Progressive tricuspid regurgitation and elevated pressure gradient after transvenous permanent pacemaker implantation

Abstract Background The association of postimplant tricuspid regurgitation (TR) and heart failure (HF) hospitalization in patients without HF and preexisting abnormal TR and TR pressure gradient (PG) remain unclear. Hypothesis This study aimed to explore the clinical outcomes of progressive postimplant TR after permanent pacemaker (PPM) implantation. Methods A total of 1670 patients who underwent a single ventricular or dual‐chamber transvenous PPM implantation at our hospital between January 2003 and December 2017 were included in the study. Patients with prior valvular surgery, history of HF, and baseline abnormal TR and TRPG were excluded. Finally, a total of 1075 patients were enrolled in this study. Progressive TR was defined as increased TR grade of ≥2 degrees and TRPG of >30 mmHg after implant. Results In 198 (18.4%) patients (group 1) experienced progressive postimplant TR and elevated TRPG, whereas 877 patients (group 2) did not have progressive postimplant TR. Group 1 had larger change in postimplant TRPG (group 1 vs. group 2; 12.8 ± 9.6 mmHg vs. 1.1 ± 7.6 mmHg; p < .001) than group 2. Group 1 had a higher incidence of HF hospitalization compared to group 2 (13.6% vs. 4.7%; p < .001). Preimplant TRPG (HR: 1.075; 95% confidence interval [CI]: 1.032–1.121; p = .001) was an independent predictor of progressive postimplant TR. Conclusions After a transvenous ventricular‐based PPM implantation, 18.4% of patients experienced progressive postimplant TR and elevated TRPG. Higher preimplant TRPG was an independent predictor of progressive postimplant TR.


| INTRODUCTION
In 1959, an endocardial transvenous lead was firstly introduced for permanent cardiac pacing, which has great benefits in reducing cardiac morbidity and mortality related to symptomatic bradycardia. 1,2 However, the introduction of transvenous right ventricular pacing leads across the tricuspid valve can be associated with the development of tricuspid regurgitation (TR) and elevated tricuspid regurgitation pressure gradient (TRPG). Indeed, the prevalence of TR was increased in patients with transvenous permanent pacemaker (PPM) compared with the general population. 3 One previous reported that 21.2% of patients developed worsening TR degree after the transvenous lead implantation and a higher rate of worsening TR in patients with implantable cardioverter defibrillator (ICD) lead compared with PPM. 4 Another study showed that device type and number of leads placed did not affect the worsening degree of postimplant TR. 5 TR is associated with heart failure (HF) and is related to right ventricular pressure and volume overloading. 6 In addition, elevated TRPG is associated with poor prognosis in the patients with HF. TR is also an important prognostic factor in patients with moderate or severe mitral regurgitation. 7 The underlying mechanisms of transvenous cardiac pacing-related TR is not fully understood. Several mechanisms have been proposed that included a mechanical effect of the lead interfering the motion of the tricuspid leaflets, RV pacing-induced desynchronization 8,9 and leads related tricuspid leaflet injury or perforation, entanglement, impingement, or adherence to the tricuspid valve. 8 One study reported that worsening TR occurred only in the chronic phase over 2 years, whereas another study reported a temporal trend toward increasing TR both acutely and chronically over 4 years after cardiac devices implantation. 5,10 Therefore, the prevalence of increased degree of postimplant TR remains conflicting.
Moreover, the association of postimplant TR and HF hospitalization in patients without HF and preexisting abnormal TR and abnormal TRPG remains unclear. Accordingly, we conducted this study to assess the prevalence of TR after cardiac device implantation and determine its clinical significance on HF hospitalization in a large retrospective cohort after transvenous ventricular-based PPM implantation. Patients with severe valvular heart disease and/or prior valvular surgery, HF and left ventricular ejection fraction (LVEF) <50%, dilated cardiomyopathy, hypertrophic cardiomyopathy, and preexisting abnormal (mild-moderate, moderate or severe) TR and abnormal (>30 mmHg) TRPG, suggestive of possible pulmonary hypertension, 11 were excluded. Patients without follow-up records for PPM and without complete follow-up echocardiography were also excluded (Supplemental Figure S1). Finally, a total of 1075 patients were enrolled in this study and were divided into two groups: group 1 consisted of 198 patients with increased degree of postimplant TR (≥2 degrees) and abnormal TRPG and group 2 consisted of 877 patients without increased degree of postimplant TR and abnormal TRPG.

| Patient population
Patients with dual-chamber PPM implantation underwent pacing in the dual chamber rate-adaptive mode, whereas patients with single ventricular PPM implantation underwent pacing in the ventricularinhibited rate-adaptive mode. General demographics, comorbidities, lead positions, pacing QRS durations, pacing percentages, echocardiographic parameters, HF hospitalization, and cardiovascular and allcause mortality were compared between the groups.
Baseline electrocardiographic (ECG) and echocardiographic parameters were obtained at nearest to the implant date. After implantation, pacing-lead locations were determined using anteroposterior, right-oblique, and left-oblique views under fluoroscopy. The pacing QRS duration was measured from the surface 12-lead ECG within 3 days after PPM implantation. Patients visited the outpatient department at regular intervals (3-6 months). PPM records were obtained at regular intervals, and the ventricular pacing percentage was obtained by telemetry.

| Ethical statement
This study conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved for human research by the institutional review committee of Kaohsiung Chang Gung Memorial Hospital. All patients were informed to be enrolled in our PPM registry when PPM implantation and did not need informed consent due to the retrospective study.

| Echocardiography
Echocardiographic parameters, including left atrial (LA) dimension, LVEF, LV end-diastolic volume (LVEDV), and TR grade/TRPG, were measured using GE Vivid 9 or Philips IE33. LVEF and LVEDV were quantified by the M-mode and corrected by the twodimensional guided biplane Simpson's method of disc measurements.
Baseline echocardiography was performed before implantation.
Follow-up echocardiography was performed at 2-year intervals thereafter in the absence of clinical events or at the onset of HF.

| Definition
Progressive TR was defined as increased TR grade of ≥2 degrees and TRPG of >30 mmHg after implant, and prior study showed that pulmonary hypertension was suspected when TRPG at rest >30 mmHg. 11 Moderate TR (grade III) was defined as a regurgitant jet extending to less than half of the right atrium, whereas severe TR (grade IV) as a jet extending to more than half of the length of the

| Study end-points
The primary study endpoint was TR progression (TR grade ≥ 3) and abnormal TRPG levels (PG >30 mmHg). The secondary study endpoints were late-onset atrial fibrillation, HF hospitalization, sudden death or ventricular tachyarrhythmias, cardiovascular mortality, and all-cause mortality.

| Statistical analysis
Data are presented as mean ± SD or numbers (percentages      vs. 14.1%; p = .503) did not differ between the two groups during follow-up period (Table 3). In one retrospective cohort study, significant lead-induced TR was associated with a significantly increased incidence of all-cause mortality and HF events in patients after PPM implantation. 18 Other studies also reported postimplant TR to be an independent risk factor for late death. 5

| Study limitations
One limitation of this study is its retrospective nature, including data from only one medical center. Because of older age, the allcause mortality rate was relatively high in this study. Another limitation was the absence of baseline and follow-up right heart size and function by echocardiography. However, we still provided important information about lead-related postimplant TR progression and its associated outcomes in patients with transvenous ventricular-based PPM.

| CONCLUSIONS
After a transvenous ventricular-based PPM implantation, 18.4% of patients experienced progressive postimplant TR and elevated TRPG.
Patients with progressive postimplant TR had a higher incidence of HF hospitalization. Higher preimplant TRPG was an independent predictor of progressive postimplant TR.

CONFLICT OF INTEREST
The author declares there is no potential conflict of interest. Chen. All authors have read and approved the manuscript.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.