Discussion
Right and left sided OTVA are often considered to be the same entity.
They exhibit similar rates of inducibility during an
electrophysiological study, have similar findings on magnetic resonance
imaging and respond equally to both adenosine and verapamil, suggesting
a common underling electrophysiological mechanism (cyclic adenosine
monophosphate-mediated delayed afterdepolarisations) (8).
Embryologically, the outflow tracts are also both formed from a common
primitive heart tube, rather than having separate origins (8,9).
Adrenergic tone has been shown to be an important influence on all OTVA
(10). Furthermore, whilst the autonomic nervous system (ANS) influences
VE activity, the presence of modest burden ectopy has also been shown to
alter the activity of cardiac neurons and VE-induced cardiomyopathy can
be characterised by sympathetic hyperinnervation, which may exacerbate
arrhythmogenesis (11,12). This suggests a bidirectional relationship
between the ANS and VE.
Although these studies show mechanistic similarities between RVOT and
LVOT, we have demonstrated that the behaviour of OTVA across a 24-hour
period is dependent on SOO, which must imply a difference in the
underlying mechanisms, or perhaps a difference in the autonomic
influence on VE activity. We postulate that the differential balance
between the parasympathetic and sympathetic innervation may be different
in the two outflow tracts. This hypothesis is supported by canine
models, where a higher density of sympathetic fibres, compared to
parasympathetic fibres, has been identified in the RVOT (13). The
density of these fibres is also particularly high at sites where VE and
VT can be induced using high frequency electrical stimulation (14).
In human subjects, right-sided OTVA are known to be induced by periods
of wakefulness and activity and are less pronounced during periods of
sleep, further supporting a role for sympathetic hyperinnervation in the
RVOT (13–15). Aortic root ganglionic plexi, in the region of the LVOT,
have also been shown to have a higher relative density of
parasympathetic (cholinergic) neurons compared to sympathetic
(adrenergic) neurons (16).
Our data show that whilst the overall number of total VE as well as
bigeminy/trigeminy episodes was higher in the LVOT group, the
variability in both of these parameters was greater in the RVOT group,
with wide fluctuations in VE activity throughout a 24-hour period and a
greater probability of quiescent hours. This suggests that right-sided
OTVA appears to be responsive to changes in sympathetic tone, whereas
left-sided OTVA is less responsive to autonomic influences and has far
more consistent activity throughout the day and night. This may also
partially explain the predilection to LV systolic dysfunction that is
more commonly observed in left-sided OTVA since there are no periods
when the ventricle is given the opportunity to recover from the
mechanically deleterious effects of frequent ectopy (4,17). The greater
VE variability seen particularly in the morning hours (06:00-12:00) in
the RVOT cohort occurs during a period of transition from sleep to
wakefulness and a corresponding physiological surge in catecholamines
that is seen during these hours (18) and contrasts with the more stable
VE burden seen throughout the day in the LVOT cohort. This gives further
evidence for a key role of the ANS in the behaviour of these
arrhythmias.
Numerous morphological ECG algorithms have been developed to
differentiate OTVA with right and left sided SOO. However, these are
limited by the complex 3-dimensional anatomy of the outflow tracts
(3,5,6), where subtle variations in ECG electrode positioning, cardiac
rotation, or body habitus can all impact the QRS morphology of both
sinus and ectopic beats (5,19,20). Parameters developed in an attempt to
correct for cardiac rotation, such as TZI, correct for some but not all
such limitations.
In this study we have devised and validated two novel non-morphological
parameters for predicting SOO based on variations in ectopy activity
over a 24-hour period. When applied prospectively both parameters are
highly effective, with diagnostic accuracy comparing favourably to
current ECG prediction parameters. Our parameters would not be impacted
by cardiac rotation, chest wall shape or ECG electrode position. An
example case is displayed in Figure 4. In this case a 60 year old female
has OTVA with a LBBB morphology in which the ECG parameters offer
diverging opinions on the likely SOO; TZI predicting a left sided origin
and V2S/V3R a right sided origin. In this example our novel parameters
both predict that the SOO is right sided, which was confirmed on
mapping. Since a 24-hour ECG monitor is nearly universal in the
assessment of OTVAs, we find these two parameters to be particularly
useful and easy to implement in clinical practice with a high degree of
objectivity and reproducibility.