High-density Mapping Guided Pulmonary Vein Isolation for Treatment of Atrial Fibrillation - Two-year clinical outcome of a single center experience.

Pulmonary vein isolation (PVI) as interventional treatment for atrial fibrillation (AF) aims to eliminate arrhythmogenic triggers from the PVs. Improved signal detection facilitating a more robust electrical isolation might be associated with a better outcome. This retrospective cohort study compared PVI procedures using a novel high-density mapping system (HDM) with improved signal detection vs. age- and sex-matched PVIs using a conventional 3D mapping system (COM). Endpoints comprised freedom from AF and procedural parameters. In total, 108 patients (mean age 63.9 ± 11.2 years, 56.5% male, 50.9% paroxysmal AF) were included (n = 54 patients/group). Our analysis revealed that HDM was not superior regarding freedom from AF (mean follow-up of 494.7 ± 26.2 days), with one- and two-year AF recurrence rates of 38.9%/46.5% (HDM) and 38.9%/42.2% (COM), respectively. HDM was associated with reduction in fluoroscopy times (18.8 ± 10.6 vs. 29.8 ± 13.4 min; p < 0.01) and total radiation dose (866.0 ± 1003.3 vs. 1731.2 ± 1978.4 cGy; p < 0.01) compared to the COM group. HDM was equivalent but not superior to COM with respect to clinical outcome after PVI and resulted in reduced fluoroscopy time and radiation exposure. These results suggest that HDM-guided PVI is effective and safe for AF ablation. Potential benefits in comparison to conventional mapping systems, e.g. arrhythmia recurrence rates, have to be addressed in randomized trials.

Alteration of Endothelin 1, MCP-1 and Chromogranin A in patients with atrial fibrillation undergoing pulmonary vein isolation.

BACKGROUND: The relation between arrhythmias and stress is known. The aim of our current study was to elucidate whether plasma levels of previously described stress parameters are altered in highly symptomatic patients with atrial fibrillation (AF) per se and in patients undergoing ablation therapy by pulmonary vein isolation (PVI). METHODS: 96 patients with AF undergoing PVI were recruited. Plasma levels of Endothelin-1 (ET-1), MCP-1 and Chromogranin-A (CGA) were measured before and three months after ablation completed with clinical follow-up with respect to AF recurrence. Additionally, we examined 40 healthy age- and sex-matched volunteers as a reference. RESULTS: Symptomatic AF patients showed increased levels of ET-1 compared to healthy controls (2.62pg/ml vs. 1.57pg/ml; p<0.01). Baseline levels of ET-1 were higher in patients presenting with AF after PVI (2.96pg/ml vs. 2.57pg/ml;p = 0.02). The temporal comparison revealed decreased ET-1 levels in patients without (2.57pg/ml vs. 2.33pg/ml; p<0.01) and unchanged ET-1 levels in patients with AF after PVI. Baseline MCP-1 was increased in AF patients vs. controls (268pg/ml vs. 227 pg/ml; p = 0.03). Both groups, with and without AF after PVI, showed an increase of MCP-1 compared to baseline (268pg/ml vs. 349pg/ml;p<0.01; 281pg/ml vs. 355pg/ml;p = 0.03). CGA was lower in AF patients compared to healthy controls (13.8ng/ml vs. 25.6ng/ml;p<0.01). Over time patients without AF after PVI showed an increase of CGA (14.2ng/ml vs. 20.7ng/ml;p<0.01). No change was observed in patients with AF after PVI. CONCLUSION: Our study demonstrated dysregulated levels of ET-1, MCP-1 and CGA in symptomatic AF patients. We could demonstrate an association between ET-1 to presence or absence of AF. Furthermore, we could show that a decrease of ET-1 as well as an increase of CGA after PVI, representing a trend towards control cohort levels, were both associated with restoration of sinus rhythm. These results provide new insights into the role of stress-related biomarkers in AF and AF treatment by ablation therapy.

Genotype-phenotype dilemma in a case of sudden cardiac death with the E1053K mutation and a deletion in the SCN5A gene.

Mutations in the cardiac sodium channel gene SCN5A may result in various arrhythmia syndromes such as long QT syndrome type 3 (LQTS), Brugada syndrome (BrS), sick sinus syndrome (SSS), cardiac conduction diseases (CCD) and possibly dilated cardiomyopathy (DCM). In most of these inherited cardiac arrhythmia syndromes the phenotypical expression may range from asymptomatic phenotypes to sudden cardiac death (SCD). A 16-year-old female died during sleep. Autopsy did not reveal any explanation for her death and a genetic analysis was performed. A variant in the SCN5A gene (E1053K) that was previously described as disease causing was detected. Family members are carriers of the same E1053K variant, some even in a homozygous state, but surprisingly did not exhibit any pathological cardiac phenotype. Due to the lack of genotype-phenotype correlation further genetic studies were performed. A novel deletion in the promoter region of SCN5A was identified in the sudden death victim but was absent in other family members. These findings demonstrate the difficulties in interpreting the results of a family-based genetic screening and underline the phenotypic variability of SCN5A mutations.

Safety and efficacy in ablation of premature ventricular contraction: data from the German ablation registry.

BACKGROUND: Patients with frequent premature ventricular contractions (PVCs) are often highly symptomatic with significantly reduced quality-of-life. We evaluated the outcome and success of PVC ablation in patients in the German Ablation Registry. METHODS: The German Ablation Registry is a nationwide prospective multicenter database of patients who underwent an ablation procedure, initiated by the "Stiftung Institut für Herzinfarktforschung" (IHF), Ludwigshafen, Germany. Data were acquired from March 2007 to May 2011. Patients underwent PVC ablation in the enrolling ablation centers. RESULTS: A total of 408 patients (age 53.5 ± 15 years, 55 % female) undergoing ablation for PVCs were included. 32 % of patients showed a co-existing structural heart disease. Acute ablation success of the procedure was 82 % in the overall patient group. In patients without structural heart disease, acute success was significantly higher compared with patients with structural heart disease (86 vs. 74 %, p = 0.002). All patients were discharged alive after a median of 3 days. No patient suffered an acute myocardial infarction, stroke, or major bleeding. After 12 months' follow-up, 99 % of patients were still alive showing a significant different mortality between patients with structural heart disease compared with those without (2.3 vs. 0 %, p = 0.012). In addition, 76 % of patients showed significantly improved symptoms after 12 months of follow-up. CONCLUSION: Based on the data from this registry, ablation of PVCs is a safe and efficient procedure with an excellent outcome and improved symptoms after 12 months.

Remote monitoring of implantable cardioverter-defibrillators. Problems and implications using a telemonitoring system.

The rising number of implantable devices has led to an increase in device-related workload, e.g., regular interrogation follow-up visits. Telemonitoring systems for implantable cardioverter-defibrillators (ICDs) seem to be a promising tool for reducing workload and costs, and they have the potential of optimizing patient care. However, issues such as practical functionality of ICD telemonitoring in daily routine may affect its broad implementation. The objective of this study was to evaluate potential problems during the implementation of a telemonitoring system, Medtronic CareLink™ (CL™) with respect to the installation and data transmission process. A total of 159 patients with ICDs who were equipped with the CL™ system were evaluated and followed up for 16 months regarding the success rate of the first data transmission via the telemonitoring system. In this cohort, a high rate of nontransmission of 23.9 % was observed after the 16-month follow-up. A detailed interview of these patients (no transmission) revealed that the main reasons for failed transmissions were due to the patients' loss of interest in the concept (approximately 50 %) as well as technical problems (approximately 25 %) with setting up the system. These results indicate that telemonitoring systems bear potential problems and that the evaluation of patient motivation and technical support options seems to play an important role in establishing the functionality of these systems.

[Magnetic resonance imaging of hypertrophic cardiomyopathy : evaluation of diastolic function]. / MRT-Bildgebung bei hypertropher Kardiomyopathie (HCM) : Evaluation der diastolischen Funktion.

Hypertrophic cardiomyopathy (HCM) has a prevalence of approximately 0.2% and is clinically asymptomatic in many patients or presents with unspecific symptoms. This explains the importance of imaging for the diagnosis of HCM as well as for the assessment of the clinical course. The definitive finding in HCM is myocardial hypertrophy with thickening of the ventricular wall ≥ 15 mm. While echocardiography is an excellent screening tool magnetic resonance imaging (MRI) allows a comprehensive analysis of the heart in HCM. This includes a detailed analysis of the distribution and extent of myocardial hypertrophy, a thorough evaluation of systolic and diastolic cardiac function, the assessment of the presence and extent of dynamic outflow tract obstruction as well as the description of the systolic anterior motion (SAM) phenomenon of the mitral valve with secondary mitral insufficiency. When contrast material is administered, additional information about myocardial perfusion as well as the presence and extent of myocardial fibrosis can be obtained. This study compared systolic functional parameters as well as end systolic and end diastolic wall thickness of patients with and without diastolic dysfunction.

[Molecular mechanisms of atrial fibrillation: potential role of microRNAs as new therapeutic targets and potential biomarkers]. / Molekulare Mechanismen von Vorhofflimmern: Potenzielle Rolle der microRNAs als neues therapeutisches Ziel und als möglicher Biomarker.

Atrial fibrillation represents the most common form of clinical arrhythmia in daily routine. However, current therapeutic options are still limited and a better understanding of the underlying molecular mechanisms is expected to contribute to the development of new therapeutic strategies. The scientific field of microRNA research has received a lot of attention in recent years, especially regarding cardiovascular research. This article gives a brief overview of the most recent developments in microRNA research in the field of atrial fibrillation and atrial remodelling processes. Furthermore, the clinical perspective of microRNAs as new therapeutic targets and as potential biomarkers is discussed.

[A rest or arrest--asystolic episodes of 7 seconds in a 22-year-old athlete]. / 22-jähriger Sportler mit Sinusarrest und Pausen bis 7 Sekunden.

A 22-year-old athlete with nocturnal asymptomatic episodes of transient sinus arrest/sinoatrial block up to 7.3 s and recurrent inappropriate sinus tachycardias which had been incidentally found during Holter electrocardiography diagnostics is presented. In spite of extensive diagnostic work-up including invasive procedures like coronary angiography and electrophysiological study, no causal etiology was found. Based on the normal findings and the lack of symptoms, we decided not to implant a permanent pacemaker. After 14 months, the patient is still asymptomatic. Howerver, the 24-h Holter electrocardiography shows unchanged frequency of nocturnal transient sinus arrest episodes.

Mortality due to myocardial infarction in the Bavarian population during World Cup Soccer 2006.

BACKGROUND: Previously, we had demonstrated that the World Cup Soccer 2006 provoked levels of emotional stress sufficient to increase the incidence of acute cardiovascular events. We sought to assess whether mortality was also increased as a result. METHOD: We analyzed daily data on mortality due to myocardial infarction (MI) and total mortality using data from the Bavarian State Office for Statistics. We retrospectively assessed study periods from 2006, 2005 and 2003. Quasi-Poisson regression with a log link to model the number of daily deaths was used. To be able to account for a possible delay, we also fitted a cubic distributed lag quasi-Poisson model for both 1 and 2 weeks post-exposure. RESULTS: A total of 6,699 deaths due to MI were investigated. No increase in death was found on days of World Cup matches either with or without German participation compared to the matched control periods. In addition, none of the analyses showed a significant effect of the (lagged) exposure to the risk period. Likewise, total mortality rates remained unchanged over the entire period of our analysis. CONCLUSION: During World Cup Soccer, the number of deaths due to myocardial infarction was not measurably increased compared to a matched control period. Thus, we could not demonstrate a translation of a stress-induced increase of cardiac morbidity into a noticeable increase in mortality. However, our findings are based on a public mortality registry, which may be flawed in many ways, regarding ascertainment of causes of death, in particular.

[Multimorbidity and successful aging: the population-based KORA-Age study]. / Multimorbidität und erfolgreiches Altern: Ein Blick auf die Bevölkerung im Rahmen der KORA-Age-Studie.

BACKGROUND: The objective of the KORA-Age research consortium is to assess the determinants and consequences of multimorbidity in the elderly and to look into reasons for successful aging in the general public. PATIENTS AND METHODS: In the KORA-Age cohort study 9,197 persons were included who where born in the year 1943 or before and participants of previous KORA cohort studies conducted between 1984 and 2001 (KORA: Cooperative Health Research in the Region of Augsburg). The randomized intervention study KORINNA (Coronary infarct follow-up treatment in the elderly) tested a nurse-based case management program with 338 patients with myocardial infarct and included an evaluation in health economics. RESULTS: A total of 2,734 deaths were registered, 4,565 participants submitted a postal health status questionnaire and 4,127 participants were interviewed by telephone (response 76.2% and 68.9% respectively). A gender and age-stratified random sample of the cohort consisting of 1,079 persons took part in a physical examination (response 53.8%). CONCLUSION: The KORA-Age consortium was able to collect data in a large population-based sample and is contributing to the understanding of multimorbidity and successful aging.

Static and Dynamic Electrocardiographic Patterns Preceding Torsades de Pointes in the Acquired and Congenital Long QT Syndrome.

The arrhythmogenic mechanisms involved in the triggering of the polymorphic ventricular tachycardia called torsades de pointes (TdPs) remains to be elucidated. In this work, we investigated the static and dynamic profiles of the repolarization interval from the surface electrocardiogram recorded in healthy individuals and in cardiac patients with TdPs. We implemented this analysis just prior to the arrhythmia onset and we computed the delta values based on baseline periods (1 hour prior to event). We measured QT/QTc prolongation, QT variability, ventricular ectopic beats (VPBs) frequency, T-wave amplitude, T-peak to T-end interval, and T-wave complexcity. The analysis of these parameters in reference to baseline revealed 1) an increased QTc variability, 2) the presence of VPCs, and 3) the profound changes in T-loop morphology in patients developing TdPs.

[64-year old patient with tachycardia and signs of heart failure]. / 64-jähriger Patient mit Herzrasen und Zeichen einer Herzinsuffizienz.

We report on a 64-year old patient with known Morbus Osler and high cardiac output failure due to distinct arterio-venous malformations of the liver. Since the patient suffered from severe right heart insufficiency despite optimized medical therapy, we decided to conduct an interventional occlusion of the hepatic shunts in three single sessions. The transient elevation of transaminases was reversible. After interventional therapy cardiac output decreased from 20 l/min to 15 l/min (25%) leading to a reduction of diuretic dosage and a sustained stabilization of the clinical condition.

Polymorphisms in the cardiac sodium channel promoter displaying variant in vitro expression activity.

Variable transcription of the cardiac sodium channel gene is a candidate mechanism determining arrhythmia susceptibility. We have previously cloned and characterized the core promoter and flanking region of SCN5A, encoding the cardiac sodium channel. Loss-of-function mutations in this gene have been reported in approximately 20% of patients with Brugada syndrome, an inherited cardiac electrical disorder associated with a high incidence of life-threatening arrhythmias. In this study, we identified DNA variants in the proximal 2.8 kb promoter region of SCN5A and determined their frequency in 1,121 subjects. This population consisted of 88 Brugada syndrome patients with no SCN5A coding region mutation, and 1,033 anonymized subjects from various ethnicities. Variant promoter activity was assayed in CHO cells and neonatal cardiomyocytes by transient transfection of promoter-reporter constructs. Single-nucleotide polymorphisms (SNPs) were identified at approximately 1/200 base pairs which are: 11 in the 5'-flanking region, 1 in exon 1, and 5 in intron 1. In addition, a haplotype consisting of two SNPs in complete linkage disequilibrium was identified. Minor allele frequencies were >5% in at least one ethnic panel at 5/19 polymorphic sites. In vitro functional analysis in cardiomyocytes identified four variants with significantly (P<0.05) reduced reporter activity (up to 63% reduction). The largest changes were seen with c.-225-1790 G>A, which reduced reporter activity by 62.8% in CHO cells and 55% in cardiomyocytes. From these results, we can conclude that the SCN5A core promoter includes multiple DNA polymorphisms with altered in vitro activity, further supporting the concept of interindividual variability in transcription of this cardiac ion channel gene.

[Genetics of atrial fibrillation: rare mutations, common variants and clinical relevance?]. / Genetik von Vorhofflimmern: seltene Mutationen, häufige Genvarianten und klinische Relevanz?

Atrial fibrillation (AF) is considered the, by far, the most common arrhythmia of man, affecting millions of patients worldwide. The high socio-economic relevance is due to several severe complications and therefore requires profound scientific research in the field of etiology and treatment options. Atrial fibrillation typically occurs in the older patient who often suffers from a number of underlying diseases that act as predisposing factors. That genetics contribute strongly to this rhythm disorder is therefore not evident at a first glance. However, there are a number of investigations that prove familial accumulation for lone AF. Furthermore it is remarkable that many older patients suddenly develop atrial fibrillation without underlying disease, while others remain in sinus rhythm although suffering from a series of risk factors. Considering all this, genetic interference becomes most probable. Therefore in the recent past remarkable endeavours have been ventured to clarify the genetic basis of both lone AF and AF in the context of underlying diseases. For the former, until now four different genetic loci and three disease genes have been identified as causative. Concerning AF in the general population, mainly studies turning the spotlight on single-nucleotide polymorphisms (SNPs) have been applied. It is assumed that SNPs in disease-causing genes are distributed differentially among healthy and diseased individuals. These differences in frequency have been investigated with case-control studies. Up to now six different genes have been found to be associated with AF, including the genes for angiotensin-converting enzyme, angiotensinogen and several cardiac ion channels. Promising new technologies, especially high-throughput SNP genotyping and the genome wide scan for new candidate genes using chip arrays capable of genotyping up to 500 000 SNPs at a time, will multiply the speed to achieve new results. With that the possibility, approaches to optimize existing therapies and to open up new pathways to treat AF.

Acute respiratory distress syndrome with transiently impaired left ventricular function and Torsades de Pointes arrhythmia unmasking congenital long QT syndrome in a 25-yr-old woman.

We report a case of recurrent episodes of Torsades de Pointes arrhythmia in the setting of transiently impaired left ventricular ejection fraction, acute respiratory distress syndrome, transient hypokalaemia and QT-prolonging drugs, in a previously healthy 25-yr-old female patient. In the course of the clinical and genetic work-up this patient was newly diagnosed with a mutation in KCNH2 encoding the alpha-subunit of the human repolarizing potassium channel I(Kr). This case report illustrates the multivariate nature of long-QT syndrome, and emphasizes the usefulness of a pharmacological test for repolarization abnormalities.

Long QT syndrome. Why does sex matter?

There is increased awareness of the extent to which cardiac function is influenced by gender. One of the most dramatic and potentially lethal differences is that seen in cardiac repolarization reflected in the QT interval of the surface ECG. Gender differences in QT and QTc intervals have been observed to change during the lifetime in the general population. These differences can be explained to a large extent by sex hormone driven differences in gene expression of myocardial ion channels. Numerous studies have shown that women's risk to suffer arrhythmias in the context of QT prolonging drugs is doubled compared to men. For familial long QT syndrome there is no conclusive evidence for gender effects with respect to disease onset or mortality. Only subgroup analysis by genotype demonstrated a higher risk in female patients carrying mutations in the LQT2 locus. Special attention should be given to drug-induced QT prolongation in women.

Bioinformatics for medical diagnostics: assessment of microarray data in the context of clinical databases.

MOTIVATION: To identify genes suitable for medical diagnostics microarray data is assessed in the context of clinical databases, which store complex information about the patient phenotype. The wealth of data and lacking standards make it difficult to analyse this kind of data. RESULTS: We present a workflow for exploratory analysis of microarray data together with clinical data consisting of four steps: definition of clinically meaningful research questions in a masterfile, generation of analysis files, selection and characterization of differentially expressed genes, and estimation of classification accuracy. We applied this workflow to large data sets from the field of cardiology and oncology (n~500 patients). Systematic data management of microarray data and clinical data helps to make results more transparent and comparable.

Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure.

The high incidence of sudden death in heart failure may reflect an increased propensity to abnormal repolarization and long Q-T interval-related arrhythmias. If so, cells from failing hearts would logically be expected to exhibit a heightened susceptibility to early afterdepolarizations (EAD). We found that midmyocardial ventricular cells isolated from dogs with pacing-induced heart failure exhibited an increased action potential duration and many more EAD than cells from nonpaced controls; this was the case both under basal conditions (P < 0.01) and after lowering external K(+) concentration ([K(+)](o)) to 2 mM and exposing cells to cesium (3 mM; P < 0.05). An unexpected finding was the occurrence of spontaneous depolarizations (SD, >5 mV) from the resting potential that were not coupled to prior action potentials. These SD were observed in 20% of failing cells (n = 5 of 25) under basal ionic conditions but in none of the normal cells (n = 0 of 27, P < 0.05). The net inward current that underlies SD is not triggered by Ca(2+) oscillations and thus differs fundamentally from the currents that underlie delayed afterdepolarizations. We conclude that cardiomyopathic canine ventricular cells are intrinsically predisposed to EAD and SD. Because EAD have been linked to the pathogenesis of torsade de pointes, our results support the hypothesis that sudden death in heart failure often arises from abnormalities of repolarization. The frequent occurrence of SD points to a novel cellular mechanism for abnormal automaticity in heart failure.