Abstract
Cardiac implantable electronic devices (CIEDs) have been increasingly used in the management of various rhythm disorders amidst an aging population with more prevalent cardiovascular comorbidities. Although generally well-tolerated and safe, implantation of CIEDs may result in or worsen tricuspid regurgitation (TR), which is associated with a higher risk of morbidity and mortality. Several mechanisms of TR following device implantation have been proposed, and multiple diagnostic tests, percutaneous and surgical interventions, and alternative pacing methods have been developed to address this. CIED-related TR thus requires a multidisciplinary team of experts in cardiac imaging, interventional cardiology, electrophysiology, and cardiothoracic surgery with a comprehensive understanding of this multifaceted disease. The objective of this review is to summarize the epidemiology, clinical presentation, and management of CIED-related TR.
Introduction
Cardiac implantable electronic devices (CIEDs) have been increasingly used in the management of various rhythm disorders amidst an aging population with more prevalent cardiovascular comorbidities. Over 730,000 permanent pacemakers (PPMs) and 330,000 implantable cardioverter defibrillators (ICDs), including cardiac resynchronization therapy (CRT) devices, are implanted annually worldwide. Although generally well-tolerated and safe, implantation of CIEDs may result in or worsen tricuspid regurgitation (TR), which is associated with a higher risk of heart failure and mortality. , Several mechanisms of TR following CIED implantation have been postulated, which can broadly be categorized as implantation-, pacing-, and device-related. While the cause of CIED-induced TR is likely a multifaceted combination of all the above, there is no consensus on the predominant mechanism due to conflicting data. This makes it challenging to determine the optimal management strategy for these patients. However, novel interventional and surgical options have been developed to address these challenges. This multidisciplinary review article aims to review the epidemiology, clinical presentation and outcomes, diagnostic approaches, and management of CIED-related TR in light of the emerging transcatheter treatment solutions that have been recently approved by US Food and Drug Administration (FDA).
Epidemiology and Clinical Outcomes
Significant TR (of at least moderate severity) is common and affects up to 12% of patients. Etiologies are typically categorized as primary (i.e., CIED-related, endocarditis, and myxomatous degeneration) or secondary (i.e., functional from atrial enlargement and dysfunction, left ventricular dysfunction, and pulmonary hypertension), with the latter accounting for the majority of cases (90%). After initial reports in the late 1900s, CIED-related TR has become increasingly recognized and involves complex management, leading to its proposal as a third distinct mechanism. , The prevalence of CIED-related TR varies significantly with estimates between 7% and 40%. , , The variability is explained by retrospective studies with small sample sizes and short-term follow-up, different echocardiographic techniques, and inconsistent grading definitions of TR. One prospective study, including over 35,000 echocardiograms at ten Spanish medical centers, found that CIED-related TR represented 66% of the cases of primary TR and 5% of all cases of significant TR. Another prospective study found that the prevalence of moderate or severe CIED-related TR was 5% after CIED implantation. Further prospective studies with standard assessment methods and accepted TR grading criteria are needed to understand the true prevalence of this morbid condition.
The natural history of CIED-related TR follows that of other etiologies with progressive regurgitation, adverse right ventricular remodeling, pulmonary hypertension, heart failure, and increased mortality. Early ICD studies hinted at the increased risk of heart failure and death despite a reduction in sudden death. , However, the possibility that an endocardial lead could cause significant TR and associated heart failure was not widely recognized at that time. , Symptoms typically represent those of right heart failure, including dyspnea, hepatomegaly, ascites, and peripheral edema. With regard to outcomes, increasing TR severity, regardless of etiology, has been shown to be a significant predictor of mortality independent of biventricular function, pulmonary hypertension and atrial fibrillation. , Similarly, CIED-related severe TR has been associated with a poor prognosis with increased risk of heart failure hospitalization, tricuspid valve intervention, CRT upgrade, and mortality. , In a retrospective study of 18,800 patients with CIED, significant TR was greater in patients with CIED compared to those without (23.8 vs. 7.7%). Furthermore, this severity of TR was associated with a 1.6 to 2.5-fold increased risk of all-cause mortality. Also, in patients undergoing CIED, baseline right ventricular dilation was associated with worse TR and portends worse survival. These studies highlight that timely recognition and intervention of CIED-related TR may represent an opportunity to improve morbidity and mortality.
Mechanisms of Tricuspid Regurgitation
Transvenous PPMs, ICDs, and CRT devices are typically implanted with a lead that crosses the tricuspid valve and is fixated in the right ventricle. The posterior and septal leaflets of the tricuspid valve appear to be the most commonly affected by transvenous leads ( Figure 1 ). Although demonstration of lead–leaflet interaction is sufficient to diagnose CIED-related TR, causality is rarely established. More often, CIED and TR coexist, and a causal relationship is assumed when new TR is diagnosed or pre-existing TR worsens following CIED implantation.
Mechanisms of CIED-related TR are categorized into implantation-related, pacing-related, and device-related ( Table 1 ). Implantation technique is operator-dependent and has changed over time. Some argue that direct crossing of the tricuspid valve may result in less trauma to the tricuspid valve apparatus relative to the “prolapsing” technique, but this has not been extensively studied. Silicone-insulated leads, higher number of leads crossing the tricuspid annulus, presence of bulkier and stiffer defibrillator leads, and implant location in the apex instead of the right ventricular outflow tract have all been implicated as possible predictors of TR following CIED implantation. However, the majority of these studies are small, retrospective studies, often with conflicting results.
| Implantation | Pacing | Device |
|---|---|---|
|
|
|
| ||
| ||
| ||
|
∗ Controversial due to a lack of, conflicting, or biased data.
While right ventricular pacing has been associated with worsening TR, a higher pacing burden has not been shown to correlate with this. , , , It is thus thought to be an alteration of right ventricular geometry with pacing that can occur irrespective of pacing burden, which is in contrast to the worsening mitral regurgitation seen as a result of dyssynchronous contraction of the interventricular septum. , , Transvenous leads can also disrupt the tricuspid valve apparatus via impingement of or adherence to a leaflet, perforation, laceration, or avulsion of a leaflet, interference with the subvalvular apparatus, and predisposition to thrombus formation and endocarditis. , Due to these unique mechanisms of TR, CIED-related TR has been reclassified from “primary” TR to its own separate etiologic entity to emphasize the distinct diagnostic approach and multidisciplinary management that it warrants.
Diagnostic Approaches
Echocardiography remains a cornerstone in the evaluation of CIED-related TR. Echocardiography allows for detailed assessment of the tricuspid valve apparatus integrity, device lead interactions, and quantification of regurgitant severity by utilizing both 2D and, more recently, 3D imaging modalities. Furthermore, echocardiography plays a key role in assessing the impact of CIED-related TR on cardiac function and the associated hemodynamic consequences. Incorporation of advanced echocardiographic techniques, such as Doppler imaging and strain analysis, improves the sensitivity and specificity of diagnosing TR. , The ability to dynamically visualize cardiac structures with ultrasound aids in identifying key mechanisms of TR discussed above.
It is for these reasons that candidates for CIED implantation should ideally have a comprehensive baseline transthoracic echocardiogram with a focus on the tricuspid valve and right ventricle prior to implantation, as this would inform an interdisciplinary discussion about whether valve-sparing strategies should be pursued instead. Moreover, it would facilitate timely recognition of new or worsening TR post-implant. Transesophageal echocardiography is the imaging modality of choice to assess CIED-related TR and help distinguish it from other incidental causes of TR. Incorporation of 3D echocardiography allows for more reliable visualization of the device lead, tricuspid valve, and mechanism of TR. ,
Cardiac computed tomography can provide important complementary information, especially if transvenous lead extraction (TLE) is being considered. It can help assess lead fibrosis and vein stenosis and, in some instances, provide insight into the possible lead-leaflet interaction and mechanism of CIED-related TR that may not have been fully visualized by echocardiography. , It is also useful in planning for implantable transcatheter valves and the need for lead jailing, as discussed below. However, a major limitation of cardiac computed tomography is the significant blooming artifact that can be caused by CIED leads, which makes interpretation challenging. Similarly, despite cardiac magnetic resonance imaging being shown to be safe for both conditional and nonconditional devices, it is significantly limited by artifacts related to CIED type and size (worst in CRT-defibrillators and subcutaneous ICDs). Visualization of the tricuspid leaflets is often difficult, but it may be possible to quantify right ventricular size, volumes, function, remodeling, fibrosis, and TR.
Medical Therapy
Diuretics remain central in the medical management of CIED-related TR and symptomatic right heart failure. Loop diuretics can be augmented with aldosterone antagonists, but data are lacking regarding the long-term outcomes of conservative medical management in CIED-related TR as more invasive strategies, discussed below, are often pursued. This is largely due to the challenge in increasing dosage of diuretics due to kidney dysfunction from cardiorenal syndrome or diuretic-induced acute kidney injury and hemodynamic instability from impaired cardiac output.
Transvenous Lead Extraction
The decision to pursue TLE is complex and should involve a multidisciplinary team to try to predict the probability of improving or worsening TR and to weigh the risks of procedural complications. Despite the improving safety and efficacy of TLE, there are still no prospective data or guideline recommendations addressing TLE in severe TR in the absence of infection. On one hand, CIED-related TR that is left untreated is associated with adverse right ventricular remodeling and tricuspid annular dilation, resulting in irreversible severe TR, as well as increased mortality estimated between 40 and 75%. , On the other hand, some studies have reported that as little as 25% to 35% of patients had successful TLE and improvements in CIED-related TR. , Furthermore, severe injuries to the tricuspid valve apparatus have been reported to occur in 2.5% of cases, but with any grade increase of TR occurring in as much as 11.5% of cases. , This highlights the importance of a thorough assessment of the cause of TR in the presence of CIEDs. In patients where the TR is thought to be CIED-related and without significant right ventricular dysfunction or tricuspid annular dilation, TLE should be considered. Procedural volume and technical expertise are also important considerations. Consequently, it is crucial to refer these patients to specialized valve centers with a multidisciplinary heart team capable of meticulously weighing the risks and benefits. Although longer lead dwell time has been shown to be a risk factor for acute TR worsening after TLE, there are insufficient data regarding whether mechanical sheaths, laser sheaths, femoral snares, and other specific techniques are associated with the risk of worsening TR. , The role of TLE to avoid lead jailing and facilitate percutaneous treatments discussed below remains unclear.
Percutaneous Treatment
Percutaneous therapies to treat significant TR have recently gained significant attention, particularly given the expansion of available therapeutic options, including transcatheter edge-to-edge repair (TEER), transcatheter valve replacement, heterotopic bi-caval valve placement, and transcatheter annuloplasty. Many of these therapeutic options remain investigational with limited observational data or with small numbers of patients, and several challenges lie ahead regarding patient selection and procedural planning due to the complex structural milieu that results in significant TR. Furthermore, questions regarding the efficacy of these therapies for CIED-related TR remain unexplored. This is in part due to the fact that many randomized controlled trials exclude patients with CIED-related TR with lead impingement or adherence clearly demonstrated.
TEER is a well-established technique for mitral valve repair and has been utilized in the treatment of significant TR ( Figure 2 ). TEER devices include the MitraClip and TriClip systems (Abbott Laboratories) and the PASCAL Precision System (Edwards Lifesciences). Use of the MitraClip system on the tricuspid valve has been reported in single-center and multinational registries since the approval for use on the mitral valve. Many of these nonrandomized studies report a reduction in the degree of TR as well as symptom, functional, and/or clinical improvement, while excluding patients with pacemaker lead-related TR. As an example, a propensity-matched case-control study from the TriValve registry (22 European and North American centers) evaluated multiple different transcatheter tricuspid valve therapies, with the MitraClip being the dominant system studied. Overall survival and survival free from heart failure were significantly higher in the TEER group. A right ventricular lead was present five times more often in the TEER group than in the control group, while the benefit of TEER was not as robust in the presence of a a right ventricular lead.
The TriClip device recently gained approval for use in the United States, and the TriClip and PASCAL systems have received CE MARK. The TRILUMINATE study reported on 350 patients randomized 1:1 to TriClip and medical therapy vs. medical therapy alone. , Safety was established with 98.3% freedom from major adverse events at 30 days, the degree of TR was significantly reduced and sustained to 1 year, and health status was markedly improved as determined by survival and Kansas City Cardiomyopathy Questionnaire scores. Patients were excluded if device leads were present that would prevent appropriate placement of the TriClip device, and 16% of patients in the TEER group had a CIED in place. At 1 year, 3% of patients in each group required placement of a CIED, suggesting that tricuspid TEER does not carry a risk of conduction disturbance. A common theme in the literature is a subjective and ill-defined assessment of the role a trans-tricuspid device lead may play during a transcatheter intervention for TR and a lack of statistics regarding the exclusion of patients due to the presence of CIEDs. It should be noted that the presence of any lead through the tricuspid valve can pose a challenge to tricuspid TEER due to both the presence of the lead in the jet area and the shadowing artifact that can make imaging guidance suboptimal (especially for device placement posterior to the lead). A representative case of CIED-related severe TR resulting in lead extraction and tricuspid TEER is presented in Figure 3 . Additional studies are required to examine how to proceed with tricuspid TEER in the presence of CIED, regardless of whether the TR is induced by the CIED, whether TEER can be utilized in combination with TLE, and whether there are long-term interactions when both CIED leads and TEER devices are present.
