S in u s Node S paring Hyb r id Thoracoscopic Ablation O ut comes in P a tients with I nappropriate S inus T achycardia (SUSRUTA-IST) Registry

BACKGROUND Medical treatment of inappropriate sinus tachycardia (IST) remains suboptimal. Radiofrequency sinus node (RF-SN) ablation has poor success and higher complication rates. OBJECTIVE We aimed to compare clinical outcomes of the novel SN sparing hybrid ablation technique with those of RF-SN modi ﬁ cation for IST management. METHODS This is a multicenter prospective registry comparing the SN sparing hybrid ablation strategy with RF-SN modi ﬁ cation. The hybrid procedure was performed using an RF bipolar clamp, isolating superior vena cava/inferior vena cava with the creation of a lateral line across the crista terminalis while sparing the SN region (iden-ti ﬁ ed by endocardial 3-dimensional mapping). RF-SN modi ﬁ cation was performed by endocardial and/or epicardial mapping and ablation at the site of earliest atrial activation. RESULTS Of the 100 patients (hybrid ablation group, n 5 50; RF-SN group, n 5 50), 82% were women, and the mean age was 22.8 years. Normal sinus rhythm and rate were restored in all patients in the hybrid group (vs 84% in the RF-SN group; P 5 .006). Hybrid ablation was associated with signi ﬁ cantly better improvement in mean daily heart rate and peak 6-minute walk heart rate compared with RF-SN ablation. The RF-SN group had a signi ﬁ cantly higher rate of redo procedures (100% vs 8%; P , .001), phrenic nerve injury (14% vs 0%; P 5 .012), lower acute pericarditis (48% vs 92%; P , .0001), permanent pacemaker implantation (50% vs 4%; P , .0001) than did the hybrid ablation group. CONCLUSION The novel sinus node sparing hybrid ablation procedure appears to be more ef ﬁ cacious and safer in patients with symptomatic drug-resistant IST with long-term durability than RF-SN ablation.


Introduction
Inappropriate sinus tachycardia (IST) is a cardiac dysautonomic disorder characterized by a resting heart rate (HR) of more than 100 beats/min, a mean 24-hour HR of more than 90 beats/min, and an exaggerated response to exercise or stress and associated with debilitating symptoms-palpitations, generalized weakness, dizziness, tremors, exercise intolerance, and near syncope. 1,2 There exists no long-term, prospective, placebo-controlled clinical trial demonstrating any significant improvement in clinical outcomes.
Pharmacotherapy remains the first-line treatment of IST with b-blockers, calcium channel blockers, or ivabradine (I f channel blocker) with relatively low success. 2 The duration of medical therapy might be indeterminate, with a substantial number of patients either responding inadequately or having no response, despite prolonged therapy. Radiofrequency (RF) catheter ablation involving sinus node (SN) modification has been a potential alternative in these patients with IST refractory to medical therapy, although associated with limited long-term procedural efficacy and a high symptom recurrence rate. 3 Studies have demonstrated long-term freedom from IST at 6-month follow-up ranged from 23% to 85%, 4-6 with high procedural complications-permanent pacemaker implantation, phrenic never paralysis, or transient superior vena cava (SVC) syndrome. 3,7 Alternatively, more recently, a novel SN sparing hybrid thoracoscopic ablation procedure has been reported with promising initial results. 8 There is evolving evidence to confirm that pacemaker activity is not just limited to the superior aspect of the sinoatrial node (SAN). There are 2 spatially distinct dominant pacemakers: a superior SAN near the SVC and an inferior SAN near the inferior vena cava (IVC). The postganglionic sympathetic inputs feed into these areas along with the crista terminalis (CT). 9 So, a hybrid lesion set that isolates both the superior and inferior SANs and regional sympathetic denervation with a hybrid ablation lesion set probably results in the effective outcomes noted in early clinical studies. 8,9 The current literature on the nonpharmacological therapeutic interventions for IST is limited, with no clear consensus on its management-RF-SN modification vs surgical or hybrid thoracoscopic ablation approach. 10 Therefore, we aimed to compare clinical outcomes of the SN sparing hybrid ablation approach with RF-SN modification for IST management.

Methods
This is a multicenter prospective registry comparing the SN sparing hybrid ablation strategy using surgical thoracoscopic video-assisted epicardial ablation combined with concomitant endocardial 3-dimensional (3D) mapping and ablation (n 5 50) with standard catheter-based RF-SN modification (n 5 50) ( Figure 1). The diagnosis of IST was made after ruling out other primary causes of sinus tachycardia. All patients had failed to respond to the maximum tolerated doses of pharmacological therapy (b-blockers, calcium channel blockers, or ivabradine) before being considered for ablation. All patients underwent baseline 12-lead electrocardiography to assess the P-wave morphology and were monitored through an implantable loop recorder to assess average daily HR trends and activity levels. The additional evaluation included preprocedure transthoracic echocardiography, cardiac computed tomography, cardiac magnetic resonance imaging, and exercise stress testing on the basis of the patient's clinical situation and the treating physician's discretion. The study was approved by the human subject committee and institutional review board. The CONSORT diagram of patient selection is depicted in Figure 1.

Electrophysiology study, mapping, and ablation
Hybrid thoracoscopic ablation with adjunct endocardial mapping The hybrid thoracoscopic ablation strategy for IST has been previously described. 8 Briefly, antiarrhythmic drugs and bblockers were discontinued at least 5 half-lives before ablation. All procedures were performed under general anesthesia with intubation and mechanical ventilation (without using paralytic agents). After single lung ventilation (and right lung deflation), the right side of the chest was accessed via three 5-mm ports-midaxillary port for camera access and the anterior axillary port at the level of third and seventh intercostal spaces, respectively, for instruments (locations Figure 1 Flowchart showing the 2 patient (Pt) cohorts undergoing hybrid ablation and radiofrequency sinus node ablation. of these ports varied slightly depending on individual patient anatomy). Subsequently, CO 2 was insufflated at up to 8 mm Hg to increase the working space (by pushing the diaphragm inferiorly and the heart leftward). Using endoscopic coagula-tion hook and scissors, pericardial space was accessed 2 cm anterior to the right phrenic nerve (toward the SVC and IVC, respectively). The oblique sinus was then exposed by reflecting the pericardium around the IVC ( Figure 2).  Simultaneous bilateral femoral vein accesses were obtained using the modified Seldinger technique and ultrasound guidance. All patients underwent a 3D activation map of the right atrium (RA) by using a multipolar mapping catheter and an appropriate compatible mapping system (CARTO-3 [24%] or NavX, EnSite Precision [76%]). After the creation of the activation map, a bipolar RF clamping device (EMR, AtriCure Inc., Mason, OH) was positioned near the SVC-RA and IVC-RA junction, respectively. Subsequently, ablation was performed along the CT (with the posterior jaw in the oblique sinus and anterior jaw over the Waterston groove). The final lesion set included ablation along the SVC-RA junction and IVC-RA junction and consequently connecting the lesion set laterally along the CT (on the basis of the embryological development of the venous heart pole). 11 Adjunct endocardial ablation was performed in select patients (46% of patients) to complete the linear ablation procedure along the CT connecting the SVC and IVC ( Figure 3). The end point of ablation was at least a 25% reduction in HR acutely or accelerated junctional rhythm as defined in multiple previous studies. 4,5,8,[12][13][14] After the completion of the lesion set, junctional rhythm ensues, with subsequent recovery of slow sinus rhythm. The pericardial reflections were subsequently closed, and the right lung was reinflated. Patients recuperated in the intensive care unit (ICU) until the pericardial drain was removed.

Conventional endocardial and epicardial mapping and ablation
Bilateral femoral vein access was obtained using the modified Seldinger technique and ultrasound guidance. A baseline electrophysiology study was performed (both on and off isoproterenol infusion and during the washout period) to exclude other mechanisms of supraventricular tachycardia. Epicardial access was obtained using the micropuncture needle as needed (48% of patients [n 5 24]). Subsequently, a steerable epicardial sheath was positioned in the pericardial space. A detailed 3D epicardial and endocardial activation map of the RA was created using a multipolar mapping catheter and appropriate compatible mapping system (CARTO-3 [44%] or EnSite Precision [40%] or Rhythmia [12%]). High output pacing with phrenic nerve capture was used to trace the course of the phrenic nerve. To deflect the phrenic nerve away from the site of earliest activation, the peripheral vascular balloon was then advanced through the steerable sheath and positioned epicardially and inflated with contrast. High output pacing confirmed no phrenic nerve capture at the site of earliest activation. RF ablation was performed at the site of earliest atrial activation endocardially and epicardially (as needed) ( Figure 4).
All patients received postprocedural intrapericardial steroids and/or colchicine to prevent acute postprocedural pericarditis. For patients who underwent hybrid ablation, patient-controlled analgesia was also administered. HR was monitored using the implantable loop recorders. Preprocedural and postablation mean daily HRs were determined at 3, 6, and 12 months. A 6-minute walk test was administered, and peak HR was assessed at baseline and during the followup period.

Clinical outcomes
The primary outcome of the study was restoration of sinus rhythm and reduction in mean daily HR during the follow-up period. The secondary outcomes of the study were (1) number of redo ablation procedures, (2) procedure-related complications and the need for a permanent pacemaker (acutely postablation and during the follow-up period), and (3) assessment of quality of life (QoL) -SF-36 scoring system, anxiety -Self-rating Anxiety Score (SAS), and depression -Zung Self-rating Depression Score (SDS) scores pre-and post intervention.

Statistical analysis
Continuous variables were summarized using mean 6 SD, while categorical variables were summarized as count and percentage of the total. Comparison analysis between groups was performed using an unpaired t test, Mann-Whitney U test, c 2 test, or Fisher exact, as appropriate. The SF-36 QoL domain values, SAS, and SDS scores are expressed as the median and interquartile range for survey assessments. All tests were 2-tailed, and a P value less than .05 was considered statistically significant. All statistical analyses were performed using STATA SE 14.0 (StataCorp, College Station, TX) and GraphPad Prism 8 (GraphPad Software, La Jolla, CA).

Preprocedure patient characteristics
A total of 100 patients (hybrid ablation group, n 5 50; RF-SN ablation group, n 5 50) were included in the study, of whom 82% were women, and the mean age was 22.8 6 0.75 years. The 2 groups were well balanced with respect to major baseline demographic characteristics. The only significant difference between the 2 groups was low mean resting HR and increased fraction of patients treated with ivabradine or class Ic antiarrhythmic agents in the hybrid ablation group than in the RF-SN group. Forty percent of patients in the hybrid ablation group vs 24% in the RF-SN group (P 5 .13) had prior electrophysiology study to treat typical atrial flutter and atrioventricular reentrant tachycardia. Table 1 highlights the baseline characteristics of the study population.

Acute clinical outcomes
All procedures (in both groups) were performed under general anesthesia (without any paralytic use). The mean sinus rates were significantly higher in the RF-SN group than in the hybrid ablation group both during the resting state and in the electrophysiology laboratory (114.84 61:22 beats/min vs 111.3 61:29 beats/min; P , .0001 and 118.8 6 1:43 vs 111.76 6 5:96 beats=min}, respectively; P , .0001, respectively). The sinus rates during isoproterenol infusion were Values are presented as mean 6 SD or n (%). AVNRT 5 atrioventricular node reentry tachycardia; HR 5 heart rate; RF 5 radiofrequency. similar in the RF-SN group and in the hybrid ablation group (149.58 61:68 vs 146:7561:33 respectively; P 5 .5).
After SN modification, a significant reduction in sinus rates were observed in the hybrid ablation group (61 6 9:32 beats/ min or 976 6 22.9 ms) as compared with the RF-SN group (82.28 6 2:38 or 811624:3 msÞðP,:0001 for bothÞ. Acutely postablation, a higher number of patients in the hybrid ablation group exhibited junctional rhythm (56%) vs the RF-SN group (22%) (P , .001). Normal sinus rhythm was restored in all patients in the hybrid ablation group vs 84% in the RF-SN group (P 5 .006) postablation. Table 2 highlights the acute clinical outcomes and ablation characteristics of the study population.

Impact on the mean resting HR and 6-minute walk HR response
Patients in the hybrid ablation group had a significant improvement in mean daily HR at 3, 6, and 12 months as compared with patients in the RF-SN ablation group. A similar improvement was seen in HR response to the 6minute walk test (Table 2) (Online Supplemental Figure 1).

Length of hospital stay and procedure complications
Patients in the hybrid ablation group had increased ICU stay as compared with those in the RF-SN group (1.12 6 0:22 vs 0.2 6 0.12; P , .0001). Conversely, the non-ICU stay was significantly higher in the RF-SN group than in the hybrid ablation group (4.2 6 1.5 vs 2.92 6 0:31; P,:0001Þ: Acute pericarditis was the most common complication (n 5 70) and, as expected, higher in the hybrid ablation group (n 5 46) than in the RF-SN group (n 5 24) (92% vs 48%; P , .0001). There were no cases of phrenic nerve injury in the hybrid group vs 14% of patients (n 5 7) with right hemidiaphragm stunning in the RF-SN group (P , .01). No patients in either group required conversion to an open surgical intervention. Six percent of patients in the hybrid ablation group (n 5 3) experienced pleural effusion (Table 3).

Long-term clinical outcomes
All patients in the RF-SN ablation group underwent a redo ablation procedure as compared with only 8% of patients in the hybrid ablation group during the follow-up period. Thirty-six percent of patients in the RF-SN group had 3 procedures, and 8% had 4 procedures for symptomatic reentrant tachycardias. These were mostly due to the gaps in the crista lesion set. Seventy-eight percent of patients in the hybrid ablation group (n 5 22) were able to discontinue all their rate-controlling drugs after the first procedure, while 100% of patients in the RF-SN group (n 5 50) needed to stay on the drugs. Six percent of patients reported recurrent palpitations in the hybrid ablation group, but were not symptomatic Values are presented as mean 6 SD or n (%). HR 5 heart rate; RF-SN 5 radiofrequency sinus node.
enough to necessitate redo ablation or medication initiation. In patients (n 5 70) who developed acute postprocedure pericarditis, only 10 patients (14.28%; hybrid ablation group, n 5 4; RF-SN group, n 5 6) exhibited chronic pericarditis during the follow-up period. There was a higher prevalence of pacemaker implantation in the RF-SN group than in the hybrid ablation group (50% vs 2%, respectively; P , .0001) for chronotropic incompetence. Of the 7 patients in the RF-SN group who exhibited right hemidiaphragm stunning, 4 (57.14%) had persistent right hemidiaphragm paralysis during follow-up ( Table 3).

Impact of the procedure on anxiety, depression, and QoL scores
There was a significant improvement in the SAS, SDS, and most of the SF-36 functional domain scores from baseline to 6 months postprocedure in both groups. However, the improvement in the scores was much higher in the hybrid ablation group than in the RF-SN group (Online Supplemental Table 1).

Discussion
Our study demonstrates that the SN sparing novel hybrid ablation approach appears to be efficacious and safe in patients with symptomatic drug-resistant IST with long-term durability. The main findings of our study are as follows: (1) the hybrid ablation approach was effective in restoring normal sinus rhythm and rate acutely and maintaining an acceptable mean daily HR and peak HR after the 6-minute walk test at follow-up through 12 months as compared with the RF-SN approach; (2) the hybrid ablation technique required significantly lower repeat ablation procedures than did RF-SN ablation; (3) hybrid ablation was associated with a higher incidence of acute pericarditis with no significant difference in long-term symptoms of pericarditis; (4) the RF-SN group had a higher risk of phrenic nerve injury and SN injury needing a permanent pacemaker (50%); and (5) both ablation approaches improved anxiety, depression, and several domains of SF-36 QoL bodily function domain scores, with a higher improvement in the hybrid ablation group.
The SN is a crescent or ellipsoid-shaped structure located subepicardially within the sulcus terminalis with its superior extension along the SVC-RA junction and an inferior extension along the CT (Figure 2). SN modification for IST is therefore technically challenging primarily owing to the need for extensive ablation in the superior RA and the risk of inadvertent phrenic nerve injury (that runs posterolateral to the SVC and along the lateral RA). 4,15 In addition, the SN exhibits a broad area of activation with multiple migratory subsidiary activation foci (Online Supplemental Figure 2), thus limiting the long-term freedom from arrhythmia recurrence, unlike other focal arrhythmias such as atrial tachycardia-thus accounting for multiple redo catheter ablation procedures. 16,17 Epicardial mapping and ablation are often performed as an adjunct to endocardial ablation to achieve long-term procedure success. Although this approach allows for targeting the site of earliest atrial activation epicardially and displacement of the right phrenic nerve (via inflation of the noncompliant peripheral balloon in the pericardial space), the long-term success rate with this approach has been variable. 15 This is primarily driven by the failure to achieve a transmural lesion (due to thick CT) and anatomical barriers (phrenic nerve and epicardial coronary artery), thus impeding long-term procedure success, as noted in our study where all patients in the RF-SN group underwent redo ablation. Hybrid thoracoscopic ablation for the treatment of IST is, therefore, a viable alternative where the phrenic nerve can be moved away from the target site, successfully isolating the SAN area from the right atrial sympathetic inputs. Once the pericardium is open, ablation from the endocardial surface is harder as the tissue does not offer much stability. It is much easier and safer to fill in the gaps with smaller lesions. We suspect that performing an effective endocardial lesion set without the support of the pericardium outside the RA is probably a much difficult task. The hybrid ablation approach could reduce procedure-related complications and improve the long-term procedure success rate and patient's QoL. We believe that the hybrid ablation lesion set results in regional sympathetic denervation at the level of the RA while sparing the SN, thus explaining a more effective HR control, a reduced risk of SN injury, and the need for a permanent pacemaker. Values are presented as mean 6 SD or n (%). ICU 5 intensive care unit; RF 5 radiofrequency; VATS 5 video-assisted thoracoscopic surgery.
The surgical approach for the treatment of IST was first described in 1984 by Yee et al, 18 where circumferential incision in the RA was performed (dividing into the superior and inferior segments), eventually resulting in a junctional escape rhythm. With the advent of cryoablation and RF energy, surgical ablation has advanced significantly over the decadesthus avoiding surgical incision, reducing procedure time, and avoiding cardiopulmonary bypass. [19][20][21][22] Bipolar RF ablation clamps have been effective in creating transmural ablation lesions (as demonstrated in animal studies), which is a technical limitation of the currently available unipolar catheter-based RF ablation approach. 23 Thoracoscopic hybrid ablation is therefore advantageous over standard RF-SN ablation as shown in our study with a higher success rate because of (1) efficient energy delivery around the area of interest under direct visualization, (2) simultaneous endocardial activation mapping localizing the area of earliest atrial activation and precise ablation, and (3) minimal risk of phrenic nerve injury. This is the first study demonstrating that the SN sparing novel thoracoscopic hybrid ablation approach is more efficacious and safer than the conventional RF-SN modification approach in patients with symptomatic drug-resistant IST with long-term durability.
Despite its slightly higher level of invasiveness, the risk of complications associated with general anesthesia, pneumothorax, or conversion to open heart surgery remains low compared to the RF-SN ablation approach. 17 No patients in the hybrid ablation group required conversion to an open surgical intervention. Not unexpected, in our study, although patients in the hybrid group had increased ICU stay while the pericardial drain was in place postprocedurally and acute procedure-related pericarditis (managed medically), there were no long-term sequelae as compared with the RF-SN group. Unlike the RF-SN group, where repeated ablation procedures were needed to control the HR, ultimately resulting in SN injury (thus necessitating permanent pacemaker implantation), hybrid ablation was not associated with repeated ablation procedures and a significantly lower rate of pacemaker implantation. This not only suggests both short-and long-term procedure safety, but is also reflective of improved surgical expertise and greater institutional experience consistent with a learning curve, resulting in no pericardial complications and low incidence of overall complications and cardiac complication rates. Thus, given overall higher procedural safety and efficacy, as compared with RF-SN ablation, hybrid ablation could be considered as a viable therapeutic approach in patients with recurrent symptomatic IST refractory to medical therapy ( Figure 5).

Limitations
Several potential limitations deserve special mention. Since all procedures were performed by high-volume experienced operators, findings should not be generalized to lowvolume operators. Also, extensive experience with the hybrid ablation approach (ie, atrial fibrillation or ventricular arrhythmia ablation) explains minimal to no procedurerelated complications. The increase in the mean number of ICU stays after hybrid ablation could account for increased health care utilization; however, this can be partially equipoised by higher procedure success (thus avoiding redo ablation compared with RF-SN ablation) and low procedure-related complications. Although 1 previous study 8 (with no comparator arm) demonstrated procedural safety and efficacy, ours is the first study demonstrating the safety and effectiveness of the hybrid ablation approach compared with the RF-SN ablation approach.
The pathophysiology of IST is poorly understood, and the superiority of the hybrid approach cannot be clearly explained. The strategic isolation of the SVC/IVC/CT could probably result in regional sympathetic denervation while sparing the SN, thereby explaining the positive outcomes of the hybrid ablation procedure. Gaps in the lateral CT line can create iatrogenic reentrant atrial arrhythmias that might have to be dealt with, by a repeat procedure, even though such risk is lower (with only 2 patients having reentrant tachycardia because of the gap in the crista lesion that was promptly mapped and ablated), and longer follow-up data (beyond 12 months) are needed to ascertain. We did not have systematic Holter data from these patients to comment on the heart rate variablity changes pre-and post procedure. In the future, we should consider extensive autonomic investigation with vagal stimulation, acute stellate ganglion stimulation, and long-term heart rate variablity study to confirm the proposed sympathetic denervation theory. An appropriately sized multicenter randomized controlled trial will be needed to test the reproducibility of these results.

Conclusion
SN sparing novel hybrid ablation appears to be efficacious and safe in patients with symptomatic drug-resistant IST with better long-term durability than does RF ablation for SN modification.