Estimates of the prevalence and importance of significant tricuspid regurgitation (STR) related to implantable device leads are based mainly on case reports, small observational studies, or mixed samples that include defibrillators. We sought to assess whether patients with permanent pacemaker (PPM) leads have an increased risk of STR and to determine mortality associated with PPM-related TR in a large longitudinal single-center cohort. We examined the prevalence of STR (defined as moderate-severe or ≥3+) among all echocardiograms performed from 2005 to 2011 excluding those with defibrillators. We then examined mortality risk according to the prevalence of PPM and STR after adjusting for cardiac co-morbidities, left ventricular systolic/diastolic function, and pulmonary artery hypertension. We screened 93,592 echocardiograms (1,245 with PPM) in 58,556 individual patients (634 with PPM). The prevalence of STR was higher in patients after PPM placement (mean age 79 ± 3 years; 54% men) compared with those without a PPM (adjusted odds ratio 2.32; 95% confidence interval [CI] 1.54 to 3.49; p <0.0001). Among patients with a PPM lead, the presence of STR was associated with increased mortality (adjusted hazard ratio 1.40; 95% CI 1.04 to 2.11, p = 0.027, vs no STR). Compared with having neither a PPM lead nor STR, adjusted hazard ratios for death were 2.13 (95% CI 1.93 to 2.34) for STR but no PPM, 1.04 (0.89 to 1.22) for PPM without STR, and 1.55 (1.13 to 2.14) for PPM with STR. In conclusion, in a sample comprising >58,000 individual patients, PPM leads are associated with higher risk of STR after adjustment for left ventricular systolic/diastolic function and pulmonary artery hypertension; similarly to STR from other cardiac pathologies, PPM-related STR is associated with increased mortality.
Tricuspid regurgitation (TR) is a common valvular lesion with 1.6 million people in the United States affected by at least moderate-to-severe TR. It can be functional (secondary to right or left heart disease) or structural (from primary leaflet pathology). Significant tricuspid regurgitation (STR) from unselected causes can be associated with worsening congestive heart failure and decreased survival.
Device-related STR usually results from either damage of the tricuspid valve (perforation/laceration of leaflets or lead entrapment resulting in scar tissue) or interference with valve coaptation. Another proposed mechanism is asynchrony, resulting from abnormal right ventricular activation from a permanent pacemaker (PPM). Specifically, in patients paced in the ventricular demand mode, pseudo-TR can occur as a result of contraction of the atrium against a closed tricuspid valve, which can be corrected by restoring atrioventricular synchrony. When clinically significant, management typically involves percutaneous extraction of the offending leads or surgical treatment in some patients with advanced valvular disease. Previous literature regarding lead-related STR after implantation of a PPM or other cardiac devices, such as an implanted cardioverter defibrillator (ICD) and/or cardiac resynchronization therapy (CRT) device, has important limitations. It is largely based on case reports or observational studies, often shows discordant results, lacks data on outcomes, or fails to include a control group without an implantable device. Similarly, some studies include patients with ICDs and/or CRT devices, who usually have depressed left ventricular (LV) systolic function and advanced heart failure, leading to strong confounding by indication. We sought to establish whether patients with transvenous PPM leads have an increased risk of STR and to determine all-cause mortality associated with lead-related TR in a large longitudinal single-center cohort.
Methods
A longitudinal single-center cohort was selected from 121,040 consecutive echocardiograms (69,412 individual patients) performed at the Beth Israel Deaconess Medical Center from January 2005 to December 2011. Echocardiographic reports were created and stored using an inhouse software system (ENCOR, Beth Israel Deaconess Medical Center, Boston, MA) that allowed targeted queries. Among patients with diagnosis of a “right atrial/ventricular wire” on echocardiographic report, we excluded those with temporary leads, ICDs, and CRT devices using a combination of electrophysiology reports, International Classification of Diseases, Ninth Revision ( ICD9 ) codes, and review of medical records. We also excluded patients who underwent PPM implantation but did not undergo postimplantation echocardiogram at our institution. Our final sample size was 93,592 echocardiograms (85,997 transthoracic and 7,595 transesophageal studies) (1,245 with PPM) among 58,556 individual patients (634 with PPM). This study was approved by the Beth Israel Deaconess Medical Center Institutional Review Board that waived informed consent.
The following baseline clinical variables were extracted from the electronic echocardiographic reports: age, gender, body mass index, heart rate, and systolic blood pressure. The following additional variables were obtained from ICD9 codes: number of hospitalizations in the previous year, history of coronary artery disease, myocardial infarction, hypertension, and diabetes. Among the postimplantation characteristics of patients with PPM and STR, we assessed number of ventricular leads as demonstrated by chest x-ray and/or implantation reports.
All study participants underwent standard 2-dimensional echocardiography with a commercially available system (Vivid 7 or Vivid i; General Electric Ultrasound, Fairfield, CT) that used a 2.5-MHz transducer. Images included parasternal, apical, and subcostal views for transthoracic studies. Pertinent cardiac structures were assessed by advancing the imaging plane from 0° to 150° with the probe in the mid-esophagus for transesophageal studies. Valvular regurgitation was estimated visually for both transthoracic and transesophageal echocardiograms using color flow Doppler. In addition to TR (mild 1+, mild-moderate 1 to 2+, moderate 2+, moderate-severe 3+, and severe 4+), echocardiographic characteristics included right ventricular dilation (basal diameter ≥4.2 cm) and visual systolic dysfunction, pulmonary artery systolic pressure (PASP) (assessed both as a continuous and categorical variable—moderate or more pulmonary hypertension defined as ≥37 mm Hg), LV ejection fraction by visual estimation, mitral regurgitation (similar gradation to TR), mitral stenosis (mild, moderate, severe based on mitral valve area and/or mean transvalvular gradient), and presence of a mitral annular ring or prosthesis. In transthoracic studies, LV diastolic function was assessed using transmitral flow Doppler velocities and tissue Doppler imaging–derived mitral annular velocities. Transmitral early (E) and late (A) diastolic velocities were obtained using pulse-wave Doppler in the apical 4-chamber view at the tips of the mitral leaflets. Peak early diastolic septal and lateral myocardial velocities were measured by tissue Doppler imaging and averaged to calculate the mean early diastolic myocardial velocity (E′). The E/E′ ratio was then obtained as a measure of LV filling pressures. Significant diastolic dysfunction was defined as E/E′ ratio ≥13. STR was defined as ≥3+ (moderate-severe or more). Previous literature has shown good interobserver variability in qualitative assessment of TR. PASP was calculated as the sum of the tricuspid jet gradient (assessed by Doppler) and right atrial pressure. Right atrial pressure was estimated by visualizing the inferior vena cava and its response to respiration. Patients with other causes of primary TR (tricuspid valve vegetation, ring, rheumatic deformity, Epstein anomaly, or prolapse) were excluded.
We first assessed the prevalence of STR and the degree of TR change over time using the comparison between echocardiograms after PPM implantation and echocardiograms before PPM implantation or without PPM during the January 2005 and December 2011 time frame. We then examined the risk of all-cause mortality in study patients from the time of their last echocardiogram through October 2014 according to the prevalence of PPM and STR. Mortality assessment was based on internal medical records, with periodic links of our patient registries to the Social Security Death Index.
Clinical and echocardiographic characteristics were compared between the 2 groups (PPM and no PPM). We used t tests to compare continuous variables and Fisher’s exact tests to compare binary variables.
We first performed logistic regression to estimate the association of having a PPM with prevalence of significant TR. We accounted for repeated echocardiograms within subject using generalized estimating equations (GEE). Multivariable models were estimated adjusting for age, gender, body mass index, systolic blood pressure, history of coronary heart disease, diabetes, hypertension, number of hospitalizations in the previous year, and echo parameters (LV ejection fraction, mitral regurgitation ≥3+, any degree of mitral stenosis, history of mitral valve repair or replacement, E/E′ ratio ≥13, and PASP ≥37 mm Hg). As a sensitivity analysis, we repeated our analysis of PPM and STR using a propensity score approach, greedy matching subjects with a PPM on a 1:5 basis with those without one, and repeating GEE analyses with adjustment for remaining imbalances.
We next used the Bhapkar test to assess the change in the proportion of patients with 0 to 1+, 1 to 2+, 2+, 3+, and 4+, respectively, between pre-implantation and postimplantation echocardiograms in the subset of patients with echocardiograms in both time periods. We also performed longitudinal analyses using GEE with an autoregressive correlation structure to assess the association between having a PPM and TR change over time (i.e., the TR × time slope). Patients with STR at entry were excluded from this analysis.
We performed multivariable logistic regression analysis to assess determinants of STR within the PPM group among clinical and echocardiographic characteristics. In these analyses, we again used GEE to account for multiple echocardiograms within individual.
Finally, we used Cox proportional hazards models to examine associations of STR with death after adjusting for all the variables mentioned earlier except for PASP ≥37 mm Hg (given the potential position of pulmonary hypertension as an intermediate between TR and death). All analyses were conducted using SAS, version V9.3 (Cary, North Carolina). A 2-sided p value <0.05 was the criterion for statistical significance.
Results
Baseline clinical characteristics of the study sample are listed in Table 1 . The PPM group (n = 1,245) was older and had a higher prevalence of coronary artery disease, diabetes, and hypertension compared with the group without PPM (n = 92,347) (all p <0.05). The number of all hospitalizations in the previous year was similar between the 2 groups. Of the patients with PPM and STR, the majority (197 of 204 or 96%) had 1 ventricular lead and only 7 (3%) had 2 ventricular leads.
| Variable | Permanent Pacemaker | ||
|---|---|---|---|
| Yes (N = 1245) | No (N = 92347) | P value | |
| Age (years) | 80 ± 10 | 62 ± 17 | < 0.0001 |
| Men | 675 (54%) | 46017 (50%) | 0.002 |
| BMI (kg/m 2 ) | 27 ± 6 | 28 ± 7 | < 0.0001 |
| Hypertension | 427 (34%) | 22788 (25%) | < 0.0001 |
| SBP (mmHg) | 129 ± 41 | 126 ± 26 | 0.049 |
| Heart rate (beats/min) | 72 ± 14 | 74 ± 20 | < 0.0001 |
| Diabetes mellitus | 344 (28%) | 14535 (16%) | < 0.0001 |
| Coronary artery disease | 514 (41%) | 19363 (21%) | < 0.0001 |
| All hospitalizations | 0.13 ± 0.5 | 0.13 ± 0.6 | 0.89 |
| Tricuspid regurgitation ≥ 3+ | 204 (16%) | 2277 (2%) | < 0.0001 |
| Right ventricular dilatation | 356 (29%) | 9415 (10%) | < 0.0001 |
| Right ventricular dysfunction | 209 (17%) | 7055 (8%) | < 0.0001 |
| PASP (mmHg) | 35 ± 11 | 29 ± 11 | 0.002 |
| PASP ≥ 37 mmHg | 367 (29%) | 10757 (12%) | < 0.0001 |
| LVEF (%) | 48 ± 5 | 53 ± 5 | < 0.0001 |
| MV repair or replacement | 105 (8%) | 1811 (2%) | < 0.0001 |
| Any mitral stenosis | 41 (3%) | 1206 (1%) | < 0.0001 |
| Mitral regurgitation ≥ 3+ | 86 (7%) | 2901 (3%) | < 0.0001 |
| E/E’ > 13 | 116 (9%) | 4344 (5%) | < 0.0001 |
Echocardiographic characteristics are compared in Table 1 based on the presence of a PPM. The group with PPM had slightly lower average LV ejection fraction (but still >40%), higher prevalence of mitral valve disease (treated or untreated), larger number of patients with a dilated or hypokinetic right ventricle, and higher PASP (all p <0.05).
The prevalence of STR was over twofold higher in patients after PPM implantation compared with those without PPM, even in highly adjusted models (adjusted odds ratio [OR] 2.32; 95% confidence interval [CI] 1.54 to 3.49; p <0.0001). The association between STR and PPM remained highly significant (OR 2.48; CI 1.87 to 3.29; p <0.0001) even after potential over-adjustment for right ventricular dilation and systolic dysfunction, which may be consequences of STR. In propensity score analyses comparing 1,245 observations with a PPM to a matched group of 5,471 without one, groups were similar except for modest significant differences in age, prevalence of coronary artery disease, mitral valve surgery, right ventricular dilation, and LV ejection fraction ( Supplementary Table 1 ). The adjusted OR for STR in this matched group was 2.60 (2.05 to 3.30).
When we examined the predictors of STR within the PPM group, BMI, heart rate, history of mitral valve repair or replacement, ≥3 + MR, PASP ≥37 mm Hg, and right ventricular dilation remained significant in the multivariate regression analysis ( Table 2 ).
