Biomedical subjects

David France

Publications and source records attributed to David France.

9 recordsLinked to original sources

PubMed2005

Focal gap junction uncoupling and spontaneous ventricular ectopy.

Genetic studies in the mouse have demonstrated that conditional cardiac-restricted loss of connexin43 (Cx43), the major ventricular gap junction protein, is highly arrhythmogenic. However, whether more focal gap junction remodeling, as is commonly seen in acquired cardiomyopathies, influences the propensity for arrhythmogenesis is not known. We examined electrophysiological properties and the frequency of spontaneous and inducible arrhythmias in genetically engineered chimeric mice derived from injection of Cx43-deficient embryonic stem cells into wild-type recipient blastocysts. Chimeric mice had numerous well-circumscribed microscopic Cx43-negative foci in their hearts, comprising approximately 15% of the total surface area as determined by immunohistochemical analysis. Systolic function in the chimeric mice was significantly depressed as measured echocardiographically (19.0% decline in fractional shortening compared with controls, P < 0.05) and by invasive hemodynamics (17.6% reduction in change of pressure over time, P < 0.01). Chimeras had significantly more spontaneous arrhythmic events than controls (P < 0.01), including frequent runs of nonsustained ventricular tachycardia in some of the chimeric mice. However, in contrast to mice with conditional cardiac-resricted loss of Cx43 in the heart, no sustained ventricular tachyarrhythmias were observed. We conclude that focal areas of uncoupling in the myocardium increase the likelihood of arrhythmic triggers, but more widespread uncoupling is required to support sustained arrhythmias.

Animals↗

PubMed2004

Transitions in ventricular activation revealed by two-dimensional optical mapping.

While cardiac function in the mature heart is dependent on a properly functioning His-Purkinje system, the early embryonic tubular heart efficiently pumps blood without a distinct specialized conduction system. Although His-Purkinje system precursors have been identified using immunohistological techniques in the looped heart, little is known whether these precursors function electrically. To address this question, we used high-resolution optical mapping and fluorescent dyes with two CCD cameras to describe the motion-corrected activation patterns of 76 embryonic chick hearts from tubular stages (stage 10) to mature septated hearts (stage 35). Ventricular activation in the tubular looped heart (stages 10-17) using both calcium-sensitive fluo-4 and voltage-sensitive di-4-ANEPPS shows sequentially uniform propagation. In late looped hearts (stages 18-22), domains of the dorsal and lateral ventricle are preferentially activated before spreading to the remaining myocardium and show alternating regions of fast and slow propagation. During stages 22-26, action potentials arise from the dorsal ventricle. By stages 27-29, action potential breakthrough is also observed at the right ventricle apex. By stage 31, activation of the heart proceeds from foci at the apex and dorsal surface of the heart. The breakthrough foci correspond to regions where putative conduction system precursors have been identified immunohistologically. To date, our study represents the most detailed electrophysiological characterization of the embryonic heart between the looped and preseptated stages and suggests that ventricular activation undergoes a gradual transformation from sequential to a mature pattern with right and left epicardial breakthroughs. Our investigation suggests that cardiac conduction system precursors may be electrophysiologically distinct and mature gradually throughout cardiac morphogenesis in the chick.

Action Potentials↗

PubMed2002

Neuregulin-1 promotes formation of the murine cardiac conduction system.

The cardiac conduction system is a network of cells responsible for the rhythmic and coordinated excitation of the heart. Components of the murine conduction system, including the peripheral Purkinje fibers, are morphologically indistinguishable from surrounding cardiomyocytes, and a paucity of molecular markers exists to identify these cells. The murine conduction system develops in close association with the endocardium. Using the recently identified CCS-lacZ line of reporter mice, in which lacZ expression delineates the embryonic and fully mature conduction system, we tested the ability of several endocardial-derived paracrine factors to convert contractile cardiomyocytes into conduction-system cells as measured by ectopic reporter gene expression in the heart. In this report we show that neuregulin-1, a growth and differentiation factor essential for ventricular trabeculation, is sufficient to induce ectopic expression of the lacZ conduction marker. This inductive effect of neuregulin-1 was restricted to a window of sensitivity between 8.5 and 10.5 days postcoitum. Using the whole mouse embryo culture system, neuregulin-1 was shown to regulate lacZ expression within the embryonic heart, whereas its expression in other tissues remained unaffected. We describe the electrical activation pattern of the 9.5-days postcoitum embryonic mouse heart and show that treatment with neuregulin-1 results in electrophysiological changes in the activation pattern consistent with a recruitment of cells to the conduction system. This study supports the hypothesis that endocardial-derived neuregulins may be the major endogenous ligands responsible for inducing murine embryonic cardiomyocytes to differentiate into cells of the conduction system.

Animals↗

PubMed2002