title: Cardiac resynchronization therapy and phase resetting of the sinoatrial node: a conjecture.
abstract: Congestive heart failure is a severe chronic disease often associated with disorders that alter the mechanisms of excitation-contraction coupling that may result in an asynchronous left ventricular motion which may further impair the ability of the failing heart to eject blood. In recent years a therapeutic approach to resynchronize the ventricles (cardiac resynchronization therapy, CRT) has been performed through the use of a pacemaker device able to provide atrial-based biventricular stimulation. Atrial lead senses the spontaneous occurrence of cells depolarization and sends the information to the generator which, in turn, after a settled delay [atrioventricular (AV) delay], sends electrical impulses to both ventricles to stimulate their synchronous contraction. Recent studies performed on heart rate behavior of chronically implanted patients at different epochs after implantation have shown that CRT can lead to sustained overall improvement of heart function with a reduction in morbidity and mortality. At this moment, however, there are no studies about CRT effects on spontaneous heart activity of chronically implanted patients. We performed an experimental study in which the electrocardiographic signal of five subjects under chronic CRT was recorded during the activity of the pacemaker programmed at different AV delays and under spontaneous cardiac activity after pacemaker deactivation. The different behavior of heart rate variability during pacemaker activity and after pacemaker deactivation suggested the hypothesis of a phase resetting mechanism induced by the pacemaker stimulus on the sinoatrial (SA) node, a phenomenon already known in literature for aggregate of cardiac cells, but still unexplored in vivo. The constraints imposed by the nature of our study (in vivo tests) made it impossible to plan an experiment to prove our hypothesis directly. We therefore considered the best attainable result would be to prove the accordance of our data to the conjecture through the use of models and physical considerations. We first used the data of literature on far-field effects of cardiac defibrillators to prove that the pacemaker impulses delivered to the two ventricles were able to induce modifications in membrane voltage at the level of the SA node. To simulate a phase resetting mechanism of the SA node, we used a Van der Pol modified model to allow the possibility of changing the refractory period and the firing frequency of the cells separately. With appropriate parameters of the model we reproduced phase response curves that can account for our experimental data. Furthermore, the simulated curves closely resemble the functional form proposed in literature for perturbed aggregate of cardiac cells. Despite the small sample of subjects investigated and the limited number of ECG recordings at different AV delays, we think we have proved the plausibility of the proposed conjecture.
authors.affiliation: Institute of Clinical Physiology, CNR, via Moruzzi, 1- Pisa, 56124 Italy. cantini@ifc.cnr.it
authors.forename: Federico
authors.initials: F
authors.lastname: Cantini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Varanini
authors.forename: Alberto
authors.initials: A
authors.lastname: Macerata
authors.forename: Marcello
authors.initials: M
authors.lastname: Piacenti
authors.forename: Maria-Aurora
authors.initials: MA
authors.lastname: Morales
authors.forename: Rita
authors.initials: R
authors.lastname: Balocchi
mesh_terms: D000200:Action Potentials; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology* / Q000517:prevention & control*; D001683:Biological Clocks; D002304:Cardiac Pacing, Artificial / Q000379:methods*; D003198:Computer Simulation; D006333:Heart Failure / Q000503:physiopathology* / Q000517:prevention & control; D006801:Humans; D008955:Models, Cardiovascular; D009200:Myocardial Contraction; D009991:Oscillometry / Q000379:methods; D012849:Sinoatrial Node / Q000503:physiopathology*; D013813:Therapy, Computer-Assisted / Q000379:methods