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SUMMARY 1. The pacemaker site is known to shift away from the sinoatrial (SA) node in response to autonomic stimuli. 2. To test whether the shifting of the impulse-initiation site that occurs during autonomic nerve stimulation can be explained by the spatial distributions of β-adrenoceptor and muscarinic receptors, we obtained densities (Bmax) and dissociation constants (Kd) for these receptors in three regions along the sulcus terminalis (the SA node itself and regions superior and inferior to it) and a region of the right atrial appendage in the dog. 3. The Bmax values for [125I]-iodocyanopindolol binding to β-adrenoceptors were not different among the four regions. The Bmax value for [3H]-quinuclidinyl benzilate binding to muscarinic receptors was significantly higher in the SA node area than in any other region (P < 0.01), although there was no difference among the other three regions. 4. For each receptor, Kd values were similar among the four regions. 5. These results suggest that spatial variations in the densities of β-adrenoceptors and muscarinic receptors are not important for shifting the impulse-initiation site and that other factors, such as non-uniform innervation by autonomic nerve fibres, may be mainly responsible for the pacemaker shift induced by autonomic nerve stimulation.

Some parasympathetic ganglionic cells are located in the epicardial fat pad between the medial superior vena cava and the aortic root (SVC-Ao fat pad) of the dog. We investigated whether the ganglionic cells in the SVC-Ao fat pad control the right atrial contractile force, sinus cycle length (SCL), and atrioventricular (AV) conduction in the autonomically decentralized heart of the anesthetized dog. Stimulation of both sides of the cervical vagal complexes (CVS) decreased right atrial contractile force, increased SCL, and prolonged AV interval. Stimulation of the rate-related parasympathetic nerves to the sinoatrial (SA) node (SAPS) increased SCL and decreased atrial contractile force. Stimulation of the AV conduction-related parasympathetic nerves to the AV node prolonged AV interval. Trimethaphan, a ganglionic nicotinic receptor blocker, injected into the SVC-Ao fat pad attenuated the negative inotropic, chronotropic, and dromotropic responses to CVS by 33∼37%. On the other hand, lidocaine, a sodium channel blocker, injected into the SVC-Ao fat pad almost totally inhibited the inotropic and chronotropic responses to CVS and partly inhibited the dromotropic one. Lidocaine or trimethaphan injected into the SAPS locus abolished the inotropic responses to SAPS, but it partly attenuated those to CVS, although these treatments abolished the chronotropic responses to SAPS or CVS. These results suggest that parasympathetic ganglionic cells in the SVC-Ao fat pad, differing from those in SA and AV fat pads, nonselectively control the atrial contractile force, SCL, and AV conduction partially in the dog heart.

No data are available for the direct effect of C-type natriuretic peptide (CNP) on atrioventricular (AV) conduction in mammalian hearts. Thus we studied the dromotropic effects of CNP-22 injected into the AV node artery in autonomically decentralized hearts in open-chest, anesthetized dogs. CNP decreased AV interval (AV conduction time) in a dose-dependent manner with increase in coronary artery blood flow rate in six anesthetized dogs. Isosorbide dinitrate did not affect AV interval, but it increased coronary artery blood flow rate. A guanylyl cyclase-linked natriuretic peptide receptor antagonist, HS-142–1, inhibited the decreases in AV interval and the increases in coronary blood flow rate in response to CNP, whereas propranolol did not affect the positive dromotropic response to CNP. These results demonstrate that CNP decreases AV interval and increases coronary artery blood flow rate mediated by a guanylyl cyclase-linked natriuretic peptide receptor, but not β-adrenoceptor, in the dog heart.

An 82-year-old woman with 2:1 atrioventricular block underwent a pacemaker implantation procedure, but a tined lead became entrapped by the Chiari network. All manipulations failed to achieve release of the electrode, by which the atrial electrical potential could be recorded. Tines equipped near the tip of a pacemaker lead are intended to prevent dislodgment, but entrapment of the tined tip by intracardiac structures is probable. Together with another screw-in ventricular lead, this entrapped tined lead could act as a dual chamber pacemaker in VDD mode.

Prolongation of total filtered P wave duration (Ad) and low root mean square voltages for the last 20 ms of the P wave (LP20) on a P wave-triggered signal-averaged electrocardiogram (PSAECG) are typically observed in paroxysmal atrial fibrillation (PAF) patients. A shortening of atrial refractoriness and intra-atrial conduction delay (atrial remodeling) have been shown to occur in response to PAF. We, therefore, investigated the effects of spontaneous termination of PAF on the parameters of PSAECG.We measured the Ad, LP20 and left atrial (LA) diameter by ultrasonic echocardiography before, within 1 h after, and 3 and 12 months after PAF termination in patients with no structural heart disease (n=11).The PAF duration was 16+/-5 h. The Ads before, within 1 h after, and 3 and 12 months after PAF were 137+/-4, 148+/-4, 137+/-6, and 135+/-7 ms, respectively. The Ad within 1 h after PAF was significantly (P0.01) longer than at the other three acquisition points. Although the LP20 within 1 h after PAF termination was not significantly different from the other three points, the change in LP20 (within 1 h after PAF-before PAF, -1.1+/-0.4 microV) in the long PAF duration group was significantly (P0.05) greater than that of the short PAF duration group. LA diameter was unchanged at all points.These data suggest that PAF results in prolongation of Ad after termination of PAF.

Autonomic Regulation of Pacemaker Sites.Introduction: Parasympathetic activity predominates over sympathetic activity not only with respect to heart rate but also with respect to the pacemaker location in the dog heart. After we removed the parasympathetic neural elements in the sinoatrial (SA) fat pad in the right atrium, we observed that cervical vagus stimulation did not decrease the atrial rate, but it did suppress the increase in rate evoked by sympathetic stimulation. We determined whether the pacemaker rate and location were affected by presynaptic or postsynaptic mechanisms. Methods and Results: We determined the earliest activation site by means of isochronic activation mapping of the right atrium of open chest, anesthetized dog hearts. An electrode array, which consisted of 48 unipolar electrodes, was used to record atrial activation. This array covered the three main pacemaker regions, including the SA node region. After parasympathetic nerve fibers in the SA fat pad had been denervated, vagus stimulation at 10 and 30 Hz did not decrease the heart rate, but it attenuated the increase in heart rate evoked by sympathetic stimulation or isoproterenol. Vagus stimulation at 10 Hz during sympathetic stimulation did not shift the earliest activation site from the superior pacemaker region to the SA node region in 11 of 18 experiments. However, vagus stimulation at 10 Hz during isoproterenol infusion shifted the earliest activation site to the SA node region in 11 of 13 experiments. More intense vagus stimulation during combined sympathetic stimulation or isoproterenol infusion shifted the earliest activation site to the SA node or the inferior pacemaker region in 15 of 18 and in all experiments, respectively. Conclusion: The results suggest that activation of parasympathetic elements not located in the SA fat pad attenuates the increase in heart rate and the shift in pacemaker location evoked by sympathetic activation. The sympathetic and parasympathetic effects interact at presynaptic and postsynaptic sites in the dog heart.

There is no data about whether botulinum neurotoxin inhibits the parasympathetic ganglionic neurotransmission in the heart, although botulinum toxin as a clinical drug inhibits the release of acetylcholine at the neuromuscular junction. Therefore, we investigated whether botulinum toxin (type A) injected into the sinoatrial (SA) fat pad inhibits decreases in heart rate induced by stimulation of the preganglionic parasympathetic nerves in the heart of the anesthetized dog. Stimulation of the parasympathetic nerves in the SA fat pad (SAP stimulation) prolonged the atrial interval but not the atrioventricular (AV) interval, and cervical vagus nerve stimulation (CV stimulation) prolonged both atrial and AV intervals. After botulinum toxin (20 or 25 mouse units) was injected into the SA fat pad, it gradually inhibited the prolongation of the atrial interval evoked by SAP and CV stimulations but not the prolongation of the AV interval evoked by CV stimulation. Conditioning successive stimulation of the cervical vagus nerves accelerated the inhibition by botulinum toxin of the chronotropic response to CV stimulation. These results indicate that selective injection of botulinum toxin into the SA fat pad blocks bradycardia mediated by parasympathetic ganglionic activation in the dog heart.

Atrial electrical remodeling is thought to be the cause of the maintenance of atrial fibrillation (AF). Although the initiation and maintenance of AF is partially associated with autonomic nervous tone, vagally mediated AF does not tend to become permanent. Therefore, the effects of preceding vagal stimulation (VS) on the atrial effective refractory period (ERP) under electrical remodeling conditions were investigated in anesthetized dogs. Atrial ERPs were measured at 5 sites before and after a 7-h period of atrial rapid pacing in the control group. In the VS group, the vagus nerve was stimulated for 20 min before a period of atrial rapid pacing. Atrial rapid pacing shortened the ERP at each site in the control group (electrical remodeling). On the other hand, atrial rapid pacing after VS did not shorten the ERP at any site in the VS group. Tetrodotoxin, which was administered into the fatty tissue overlying the right atrial side of the right pulmonary vein junctions, blocked the protective effect of VS against the shortening of the ERP induced by atrial rapid pacing. In contrast, atropine did not interfere with such protective effects. These results suggest that VS prior to atrial rapid pacing protects the atrium from atrial electrical remodeling.

Effects of a Na+/Ca2+ exchanger inhibitor, KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl] isothiourea methanesulfonate), on the sinoatrial nodal pacemaker activity, atrial contractility and ventricular contractility were investigated in the isolated and blood-perfused right atrium and left ventricle of the dog. KB-R7943 (0.03- 3 micromol) induced negative inotropic effects and negative followed by positive chronotropic effects in the right atrium and negative inotropic effects in the left ventricle. Neither atropine nor hexamethonium affected the cardiac responses to KB-R7943. Propranolol attenuated the positive chronotropic response to KB-R7943 but imipramine did not. Tetrodotoxin potentiated the positive chronotropic response to KB-R7943 in 6 of 11 isolated atria. When NaCl infusion increased atrial contractile force and atrial rate, KB-R7943-induced negative inotropic and chronotropic responses were attenuated in a dose-dependent manner. CaCl2 infusion potentiated the negative chronotropic response to KB-R7943 but did not affect the inotropic response significantly. On the other hand, ouabain (17 nmol) attenuated the negative inotropic response, but not chronotropic response, to KB-R7943. These results suggest that KB-R7943-induced cardiac effects relate to the Na+ activity, probably mediated through the Na+/Ca2+ exchanger, and the Na+/Ca2+ exchanger modifies the pacemaker activity and myocardial contractility in the dog heart.

Autonomic Effect on Pacemaker Location. introduction: The site of impulse origin in the right atrium generally is considered to be a single static locus within the sinoatrial (SA) node. Previous investigators showed that the pacemaker site may shift due to changes in sympathetic or parasympathetic neural activity. We investigated the interactions between sympathetic and parasympathetic influences on the site of impulse initiation in the right atrium in anesthetized dogs. Methods and Results: We determined the site of impulse initiation and the spread of excitation over the anterior and posterior regions of the right atrium by a matrix of 48 unipolar recording electrodes. We assessed the spread of excitation at 3-nisec intervals by constructing isochronal activation sequence maps. Sympathetic stimulation increased the frequency of atrial excitation (i.e., the heart rate), but also shifted the earliest activation region (EAR) from a locus in the SA node to a locus in the superior vena cava (the superior pacemaker site). Vagus stimulation decreased the heart rate and shifted the EAR to a lower site in the SA node or a site in the interior right atrium along the sulcus terminalis (the inferior pacemaker site). A short period of vagus stimulation during a more prolonged sympathetic stimulation elicited a larger decrease in rate than did vagus stimulation alone and shifted the EAR from the superior site to the SA node or to the inferior site. After atropine, combined stimulation shifted the EAR to the superior site, but propranolol did not change EAR location. Conclusion: Our results suggest that parasympathetic activity predominates over sympathetic activity not only on heart rate, but also on the location of the EAR in the anesthetized dog.

Parenchymal manifestations of pulmonary sarcoidosis include a diffuse, symmetric, reticulonodular interstitial pattern, a fibrotic pattern, and an acinar pattern. Large pulmonary nodules in sarcoidosis are rare, and their frequency (> 1 cm in diameter) has been estimated at 2-4%. We report a rare case of sarcoidosis associated with large bilateral pulmonary nodules. These nodules reached up to 7 cm in diameter, which is larger than any others reported previously. Furthermore, these nodular lesions developed within only 6 months of normal chest X-ray results and were not found to accompany bilateral hilar lymph adenopathy, which is observed in the usual course of sarcoidosis. As described above, this case of pulmonary sarcoidosis was significant not only in terms of the large size of the nodules but also the unique chest X-ray course.

A 27-year-old female with short stature and mild hearing loss was diagnosed as having focal-segmental glomerulosclerosis by renal biopsy at our hospital. One year later she developed progressive renal dysfunction and cardiac failure and was admitted again to our hospital for evaluation. Though her only neurological disorder was mild hearing loss, her short stature and elevated lactate and pyruvate values in cerebrospinal fluid suggested mitochondrial cytopathy. A muscle biopsy specimen of the left biceps brachii, using modified Gomori trichrome stain, showed a typical image of ragged-red fibers, and an increased number of giant mitochondria with paracrystalline inclusions were visible by electron microscopy. Mitochondrial DNA from the skeletal muscle showed an A-to-G transition at 3243 of transfer RNALeu(UUR), the common point mutation for mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. These data confirmed the diagnosis of atypical mitochondrial cytopathy with renal and heart involvement. Mitochondrial cytopathies are often associated with hypertrophic cardiomyopathy but rarely with renal disease. Among the few reported cases with associated renal disease, most included renal tubular disorders; few cases with focal glomerular sclerosis are known. The present case of atypical mitochondrial cytopathy was characterized by a unique clinical course and rare complications with focal-segmental glomerulosclerosis.