is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.98.15.1517
1998;98:1517-1524Circulation.
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Gross and Microscopic Pathological Changes AssociatedWith Nonthoracotomy Implantable Defibrillator Leads
Andrew E. Epstein, MD; G. Neal Kay, MD; Vance J. Plumb, MD;Sharon M. Dailey, MD; Peter G. Anderson, DVM, PhD
Background—Although the effects of epicardial implantable cardioverter-defibrillator (ICD) leads on underlying cardiactissue have been reported, the gross and microscopic changes associated with endocardial ICD leads are less welldescribed. This study describes the gross and microscopic changes associated with endocardial ICD leads in humans.
Methods and Results—The hearts from 8 patients were examined. At the time of ICD implantation, the patients’ mean agewas 47611 years, and the left ventricular ejection fraction was 0.2460.10. Four patients had ischemic heart disease, and4 had dilated cardiomyopathy. Five hearts were examined after transplantation; 3, after death. The electrode-myocardialinterfaces were characterized by intense endocardial fibrosis and were remarkably consistent. Each lead was encased bya ring of fibroelastic tissue, and there was fibrosis of the right ventricular myocardium adjacent to the leads. Fibrosisinvolved the tricuspid valve in 5 patients, and 1 had perforation of the valve by the lead. Microscopically, interstitialfibrosis was adjacent to each lead in the current path of ICD shocks. Acute cell injury was present only in the heartsthat had received recent shocks.
Conclusions—The ICD electrode-myocardial interface is characterized by intense fibrosis. The fibrosis associated withendocardial ICD leads and the cumulative acute damage produced by defibrillation discharges may explain changes inthe defibrillation and pacing thresholds and the difficulty of lead extraction that can be encountered with transvenousICD systems.(Circulation. 1998;98:1517-1524.)
Key Words: arrhythmian death, suddenn defibrillation n fibrillation
A lthough the effects of epicardial defibrillator leads onunderlying cardiac tissue have been reported in ani-
mals1–6 and humans,7,8 the gross and microscopic changesassociated with endocardial implantable cardioverter-defibrillator (ICD) leads are less well described,9–14especiallyin humans.15–17 Similarly, although the electrode-endocardialinterface for transvenous pacing leads is well described,18–21
the interface for defibrillation leads has received little atten-tion.15 In the case of endocardial pacing leads, there is asequence of local events that follow implantation consistingof injury, acute inflammation, chronic inflammation, granu-lation tissue formation, foreign body reaction, and fibro-sis.18–21 In the case of transvenous ICD leads, the electricalinjury produced by shocks confounds the previously de-scribed sequence of events associated with the tissue responseto an endocardial pacing lead. The morphological changesassociated with transvenous ICD leads and the tissue injuryand healing associated with ICD shocks may be responsiblefor the sequential progression of electrical phenomena thathave been observed with these leads clinically, includingelevation of the pacing threshold22 and changes in the defi-brillation threshold,23–25 defibrillation lead system imped-ance,26 and electrogram.27–29 This article describes the gross
and microscopic changes associated with nonthoracotomyICD leads in humans.
MethodsPathology ProtocolThe hearts of 8 patients with transvenous ICD leads were examinedin accordance with institutional guidelines. Photographs were takenof the gross anatomy, and the hearts were then sectioned to visualizethe ICD lead and its interface with the endocardium. Thereafter, thehearts were fixed in formalin, and tissue sections were embedded inparaffin by use of standard histology techniques. These serial 5-mmsections were examined microscopically with hematoxylin and eosinstain, and Gomori’s aldehyde fuchsin trichrome stain was used toidentify muscle, fibrous connective tissue, and elastic tissue.
ICD Lead SystemsThe ICD leads were manufactured by Cardiac Pacemakers, Inc(Endotak series) in 7 cases and Ventritex, Inc (TVL series) in 1 case.Each of these leads uses distal tip and spring electrodes in anintegrated bipolar system for sensing, pacing, and defibrillation. Thesurface areas and lengths of the distal coils of these leads rangedfrom 295 to 470 mm2 and 3.6 to 5.0 cm, respectively. None of theseleads were steroid eluting.
Statistical AnalysisQuantitative data are expressed as mean6SD.
Received February 25, 1998; revision received May 27, 1998; accepted June 9, 1998.From the Division of Cardiovascular Disease, Department of Medicine (A.E.E., G.N.K., V.J.P., S.M.D.), and the Department of Pathology (P.G.A.),
University of Alabama, Birmingham.Correspondence to Andrew E. Epstein, MD, Division of Cardiovascular Disease, University of Alabama at Birmingham, University Station, THT 321L,
Study PatientsThe hearts from 8 patients were available for evaluation.Their demographic data are shown in Table 1. Five specimenswere obtained at cardiac transplantation, and 3 were obtainedafter death. Of those who died, the first expired after aself-inflicted gunshot wound (patient 1) and has been re-ported previously.15 The other deaths occurred in patientsawaiting cardiac transplantation, 1 of progressive heart failureand cardiogenic shock (patient 3), and 1 of cardiac arrest(patient 6).
ICD Lead System DataData regarding the ICD leads are presented in Table 2. Thosemanufactured by Cardiac Pacemakers, Inc had deliveredmonophasic shocks in 4 cases and biphasic shocks in 3 cases,by both external testing equipment and the implanted ICDs.The Ventritex lead had been used to deliver only biphasicshocks via an external testing device and a biphasic ICD.
Gross MorphologyThe gross anatomical findings were consistent among allcases. Each lead had been implanted at the right ventricularapex and entwined in trabeculae (Figure 1). The tip of thelead was embedded in the right side of the interventricular
septum in 5 cases but in the right ventricular free wall in 3cases.
In all 7 cases of chronic lead implantation, there was anencircling band of fibroelastic tissue surrounding the lead(Figures 1 and 2). This band encased the lead up to the levelof the tricuspid valve, and in 5 cases, it actually attached thelead to the valve itself (Figure 1). In 1 case, the lead hadpenetrated a valve leaflet (Figure 1B). The lead of patient 6was implanted 8 days before death (Figure 1C and 1D). It waseasily extracted by the application of mild tension. In thiscase, there was no fibrous tissue encasing the lead. Instead,there was thrombotic material adherent to it and the imme-diately adjacent myocardium. Traction was applied to thelead of patient 3 to explant it at autopsy. Even though enoughtension was applied to separate the wire coils of the lead,myocardium still remained attached (Figure 1F).
Microscopic ChangesAfter removal of the leads by traction and incision of thesurrounding fibroelastic band, the interventricular septumwas sectioned transversely, starting just below the lead andextending basally at 3- to 5-mm intervals (Figure 2). In allcases, there was a dense fibroelastic reaction at the electrode-myocardial interface. This reaction was most severe at the tipof the electrode and extended up the lead, producing a ring offibroelastic tissue surrounding the lead and a fibrous scar inthe adjacent myocardium (Figure 2) ranging from 250 to1200 mm in thickness. The trichrome stain (Figure 2B and2C) demonstrates that this fibroelastic tissue contains bothfibrous connective tissue (green) and elastic tissue (purple).
The fibroelastic tissue scar associated with the leads wasfocal and well circumscribed. Adjacent to this confluentscar were variable degrees of interstitial fibrous connectivetissue insinuated between the myocardial fibers of theinterventricular septum. In many cases, there was aninteresting radial pattern of interstitial fibrosis, almostsuggesting lines of electrical injury from focal points onthe ICD lead (Figure 2C).
In patient 2, who received shocks 7 days before death, andin patient 6, who had received shocks on the day of death,there was evidence of acute cell injury (Figure 3). In thesepatients, there were small areas of necrosis within theinterventricular septum near the leads and no evidence of
TABLE 1. Demographics
PatientAge
(at Implant), y Sex LVEF SubstrateCircumstanceof Examination
1 68 M 0.18 CAD Death
2 42 M 0.35 CM Transplantation
3 35 M 0.18 CM Death
4 39 M 0.10 CM Transplantation
5 41 F 0.29 CM Transplantation
6 51 M 0.17 CAD Death
7 38 M 0.42 CAD Transplantation
8 60 M 0.20 CAD Transplantation
Mean6SD 47611 z z z 0.2460.10 z z z z z z
LVEF indicates left ventricular ejection fraction; CAD, coronary arterydisease; and CM, cardiomyopathy.
TABLE 2. Lead Data
PatientLead Model
(Manufacturer)ICD Model
(Manufacturer)Implant
Duration, dTotal
Shocks, nTotal
Energy, JDays SinceLast Shock
1 0062 (CPI) 1550 (CPI) 202 34 865 29
2 0062 (CPI) 1555 (CPI) 676 81 2670 7
3 0054 (CPI) 1520/1555 (CPI) 1585 38 991 65
4 0062 (CPI) 1555 (CPI) 672 32 960 215
5 RV-1101 (VTX) V112D (VTX) 428 21 464 309
6 0125 (CPI) 1740 (CPI) 8 7 186 0
7 0064 (CPI) V100 (VTX) 960 13 174 924
8 0075 (CPI) 1720 (CPI) 591 11 209 458
Mean6SD z z z z z z 6406452 30622 8306763 2516297
CPI indicates Cardiac Pacemakers, Inc; VTX, Ventritex, Inc.
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acute necrosis in any other areas of the heart. Patency ofblood vessels in the areas of fibrosis suggests that the changeswere not due to ischemia.
Finally, the microscopic findings observed in the heartswith chronically implanted ICD leads were apparently relatedto the leads themselves. Sarcoidosis was found unexpectedlyin patient 4 at pathological examination. The fibrosis associ-ated with the ICD lead was distinct from that associated withthe sarcoid (Figure 4A and 4B). Patient 8 had both pacemakerand ICD leads (Figure 4C and 4D). Minimal fibrosis associ-ated with the pacemaker lead contrasts with marked fibrosisassociated with the ICD lead. Furthermore, in this and allother patients, the interstitial fibrosis was always in theseptum along the current pathway of ICD shocks. In contrast,myocardium not in the current pathway, such as the free wall,was devoid of these changes (Figure 4D).
DiscussionThe electrode-myocardial interfaces of the hearts examined inthis study were characterized by intense endocardial fibrosis.Each lead was encased by a ring of fibroelastic tissue andassociated with fibrosis of the interventricular septum andoften the right ventricular free wall. Fibrosis involved thetricuspid valve in 5 patients, and the lead perforated the valvein 1 patient. Microscopically, interstitial fibrosis was adjacentto each lead, and acute cell injury was present only in patientswho had recent shocks. The observed pathological changesmay explain changes in pacing and defibrillation thresholds,defibrillation impedance, and sensing performance that havebeen reported.22–29 The fibrosis almost certainly explains thedifficulty that can be encountered when transvenous ICDleads are explanted.
The inflammatory reaction incited by pacemaker leads hasbeen well described.18–21 A well-orchestrated response totissue injury begins with thrombus formation and activationof the complement and fibrinolytic systems. Fluid, protein,and blood cells enter tissue adjacent to the lead, producing anacute inflammatory reaction mediated by neutrophils, macro-phages, foreign body giant cells, and fibroblasts. Granulationtissue forms that progresses to a fibrous connective tissuescar.
There is ample evidence that transthoracic, epicardial, andendocardial shocks can all cause myocardial damage. Dahl etal30 showed that transthoracic shocks caused myocardialnecrosis in dogs and that shorter time intervals betweendischarges and small paddle sizes led to greater necrosis.Thus, repetitive shocks from small ICD endocardial leadsmight also cause myocardial injury. Furthermore, Babbs etal31 showed that the effective, damaging, and lethal electricaldoses of transthoracic shocks led to injury and mortality in adose-dependent manner. Van Vleet et al32 concluded thatsingle transthoracic damped sinusoidal shocks were accom-panied by a large margin of safety over the defibrillationthreshold, with a 12-fold suprathreshold shock required toproduce death, a 6-fold suprathreshold shock required toproduce macroscopic damage, and a 3-fold suprathresholdshock necessary to induce microscopic damage. BecauseICDs usually operate at much lower energies, the chance oftissue injury may be minimized. However, endocardial deliv-
ery may be more hazardous. Doherty et al3 showed that thethreshold for significant injury was'30 J in dogs receivingcountershocks applied directly to the heart.
The myocardial changes associated with endocardial defi-brillator leads are probably attributable to both shocks them-selves and a foreign body reaction. Van Vleet et al9 implantedleads in dogs to which no shocks were given. At necropsy,cardiovascular changes included formation of a fibroussheath over the lead along its course in the veins, right atrium,and right ventricle; adhesion of the leads to adjacent venousand cardiac structures, including the tricuspid valve; endocar-dial fibrosis; and partial penetration of the myocardium at theapex of the right ventricle by the lead tips. Many of thesechanges were observed in our human counterparts.
Transvenous shocks in animals are associated with myo-cardial necrosis. Barker-Voelz et al11 showed that necrosiswas concentrated at the distal electrode through which shockswere given. Because all animals were killed 48 hours aftershock delivery, the development of fibrosis could not beassessed. However, Van Vleet et al12 assessed cardiac damagein dogs with chronically implanted defibrillation electrodesthrough which 4 episodes of multiple shocks were delivered.At 26 weeks, mechanical injury from the lead on the rightside of the heart was manifest by endocardial fibrosis andfibrous sheath formation. Although the fibrosis was mostmarked at contact points adjacent to portions of the leads thatwere not adherent to the myocardium, flat areas of endocar-dial fibrosis were seen at the electrode-myocardial interface,and the leads were covered by an extensive fibrotic sheath asin our patients. Although microscopic evidence of necrosiswas detected in 50% of the dogs, the severity was felt to beinsignificant.
Because of the injury produced, high-energy shocks havebeen used to produce animal models of left ventricularfailure.33,34 Nevertheless, energies used are much greater thanthose used clinically for defibrillation, virtually always.100J. However, because the work discussed above demonstratesa dose-response relationship for myocardial injury, lower-energy shocks may have important effects that could bedifficult to recognize clinically. For example, Perkins et al16
described changes in the hearts of 4 men who died as a resultof myocardial infarction and were treated for recurrentcardiac arrest with 8 to 55 countershocks of 2.5 to 50 Jdelivered via a temporary catheter. Myocardial necrosissecondary to the catheter was present in 1 of the 4 heartsstudied. Similarly, Avital et al8 reported the absence ofdetectable myocardial injury in patients receiving intraoper-atively or spontaneous shocks after operation.
Both interstitial and confluent (replacement) fibroses wereassociated with ICD leads. Interstitial fibrosis itself is notunique to patients with cardiomyopathy.35,36 On the otherhand, confluent fibrosis is less frequent in nonischemiccardiomyopathy35 but is the norm in patients with scarsresulting from myocardial infarction.36 Although in bothpatients with coronary artery disease and dilated cardiomy-opathy scaring is more prominent on the left rather than theright side of the heart, our patients had extensive interstitialfibrosis on the right side of the heart adjacent to the lead,
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suggesting a relationship between the presence of the leadand the scars themselves.
Clinical ImplicationsFirst, there is an increase in the defibrillation threshold thatoccurs with time in patients with nonthoracotomy ICDsystems.23–26 One possible cause is myocardial fibrosis at theelectrode-tissue interface. Because this threshold increase ismore common for ICD systems that deliver monophasic thanthose that deliver biphasic shocks, it is possible that biphasicshocks not only defibrillate more effectively but also cause
less cellular dysfunction than monophasic shocks. We saw nodifferences in the histology of patients with monophasic andbiphasic ICDs. Furthermore, because ICD leads differ fromstandard bradycardia pacing leads (stiffer, larger, exposedcoil), factors other than shocks may be important in thegenesis of fibrosis.9 Because it is the coils and shocksdelivered through them that seem to incite the fibroticreaction, there is no reason to suspect that the reportedchanges are specific to any one manufacturer or material.
For non–steroid-eluting pacemaker leads, the pacingthreshold increases in a time-dependent manner, usually
Figure 2. A, Serial sections of interventricular septum starting near distal end of ICD lead and extending basally at 3- to 5-mm intervalsfrom patient 2, who underwent cardiac transplantation 676 days after ICD implantation and 7 days after last defibrillator shock. Eachsection is oriented with right ventricular surface of interventricular septum (R) at the top and left ventricular surface (L) at bottom. Eachheart with long-term implanted leads displayed this characteristic fibroelastic tissue that encircled the lead (curved arrow). B,Trichrome-stained histological section of this fibroelastic tissue (curved arrow) that encircled lead (L). Note fibrous connective tissue(green) with some elastic tissue (purple) forming this encircling band. C, Lower-power photomicrograph of trichrome-stained section ofbottom section of tissue from A. Band of fibroelastic tissue (curved arrow) encircles lead, and beneath in myocardium lies fibrous con-nective tissue (F). Area of confluent fibrous connective tissue immediately adjacent to lead also extends into surrounding myocardium,forming radial pattern of interstitial fibrosis (arrows), suggesting that shocks had caused lines of electrical injury.
Figure 1. A, ICD lead (arrow) of patient 2 as it appeared looking through right atrium (RA), across tricuspid valve (TV), and into rightventricle (arrowhead). The distal spring was embedded in right side of interventricular septum and encased in dense fibroelastic tissue.B, Lead from patient 4 (arrow) penetrating the tricuspid valve and embedded in endocardium of right side of interventricular septum.This long-term implanted lead was also encased in dense fibroelastic tissue (arrowhead). C and D, Lead from patient 6, the only onenot implanted long term. Where lead (arrow) crosses tricuspid valve, there is accumulation of thrombotic material connecting lead tovalve leaflet. D, Thrombotic material at distal portion of lead (arrow) but no fibrosis. E, Close-up view of heart in A. Longitudinal incisionmade along the lead reveals dense fibroelastic tissue that encases lead and attaches it to tricuspid valve. F, Distal portion of lead frompatient 3 and section of interventricular septum (IVS). Despite application of enough tension to separate wire coils of distal spring(arrow), myocardium remained attached to lead.
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within the first 2 months.19 In contrast, the pacing thresholdfor transvenous ICD leads increases over time without anearly peak.22 This may be another consequence of fibrosis atthe electrode-tissue interface. With the introduction ofsteroid-eluting transvenous ICD leads, fibrosis at theelectrode-tissue interface and other alterations, such as in-creases in the defibrillation and pacing thresholds, may beattenuated. Serial pacing threshold data are not available forour patients because the first 4 had devices that did not havepacing capability; of the 4 others, 1 died 8 days after ICDimplantation; and 2 followed elsewhere had no threshold dataavailable.
Although “proarrhythmia” from ICDs is an infrequentlyreported event, arrhythmia exacerbation by ICDs does oc-cur.37–39 When observed, it is usually a consequence of thedelivery of therapy, arrhythmia acceleration, or new arrhyth-mias. On the other hand, the myocardial fibrosis that developsat the electrode-tissue interface may be responsible for newreentry circuits and possibly arrhythmogenesis.40–42
As ICD leads age, lead failure will be recognized withgreater frequency.43 The fibrous sheath that develops aroundpacemaker leads sometimes necessitates the use of dilatingsheaths and forceful traction for extraction. Given the moreintense inflammatory reaction and larger fibrous sheaths thatencase ICD leads and attach to intracardiac structures, such as
the tricuspid valve, more complicated extraction is to beexpected. The contrasting degrees of fibrosis associated withthe pacemaker and ICD leads in patient 8 provide support forthis speculation (Figure 4).
Study LimitationsOur discussion of the clinical implications of the findingsreported here is purely speculative. First, we do not havepacing or defibrillation threshold data for the patients studiedto correlate the intensity of the fibrotic changes with alter-ations of these parameters. Second, although we suggest thatthe explantation of ICD leads is more difficult than ofpacemaker leads, comparative data are not available. Finally,because our series was small and all patients either had diedor had their hearts examined after cardiac transplantation, thisseries may not be representative of all patients with trans-venous ICD leads. Nevertheless, the consistency of thefindings suggests that these morphological changes may becommon to all patients with these lead systems.
Areas for Future StudyWith the advent of more efficacious waveforms and energydelivery systems, defibrillation may be accomplished withless energy that in turn could lead to less myocardial damage.Furthermore, steroid-eluting leads may cause less myocardial
Figure 3. A and B, Acute cell injury and necrosis that result, in addition to long-term changes, when recent shocks were delivered. A,Higher-power photomicrograph of trichrome-stained tissue section from C. In addition to chronic fibrosis (F), acute necrosis is alsopresent (arrows). B, High-power photomicrograph of one area of acute cell injury with necrotic myocytes intermixed with fibrosis (green)and normal myocytes (red). C, Low-power view of a hematoxylin and eosin–stained section from patient 6, who received ICD system 8days before death showing endocardial surface at point of lead contact. Thrombotic material adheres to endocardial surface immedi-ately beneath lead (asterisk). Arrows outline multifocal areas of acute myocyte necrosis in myocardium adjacent to lead. No acute myo-cyte necrosis was evident in areas away from lead. D, High-power view of myocyte necrosis (arrows) shown in C.
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fibrosis. These events could make changes in the defibrilla-tion and pacing thresholds less important clinically. Whetherthe pathological changes described here will also be ofimportance in atrial defibrillation is unknown. Further studyis required.
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Figure 4. A, Gross photograph of interventricular septum from patient 4 who had received no shocks in the preceding 215 days beforetransplantation. Sarcoidosis was unexpectedly demonstrated at pathological examination. As with other long-term implanted leads, thisone was encased in fibroelastic tissue (curved white arrow) with discrete band of fibrous connective tissue (arrows) adjacent to lead.Dense linear fibrotic band traversed interventricular septum. Fibrotic tissue associated with lead is not distinctly different than fibrousconnective tissue associated with sarcoid (curved black arrow) but clearly separated from sarcoid reaction. B, Low-power trichrome-stained section of A. Fibroelastic tissue surrounds lead (L); dense fibrotic tissue radiates from lead and extends across interventricularseptum (arrows); fibrous tissue is associated with sarcoid reaction (curved arrow). C, Endocardial surface of right ventricular free wall ofpatient 8, who had both pacemaker (arrow) and ICD (curved arrow) leads implanted. D, Hematoxylin and eosin–stained section fromarea in C. Rim of fibroelastic tissue encircles ICD lead and focus of endocardial fibrosis at point of pacemaker lead contact. Fibrosiswas more pronounced in association with ICD lead and more attenuated with smaller, smoother pacemaker lead. Because free-wallmyocardium was not in current pathway, interstitial fibrosis was absent.
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