PET/CT-identified atrial hypermetabolism is an index of atrial inflammation in patients with atrial fibrillation.

BACKGROUND: Although atrial inflammation has been implicated in the pathophysiology of atrial fibrillation (AF), the identification of atrial inflammation remains challenging. We aimed to establish a positron emission tomography/computed tomography (PET/CT) protocol with 18Fluor-labeled fluorodeoxyglucose (18F-FDG) for the detection of atrial hypermetabolism as surrogate for inflammation in AF. METHODS: We included n = 75 AF and n = 75 non-AF patients undergoing three common PET/CT protocols (n = 25 per group) optimized for the detection of (a) inflammation and (b) malignancy in predefined fasting protocols, and (c) cardiac viability allowing for maximized glucose uptake. 18F-FDG-uptake was analyzed in predefined loci. RESULTS: Differences of visual atrial uptake in AF vs non-AF patients were observed in fasting (inflammation [13/25 vs 0/25] and malignancy [10/25 vs 0/25]) protocols while viability protocols showed non-specific uptake in both the groups. In the inflammation protocol, AF patients showed higher uptake in the right atrium [(SUVmax: 2.5 ± .7 vs 2.0 ± .7, P = .01), atrial appendage (SUVmax: 2.4 ± .7 vs 2.0 ± .6, P = .03), and epicardial adipose tissue (SUVmax: 1.4 ± .5 vs 1.1 ± .4, P = .04)]. Malignancy and viability protocols failed to differentiate between AF and non-AF. CONCLUSION: Glucose uptake suppression protocols appear suitable in detecting differential atrial 18F-FDG uptake between AF and non-AF patients. Imaging-based assessment of inflammation might help to stratify AF patients offering individualized therapeutic approaches.

Role of catheter location on local impedance measurements and clinical outcome with the new direct sense technology in cardiac ablation procedures.

Background: A novel catheter technology (direct sense, DS) enables periprocedural local impedance (LI) measurement for estimation of tissue contact during radiofrequency ablation (RFA) for real-time assessment of lesion generation. This measure reflects specific local myocardial conduction properties in contrast to the established global impedance (GI) using a neutral body electrode. Our study aimed to assess representative LI values for the cardiac chambers, to evaluate LI drop in response to RF delivery and to compare those values to established GI measures in patients undergoing RFA procedures. Methods and Results: Seventy-three patients undergoing RFA with the DS technology were included. Within the cardiac chambers, baseline LI was significantly different, with the highest values in the left atrium (LA 107.5 ± 14.3 Ω; RV 104.6 Ω ± 12.9 Ω; LV 100.7 Ω ± 11.7 Ω, and RA 100.5 Ω ± 13.4 Ω). Baseline LI was positively correlated to the corresponding LI drop during RF delivery (R2 = 0.26, p = 0.01) representing a promising surrogate of lesion generation. The observed mean LI drop (15.6 ± 9.5 Ω) was threefold higher as GI drop (4.9 ± 7.4 Ω), p < 0.01. We evaluated the clinical outcome in a subgroup of patients undergoing DS-guided pulmonary vein isolation, which was comparable regarding arrhythmia recurrence to a conventional ablation cohort (57 % vs 50 %, p = 0.2). Conclusion: We provide detailed information on LI measures in electrophysiological procedures with significant differences within the cardiac chambers highlighting that RFA-related LI drop can serve as a promising surrogate for real-time assessment of lesion generation. Guiding the electrophysiologist in RFA procedures, this additional information promises to improve safety profile and success rates in the interventional treatment of arrhythmias.

Ectopic expression of S28A-mutated Histone H3 modulates longevity, stress resistance and cardiac function in Drosophila.

Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo, we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress. Morphological and functional analysis of heart tubes revealed smaller luminal areas and thicker walls accompanied by moderately improved cardiac function after acute stress induction. Whole-exome deep gene-sequencing from isolated heart tubes revealed phenotype-corresponding changes in longevity-promoting and myotropic genes. We also found changes in genes controlling mitochondrial biogenesis and respiration. Analysis of mitochondrial respiration from whole flies revealed improved efficacy of ATP production with reduced electron transport-chain activity. Finally, we analyzed posttranslational modification of H3S28 in an experimental heart failure model and observed increased H3S28 phosphorylation levels in HF hearts. Our data establish a critical role of H3S28 phosphorylation in vivo for life span, stress resistance, cardiac and mitochondrial function in Drosophila. These findings may pave the way for H3S28 phosphorylation as a putative target to treat stress-related disorders such as heart failure.

Current controversies in determining the main mechanisms of atrial fibrillation.

Despite considerable basic research into the mechanisms of atrial fibrillation (AF), not much progress has been made in the prognosis of patients with AF. With the exception of anticoagulant therapy, current treatments for AF still do not improve major cardiovascular outcomes. This may be due partly to the diverse aetiology of AF with increasingly more factors found to contribute to the arrhythmia. In addition, a strong increase has been seen in the technological complexity of the methods used to quantify the main pathophysiological alterations underlying the initiation and progression of AF. Because of the lack of standardization of the technological approaches currently used, the perception of basic mechanisms of AF varies widely in the scientific community. Areas of debate include the role of Ca(2+) -handling alterations associated with AF, the contribution and noninvasive assessment of the degree of atrial fibrosis, and the best techniques to identify electrophysiological drivers of AF. In this review, we will summarize the state of the art of these controversial topics and describe the diverse approaches to investigating and the scientific opinions on leading AF mechanisms. Finally, we will highlight the need for transparency in scientific reporting and standardization of terminology, assumptions, algorithms and experimental conditions used for the development of better AF therapies.

An update on atrial fibrillation in 2014: From pathophysiology to treatment.

Atrial fibrillation (AF) is the most frequently encountered cardiac arrhythmia. The trigger for initiation of AF is generally an enhanced vulnerability of pulmonary vein cardiomyocyte sleeves to either focal or re-entrant activity. The maintenance of AF is based on a "driver" mechanism in a vulnerable substrate. Cardiac mapping technology is providing further insight into these extremely dynamic processes. AF can lead to electrophysiological and structural remodelling, thereby promoting the condition. The management includes prevention of stroke by oral anticoagulation or left atrial appendage (LAA) occlusion, upstream therapy of concomitant conditions, and symptomatic improvement using rate control and/or rhythm control. Nonpharmacological strategies include electrical cardioversion and catheter ablation. There are substantial geographical variations in the management of AF, though European data indicate that 80% of patients receive adequate anticoagulation and 79% adequate rate control. High rates of morbidity and mortality weigh against perceived difficulties in management. Clinical research and growing experience are helping refine clinical indications and provide better technical approaches. Active research in cardiac electrophysiology is producing new antiarrhythmic agents that are reaching the experimental clinical arena, inhibiting novel ion channels. Future research should give better understanding of the underlying aetiology of AF and identification of drug targets, to help the move toward patient-specific therapy.

[Cardiovascular pharmacotherapy. Risks and adverse effects]. / Kardiovaskuläre Pharmakotherapie. Risiken und Nebenwirkungen.

Adverse side effects of drugs are a significantly underestimated problem in modern medicine. In this review article, we summarize common adverse side effects of cardiovascular drugs. In particular, we highlight the factors promoting these adverse side effects in patients, including reduced hepatic or renal clearance in elderly patients that often requires dosage adjustment. Pharmacodynamic and pharmacokinetic interactions between drugs (e.g. through the cytochrome P450 system or P-glycoproteins) can modify the plasma concentration of many compounds, thereby also increasing the likelihood of unwanted side effects. The most prominent cardiac side effects include arrhythmias, e.g. atrioventricular (AV) block, drug-induced long-QT syndrome and torsade de pointes and altered inotropy. Non-cardiac side effects are subsequently discussed grouped by drug class. A better understanding of the risks and side effects of cardiovascular drugs is expected to reduce the mortality and morbidity associated with adverse side effects.

Transverse tubules are a common feature in large mammalian atrial myocytes including human.

Transverse (t) tubules are surface membrane invaginations that are present in all mammalian cardiac ventricular cells. The apposition of L-type Ca(2+) channels on t tubules with the sarcoplasmic reticulum (SR) constitutes a "calcium release unit" and allows close coupling of excitation to the rise in systolic Ca(2+). T tubules are virtually absent in the atria of small mammals, and therefore Ca(2+) release from the SR occurs initially at the periphery of the cell and then propagates into the interior. Recent work has, however, shown the occurrence of t tubules in atrial myocytes from sheep. As in the ventricle, Ca(2+) release in these cells occurs simultaneously in central and peripheral regions. T tubules in both the atria and the ventricle are lost in disease, contributing to cellular dysfunction. The aim of this study was to determine if the occurrence of t tubules in the atrium is restricted to sheep or is a more general property of larger mammals including humans. In atrial tissue sections from human, horse, cow, and sheep, membranes were labeled using wheat germ agglutinin. As previously shown in sheep, extensive t-tubule networks were present in horse, cow, and human atrial myocytes. Analysis shows half the volume of the cell lies within 0.64 ± 0.03, 0.77 ± 0.03, 0.84 ± 0.03, and 1.56 ± 0.19 µm of t-tubule membrane in horse, cow, sheep, and human atrial myocytes, respectively. The presence of t tubules in the human atria may play an important role in determining the spatio-temporal properties of the systolic Ca(2+) transient and how this is perturbed in disease.

Pathology-specific effects of the IKur/Ito/IK,ACh blocker AVE0118 on ion channels in human chronic atrial fibrillation.

BACKGROUND AND PURPOSE: This study was designed to establish the pathology-specific inhibitory effects of the IKur/Ito/IK,ACh blocker AVE0118 on atrium-selective channels and its corresponding effects on action potential shape and effective refractory period in patients with chronic AF (cAF). EXPERIMENTAL APPROACH: Outward K+-currents of right atrial myocytes and action potentials of atrial trabeculae were measured with whole-cell voltage clamp and microelectrode techniques, respectively. Outward currents were dissected by curve fitting. KEY RESULTS: Four components of outward K+-currents and AF-specific alterations in their properties were identified. Ito was smaller in cAF than in SR, and AVE0118 (10 microM) apparently accelerated its inactivation in both groups without reducing its amplitude. Amplitudes of rapidly and slowly inactivating components of IKur were lower in cAF than in SR. The former was abolished by AVE0118 in both groups, the latter was partially blocked in SR, but not in cAF, even though its inactivation was apparently accelerated in cAF. The large non-inactivating current component was similar in magnitude in both groups, but decreased by AVE0118 only in SR. AVE0118 strongly suppressed AF-related constitutively active IK,ACh and prolonged atrial action potential and effective refractory period exclusively in cAF. CONCLUSIONS AND IMPLICATIONS: In atrial myocytes of cAF patients, we detected reduced function of distinct IKur components that possessed decreased component-specific sensitivity to AVE0118 most likely as a consequence of AF-induced electrical remodelling. Inhibition of profibrillatory constitutively active IK,ACh may lead to pathology-specific efficacy of AVE0118 that is likely to contribute to its ability to convert AF into SR.

[New antiarrhythmic drugs for therapy of atrial fibrillation: I. Ion channel blockers]. / Neue Antiarrhythmika in der Therapie des Vorhofflimmerns--I. Ionenkanalblocker.

During the last ten years we have made substantial progress in our understanding of the underlying mechanisms of atrial fibrillation. The high rate associated alterations in electrical and structural properties of the atria, referred to as atrial remodeling, promote the progression of atrial fibrillation. The development of new therapeutic approaches addresses three different directions: (i) prevention of atrial remodeling, especially of structural remodeling; (ii) increase of long-term efficacy of currently used drugs and improvement of their side-effect profile; and (iii) design of atria- and pathology-specific antiarrhythmic drugs without concomitant proarrhythmic effects in the ventricles. The current review outlines the pathophysiology of atrial fibrillation and focuses on electrical remodeling. The properties of new antiarrhythmic drugs for atrial fibrillation are discussed in detail.

[New antiarrhythmic drugs for therapy of atrial fibrillation: II. Non-ion channel blockers]. / Neue Antiarrhythmika in der Therapie des Vorhofflimmerns--II. Nicht-Ionenkanalblocker.

The therapeutic approach to atrial fibrillation is difficult and challenging. The effect of "classical" antiarrhythmic agents is based on their inhibitory effects on various ion channels. However, therapeutic benefit of these agents is often limited. The primary goal of this article is to discuss new therapeutic approaches using non-ion channel blocking drugs in the treatment of atrial fibrillation. Some of the substances discussed in this article have been used already in the clinical practice. Others, for example gentherapeutic approaches, are still in the experimental state. In contrast to ion channel blocking agents their efficacy is based on the suppression of structural remodeling. Hence, it can be assumed that due to these effects they may also be beneficial in the primary prevention of atrial fibrillation.

The G protein-gated potassium current I(K,ACh) is constitutively active in patients with chronic atrial fibrillation.

BACKGROUND: The molecular mechanism of increased background inward rectifier current (IK1) in atrial fibrillation (AF) is not fully understood. We tested whether constitutively active acetylcholine (ACh)-activated I(K,ACh) contributes to enhanced basal conductance in chronic AF (cAF). METHODS AND RESULTS: Whole-cell and single-channel currents were measured with standard voltage-clamp techniques in atrial myocytes from patients with sinus rhythm (SR) and cAF. The selective I(K,ACh) blocker tertiapin was used for inhibition of I(K,ACh). Whole-cell basal current was larger in cAF than in SR, whereas carbachol (CCh)-activated I(K,ACh) was lower in cAF than in SR. Tertiapin (0.1 to 100 nmol/L) reduced I(K,ACh) in a concentration-dependent manner with greater potency in cAF than in SR (-logIC50: 9.1 versus 8.2; P<0.05). Basal current contained a tertiapin-sensitive component that was larger in cAF than in SR (tertiapin [10 nmol/L]-sensitive current at -100 mV: cAF, -6.7+/-1.2 pA/pF, n=16/5 [myocytes/patients] versus SR, -1.7+/-0.5 pA/pF, n=24/8), suggesting contribution of constitutively active I(K,ACh) to basal current. In single-channel recordings, constitutively active I(K,ACh) was prominent in cAF but not in SR (channel open probability: cAF, 5.4+/-0.7%, n=19/9 versus SR, 0.1+/-0.05%, n=16/9; P<0.05). Moreover, IK1 channel open probability was higher in cAF than in SR (13.4+/-0.4%, n=19/9 versus 11.4+/-0.7%, n=16/9; P<0.05) without changes in other channel characteristics. CONCLUSIONS: Our results demonstrate that larger basal inward rectifier K+ current in cAF consists of increased IK1 activity and constitutively active I(K,ACh). Blockade of I(K,ACh) may represent a new therapeutic target in AF.

Teaching antiarrhythmic therapy and ECG in simulator-based interdisciplinary undergraduate medical education.

BACKGROUND: Third-year students in the Dresden Medical School Programme undergo a 6 week course 'Basics of Drug Therapy' in a problem-based learning curriculum. As part of this course a practical seminar about antiarrhythmic drugs and ECG was set up. This study was conducted to evaluate the use of a simulator in this course. METHODS: A total of 234 students were randomly allocated to receive instructions with (Group S) or without (Group C [control]) the use of a simulator. After a lecture on antiarrhythmic drugs, arrhythmias were presented to Group S using an advanced life support (ALS) manikin. The students were asked to administer a drug or to defibrillate, and the outcome was shown on the monitor. The students in Group C were presented with ECG charts without a simulator. The course was evaluated by a questionnaire and multiple-choice questions (MCQ) about arrhythmias. RESULTS: We received 222 questionnaires. The content-time ratio was rated almost perfect in both groups, but the students in Group S rated the course better suited to link theory and practice. Students in Group S considered the simulator helpful and a good tool for teaching, and the extra effort to be worthwhile. A significantly higher number of students in Group S preferred electric cardioversion as therapy for ventricular tachycardia. CONCLUSIONS: An ALS manikin can be an effective tool in teaching clinical pharmacology.

Simple two-electrode biosignal amplifier.

A simple, cost effective circuit for a two-electrode non-differential biopotential amplifier is proposed. It uses a 'virtual ground' transimpedance amplifier and a parallel RC network for input common mode current equalisation, while the signal input impedance preserves its high value. With this innovative interface circuit, a simple non-inverting amplifier fully emulates high CMRR differential. The amplifier equivalent CMRR (typical range from 70-100 dB) is equal to the open loop gain of the operational amplifier used in the transimpedance interface stage. The circuit has very simple structure and utilises a small number of popular components. The amplifier is intended for use in various two-electrode applications, such as Holter-type monitors, defibrillators, ECG monitors, biotelemetry devices etc.

L-type Ca2+ current downregulation in chronic human atrial fibrillation is associated with increased activity of protein phosphatases.

BACKGROUND: Although downregulation of L-type Ca2+ current (I(Ca,L)) in chronic atrial fibrillation (AF) is an important determinant of electrical remodeling, the molecular mechanisms are not fully understood. Here, we tested whether reduced I(Ca,L) in AF is associated with alterations in phosphorylation-dependent channel regulation. METHODS AND RESULTS: We used whole-cell voltage-clamp technique and biochemical assays to study regulation and expression of I(Ca,L) in myocytes and atrial tissue from 148 patients with sinus rhythm (SR) and chronic AF. Basal I(Ca,L) at +10 mV was smaller in AF than in SR (-3.8+/-0.3 pA/pF, n=138/37 [myocytes/patients] and -7.6+/-0.4 pA/pF, n=276/86, respectively; P<0.001), though protein levels of the pore-forming alpha1c and regulatory beta2a channel subunits were not different. In both groups, norepinephrine (0.01 to 10 micromol/L) increased I(Ca,L) with a similar maximum effect and comparable potency. Selective blockers of kinases revealed that basal I(Ca,L) was enhanced by Ca2+/calmodulin-dependent protein kinase II in SR but not in AF. Norepinephrine-activated I(Ca,L) was larger with protein kinase C block in SR only, suggesting decreased channel phosphorylation in AF. The type 1 and type 2A phosphatase inhibitor okadaic acid increased basal I(Ca,L) more effectively in AF than in SR, which was compatible with increased type 2A phosphatase but not type 1 phosphatase protein expression and higher phosphatase activity in AF. CONCLUSIONS: In AF, increased protein phosphatase activity contributes to impaired basal I(Ca,L). We propose that protein phosphatases may be potential therapeutic targets for AF treatment.

Two-electrode low supply voltage electrocardiogram signal amplifier.

Portable biomedical instrumentation has become an important part of diagnostic and treatment instrumentation, including telemedicine applications. Low-voltage and low-power design tendencies prevail. Modern battery cell voltages in the range of 3-3.6 V require appropriate circuit solutions. A two-electrode biopotential amplifier design is presented, with a high common-mode rejection ratio (CMRR), high input voltage tolerance and standard first-order high-pass characteristic. Most of these features are due to a high-gain first stage design. The circuit makes use of passive components of popular values and tolerances. Powered by a single 3 V source, the amplifier tolerates +/- 1 V common mode voltage, +/- 50 microA common mode current and 2 V input DC voltage, and its worst-case CMRR is 60 dB. The amplifier is intended for use in various applications, such as Holter-type monitors, defibrillators, ECG monitors, biotelemetry devices etc.