compared with the amplitudes for Afl (1.3 +/- 0.5 mV; p < 0.02) and AF (0.7 +/- 0.5 mV; p < 0.001). Low amplitudes were not observed during SR and rarely during Afl (1.6 +/- 3.1%), but they were observed 19.9 +/- 15.9% of the time during AF (p < 0.05). The correlation coefficients between SR and AF amplitudes were r = 0.25, between SR and Afl amplitudes r = 0.31, and between AF and Afl amplitudes r = 0.41. During the ventricular fibrillation conversion test 9 patients were in continuous SR. The P-wave amplitude before the induction of ventricular fibrillation was 2.1 +/- 1.4 mV. The signal during ventricular fibrillation decreased to 1.1 +/- 0.7 mV and increased immediately after the termination of ventricular fibrillation to 1.6 +/- 0.8 mV. CONCLUSIONS: The recorded unfiltered signals indicate that SR as well as AF and Afl can immediately be detected after the implantation of the new free-floating single-pass defibrillation lead. High signal amplitude during SR did not predict high amplitude during AF or Afl. During induced ventricular fibrillation the P-wave amplitude decreased intermittently.

In-vivo electrophysiological study in mice with chronic anterior myocardial infarction.

INTRODUCTION: An increasing number of genetically altered mice with specific molecular cardiac defects are being assessed by electrophysiological studies and ECG monitoring. This approach should allow for the identification of critical genes involved in the arrhythmogenesis in myocardial infarction. Therefore it was the aim of this study to establish a standard for the in-vivo electrophysiological characteristics in the mouse model of chronic anterior myocardial infarction. METHODS AND RESULTS: Using a minimized, invasive, in-vivo electrophysiological study, surface ECG parameters, sinus node function, atrial, atrio-ventricular and ventricular conduction and ventricular repolarization, and enhanced vulnerability to atrial and ventricular arrhythmia were studied in 20 wild-type C57BL/6 mice either under control or 11 weeks after large anterior myocardial infarction induced by ligation of the left anterior descending coronary artery. Telemetric ECG recording was performed in the same animals at baseline unrestrained, conscious condition to study surface ECG parameters, heart rate variability and the prevalence of supraventricular and ventricular arrhythmia. During electrophysiological study, infarcted mice showed an 81% increase of the angle of the QRS axis (p < 0.001) and a prolongation of the P wave by 23% (p = 0.01), the QRS complex by 39% (p = 0.001), the QT interval by 23% (p<0.05), the QT(c) interval by 30% (p < 0.005) and the JT(c) interval by 31% (p < 0.05) in comparison to control animals. Furthermore, there was a prolongation of the atrio-ventricular interval by 28% (p < 0.0005) and the atrio-ventricular functional refractory period by 26% in infarcted animals (p < 0.05), and inducibility of ventricular tachycardia in 4 of 6 infarcted versus in none of control animals (0 < 0.01). During telemetric ECG recording, there was a marked increase in ventricular ectopic activity in infarcted mice in comparison to controls (p < 0.05). Heart rate and time- and frequency-domain of heart rate variability were not significantly different in both groups (p > 0.05, respectively). CONCLUSIONS: The mouse model of chronic anterior myocardial infarction is associated with significant atrial and ventricular conduction disturbances and vulnerability to ventricular arrhythmia and thus may provide a highly valuable tool to study molecular determinants of arrhythmogenesis in myocardial infarction.

Comparison of a novel, single-lead atrial sensing system with a dual-chamber implantable cardioverter-defibrillator system in patients without antibradycardia pacing indications: results of a randomized study.

BACKGROUND: Supraventricular tachyarrhythmias are the main cause for inappropriate therapy by implantable cardioverter-defibrillators (ICDs). For better rhythm discrimination, an atrial electrogram is helpful and usually obtained from an additional atrial lead, even in the absence of sinus node or atrioventricular nodal disease. An A+-ICD system with integrated atrial sensing rings mounted 15 to 18 cm from the tip of an ICD lead may obviate the need to implant a separate atrial lead. The aim of the study was to compare the novel A+-ICD and a conventional dual-chamber (DR)-ICD. METHODS AND RESULTS: Two hundred forty-nine patients with standard ICD indications but no requirement for antibradycardia pacing were randomized to receive an A+-ICD (n=124) or a DR-ICD (n=125). Implantation details, need for ICD system revision, long-term sensing, documented arrhythmia episodes, and the respective rhythm discrimination during follow-up were analyzed. The implantation time was significantly shorter in the A+-ICD group (67±30 vs 79±30 minutes, P=0.003). Mean P-wave amplitudes were 3.5±0.8 mV (A+-ICD) and 3.2±0.6 mV (DR-ICD) and remained stable during the follow-up period of 12 months. Surgical revision was necessary in 13 patients in the DR-ICD and 10 in the A+-ICD group. All 593 ventricular tachyarrhythmia episodes were correctly discriminated. Sensitivity and specificity of supraventricular tachyarrhythmia discrimination were not different between the study groups. CONCLUSIONS: The novel A+-ICD system can be implanted faster and is equivalent to a standard DR-ICD with regard to the detection of ventricular tachyarrhythmias and supraventricular tachyarrhythmias. It represents a useful alternative to obtain atrial sensing.

Adenylate-cyclase VI transforms ventricular cardiomyocytes into biological pacemaker cells.

INTRODUCTION: When sinus node or atrioventricular (AV) node cells are damaged by disease, the implantation of an artificial cardiac pacemaker becomes necessary. In search for a biological alternative, the objective of this study was to demonstrate whether in vivo adenoviral gene transfer of Adenylate-Cyclase type VI (AC-VI) can create biological pacemaker activity in a porcine AV node block model. Genetic therapy of arrhythmic disorders of the heart has been subject of extensive studies. Cyclic AMP is generated in response to Beta-adrenergic receptor stimulation and also binds to HCN channels, where it regulates spontaneous rhythmic activity in the sinus node. MATERIALS AND METHODS: Adenoviruses encoding either AC-VI or Beta-Galactosidase (lacZ) gene were injected into the lateral wall of the left ventricle of adult pigs via anterolateral thoracotomy at a dose of 10(10) virus particles each. After 12 days, the AV node was ablated and three-dimensional electrophysiological cardiac mapping was performed using the Ensite electro-anatomical system. RESULTS: After rapid ventricular pacing and administration of Isoprenalin, all animals of the AC-VI group exhibited an escape rhythm originating from the area of the left ventricular injection site at a rate of 100 + 7 beats/min (n = 5), whereas the escape rhythms in the control group (n = 4) originated from the right ventricle. Western blot analysis of the injection sites revealed significantly higher expression of AC-VI in the respective group as compared with the control group. CONCLUSIONS: Our study demonstrates that AC-VI gene transfer has the potential to create a biological pacemaker system.