Histological properties of oscillating intracardiac masses associated with cardiac implantable electric devices

Abstract Background There have been a few cases of echogenic cardiac implantable electric device (CIED) lead‐associated oscillating intracardiac masses (ICMs) in leads imaged by echocardiography. The histological properties of ICMs could help clarify the etiological diagnosis. Although there is extensive literature on mass size, the histological properties of such masses have not been characterized. The aim of this research was to clarify the histological features of oscillating ICMs in CIED patients. Methods Preoperative echocardiography was performed in all candidates for CIED removal. In the patients with ICMs, specimens were obtained by 3 methods: direct tissue collection during open‐heart surgery; tissue collection together with the CIED lead during transvenous extraction; and tissue collection by catheter vacuum during transvenous CIED removal. A standard histopathological examination of ICM tissue was performed. Results A total of 106 patients underwent lead removal in our institute (April 2009‐March 2018); 14 patients had an ICM (13.2%), and 7 specimens were obtained in patients with CIED lead‐related ICM. Following histological examination, 2 types of ICM were identified: one mainly composed of thickened endocardium (EN type; 3 patients), and the other mainly an aggregate of inflammatory cells as a neutrophil cell (NC type; 4 patients). Conclusions Two histological types of intracardiac masses, including a thickened endocardium type and a neutrophil cell type, were identified. These classifications might help make an accurate histological diagnosis of lead‐associated intracardiac masses.


| INTRODUC TI ON
On the basis of clinical trials including large populations of patients with cardiac implantable electrical devices (CIEDs), the number of CIED patients has significantly increased over the last decade. 1 However, candidates requiring removal of CIED systems have also been increasing at an astounding rate. [2][3][4] The reasons for removal in the majority of these candidates were lead dysfunction, cardiac device-related endocarditis (CDRIE), and local device infection including pocket infection. 5,6 In particular, CDRIE has the potential to increase mortality and morbidity; therefore, prompt recognition and management of CDRIE may improve patient outcomes. According to the 2017 HRS statements on lead management, the presence of an echocardiographic right-side intracardiac mass (ICM) on CIED leads is critical for the accurate diagnosis of CDRIE, determining the need for CIED system removal. 2 With the development of echocardiography (ie, transesophageal echocardiography [TEE]), the incidence of CIED lead-associated masses has been reported to be 1%-14% as endocarditis and as incidental detection on echocardiographic studies (transthoracic echocardiography [TTE] and TEE). 5,[7][8][9] In the clinical setting, the determination of the etiology of an echogenic mass remains challenging. There are not a few patients with echogenic ICMs without systemic infection or venous thromboembolism. 10 Today, the main clinical question is whether an ICM represents a thrombus or vegetation, but distinguishing a vegetation from a thrombus is difficult in clinical practice. Therefore, the histological characteristics of ICMs need to be evaluated. However, the histological properties of intracardiac masses have not been investigated. Understanding the histological characteristics of ICMs may help clarify their etiology.
The purpose of this investigation was to further elucidate the histological origins of ICMs in CIED patients.   was also on standby in the operating room throughout the procedure.

| Transvenous procedure
Standard methods for transvenous lead extraction were performed.
The leads were extracted using the subclavian approach. Laserassisted lead extraction was attempted through an excimer laser sheath (SLS II or GL, DVX) with a locking stylet.
Following transvenous lead extraction, some of the ICMs were remained in the right atrium. The remaining ICM was suctioned using an aspiration catheter (Launcher 8-Fr, Medtronic) with the area accessed via a femoral vein approach. Several specimens were obtained using this method.

| Open-heart surgery
During open-heart surgery, extracorporeal circulation was introduced through a median sternotomy. Conventional bicaval cannulation was used during the open-heart procedure. Both great veins had a tourniquet applied to control bleeding during the time of incision of the right atrium. The tips of the atrial and ventricular leads were removed directly through the right atrial incision. During or before cardiopulmonary bypass, an excimer laser sheath was used to ablate lead adhesions through the subclavian vein and the superior vena cava. A sheath was inserted from an antegrade subclavian vein or retrograde superior vena cava according to lead condition. ICMs and leads were removed entirely via the open-heart procedure with laser sheath-assisted lead extraction.

| Echocardiographic study
All patients underwent TTE before surgery. A subset of patients also underwent TEE. An ICM was defined as an oscillating mass found on a lead and confirmed in multiple views by TTE or TEE. The location of the ICM was determined by echocardiography. ICM morphology (diameter and number) was also examined using the data obtained from the echocardiogram. The diameter was measured in the longest length of the ICM. The number of ICMs was counted in multiple echocardiogram views. Cardiologists or echocardiologists overviewed all echocardiogram data.

| Statistical analysis
All continuous variables are expressed as means ± SD of the mean.
All categorical variables are reported as numbers (%) of patients. A paired Student's t test was used to compare all the continuous variables. Categorical variables were analyzed using a chi-squared test.
Significance was accepted at P < .05. All statistical analyses were performed using SPSS version 22.0 (SPSS Inc).

| Histological evaluation of intracardiac masses
Seven specimens were obtained from patients with CIED lead-related ICMs. Analysis of the histological features of the ICMs showed that there were 2 major histological types ( Figure 1). The first type was composed of fibrous tissue whose principal component was thickened endocardium (endocardium type; EN type). Figure 1A,B shows the distinctive findings of EN type with Elastic-Masson-Goldner (EMG) stain. The mass had polypoid collagenous tissue protruding from the endocardium. The second type was primarily composed of an aggregate of neutrophils as inflammatory cells and/or fresh fibrin (neutrophil cell type; NC type). Figure 1C,D shows the typical structure of the NC type formed mainly from fresh fibrin with inflammatory cell infiltration, consisting primarily of neutrophil cells, with hematoxylin-eosin stain.

| Patients' demographics
The demographics of the patients with the 2 types of ICM are summarized in Table 1  The clinical presentations are summarized in Table 2 On the other hand, no EN type patients had a positive blood culture.

| Echocardiographic study
On echocardiographic study, the ICMs related to the right-sided leads were evaluated, and their morphological characteristics (shape, number, size, and location) and qualitative features (echogenicity) were assessed.

| ICM morphology: shape, number, size, and location
Intracardiac mass shapes were classified as solitary round in shape, multilocular lobular types, and mixed types (Figure 2A,B). All EN type ICMs were observed as solitary caulescent round shapes ( Figure 2A). On the other hand, in the NC type, all ICMs had multilocular lobular shapes ( Figure 2B). Two patients had a solitary mass, whereas the other patients showed signs of multiple ICMs. Some of the NC type patients had ICMs with strips.
Comparing the maximum lengths of the ICMs, the NC type was significantly longer (2.8 ± 0.7 cm) than the EN type (1.4 ± 0.1 cm, P = .03, Figure 3C). Concerning ICM location, EN type ICMs were in the right atrium on multiple echocardiogram views. Two EN type ICMs were attached to atrial leads ( Figure 3A, black and white mass).
The other EN type ICM was attached to the ventricular lead and tricuspid orifice ( Figure 3A, blue mass). In the NC type, most ICMs were in the right atrium ( Figure 3B). An ICM was also identified in the right ventricle ( Figure 3B, yellow mass). The other ICM was located at the superior vena cava and attached over the RA and RV leads ( Figure 3B, black mass). In one of the patients who had multiple ICMs, the ICMs were located at the center of the right atrium, the superior vena cava, and the coronary sinus ostium ( Figure 3B, blue masses).

| D ISCUSS I ON
This study showed 2 histological types of CIED lead-related ICMs.
The main structure of the first type was composed of layered elastic tissue, which was defined as thickened endocardium (EN type, Figure 1A,B). The second type was principally formed by inflammatory cell infiltration, primarily neutrophils, with fibrin on hematoxylin-eosin staining (NC type, Figure 1C The primary structures of the EN type ICMs consisted of thickened endocardium. Considering these histological features, the EN type ICM might be related to a fibrous sheath covering the CIED leads. After the implantation of the leads, fibrin deposits around the leads. This fibrin ultimately forms into connective tissue resulting in full coverage of the leads. 10,[12][13][14] It might be highly likely that the so-called "ghosts" are the same histological strain as the EN type ICM. 15 "Ghosts" are detected as residual floating fibrous tissue after transvenous lead extraction by echocardiography. In EN type ICMs, 2 cases were detected before lead extraction, and the other one was observed after lead extraction around the tricuspid valve orifice. Two of EN type ICMs were at in the cavity with right atrial leads and the other one was placed on tricuspid orifice (see Figure 3; left panel). We speculate the outgrowth process of the floating EN type ICM. In the right atrium, the prevalent atrial blood flow pattern is vortical flow and/or vortices flows. 16 Vortical flow caused low wall shear stress. 17 The leads and the fibrosis sheath were exposed by vortices and low wall shear stress.
Low shear stress causes endothelial cells injury on lead surface fibrotic tissue and provokes the neointimal hyperplasia. 18,19 In line with this process, hyperplastic fibrosis grows on the endocardial surface and into the RA cavity as the EN type ICMs.  [20][21][22] In clinical practice, the major question is whether an ICM represents a thrombus or vegetation. 10

| CON CLUS IONS
This investigation used histopathological analysis to identify 2 types of ICMs in patients with CIEDs: a thickened endocardium type and an inflammatory cell type. These 2 types of ICMs showed distinct characteristics with respect to morphology, location, and number on echocardiographic assessment.