Intermittent atrial tachycardia promotes repolarization alternans and conduction slowing during rapid rates, and increases susceptibility to atrial fibrillation in a free-behaving sheep model.

INTRODUCTION: Paroxysmal atrial fibrillation (AF) may be triggered by intermittent atrial tachycardia, and ultimately lead to persistent AF. However, the mechanisms by which intermittent atrial tachycardia promotes sustained AF are not well understood. METHODS AND RESULTS: Eight sheep were chronically implanted with 2 pacemakers for the recording of broadband right atrial unipolar electrograms, and for the delivery of electrophysiological stimulation protocols and intermittent right atrial tachycardia. Right atrial kinetics of activation recovery interval (ARI) as a surrogate for action potential duration, of conduction time and velocity, and of repolarization alternans were analyzed at incremental pacing rates during the remodeling process induced by weeks of intermittent atrial tachycardia until the development of sustained AF. Intermittent atrial tachycardia decreased ARI and blunted its rate adaptation, facilitated atrial capture, and slowed conduction at high rates, and increased susceptibility to pacing-induced AF. In spite of blunted ARI rate adaptation, right atrial repolarization alternans was maintained during remodeling, and further increased in magnitude just before rapid pacing-induced AF. CONCLUSION: This study suggests that weeks of intermittent right atrial tachycardia result in a gradual electrical remodeling favorable for wavebreaks and reentry that may facilitate fibrillation.

Analyses of a novel SCN5A mutation (C1850S): conduction vs. repolarization disorder hypotheses in the Brugada syndrome.

AIMS: Brugada syndrome (BrS) is characterized by arrhythmias leading to sudden cardiac death. BrS is caused, in part, by mutations in the SCN5A gene, which encodes the sodium channel alpha-subunit Na(v)1.5. Here, we aimed to characterize the biophysical properties and consequences of a novel BrS SCN5A mutation. METHODS AND RESULTS: SCN5A was screened for mutations in a male patient with type-1 BrS pattern ECG. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in HEK293 cells. Sodium currents (I(Na)) were analysed using the whole-cell patch-clamp technique at 37 degrees C. The electrophysiological effects of the mutation were simulated using the Luo-Rudy model, into which the transient outward current (I(to)) was incorporated. A new mutation (C1850S) was identified in the Na(v)1.5 C-terminal domain. In HEK293 cells, mutant I(Na) density was decreased by 62% at -20 mV. Inactivation of mutant I(Na) was accelerated in a voltage-dependent manner and the steady-state inactivation curve was shifted by 11.6 mV towards negative potentials. No change was observed regarding activation characteristics. Altogether, these biophysical alterations decreased the availability of I(Na). In the simulations, the I(to) density necessary to precipitate repolarization differed minimally between the two genotypes. In contrast, the mutation greatly affected conduction across a structural heterogeneity and precipitated conduction block. CONCLUSION: Our data confirm that mutations of the C-terminal domain of Na(v)1.5 alter the inactivation of the channel and support the notion that conduction alterations may play a significant role in the pathogenesis of BrS.

Activation of Transient Receptor Potential Canonical 3 (TRPC3)-mediated Ca2+ Entry by A1 Adenosine Receptor in Cardiomyocytes Disturbs Atrioventricular Conduction.

Although the activation of the A(1)-subtype of the adenosine receptors (A(1)AR) is arrhythmogenic in the developing heart, little is known about the underlying downstream mechanisms. The aim of this study was to determine to what extent the transient receptor potential canonical (TRPC) channel 3, functioning as receptor-operated channel (ROC), contributes to the A(1)AR-induced conduction disturbances. Using embryonic atrial and ventricular myocytes obtained from 4-day-old chick embryos, we found that the specific activation of A(1)AR by CCPA induced sarcolemmal Ca(2+) entry. However, A(1)AR stimulation did not induce Ca(2+) release from the sarcoplasmic reticulum. Specific blockade of TRPC3 activity by Pyr3, by a dominant negative of TRPC3 construct, or inhibition of phospholipase Cs and PKCs strongly inhibited the A(1)AR-enhanced Ca(2+) entry. Ca(2+) entry through TRPC3 was activated by the 1,2-diacylglycerol (DAG) analog OAG via PKC-independent and -dependent mechanisms in atrial and ventricular myocytes, respectively. In parallel, inhibition of the atypical PKCζ by myristoylated PKCζ pseudosubstrate inhibitor significantly decreased the A(1)AR-enhanced Ca(2+) entry in both types of myocytes. Additionally, electrocardiography showed that inhibition of TRPC3 channel suppressed transient A(1)AR-induced conduction disturbances in the embryonic heart. Our data showing that A(1)AR activation subtly mediates a proarrhythmic Ca(2+) entry through TRPC3-encoded ROC by stimulating the phospholipase C/DAG/PKC cascade provide evidence for a novel pathway whereby Ca(2+) entry and cardiac function are altered. Thus, the A(1)AR-TRPC3 axis may represent a potential therapeutic target.

New measurements of radial velocities in clusters of galaxies

Redshifts for 100 galaxies in 10 clusters of galaxies are presented based on data obtained between March 1984 and March 1985 from Calar Alto, La Palma, and ESO, and on data from Mauna Kea. Data for individual galaxies are given, and the accuracy of the velocities of the four instruments is discussed. Comparison with published data shows the present velocities to be shifted by + 4.0 km/s on average, with a standard deviation in the difference of 89.7 km/s, consistent with the rms of redshift measurements which range from 50-100 km/s.

Conduction mechanisms and charge storage in Si-nanocrystals metal-oxide-semiconductor memory devices studied with conducting atomic force microscopy

In this work, we demonstrate that conductive atomic force microscopy (C-AFM) is a very powerful tool to investigate, at the nanoscale, metal-oxide-semiconductor structures with silicon nanocrystals (Si-nc) embedded in the gate oxide as memory devices. The high lateral resolution of this technique allows us to study extremely small areas ( ~ 300nm2) and, therefore, the electrical properties of a reduced number of Si-nc. C-AFM experiments have demonstrated that Si-nc enhance the gate oxide electrical conduction due to trap-assisted tunneling. On the other hand, Si-nc can act as trapping centers. The amount of charge stored in Si-nc has been estimated through the change induced in the barrier height measured from the I-V characteristics. The results show that only ~ 20% of the Si-nc are charged, demonstrating that the electrical behavior at the nanoscale is consistent with the macroscopic characterization.

Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

A Heterozygous Deletion Mutation in the Cardiac Sodium Channel Gene SCN5A with Loss- and Gain-of-Function Characteristics Manifests as Isolated Conduction Disease, without Signs of Brugada or Long QT Syndrome.

BACKGROUND: The SCN5A gene encodes for the α-subunit of the cardiac sodium channel NaV1.5, which is responsible for the rapid upstroke of the cardiac action potential. Mutations in this gene may lead to multiple life-threatening disorders of cardiac rhythm or are linked to structural cardiac defects. Here, we characterized a large family with a mutation in SCN5A presenting with an atrioventricular conduction disease and absence of Brugada syndrome. METHOD AND RESULTS: In a large family with a high incidence of sudden cardiac deaths, a heterozygous SCN5A mutation (p.1493delK) with an autosomal dominant inheritance has been identified. Mutation carriers were devoid of any cardiac structural changes. Typical ECG findings were an increased P-wave duration, an AV-block I° and a prolonged QRS duration with an intraventricular conduction delay and no signs for Brugada syndrome. HEK293 cells transfected with 1493delK showed strongly (5-fold) reduced Na(+) currents with altered inactivation kinetics compared to wild-type channels. Immunocytochemical staining demonstrated strongly decreased expression of SCN5A 1493delK in the sarcolemma consistent with an intracellular trafficking defect and thereby a loss-of-function. In addition, SCN5A 1493delK channels that reached cell membrane showed gain-of-function aspects (slowing of the fast inactivation, reduction in the relative fraction of channels that fast inactivate, hastening of the recovery from inactivation). CONCLUSION: In a large family, congregation of a heterozygous SCN5A gene mutation (p.1493delK) predisposes for conduction slowing without evidence for Brugada syndrome due to a predominantly trafficking defect that reduces Na(+) current and depolarization force.

Internal and external fluctuations around nonequilibrium steady states in one-dimensional heat-conduction problems

Thermal fluctuations around inhomogeneous nonequilibrium steady states of one-dimensional rigid heat conductors are analyzed in the framework of generalized fluctuating hydrodynamics. The effect of an external source of noise is also considered. External fluctuations come from temperature and position fluctuations of the source. Contributions of each kind of noise to the temperature correlation function are computed and compared through the study of its asymptotic behavior.

Note on seismic hazard assessment using gradient of uplift velocities on the Turan Block (Central Asia)

Uplift gradients can provide the location of highly strained zones, which can be considered to be seismic. The Turan block (Central Asia) contains zones with high gradient of uplift velocities, above the threshold 0.04mm km-1year-1. Some of these zones are associated with important seismic activity and others are not correlated with any recent important recorded earthquakes, however, recent faults scarps as well as diverted rivers may indicate a recent tectonic activity. This threshold of gradient is probably a significant rheologic property of the upper crust. On the basis of these considerations the Uzboy river area is proposed as a potential high seismic hazard zone.

Specific inhibition of HCN channels slows rhythm differently in atria, ventricle and outflow tract and stabilizes conduction in the anoxic-reoxygenated embryonic heart model.

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are expressed in pacemaker cells very early during cardiogenesis. This work aimed at determining to what extent these channels are implicated in the electromechanical disturbances induced by a transient oxygen lack which may occur in utero. Spontaneously beating hearts or isolated ventricles and outflow tracts dissected from 4-day-old chick embryos were exposed to a selective inhibitor of HCN channels (ivabradine 0.1-10microM) to establish a dose-response relationship. The effects of ivabradine on electrocardiogram, excitation-contraction coupling and contractility of hearts submitted to anoxia (30min) and reoxygenation (60min) were also determined. The distribution of the predominant channel isoform, HCN4, was established in atria, ventricle and outflow tract by immunoblotting. Intrinsic beating rate of atria, ventricle and outflow tract was 164+/-22 (n=10), 78+/-24 (n=8) and 40+/-12bpm (n=23, mean+/-SD), respectively. In the whole heart, ivabradine (0.3microM) slowed the firing rate of atria by 16% and stabilized PR interval. These effects persisted throughout anoxia-reoxygenation, whereas the variations of QT duration, excitation-contraction coupling and contractility, as well as the types and duration of arrhythmias were not altered. Ivabradine (10microM) reduced the intrinsic rate of atria and isolated ventricle by 27% and 52%, respectively, whereas it abolished activity of the isolated outflow tract. Protein expression of HCN4 channels was higher in atria and ventricle than in the outflow tract. Thus, HCN channels are specifically distributed and control finely atrial, ventricular and outflow tract pacemakers as well as conduction in the embryonic heart under normoxia and throughout anoxia-reoxygenation.

Functional and morphological evidence for a ventricular conduction system in zebrafish and Xenopus hearts.

Zebrafish and Xenopus have become popular model organisms for studying vertebrate development of many organ systems, including the heart. However, it is not clear whether the single ventricular hearts of these species possess any equivalent of the specialized ventricular conduction system found in higher vertebrates. Isolated hearts of adult zebrafish (Danio rerio) and African toads (Xenopus laevis) were stained with voltage-sensitive dye and optically mapped in spontaneous and paced rhythms followed by histological examination focusing on myocardial continuity between the atrium and the ventricle. Spread of the excitation wave through the atria was uniform with average activation times of 20 +/- 2 and 50 +/- 2 ms for zebrafish and Xenopus toads, respectively. After a delay of 47 +/- 8 and 414 +/- 16 ms, the ventricle became activated first in the apical region. Ectopic ventricular activation was propagated significantly more slowly (total ventricular activation times: 24 +/- 3 vs. 14 +/- 2 ms in zebrafish and 74 +/- 14 vs. 35 +/- 9 ms in Xenopus). Although we did not observe any histologically defined tracts of specialized conduction cells within the ventricle, there were trabecular bands with prominent polysialic acid-neural cell adhesion molecule staining forming direct myocardial continuity between the atrioventricular canal and the apex of the ventricle; i.e., the site of the epicardial breakthrough. We thus conclude that these hearts are able to achieve the apex-to-base ventricular activation pattern observed in higher vertebrates in the apparent absence of differentiated conduction fascicles, suggesting that the ventricular trabeculae serve as a functional equivalent of the His-Purkinje system.

P-wave velocities of samples from the Penninic of the western Alps along NFP20-west seismic-reflection profiles

Using the transit pulse method, we have determined compressional wave velocities of rocks from various geological units belonging to the Penninic zone along the NFP20-West profiles of the Swiss western Alps. The velocities have been measured at confining pressures up to 400 MPa, along three orthogonal axes defined by the macrostructure of the rocks. The samples analysed show a degree of metamorphism ranging from greenschist to eclogite facies. This collection includes schists, dolomites, gneisses and ophiolitic rocks. The mean velocities range from 5.9 km/s for a quartzitic calcschist to 7.9 km/s for an eclogitic metagabbro. The velocity anisotropy is as high as 20 %. The range of acoustic impedance is wide, from 15 to 27 10(6) kg/m2s. From these measurements, normal incident reflection coefficients for likely rock assemblages within and between geological units were estimated in order to interpret zone of the strong reflections recorded along the seismic profiles. Reflection coefficients as high as 0.17 could be determined.

Interpretation of lesions of the cardiac conduction system in cocaine-related fatalities.

This study examines cases of chronic drug users who died suddenly after drug administration. Victims were young subjects, aged from 19 to 35 from Switzerland and known to the police as long-term drug users. The circumstances of death suggested the occurrence of a sudden, unexpected death. Some victims were undergoing methadone treatment. In each case, a forensic autopsy and toxicological analyses were performed at the Institute of Forensic Medicine in Lausanne in Switzerland between 2002 and 2004, including hair analysis as a means to establish chronic drug use in general, and cocaine use in particular. The conduction system was examined histologically and cases showing potentially lethal changes were chosen for this report. The most frequent lesions found were severe thickening of the atrioventricular node artery, intranodal and perinodal fibrosis, and microscopic foci of chronic inflammatory infiltration. The authors conclude that pathological lesions in the conduction tissue may play a role in the occurrence of death attributed to intoxication consecutive to cocaine ingestion.