Author + information
- Received May 22, 2018
- Revision received August 20, 2018
- Accepted August 20, 2018
- Published online November 19, 2018.
- Rohith Nayak, BAa,
- Timothy M. Fernandes, MD, MPHb,
- William R. Auger, MDa,
- G. Victor Pretorius, MBChBc,
- Michael M. Madani, MDc and
- Ulrika M. Birgersdotter-Green, MDd,∗ ()
- aDepartment of Medicine, School of Medicine, University of California, San Diego, La Jolla, California
- bDivision of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, California
- cDepartment of Surgery, University of California, San Diego, La Jolla, California
- dDivision of Cardiovascular Medicine, University of California, San Diego, La Jolla, California
- ↵∗Address for correspondence:
Dr. Ulrika Birgersdotter-Green, Pacemaker and ICD Services, UC San Diego Health, Cardiac Electrophysiology, Division of Cardiovascular Medicine, University of California, San Diego, 9452 Medical Center Drive, MC 7411, Altman Building, 3rd Floor, Room 3E-313, La Jolla, California 92037.
Objectives This study aimed to identify the prevalence of cardiac implantable electronic devices (CIEDs) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and to describe the associated disease burden.
Background CTEPH is a debilitating disease, now potentially curable with pulmonary thromboendarterectomy (PTE). The contribution of CIEDs to thrombosis in this patient population has not been previously studied.
Methods The charts of 982 CTEPH patients, who underwent PTE between January 1, 2009, and December 31, 2015 at University of California-San Diego (UCSD) Medical Center, were reviewed for pacemakers or implantable cardioverter defibrillators (ICDs) implanted before surgery.
Results Among 982 CTEPH patients who underwent PTE, 14 had pacemakers and 3 had ICDs, giving 17 CIEDs and a prevalence of 1.7%. Of these 17 CIEDs, 6 devices were extracted intraoperatively, and 5 of 6 devices were replaced with epicardial leads. Furthermore, of the 950 patients classified by intraoperative UCSD level, 12 of 17 (70.6%) patients with CIEDs had distal disease versus 241 of 933 (25.8%) patients without CIEDs (p = 0.0002). The prevalence of known venous thromboembolism (VTE) was 50% in CIED patients compared with 78.6% in patients without CIEDs (p = 0.018).
Conclusions At 1.7%, the prevalence of CIEDs in the PTE population was higher than previously reported values, which estimated CIED prevalence between 0.16% and 0.47% in the general population. Moreover, CTEPH patients with CIEDs were more strongly associated with distal disease burden and less likely to have had previous VTE, which suggested that CIEDs may be a nidus for small clots that embolize distally in the pulmonary vasculature.
Pulmonary hypertension, which is characterized by mean arterial pressure ≥25 mm Hg at rest in the pulmonary vasculature, is a progressive and debilitating disease with a number of underlying etiologies (1,2). One cause of pulmonary hypertension is chronic pulmonary thromboembolic disease, which is characterized by recurrent, obstructive clots within the pulmonary vasculature (3). Thrombi within the pulmonary vasculature can occur in the aftermath of an incompletely resorbed pulmonary embolism (PE), and over time, constant obstruction and vascular remodeling within the pulmonary artery can lead to chronic thromboembolic pulmonary hypertension (CTEPH) (4).
Unlike other causes of severe pulmonary hypertension, CTEPH is potentially curable without lung transplantation through a surgical procedure known as pulmonary thromboendarterectomy (PTE). The surgery effectively removes obstructing thrombi from the pulmonary vasculature and significantly reduces disease burden by improving ventilation/perfusion scan (V/Q) mismatch, right heart dysfunction, and tricuspid regurgitation (1,2,5). PTE has achieved remarkable results in decreasing CTEPH disease burden and can deliver a complete cure in >90% of patients (5,6).
One of the central questions about CTEPH is why some patients are more susceptible than others in developing recurrent thromboembolic disease. CTEPH patients are more likely to be coagulopathic than the general population, but it is important to consider other contributing factors as well. We have observed incidental lead thrombi in CTEPH patients with cardiac implantable electronic devices (CIEDs), which suggests that leads may be a nidus for clot formation in these patients. Leads as a potential contributor to thrombus formation in CTEPH patients is a topic that has not been formally studied in the literature. This study aimed to identify the prevalence of CIEDs in patients who underwent PTE at the University of California-San Diego (UCSD) Medical Center and to describe the associated disease burden.
The study included 982 patients who underwent PTE between January 1, 2009 and December 31, 2015 at UCSD Medical Center. Each patient’s electronic medical record was reviewed for presence of an CIED implanted before surgery. Device type and model, lead indication, and intraoperative changes in lead management, including extraction and replacement, were obtained. Demographic information, including age, sex, body mass index (BMI), functional capacity (according to the World Health Organization), and comorbidities, was collected. Pre-operative and post-operative hemodynamic data were also recorded.
Level of disease
During surgery, the endarterectomy specimens of CTEPH patients were classified by intraoperative UCSD level, depending on what level of pulmonary vasculature was affected. The classification system is as follows. Type 1 refers to a proximal, large vessel clot in the main pulmonary artery. Type 2 refers to chronic fibrotic disease in the main pulmonary artery and clot in the lobar vessels. Type 3 represents a distal clot in the segmental and subsegmental branches. Finally, type 4 disease affects intrinsic small vessels and is often inoperable (5,6). Patients with type 3 or 4 lesions bilaterally are designated as having distal disease; all other patients are classified as having proximal disease. During chart review, each patient’s disease level was documented from the PTE operative notes.
All statistical analyses were completed using SPSS software version 25.0 (IBM, Armonk, New York). Continuous variables were expressed as mean ± SD; categorical variables were expressed as counts and percentages. Continuous variables were analyzed with the Student’s t-test for normally distributed data. Categorical variables were compared with the chi-square test and the Fisher exact test for small sample sizes. A 2-sided p value of <0.05 was used for all analyses.
The study included 17 CTEPH patients with CIEDs (70.6% men; mean age: 58.0 ± 14.4 years) and 965 CTEPH patients without CIEDs (51.2% men; mean age: 52.1 ± 14.7 years). Compared with CTEPH patients without CIEDs, patients with CIEDs had a distribution of World Health Organization functional class that was more severe (p = 0.03). The CIED group had a higher prevalence of coronary artery disease (35.3% vs. 14.4%; p = 0.02) and chronic kidney disease (29.4% vs. 13.3%; p = 0.05), but other comorbidities, such as diabetes, hypertension, hyperlipidemia, chronic obstructive pulmonary disease, and asthma were similar between the 2 groups. The prevalence of known previous venous thromboembolism (VTE) was 50% in CIED patients compared with 78.6% in patients without CIEDs (p = 0.018). Additional demographic information is shown in Table 1.
Pre-operative and post-operative hemodynamics
As shown in Table 2, CTEPH patients with CIEDs had a pre-operative mean pulmonary artery pressure of 41.8 ± 6.1 mm Hg, a cardiac index of 2.2 ± 0.5 l/min/m2, and a pulmonary vascular resistance of 600.9 ± 243.0 dyn-s/cm5. CTEPH patients without CIEDs had comparable pre-operative hemodynamics (Table 2). CTEPH patients with CIEDs had a left ventricular ejection fraction (LVEF) of 62.9 ± 11.9% compared with an LVEF of 67.4 ± 7.0% in CTEPH patients without CIEDs (p = 0.01).
Post-operatively, CTEPH patients with CIEDs did not significantly differ from those without CIEDs in mean pulmonary artery pressure (25.8 ± 7.4 mm Hg vs. 24.3 ± 7.2 mm Hg; p = 0.42). Final mean pulmonary vascular resistance in the CIED group was 256.9 ± 106.0 dyn-s/cm5 compared with 242.0 ± 122.2 dyn-s/cm5 in patients without CIEDs (p = 0.63). The change in pulmonary vascular resistance between groups following surgery was also not significant (343.9 ± 242.3 dyn-s/cm5 vs. 429.5 ± 328.7 dyn-s/cm5; p = 0.09) (Table 3).
Prevalence of CIEDs in PTE population
Among 982 total CTEPH patients who underwent PTE, 14 had pacemakers and 3 had implantable cardioverter-defibrillator (ICDs), giving a total of 17 CIEDs, for a prevalence of 1.7%. The 14 pacemakers were further categorized as dual chamber (n = 7), single chamber unipolar (n = 1), single chamber bipolar (n = 1), and unknown (n = 5). All 3 of the ICD devices were dual chamber. Indications for CIED placement included sick sinus syndrome (n = 9), symptomatic bradycardia (n = 2), idiopathic cardiomyopathy (n = 2), third-degree atrioventricular block (n = 1), tachycardia-bradycardia syndrome (n = 1), prolonged QT syndrome (n = 1), and junctional rhythm (n = 1). In addition, 2 of the 17 CIED patients had a history of device infections that required device extraction and eventual replacement.
Intraoperative lead management and level of disease
Among the 17 CTEPH patients with CIEDs, 6 patients (35.3%) had their devices extracted intraoperatively, and 5 of these 6 patients (83.3%) had their devices replaced with epicardial leads (Table 4). One patient had a new dual-chamber permanent pacemaker placed during surgery. Furthermore, patients with CIEDs had more distal chronic thromboembolic disease than those without devices, defined as UCSD level 3 or 4. Of the 950 patients classified by intraoperative UCSD level, 12 of 17 (70.6%) patients with CIEDs had distal disease versus 241 of 933 (25.8%) patients without CIEDs (p = 0.0002) (Table 5).
In this retrospective analysis of patients referred for PTE, we found a CIED prevalence of 1.7% among patients with CTEPH; furthermore, CIEDs were associated with an increased prevalence of distal chronic thromboembolic disease. At 1.7%, the CIED prevalence in the UCSD PTE population was much higher than all previously reported national estimates of CIEDs in the general population (7–13). Furthermore, the incidence of known VTE in the CIED population who were diagnosed with CTEPH was significantly lower than the CTEPH population at-large. This suggested that CIEDs might give rise to small thrombi on the wires, which might cause silent pulmonary emboli (Figures 1 and 2). Ultimately, these silent pulmonary emboli could contribute to the development of CTEPH in susceptible individuals. Because of the lack of a CTEPH negative reference group in this study, the higher prevalence of CIEDs observed in this CTEPH cohort, compared with other registries, might also reflect differences in baseline comorbid conditions among populations.
The role of blood-contacting medical devices (e.g., stents, vascular grafts, and heart valves in thrombus formation) has been well documented in the biomaterials literature. It is likely that CIEDs, like other artificial surfaces in the blood stream, promote clotting through a complex cascade of protein adsorption, cell adhesion, thrombin generation, and complement activation (14).
A number of previous studies specifically substantiated the phenomenon of lead thrombogenicity. In a 7-year prospective study, which included both children and adults, Bar-Cohen et al. (15) found partial and total venous obstruction in patients with CIEDs, regardless of age, body surface area change, lead type, age at implantation, and number of leads placed. A recent population-based cohort study by Pederson et al. (16) found a 3-month VTE risk of 0.3% and 5-year VTE risk of 1.9% after ICD implantation. Moreover, multiple studies examined intracardiac lead thrombi. In a retrospective cohort study of patients with previous pacemakers or ICD implantation who underwent intracardiac echocardiography for ablation of atrial fibrillation, atrial flutter, or ventricular tachycardia, Supple et al. (17) found 26 of 86 (30%) patients with intracardiac lead thrombi. The post-mortem analysis by Novak et al. (18) in deceased patients with pacemakers and ICD leads demonstrated a similar rate (28%) of intracardiac lead thrombi and showed that a number of patients had simultaneous venous and intracardiac thrombi. There were no studies to date to compare the potential thrombogenicity of specific lead materials (e.g., silicone and polyurethane); the sample size of CIEDs in our study was too small to draw conclusions regarding the thrombogenicity of these materials.
Previous studies mentioned that CIEDs might be a potential risk factor for distal disease burden in CTEPH patients, but none of these studies formally investigated or quantified this hypothesis (5). Our analysis demonstrated that CTEPH patients with CIEDs were more strongly associated with distal disease, which suggested that leads might be a nidus for the development of small clots that embolize to the segmental and subsegmental vessels of the pulmonary vasculature. Thrombi within these more distal vessels are more difficult to remove during surgery and might even make the disease inoperable at some institutions (19). However, at UCSD, despite the higher risk of distal disease, CTEPH patients with CIEDs had comparable post-operative hemodynamics and outcomes as those in CTEPH patients without devices. This implied that CTEPH patients with CIEDs are good candidates for PTE, and that surgeons should continue to operate on these patients while considering the removal of CIEDs from the blood stream to decrease the risk of recurrent disease.
Although we included a large number of CTEPH patients, our study was a retrospective analysis from a single medical center. Moreover, the absence of a negative reference group prevented us from drawing definitive conclusions about causality.
CIEDs are more prevalent in the CTEPH population than the general population and are associated with more distal disease. Electrophysiologists should consider CTEPH as a potential cause of dyspnea in patients with long-standing devices and those with known clots on wires. These patients can be screened for CTEPH with a VQ scan; those with abnormal perfusion should be referred for thorough evaluation of CTEPH and determination of surgical candidacy by centers that offer PTE surgery.
COMPETENCY IN MEDICAL KNOWLEDGE 1: CTEPH may be a potential late complication of CIED placement in susceptible patients.
COMPETENCY IN MEDICAL KNOWLEDGE 2: CTEPH patients with CIEDs are associated with more distal disease burden; however, they remain good candidates for PTE.
TRANSLATIONAL OUTLOOK 1: Electrophysiologists should consider CTEPH as a potential cause of dyspnea in patients with CIEDs and initiate further clinical workup.
Dr. Fernandes has been a consultant for MSD/Bayer; and has been a speaker for Bayer Pharmaceuticals. Dr. Auger has been a consultant for MSD/Bayer; and has received grant support from Bayer. Dr. Madani has been consultant for MSD/Bayer, Johnson & Johnson, and Wexler Surgical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- body mass index
- cardiac implantable electronic device
- chronic thromboembolic pulmonary hypertension
- implantable cardioverter-defibrillator
- left ventricular ejection fraction
- pulmonary embolism
- pulmonary thromboendarterectomy
- University of California-San Diego
- venous thromboembolism
- Received May 22, 2018.
- Revision received August 20, 2018.
- Accepted August 20, 2018.
- 2018 American College of Cardiology Foundation
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