Function and dysfunction of human sinoatrial node

Sinoatrial node (SAN) automaticity is jointly regulated by a voltage (cyclic activation and deactivation of membrane ion channels) and Ca(2+) clocks (rhythmic spontaneous sarcoplasmic reticulum Ca(2+) release). Using optical mapping in Langendorff-perfused canine right atrium, we previously demonstrated that the β-adrenergic stimulation pushes the leading pacemaker to the superior SAN, which has the fastest activation rate and the most robust late diastolic intracellular calcium (Cai) elevation. Dysfunction of the superior SAN is commonly observed in animal models of heart failure and atrial fibrillation (AF), which are known to be associated with abnormal SAN automaticity. Using the 3D electroanatomic mapping techniques, we demonstrated that superior SAN served as the earliest atrial activation site (EAS) during sympathetic stimulation in healthy humans. In contrast, unresponsiveness of superior SAN to sympathetic stimulation was a characteristic finding in patients with AF and SAN dysfunction, and the 3D electroanatomic mapping technique had better diagnostic sensitivity than corrected SAN recovery time testing. However, both tests have significant limitations in detecting patients with symptomatic sick sinus syndrome. Recently, we reported that the location of the EAS can be predicted by the amplitudes of P-wave in the inferior leads. The inferior P-wave amplitudes can also be used to assess the superior SAN responsiveness to sympathetic stimulation. Inverted or isoelectric P-waves at baseline that fail to normalize during isoproterenol infusion suggest SAN dysfunction. P-wave morphology analyses may be helpful in determining the SAN function in patients at risk of symptomatic sick sinus syndrome

The Calcium and Voltage Clocks in Sinoatrial Node Automaticity

Recent evidence indicates that the voltage (cyclic activation and deactivation of membrane ion channels) and Ca2+ clocks (rhythmic spontaneous sarcoplasmic reticulum Ca2+ release) jointly regulate sinoatrial node (SAN) automaticity. Since the intact SAN is a heterogeneous structure that includes multiple different cell types interacting with each other, the relative importance of the voltage and Ca2+ clocks for pacemaking may be variable in different regions of the SAN. Recently, we performed optical mapping in isolated and Langendorff-perfused canine right atria. We mapped the intracellular calcium (Cai) and membrane potentials of the intact SAN simultaneously. Using previously described criteria of the timing of the late diastolic Cai elevation (LDCAE) relative to the action potential upstroke to detect Ca2+ clock activity, we demonstrated that the sinus rate increased and the leading pacemaker shifted to the superior SAN with the robust LDCAE during β-adrenergic stimulation. We also showed that the LDCAE was caused by spontaneous diastolic SR Ca2+ release and was closely related with heart rate changes. We conclude that the Ca2+ and voltage clocks work synergistically to generate SAN automaticity

Successful Catheter Ablation of Atrial Tachycardia Originating from the Non-coronary Aortic Sinus

We report a rare case of atrial tachycardia originating from the non-coronary aortic sinus. After failed radiofrequency (RF) energy applications at right His-bundle region, the complete elimination of atrial tachycardia was achieved with an RF energy application in the non-coronary aortic sinus. With the review of other papers, this report emphasizes the importance of mapping in the non-coronary aortic sinus in focal atrial tachycardia near the atrioventricular node or near the Hisbundle

Use of a Tunneling Technique to Achieve a Lower Defibrillation Threshold during Implantable Cardioverter Defibrillator Implantation via the Right Subclavian Vein

A 56-yr-old man with aborted sudden cardiac death underwent implantable cardioverter defibrillator (ICD) implantation. While the ICD was being implanted, a left subclavian venogram failed to visualize the left subclavian vein, which was attributed to likely prolonged indwelling of the left subclavian sheath for venous access. Accordingly, the right subclavian vein was punctured and the ICD lead was diverted from the right side area to the active Can in the left pectoral area by tunneling over the sternum for high defibrillation threshold. The approach used in this case may be considered in patients who had difficult left subclavicular venous access and it may be prudent to save the left subclavian vein for ICD implantation in patients with fatal tachyarrhythmia

Heart Rate Acceleration of a Subsidiary Pacemaker by β-Adrenergic Stimulation

BACKGROUND AND OBJECTIVES: Recent evidence indicates that the membrane voltage and Ca(2+) clocks jointly regulate sinoatrial node (SAN) automaticity. However, the mechanism of heart rhythm acceleration of the subsidiary pacemaker (SP) during β-adrenergic stimulation is still unknown. Here we tested the hypothesis that the heart rate acceleration of the SP by β-adrenergic stimulation involves synergistic interactions between both clock mechanisms. SUBJECTS AND METHODS: We performed optical mapping and pharmacological interventions in 15 isolated Langendorff-perfused canine right atriums (RA). The SP model was produced by ligation of the SAN artery at the mid portion of the sulcus terminalis. RESULTS: In the 6 RAs with an intact SAN, 1 µmol/L isoproterenol infusion increased the heart rate from 82±9 to 166±18 bpm (102%) with late diastolic Ca(i) elevation (LDCAE) at the superior SAN. However, in the 6 SP models, the heart rate increased from 55±10 bpm to 106±11 bpm (92%, p=0.005) without LDCAE at the earliest activation site. The isoproterenol induced heart rate increase was reversed to 74±5 bpm (33% from baseline) by administering an infusion of the funny current blocker ZD 7288 (3 µmol/L, n=3), whereas, it was suppressed to 69±7 bpm (24% from baseline) by sarcoplasmic reticulum (SR) Ca(2+) emptying with administering ryanodine (10 µmol/L) plus thapsigargin (200 nmol/L, n=3). The isoproterenol induced heart rate increase was completely abolished by combined treatment with funny current blocker and SR Ca(2+) emptying (n=3). CONCLUSION: Acceleration of the Ca(2+) clock in the SP plays an important role in the heart rate acceleration during β-adrenergic stimulation, and this interacts synergistically with the voltage clock to increase the heart rate.ope

Carvedilol Analogue Modulates both Basal and Stimulated Sinoatrial Node Automaticity

The membrane voltage clock and calcium (Ca(2+)) clock jointly regulate sinoatrial node (SAN) automaticity. VK-II-36 is a novel carvedilol analog that suppresses sarcoplasmic reticulum (SR) Ca(2+) release but does not block the β-receptor. The effect of VK-II-36 on SAN function remains unclear. The purpose of this study was to evaluate whether VK-II-36 can influence SAN automaticity by inhibiting the Ca(2+) clock. We simultaneously mapped intracellular Ca(2+) and membrane potential in 24 isolated canine right atriums using previously described criteria of the timing of late diastolic intracellular Ca elevation (LDCAE) relative to the action potential upstroke to detect the Ca(2+) clock. Pharmacological interventions with isoproterenol (ISO), ryanodine, caffeine, and VK-II-36 were performed after baseline recordings. VK-II-36 caused sinus rate downregulation and reduced LDCAE in the pacemaking site under basal conditions (P < 0.01). ISO induced an upward shift of the pacemaking site in SAN and augmented LDCAE in the pacemaking site. ISO also significantly and dose-dependently increased the sinus rate. The treatment of VK-II-36 (30 μmol/l) abolished both the ISO-induced shift of the pacemaking site and augmentation of LDCAE (P < 0.01), and it suppressed the ISO-induced increase in sinus rate (P = 0.02). Our results suggest that the sinus rate may be partly controlled by the Ca(2+) clock via SR Ca(2+) release during β-adrenergic stimulation

Successful Catheter Ablation of Focal Automatic Left Ventricular Tachycardia Presented with Tachycardia-Mediated Cardiomyopathy

Non-reentrant focal tachycardias occur spontaneously, facilitated by catecholamine infusion, but they cannot be initiated or terminated with programmed stimulation. These tachycardias exhibit early activation before the QRS, however, do not typically show the mid-diastolic potential that is crucial for reentrant tachycardia maintenance. Electrophysiological studies are useful for distinguishing focal from macro-reentrant ventricular tachycardia. We report herein a case of patient without a history of structural heart disease who presented with a focal Purkinje ventricular tachycardia and heart failure. The focal Purkinje ventricular tachycardia was eliminated by radiofrequency catheter ablation. All of the patien's symptoms were improved after ablation