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Percutaneous Pulmonary Valve Implantation Alters Electrophysiologic Substrate

Background Percutaneous pulmonary valve implantation (PPVI) is first‐line therapy for some congenital heart disease patients with right ventricular outflow tract dysfunction. The hemodynamics improvements after PPVI are well documented, but little is known about its effects on the electrophysiologic substrate. The objective of this study is to assess the short‐ and medium‐term electrophysiologic substrate changes and elucidate postprocedure arrhythmias. Methods and Results A retrospective chart review of patients undergoing PPVI from May 2010 to April 2015 was performed. A total of 106 patients underwent PPVI; most commonly these patients had tetralogy of Fallot (n=59, 55%) and pulmonary insufficiency (n=60, 57%). The median follow‐up time was 28 months (7‐63 months). Pre‐PPVI, 25 patients (24%) had documented arrhythmias: nonsustained ventricular tachycardia (NSVT) (n=9, 8%), frequent premature ventricular contractions (PVCs) (n=6, 6%), and atrial fibrillation/flutter (AF/AFL) (n=10, 9%). Post‐PPVI, arrhythmias resolved in 4 patients who had NSVT (44%) and 5 patients who had PVCs (83%). New arrhythmias were seen in 16 patients (15%): 7 NSVT, 8 PVCs, and 1 AF/AFL. There was resolution at medium‐term follow‐up in 6 (86%) patients with new‐onset NSVT and 7 (88%) patients with new‐onset PVCs. There was no difference in QRS duration pre‐PPVI, post‐PPVI, and at medium‐term follow‐up (P=0.6). The median corrected QT lengthened immediately post‐PPVI but shortened significantly at midterm follow‐up (P<0.01). Conclusions PPVI reduced the prevalence of NSVT. The majority of postimplant arrhythmias resolve by 6 months of follow‐up.

C ongenital heart disease patients with right ventricular outflow tract (RVOT) dysfunction have an increased prevalence of arrhythmias associated with increasing age, prior cardiac surgeries, QRS duration (QRSd), and degree of pulmonary regurgitation and stenosis. 1,2 Percutaneous pulmonary valve implantation (PPVI) using the Melody (Medtronic Inc, Minneapolis, MN) valve has become a safe and feasible alternative treatment option to surgical pulmonary valve replacement. 3,4 Because PPVI does not include incisions in the RV myocardium, it serves as a better model to evaluate any hemodynamics and electrophysiologic substrate changes with pressure and volume load reduction. Improvements in hemodynamics parameters after the procedure have been demonstrated in several reports. [5][6][7][8][9] However, few reports have investigated changes in ECG parameters along with the prevalence and type of arrhythmias post-PPVI. 10,11 The goals of this study are to (1) describe the short-term and medium-term changes to the electrophysiologic substrate (as identified by surface ECG) in patients following PPVI and (2) determine the type and prevalence of arrhythmias (including premature ventricular complexes [PVCs], nonsustained ventricular tachycardia [NSVT], and atrial fibrillation/atrial flutter [AF/AFL]) in post-PPVI patients.

Methods
On obtaining full approval from the institutional review board at Washington University in St. Louis School of Medicine (waiver of consent), we undertook a retrospective chart review of patients who underwent PPVI in the pulmonary valve position at St. Louis Children's Hospital from May 1, 2010 to April 30, 2015. The previously described inclusion criteria for PPVI include (1) RV systolic pressure greater than two thirds of systemic with symptoms or (2) RV systolic pressure greater than three fourths of systemic in absence of symptoms or (3) moderate/severe pulmonary regurgitation with either symptoms or severe RV dysfunction or severe RV dilatation or impaired exercise capacity. 5,12 Patients were excluded if the Melody valve (Medtronic Inc, Minneapolis, MN) was implanted in the branch pulmonary arteries or tricuspid position (n=4). Patients were classified as having predominantly pulmonary insufficiency (PI) if they had at least moderate pulmonary regurgitation on echocardiography; they were classified as having predominantly pulmonary stenosis (PS) if they had a mean RVOT gradient ≥35 mm Hg on echocardiogram. When the gradient could not be determined due to poor acoustic windows, a systolic gradient ≥35 mm Hg during the catheterization was used as the inclusion criterion for the pulmonary stenosis group. Patients with both stenosis and insufficiency were included in the mixed-lesion group (PS/PI). Charts were then reviewed for demographic information, clinical and procedural characteristics, and electrophysiologic data (including ECGs, 24-hour Holter monitors, electrophysiology studies [EPS], cardiac rhythm device reports and transmissions, and telemetry). ECGs preprocedure, 24 hours postprocedure, and at last follow-up visit were analyzed. Corrected QT (QTc) intervals were calculated using the Bazett formula. Postprocedural overnight telemetry alarms and Holter monitors preand postprocedure were reviewed for ECG changes and arrhythmia. Right bundle branch block (RBBB) was defined as a QRS duration of ≥120 milliseconds. NSVT was defined as 3 or more consecutive PVCs with rates faster than 180 beats per minute.

Statistical Analysis
Summary data are presented as frequency with percentage. Continuous data are not normally distributed and therefore are presented as median with interquartile range. The Wilcoxon signed-ranks test and the Friedman test were used to compare continuous data. The Fisher exact test was used to compare nominal variables between pre-and post-PPVI groups. Statistical significance was defined as P<0.05. All statistical analyses were performed using SPSS statistical software (version 22.0; IBM Corp, Armonk, NY).

Patient Clinical Data
A total of 106 patients, 40 female (38%) and 66 male (62%), were included in this study. Median age at the time of the     Figure 2). Subgroup analysis by cardiac diagnosis or type of RVOT dysfunction yielded similar results (Table 2). Interestingly, the median pre-PPVI QTc of patients with pulmonary stenosis was shorter than that of patients with pulmonary regurgitation (P=0.07), whereas the median post-PPVI QTc of patients with pulmonary stenosis was longer than that of patients with pulmonary regurgitation (P<0.001).  Figure S1).

Arrhythmia Burden
Pre-PPVI, 27/106 patients (25%) had documented arrhythmias. Nine patients (8%) had NSVT, 6 patients (6%) had frequent PVCs, 10 patients (10%) had atrial AF/AFL, and 2 patients (2%) had supraventricular tachycardia. Only 2/8  (25%) patients with pre-PPVI VT, and no patient with pre-PPVI AF/AFL was in the PS group. New-onset arrhythmias immediately post-PPVI include 7 patients with NSVT, 8 patients with PVCs, and 1 patient with AF/AFL. These arrhythmias were recorded on overnight telemetry. Once again, there were very few PS-only patients (3/16, 19%) in this cohort. At follow-up, these new-onset arrhythmias resolved in 86% of NSVT cases and 88% of PVCs cases. Two out of 8 patients with new-onset PVCs were started on b-blockers, which were discontinued at their 6-month followup. Two out of 7 patients with new-onset NSVT were started on amiodarone. One of these patients was taken off the amiodarone at 6 months of follow-up. The second patient continued to be maintained on amiodarone without documented recurrence of NSVT. One patient was started on a b-blocker and continued to be on this medication because he had persistent documented PVCs.   new-onset/persistent ECG changes at follow-up (n=8), there were equal numbers of patients who had improved RV size versus no appreciable change by follow-up echo. In the 19 patients who had resolved ECG changes at follow-up, 10 patients had improved RV size, whereas 9 patients did show changes on follow-up echo. There appeared to be no correlation between RV size and ECG changes.

Discussion
To our knowledge, this study is the first to evaluate changes in the electrophysiologic substrate and arrhythmia burden of patients undergoing PPVI. Novel findings of this study include the observations of acute newly developing ST/T changes and arrhythmias such as frequent isolated PVCs and NSVT immediately post-PPVI. Moreover, the study was able to document improvement in the electrophysiologic substrate changes and arrhythmia burden at medium-term follow-up.
Two previous studies have examined the effects of PPVI on surface ECG parameters. Plymen et al 10 studied conduction (QRSd) and repolarization (QTc, QT, and JT dispersion) parameters, and Piotrowicz et al 11 studied parameters of RV hypertrophy. Similar to previous reports, our study did not find a significant change in QRSd post-PPVI in the overall cohort. However, Plymen et al 10 found significant shortening of QRSd in patients with pulmonary regurgitation.
QRSd has served as a marker to assess the risk of arrhythmic death in congenital heart disease patients (particularly ToF) with RVOT dysfunction. 2,13 Patients with PI who do not undergo pulmonary valve replacement or PPVI have an increase in QRSd of 2 to 4 milliseconds per year that is associated with increasing right ventricular end-diastolic volume (RVEDV). 1,14,15 Because RVEDV decreases postsurgical pulmonary valve replacement, the procedure has been postulated to improve the arrhythmia burden in patients with chronic PI. 16 Given the fact that PPVI serves as a better model to study the effects of improvements in hemodynamics on QRSd, Plymen et al's 10 particular findings could represent the true proportional relationship between improvement in RVEDV and decreasing QRSd. Unlike Plymen et al, 10 this study did not find a significant shortening of QRSd in the cohort of patients with purely pulmonary insufficiency. The reason for this discrepancy might reside in the fact that our sample size is too small to discern such difference.
Consistent with Plymen et al, the QTc in our study uniformly increased immediately post-PPVI but shortened beyond baseline at follow-up, regardless of type of RVOT dysfunction. QTc is a parameter of repolarization and a surrogate measurement of local action potential duration. It is recognized that myocardial stretch, via contraction-excitation feedback, increases monophasic action potential duration and causes afterdepolarizations, which in turn can cause triggered activity and generate the appropriate conditions for reentrant arrhythmias. 17 Contraction-excitation feedback has been demonstrated in both increased pressure and volume load conditions. [18][19][20] For example, in the lamb, chronic PI led to inhomogeneity of right ventricular activation, decreased conduction velocity, and increased intracellular resistivity. These changes might contribute to the observed increased susceptibility to stretch-induced arrhythmias of the right ventricle. 19,20 Furthermore, when compared with the hypertrophied human myocardium, the dilated myocardium had longer steady-state action potential duration. 21 Consistent with this observation, our study showed that patients with PI had longer QTc than PS patients. Contraction-excitation feedback and alterations in the local ventricular repolarization also explain the significant lengthening of QTc post-PPVI as previously demonstrated in the context of pulmonary valve valvuloplasty in PS patients. 18 According to contractionexcitation theory, repolarization duration is inversely proportional to the mechanical stress on the myocardium. Therefore, repolarization duration should be the longest after successful reduction in afterload seen with repetitive balloon occlusions of the RVOT during placement of stents and the pulmonary valve in PPVI. Consistent with this observation, our study showed that patients with PS had significantly longer QTc than PI patients immediately post-PPVI. It is important, therefore, to recognize that abnormalities in both depolarization and repolarization contribute to the increased risks of developing arrhythmia in patients with RVOT dysfunction. 21 The finding that QRSd and QTc stabilized and improved post-PPVI suggests that favorable changes in hemodynamics would translate into more stable myocardial depolarization and repolarization and reduce the risk of arrhythmias. Longer-term follow-up would be needed to monitor QRSd and QTc changes.
Other ST/T changes (such as nonspecific ST/T changes, T-wave inversion, and ST depression) were also observed immediately post-PPVI. These changes most likely reflect transient ischemic injury that follows repeated total balloon occlusions of the RVOT during RVOT angioplasty, transient absent cardiac output during the check for coronary artery compression, and rapid ventricular pacing during 3-dimensional rotational angiography in certain cases, or perhaps coronary artery spasm caused by selective coronary angiographies. These changes could also reflect the acute changes in hemodynamics with the newly placed valve, anesthesia effect, or possibly mechanical trauma of catheter manipulation during the procedure. Interestingly, the majority of these ST/T changes disappeared over time.
Despite favorable changes in measureable surface ECG parameters, the long-term effects of RV remodeling on the arrhythmias burden are unknown. Our mean follow-up period is 31 months, which exceeds that of Plymen et al 10   significant decrease in the prevalence of monomorphic VT. The prevalence of AF/AFL also decreased, albeit nonsignificantly. Overall, our study reported a substantial decrease in the prevalence of NSVT and PVCs post-PPVI. There was a significant incidence of new PVCs and NSVT immediately post-PPVI. Importantly, most of these new arrhythmias resolved after 6 months postprocedure. Some of the patients required short-term antiarrhythmic therapy with a b-blocker or amiodarone that was discontinued at their 6-month followup. We attribute these changes to the irritability caused by stents placed in the RVOT prior to the Melody valve placement and possibly due to contraction-excitation feedback caused by myocardial stretch associated with the repetitive balloon occlusion of the RVOT during placement of stents and the pulmonary valve in PPVI. Moreover, previous studies have shown that ventricular ectopy may be caused by afterdepolarizations associated with increase in mechanical stress. 28,29 These arrhythmias would resolve once the stents completely endothelialized and hemodynamics reached a better steady state. Unfortunately, many of the patients in our cohort received prestenting of the RVOT, precluding any analysis of the effect of prestenting on arrhythmia burden. Finally, PVCs and NSVT may be related to the underlying anatomical heart defect, focal scarring, fibrosis, or surgical suture lines rather than to right ventricular outflow tract dysfunction.

Limitations
This is a single-center retrospective study, with patient attrition over time, which limited the power of our analysis. Additionally, our cohort was heterogeneous in their anatomical lesions, hemodynamics, and clinical status prior to the procedure. Therefore, we predict that there is variability in the beneficial effects of improved hemodynamics on the electrophysiology substrate and measurable ECG parameters. An improved sample size would allow us to perform more detailed subgroup analyses to better tease out the different effects of PPVI. Despite most patients with previously or newly diagnosed arrhythmias undergoing follow-up Holter monitor evaluation at 6-month follow-up, there was no uniform protocol for monitoring of PVCs and NSVT over the follow-up period, which may lead to an overestimation in the prevalence reduction of these arrhythmias. Although our mean follow-up period is reasonable at 31 months, long-term follow-up is still needed to both assess the measurable ECG parameters and provide better correlation with the arrhythmia burden. Last, a potential limitation is that changes to the QTc may be secondary to anesthesia, other medications, or electrolyte anomalies. Patients in this study had ECGs obtained the morning following PPVI placement, and changes to the QTc were based on preprocedural ECG-as a result, each patient was his or her own control.

Conclusions
Our study demonstrates that PPVI stabilizes the QRSd and shortens the QTc in congenital heart disease patients with RVOT dysfunction. Furthermore, there is a substantial decrease in the prevalence of NSVT and PVCs post-PPVI. Finally, acute changes to the electrophysiologic substrate and arrhythmia burden immediately post-PPVI improve over time at midterm follow-up. These findings suggest that PPVI is a beneficial procedure from an electrophysiologic standpoint. Further prospective and long-term studies would be needed to further define and assess the causal effects of PPVI on electrophysiologic changes in these patients.

Disclosures
Balzer is a proctor for Medtronic, Inc. Silva receives research and fellowship support from Medtronic, Inc. The remaining authors have no disclosures to report.