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David J Christini

Publications and source records attributed to David J Christini.

7 recordsLinked to original sources
PubMed2003

MinK-related peptide 2 modulates Kv2.1 and Kv3.1 potassium channels in mammalian brain.

Delayed rectifier potassium current diversity and regulation are essential for signal processing and integration in neuronal circuits. Here, we investigated a neuronal role for MinK-related peptides (MiRPs), membrane-spanning modulatory subunits that generate phenotypic diversity in cardiac potassium channels. Native coimmunoprecipitation from rat brain membranes identified two novel potassium channel complexes, MiRP2-Kv2.1 and MiRP2-Kv3.1b. MiRP2 reduces the current density of both channels, slows Kv3.1b activation, and slows both activation and deactivation of Kv2.1. Altering native MiRP2 expression levels by RNAi gene silencing or cDNA transfection toggles the magnitude and kinetics of endogenous delayed rectifier currents in PC12 cells and hippocampal neurons. Computer simulations predict that the slower gating of Kv3.1b in complexes with MiRP2 will broaden action potentials and lower sustainable firing frequency. Thus, MiRP2, unlike other known neuronal beta subunits, provides a mechanism for influence over multiple delayed rectifier potassium currents in mammalian CNS via modulation of alpha subunits from structurally and kinetically distinct subfamilies.

Action Potentials↗
PubMed2003

Antispiral waves in reaction-diffusion systems.

We report spontaneous antispiral wave formation in typical reaction-diffusion systems. Our findings qualitatively reproduce a series of phenomena recently observed in a Belousov-Zhabotinsky-type chemical reaction. We found that antispiral waves can occur only near the Hopf bifurcation, when the system is characterized by small amplitude oscillatory (as opposed to excitable) dynamics. For reaction-diffusion systems in the vicinity of the Hopf bifurcation, the specific conditions required for antispiral formation are established here through theoretical analyses and numerical simulations. Thus, this work provides a comprehensive description of the mechanisms underlying antispiral waves in reaction-diffusion systems.

Journal Article↗
PubMed2003

Endocardial detection of repolarization alternans.

Repolarization alternans (RPA) is prognostic of sudden cardiac death and is thought to be mechanistically linked to the initiation of ventricular tachyarrhythmias. Thus, implantable cardiac device detection of RPA may be therapeutically valuable. Because alternans detection is currently limited to surface electrocardiograms, we investigated whether RPA could be measured using a single right-ventricular endocardial lead in humans. Such a location was chosen because it is consistent with the requirements for long-term implantable-device implementation. During diagnostic electrophysiological testing, 28 patients (23 male, 5 female; 61 +/- 15 years) were evaluated for surface T-wave alternans (TWA; the current "gold standard" for RPA detection) and endocardial RPA during 5 min of 550-ms right-atrial pacing. Power spectral analysis indicated that 11/28 patients had both surface TWA and endocardial RPA, 9/28 patients had neither, and 8/28 patients had discordant results (71% concordance; p = 0.02). Importantly, unlike surface TWA, endocardial RPA was detectable on a beat-to-beat basis. Given the putative mechanistic link between RPA and ventricular arrhythmias, beat-to-beat endocardial RPA detection might be of diagnostic or therapeutic utility.

Algorithms↗
PubMed2003

Genetically engineered biologically based hemostatic bioassay.

Real-time direct measures of hemostatic parameters in vivo are required for optimizing the dynamic delivery of coagulation modifying pharmacotherapies. Typical sensors of physiologic functions in vivo, however, have only a restricted array of sensory inputs, and thus limited capacity to monitor thrombotic and hemostatic activity. To overcome this limitation we have developed a genetically engineered excitable cell line that can be potentially used for an implantable thrombin biosensor. Specifically, we have generated stem cell-derived cardiac myocyte aggregates overexpressing the human thrombin receptor, protease activated receptor-1 (PAR-1), which exploit the inherent electropotential input-output relationship of the cells to detect local changes in thrombin activity. In vitro, the signaling activity of PAR-1 cardiac myocytes was highly responsive to thrombin, inducing a sixfold increase in intracellular cAMP as compared with a twofold increase in control cells. In vivo, the engineered myocytes also detected alterations in local coagulation potential. Specifically, PAR-1 engineered cells implanted in vivo detected local increases in thrombin with a doubling in chronotropic activity compared with a 50% increase in control aggregates. Overall these studies demonstrate the potential of genetic engineering to expand the physiologic signals recognized by excitable cells, and may facilitate the translation of this approach for the real-time monitoring of hemostatic function in vivo.

Animals↗
PubMed2002

Termination of reentry in an inhomogeneous ring of model cardiac cells.

Reentrant waves propagating in a ring or annulus of excitable media are a model of the basic mechanism underlying a major class of irregular cardiac rhythms known as anatomical reentry. Such reentrant waves are terminated by rapid electrical stimulation (pacing) from an implantable device. Because the mechanisms of such termination are poorly understood, we study pacing of anatomical reentry in a one-dimensional ring of model cardiac cells. For realistic off-circuit pacing, our model-independent results suggest that circuit inhomogeneities, and the electrophysiological dynamical changes they introduce, may be essential for terminating reentry in some cases.

Action Potentials↗
PubMed2002

Enhanced myocyte-based biosensing of the blood-borne signals regulating chronotropy.

Biosensors play a critical role in the real-time determination of relevant functional physiological needs. However, typical in vivo biosensors only approximate endogenous function via the measurement of surrogate signals and, therefore, may often lack a high degree of dynamic fidelity with physiological requirements. To overcome this limitation, we have developed an excitable tissue-based implantable biosensor approach, which exploits the inherent electropotential input-output relationship of cardiac myocytes to measure the physiological regulatory inputs of chronotropic demand via the detection of blood-borne signals. In this study, we report the improvement of this application through the modulation of host-biosensor communication via the enhancement of vascularization of chronotropic complexes in mice. Moreover, in an effort to further improve translational applicability as well as molecular plasticity, we have advanced this approach by employing stem cell-derived cardiac myocyte aggregates in place of whole cardiac tissue. Overall, these studies demonstrate the potential of biologically based biosensors to predict endogenous physiological dynamics and may facilitate the translation of this approach for in vivo monitoring.

Animals↗