DISCUSSION
This is the first case series reporting the acute and long-term results
of a novel anatomical approach for SNM to treat IST targeting the AR
under ICE guidance. The main findings of our study are as follows: 1.
ICE allowed real-time visualization of the lateral and septal aspects of
the AR at the level of the SVC-RA junction; 2. RF applications at the AR
earliest activation site during maximally tolerated isoproterenol
infusion (up to 10 mcg/min), produced a suboptimal reduction of the HR
in all patients; 3. Extending the ablation lesion set from the earliest
site at the AR towards its septal region led to acute and long-term
modulation of the SN in all patients without the need to extend the
ablation lesion set towards the lateral/posteroinferior extension, thus
avoiding risk for PN damage or SN dysfunction.
The importance of the recognition of the AR for SNM by ICE was
previously described by Asirvatham et al. who reported a case of a
48-year-old woman with multiple failed ablation procedures for IST
performed at the high posterolateral RA earliest site of
activation7. The patients underwent a repeat procedure
showing early activation at the lateral aspect of the SCV-RA. However,
detailed 3D mapping under ICE visualization demonstrated an even earlier
activation site in the AR area, where RFA was effective and led to
definitive control of the patient’s arrhythmia and symptoms. In our
study, ICE also facilitated the identification of the AR early
activation sites, initially masked in all the patients during contact
activation mapping, by extrapolation of early activation sites between
the SCV and the RA. Our approach included correction of this
extrapolation based on tagged points on the surface of the AR, taken
with the ablation catheter under ICE guidance, and including those
activation points on the corrected anatomy, which included the AR. Based
on our case experience and anatomical understanding of this region, we
believe AR recognition by ICE increases procedure efficacy and safety,
by focusing the mapping and ablation efforts on the AR and preventing
unnoticed ablation inside the right atrial appendage. Notably, mapping
and ablation of the earliest activation sites alone did not produce the
desired HR reduction of around 25%. However, an anatomic extension of
the ablation lesion set towards the septal aspect of the AR, performed
independently of the local activation times, produced a transient HR
increment followed by a significant HR reduction >25% and
a change in the P wave axis. These findings suggest that part of the SN
complex was located in the septal region, but it was not identified by
the activation mapping under the isoproterenol effect. Notably, the
reduction of the HR was sustained during follow-up, measured by cardiac
monitoring and stress ECG, and associated with symptomatic relief.
Despite the encouraging results of this novel anatomic approach to
modulate the SN, our investigation does not provide insight into the
mechanistic role of the septal aspect of the AR on IST. Furthermore,
empirically extending the ablation target to the septal and not the
lateral region of the AR, may not achieve the desired HR modulatory
effect in some patients, owing to different characteristics in their SN
anatomy and extensions. Anatomical studies traditionally describe the SN
complex as a crescent-shape structure with a “comma” disposition, in
which the “head” lies subepicardial within the terminal groove, formed
by the lateral junction of the SCV with RA, and the “tail” extends
toward the posteroinferior aspect of the CT reaching the inferior vena
cava and RA junction9,10 (Fig. 1a). This usual
“comma” depiction of the SN complex on anatomic drawings, has directed
efforts of mapping and ablation for SNM to the lateral SVC-RA junction
where the PN resides. Although the “comma” anatomical disposition is
the most prevalent, a “horseshoe” arrangement of the SN has also been
found in around 12% of hearts9. In the “horseshoe”
arrangement, the SN complex is situated both medial (“head”) and
lateral (“tail”) to the mid-line of the SCV-RA junction at the
AR10 (Fig. 4 a, b). This anatomic variation of the SN
showing an extension towards the septal aspect of the SCV-RA junction
seems to be validated by the first “in situ” 3-D visualization of the
human cardiac conduction system performed by means of advanced imaging
tools of virtual CT dissection on human cadavers11(Fig. 4 c). Based on this anatomic variation, it is plausible that the
extension of RF ablation from the earliest activation site at the AR
towards its septal region could explain the results of our proposed
approach described in this study. As mentioned previously, the usual
target for SNM is defined as the earliest activation site on the AR
under the effect of Isoproterenol. A concept based on physiological
studies demonstrating shifting of earliest activation from the “tail”
to the “head “of the SN complex under progressive HR
increments4. However, if patients do not tolerate high
doses of Isoproterenol during the procedure, it is possible that the
most anterosuperior aspect and septal extension of the SN are not
activated, and therefore not targeted, leading to suboptimal results,
unless extending the lesion empirically towards the septal AR is
performed (electro-anatomical approach). Coincidentally, an
electroanatomic analysis of the sinus impulse propagation in normal
human atria has shown that the area of earliest activation in the RA has
a “spindle” shape in 5 of 7 patients and a “horseshoe” shape in the
remaining 2 located between the SCV-RA junction, which could represent
the functional characterization of this anatomic SN
variation12. Finally, it is possible that the
extension of RF delivery toward the septal aspect of the SCV-RA junction
at the AR in proximity to the interatrial groove could produce a
modification of the neural input of the SN with an additive
neuromodulatory effect. Interrupting autonomic nervous input to the
sinus node by isolating right pulmonary veins, superior vena cava, and
ablating fat tissue surrounding the sinus node is an integral part of
the surgical treatment of IST13. A recently published
SN sparing hybrid ablation technique including RF bipolar clamp
isolation of the superior and inferior vena cava and lateral ablation
line across the Crista terminalis while sparing the SN region (plus
adjunct RF endocardial touch-up to complete lesion sets in 46% of
cases); was compared to a conventional SNM approach (endocardial and/or
epicardial mapping and RF ablation at the site of earliest atrial
activation) in 100 consecutive patients (50 in each
group)14. The SN sparing hybrid ablation group showed
a significant acute and long-term improvement in mean daily heart rate
and peak 6-minute walk heart rate15. These results are
consistent with our small study population, but with a much more
simplistic approach. As mentioned previously, perhaps the anatomic
disposition of the SN complex with a “horseshoe” type and a regional
neuromodulatory effect explains why our conservative approach led to
excellent acute and long-term results.
Beyond the anatomical explanation of plausibility, it seems that the
neuromodulation could play an important role in our results. First, in
the body of the sinus node, there is a higher concentration of
sympathetic neurons compared to parasympathetic postganglionic
neurons16. Since the target of our approach is the
body of the sinus node, the ratio of sympathetic neurons removed
compared to parasympathetic neurons would be greater, with a result of a
predominance of the parasympathetic ones. This is a simplistic
explanation; however. As we mentioned in our approach, ablation lesions
were extended towards the septal region of the AR where the dorsal right
atrial ganglionated subplexus (DRAsGP) is located. DRAsGP spread widely
into the dorsal and lateral right atrium, including the sinoatrial nodal
region and the superior surface of the right atrial
appendage17. The ablation effect on sympathetic and
parasympathetic neurons may explain an improved regulatory effect over
the SN hyperactivity seen in IST patients, but this autonomic
interaction is more complex than a simple calculation of the number of
fibres or GPS ablated.
One question yet to be resolved is why, despite an inadvertent
parasympathetic ganglion modulation, a decrease in heart rate was
documented in our results. The answer to this question can be addressed
by a feature of the sinus node known as functional inhomogeneity, which
refers to the difference in the concentration of autonomic receptors
along the sinus node, and how 3 areas in the sinus node can be
discriminated that have a different response to neurohumoral influences.
When performing our ablation approach, the target would be the upper
part of the sinus node, leaving cells with a diminished response to
neurotransmitters as a guide for the pacemaker. On the contrary, if the
conventional ablation method is chosen, it is likely that the target
will be cells from the upper zone and transition, leaving cells with a
high sensitivity to adrenaline as a subsidiary pacemaker and it could
explain why patients could persist with tachycardia18.
Finally, after explaining our findings from an anatomical and functional
point of view, another possible explanation could be the injury to the
sinus node artery. Scanavacca et al19 published a case
series, where they documented injury to the sinus node artery after
performing cardiac denervation procedures with a frequency of 4.76%.
This was presented and confirmed by CT after performing ablation in the
area of the cavo-atrial junction and the area between the SVC and the
aorta, the latter is a target for ablation in our approach for
modulation of the sinus node, however in none of our patients presented
acute signs of sinus dysfunction.