Search

Proper mitotic progression is crucial for maintenance of genomic integrity in proliferating cells and is regulated through an intricate series of events, including protein phosphorylation governed by a complex network of protein kinases. One kinase family implicated in the regulation of mitotic progression is protein kinase CK2, a small family of enzymes that is overexpressed in cancer and induces transformation in mice and cultured fibroblasts. CK2alpha, one isoform of the catalytic subunits of CK2, is maximally phosphorylated at four sites in nocodazole-treated cells. To investigate the effects of CK2alpha phosphorylation on mitotic progression, we generated phosphospecific antibodies against its mitotic phosphorylation sites. In U2OS cells released from S-phase arrest, these antibodies reveal that CK2alpha is most highly phosphorylated in prophase and metaphase. Phosphorylation gradually decreases during anaphase and becomes undetectable during telophase and cytokinesis. Stable expression of phosphomimetic CK2alpha (CK2alpha-4D, CK2alpha-4E) results in aberrant centrosome amplification and chromosomal segregation defects and loss of mitotic cells through mitotic catastrophe. Conversely, cells expressing nonphosphorylatable CK2alpha (CK2alpha-4A) show a decreased ability to arrest in mitosis following nocodazole treatment, suggesting involvement in the spindle assembly checkpoint. Collectively, these studies indicate that reversible phosphorylation of CK2alpha requires precise regulation to allow proper mitotic progression.

Aims This study was performed to develop and externally validate prediction models for appropriate implantable cardioverter-defibrillator (ICD) shock and mortality to identify subgroups with insufficient benefit from ICD implantation. Methods and results We recruited patients scheduled for primary prevention ICD implantation and reduced left ventricular function. Bootstrapping-based Cox proportional hazards and Fine and Gray competing risk models with likely candidate predictors were developed for all-cause mortality and appropriate ICD shock, respectively. Between 2014 and 2018, we included 1441 consecutive patients in the development and 1450 patients in the validation cohort. During a median follow-up of 2.4 (IQR 2.1–2.8) years, 109 (7.6%) patients received appropriate ICD shock and 193 (13.4%) died in the development cohort. During a median follow-up of 2.7 (IQR 2.0–3.4) years, 105 (7.2%) received appropriate ICD shock and 223 (15.4%) died in the validation cohort. Selected predictors of appropriate ICD shock were gender, NSVT, ACE/ARB use, atrial fibrillation history, Aldosterone-antagonist use, Digoxin use, eGFR, (N)OAC use, and peripheral vascular disease. Selected predictors of all-cause mortality were age, diuretic use, sodium, NT-pro-BNP, and ACE/ARB use. C-statistic was 0.61 and 0.60 at respectively internal and external validation for appropriate ICD shock and 0.74 at both internal and external validation for mortality. Conclusion Although this cohort study was specifically designed to develop prediction models, risk stratification still remains challenging and no large group with insufficient benefit of ICD implantation was found. However, the prediction models have some clinical utility as we present several scenarios where ICD implantation might be postponed.

Deep-water sediments in the Molasse Basin, Austria, were deposited in a narrow foreland basin dominated by a large channel belt located between the steep Alpine fold and thrust belt to the south and the gentler northern slope off the Bohemian Massif. Several gas fields occur outside the channel belt, along the outer bend of a large meander. Accumulation of these overbank sediments reflects a complicated interplay between slope accommodation and debris-flow and turbidity-flow interaction within the channel. The tectonically oversteepened northern slope of the basin (ca 2 to 3°) developed a regionally important erosional surface, the Northern Slope Unconformity, which can be traced seismically for >100 km in an east–west direction and >20 km from the channel to the north. The slope preserves numerous gullies sourced from the north that eroded into the channel belt. These gullies were ca 20 km long, 15 km long, plugged and forced the main channel to step abruptly ca 7 km to the south. This resulted in development of an abrupt turn in the channel pathway that propagated to the east and probably played a role in forming a sinuous channel later. As debris-flow topography was healed, flows spread out onto narrow area between the main channel and northern slope forming a broad fine-grained apron that serves as the main gas reservoir in this area. This model of the overbank splay formation and the resulting stratigraphic architecture within the confined basin could be applied in modern and ancient systems or for subsurface hydrocarbon reservoirs where three-dimensional seismic-reflection data is limited. This study elucidates the geomorphology of the oversteepened slope of the under-riding plate and its effects on the sedimentation.

Geostatistical modeling originated within the mining industry to estimate average minable ore grade from large support volumes given samples measured on small volume support. In petroleum geostatistics, the goal is more equivocal due to several different scales of support of input data, which are often incongruent with the desired prediction scale. More specifically, the goal is to utilize indirect measurements (e.g., seismic data) from a scale larger than the prediction scale for fine-scale spatial distributions of facies and petrophysical properties grounded by undersampled point data (e.g., well-log data). (Note, volume support is a geostatistical term that describes the size or resolution of the sample or measurement.)

Lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropionamide; formerly harkoseride, SPM 927; Vimpat), has been recently approved by US and European regulatory authorities for use as add-on therapy for partial-onset seizures in adults. Because a number of anti-epileptic drugs are used to treat conditions beyond epilepsy, including anxiety, in the present study we investigated the anxiolytic potential of lacosamide in a conditioned emotional response (CER) model in rat, and the mouse marble burying assay. In each test lacosamide produced a significant effect consistent with anxiolysis, i.e. lacosamide increased suppression ratio in the CER test, and reduced the number of marbles buried in the marble burying assay. The doses necessary for an anxiolytic effect were higher than those necessary for efficacy in seizure tests conducted in the same species. For example in the mouse, the lacosamide oral ED(50) in the maximal electroshock seizure (MES) and 6 Hz tests was 5.3 and 9.6 mg/kg respectively, and the minimal effective dose in the marble burying assay was 30 mg/kg. In both seizure and anxiety tests, the (S)-enantiomer of lacosamide was inactive suggesting a similar mechanism of action, possibly use-dependent inhibition of sodium channel function (Errington et al., 2008). Efficacy in the CER model was equivalent to diazepam and pregabalin (Lyrica). In tests of side-effects, lacosamide had no effect on choice accuracy in the delayed match to position task of working memory, although at the 30 mg/kg dose, response rates and response latencies were significantly affected. In sum, the present results identify for the first time, an anxiolytic potential of lacosamide.

Protein kinase CK2 exhibits oncogenic activity in mice and is over-expressed in a number of tumors or leukemic cells. On the basis of its amino acid sequence and a wealth of experimental information, CK2 has traditionally been classified as a protein serine/threonine kinase. In contrast to this traditional view of CK2, recent evidence has shown that CK2 can also phosphorylate tyrosine residues under some circumstances in vitro and in yeast. In this study, we provide definitive evidence demonstrating that CK2 also exhibits tyrosine kinase activity in mammalian cells. Tyrosine phosphorylation of CK2 in cells and in CK2 immunoprecipitates is dependent on CK2 activity and is inhibited by the CK2 selective inhibitor 4,5,6,7-tetrabromobenzotriazole. Examination of phosphotyrosine profiles in cells reveals a number of proteins, including CK2 itself, which exhibit increased tyrosine phosphorylation when CK2 levels are increased. Peptide arrays to evaluate the specificity determinants for tyrosine phosphorylation by CK2 reveal that its specificity for tyrosine phosphorylation is distinct from its specificity for serine/threonine phosphorylation. Of particular note is the requirement for an aspartic acid immediately C-terminal to the phosphorylatable tyrosine residue. Collectively, these data provide conclusive evidence that CK2 catalyzes the phosphorylation of tyrosine residues in mammalian cells, a finding that adds a new level of complexity to the challenge of elucidating its cellular functions. Furthermore, these results raise the possibility that increased CK2 levels that frequently accompany transformation may contribute to the increased tyrosine phosphorylation that occurs in transformed cells.

LQTS may cause sudden cardiac death (SCD), but the mechanisms linking gene mutations to ventricular fibrillation (VF) are unclear.To determine whether ventricular activation delays in congenital long QT syndrome (LQTS) are associated with VF and to describe these delays clinically by measuring activation through ventricular myocardium after a premature extrastimulus.Forty-six patients with LQTS, including 16 with VF (LQTS VF) were investigated, and the results were compared with those from 24 patients with hypertrophic cardiomyopathy and VF (HCM VF). Electrograms in response to premature stimuli were analyzed for increases in electrogram duration (DeltaED) and the S1S2 coupling intervals at which electrogram latency starts to increase (S1S2(delay)). Two piecewise continuous straight line segments were fitted to the last electrogram deflection as a function of S1S2 interval in the LQTS and HCM VF populations, and the difference in their gradient (alpha) was taken as an index of the abruptness of the onset of this delay.Thirteen LQTS VF and six LQTS non-VF patients had values of DeltaED and S1S2(delay) comparable to those in HCM VF patients, while the remainder (three LQTS VF and 24 LQTS non-VF) had lower values (P.001). There was only a weak correlation between delay and the corrected QT interval. The HCM and LQTS VF patients could be separated by the value of alpha (P.01), with the LQTS patients having a more abrupt onset of delay.Large delays in ventricular activation after an extrastimulus occur in patients with the LQTS, especially those with VF. The change in delay is abrupt in the LQTS, indicating sudden block to activation creating a dynamic substrate for arrhythmogenesis.

Aims The experiences of patients who received shocks from their implantable cardioverter defibrillator (ICD) and how these events affect their overall adjustment are poorly understood. Our goal was to evaluate quality of life and psychological well-being, and the prevalence of, and changes in, depression and anxiety of patients who did or did not experience defibrillatory shocks in the first 12 months after ICD implantation. In total 167 patients were monitored after discharge. Four self-administered questionnaires were used. The first assessment took place before ICD implantation, the remaining three at 1, 6 and 12 months after discharge. Results We classified patients into three shock groups and one no shock group. A small group of ICD recipients (26%) received ICD shock delivery, usually during the last 6 months of the study. Borderline significant differences were found within the groups over time regarding physical role limitations (P < 0:051). Those who experienced shocks throughout the year (group 1) felt more limited in their daily activities due to physical or mental problems. All groups reported an improvement in their health (P < 0:001). Overall quality of life did not change significantly after 6 months. Anxiety and depression did not change significantly over time. In total 22–66% of patients reported clinically significant depressive symptoms throughout the first year, and 31–83% clinically significant symptoms of anxiety. ICD recipients who had experienced a shock were significantly more anxious one-year postdischarge than those who had not received a shock. Conclusions Overall quality of life and psychological wellbeing did not change in ICD recipients, irrespective of whether they experienced defibrillatory shocks. The high prevalence of depression and anxiety can be interpreted as a response to the perceived physical and mental problems regarding daily activities. Our data indicate that patients who have experienced an ICD shock do not adapt well to living with an ICD, they are more anxious than ICD recipients who received no shocks. However, the anticipation of having another shock after experiencing one is less stressful than that of the first shock. We conclude that the lasting psychological distress will not dissipate spontaneously or naturally and that psychosocial interventions may be warranted.

Background— The mechanism by which structural barriers promote wave break and fibrillation is unclear. Conduction velocity (CV) restitution is an important determinant of wave break. Abnormal CV restitution is associated with ventricular fibrillation in patients with heart disease and arises preferentially in fibrotic myocardium. We hypothesize that tissue discontinuities imposed by structural barriers cause abnormal CV restitution. Methods and Results— Tissue discontinuities were simulated in cultures of neonatal rat heart cells grown in 8-armed star patterns. Premature stimulation was applied at the extremity of 1 arm (n=12) while extracellular electrograms were recorded at 24 sites throughout the star. Action potentials were recorded at the following 3 sites: in the stimulated arm and at the discontinuity both proximal to and distal from the star center. Extracellular recordings revealed progressive increases in activation delay (indicative for abnormal CV restitution) only at the discontinuity from arms proximal to the star center. The mean increase in delay was 0.81±0.41 ms/10 ms for recording sites proximal to and 3.13±0.58 ms/10 ms for sites distal from this discontinuity. Depolarizing currents were determined in single cells during premature stimulation and for voltage configurations similar to those arising at the discontinuity. Both voltage-clamp measurements and computer simulations showed that delay at the discontinuity was associated with biphasic, prolonged activation and delayed inactivation of depolarizing current. Conclusions— Tissue discontinuities cause abnormal CV restitution. Rapid increase in activation after an initial slow activation and delayed inactivation at the discontinuity lengthen the duration of depolarizing current and cause the abnormal restitution.

Background— Slowed or delayed myocardial activation and dispersed refractoriness predispose to reentrant excitation that may lead to ventricular fibrillation (VF). Increased ventricular electrogram duration (ΔED) in response to extrastimuli and increased S1S2 coupling intervals at which electrogram duration starts to increase (S1S2 delay ) are seen both in hypertrophic cardiomyopathy (HCM) in those at risk of VF and in patients with idiopathic VF (IVF). Methods and Results— ΔED and S1S2 delay have been measured using paced electrogram fractionation analysis in 266 patients with noncoronary heart disease. Of these, one group of 61 patients had a history of VF and included 21 HCM, 17 IVF, 13 long-QT syndrome (LQTS), 5 dilated cardiomyopathy (DCM), and 5 others. These were compared with 205 patients with similar diseases with no VF history (non-VF group) and a control group (n=12) without heart disease. Results from HCM VF patients (ΔED, 19±3.3 ms; S1S2 delay , 350±9.7 ms) differed sharply from observations in HCM non-VF patients (ΔED, 7.3±1.35 ms; S1S2 delay , 312±6.7 ms; P delay , 344±11.2) than DCM non-VF patients (ΔED, 5.8±1.87 ms; S1S2 delay , 311±5.7 ms; P delay , 343±13.8 ms) and LQTS non-VF patients (ΔED, 11.0±2.7 ms; S1S2 delay , 320±5.4 ms; P Conclusions— Slowed or delayed myocardial activation is a common feature in patients with noncoronary heart disease with a history of VF, and its assessment may allow the prospective prediction of VF risk in these patients.

Background — Progressive activation delay starting at long coupling intervals of premature stimuli has been shown to correlate with sudden cardiac death in patients with hypertrophic cardiomyopathy. The purpose of this study was to elucidate the mechanism of increased activation delay in chronically diseased myocardium. Methods and Results — High-resolution unipolar mapping (105, 208, or 247 recording sites with interelectrode distances of 0.8, 0.5, or 0.3 mm, respectively) of epicardial electrical activity was carried out during premature stimulation in 11 explanted human hearts. The hearts came from patients who underwent heart transplantation and were in the end stage of heart failure (coronary artery disease, 4; hypertrophic cardiomyopathy, 1; and dilated cardiomyopathy, 6). Eight hearts were Langendorff-perfused. Epicardial sheets were taken from the remaining hearts and studied in a tissue bath. Activation maps and conduction curves were constructed and correlated with histology. Conduction curves revealing prominent increase of activation delay were associated with zones of dense, patchy fibrosis with long fibrotic strands. Dense, diffuse fibrosis with short fibrotic strands only marginally affected conduction curves. The course of conduction curves in patchy fibrotic areas greatly depended on the direction of propagation relative to fiber direction. Conclusions — The study demonstrates that in chronically diseased human myocardium, nonuniform anisotropic characteristics imposed by long fibrotic strands cause a progressive increase of activation delay, starting at long coupling intervals of premature stimuli. The increase strongly depends on the direction of the wave front with respect to fiber direction and the architecture of fibrosis.

Background —Estimation of the 3-dimensional (3D) position of ablation electrodes from fluoroscopic images is inadequate if a systematic lesion pattern is required in the treatment of complex arrhythmogenic substrates. Methods and Results —We developed a new technique for online 3D localization of intracardiac electrodes. Regular catheter electrodes are used as sensors for a high-frequency transthoracic electrical field, which is applied via standard skin electrodes. We investigated localization accuracy within the right atrium, right ventricle, and left ventricle by comparing measured and true interelectrode distances of a decapolar catheter. Long-term stability was analyzed by localization of the most proximal His bundle before and after slow pathway ablation. Electrogram recordings were unaffected by the applied electrical field. Localization data from 3 catheter positions, widely distributed within the right atrium, right ventricle, or left ventricle, were analyzed in 10 patients per group. The relationship between measured and true electrode positions was highly linear, with an average correlation coefficient of 0.996, 0.997, and 0.999 for the right atrium, right ventricle, and left ventricle, respectively. Localization accuracy was better than 2 mm, with an additional scaling error of 8% to 14%. After 2 hours, localization of the proximal His bundle was reproducible within 1.4±1.1 mm. Conclusions —This new technique enables accurate and reproducible real-time localization of electrode positions in cardiac mapping and ablation procedures. Its application does not distort the quality of electrograms and can be applied to any electrode catheter.

Estimation of the 3-dimensional (3D) position of ablation electrodes from fluoroscopic images is inadequate in the ablation of complex arrhythmogenic substrates. We developed a new technique for real-time 3D localization of intracardiac electrodes. Regular catheter electrodes are used as sensors for a high-frequency transthoracic electrical field, which is applied via standard skin electrodes. We investigated localization accuracy by comparing measured and true interelectrode distances between the tip and the 10th electrode of a decapolar catheter, and the tip and the 4th electrode of a quadripolar catheter during catheter ablation procedures. Long-term stability was analyzed by localization of the proximal His bundle before and after slow pathway ablation. Accuracy achieved with the 54-mm distance between the two outer electrodes of the decapolar catheters was 101% +/- 15%, 95% +/- 10%, and 97% +/- 8% in the right atrium, right ventricle, and left ventricle, respectively. During catheter ablation procedures, the measured distance between the tip and 4th electrode of the mapping catheter was 100% +/- 15% in atrial flutter, 100% +/- 12% in slow pathway ablation, and 100% +/- 14% in ablations for left ventricular tachycardia. After 2 hours, localization of the proximal His bundle was reproducible within 1.4 +/- 1.1 mm. The LocaLisa technique allows for reproducible, real-time nonfluoroscopic 3D visualization of standard mapping and ablation catheters and is sufficiently accurate for the creation of linear radiofrequency lesions. The freedom of catheter choice makes the LocaLisa system an invaluable tool in catheter mapping and ablation procedures.

Acquired coronary artery fistulas (CCFs) are infrequently detected during conventional coronary angiography. To delineate the characteristics of congenital (first part) and acquired (second part) CCFs in adults, a PubMed search was conducted for papers dealing with congenital or acquired CCFs. None of the publications describing patients with coronary-vascular fistulas were included. Papers dealing with pediatric subjects were excluded. From the world literature, a total of 243 adult patients were selected who had congenital (n = 159/243, 65%) and acquired (n = 84/243, 35%) CCFs. Among the acquired types (n = 72, 85.7%) were traumatic (iatrogenic (n = 65/72, 90%), accidental (n = 7/72, 10%) and (n = 12, 14.3%) spontaneously developing in relation to severe coronary atherosclerosis or myocardial infarction. A high incidence of spontaneous resolution of iatrogenic CCFs resulting from endomyocardial biopsy or following post-septal myectomy was reported. Spontaneous CCFs associated with myocardial ischemia or infarction resolved completely in 8% of the subjects. Early surgical intervention was the treatment of choice in acquired traumatic accidental CCFs. The congenital types are addressed in a previous issue of this journal (first part). In this review (second of two parts, part II), we describe the acquired coronary-cameral fistulas.

This article presents a comparison of the costs and the cost effectiveness of defibrillator implantation in a hypothetical scenario for the years 1996-2000, with recently reported actual data from the Dutch prospective study over the years 1989-1993. Recently, technological advances in pulse generator and leads have revolutionized implantable cardioverter-defibrillator (ICD) therapy. Major advances include (1) transvenous single lead positioning and (2) tremendously reduced size, combined with prolonged longevity of the pulse generator. Both have simplified implantation technique and provided for superior effectiveness and lower costs. This suggests that a more favorable cost-effectiveness is to be expected. The study group reported here consisted of patients successfully resuscitated after cardiac arrest due to malignant ventricular tachyarrhythmias in the chronic stage of myocardial infarction. During a mean follow-up of 27 months, starting on the day of therapeutic decision making, total costs and the cost-effectiveness ratio were estimated. Actual data from the prospective study in 1989-1993 are compared with a hypothetical scenario for 1996-2000. Mortality and costs for hospitalization per day, per procedure, and per device are taken from the prospective study and equalized for both scenarios. Transthoracic lead positioning and abdominal implantation of a Ventak P (CPI) defibrillator with +/- 3 years longevity were characteristic of the recently completed prospective study. The hypothetical future scenario uses the Ventak Mini-2 with assumed 5 years longevity, implanted pectorally and connected to a single transvenous lead. Implantation will be carried out in the catheterization laboratory and as first-choice treatment. Due to prolonged longevity of the device and shorter hospitalization, a cost reduction of US $11,530 per patient is expected. Total costs per patient in the 1989-1993 prospective study in the (1) conventional arm (drugs first choice), (2) early ICD arm (ICD first choice), and (3) early ICD arm in the 1996-2000 study (ICD first choice) are $63,032, $56,067, and $44,537, respectively. The corresponding cost-effectiveness ratios are $87, $64, and $51 per day alive, respectively. Thus, it appears that modem ICD technology will be associated with an increasing reduction in healthcare costs, at least in selected patients. This reduction is associated with a more favorable cost-effectiveness ratio.

International audience; RATIONALE: Antiepileptic drugs (AEDs) have been available for many years; yet, new members of this class continue to be identified and developed due to the limitations of existing drugs, which include a propensity for cognitive impairment. However, there is little preclinical information about the cognitive effects they produce, which clinically include deficits in attention and slowing of reaction time. OBJECTIVES: The purpose of this study was to profile two first-generation AEDs, phenytoin and valproate, and three second-generation AEDs, levetiracetam, pregabalin and lacosamide. Initially, each drug was examined across a range of well characterised preclinical seizure tests, and then each drug was evaluated in the five-choice serial reaction time test (5-CSRTT) based on efficacious doses from the seizure tests. MATERIALS AND METHODS: Each AED was tested for anti-seizure efficacy in either (1) the maximal electroshock seizure test, (2) s.c. PTZ seizure test, (3) amygdala-kindled seizures and (4) the genetic absence epilepsy rat of Strasbourg model of absence seizures. On completion of these studies, each drug was tested in rats trained to asymptotic performance in the 5-CSRTT (0.5 s SD, 5 s ITI, 100 trials). Male rats were used in all studies. RESULTS: Each AED was active in at least one of the seizure tests, although only valproate was active in each test. In the 5-CSRT test, all drugs with the exception of levetiracetam, significantly slowed reaction time and increased omissions. Variable effects were seen on accuracy. The effect on omissions was reversed by increasing stimulus duration from 0.5 to 5 s, supporting a drug-induced attention deficit. Levetiracetam had no negative effect on performance; indeed, reaction time was slightly increased (i.e. faster). CONCLUSIONS: These results highlight somewhat similar effects of phenytoin, valproate, pregabalin and lacosamide on attention and reaction time, and comparison to efficacious doses from the seizure tests support the view that there may be a better separation with the newer AEDs. Levetiracetam had no detrimental effect in the 5-CSRTT, which may be consistent with clinical experience where the drug is considered to be well tolerated amongst the AED class.

A 61-year-old woman with dilated cardiomyopathy, who previously underwent successful radiofrequency catheter ablation for atrial flutter, developed monomorphic ventricular tachycardia (VT). The site of VT origin was the inferobasal right ventricle adjacent to the previous atrial isthmus ablation area. The most likely mechanism for the VT was scar-related reentry, the scar being the result of previous radiofrequency lesions in the atrial isthmus. The VT was successfully ablated.

Proper mitotic progression is crucial for maintenance of genomic integrity in proliferating cells and is regulated through an intricate series of events, including protein phosphorylation governed by a complex network of protein kinases. One kinase family implicated in the regulation of mitotic progression is protein kinase CK2, a small family of enzymes that is overexpressed in cancer and induces transformation in mice and cultured fibroblasts. CK2alpha, one isoform of the catalytic subunits of CK2, is maximally phosphorylated at four sites in nocodazole-treated cells. To investigate the effects of CK2alpha phosphorylation on mitotic progression, we generated phosphospecific antibodies against its mitotic phosphorylation sites. In U2OS cells released from S-phase arrest, these antibodies reveal that CK2alpha is most highly phosphorylated in prophase and metaphase. Phosphorylation gradually decreases during anaphase and becomes undetectable during telophase and cytokinesis. Stable expression of phosphomimetic CK2alpha (CK2alpha-4D, CK2alpha-4E) results in aberrant centrosome amplification and chromosomal segregation defects and loss of mitotic cells through mitotic catastrophe. Conversely, cells expressing nonphosphorylatable CK2alpha (CK2alpha-4A) show a decreased ability to arrest in mitosis following nocodazole treatment, suggesting involvement in the spindle assembly checkpoint. Collectively, these studies indicate that reversible phosphorylation of CK2alpha requires precise regulation to allow proper mitotic progression.

AIMS: A linear lesion between the left inferior pulmonary vein orifice and mitral annulus, the so-called mitral isthmus, may improve the success of catheter ablation for atrial fibrillation. Gaps in the lesion line, however, may facilitate left atrial flutter. The aim of the study was to determine the optimal location of the lesion line by serial sectioning of the isthmus area. METHODS AND RESULTS: In a post-mortem study of 16 patients with normal left atria, serial sections of the isthmus area from 10 mm superior to and 30 mm inferior to the isthmus were studied by light microscopy. The length of the isthmus was 35+/-7 mm. On average, the muscle sleeve around the coronary sinus ended 10 mm inferior to the isthmus. The prevalence of a ramus circumflexus

Background. The experiences of how patients live with an implantable cardioverter defibrillator are still poorly understood. Only a few qualitative studies have investigated this phenomenon. This paper was undertaken as part of a larger project to evaluate quality of life and psychological well-being in those survivors of cardiac arrest who have received an implantable cardioverter defibrillator. Aims and objectives. The aim of this qualitative study was to explore how implantable cardioverter defibrillator recipients perceive their lives during the first year after implantation of the device. Methods. A sample of 21 patients who received an implantable cardioverter defibrillator was interviewed during three consecutive periods: one, six and 12 months postdischarge from the hospital. The semi-structured interviews were based on insights gained from a literature review. The transcripts were subjected to content analysis. Results. Analysis of the data revealed seven major categories: physical deterioration, cognitive changes, perceived social support, dependency, contact with the doctor, confrontation with mortality and uncertainty surrounding having a shock. Anxiety, uncertainty, disappointment, frustration, unexpected barriers, acceptance of and dependency on the implantable cardioverter defibrillator played a major role in the lives of implantable cardioverter defibrillator recipients. Well-being improved throughout the year. During the first months after discharge from the hospital the focus was on regaining physical health. During the early postimplantation period both the implantable cardioverter defibrillator recipient and family members had adapted to the situation. Reflection on the impact and consequences of the cardiac arrest was reported more often in the late postimplantation period. Conclusions. Content analysis is a resourceful approach giving answers to questions that have hardly been addressed within the domain of cardiology. Implantable cardioverter defibrillator recipients face a complex first year, especially the first 6 months. Cognitive deterioration and confrontation with mortality are problems that need to be researched further. Relevance to clinical practice. Caregivers are able to explain to future patients what they can expect in the first year after implantation. Caregivers may become more receptive to physical, psychological and social limitations and to emotional and social problems that occur in implantable cardioverter defibrillator recipients, enabling them to act upon them.

Background— During a catheter ablation procedure for selective electrical isolation of pulmonary vein (PV) ostia, the size of these ostia is usually estimated using fluoroscopic angiography. This measurement may be misleading, however, because only the projected supero/inferior ostium diameters can be measured. In this study, we analyzed 3-dimensional magnetic resonance angiographic (MRA) images to measure the minimal and maximal cross-sectional diameter of PV ostia in relation to the diameter that would have been projected on fluoroscopic angiograms during a catheter ablation procedure. Methods and Results— In 42 patients with idiopathic atrial fibrillation who were scheduled for selective electrical isolation of PV ostia, the minimal and maximal diameters of these ostia were measured from 3-dimensional MRA images. Thereafter, these images were oriented in a 45° right or left anterior oblique direction and the projected diameter of the PV ostia were measured again. The average ratio between maximal and minimal diameter was 1.5±0.4 for the left and 1.2±0.1 for the right pulmonary vein ostia. Because of the orientation and oval shape of especially the left pulmonary vein ostia, their minimal diameters were significantly smaller than the projected diameters. Conclusion— Pulmonary vein ostia, especially those at the left, are oval with the short axis oriented approximately in the antero/posterior direction. Consequently, PV ostia may sometimes be very narrow despite a rather normal appearance on angiographic images obtained during a catheter ablation procedure.

Background Previous studies indicate that the implantable cardioverter defibrillator (ICD) has a large impact on the quality of life of patients. The effects of having an ICD over longer periods of times has been less studied. Objective To assess the quality of life and well-being of cardiac arrest survivors who have received an implantable cardioverter defibrillator (ICD) or other treatment. Methods 168 patients were monitored for 1 year and completed four questionnaires. Results No differences were found between the two treatments regarding quality of life (except for pain, ICD patients perceived less pain) and well-being. A significant improvement in physical and social function, and in mental health was found in the first 6 months. Older patients (60 years or older) perceived less improvement in their health than younger patients. Women reported having poorer social function. The prevalence of anxiety and probable depression was high irrespective of the treatment received: anxiety and depressive symptoms did not change significantly between 1 and 12 months after discharge. Patients with higher anxiety scores experienced less improvement in health and patients with more depressive symptoms experienced poorer social function. Conclusions The prevalence of anxiety and probable depression was high in cardiac arrest survivors. Probable depression affected social function. Those patients who felt anxious experienced less health improvement. Quality of life and well-being were not affected by the type of treatment. We conclude that surviving an out-of-hospital cardiac arrest has a greater impact on patients than the treatment received. (Europace 2002; 4: 417–425)

MOLENSCHOT, M., et al.: Catheter Ablation of Incisional Atrial Tachycardia Using a Novel Mapping System: LocaLisa. Incisional atrial tachycardia occurs due to reentry around surgical scars. Pharmacological therapy is often ineffective. This study assessed the efficacy of a novel mapping system (LocaLisa) in facilitating catheter ablation of incisional atrial tachycardia circuits. Eight consecutive patients (four men, four women) with incisional atrial tachycardia (median age 23.5 years, range 9–44) following previous repair of congenital heart defects underwent transcatheter mapping and ablation of the arrhythmogenic substrate using a mapping system (LocaLisa) that allows localization of endocardial electrodes in a three-dimensional space. Critical isthmuses for the tachycardia circuits were identified by demonstrating concealed entrainment using standard pacing and mapping techniques. Scars and natural anatomic barriers were marked on the LocaLisa image. Lines of block were created by radiofrequency current application between scars and natural anatomic barriers, or between two scars, to close isthmuses demonstrated to be critical for the reentrant circuit. All lines of block were verified in both directions. All reentrant circuits around incisions were successfully ablated. Seven additional tachycardia mechanisms were identified in four patients (common atrial flutter [n = 4], atrioventricular nodal [AVN] reentry [n = 2], ectopic atrial tachycardia [n = 1]) and were also ablated in a single session. The mean fluoroscopy time was 28.4 ± 13.8 minutes. All patients are arrhythmia-free at a median follow-up of 20 (6–22) months. The LocaLisa mapping system is effective for identification of scars and ablation targets, for confirming lines of block, and facilitating ablation of complex reentrant circuits.

The regulatory subunit of protein kinase CK2, designated CK2beta, exists both free in cells and in complexes with the CK2 catalytic subunits. Growing evidence suggests that CK2beta has functions dependent and independent of the CK2 catalytic subunits. There have been indications that CK2beta has functions associated with DNA damage responses and in the control of cell proliferation. For example, transient and stable constitutive overexpression of CK2beta in mammalian cells was previously shown to perturb cell cycle progression and to attenuate proliferation. To systematically investigate the molecular mechanisms responsible for these effects of CK2beta on cell proliferation, we generated human osteosarcoma U2OS cell lines with tetracycline-regulated expression of CK2beta. Increased expression of CK2beta results in increases in total cellular CK2 activity, but no changes in cell cycle profiles or proliferation. Furthermore, following exposure to ultraviolet radiation, p53 induction was identical regardless of the levels of CK2beta in cells. Mouse 3T3-L1 cells stably transfected with CK2beta also showed no alterations in cell proliferation. The differences between these results and those previously reported emphasize the complex nature of CK2beta and its cellular functions. Furthermore, these results indicate that increased expression of CK2beta is not by itself sufficient to effect alterations in cell proliferation.

Aims Some patients with idiopathic ventricular fibrillation may suffer from the Brugada syndrome. The diagnostic criteria for the Brugada syndrome are uncertain and arbitrarily set. Therefore, we studied the prevalence of the Brugada syndrome using various diagnostic criteria and long-term follow-up in 37 idiopathic ventricular fibrillation patients. Methods and Results Idiopathic ventricular fibrillation was diagnosed after thorough clinical evaluation in 37 survivors of an out-of-hospital cardiac arrest referred to our institute (UMC Utrecht). Retrospectively, nine patients (24%, group I) were classified as potentially having the Brugada syndrome based on the presence of (in)complete right bundle branch block and ST-segment elevation in leads V1–V3of ≥1mm. Only three patients (8%, group II) showed (in)complete right bundle branch block and ≥2mm ST-segment elevation. With the intermittent presence of these ECG features and/or their (re)appearance with class I antiarrhythmic drugs included as criteria, the percentage of the Brugada syndrome was attenuated in group I (2/37; 5%) and group II (1/37; 3%). Sixteen (43%) of all idiopathic ventricular fibrillation patients (mean follow-up 77±41 months) had a recurrent episode of syncope, ventricular tachyarrhythmias or sudden death. Recurrence rate was 3/9 (33%) in Brugada patients group I, 2/3 (66%) in group II and 13/28 (46%) in patients without the Brugada syndrome ( P =ns). Conclusions Depending on the diagnostic criteria used, the Brugada syndrome was observed in 3% to 24% of patients with idiopathic ventricular fibrillation, underlining the importance of defining the precise diagnostic criteria in these patients. For all idiopathic ventricular fibrillation patients, the ventricular tachyarrhythmia recurrence rate was substantial during an average follow-up of more than 6 years.

This is a case series and review of the literature adding 11 new cases. Coronary-cameral fistulas (CCFs) are infrequent anomalies which are in general co-incidentally found during diagnostic coronary angiography (CAG). To delineate the characteristics of congenital and acquired CCFs in adults, we performed a PubMed search for papers dealing with congenital or acquired CCFs in adults. Publications on coronary-vascular fistulas or paediatric subjects were not included. From the world literature, a total of 243 adult patients were identified who had congenital (65%) or acquired (35%) CCFs. In this review, which is part one of a two-part series on CCFs, we describe and discuss the congenital fistulas, give an overview on the published literature and report details of our own series of 11 patients with MMFs and solitary macro CCFs. Of the congenital group, 85% were small or large solitary macro CCFs (cut-off 1.5 mm) and 15% were coronary artery-ventricular multiple micro-fistulas (MMFs). Apical hypertrophic cardiomyopathy was reported in some of the reviewed subjects with MMFs (3/24 = 13%) but not was seen in our own series. Conservative medical management was generally the treatment of choice in congenital MMFs; prophylactic implantable cardioverter defibrillators (ICD) were implanted in 2/24 (8%) of subjects, especially when extensive micro-fistulisations were involved. None of the patients of our own series required an ICD, as the MMFs were of limited size. Congenital or acquired CCFs in adults are infrequent anomalies having a wide spectrum of clinical presentation may varies from asymptomatic to severely devastating states requiring different treatment modalities.