Usefulness of pre-procedure cavotricuspid isthmus imaging by modified transthoracic echocardiography for predicting outcome of isthmus-dependent atrial flutter ablation.

BACKGROUND: Anatomic characteristics of the cavotricuspid isthmus (CTI) have been reported to be related to the outcome of atrial flutter ablation therapy. However, preprocedural evaluation of CTI anatomy using modified transthoracic echocardiography to guide atrial flutter ablation has not been well described. METHODS: Transthoracic echocardiography was prospectively performed before atrial flutter ablation in 42 patients with typical CTI-dependent atrial flutter. A modified apical long-axis view was designed to visualize and evaluate anatomic characteristics of the CTI and Eustachian ridge (ER). A prominent ER, extending from the inferior vena cava to the interatrial septum, is defined as an extensive ER. RESULTS: Twenty-eight patients had straightforward ablation procedures, and 14 patients had difficult ablation procedures. Two patients with difficult procedures had unsuccessful ablation. Multivariate analysis (using CTI length, the presence of a pouch or recess, ER morphology, and significant tricuspid regurgitation as variables) showed that the presence of extensive ER was the only independent predictor of a difficult ablation procedure. The ablation time in patients with extensive ER (n = 13) was significantly longer than in those patients with nonextensive ER (n = 29) (1,638.4 ± 1,548.3 vs 413.8 ± 195.5 sec, P = .015). The incidence of difficulty in achieving bidirectional isthmus block was also higher in patients with extensive ER (10 of 13 vs four of 29, P < .001). CONCLUSION: Preprocedural transthoracic echocardiography using a modified apical long-axis view is useful to characterize the morphology of the CTI and the ER. An extensive ER is a strong predictor for difficult ablation of CTI-dependent atrial flutter.

Changes in peptidergic nerves in the atrioventricular valves of streptozotocin-induced diabetic rats: a confocal microscopy study.

Several previous studies have described the distribution of neuropeptide Y (NPY)-like and calcitonin gene related peptide (CGRP)-like immunoreactive nerve fibres in the atrioventricular valves of humans and various animals. It has been suggested that peptide-containing nerve fibres might have motor or sensory roles in valvular function. Although there is evidence that diabetic changes occur in the sympathetic (preganglionic and postganglionic), parasympathetic (vagal) and peptidergic nerves of rats, the changes of peptide-containing nerve fibres in the atrioventricular valves of the diabetic rat have not been studied. The distribution, relative density and staining intensity of NPY-like and CGRP-like immunoreactive nerve fibres in the mitral and tricuspid valves were studied in whole mount preparations using confocal microscopy with a computer-assisted image analysis system. Streptozotocin-induced diabetic and control rats were sacrificed at 12 and 24 months. The nerve staining intensity within the tricuspid valve was greater than the mitral valve in both control (P < 0.01) and diabetic (P < 0.001) rats. Nerve density in the anterior leaflet was greater than the posterior leaflet of the mitral valve. However, the anterior leaflet of the mitral and tricuspid valves showed a decreased number of nerve fibres, followed by drastic reduction in the staining intensities for both the peptides studied (P < 0.001) in the long-term diabetic rat. The decrease in the number of nerve fibres that follow the mechanical interruption of nerves raises the possibility that cycles of degeneration may occur. It is suggested that these peptide-containing nerve fibres in the atrioventricular valves may be involved in valvular dysfunction in the diabetic state.

Distribution of PGP 9.5, TH, NPY, SP and CGRP immunoreactive nerves in the rat and guinea pig atrioventricular valves and chordae tendineae.

The distribution of nerves immunoreactive to protein gene product 9.5 (PGP 9.5), tyrosine hydroxylase (TH), neuropeptide Y (NPY), substance P (SP) and calcitonin gene related peptide (CGRP) antisera was investigated in the atrioventricular valves of the Sprague-Dawley rat and the Dunkin-Hartley guinea pig using confocal and epifluoresence microscopy. No major differences were noted between the innervation of the mitral and tricuspid valves in either species. For all antisera the staining was more extensive in the guinea pig valves. Two distinct nerve plexuses separated by a 'nearly nerve free' zone were identified in both species with each antiserum tested. This was most apparent on the anterior cusp of the mitral valve. The major nerve plexus extends from the atrioventricular ring through the basal, intermediate and distal zones of the valves towards the free edge of the valve cusp. These nerve bundles, arranged as primary, secondary and tertiary components, ramify to the free edge of the valve and extend to the attachment of the chordae. They do not contribute to the innervation of the chordae tendineae. The second, minor chordal plexus, runs from the papillary muscles through the chordae tendineae and passes parallel to the free edge of the cusp. The nerves of this minor plexus are interchordal, branching to terminate mainly in the distal zone, free edge of the valve cusp and adjacent chordae tendineae. Some interchordal nerve fibres loop from a papillary muscle up through a chorda, along the free edge and pass down an adjacent chorda into another papillary muscle. The nerve fibres of the major and minor plexuses intermingle although no evidence was found for interconnectivity between them. In the distal zone between the major plexus which extends from the base of the valve and the minor chordal plexus there is a zone completely free of nerves staining with antisera to TH and NPY. Occasional nerves which stained positive for PGP 9.5, SP and CGRP immunoreactivities crossed this 'nearly nerve free zone' passing either from the chordal/free edge nerves to the intermediate and basal zones or vice versa. An additional small nerve plexus which displayed immunoreactivity to CGRP antiserum extended from the atrioventricular ring into the basal zone of the valve cusp. Not all chordae tendineae displayed immunoreactive nerve fibres. It is concluded that the innervation patterns of the sensory and sympathetic neurotransmitters and neuropeptides examined in the atrioventricular valves of the rat and guinea pig are ubiquitous in nature. The complexity of the terminal innervation network of the mammalian atrioventricular valves and chordae tendineae may contribute to the complex functioning of these valves in the cardiac cycle.

Characteristics of distribution of peptide-containing nerve fibres in the atrioventricular valves of the rat.

The distribution of vasoactive intestinal polypeptide-, neuropeptide Y-, and calcitonin gene-related peptide-immunoreactive nerve fibres was investigated in the atrioventricular valves of the rat. These nerve fibres were visualized by immunostaining of whole-mount preparations by the avidin-biotin-peroxidase complex method. Vasoactive intestinal polypeptide-immunoreactive nerve fibres were observed mainly in the anterior cusp of the mitral valve and, to a lesser extent, in the medial cusp of the tricuspid valve. Numerous neuropeptide Y-immunoreactive nerve fibres were found covering all of the cusps. Both types of peptidergic nerve fibre formed dense networks that consisted of interlacing and anastomosing nerve fibres. Calcitonin gene-related peptide-immunoreactive nerve fibres were seen in every cusp, but did not form a fine network. These results provide detailed anatomical information for evaluation of the possible roles of each type of peptide-containing nerve fibre in the function of atrioventricular valves.

Histopathologic studies of innervation of normal and prolapsed human mitral valves.

We evaluated the distribution of the nerves in valve tissue of humans to clarify the relationship between mitral valve prolapse and autonomic nerve dysfunction. We studied 15 autopsy specimens of normal mitral valve, 10 prolapsed mitral valves, five each of normal tricuspid, aortic, and pulmonary valves, and three prolapsed mitral valves obtained at cardiac surgery. Immunohistochemical studies utilized the avidinbiotin peroxidase complex (ABC) method and several nerve-related antigens: 1) S-100 protein, glial fibrillary acidic protein (GFAP), and neurofilament protein (NFP) as markers of glial and Schwann cells of the nervous system; 2) choline acetyltransferase (ChAT) to identify cholinergic nerve endings; 3) neuropeptide Y (NPY), a neuropeptide that is distributed in accordance with sympathetic nerves; and 4) calcitonin gene-related peptide (CGRP), a neuropeptide that is distributed in accordance with afferent nerves. Distribution of adrenergic nerve fibers was also examined by fluorescence method. Morphology of nerve endings of the normal mitral valve was studied by electron microscopy. In normal valves, distributions of S-100 protein, GFAP, and NFP immunoreactivities were clearly visible along the subendocardial site on the coaptation aspect of the base-to-body portion of each valve, regardless of the kind of valve. In contrast, there was only a scanty distribution of these reactivities on the physiologic coaptation area of the tip. In prolapsed mitral valves, there was no distribution of S-100-positive protein or other nerve-related antigens in areas of the valve with myxomatous degeneration. Distribution of CGRP, ChAT, and NPY immunoreactivities, and adrenergic fluorescence, were the same as those of the nerve-related antigens in both normal and prolapsed mitral valves. Electron microscopic study of the atrial aspect of normal mitral valves revealed numerous small axons with aggregations of small clear vesicles, indicating cholinergic features. The results suggest that the subendocardial site on the atrial aspect at the middle portion of the mitral valve is rich in nerve endings, including the afferent nerves, and that mechanical stimuli from this area caused by abnormal coaptation in mitral valve prolapse may produce an improper circuit in autonomic nerve function between the central and mitral valve nervous systems.

Ultrastructural evidence for innervation of the endothelium and interstitial cells in the atrioventricular valves of the Japanese monkey.

BACKGROUND: A rich supply of nerves to the atrioventricular valve has been demonstrated. The role of the valvular nerves is still controversial because the target sites of the nerves have not been confirmed. METHODS: The innervation of the atrioventricular valves of the Japanese monkey (Macaca fuscata) was examined by acetylcholinesterase staining and electron microscopy. Immunoreactivity for neuropeptide Y (NPY) was also investigated by a post-embedding immunogold method. RESULTS: The valvular nerve elements were clearly concentrated between the endothelium and interstitial cells on the atrial side of cusps. Naked axon terminals were observed to make direct contact (20-nm gaps) with interstitial cells and also to be in close proximity (approximately 200-nm cleft) to the endothelium. NPY immunoreactivity was clearly detected on the large granular vesicles in some terminals that were in close proximity to interstitial cells and/or the endothelium. CONCLUSION: The present study suggests that the extensive innervation of the atrioventricular valve, which includes NPY-containing nerves, might affect valvular function via interstitial cells and/or the endothelium.

Nerve fibres containing neuropeptide Y in the atrioventricular valves of Japanese monkey and rat; a light and electron microscopic study.

Dense distribution of varicose fibres containing neuropeptide Y-like immunoreactivity (NPY-LI) was found in the atrioventricular valves of the Japanese monkey, and moderately in the rat. The immunoelectron microscopy using immunogolds resulted in the localization of NPY-LI within the dense-cored vesicles which existed with the small clear vesicles in the unmyelinated axons near the endocardium. These NPY-LI-containing fibres may participate in regulation of vasomotor role or other functions of the atrioventricular valves.

Morphological study on vagal innervation in human atrioventricular valves using histochemical method.

To demonstrate innervation in human atrioventricular valves, we examined the tricuspid and mitral valves of apparently normal autopsied hearts of four men (ages ranging from 50 to 74 years). Whole valve tissues were stained for acetylcholinesterase by a histochemical method. Acetylcholinesterase-positive nerve fibers with a diameter of 2 to 5 microns were distributed widely in the deep atrialis of the atrioventricular valves and partly in the fibrosa. The nerve fibers formed a network or plexus from the base to the anatomical edge of the valves. Meshes of the nerve fiber network were more dense towards the base and at the commissure than either towards the edge or at the body. Thicker nerve fibers, which were interspersed coarsely in the leaflets, were intercalated by special varicose apparatuses at a few sites in their long running course. On the contrary, thinner nerve fibers which were distributed abundantly, ended, as a rule, in small dotor brush-like formations. Approximately half of the chordae tendineae were innervated by the nerve fibers. The mode of vagal innervation suggests that the nerve system may assist valve movement by moderating myocyte contraction in the valve base and change valve structure by sensing a stress in the valves.

Catheter ablation of atrial flutter circuits.

Atrial flutter (AF) mapping has shown circular activation in the right atrium (RA), with a "counterclockwise" rotation in a frontal view. The myocardial isthmus between the inferior vena cava and the tricuspid valve (IVC-T) closes the activation circuit in its caudal end. The reproducibility of this activation pattern, and the fact that some "rare" AF with a "clockwise" rotation of activation use the same circuit, suggests that reentry is greatly facilitated by the anatomical arrangement of the caudal end of the RA. This suggested that ablation of the IVC-T isthmus may interrupt AF and prevent its recurrence. We have applied radiofrequency (RF) current to the IVC-T isthmus in nine patients, producing sudden interruption of activation at this point in five (all those treated with large surface electrode catheters). In three others, RF produced acceleration or disorganization, leading to interruption. Preliminary follow-up data suggest a favorable effect on AF recurrence, either by preventing it, or by making antiarrhythmic drugs effective.

[Vagal innervation in the human atrioventricular valves].

Innervation of the human atrioventricular (AV) valves is microscopically studied by histopathological methods. The tricuspid and mitral valves of 4 autopsied hearts of adult men (age range from 50 to 74 years old) without any cardiovascular diseases were stained for acetylcholine-esterase by histochemical method in the medium containing acetylthiocholine iodide. Acetylcholine-esterase positive nerve fibers of 2 to 50 microns in diameter were widely distributed in the subepicardial space of the atrial of the AV valve. They formed a coarse network of the nerve elements from the valve base to the anatomical edge. The nerve network was more dense at the valve ring and base, as well as at the commissure, than at the edge and body. Some thick nerve fibers ran in the chordae tendineae. The thick fibers were intercalated with varicose-like special structures at several places in the leaflets, which seemed to be a kind of sensory apparatus. The thin nerve fibers ended, as usual, at small dot or brush-like apparatus. It is widely accepted that the acetylcholine-esterase positive nerve fibers are identical with vagal nerves which are insisted on participating in development of mitral valve prolapse syndrome. We suggest that the vagal innervation in the AV valves could play an important role for valvular function.

Variations in atrioventricular valve innervation in four species of mammals.

In this series of studies, the innervation patterns of whole-mount preparations of bicuspid and tricuspid valves were studied by light microscopy in the mouse, rat, guinea pig, and opossum. The acetylcholinesterase-positive networks of nerve fibers showed many similarities in the basic patterns of valve innervation in all of the species studied, but several interspecies variations were observed. The basal zone of the valve adjacent to the fibromuscular atrioventricular ring displayed the most dense plexus of nerves, with acetylcholinesterase-positive fibers being seen across the width of the valve. In the intermediate zone of the valve, less dense plexuses of nerve fibers were found; and these were more numerous in the cuspal areas and less numerous in the intervening commissural areas. In the distal portions of the valve, nerve networks arborized extensively, with some of their nerve fibers extending toward the chordae tendineae and the free edges of the valve cusps. Only in the guinea pig and opossum did these fibers reach the free margin of the valve cusp, where they either ended directly as free nerve endings or lay parallel to the free edge of the cusp, often running between adjacent chordae tendineae. Although the patterns of innervation were similar in both bicuspid and tricuspid valves, the innervation density of the bicuspid valve was greater than that of the tricuspid valve for each species examined. A distinguishing feature of guinea pig and opossum tricuspid valves was that their chordae tendineae were relatively more prominent and more densely innervated than the bicuspid chordae tendineae. Free nerve endings with no light microscopic evidence of specialization were present throughout the bicuspid and tricuspid valves of all species studied. Some nerve endings in the opossum showed evidence of specialization, with brush-like arborizations leading to presumed free terminals seen chiefly in the distal zone of the valve cusps. Although some general tendencies were apparent, we have demonstrated that interspecies heterogeneity exists in the terminal networks of the atrioventricular valves of mouse, rat, guinea pig, and opossum.

Development of the autonomic ground plexus in the atrioventricular valves of the rat.

The development of the adrenergic and cholinergic innervation of the rat atrioventricular valves was studied in whole mount stretch preparations. Specimens obtained from rats ageing 2-30 days were processed for the histofluorescence and enzyme histochemical demonstration of monoamines and acetylcholinesterase (AChE) activity, respectively. Adrenergic and AChE-positive nerve fibres could be detected from the 9-10th postnatal days onwards. Fluorescence microscopy showed the presence of many brightly fluorescent mast cells in the close vicinity of the ingrowing terminals. The presence of mast cells during early stages of development of the ground plexus may be related either to the preneural state of the tissue or the structural and/or functional maturation of the autonomic nerve terminals.

[Vascular-nervous relationships in the valves of the heart]. / O sosudisto-nervnykh otnosheniiakh v klapanakh serdtsa

Method of silver nitrate impregnation was used in order to study 50 preparations of not-changed atrioventricular valves of the heart of domestic bulls and 30 preparations of the same valves of adult humans. It has been shown that in heart valves there are certain relationships between striated muscle fibres, blood vessels and nerve elements. The nerve structures of the valves are represented by nerve bundles of different thickness. In their composition there are comparatively thin non-myelinated and thicker myelinated fibres. Towards the free edge of cusps the nerve bundles become thinner and the nerve trunks give off separate thin nerve fibres disposed along the vessels of a capillary type and in some places getting around them. In certain portions of cusps the nerve bundles, some of which have zigzag sinuosity, cross blood vessels in different directions. In man the major mass of blood vessels and nerve elements are disposed near the base of the valve cusps, accompanying the muscle fibre bundles penetrating from the base side. In the bull heart valves an amount of blood vessels and nerve elements is found in considerable portions of the cusps not connected with muscle fibres.