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Wavefront propagation in cardiac tissue is affected greatly by the geometry of the wavefront. We describe a computer-controlled stimulator system that creates reproducible wavefronts of a predetermined shape and orientation for the investigation of the effects of wavefront geometry. We conducted demonstration experiments on isolated perfused rabbit hearts, which were stained with the voltage-sensitive dye, di-4-ANEPPS. The wavefronts were imaged using a laser and a charge-coupled device (CCD) camera. The stimulator and imaging systems have been used to characterize the relationship between wavefront velocity and fiber orientation. This approach has potential applications in investigating curvature effects, testing numerical models of cardiac tissue, and creating complex wavefronts using one-, two-, or three-dimensional electrode arrays.
Registration of 3D segmented cardiac images with tracked electrophysiological data has been previously investigated for use in cardiac mapping and navigation systems. However, dynamic cardiac 4D (3D + time) registration methods do not presently exist. This paper introduces two new 4D registration methods based on the popular iterative closest point (ICP) algorithm that may be applied to dynamic 3D shapes. The first method averages the transformations of the 3D ICP on each phase of the dynamic data, while the second finds the closest point pairs for the data in each phase and performs a least squares fit between all the pairs combined. Experimental results show these methods yield more accurate transformations compared to using a traditional 3D approach (4D errors: Translation 0.4mm, Rotation 0.45 degrees vs. 3D errors: Translation 1.2mm, Rotation 1.3 degrees) while also increasing capture range and success
Cardiac motion is one of the main sources of artifacts in epifluorescence imaging experiments. It can cause significant error in electrophysiological measurements such as action potential duration. We present a novel approach that uses image registration based on maximization of mutual information to correct for in-plane cardiac motion in such experiments. The approach is relatively fast (a few seconds per frame) and is performed entirely post acquisition. The image registration approach is an alternative to traditional approaches such as mechanical restraint of the heart or addition of chemical uncouplers. Our results show that the image registration method significantly reduces motion-related artifacts in experimental data.
OBJECTIVE - Previous studies have used acetylcholinesterase (AChE) histochemistry to identify cholinergic nerves in the heart, but this enzyme is not a selective marker for cholinergic neurons. This study maps cholinergic innervation of guinea pig heart using a new antibody to the human high-affinity choline transporter (CHT), which is present only in cholinergic nerves.
METHODS - Immunohistochemistry was used to localize CHTs in frozen and paraffin sections of heart and whole mount preparations of atrial ganglionated nerve plexus. AChE-positive nerve fibers were identified in sections from separate hearts for comparison.
RESULTS - Control experiments established that the antibody to human CHT selectively labeled cholinergic neurons in the guinea pig. CHT-immunoreactive nerve fibers and AChE-positive nerves were very abundant in the sinus and AV nodes, bundle of His, and bundle branches. Both markers also delineated a distinct nerve tract in the posterior wall of the right atrium. AChE-positive nerve fibers were more abundant than CHT-immunoreactive nerves in working atrial and ventricular myocardium. CHT-immunoreactive nerves were rarely observed in left ventricular free wall. Both markers were associated with numerous parasympathetic ganglia that were distributed along the posterior atrial walls and within the interatrial septum, including the region of the AV node.
CONCLUSIONS - Comparison of labeling patterns for CHT and AChE suggests that AChE histochemistry overestimates the density of cholinergic innervation in the heart. The distribution of CHT-immunoreactive nerve fibers and parasympathetic ganglia in the guinea pig heart suggests that heart rate, conduction velocity, and automaticity are precisely regulated by cholinergic innervation. In contrast, the paucity of CHT-immunoreactive nerve fibers in left ventricular myocardium implies that vagal efferent input has little or no direct influence on ventricular contractile function in the guinea pig.
BACKGROUND - Mutations in the gamma2 subunit (PRKAG2) of AMP-activated protein kinase produce an unusual human cardiomyopathy characterized by ventricular hypertrophy and electrophysiological abnormalities: Wolff-Parkinson-White syndrome (WPW) and progressive degenerative conduction system disease. Pathological examinations of affected human hearts reveal vacuoles containing amylopectin, a glycogen-related substance.
METHODS AND RESULTS - To elucidate the mechanism by which PRKAG2 mutations produce hypertrophy with electrophysiological abnormalities, we constructed transgenic mice overexpressing the PRKAG2 cDNA with or without a missense N488I human mutation. Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction. Electrophysiological testing demonstrated alternative atrioventricular conduction pathways consistent with WPW. Cardiac histopathology revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes. These anomalous microscopic atrioventricular connections, rather than morphologically distinct bypass tracts, appeared to provide the anatomic substrate for ventricular preexcitation.
CONCLUSIONS - Our data establish PRKAG2 mutations as a glycogen storage cardiomyopathy, provide an anatomic explanation for electrophysiological findings, and implicate disruption of the annulus fibrosis by glycogen-engorged myocytes as the cause of preexcitation in Pompe, Danon, and other glycogen storage diseases.
INTRODUCTION - Due to the lack of good molecular markers, for decades the morphogenetic origin of the cardiac conduction system has been a matter of debate. More recently, the spatial expression of minK-lacZ in the adult mouse heart has been shown, for the larger part, to be coincident with the conduction tissues.
METHODS AND RESULTS - To trace the embryonic development of this system, we performed an analysis of the expression of this construct throughout early cardiac development. Expression was first seen at the eighth embryonic day. Subsequently, discrete rings were found at the sinuatrial, atrioventricular, interventricular, and ventriculoarterial junctions. With time, the expression became restricted to boundary regions of the heart, such as the hinges of the leaflets of the pulmonary and aortic valves, the atrioventricular rings, and the venous valves, as well as becoming incorporated into the definitive conduction tissues themselves. In the postnatal heart, the areas retaining minK-lacZ positivity outside of the definitive conduction tissues are known to be the site of origin of abnormal cardiac rhythms, suggesting that ectopic foci may derive from tissues that share a common developmental pathway with the definitive conduction system.
CONCLUSION - Our findings suggest that the boundary regions between compartments, along with the atrioventricular conduction axis, share a common developmental pathway.
The minK gene encodes a 129-amino acid peptide the expression of which modulates function of cardiac delayed rectifier currents (IKr and IKs), and mutations in minK are now recognized as one cause of the congenital long-QT syndrome. We have generated minK-deficient mice in which the bacterial lacZ gene has been substituted for the minK coding region such that beta-galactosidase expression is controlled by endogenous minK regulatory elements. In cardiac myocytes isolated from wild-type neonatal mice, IKs is rarely recorded, while IKr is common. In minK (-/-) myocytes, IKs is absent and IKr is significantly reduced and its deactivation slowed; these results further support a role for minK in modulating both IKs and IKr. Despite these changes, ECGs in (+/+) and (-/-) animals are no different at adult and at neonatal stages. ECG responses to isoproterenol are also similar in the 2 groups. beta-Galactosidase staining in postnatal minK (-/-) hearts is highly restricted, to the sinus-node region, caudal atrial septum, and proximal conducting system. Moreover, as early as embryonal day 11, segmentally restricted beta-galactosidase expression is observed in the portions of the sinoatrial and atrioventricular junctions that are thought to give rise to the conducting system, thereby implicating minK expression as an early event in conduction system development. More generally, the restricted nature of minK expression in the mouse heart suggests species-specific roles of this gene product in mediating the electrophysiological properties of the heart.
Accessory atrioventricular pathways, the anatomical structures responsible for the preexcitation syndromes, may result from a developmental failure to eradicate the remnants of the atrioventricular connections present during cardiogenesis. To study whether preexcitation syndromes could also be transmitted genetically, we determined the prevalence of preexcitation in the first-degree relatives of 383 of 456 consecutive patients (84 percent) with electrophysiologically proved accessory pathways. We compared the observed prevalence of preexcitation among the 2343 first-degree relatives with the frequency reported in the general population (0.15 percent). For 13 of the 383 index patients (3.4 percent), accessory pathways were documented in one or more first-degree relatives. At least 13 of the 2343 relatives identified (0.55 percent) had preexcitation; this prevalence was significantly higher than that in the general population (P less than 0.0001). Identification of affected relatives may have been incomplete because clinical information was obtained only about symptomatic relatives. Patients with familial preexcitation have a higher incidence of multiple accessory pathways and possibly an increased risk of sudden cardiac death. Our data suggest a hereditary contribution to the development of accessory pathways in humans. The pattern of inheritance appears to be autosomal dominant.
The conduction system functions of atrioventricular sequential contractions, atrioventricular delay, and coordination of ventricular contraction were examined in rat embryos at the earliest functional stage of cardiac development (before cardiac looping, n = 6) and shortly after looping (n = 15). Atrioventricular sequential contractions were observed in all embryos, and contractions appeared to originate in the left sinus horn. Atrioventricular delay was present in both prelooped (132 +/- 32 ms) and looped (141 +/- 15 ms) hearts. Before looping, contractions traveled from proximal ventricle to bulbus cordis, a distance of 253 +/- 27 microns, in 72 +/- 22 ms. After looping, contractions crossed an increased intraventricular distance (520 +/- 28 microns, p less than 0.005) in substantially less time (16 +/- 7 ms, p less than 0.005). Sinoatrial and atrioventricular nodal functions are emulated in both prelooped and looped hearts of early mammalian embryos, and His-Purkinje system function is emulated in looped hearts.