Ventricular fibrillation (VF) is a major cause of sudden death, and sympathoexcitation is strongly associated with VF initiation, which can occur in a structurally normal heart. Steep repolarization gradients (RGs) have been shown to be characteristic of cardiac substrates that permit VF, with functional reentry as a key driving mechanism in structurally normal hearts. We hypothesized that due to regional innervation by cardiac sympathetic nerves, sympathoexcitation may result in stepper RGs which may underlie the relationship between sympathetic activation and VF in structurally normal hearts. The aim of this project was to examine whether sympathoexcitation alters the RG in normal hearts and whether during the initiation of VF steep RGs are present.
Repolarization times (RTs) were recorded using a 64-electrode array placed on the ventricular epicardium of 11 healthy pigs at baseline (BL) and during right and left stellate ganglion stimulation (RSGS, LSGS respectively). Left and right stellate ganglia were stimulated with repeated square-wave pulses at a frequency of 4Hz, 4ms duration for 30 seconds. Stimulation amplitude was set at the amplitude at which blood pressure and/or heart rate increased by 10% (generally 1-8milliamps (mA)). Cardiac sympathetic activation was also confirmed by surface T-wave changes. Bi-polar electrodes were placed around each stellate ganglion (superior and inferior) for stimulation, with the cathode being superior. Spatial electrical maps were generated (MAP3D, Utah Bio-Computing) from which RGs were obtained at BL, and during RSGS and LSGS.
Global and maximal gradients were generated from these maps. RG was calculated using the equation below:
Repolarization gradient (ms/mm) = ∆ repol time between 2 electrodes/ distance between 2 electrodes
Given the stochastic nature of VF initiation during sympathoexcitation, we examined whether steeper RGs seen during SGS could initiate VF in 2-D simulation cardiac tissue, with the same dimensions as that mapped in the heart.
Mean RT shortened from 433±74 ms at BL to 375±55 ms during RSGS and 420±63 during LSGS across subjects (p=0.0091 for RSGS and p=0.122 for LSGS). Related to the pattern of innervation, RGs (ms/mm) at baseline (-4.05±18) were changed by RSGS to 6.97±8 and by LSGS to 4.63±7. To demonstrate that the RGs are steepened by SGS, beta-adrenergic receptor blockers were administered during SGS, which reduced the magnitude of the RG. Two episodes of spontaneous VF occurred during sympathoexcitation. In one episode, RG was increased by (219 %) and in the other, RG was not significantly changed (5.5 ms/mm to 5.0 ms/mm). Since spontaneous VF is uncommon (and stochastic), we examined whether simulating basal and sympathoexcited RGs seen in experiments would result in VF. RT data from experimental conditions were simulated in 2-D tissue using a rabbit ventricular action potential model. Appropriately timed premature stimuli resulted in VF in tissue matching RGs during sympathoexcitation (9.2ms/mm) but not at basal states (6.0ms/mm).
These data suggest the hypothesis that altered RGs during sympathoexcitation contribute to VF risk. However, additional studies are needed to provide conclusive evidence to show the effect of sympathoexcitation on RG.