Background The site of origin and pattern of excitation within the human sinoatrial node (SAN) has not been directly mapped. Objective We hypothesized that the human SAN is functionally insulated from the surrounding atrial myocardium except for several exit pathways which electrically bridge the nodal tissue and atrial myocardium. Methods The SAN was optically mapped in coronary perfused preparations from non-failing human hearts (n=4, age 54±15 years) using dye Di-4-ANBDQBS and Blebbistatin. SAN 3D structure was reconstructed using histology. Results Optical recordings from the SAN had diastolic depolarization and multiple upstroke components, which corresponded to the separate excitations of the SAN and atrial layers. Excitation originated in the middle of the SAN (66±17 BPM), then slowly (1–18 cm/s) and anisotropically spread. After a 82±17 ms conduction delay within the SAN, the atrial myocardium was excited via superior, middle, and/or inferior sinoatrial conduction pathways. Atrial excitation was initiated 9.4±4.2 mm from the leading pacemaker site. The oval 14.3±1.5 × 6.7±1.6 × 1.0±0.2 mm SAN structure was functionally insulated from the atrium by connective tissue, fat, and coronary arteries, except for these pathways. Conclusion These data demonstrated for the first time the location of the leading SAN pacemaker site, the pattern of excitation within the human SAN, and the conduction pathways into the right atrium. The existence of these pathways explained why, even during normal sinus rhythm, atrial breakthroughs could arise from a region parallel to the CT that is significantly larger (26.0±7.8 mm) than the area of the anatomically defined SAN.

Abstract-Surface electrode recordings cannot delineate the activation within the human or canine sinoatrial node (SAN) because they are intramural structures. Thus, the site of origin of excitation and conduction pathway(s) within the SAN of these mammals remains unknown. Canine right atrial preparations (nϭ7) were optically mapped. The SAN 3D structure and protein expression were mapped using immunohistochemistry. SAN optical action potentials had diastolic depolarization and multiple upstroke components that corresponded to the separate excitations of the node and surface atrial layers. Pacing-induced SAN exit block eliminated atrial optical action potential components but retained SAN optical action potential components. Excitation originated in the SAN (cycle length, 557Ϯ72 ms) and slowly spread (1.2 to 14 cm/sec) within the SAN, failing to directly excite the crista terminalis and intraatrial septum. After a 49Ϯ22 ms conduction delay within the SAN, excitation reached the atrial myocardium via superior and/or inferior sinoatrial exit pathways 8.8Ϯ3.2 mm from the leading pacemaker site. The ellipsoidal 13.7Ϯ2.8/4.9Ϯ0.6 mm SAN structure was functionally insulated from the atrium. This insulation coincided with connexin43-negative regions at the borders of the node, connective tissue, and coronary arteries. During normal sinus rhythm, the canine SAN is functionally insulated from the surrounding atrial myocardium except for 2 (or more) narrow superior and inferior sinoatrial exit pathways separated by 12.8Ϯ4.1 mm. Conduction failure in these sinoatrial exit pathways leads to SAN exit block and is a modulator of heart rate. The clinical signs of SAN dysfunction include bradycardia, sinus pauses, sinus arrest, sinus exit block, and reentrant arrhythmias. 3,4 Although the syndrome may have many causes and commonly affects elderly persons, it usually is idiopathic. 5 Studies of human SAN function are complicated by the inability of epior endocardial mapping to detect the origin and slow propagation of action potentials (APs) within the SAN before it activates adjacent atrial myocardium. 6,7 Sinus rhythm (SR) is physiologically controlled by autonomic modulation of pacemaker ion channels, 8 calcium handling, 9 and shifts of the leading pacemaker site. 10 -12 Anatomic structure and electrophysiological heterogeneity play important roles in SAN excitation under various conditions. 6 Recently, we investigated activation patterns in the rabbit SAN using optical mapping, 13 which is the only available technology that allows the resolution of simultaneous changes in the activation pattern and AP morphology from multiple sites. In that study, we demonstrated that the rabbit SAN is functionally insulated from the atrial septum. 13 However, the rabbit SAN is essentially a 2D structure 14 in contrast to the 3D structure of the canine 7,15,16 and human 17,18 SANs. Bromberg et al 7 suggested that the canine SAN may be functionally insulated from the surrounding atrial myocytes, except for a limited number of exit si...

To assess the effectiveness of bromocriptine in reducing the size of PRL-secreting macroadenomas with extrasellar extension, we conducted a prospective multicenter trial in patients without prior radiotherapy, applying a standard protocol of treatment and tumor size evaluation. Basal serum PRL levels [1441 +/- 417 (+/- SEM) ng/ml for women; 3451 +/- 1111 ng/ml for men] fell in all patients and to 11% or less of basal values in all patients but 1. Normal PRL levels were reached in 18 of the 27 patients. In 13 patients (46%), tumor size was reduced by greater than 50%, in 5 patients (18%) by about 50%, and in 9 patients (36%) by approximately 10-25%. The extent of tumor size reduction did not correlate with basal PRL, nadir PRL, percent fall in PRL, or whether PRL levels reached normal. However, a reduction in PRL levels always preceded any detectable change in tumor size. In 19 patients, reduction in tumor size was evident by 6 weeks, but in the other 8, such reduction was not noted until the 6 month evaluation. In the 4 patients in whom bromocriptine was discontinued at the end of 1 yr, tumor reexpansion occurred in 3. Visual fields improved in 9 of the 10 patients in whom they were abnormal. Because of the excellent results found in most of the patients in this series, we suggest that therapy with bromocriptine should be considered as initial management for patients with PRL-secreting macroadenomas.