Abstract

The implantation of cardiac implantable electronic devices (CIEDs) may result in or worsen previously existing tricuspid regurgitation (TR). The prevelence of lead-related tricuspid regurgitation (LRTR) in patients with CIEDs is between 7.2% and 44.7% when the degree of worsening TR is not reported, or from 9.8% and 38% when it is diagnosed as worsening of TR severity by at least 2 grades after a CIED has been implanted. It has been suggested that a CIED lead positioned over or pinning a leaflet may be the main cause of TR in this patient population. The septal and posterior leaflets of the tricuspid valve have been reported to be the most affected by CIED leads. Severe LRTR is related to the development of heart failure (HF) or worsening of previously existing dysfunction; it is also associated with elevated mortality. However, there are no definitive predictors of LRTR development or standardized methods of treatment. Some studies have suggested that imaging-guided lead placement can reduce the occurrence of LRTR. This review summarizes current knowledge concerning the development, evaluation, consequences, and management of LRTR.

Key words: cardiac implantable electronic devices, lead-related tricuspid regurgitation, heart failure

Introduction

The etiology of tricuspid regurgitation (TR) is predominantly functional (93% of cases) and includes left- and right-sided heart failure (HF), dysfunction of the aortic and mitral valves, pulmonary hypertension (PH), and arrhythmias. The incidence of isolated TR induced by atrial fibrillation is estimated to be approx. 8% of cases.¹ The prevalence of significant TR among patients with a cardiac implantable electronic device (CIED) has not been precisely determined and varies from 7.2% to 44.7%^{2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23} or from 9.8% to 38%^{4, 12, 18, 21, 23, 24} when it is diagnosed as worsening of TR severity by at least 2 grades after a CIED has been implanted. A summary of current studies on TR occurrence after the implantation of CIED is presented in Table 1. Lead-related tricuspid regurgitation (LRTR) is associated with the development of HF and increased mortality,^{5, 6, 21, 25} yet different authors have different views about its clinical relevance. The differences between reports concerning TR and CIEDs include the number of patients, the type of investigated CIED, the method of TR assessment, and definitions of its significance.⁹

Imaging techniques for the assessment of lead position

Two-dimensional echocardiography

Conventional 2D transthoracic echocardiography (TTE) has limitations in its anatomical assessment of the tricuspid valve (TV) because only 2 leaflets can be visualized simultaneously on the atypical parasternal view. Furthermore, the posterior leaflet can only be seen on the right ventricular two-chamber view. Therefore, identifying a relationship between the leaflets and a CIED lead can be a challenging task.³ The evaluation of LRTR severity is based on standard criteria of the right ventricle (RV) and TV assessment. It includes RV dimensions, fractional area change, tricuspid annular plane systolic excursion (TAPSE), right ventricular systolic pressure, proximal isovelocity surface area (PISA), vena contracta, effective regurgitant orifice, and regurgitation volume.^{10, 12, 13, 24, 26, 27} To avoid an underestimation of LRTR, it is crucial to record regurgitant flow during inspiration. Massive TR in a patient with a CIED and calculated strain of the RV are shown in Figure 1.

Three-dimensional echocardiography

Some limitations of conventional TTE can be overcome using 3D echocardiography.^{28, 29} It enables clinicians to make a complete assessment of the anatomy of the TV and subvalvular apparatus, as well as the geometry, volume and ejection fraction of the RV. The optimal view to enable visualization of all the TV leaflets and commissures is the en face view with the septal leaflet located at the 6 o’clock position.²⁸ In patients with CIEDs, 3D echocardiography makes it possible to identify the lead position and localize a leaflet prolapse, perforation or vegetations, in addition to the origin of the regurgitation jet. The 3D technique may be helpful in the evaluation of the TV orifice area for grading tricuspid stenosis.^{28, 30} It substantially improves the determination of the mechanism of valve dysfunction and is feasible in 74–94.2% of patients with CIEDs.^{3, 16, 31}

Transesophageal echocardiography

Transesophageal echocardiography (TEE) should be considered a complementary technique of imaging in nonconclusive assessment of lead position. Moreover, TEE seems to be a more accurate method for evaluating TR severity. Lin et al. performed preoperative TTE in patients with LRTR undergoing cardiac surgery, and TR severity was underestimated in 37% of patients in subsequent intraoperative TEE.³² In Figure 2, TV imaging methods and lead position in TEE are presented. Figure 3 explains how to assess TR and lead position.

Chest radiography

Chest radiography is used to determine the dislocation of the leads and their position in relation to each other, as well as to check their continuity. Pang et al. in their study divided the RV region with 3 horizontal lines to assess the lead position in the posteroanterior (PA) view using fluoroscopy. Those regions are referred to as right ventricular outflow tract (RVOT) (superior region), middle RV and inferior region, with the last one divided into RV inflow and RV apex.³³ Yu et al. assessed the position of the leads on chest radiography in the PA view and found that nonapical RV lead position was not as often associated with TV interference as apical RV lead position.³⁴

Techniques for implantation of CIEDs

The implantation of CIEDs is performed under fluoroscopic guidance. The tip of the lead is directed toward the interventricular septum (IVS) or RV apex. The 3 most commonly used techniques are³⁵:

1. “Prolapsing” – the lead is put into the right atrium (RA) with an inner stylet 5–10 cm from the lead tip and pushed to create a limp loop hanging on the tricuspid annulus. Next, the lead is slightly retracted, and the stylet is slipped forward for prolapsing the lead to the RV. The tip of the lead may hook on the TV or trabeculation, with the remaining part of the lead hanging within the RV. In such situation, the stylet is pushed forward to free the lead tip, or the stylet and lead are slightly withdrawn together while still maintaining the loop shape of both of them in order to enable prolapsing of the lead to the RV in the next step. This operation should be performed very cautiously because overly vigorous movements can result in entanglement of the lead within the chordae tendineae or injury of the TV and subvalvular apparatus;

2. “Direct crossing” – used especially for leads with a larger diameter. The inner stylet is reshaped to gain less curvature, and the lead is advanced directly from the RA into the RV. As the adjustment of the tip location (by moving and rotating the lead body or ejecting and retracting the inner stylet) is performed after crossing the TV, it may lead to damage of the TV and subvalvular apparatus;

3. “Dropping down” – this technique is also used for thicker leads. The lead is inserted into the RV with the inner stylet maintained in the large curvature, which results in reaching the RV outflow tract by the lead tip directly after crossing the TV. If the tip is too high within the RVOT or the desired position is the IVS, the lead has to be withdrawn. If the final location of the lead tip is the RV apex, the stylet is replaced with a straight one and slipped forward through the lead with simultaneous withdrawal of the lead, which makes the tip “drop down” to the apex.

Mechanisms of lead-related tricuspid valve dysfunction and regurgitation

Many studies have indicated that CIEDs directly affect the function and structure of the TV.^{3, 6, 8, 16, 20, 22, 30, 31, 32, 36} The mechanisms of LRTR include the following:

1. Leaflet perforation^{6, 29, 32};

2. Damage of the subvalvular apparatus; chordae tendineae entanglement or rupture and papillary muscle perforation^{32, 36, 37};

3. Leaflet impingement by a lead or limitation of the movement of a leaflet caused by adherence to the lead^{3, 9, 20, 29, 31, 32, 36};

4. Fibrosis involving the lead and the TV³²;

5. Device-related infections.

The technique of CIED implantation has an impact on the occurrence of LRTR. According to Trankle et al. and Chang et al., “prolapsing” reduces the risk of perforation and laceration of the TV leaflets and subvalvular apparatus. Rajappan, in turn, indicated that “direct crossing” results in a lower risk of damage to the TV apparatus and the development of TR.^{30, 35, 38} The position of the lead tip is very important. Septal pacing is regarded as more physiological and less associated with the progression of HF.35 Alizadeh et al. found an association between apical pacing and tricuspid and mitral valve regurgitation.¹⁹ On the other hand, in a study by Cheng et al., a significant increase in proximal isovelocity surface area (PISA) radius was shown in patients with the lead tip in the IVS compared to those with the lead tip in the RV apex or the outflow tract.³¹ Placement of the lead within the IVS more often affects the chordae tendineae and causes adherence of the lead to the septal or posterior leaflet, reducing their mobility and inducing TR. In some studies, placing the lead within the RVOT was the position least often related to TR worsening.^{39, 40}

Positioning the lead in the “center of the valve”^{3, 16, 31, 41} or in the anterior, especially posteroseptal commissure, results in only minimal restriction of the leaflet motion.^{3, 16, 20, 31, 42} In that context, a promising method of visualization of the TV and optimization of the implantation of a cardiac device’s leads is 3D TTE.^{6, 16} Gmeiner et al. carried out lead implantation guided with TEE, which resulted in no worsening of TR compared to the control group (p < 0.001); this makes TEE an alternative for procedures performed only with fluoroscopy.⁴³

Polewczyk et al. indicated that loops formed due to an excess of atrial or ventricular leads falling into the TV orifice may cause irritation of the leaflets and their malcoaptation.³⁶ Many authors have suggested that it is not merely the presence of the lead between the leaflets or within the TV commissures but irritation or pinning of the leaflets by the lead that is the main cause of TV dysfunction.^{3, 8, 16, 20, 31} The septal and posterior leaflets are reported to be the most often affected.^{3, 8, 9, 16, 20, 31, 32, 37} Henry et al. presented interesting cases of explanted hearts obtained from patients with CIEDs who had undergone cardiac transplantation. In their study, 40% of the cases showed device/lead interference with the TV. Three cases showed interference with the leaflets (the septal leaflet in 2 cases and the anterior leaflet in 1 case), while another 3 cases – interference with the subtricuspid apparatus.³⁷

According to some authors, the type of CIED has an impact on the development of LRTR. In comparison to pacemakers, there is a greater risk of LRTR with implantable cardioverters/defibrillators (ICDs) and cardiac resynchronization therapy defibrillators (CRT-Ds)^{10, 14} due to the larger diameter of the defibrillation leads. Other authors did not find significant differences in TR occurrence between patients with pacemakers and those with other types of CIEDs.^{4, 5, 13, 16, 21, 22, 23}

Many authors have investigated the relationship between TR development and the mode²² or percentage of cardiac pacing.^{5, 11, 23, 24, 38} In a study by Fanari et al., RV pacing dependence had no effect on the worsening of TR severity (39% for a high frequency of RV pacing compared to 45% for a low frequency of RV pacing; p = 0.52). This was similar for the mode of stimulation (43.2% in single-chamber ventricular pacing compared to 45.6% in dual-chamber stimulation; p = 0.5).²²

Predictors of TV regurgitation development in patients with CIEDs

Apart from the technical aspects described above, other factors can affect the function of the TV after CIED implantation. The dilatation of the RV plays a significant role in the development of TV regurgitation after CIED implantation,^{3, 6, 9, 12, 23, 30} as does impairment of the systolic or diastolic function of the left ventricle (LV).^{30, 38, 44} Other risk factors mentioned in reports include increased RA area,^{20, 23} elevated right atrial pressure^{8, 9} and elevated pulmonary systolic pressure.^{6, 23, 45} Lee et al. found that an elevated tricuspid pressure gradient before implantation is an independent predictor of progressive LRTR.¹¹ Even more risk factors for the development of TR have been reported, including age over 73 years (73 years or older according to Lee et al., 76 years according to Delling et al., and 80 years or older according to Riesenhuber et al.^{6, 12, 23}), female sex,¹² atrial fibrillation,^{12, 23} elevated heart rate,⁶ history of mitral valve dysfunction,^{6, 12, 23} and left atrial area enlargement.^{12, 23}

On the other hand, a study by Höke et al. found no significant differences in clinical, echocardiographic or device-related factors (age, sex, atrial fibrillation, history of mitral valve dysfunction, left atrial volume, type of device, or percentage of pacing) between patients with TR compared to those with no significant TR after CIED implantation.²¹

Consequences of TR

Many studies have shown that at least moderate TR is connected with increased mortality and more frequent and prolonged hospitalizations due to HF.^{4, 5, 6, 9, 11, 13, 21, 26, 46, 47} The same observations apply to LRTR, as patients with tricuspid dysfunction develop RV failure more often than patients without TR.^{4, 6, 9, 10, 21, 44} A summary of studies concerning the consequences of LRTR is presented in Table 2.

Management of LRTR

In recent years, some new treatment strategies for severe TR and LRTR have emerged. According to the current European Society of Cardiology (ESC) guidelines for the management of valvular heart disease,⁴⁸ surgery for secondary TR should be performed simultaneously with a left-sided valvular operation if the regurgitation is severe or considered when there is dilatation of the TV annulus in mild or moderate TR. Repair or replacement of the TV, independent of a left-sided operation, should also be considered in cases of severe TR that is causing symptoms or when there is dilatation of the RV in the absence of LV or RV failure and PH; this would promote reverse remodeling of the RV and improve its functional state.⁴⁹ Among asymptomatic patients, an intervention should be considered when RV dilatation or declining function is observed.⁴⁸ Severe RV/LV dysfunction or severe PH are considered contraindications for surgery. When a CIED lead is present, the technique should be adapted to the patient’s condition and the surgeon’s experience.⁵⁰ In Table 3, we summarize the statements and recommendations from various guidelines on TR caused by CIEDs. In selecting the most appropriate and safe treatment strategy for patients with LRTR, the procedures described in the following sections should be considered.

Surgical annuloplasty or valve replacement

According to the 2021 ESC Guidelines for the management of valvular heart disease, when there is no severe TV degeneration or annulus dilatation, the repair of the valve is preferred over the replacement. Wong et al. demonstrated that repair in such cases is associated with better short- and long-term outcomes in both isolated and concomitant TV surgery compared with valve replacement,⁵¹ because long-term anticoagulation is not needed and it allows for avoiding thrombosis and degeneration of the bioprosthetic valve.⁵² In the case of LRTR requiring only an annuloplasty with an open ring (without additional procedures within the leaflets), the lead may be left in the previous position. However, to avoid further complications associated with the interference between the lead and parts of the repaired valve, the lead should be placed between the artificial and native ring or removed and implanted into the coronary sinus, epicardially⁵⁰ or in another alternative position.⁵³ There are also the options of implantation of a leadless pacemaker or subcutaneous ICD (sICD). In some cases, classic implantation of a new lead within the valve is acceptable. The same rules apply to biological prostheses. When a mechanical prosthesis must be implanted, the lead cannot be placed within the valve. The implantation of a leadless pacemaker is technically impossible secondary to valve surgery, but is acceptable during the procedure.⁵⁴

Transcatheter tricuspid valve intervention

Transcatheter tricuspid valve intervention (TTVI) is an alternative treatment for patients with secondary severe symptomatic TR and contraindications for surgical intervention. It is not a standard procedure, as it still remains under evaluation and is only conducted in highly specialized centers.⁴⁸

Leaflet approximation

Lurz et al. conducted transcatheter tricuspid valve repairs using the TriClip device and demonstrated that this device was safe and effective in patients with moderate or severe TR. They achieved a significant reversal of RV remodeling in terms of size and function. However, their study did not provide information about patients with CIEDs.⁵⁵

Direct annuloplasty

Nickenig et al. presented results on the Cardioband system in patients with symptomatic and moderate to severe functional TR. This system was previously successfully applied in functional mitral regurgitation. The researchers reported a significant reduction in TR through a decrease in annular dimension, as well as a decrease in HF symptoms and improvement in quality of life. In their study, the presence of a CIED was one of the exclusion criteria.⁵⁶

Valve replacement

Fam et al. reported that the use of the EVOQUE transcatheter tricuspid valve replacement (TTVR) system brought about significant clinical improvement among patients with severe TR and right-sided HF, with high effectiveness (92% of cases) and safety. In their study, 36% of patients had transvenous pacemakers, and TTVR was successful in all cases.⁵⁷

Taramasso et al. compared medical treatment with TTVI and demonstrated that all-cause mortality and rehospitalizations at 1 year were lower among patients who received the intervention.⁵⁸ In the TriValve registry for the years 2015–2018, TTVI was conducted in 121 patients with CIEDs. Only 7 patients had isolated device-induced TR, in which the only mechanism for TR was interference between the lead and the TV components. The interventions in that registry included the following: edge-to-edge technique (MitraClip Abbott Vascular, Santa Clara, USA – 106 patients; 87%); PASCAL (Edwards Lifesciences, Irvine, USA – 1 patient; 0.8%), implantation of a coaptation device (FORMA; Edwards Lifesciences – 2 patients; 1.6%), annuloplasty (Cardioband; Edwards Lifesciences – 1 patient; 0.8%), transcatheter valve implantation (CAVI; Edwards Lifesciences – 10 patients; 8%); and NaviGate (NaviGate Cardiac Structures, Lake Forest, USA – 1 patient; 0.8%). Procedural success was achieved in 78.6% of patients, with an in-hospital mortality rate of 3.7%. Symptomatic improvement was observed at 30 days in 65.0% of patients, and survival at 12 months was 73.6 ±5.0%.⁵⁹

Transvenous lead extraction

A study by Polewczyk et al. showed an improvement in TV function after transvenous lead extraction (TLE) in 35.29% of patients. In that group, the survival rate after 5 years of follow-up was higher compared to patients without improvement after the procedure. One of the most common mechanisms of LRTR in their study was propping the leaflet upward or clamping it down using the lead (85.71%).⁶⁰ According to Glikson et al., TLE entails a high risk of TV avulsion with worsening TR.⁵⁰ Nazmul et al. reported some cases of TLE in patients with moderate or severe TR and stated that extraction did not result in a significant reduction in TR, particularly in patients with a dilated TV annulus.⁶¹

After TLE, the lead (including the defibrillation one) may be implanted in an alternative site within the RV or into the coronary sinus for LV pacing. Stimulation of the His bundle seems to be the most physiological technique and the least related to secondary TR evoked by pacing.⁶² In some cases, epicardial leads are used.⁵³ Other solutions may involve a subcutaneous ICD or a leadless pacemaker; however, in the latter case, TR secondary to RV dysfunction associated with nonphysiological distribution of electric pulses or procedural complications can also occur.^{63, 64, 65} A leadless pacemaker may also be used in combination with an sICD, or a lead can be implanted into the coronary sinus for biventricular pacing.⁶⁶ Some reports have shown good results with pericardial, extrapleural and substernal placement of defibrillator coils, separately or in conjunction with epicardial pacing leads, although their implantation requires employing surgical techniques.⁵³

Medical therapy

According to the 2021 European Society of Cardiology/European Association for Cardio-Thoracic Surgery (ESC/EACTS) Guidelines for the management of valvular heart disease, conservative therapy of TR should be reserved only for patients with severe RV failure or PH. The treatment is based on diuretics and aldosterone antagonists as well as pharmacotherapy of arterial PH. In patients with atrial fibrillation, maintenance of sinus rhythm may be helpful in the prevention of dilatation of the TV annulus and progression of TR.⁴⁸

The treatment strategy for severe TR is still not standardized, and more research is needed to establish such a strategy. Guidelines suggest that only severe RV/LV dysfunction or severe PH are considered contraindications for surgery.⁴⁸ Stocker et al. demonstrated that severe PH, defined as mean pulmonary arterial pressure (mPAP) >30 mm Hg and transpulmonary gradient >17 mm Hg, were associated with higher mortality after TTVR.⁶⁷ Taramasso et al. reported that systolic pulmonary artery pressure is the strongest parameter related to death and that patients must be treated with optimal medical therapy before the intervention, which allows for the best RV/pulmonary artery coupling in the peri-interventional period with the lowest possible RV afterload.⁵⁹ In addition, Kavsur et al. demonstrated in their study that pulmonary capillary wedge pressure (PCWP) is a predictive outcome parameter in TTVR patients. They reported that patients with a PCWP ≤ 16 mm Hg had a favorable outcome with lower mortality and morbidity. Furthermore, they suggested that right heart catheterization should be considered a routine diagnostic tool in the process of TTVR evaluation.⁶⁸ Regarding operative risk, Färber et al. suggested that the Model for End-Stage Liver Disease (MELD) score might be a tool to identify high-risk individuals among patients qualified for isolated TV surgery. In their study, classic surgical risk stratification scores of the Society of Thoracic Surgeons or the European System for Cardiac Operative Risk Evaluation (EuroSCORE II) failed to predict perioperative mortality in patients with severe liver dysfunction.⁶⁹ A proposal for the management of LRTR is presented in Figure 4.

Discussion

Tricuspid regurgitation has stood on the sidelines of medical interest for many years. In comparison to atrial and mitral valvular diseases, fewer reports about indications and treatment results have been published. In the case of LRTR, the quantity of information is even more limited.

Some authors have stated that there is a lack of evidence regarding the progression of TR after CIED implantation.^{17, 70, 71} The development of TR in patients with HF and ICDs or CRT-Ds is also questionable. Valve dysfunction may be either a result of mechanical impairment caused by a CIED^{4, 21} or an effect of the progression of LV and RV failure. Some studies have shown a reduction in TR severity through an improvement in hemodynamic function and an increase in cardiac output after normalization of heart rhythm following CIED implantation.^{12, 70}

It also remains unclear whether the progression of RV remodeling is a cause or a consequence of significant TR. Höke et al. did not identify any significant differences in RV function (TAPSE and RV fractional- area change) in patients with severe LRTR compared to patients without severe LRTR, but larger RV diastolic area (17 ±6 mm² compared to 16 ±5 mm²; p = 0.009), right atrial enlargement (39 ±10 mm compared to 36 ±8 mm; p < 0.001) and higher pulmonary arterial pressure (41 ±15 mm Hg compared to 33 ±10 mm Hg; p < 0.001) were found in patients with significant LRTR after 1–1.5 years of follow-up. However, longer follow-up periods might lead to a decrease in RV function.²¹ In addition, no significant differences were observed regarding changes in LV volume or systolic and diastolic function in patients with severe LRTR compare to patients without significant LRTR. Furthermore, the difference in the severity of mitral regurgitation was also similar in patients with compared to without significant LRTR.²¹

Seo et al. stated that LRTR might induce HF resistant to pharmacotherapy, as a result of continuous progression of TR with TV and RV remodeling.⁹ Nakajima et al. demonstrated lower effectiveness of HF pharmacotherapy in patients with LRTR in comparison with TR not related to CIEDs, which suggests a real impact of CIED on TR development.⁸ Papageorgiou et al. observed that new post-implant moderate or severe TR (hazard ratio (HR): 3.14 (95% confidence interval (95% CI): 1.29–7.63); p = 0.01) and RV impairment (HR: 2.82 (95% CI: 1.33–5.98); p = 0.01) were independent predictors of mortality.¹⁰

Confirmation of direct contact between the lead and tricuspid valvular apparatus may be challenging. The authors of this article propose that the term “LRTR” should be used in a situation when there is clear evidence of an interaction between the lead and a valve leaflet. The evidence of such an interaction are, among others:

1. Leaflet perforation^{6, 32};

2. Entanglement of the lead within the chordae tendineae^{32, 36};

3. Leaflet impingement by a lead or leaflet movement limitation caused by adherence to a lead^{3, 9, 20, 31, 32, 36};

4. Fibrosis involving the lead and TV apparatus.³²

There are many questions related to the treatment of LRTR. Lead extraction is a risky procedure, especially if it is performed many years after primary implantation. In our opinion, the decision for TLE should be considered if the interaction between the electrode and the leaflet is confirmed using 3D TTE, because the presence of an electrode in the center of the tricuspid orifice without any evidence of contact with the leaflet suggests that a change in the position of the electrode after TLE will not affect the valve’s function. The use of a leadless pacemaker or LV pacing with a lead inserted into the coronary sinus also does not prevent TR from developing.⁷² The occurrence of LRTR should be avoided using available methods, such as His bundle pacing for the most physiological way of stimulation, or the use of TEE⁴³ to implant the ventricular lead intercommissurally or in the middle-of-the-annulus position¹⁶ to minimize the interaction of the lead with TV components.

Although different authors differ in their opinions concerning the relevance of LRTR, it seems to be an important clinical problem, with an impact on right and left ventricular function and prognosis. Taking into account the low interest in TV diseases, further studies are required to formulate guidelines concerning LRTR prevention and to choose the time and method of treatment aimed at reducing the risk of complications and achieving optimal results.

Conclusions

Lead-related tricuspid regurgitation is common in patients with CIEDs. Risk factors for its development and impact on RV and LV function are difficult to predict and require further systematic clinical registries and observational studies. The preferred treatment methods for patients with LRTR have not yet been determined.