[Patients with a wearable cardioverter-defibrillator (WCD) : Prescription, function and rehabilitation support]. / Patienten mit einer tragbaren Defibrillatorweste ("wearable cardioverter-defibrillator", WCD) : Verschreibung, Wirkweise und Nachsorge.

Assessment of a permanent risk of life-threatening ventricular arrhythmia in patients with severely reduced left ventricular ejection fraction (LVEF <35%), e. g. after myocarditis, dilated cardiomyopathy, acute myocardial infarction, in patients with postpartum cardiomyopathy or implantable cardioverter-defibrillator (ICD) and cardiac resynchronization treatment plus defibrillator (CRT-D) infection with temporary explantation of the system is a medical challenge. This is time-consuming and unsafe because life-threatening ventricular arrhythmias may occur during the time of risk assessment. During this phase of risk stratification, a wearable cardioverter-defibrillator (WCD) is indicated. The WCD, which is usually worn by the patient for several months, combines continuous retrievable electrocardiogram (ECG) recordings with a reliable defibrillation capability. The prescription of a WCD guarantees safe rehabilitation procedures for patients following acute inpatient treatment. Rehabilitation measures in patients with a WCD are indicated because of the underlying systolic cardiac insufficiency due to severe myocardial disease. In almost half of the patients, who are potentially threatened by ventricular tachyarrhythmias or sudden cardiac death (SCD), the LVEF and heart failure symptoms improve under controlled medication within a few months. Thus, the risk of SCD is lowered so that in many cases a first line ICD implantation is no longer necessary. The purpose of this article is to provide recommendations for rehabilitation procedures of patients with a WCD. A review of the currently available data on WCD publications was carried out with special emphasis on the current national and international guidelines.

WCD LifeVest: risk stratification in a case of Tako-Tsubo cardiomyopathy with QT interval prolongation.

A 50-year-old woman with arterial hypertension suffered from recurrent syncope. On admission, recurrent torsades de pointes tachycardia, ventricular flutter, and ventricular fibrillation with the necessity of cardiopulmonary resuscitation were documented. After administration of ß-blocking agents, amiodarone, and magnesium, heart rhythm was stabilized. Coronary angiography excluded coronary artery disease. Echocardiography revealed apical ballooning with reduced ventricular function. The ECG showed left bundle-branch block and profound QT prolongation. A WCD (wearable cardioverter-defibrillator) LifeVest was prescribed for the patient, and, thereafter, no arrhythmias were experienced. The ECG gradually normalized; echocardiography revealed slight anteroapical hypokinesia with overall normal left ventricular function. After a period of 3 months, the patient was no longer asked to wear the LifeVest; 6 months later the patient is without any complaints.

Cardiac involvement in limb-girdle muscular dystrophy 2I : conventional cardiac diagnostic and cardiovascular magnetic resonance.

BACKGROUND: The C826A mutation in the fukutin-related protein (FKRP) gene is typically associated with autosomal recessive limb-girdle muscular dystrophy 2I (LGMD2I) but oligosymptomatic phenotypes and patients with predominant cardiac involvement are also described. OBJECTIVE: To assess cardiac involvement in patients with LGMD2I. PATIENTS: Nine patients from 5 families (2 female, 7 male) homozygous for the 826C > A FKRP mutation were included. METHODS: Additional to conventional cardiac investigations (electrocardiography and echocardiography) the patients underwent cardiovascular magnetic resonance imaging (CMR). RESULTS/CONCLUSION: Cardiac involvement was detected by CMR in eight of nine patients (reduced left ventricular ejection fraction in 6, enlargement of left ventricular end-diastolic volume in 2 and left ventricular mass in 2) and in four patients by conventional cardiac diagnostic investigations. Two of the nine patients showed no muscle weakness or atrophy but suffered myalgias; both had cardiac manifestation of the disease. CMR is a sensitive method for detecting cardiac abnormalities in patients with LGMD2I and can be used for early detection of mild or subclinical cardiac involvement.

Regulation of angiotensin II receptor subtypes during atrial fibrillation in humans.

BACKGROUND: Previous studies have suggested that atrial fibrillation (AF) is associated with the activation of the atrial angiotensin system. However, it is not known whether the expression of angiotensin II receptors changes during AF. The purpose of this study was to determine the atrial expression of angiotensin II type 1 and type 2 receptors (AT(1)-R and AT(2)-R) in patients with AF. METHODS AND RESULTS: Atrial tissue samples from 30 patients undergoing open heart surgery were examined. Eleven patients had chronic persistent AF (> or =6 months; cAF), 8 patients had paroxysmal AF (pAF), and 11 patients were in sinus rhythm. AT(1)-R and AT(2)-R were localized in the atrial tissue by immunohistochemistry and quantified at the protein and mRNA level by Western blotting and quantitative polymerase chain reaction. Both types of AT-R were predominantly expressed in atrial myocytes in all groups. The amount of AT(1)-R was reduced to 34.9% during cAF (P<0.01) and to 51.7% during pAF (P<0.05) compared with patients in sinus rhythm. In contrast, AT(2)-R was increased during cAF (246%; P=NS) and pAF (505%; P<0.01). AT(1)-R/AT(2)-R mRNA content was similar in all groups. CONCLUSIONS: AF is associated with the down-regulation of atrial AT(1)-R and the up-regulation of AT(2)-R proteins. These findings may help define the pathophysiological role of the angiotensin system in the structural remodeling of the fibrillating atria.

Increased expression of extracellular signal-regulated kinase and angiotensin-converting enzyme in human atria during atrial fibrillation.

OBJECTIVES: The purpose of this study was to determine whether atrial expression of the extracellular signal-regulated kinases Erk1/Erk2 and of the angiotensin-converting enzyme (ACE) is altered in patients with atrial fibrillation (AF). BACKGROUND: Recent studies have demonstrated that atrial fibrosis can provide a pathophysiologic substrate for AF. However, the molecular mechanisms responsible for the development of atrial fibrosis are unclear. METHODS: Atrial tissue samples of 43 patients undergoing open heart surgery were examined. Seventeen patients had chronic persistent AF (> or =6 months; CAF), 8 patients had paroxysmal AF (PAF) and 18 patients had no history of AF. Erk expression was analyzed at the mRNA (quantitative reverse transcription polymerase chain reaction), the protein (immunoblot techniques) and atrial tissue (immunohistochemistry) levels. Erk-activating kinases (MEK1/2) and ACE were analyzed by immunoblot techniques. RESULTS: Increased amounts of Erk2-mRNA were found in patients with CAF (75 +/- 20 U vs. sinus rhythm: 31 +/- 25 U; p < 0.05). Activated Erk1/Erk2 and MEK1/2 were increased to more than 150% in patients with AF compared to patients with sinus rhythm. No differences between CAF and PAF were found. The expression of ACE was three-fold increased during CAF. Amounts of activated Erk1/Erk2 were reduced in patients treated with ACE inhibitors. Patients with AF showed an increased expression of Erk1/Erk2 in interstitial cells and marked atrial fibrosis. CONCLUSIONS: An ACE-dependent increase in the amounts of activated Erk1/Erk2 in atrial interstitial cells may contribute as a molecular mechanism for the development of atrial fibrosis in patients with AF. These findings may have important impact on the treatment of AF.

Non-invasive assessment of fibrillatory activity in patients with paroxysmal and persistent atrial fibrillation using the Holter ECG.

OBJECTIVE: Automatic analysis of the frequency content of the fibrillatory baseline on the surface ECG accurately reflects the average rate of atrial fibrillation (AF). This frequency measurement correlates with the behavior of AF and predicts the response to administration of ibutilide, a new antiarrhythmic drug. Neither the temporal pattern of fibrillatory frequency in spontaneous paroxysmal or persistent AF, nor its response to chronic antiarrhythmic medication has been studied so far. METHODS AND RESULTS: Holter ECG recordings were made in 20 patients during AF. One minute ECG segments were selected for analysis. The frequency content of the fibrillatory baseline was then quantified using digital signal processing. After high-pass filtering, the QRST complexes were subtracted using a template matching algorithm. The resulting fibrillatory baseline signal was subjected to Fourier transformation, displayed as a frequency power spectrum and the peak frequency (f) was determined. In 11 patients (7 male, 4 female, age 62 +/- 10 years) 31 paroxysmal AF episodes were analyzed. Duration ranged from 1 min to 665 min (115 +/- 175 min). Initial mean peak f measured 5.1 +/- 0.7 Hz (range 3.9 to 6.9 Hz). There was a positive correlation between f and AF duration (R = 0.53, p = 0.002). AF of less than 15 min duration (n = 13) showed a lower f (4.8 +/- 0.6 Hz) when compared with longer lasting episodes (n = 18, 5.3 +/- 0.7 Hz, p = 0.03). In short AF episodes f was constant, whereas in longer-lasting episodes f increased to 5.8 +/- 0.5 Hz (p < 0.001) within 5 min. In 9 patients (9 male, age 58 +/- 8 years) with persistent AF oral antiarrhythmic drugs (amiodarone n = 5, sotalol n = 3, flecainide n = 1) were given prior to electrical cardioversion for prophylaxis of AF recurrence. Frequency measurements were obtained at baseline and 3 to 5 days after initiation of drug administration. At baseline mean f measured 6.9 +/- 0.4 Hz. Frequency was reduced by antiarrhythmic drugs to 5.8 +/- 0.4 Hz (p < 0.001). CONCLUSIONS: (1) The duration of paroxysmal AF episodes can be predicted using spectral analysis of ECG recordings of AF episodes. (2) An increase in fibrillatory frequency is associated with AF persistence. (3) This technique can be used to monitor the response to antiarrhythmic medication.

The MUSTT study: evaluating testing and treatment.

The multicenter unsustained tachycardia trial (MUSTT) tested the value of electrophysiologically guided antiarrhythmic drug therapy against no therapy in high risk coronary artery disease with poor left ventricular function (LV-EF

Perspectives: does amiodarone increase non-sudden deaths? If so, why?

Despite the antiarrhythmic efficacy of amiodarone, a definitive correlation between amiodarone treatment and increased non-arrhythmic mortality in patients with heart failure and depressed ventricular function has been reported. Results from research in the field of cardiac resynchronization therapy in heart failure may provide some explanations to this observation. We discussed the hypothetical link between amiodarone and non-arrhythmic mortality, which might have a cause--effect relationship, based on cardiac electromechanical disarrangement provoked by electrophysiological properties of amiodarone.

Case report: severe skin burn at the site of the indifferent electrode after radiofrequency catheter ablation of typical atrial flutter.

Although radiofrequency (RF) catheter ablation has been shown to be an effective treatment strategy in patients with supraventricular tachycardia, RF ablation may lead to potentially serious complications. We describe a case of a 65-year old man who was transferred for catheter ablation of typical atrial flutter. 21 RF applications (mean energy: 81+/-9 watts) were applied in the temperature-controlled mode (70 degrees C) between a 8-mm tip electrode and an indifferent electrode using a high-power RF generator (100 watts) until bi-directional atrial isthmus block was achieved. After the procedure, a third-degree skin burn (10x2 cm) was observed at the lateral edge of the adhesive indifferent electrode whereas the medial edge of the electrode was not fully attached to the skin surface. This case is one out of 1128 ablation procedures (0.09 %) at our institution using a high-power RF generator. The present study demonstrates a severe skin burn induced by mal-attachment of an indifferent electrode during RF ablation. Long RF energy application times, high-power settings, and heavy sedation may have contributed to the observed severity of skin damage.

The importance of right atrial pacing electrode position and pacing configuration for intra-atrial and inter-atrial conduction times.

Pace prevention of atrial tachyarrhythmias is based in part on the reduction of intra-atrial (IAA) and/or inter-atrial (IEA) conduction. We previously introduced a novel pacing mode using floating atrial ring electrodes on a VDD-lead (BIdirectional MO nophasic impulSe: BIMOS). The effects of BIMOS pacing on IAA and IEA conduction times has not been studied. In nine Merino sheep electrode catheters were placed at the His-Bundle (HBE), high right atrium (HRA), coronary sinus ostium (Cs-Os), and left lateral atrium (LLA). A VDD-lead was introduced with floating electrodes in the high and mid right atrium (Floating). IAA (S/P-HRA, S/P-Cs-Os, S/P-HBE, S/P-Floating), IEA conduction times (S/P-LLA), and P-wave duration (PD) were measured during sinus rhythm (S), during bipolar cathodal pacing (P) in the HRA, in the Cs-Os position, as well as during BIMOS floating pacing. The mean PD during S was significantly shorter than during HRA- (66. 6+/-12.8ms; vs. 116.2+/-11.1ms; p<0.05) and Cs-Os-P (66.6+/-12.8ms vs. 94.4+/-9.0ms; p<0.05). In comparison to HRA-P, BIMOS configuration lead to a significant reduction of the P-wave duration (116.2+/-11.1ms vs. 85. 4+/-8.8ms; p<0.05). During BIMOS pacing, the global atrial conduction time was significantly shorter than during pacing in the HRA and Cs-Os position. The results of this study demonstrate a clear reduction of IAA and IEA conduction times using BIMOS configurations compared to conventional HRA-P. Furthermore, BIMOS pacing produced a more homogeneous atrial activation when compared with conventional HRA- and Cs-Os-P.

Incidence of cutaneous vasoactivity in patients with anemia and pulmonary hypoxia.

BACKGROUND: In cutaneous laser Doppler flow (LDF)-recordings, various forms of flowmotion or vasoactivity can be observed. It is still a matter of dispute, whether flowmotion is a phenomenon of physiological or pathophysiological conditions. Therefore, we tested the hypothesis of increased vasoactivity being typical for patients with various degrees of acute and chronic anemia as well as with chronic obstructive pulmonary disease (COPD). PATIENTS AND METHODS: We examined 12 healthy controls, 14 patients with COPD with a PO2 below 60 mmHg, 16 patients with chronic and 7 patients with acute anemia with an Hb below 12 g/dl. We used a simple LDF-technique on the dorsum of the forefoot. The regularity of blood flow frequencies was determined by calculation of the coefficient of variation. RESULTS: Periods without vasoactivity (i.e. constant flow pattern) were 21% in normal controls, 7% in patients with COPD and 2% in patients with acute or chronic anemia. Mean frequencies in the four groups varied between 3.8 and 4.8 cpm, with significant changes only in the group with acute blood loss. However, vasoactivity was significantly more regular in the COPD- and anemia-groups as compared to normal controls, with coefficients of variation of 47.4% for controls, 31.8% for COPD- and 29.3% for chronic and 35.1% for acute anemia-patients. CONCLUSIONS: The present paper shows that cutaneous vasoactivity is more regular in the three examined clinical entities of systemic tissue hypo-oxygenation, i.e. chronic and acute anemia and severe COPD as compared to healthy control subjects. Therefore, we hypothesize that increased vasoactivity constitutes a regulatory defense mechanism in cases of reduced oxygenation, by improving microcirculatory blood flow distribution.

50 years of successfull human defibrillation. A history of continuing progress.

50 years ago, Claude Beck successfully performed the first cardiac defibrillation in a human. This was the beginning of a new era in cardiology as well as in general medicine. Today, defibrillation or cardioversion measures in the context of resuscitation or performed as an elective procedure is a well-established technique and every physician is familiar with it. However, 50 years ago when Beck saved the life of a 14 year old boy in the operating room, little was known about defibrillation and its therapy. This article is in memoriam of Claude Beck, who drawing the right conclusions from published experimental observations, did the right thing at the right time. The circumstances of the first human defibrillation are described and the theoretical and experimental framework available at that time is discussed.

Landscape of genetic lesions in 944 patients with myelodysplastic syndromes.

High-throughput DNA sequencing significantly contributed to diagnosis and prognostication in patients with myelodysplastic syndromes (MDS). We determined the biological and prognostic significance of genetic aberrations in MDS. In total, 944 patients with various MDS subtypes were screened for known/putative mutations/deletions in 104 genes using targeted deep sequencing and array-based genomic hybridization. In total, 845/944 patients (89.5%) harbored at least one mutation (median, 3 per patient; range, 0-12). Forty-seven genes were significantly mutated with TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 mutated in >10% of cases. Many mutations were associated with higher risk groups and/or blast elevation. Survival was investigated in 875 patients. By univariate analysis, 25/48 genes (resulting from 47 genes tested significantly plus PRPF8) affected survival (P<0.05). The status of 14 genes combined with conventional factors revealed a novel prognostic model ('Model-1') separating patients into four risk groups ('low', 'intermediate', 'high', 'very high risk') with 3-year survival of 95.2, 69.3, 32.8, and 5.3% (P<0.001). Subsequently, a 'gene-only model' ('Model-2') was constructed based on 14 genes also yielding four significant risk groups (P<0.001). Both models were reproducible in the validation cohort (n=175 patients; P<0.001 each). Thus, large-scale genetic and molecular profiling of multiple target genes is invaluable for subclassification and prognostication in MDS patients.

Multiple myeloma is affected by multiple and heterogeneous somatic mutations in adhesion- and receptor tyrosine kinase signaling molecules.

Multiple myeloma (MM) is a largely incurable plasma cell malignancy with a poorly understood and heterogeneous clinical course. To identify potential, functionally relevant somatic mutations in MM, we performed whole-exome sequencing of five primary MM, corresponding germline DNA and six MM cell lines, and developed a bioinformatics strategy that also integrated published mutational data of 38 MM patients. Our analysis confirms that identical, recurrent mutations of single genes are infrequent in MM, but highlights that mutations cluster in important cellular pathways. Specifically, we show enrichment of mutations in adhesion molecules of MM cells, emphasizing the important role for the interaction of the MM cells with their microenvironment. We describe an increased rate of mutations in receptor tyrosine kinases (RTKs) and associated signaling effectors, for example, in EGFR, ERBB3, KRAS and MAP2K2, pointing to a role of aberrant RTK signaling in the development or progression of MM. The diversity of mutations affecting different nodes of a particular signaling network appears to be an intrinsic feature of individual MM samples, and the elucidation of intra- as well as interindividual redundancy in mutations that affect survival pathways will help to better tailor targeted therapeutic strategies to the specific needs of the MM patient.

Molecular pathways of early CD105-positive erythroid cells as compared with CD34-positive common precursor cells by flow cytometric cell-sorting and gene expression profiling.

Special attention has recently been drawn to the molecular network of different genes that are responsible for the development of erythroid cells. The aim of the present study was to establish in detail the immunophenotype of early erythroid cells and to compare the gene expression profile of freshly isolated early erythroid precursors with that of the CD34-positive (CD34(+)) compartment. Multiparameter flow cytometric analyses of human bone marrow mononuclear cell fractions (n=20) defined three distinct early erythroid stages. The gene expression profile of sorted early erythroid cells was analyzed by Affymetrix array technology. For 4524 genes, a differential regulation was found in CD105-positive erythroid cells as compared with the CD34(+) progenitor compartment (2362 upregulated genes). A highly significant difference was observed in the expression level of genes involved in transcription, heme synthesis, iron and mitochondrial metabolism and transforming growth factor-ß signaling. A comparison with recently published data showed over 1000 genes that as yet have not been reported to be upregulated in the early erythroid lineage. The gene expression level within distinct pathways could be illustrated directly by applying the Ingenuity software program. The results of gene expression analyses can be seen at the Gene Expression Omnibus repository.

Targeted next-generation sequencing detects point mutations, insertions, deletions and balanced chromosomal rearrangements as well as identifies novel leukemia-specific fusion genes in a single procedure.

DNA sequence enrichment from complex genomic samples using microarrays enables targeted next-generation sequencing (NGS). In this study, we combined 454 shotgun pyrosequencing with long oligonucleotide sequence capture arrays. We demonstrate the detection of mutations including point mutations, deletions and insertions in a cohort of 22 patients presenting with acute leukemias and myeloid neoplasms. Importantly, this one-step methodological procedure also allowed the detection of balanced chromosomal aberrations, including translocations and inversions. Moreover, the genomic representation of only one of the partner genes of a chimeric fusion on the capture platform also permitted identification of the novel fusion partner genes. Using acute myeloid leukemias harboring RUNX1 abnormalities as a model system, three novel chromosomal fusion sequences and KCNMA1 as a novel RUNX1 fusion partner gene were detected. This assay has the strong potential to become an important method for the comprehensive genetic characterization of particular leukemias and other malignancies harboring complex genomes.

The Interlaboratory RObustness of Next-generation sequencing (IRON) study: a deep sequencing investigation of TET2, CBL and KRAS mutations by an international consortium involving 10 laboratories.

Massively parallel pyrosequencing allows sensitive deep sequencing to detect molecular aberrations. Thus far, data are limited on the technical performance in a clinical diagnostic setting. Here, we investigated as an international consortium the robustness, precision and reproducibility of amplicon next-generation deep sequencing across 10 laboratories in eight countries. In a cohort of 18 chronic myelomonocytic leukemia patients, mutational analyses were performed on TET2, a frequently mutated gene in myeloproliferative neoplasms. Additionally, hotspot regions of CBL and KRAS were investigated. The study was executed using GS FLX sequencing instruments and the small volume 454 Life Sciences Titanium emulsion PCR setup. We report a high concordance in mutation detection across all laboratories, including a robust detection of novel variants, which were undetected by standard Sanger sequencing. The sensitivity to detect low-level variants present with as low as 1-2% frequency, compared with the 20% threshold for Sanger-based sequencing is increased. Together with the output of high-quality long reads and fast run time, we demonstrate the utility of deep sequencing in clinical applications. In conclusion, this multicenter analysis demonstrated that amplicon-based deep sequencing is technically feasible, achieves high concordance across multiple laboratories and allows a broad and in-depth molecular characterization of cancer specimens with high diagnostic sensitivity.

[Chance for young electrophysiologists: the continuing education program "Fellowship heart rhythm"]. / Chance für junge Elektrophysiologen: Das Fortbildungsprogramm "Fellowship Herzrhythmus".

Increasing workloads, growing economical pressure and developments on the German job market for young physicians create a background which threatens an adequate education and training of physicians in many places. The"Fellowship heart rhythm" program focuses on training in clinical electrophysiology complementary to established educational initiatives, such as courses for competence in pacemaker and ICD therapy of the German Cardiac Society. Participants have to be residents with a minimum of 3 years clinical experience and should be younger than 36 years old. They should be actively involved with a long-term perspective in clinical electrophysiology. Activity in the fields of pacing, defibrillator and cardiac resynchronization therapy is required. The hospital has to be able provide the possibility of invasive electrophysiology and catheter ablation including a 3-dimensional mapping system. In 6 face-to-face meetings of 3 days each, the state of the art is presented in the topics electrophysiological studies, sudden cardiac death and defibrillation, health economy/management, catheter ablation, atrial fibrillation and heart failure and arrhythmias. The first 4 years with 2 fellowship programs have demonstrated that this project enables education at a high level, strongly supporting advances in scientific interest, individual development and medical orientation. The fellowship program facilitates the development of a network of young electrophysiologists in Germany.