Progressive Tricuspid Regurgitation and Elevated Tricuspid Regurgitation Pressure Gradient After Transvenous Permanent Pacemaker Implantation

Background The association of post-implant tricuspid regurgitation (TR) and heart failure (HF) hospitalization in patients without HF and preexisting abnormal TR and TR pressure gradient (PG) remain unclear. This study aimed to explore the clinical outcomes about progressive post-implant TR after permanent pacemaker (PPM) implantation. ventricular atrial; end-diastolic CAD:coronary artery


Background
In 1959, an endocardial transvenous lead was rstly introduced for permanent cardiac pacing, which has great bene ts 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 report demonstrated 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 de brillator (ICD) lead compared with PPM 4 . Another study showed that device type and number of leads placed did not affect the worsening degree of post-implant TR 5 .
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 lea ets, RV pacing-induced desynchronization 6, 7 and leads related tricuspid lea et injury or perforation, entanglement, impingement, or adherence to the tricuspid valve 6 . 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 5,8 . Therefore, the prevalence of increased degree of post-implant TR remains con icting. Moreover, the association of post-implant TR and heart failure (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 signi cance on HF hospitalization in a large retrospective cohort after transvenous ventricular-based PPM implantation.

Patient population
A total of 1,670 patients who underwent a single ventricular or dual-chamber transvenous PPM implantation at our hospital between January 2003 and December 2017 were included in this study.
Patients with 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 were excluded. Patients without follow-up records for PPM and without complete follow-up echocardiography were also excluded ( Fig. 1). Finally, a total of 1,075 patients were enrolled in this study and were divided into two groups: group 1 consisted of 198 patients with increased degree of post-implant TR (≥ 2 degrees) and/or abnormal TRPG and group 2 consisted of 877 patients without increased degree of post-implant TR and abnormal TRPG.     Baseline electrocardiographic (ECG) and echocardiographic parameters were obtained at nearest to the implant date. After implantation, pacing-lead locations were determined using anteroposterior, rightoblique, and left-oblique views under uoroscopy. 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 enroll 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 quanti ed by the M-mode and corrected by the two-dimensional 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.

De nition
Progressive TR was de ned as increased TR grade of ≥2 degrees and/or TRPG of >30 mmHg after implant, and TRPG of >30 mmHg was suggestive of possible pulmonary hypertension 9 . Moderate TR (grade III) was de ned 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 right atrium 10 . HF hospitalization was de ned as the occurrence of HF events according to a New York Heart Association functional class of III or IV in the absence of other alternative diagnoses. HF symptoms were classi ed as the New York Heart Association functional class II-IV required medical treatment. Cardiovascular mortality was de ned as sudden death related to arrhythmias, HF, and myocardial infarction. All-cause mortality was de ned as death related to any cause, such as sudden death with unde ned reasons, natural course, sepsis, malignancy, and cardiovascular disease.

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

Statistical analysis
Data are presented as mean ± standard deviation or numbers (percentages

Clinical outcomes of the study patients
During the follow-up period, group 1 had a signi cantly higher incidence of HF hospitalization compared to group 2 (13.6% vs. 4.7%; p < 0.001) ( Table 4 and Figure 4). However, the incidence of late-onset atrial brillation, sudden death or ventricular tachyarrhythmias, cardiovascular mortality, and all-cause mortality did not differ between the two groups (Table 4).

Univariate and multivariate Cox regression analyses of predictors of HF hospitalization
By univariate Cox regression analyses, older age, high body mass index, diabetes mellitus (DM), coronary artery disease (CAD), longer pacing QRS length, ventricular lead position at the lower septum and apex, larger pre-implant LA dimension, larger pre-implant LVEDV, larger post-implant LA dimension, larger postimplant LVEDV, lower post-implant LVEF, post-implant LVEF <40%, and progressive post-implant TR were signi cant preditors of HF hospitalization (

Discussion
In the present study, the cumulative rate of progressive TR ranged from 1.3% in the rst year to 18.4% in the sixth year. Higher pre-implant TRPG and larger post-implant LA dimension were positively associated with progressive post-implant TR, which was associated with a trend toward HF hospitalization. TR occurs mainly due to annular dilation and right ventricular enlargement, often secondary to LV dysfunction from myocardial or valvular causes, right ventricular volume and pressure overload, and cardiac chamber dilations 11 . Lead-related TR is an underdetermined problem and may be caused by lead-related tricuspid lea et injury or perforation or lead entanglement, impingement, or adherence to the tricuspid valve 6 . However, lead-related tricuspid valve injury could not be fully detected and was only observed in 12% of patients with PPM-related severe TR by transthoracic echocardiography 6 . Kim 12 . In this study, the cumulative rate of progressive post-implant TR (increased TR grade of ≥2 degrees and/or TRPG of >30 mmHg) was from 1.3% in the rst year to 18.4% in the sixth year. Moreover, higher pre-implant TRPG and larger post-implant LA dimension were independent predictors of progressive post-implant TR. Pacing-induced electrical and mechanical dyssynchrony of LV can also result in TR and MR 13 . However, in this study, pacing percentage and pacing QRS length was not associated with the development of progressive post-implant TR. In this study, larger post-implant LA size was an independent predictor of progressive post-implant TR. Our previous study showed that right and left atrial sizes were larger in patients with atrioventricular dyssynchrony after pacing 14 . Atrial enlargement is a well known predictor of atrial brillation. Utsunomiya et al reported that functional TR with a structurally normal tricuspid valve may occur secondary to chronic atrial brillation and is associated with advanced age and right atrial enlargement 15 .
In one small retrospective cohort study, signi cant lead-induced TR was associated with a signi cantly increased incidence of all-cause mortality and HF events in patients after PPM implantation 16 . Other studies also reported post-implant TR to be an independent risk factor for late death 5,13 . However, a signi cant proportion of patients in previous studies included patients with HF and receiving ICD and cardiac resynchronization therapy (CRT). Patients with ICDs and/or CRT devices usually have poor LVEF and advanced HF and consequently, higher incident HF hospitalization and mortality. In our study, we only enrolled patients receiving PPM implantation and excluded patients receiving ICD or CRT and those with prior history of HF, valvular heart disease and preexisting abnormal (mild-moderate, moderate or severe) TR and abnormal (>30 mmHg) TRPG. In this large cohort study, progressive post-implant TR was signi cantly associated with HF hospitalization in univariate analysis and was associated with a nonsigni cant trend toward HF hospitalization (p = 0.070) in multivariate analysis (Table 5), and progressive post-implant TR was not associated with cardiovascular and all-cause mortality. Therefore, patients with preserved LV function and without valve disease underwent transvenous ventricular-based pacemaker implantation should have baseline echocardiography evaluation before implant and those with higher pre-implant TRPG should have more vigorously echocardiographic follow-up for the development of progressive post-implant TR.

Study Limitations
One limitation of this study is its retrospective nature, including data from only one medical center.
Because of older age, the all-cause 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 post-implant TR progression and its associated outcomes in patients with transvenous ventricular-based PPM.  Changes of the tricuspid regurgitation pressure gradient in group 1. In group 1, the post-implant TRPG was signi cantly higher than pre-implant TRPG (p < 0.001).

Figure 3
The cumulative incident rate of progressive post-implant tricuspid regurgitation. The cumulative rate of progressive post-implant TR increased from 1.3% in the rst year to 18.4% in the sixth year.