Mechanisms of sinoatrial node dysfunction in a canine model of pacing-induced atrial fibrillation

Experimental protocol for induction of atrial fibrillation.

Atrial fibrillation and sinoatrial node dysfunction in vivo. A: Stored atrial electrogram (EGM) showing atrial fibrillation. B: Sinus pauses documented by Holter monitoring. (a) Sinus pause of 5.2 seconds during ventricular pacing at 90 bpm. (b) Sinus pause of 7 seconds during ventricular pacing at 50 bpm. p = P wave.

Impaired isoproterenol-induced heart rate increase in right atria (RA) from atrial fibrillation (AF) dogs. Isoproterenol dose–response curve was determined for 7 normal and 7 AF dogs. Compared to normal RA (squares), AF RA (circles) showed significantly impaired heart rate increase during isoproterenol infusion (P = .03).

Isoproterenol response of normal dogs. A: Epicardial photographs of perfused right atrial (RA) preparation with 35 × 35-mm optical field of view. B: Baseline. C: Isoproterenol infusion of 0.3 μmol/L. (a) RA V_m isochronal map. (b) Ca_i (red) and V_m (blue) tracings from superior (S), mid (M), and inferior (I) sinoatrial nodes. Note heart rate increase and shifting of the leading pacemaker site to the superior sinoatrial node with robust late diastolic Ca_i elevation (arrows). The unit of numbers on the RA V_m isochronal map is milliseconds. Earliest activation of the RA was considered as 0 ms. IVC = inferior vena cava; RAA = right atrial appendage; SVC = superior vena cava.

Complete absence of late diastolic Ca_i elevation in atrial fibrillation dogs during isoproterenol infusion. A: Epicardial photograph of a perfused right atrial (RA) preparation with 35 × 35-mm optical fields of view. B: Baseline. C: Isoproterenol infusion of 1.0 μmol/L. (a) RA V_m isochronal map. (b) Ca_i (red) and V_m (blue) tracings from superior (S), mid (M), and inferior (I) sinoatrial nodes. Late diastolic Ca_i elevation was not observed at any dosage of isoproterenol infusion. The unit of numbers on the RA V_m isochronal map is milliseconds. Earliest activation of the RA was considered as 0 ms. IVC = inferior vena cava; RAA = right atrial appendage; SVC = superior vena cava.

A: Transient late diastolic Ca_i elevation (LDCAE) in atrial fibrillation (AF) dogs during isoproterenol infusion. (a)–(c) show isoproterenol infusion of 0.03, 0.1, and 1.0 μmol/L, respectively. (a) Note isoproterenol-induced LDCAE at mid sinoatrial node (arrows) during isoproterenol infusion of 0.1 μmol/L. (c) Rhythm was generated from the inferior right atrium (RA). B: Complete absence of LDCAE in AF dogs during caffeine bolus injection. (a) Caffeine response in normal RA. Note increase of heart rate and superior shift of the leading pacemaker site with robust LDCAE (arrows). (b) Caffeine responses in AF RA. There was no LDCAE from the sinoatrial node. Heart rate was increased by acceleration of ectopic focus. Upper panels show RA V_m isochronal maps. Lower panels show Ca_i (red) and V_m (blue) tracings from superior (S), mid (M), and inferior (I) sinoatrial nodes, respectively. The unit of numbers on the RA V_m isochronal map is milliseconds. Earliest activation of the RA was considered as 0 ms. RAA = right atrial appendage; SVC = superior vena cava.

Origin of heart rhythm during acceleration of heart rate in each of the seven right atria (RAs) from atrial fibrillation (AF) dogs. A: AF RA without late diastolic Ca_i elevation (LDCAE) (n = 4). Note heart rate increase by acceleration of ectopic foci or inferior sinoatrial node (SAN) (black arrow). B: AF RA with transient LDCAE (n = 3). Note heart rate increase by LDCAE from mid SAN (red arrow). ISO = isoproterenol.

Impaired sarcoplasmic reticulum Ca²⁺ handing in atrial fibrillation (AF) dogs. A: Comparison of (a) slope of late diastolic Ca_i elevation (LDCAE), (b) slope of Ca_i upstroke, and (c) 90% Ca_i relaxation time measured from the superior sinoatrial node between normal and AF dogs at baseline and isoproterenol infusion. Responses after isoproterenol infusion are grouped by heart rate. B: Comparison of (a) sarcoplasmic reticulum Ca²⁺-ATPase 2a (SERCA2a) and ryanodine receptor (RyR) and (b) SERCA2a and phospholamban (PLB) at the superior sinoatrial node between normal and AF dogs. Upper and lower panels show representative immunoblot and relative values, respectively.