Coxsackie and adenovirus receptor is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia.

OBJECTIVES: The aim of this study was to investigate the modulatory effect of the coxsackie and adenovirus receptor (CAR) on ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. BACKGROUND: A heritable component in the risk of ventricular fibrillation during myocardial infarction has been well established. A recent genome-wide association study of ventricular fibrillation during acute myocardial infarction led to the identification of a locus on chromosome 21q21 (rs2824292) in the vicinity of the CXADR gene. CXADR encodes the CAR, a cell adhesion molecule predominantly located at the intercalated disks of the cardiomyocyte. METHODS: The correlation between CAR transcript levels and rs2824292 genotype was investigated in human left ventricular samples. Electrophysiological studies and molecular analyses were performed using CAR haploinsufficient (CAR(+/-)) mice. RESULTS: In human left ventricular samples, the risk allele at the chr21q21 genome-wide association study locus was associated with lower CXADR messenger ribonucleic acid levels, suggesting that decreased cardiac levels of CAR predispose to ischemia-induced ventricular fibrillation. Hearts from CAR(+/-) mice displayed slowing of ventricular conduction in addition to an earlier onset of ventricular arrhythmias during the early phase of acute myocardial ischemia after ligation of the left anterior descending artery. Expression and distribution of connexin 43 were unaffected, but CAR(+/-) hearts displayed increased arrhythmia susceptibility on pharmacological electrical uncoupling. Patch-clamp analysis of isolated CAR(+/-) myocytes showed reduced sodium current magnitude specifically at the intercalated disk. Moreover, CAR coprecipitated with NaV1.5 in vitro, suggesting that CAR affects sodium channel function through a physical interaction with NaV1.5. CONCLUSIONS: CAR is a novel modifier of ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Genetic determinants of arrhythmia susceptibility (such as CAR) may constitute future targets for risk stratification of potentially lethal ventricular arrhythmias in patients with coronary artery disease

A diet rich in unsaturated fatty acids prevents progression toward heart failure in a rabbit model of pressure and volume overload

Background-During heart failure (HF), cardiac metabolic substrate preference changes from fatty acid (FA) toward glucose oxidation. This change may cause progression toward heart failure. We hypothesize that a diet rich in FAs may prevent this process, and that dietary 3-FAs have an added antiarrhythmic effect based on action potential (AP) shortening in animals with HF. Methods and Results-Rabbits were fed a diet containing 1.25% (w/w) high oleic sunflower oil (HF-9, N 11), 1.25% fish oil (HF-3, N11), or no supplement (HF-control, N8). Subsequently, HF was induced by volume and pressure overload. After 4 months, HF-parameters were assessed, electrocardiograms were recorded, and blood and ventricular tissue were collected. Myocytes were isolated for patch clamp or intracellular Ca2-recordings to study electrophysiologic remodeling and arrhythmogenesis. Both the HF-9 and the HF-3 groups had larger myocardial FA oxidation capacity than HF control. The HF-3 group had significantly lower mean ( SEM) relative heart and lung weight (3.3-0.13 and 3.2-0.12 g kg 1, respectively) than HF control (4.8-0.30 and 4.5-0.23), and shorter QTc intervals (167-2.6 versus 182-6.4). The HF-9 also displayed a significantly reduced relative heart weight (3.6-0.26), but had similar QTc (179-4.3) compared with HF control. AP duration in the HF-3 group was 20% shorter due to increased Ito1 and IK1 and triggered activity, and Ca2-aftertransients were less than in the HF-9 group. Conclusions-Dietary unsaturated FAs started prior to induction of HF prevent hypertrophy and HF. In addition, fish oil FAs prevent HF-induced electrophysiologic remodeling and arrhythmias. © 2012 American Heart Association, Inc

Enhanced absorption Hanle effect on the Fg=F->Fe=F+1 closed transitions

We analyse the Hanle effect on a closed $F_g\to F_e=F_g+1$ transition. Two configurations are examined, for linear- and circular-polarized laser radiation, with the applied magnetic field collinear to the laser light wavevector. We describe the peculiarities of the Hanle signal for linearly-polarized laser excitation, characterized by narrow bright resonances at low laser intensities. The mechanism behind this effect is identified, and numerical solutions for the optical Bloch equations are presented for different transitions.Comment: to be published in J. Opt. B, special issue on Quantum Coherence and Entanglement (February 2001

Collective dynamics of liquid aluminum probed by Inelastic X-ray Scattering

An inelastic X-ray scattering experiment has been performed in liquid aluminum with the purpose of studying the collective excitations at wavevectors below the first sharp diffraction peak. The high instrumental resolution (up to 1.5 meV) allows an accurate investigation of the dynamical processes in this liquid metal on the basis of a generalized hydrodynamics framework. The outcoming results confirm the presence of a viscosity relaxation scenario ruled by a two timescale mechanism, as recently found in liquid lithium.Comment: 8 pages, 7 figure

Random Scattering by Atomic Density Fluctuations in Optical Lattices

We investigate hitherto unexplored regimes of probe scattering by atoms trapped in optical lattices: weak scattering by effectively random atomic density distributions and multiple scattering by arbitrary atomic distributions. Both regimes are predicted to exhibit a universal semicircular scattering lineshape for large density fluctuations, which depend on temperature and quantum statistics.Comment: 4 pages, 2 figure

The cardiac sodium channel displays differential distribution in the conduction system and transmural heterogeneity in the murine ventricular myocardium

Cardiac sodium channels are responsible for conduction in the normal and diseased heart. We aimed to investigate regional and transmural distribution of sodium channel expression and function in the myocardium. Sodium channel Scn5a mRNA and Na(v)1.5 protein distribution was investigated in adult and embryonic mouse heart through immunohistochemistry and in situ hybridization. Functional sodium channel availability in subepicardial and subendocardial myocytes was assessed using patch-clamp technique. Adult and embryonic (ED14.5) mouse heart sections showed low expression of Na(v)1.5 in the HCN4-positive sinoatrial and atrioventricular nodes. In contrast, high expression levels of Na(v)1.5 were observed in the HCN4-positive and Cx43-negative AV or His bundle, bundle branches and Purkinje fibers. In both ventricles, a transmural gradient was observed, with a low Na(v)1.5 labeling intensity in the subepicardium as compared to the subendocardium. Similar Scn5a mRNA expression patterns were observed on in situ hybridization of embryonic and adult tissue. Maximal action potential upstroke velocity was significantly lower in subepicardial myocytes (mean +/- SEM 309 +/- 32 V/s; n = 14) compared to subendocardial myocytes (394 +/- 32 V/s; n = 11; P < 0.05), indicating decreased sodium channel availability in subepicardium compared to subendocardium. Scn5a and Na(v)1.5 show heterogeneous distribution patterns within the cardiac conduction system and across the ventricular wall. This differential distribution of the cardiac sodium channel may have profound consequences for conduction disease phenotypes and arrhythmogenesis in the setting of sodium channel diseas

Self-restoration of cardiac excitation rhythm by anti-arrhythmic ion channel gating

Homeostatic regulation protects organisms against hazardous physiological changes. However, such regulation is limited in certain organs and associated biological processes. For example, the heart fails to self-restore its normal electrical activity once disturbed, as with sustained arrhythmias. Here we present proof-of-concept of a biological self-restoring system that allows automatic detection and correction of such abnormal excitation rhythms. For the heart, its realization involves the integration of ion channels with newly designed gating properties into cardiomyocytes. This allows cardiac tissue to i) discriminate between normal rhythm and arrhythmia based on frequency-dependent gating and ii) generate an ionic current for termination of the detected arrhythmia. We show in silico, that for both human atrial and ventricular arrhythmias, activation of these channels leads to rapid and repeated restoration of normal excitation rhythm. Experimental validation is provided by injecting the designed channel current for arrhythmia termination in human atrial myocytes using dynamic clamp

Quantum-state control in optical lattices

We study the means to prepare and coherently manipulate atomic wave packets in optical lattices, with particular emphasis on alkali atoms in the far-detuned limit. We derive a general, basis independent expression for the lattice operator, and show that its off-diagonal elements can be tailored to couple the vibrational manifolds of separate magnetic sublevels. Using these couplings one can evolve the state of a trapped atom in a quantum coherent fashion, and prepare pure quantum states by resolved-sideband Raman cooling. We explore the use of atoms bound in optical lattices to study quantum tunneling and the generation of macroscopic superposition states in a double-well potential. Far-off-resonance optical potentials lend themselves particularly well to reservoir engineering via well controlled fluctuations in the potential, making the atom/lattice system attractive for the study of decoherence and the connection between classical and quantum physics.Comment: 35 pages including 8 figures. To appear in Phys. Rev. A. March 199

Atrial-like cardiomyocytes from human pluripotent stem cells are a robust preclinical model for assessing atrial-selective pharmacology

Drugs targeting atrial-specific ion channels, K(v)1.5 or K(ir)3.1/3.4, are being developed as new therapeutic strategies for atrial fibrillation. However, current preclinical studies carried out in non-cardiac cell lines or animal models may not accurately represent the physiology of a human cardiomyocyte (CM). In the current study, we tested whether human embryonic stem cell (hESC)-derived atrial CMs could predict atrial selectivity of pharmacological compounds. By modulating retinoic acid signaling during hESC differentiation, we generated atrial-like (hESC-atrial) and ventricular-like (hESC-ventricular) CMs. We found the expression of atrial-specific ion channel genes, KCNA5 (encoding Kv1.5) and KCNJ3 (encoding K-ir 3.1), in hESC-atrial CMs and further demonstrated that these ion channel genes are regulated by COUP-TF transcription factors. Moreover, in response to multiple ion channel blocker, vernakalant, and K(v)1.5 blocker, XEN-D0101, hESC-atrial but not hESC-ventricular CMs showed action potential (AP) prolongation due to a reduction in early repolarization. In hESC-atrial CMs, XEN-R0703, a novel K(ir)3.1/3.4 blocker restored the AP shortening caused by CCh. Neither CCh nor XEN-R0703 had an effect on hESC-ventricular CMs. In summary, we demonstrate that hESC-atrial CMs are a robust model for pre-clinical testing to assess atrial selectivity of novel antiarrhythmic drugs