A clear diagnosis of cardiac device-related infective endocarditis (CDRIE) is crucial to drive the indication for therapy that is always expensive and requiring transvenous lead extraction (TLE) with associated mortality and risks.1 Finding intracardiac lead masses in patients with suspected endocarditis is a major criterion of the Duke diagnosis score,2 but its value in patients with cardiac implantable electronic devices (CIEDs) has been debated, as vegetations have been observed in cases of local infections,3 whereas they have not been recognized in patients with positive cultures of intravascular lead fragments.4
In CDRIE local signs at the device pocket are often prevailing,4 whereas systemic involvement may be absent. Laboratory data may be inconclusive, blood samples are frequently negative, and fever is the main presentation clue.5 Transesophageal echocardiography (TEE), indeed, is important to increase sensitivity and specificity of the diagnosis of CDRIE.6 Data are lacking about the prevalence of lead masses in true asymptomatic patients with CIED, and, at the same time, when lead masses are observed, they cannot unequivocally be associated with an infection.7
The aim of this study is to describe the prevalence of lead masses in a group of true asymptomatic patients with CIED, to identify their predictive factors and to evaluate the prognostic impact of lead masses at long-term follow-up.
Seventy-eight consecutive patients admitted to our centre for elective generator replacement and without clinical evidence of cardiac device infection (CDI) were enrolled over a 6-month period between June and December 2013. Patients were followed at in-clinic follow-up visits. The visits were scheduled at a 3-month interval during the first year after the detection of masses and yearly afterwards until June 2018 (5-year follow-up).
Exclusion criteria were signs or symptoms of suspected infection of the CIED pocket, previous pocket revisions other than elective replacement, fever or antibiotic therapy, anti-inflammatory or corticosteroid drugs administration in the last 3 months, clinical and haemodynamic instability. We also excluded patients with a poor clinical status or comorbidities likely to influence medium-term prognosis, such as oncological diseases with less than 1-year expected survival, neoplastic cachexia, advanced chronic kidney disease (defined as creatinine clearance <30 ml/min’ or need for dialysis), advanced neurological disorders (defined as disabling cognitive impairment or motor impairment), on-going severe organ or systemic infections, and advanced severe heart failure (Ambulatory IV NYHA Class, need for any hemodynamic support, bridging for heart transplantation). The inclusion and exclusion criteria are summarized in Table 1.
Demographic and clinical variables as well as CIED data were collected at enrolment (see Table 2).
Echocardiographic imaging and second-level examinations
All patients were evaluated by transthoracic echocardiography (TTE) and TEE during the same day as the procedure. Echocardiographic imaging was performed using a commercially available Philips i33 echocardiograph (Philips Medical Systems, Andover, Massachusetts, USA). Lead masses were defined as irregularly shaped, discrete echogenic masses and these were classified according to location, form and size (Fig. 1). Right ventricle (RV) dysfunction was defined as M-Mode TAPSE less than 17 mm and TDI S’ less than 9.5 cm/s.
When lead masses were found at TEE, second-level examinations were performed in the first month after generator replacement, according to the physician's choice: 18-fluorodeoxyglucose PET/computed tomography (FDG-PET/CT) and 99mTc-hexamethypropylene-amine oxime labelled autologous white blood cell scintigraphy (WBC SPECT). All patients were re-evaluated by the same TEE instrument during follow-up at 3, 6 and 12 months after generator replacement. Thereafter, TEE examination was performed according to physician choice during yearly follow-up, and in all patients at the last follow-up visit.
The primary endpoint was to evaluate the prevalence of lead masses in asymptomatic patients. Secondary endpoints were to identify predictive factors of lead masses and to define their prognostic impact at long-term follow-up.
Categorical variables (presented as numbers and percentages) were compared with the use of Pearson's chi-squared test and Fisher’ exact test. Parametric distribution of continuous variables (presented as means ± SD) was tested graphically and with Kolmorogov–Smirnov and appropriate analyses were used according to the results. Univariate Cox regression analysis and baseline variables adjustment were used to identify predictors of lead masses. All statistical analyses were performed with SPSS 21 (SPSS Inc., Chicago, Illinois, USA) and differences were considered significant at α = 0.05.
The study was performed in accordance with the latest Declaration of Helsinki and patients provided written informed consent to participate in the study and to undergo TEE for experimental purposes. The Institutional Committee on Human Research at our institution approved the protocol.
Follow-up was 60 ± 4 months. Baseline characteristics of the study population are summarized in Table 2.
Cardiovascular risk factors and comorbidities are equally distributed between patients with and without lead masses. However, a higher prevalence of heart failure was observed in patients without lead masses (P = 0.08).
Regarding the CIED system, the types of different devices [single chamber pacemakers (SC PM), dual chamber PM (DC PM), single chamber implantable cardioverter-defibrillators (SC ICD), dual chamber ICD (DC ICD) and cardiac resynchronization therapy-defibrillators (CRT-D)] were equally distributed between the two groups as the number of leads.
At TTE examination, increased thickness and hyperechogenicity of the lead was observed in seven patients; lead masses were confirmed at TEE in the same seven patients and detected in three more cases with negative TTE findings. Thus, lead masses were observed in 10 patients overall (12.8%). Specific characteristics concerning TEE-detected lead masses are summarized in Table 3.
Univariate analysis for all the baseline clinical variables, drug therapy, CIED and echocardiographic data was compelling. RV dysfunction was identified as the only independent predictor for development of lead masses [odds ratio (OR) 2.71, P = 0.010] and remained significantly associated with lead masses after baseline variables adjustment (hazard ratio 6.25, P = 0.012; Table 4). The patients with RV dysfunction showed a normal or slightly enlarged right ventricular telediastolic diameter (range: 35–45 mm) and a mild–moderate tricuspid regurgitation (range: 2–3+/4+) with a mild increase of pulmonary pressure regime (range: 35–55 mmHg).
Second-level investigations, like FDG-PET/CT (performed in six patients) and WBC SPECT (performed in four patients) were carried out in patients with lead masses found at initial evaluation. Such investigations never disclosed active signs of infection along the leads. WBC SPECT only showed increased captation at the device pocket in two patients. In these two patients, such examinations were performed 2 and 3 weeks after the replacement procedure, respectively (Supplementary Appendix, http://links/lww.com/JCM/A173).
During follow-up, TEE was repeated in all patients, disclosing lead masses unchanged or slightly reduced, and no occurrence of new ones (Fig. 2). At 5-year follow-up without any specific therapy, the asymptomatic patients with lead masses did not suffer from any CDI. One patient died for a noncardiac disease (multiple myeloma).
Lead masses in asymptomatic patients were observed in an unsuspected high percentage of about 13%. Clinical variables are equally represented in the groups with and without lead masses. The observed tendency toward a higher prevalence of heart failure in patients without lead masses was not statistically significant and because of the small group size.
Strength of the study
The strength of the study is the strict selection of the population. Moreover, the long follow-up time clears any doubt that in the absence of clinical suspicion of CDI lead masses, the findings have no clinical implications. The consecutive patient enrolment over a 6-month period is also an important criterion to rule out selection bias.
Comparison of transthoracic echocardiography and transoesophageal echocardiography findings
Increased thickness and hyper echogenicity of the lead segment is the main finding at TTE, without a clear demonstration of definite, discrete individual masses. Such thickening has been observed in 7 out of 10 patients with subsequent positive TEE findings. Similar higher sensitivity of TEE in comparison to TTE has been observed also in CDRIE populations.6,8 Probably, sensitivity of TEE is much higher in cases of ‘soft’ masses during their formation, and therefore during the acute phases of lead-related infective endocarditis (LRIE),9 but this is not the case in our study, which refers to a chronic, stable situation. TEE has been useful in confirming lead thickening, and in disclosing occasional lead masses. TEE surely helped a better definition of the shape, profile and dimensions of the lead masses, their thickness, singleness and/or multiplicity (Fig. 1), as is also well known for LRIE.8
However, a routine TEE is neither feasible nor clinically warranted for the follow-up of asymptomatic CIED patients. Our results can promote regular screening by means of TTE for lead morphology after CIED implantation. We think that at least a single baseline evaluation should be done 2–3 years after implantation or at the time of generator replacement. In performing such echocardiographic evaluation, particular attention has to be paid to the slight but significant increase of thickness of the lead profile, thus suggesting in these peculiar cases a closer examination by means of TEE. Such baseline evaluation might represent a useful comparison in the subsequent course. In cases of controversial diagnosis of CDRIE, persistence of unchanged lead masses closely addresses a noninfectious cause (Fig. 2).
Prevalence of lead masses at transoesophageal echocardiography and intracardiac echocardiography
TEE has been performed in our study in order to disclose the prevalence of lead masses in CIED patients and not for the diagnosis or evaluation of a certain/suspected cardiac disease as in other studies.7,10 In fact, our patients were admitted for elective generator replacement, representing a true ‘healthy’ noninfectious population. Moreover, the strict inclusion criteria excluded a mild previous, recent or active CDI.
Other studies evaluated the prevalence of endocavitary masses in asymptomatic patients with CIED undergoing TEE for different reasons (evaluation of valvular diseases, cardioversion, transcatheter ablation). Such settings show a prevalence of lead masses of about 5–28%,7,10,11 but these populations may suffer from selection bias because of their cardiac concomitant diseases. Moreover, these studies are retrospective,7,10 or refer only to a small segment of the focused population.11
TTE and TEE sensitivity may be too low for masses located in the upper superior vena cava (USVC). These sites can be better evaluated by intracardiac echocardiography (ICE).12,13 By means of ICE, the prevalence of intracardiac masses is 2–30%14,15 at any level in patients undergoing transcatheter ablation. In such a setting, these masses could represent the remnant of a past infectious process or more reasonably the fibrotic evolution of a thrombotic apposition. In cases of LRIE, ICE may be the only technique useful in detecting vegetations, 12,16,17 particularly fresh soft ones, or remnants or ‘ghosts’ of residual fibrous tissue or endothelial flaps floating at the USVC level and/or protruding in the right atrium after TLE.18 ICE, in comparison with TEE, has a greater sensitivity in disclosing lead masses on the ventricular lead at the tricuspid crossing, and on the tricuspid valve. This has been well documented in cases of LRIE.16 The greater sensitivity of ICE at these locations might probably be because of technical issues. ICE can detect small, soft lead masses localized in cardiac areas that are not easily scanned by TEE, such as the atrioventricular part of the right ventricular lead and the tricuspid valve, anteriorly located away from the TEE beam. Apart from its costs, ICE is an invasive procedure, and therefore it is indicated for the diagnosis of LRIE, in the presence of a definite clinical suspicion, when all the other techniques are inconclusive, or for planning or monitoring TLE.16,17,19,20 Consequently, ICE is not warranted for screening of asymptomatic, stable patients. Thus, the true prevalence and clinical significance of lead masses at USVC may be completely unknown.
Location of lead masses/right ventricular dysfunction
Interestingly, lead masses were mainly found on the atrial lead in double chamber devices and along the atrial course of the RV lead in single chamber devices. Probably this finding might be because of low flow/staunching blood in the right atrial chamber, and to the close proximity to the auricle of the tip of the atrial lead. On the contrary, the distal part/tip of the RV lead has been less frequently found with lead masses, probably because the higher mechanical stress and pulsatile contact with the endocardium might preclude lead masses formation. Furthermore, this finding might be perhaps consistent with chronic thrombotic apposition as the aetiological mechanism responsible for lead masses formation. Such an interpretation can account for the observed strict association with RV dysfunction. In fact, this seems to be the pathological setting where the well known Virchow factors (mainly stasis and turbulence) might act to increase thrombotic apposition along to CIED leads. To the best of our knowledge, this preferential location of lead masses at the atrial level has been never reported in literature.
In a different setting, such as ICE examination during ablation procedures, the occurrence of mobile lead thrombi on CIED leads, not routinely recognized by TTE, has already been studied by others.15 Interestingly, according to our results, lead thrombi were more commonly identified in the right atrium than in the right ventricle. Moreover, lead thrombi were associated with higher pulmonary artery systolic pressure, further confirming the association found in our study with RV dysfunction. Therefore, right ventricular dysfunction might represent a predisposing factor to the thrombotic process or fibrotic apposition on the catheter because of an abnormal flow pattern inside the right atrial chamber.
Lung multislice computed tomography scan
No patient underwent computed tomography (CT) lung scan. Septic pulmonary embolism is a minor Duke criterion.2 Moreover, signs of infected pulmonary embolism on CT angiography, consistent with shifting of vegetations to the pulmonary bed, and also recurrent pneumonia in CIED carriers, have been recently proposed as new Duke major criteria for the diagnosis of LRIE.21
In this context, lung multislice CT (MSCT) is considered in the diagnostic algorithm for the diagnosis of infective endocarditis in European Society of Cardiology (ESC) Guidelines.22 Indeed, in the previous version of the ESC Guidelines,23 the role of MSCT was restricted to the evaluation of infective endocarditis-associated valvular abnormalities, particularly to the assessment of the perivalvular extent of abscesses and pseudoaneurysms. Our patients were enrolled in the study before the publication of 2015 Guidelines, and we did not consider it necessary to perform CT scans in apparently ‘healthy’ subjects. The follow-up of our patients closely supports our behaviour, demonstrating that in this ‘healthy’ clinical setting, the use of MSCT does not add further significant diagnostic information and prognostic definition. With regard to this patient profile, in light of our experience, this practice should be discouraged in the future, involving significant toxicity owing to the use of contrast dye, without adding significant and useful information.
l8-Fluorodeoxyglucose PET/computed tomography and 99mTc-hexamethypropylene-amine oxime labelled autologous white blood cell scintigraphy
In 2015 ESC included two other additional tools for the diagnosis of infective endocarditis22: l8-Fluorodeoxyglucose PET/computed tomography (FDG-PET/CT) and 99mTc-hexamethypropylene-amine oxime labelled autologous white blood cell scintigraphy (WBC SPECT). In our experience, such techniques can be useful to disclose an occult or doubt infection,24,25 as demonstrated also by others 26–29 and it can confirm the sterile nature of lead masses. FDG-PET/CT, however, can show false positive findings because of abnormal hypermetabolic activity at the CIED pocket owing to recent interventions. This hypercaptation usually disappears 4–8 weeks after the procedure, and is never observed after 6 months.30
FDG-PET/CT and WBC SPECT have been performed in our patients within 1 month. The positive results of WBC SPECT in two individual patients can be viewed as a nonspecific finding because of the recent surgery. Therefore, caution should be exercised in interpreting data in cases of recent pocket procedures, and probably in such a scenario, FDG-PET/CT and WBC SPECT should not be performed.
A completely different setting lies in cases of clinical suspicion of pocket infection. It is well known that local symptoms at the pacemaker pocket may indicate a latent systemic infection.4 In this case, vegetations can be found with unexpected prevalence, and noteworthy in local infection/chronic draining sinus,3 thus confirming the infectious involvement of the whole CIED system. CDRIE has high morbidity and mortality of approximately 10–21%.31 Therefore, prompt diagnosis and treatment in such cases are mandatory, because the worst prognosis is further worsened also after a deferred TLE.32
At follow-up, none of our patients suffered from long-term infectious complications. Our study clearly demonstrates that noninfectious intracardiac masses do not influence long-term prognosis with consequent important effects on therapeutic decisions.
Are lead masses a major Duke criterion yet?
The application of classic Duke criteria7 to patients with CIED is still debated.21 The absence of vegetations, or their observation when clinical suspicion is lacking, does not allow ruling out or strengthening a clear diagnosis of CDRIE.
The CIED system may represent a peculiar setting, where differentiating between infectious vegetations and noninfectious lead masses cannot be viewed apart from the strict evaluation of the clinical scenario. Probably lead vegetations alone have low sensitivity for diagnosing LRIE, being frequently absent even in cases of proven infective involvement documented by bacteriological analysis on lead fragments.33 Probably, lead vegetations have low specificity, being observed also in absence of infection, as shown in our study.
The ‘strong’ conclusion that the modified Duke's criteria, and particularly the value of lead masses, have to be reconsidered for the diagnosis of LRIE does not seem appropriate in the context of our study. However, in CIED patients, Duke's criteria should be critically evaluated. Incidental noninfectious lead masses are not associated with increased morbidity and mortality. This has been demonstrated in other retrospective studies, where TEE has been performed for indications other than evaluation of lead masses in CIED patients.10
Our prospective long-term study strongly points out that when lead masses are accidentally disclosed by TEE performed for other indications, like before transcatheter ablation or for valve evaluation, no further diagnostic evaluation is required, like FDG-PET/CT scanning, WBC SPECT and lung MSCT. What is new and intriguing is the identification of a possible predictive factor, which may give further insights about the etiopathogenesis of noninfectious lead masses.
Our study has some limitations. First, it is a single-centre study with a small sample size. Second, we do not have any histological data of the lead masses that would be very useful to classify those findings. Third, TEE may miss some masses that, while present, are too small to be adequately visualized such as the prevalence may be underestimated.
There is evidence of clinical lead masses in asymptomatic patients with CIED, but they are not necessarily associated with an infection. The value of these findings is still debated. More studies are needed to understand the clinical role of these findings, how these can impact prognosis and indicate a specific therapy. These analyses are fundamental to reflect and reconsider the occurrence of lead masses/lead vegetations as a major diagnostic Duke's criterion of endocarditis in patients with CIED that has to be interpreted in the light of, and with regard to, the clinical ‘infectious’ or ‘sterile’ scenario.
All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
Author contributions: P.G.G. conceived, designed the study, acquired, analysed and interpreted data, drafted the manuscript and finally approved it. D.E. acquired, analysed and interpreted data, contributed to drafting the article, critically revised the manuscript and finally approved it. M.P. acquired, analysed and interpreted data, contributed to drafting the article, critically revised the manuscript and finally approved it. E.G. participated in conceiving the study, mainly performed acquisition, analysis and interpretation of data, critically revised the manuscript and finally approved it. S.F. performed interpretation of data, critically revised the manuscript and finally approved it. D.C. performed interpretation of data, critically revised the manuscript and finally approved it. C.B. critically revised the manuscript and finally approved it. C.G. critically revised the manuscript and finally approved it. M.R. is the mentorship and the head of the Department of Cardiovascular and Thoracic Diseases of our institution. He critically revised the manuscript and finally approved it, attesting the integrity, completeness and accuracy of the reported data.
All the authors have no grant support to disclose.
Conflicts of interest
There are no conflicts of interest.
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