Epicardial injection of nanoformulated calcium into cardiac ganglionic plexi suppresses autonomic nerve activity and postoperative atrial fibrillation

Michael P. O’Quinn, MD, PhD,*† Kenneth J. Dormer, PhD, FAHA,‡ Jose F. Huizar, MD, FHRS,*† Kytai T. Nguyen, PhD,x Karoly Kaszala, MD, PhD, FAHA,*† Adam Sima, PhD,k Kenneth A. Ellenbogen, MD, FHRS,* Alex Y. Tan, MD*†

BACKGROUND Imbalanced activation of the cardiac autonomic nervous system triggers postoperative atrial fibrillation (POAF). Neuronal calcium overload induces apoptosis. We hypothesize that epicardial injection of timed-release nanoformulated CaCl2 (nCaCl2) into left atrial ganglionic plexi (GP) modulates autonomic function and suppresses POAF.

OBJECTIVE The purpose of this study was to determine whether nCaCl2 GP therapy suppresses POAF.

METHODS We used a novel canine model of POAF with implanted radiotelemetry to record nerve activity (NA) from the left stellate ganglion (SNA), left cardiac vagus nerve, and GP. At week 3, nCaCl2 (n 5 7) or vehicle control (sham; n 5 3) was injected into left pulmonary vein GP (LGP), followed by right pulmonary vein GP at week 4. Atrial effective refractory period (AERP) and atrial fibrillation vulnerability (AFV) were assessed in vivo. Resting and exercise NA and heart rate (HR) were assessed before and after LGP treatment.

RESULTS AERP decreased (P , .0001) and AFV increased (P 5 .008) at week 3 vs baseline. However, nCaCl2-LGP treatment reversed these changes and restored them to baseline after 1 week (P 5 .04). Subsequent nCaCl2–right pulmonary vein GP treatment further reduced AFV (P 5 .03). In contrast, AFV increased (P 5 .001) and AERP remained decreased (P 5 .01) 1 week after sham-LGP treatment vs baseline. nCaCl2-LGP treatment reduced NA from GP (P , .02) and NA from the left cardiac vagus nerve (P , .05) and increased SNA (P , .02). Despite increased SNA, HR was decreased (P , .01) with loss of HR-SNA correlation (R 5 0.62). After sham-LGP treatment, NA was unchanged and HR-SNA remained correlated (R 5 0.95). Histology confirmed nCaCl2-GP colocalization, apoptosis, and loss of immunoreactivity in nCaCl2-treated somas.

CONCLUSION Epicardial injection of nCaCl2 into left atrial GP induced neuroapoptosis and modulated autonomic function. This reversed a postoperative reduction in AERP and suppressed POAF.

KEYWORDS Animal model; Autonomics; Cardiac surgery; Neural modulation; Postoperative atrial fibrillation

Read full article