Detection of focal source and arrhythmogenic substrate from body surface potentials to guide atrial fibrillation ablation

Focal sources (FS) are believed to be important triggers and a perpetuation mechanism for paroxysmal atrial fibrillation (AF). Detecting FS and determining AF sustainability in atrial tissue can help guide ablation targeting. We hypothesized that sustained rotors during FS-driven episodes indicate an arrhythmogenic substrate for sustained AF, and that non-invasive electrical recordings, like electrocardiograms (ECGs) or body surface potential maps (BSPMs), could be used to detect FS and AF sustainability. Computer simulations were performed on five bi-atrial geometries. FS were induced by pacing at cycle lengths of 120–270 ms from 32 atrial sites and four pulmonary veins. Self-sustained reentrant activities were also initiated around the same 32 atrial sites with inexcitable cores of radii of 0, 0.5 and 1 cm. FS fired for two seconds and then AF inducibility was tested by whether activation was sustained for another second. ECGs and BSPMs were simulated. Equivalent atrial sources were extracted using second-order blind source separation, and their cycle length, periodicity and contribution, were used as features for random forest classifiers. Longer rotor duration during FS-driven episodes indicates higher AF inducibility (area under ROC curve = 0.83). Our method had accuracy of 90.6±1.0% and 90.6±0.6% in detecting FS presence, and 93.1±0.6% and 94.2±1.2% in identifying AF sustainability, and 80.0±6.6% and 61.0±5.2% in determining the atrium of the focal site, from BSPMs and ECGs of five atria. The detection of FS presence and AF sustainability were insensitive to vest placement (±9.6%). On pre-operative BSPMs of 52 paroxysmal AF patients, patients classified with initiator-type FS on a single atrium resulted in improved two-to-three-year AF-free likelihoods (p-value < 0.01, logrank tests). Detection of FS and arrhythmogenic substrate can be performed from ECGs and BSPMs, enabling non-invasive mapping towards mechanism-targeted AF treatment, and malignant ectopic beat detection with likely AF progression.     

Protocol of a prospective study on the diagnostic value of transcranial duplex scanning of the substantia nigra in patients with parkinsonian symptoms

Background  

Parkinson's disease (PD) is the second most common neurodegenerative disorder. As there is no definitive diagnostic test, its diagnosis is based on clinical criteria. Recently transcranial duplex scanning (TCD) of the substantia nigra in the brainstem has been proposed as an instrument to diagnose PD. We and others have found that TCD scanning of substantia nigra duplex is a relatively accurate diagnostic instrument in patients with parkinsonian symptoms. However, all studies on TCD so far have involved well-defined, later-stage PD patients, which will obviously lead to an overestimate of the diagnostic accuracy of TCD.     

Endothelial Ca2+ wavelets and the induction of myoendothelial feedback

When arteries constrict to agonists, the endothelium inversely responds, attenuating the initial vasomotor response. The basis of this feedback mechanism remains uncertain, although past studies suggest a key role for myoendothelial communication in the signaling process. The present study examined whether second messenger flux through myoendothelial gap junctions initiates a negative-feedback response in hamster retractor muscle feed arteries. We specifically hypothesized that when agonists elicit depolarization and a rise in second messenger concentration, inositol trisphosphate (IP(3)) flux activates a discrete pool of IP(3) receptors (IP(3)Rs), elicits localized endothelial Ca(2+) transients, and activates downstream effectors to moderate constriction. With use of integrated experimental techniques, this study provided three sets of supporting observations. Beginning at the functional level, we showed that blocking intermediate-conductance Ca(2+)-activated K(+) channels (IK) and Ca(2+) mobilization from the endoplasmic reticulum (ER) enhanced the contractile/electrical responsiveness of feed arteries to phenylephrine. Next, structural analysis confirmed that endothelial projections make contact with the overlying smooth muscle. These projections retained membranous ER networks, and IP(3)Rs and IK channels localized in or near this structure. Finally, Ca(2+) imaging revealed that phenylephrine induced discrete endothelial Ca(2+) events through IP(3)R activation. These events were termed recruitable Ca(2+) wavelets on the basis of their spatiotemporal characteristics. From these findings, we conclude that IP(3) flux across myoendothelial gap junctions is sufficient to induce focal Ca(2+) release from IP(3)Rs and activate a discrete pool of IK channels within or near endothelial projections. The resulting hyperpolarization feeds back on smooth muscle to moderate agonist-induced depolarization and constriction.     

Mechanisms of atrial fibrillation termination by rapidly unbinding Na+ channel blockers: insights from mathematical models and experimental correlates

Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is a problem of growing proportions. Recent studies have increased interest in fast-unbinding Na(+) channel blockers like vernakalant (RSD1235) and ranolazine for AF therapy, but the mechanism of efficacy is poorly understood. To study how fast-unbinding I(Na) blockers affect AF, we developed realistic mathematical models of state-dependent Na(+) channel block, using a lidocaine model as a prototype, and studied the effects on simulated cholinergic AF in two- and three-dimensional atrial substrates. We then compared the results with in vivo effects of lidocaine on vagotonic AF in dogs. Lidocaine action was modeled with the Hondeghem-Katzung modulated-receptor theory and maximum affinity for activated Na(+) channels. Lidocaine produced frequency-dependent Na(+) channel blocking and conduction slowing effects and terminated AF in both two- and three-dimensional models with concentration-dependent efficacy (maximum approximately 89% at 60 microM). AF termination was not related to increases in wavelength, which tended to decrease with the drug, but rather to decreased source Na(+) current in the face of large ACh-sensitive K(+) current-related sinks, leading to the destabilization of primary generator rotors and a great reduction in wavebreak, which caused primary rotor annihilations in the absence of secondary rotors to resume generator activity. Lidocaine also reduced the variability and maximum values of the dominant frequency distribution during AF. Qualitatively similar results were obtained in vivo for lidocaine effects on vagal AF in dogs, with an efficacy of 86% at 2 mg/kg iv, as well as with simulations using the guarded-receptor model of lidocaine action. These results provide new insights into the mechanisms by which rapidly unbinding class I antiarrhythmic agents, a class including several novel compounds of considerable promise, terminate AF.     

A computational model of pig ventricular cardiomyocyte electrophysiology and calcium handling: Translation from pig to human electrophysiology

The pig is commonly used as an experimental model of human heart disease, including for the study of mechanisms of arrhythmia. However, there exist differences between human and porcine cellular electrophysiology: The pig action potential (AP) has a deeper phase-1 notch, a longer duration at 50% repolarization, and higher plateau potentials than human. Ionic differences underlying the AP include larger rapid delayed-rectifier and smaller inward-rectifier K⁺-currents (I_Kr and I_K1 respectively) in humans. AP steady-state rate-dependence and restitution is steeper in pigs. Porcine Ca²⁺ transients can have two components, unlike human. Although a reliable computational model for human ventricular myocytes exists, one for pigs is lacking. This hampers translation from results obtained in pigs to human myocardium. Here, we developed a computational model of the pig ventricular cardiomyocyte AP using experimental datasets of the relevant ionic currents, Ca²⁺-handling, AP shape, AP duration restitution, and inducibility of triggered activity and alternans. To properly capture porcine Ca²⁺ transients, we introduced a two-step process with a faster release in the t-tubular region, followed by a slower diffusion-induced release from a non t-tubular subcellular region. The pig model behavior was compared with that of a human ventricular cardiomyocyte (O’Hara-Rudy) model. The pig, but not the human model, developed early afterdepolarizations (EADs) under block of I_K1, while I_Kr block led to EADs in the human but not in the pig model. At fast rates (pacing cycle length = 400 ms), the human cell model was more susceptible to spontaneous Ca²⁺ release-mediated delayed afterdepolarizations (DADs) and triggered activity than pig. Fast pacing led to alternans in human but not pig. Developing species-specific models incorporating electrophysiology and Ca^2+-handling provides a tool to aid translating antiarrhythmic and arrhythmogenic assessment from the bench to the clinic.     

Floristic variation and willow carr development within a southwest England wetland

Abstract. Woodland colonization on wetlands is considered to have a detrimental effect on their ecological value, even though detailed analysis of this process is lacking. This paper provides an evaluation of the ecological changes resulting from succession of poor fen (base‐poor mire) to willow wet woodland on Goss Moor NNR in Cornwall, UK. Different ages of willow carr were associated with eight understorey communities. During willow colonization, in the ground flora, there was a progressive decrease in poor fen species and an associated increase in woodland species, which appeared to be related to an increase in canopy cover and therefore shade. The most diverse community was found to be the most recent willow and was dominated by poor fen species. The oldest willow was the second most diverse and was associated with a reduction in poor fen species and an increase in woodland species. Architectural features were used successfully to assess the general condition and structure of willow. Tree height and DBH were identified as useful parameters to accurately assess willow age in the field. The implications of active intervention to remove willow in order to conserve the full range of communities within the hydrosere are discussed.     

Lucky rugose corals on crinoid stems: unusual examples of subepidermal epizoans from the Devonian of Morocco

Berkowski, B & Klug, C. 2011: Lucky rugose corals on crinoid stems: unusual examples of subepidermal epizoans from the Devonian of Morocco. Lethaia, Vol. 45, pp. 24–33. In the fossil record, evidence for true epizoans, i.e. living animals inhabiting other living host‐animals, is rather rare. A host reaction is usually needed to proof the syn vivo‐settling of the epizoan. Herein, we provide a first report of such an epizoan biocoenosis from various strata of the Early Devonian of Hamar Laghdad, the world‐renowned Moroccan mud‐mound locality. In this case, solitary rugose corals settled as larvae on crinoid stems, perhaps at a spot where the epidermis was missing for some reason (injury, disease). Both the crinoid and the coral began to grow around each other. By doing so, the affected crinoid columnals formed a swelling, where ultimately only an opening slightly larger than the coral orifice remained. We discuss both macroecological and small‐scale synecological aspects of this biocoenosis. The coral profited from its elevated home because it reached into more rapid currents providing the polyp with more food than at the densely populated seafloor, which was probably covered by a coral‐meadow around the mounds and hydrothermal vents. □Corals, crinoids, Early Devonian, epizoans, Morocco, Rugosa.