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ORIGINAL INVESTIGATIONS

Clinical Inferences of CardiovascularImplantable Electronic Device Analysisat Autopsy

Sunil K. Sinha, MD,a Barbara Crain, MD, PHD,b Katie Flickinger, MS,b Hugh Calkins, MD,a John Rickard, MD,c

Alan Cheng, MD,a Ronald Berger, MD, PHD,a Gordon Tomaselli, MD,a Joseph E. Marine, MDa

ABSTRACT

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BACKGROUND Cardiovascular implantable electronic device (CIED) removal and interrogation are recommended at

autopsy in suspected cases of sudden cardiac death, but data on the role of nonselective post-mortem CIED (pacemaker

or defibrillator) analysis in this setting are lacking.

OBJECTIVES This study undertook an institutional registry analysis to determine the utility of systematic routine CIED

removal, interrogation, and analysis at autopsy.

METHODS From May 19, 2009, to May 18, 2015, autopsy subjects with a CIED at a Johns Hopkins University medical

institution (Baltimore, Maryland) underwent CIED removal and interrogation by an electrophysiologist for clinical

alerts. The CIED was then submitted for technical analysis by the manufacturer. The CIED interrogation, the manu-

facturer’s technical analysis, and the final autopsy report were all cataloged in the Johns Hopkins Post-mortem CIED

Registry.

RESULTS A total of 2,025 autopsies were performed; 84 subjects had CIEDs removed and analyzed. These devices

included 37 pacemakers and 47 defibrillators. Overall, 43 subjects had died suddenly, and 41 had not died suddenly.

Significant clinical alerts (sustained tachyarrhythmias or an elevated fluid index value) were seen in 62.8% cases of

sudden deaths. In the nonsudden death cohort, 19.5% displayed a significant clinical alert. Significant association of CIED

alerts were noted when comparing sudden deaths versus nonsudden deaths (p < 0.001), defibrillators versus pace-

makers (p < 0.005), and cardiac versus noncardiac causes of death (p < 0.001). Manufacturer analyses revealed a case of

premature pacemaker battery depletion, as well as a hard reset in a defibrillator as a result of cold exposure.

CONCLUSIONS Post-mortem CIED analysis was clinically useful in assisting with determination of the timing,

mechanism, and cause of death in the majority of sudden deaths and in almost 20% of nonsudden deaths. The

authors advocate CIED removal with analysis as an important diagnostic tool in all autopsies and to assist manufacturers

in identifying potentially fatal device failures. (J Am Coll Cardiol 2016;68:1255–64) © 2016 by the American College of

Cardiology Foundation.

m the aDivision of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland; bDepartment of Pathology,

ns Hopkins University School of Medicine, Baltimore, Maryland; and the cDepartment of Cardiovascular Medicine, Cleveland

nic, Cleveland, Ohio. Dr. Rickard has reported consulting for Medtronic. Dr. Cheng is currently an employee of Medtronic. All

er authors have reported that they have no relationships relevant to the contents of this paper to disclose.

nuscript received May 4, 2016; revised manuscript received June 14, 2016, accepted June 14, 2016.

ABBR EV I A T I ON S

AND ACRONYMS

CIED = cardiovascular

implantable electronic device

FDA = Food and Drug

Administration

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C ardiovascular implantable elec-tronic devices (CIEDs) encompasspermanent pacemakers, implant-

able cardioverter-defibrillators, and insert-able loop recorders. CIED analysis isrecommended at autopsy (1,2), but it israrely performed (3–5). Selective autopsy

case reports, case series, and a large study registryhave shown the utility of post-mortem CIED interro-gation but have been limited to suspected cases ofsudden cardiac death (3,6–10). Consequently, theutility of nonselective CIED analysis at autopsyregardless of suspected cause of death remains un-known. We undertook an institutional registry anal-ysis to determine the clinical role of systematicroutine CIED removal, software interrogation, andhardware analysis at autopsy.

METHODS

AUTOPSY SUBJECTS. Over a period of 6 years, fromMay 19, 2009, to May 18, 2015, all autopsies under-taken at 2 Johns Hopkins University medical in-stitutions in Baltimore, Maryland, (Johns HopkinsHospital and Johns Hopkins Bayview Medical Center)used a protocol for routine CIED identification andremoval. All autopsy subjects identified as having aCIED were included in the Johns Hopkins Post-mortem CIED Registry (“the registry”). The subjectsunderwent either complete autopsy or limited au-topsy with, at minimum, inclusion of the heart andCIED generator. Consent for autopsy was obtainedpost-mortem from next of kin or legal guardians.

SEE PAGE 1265

CIED ANALYSIS. CIED generators were routinelyremoved by an autopsy technician using recom-mended precautions (11–13). In particular, amanufacturer-specific bidirectional hex wrench wasused for disconnection of the CIED generator headerfrom the attached indwelling leads to avoid cuttingleads, which may trigger inappropriate device thera-pies and false device alerts. The CIED generator wasstored at room temperature until it was interrogatedwith a manufacturer-specific computer programmerby a board-certified clinical cardiac electrophysiolo-gist (S.K.S.). Appropriate battery and lead parameters,alerts, and electrograms were reviewed and catalogedin the registry. Significant clinical and technical alertswere also reviewed and confirmed by a second board-certified clinical cardiac electrophysiologist (J.E.M.).

SIGNIFICANT CIED ALERTS. Significant clinical alertsincluded those triggered by sustained atrial or ven-tricular tachyarrhythmias within 24 h of death or

an elevated OptiVol (Medtronic, Minneapolis, Min-nesota) fluid index >60 Ohm-days in the weeksbefore death. An elevated OptiVol fluid index in-dicates significant thoracic fluid accumulation asdetermined by elevated intrathoracic impedancemeasurements, and this software algorithm is nomi-nally activated in most defibrillators manufactured byMedtronic. By contrast, the intrathoracic impedancealert algorithm (CorVue, St. Jude Medical, St. Paul,Minnesota) found in most defibrillators manufac-tured by St. Jude Medical is not nominally activated.Significant technical alerts included premature bat-tery depletion, evidence of lead malfunction (fractureor insulation breach), or random component failure.

INACCURATE CIED ALERTS. Inaccurate technicalalerts triggered post-mortem as a result of automatedalgorithms (capture threshold, sensing, impedancetesting) and inaccurate clinical alerts caused by falseatrial or ventricular tachyarrhythmias derived fromartifact detection were not considered significant andwere not catalogued.

MANUFACTURER ANALYSIS. The CIED device wasthen submitted to the applicable manufacturer(Medtronic; Boston Scientific, Natick, Massachusetts;St. Jude Medical; or Biotronik, Lake Oswego, Oregon)for detailed technical analysis (guidelines for pro-cessing returned products are available from allmanufacturers on request). Standardized manufac-turer analysis entailed visual and mechanical in-spection, software interrogation, and stabilization ofthe device at 37�C (to mimic in vivo conditions) beforeelectrical bench testing to assess battery status,pacing and shocking capability accurately. If devicefailure was suspected, then destructive analysiswas undertaken to assess for specific componentfailure.

AUTOPSY ANALYSIS. The attending pathologist un-dertook visual inspection, anatomic dissection andmeasurements, microscopic analysis, and, whenappropriate, immunohistochemical staining, toxi-cology, and genetic studies. The attending patholo-gist was informed of the CIED interrogation resultsbefore their adjudication of the cause, mechanism,and time of death on finalization of the autopsyreport. For example, if a subject with methicillin-resistant Staphylococcus aureus sepsis syndromedied suddenly and was noted to have bacterialendocarditis at autopsy and ventricular fibrillation onpost-mortem implantable cardioverter-defibrillatorinterrogation corresponding to the time of death,then the cause of death would be “sepsis,” themechanism would be “bacterial endocarditis,” andthe time of death would be ascertained from their

TABLE 1 Demographic and Cardiovascular Implantable Electronic Device Characteristics

Autopsy SubjectsSudden Death

(n ¼ 43)Nonsudden Death

(n ¼ 41)Totals

(N ¼ 84)

Male 34 (79) 25 (61) 59 (70)

Age at death, yrs 67.0 � 13.6 61.5 � 19.4 64.3 � 16.8

Health care facility death 31 (72) 37 (90) 68 (81)

Pacemaker recipient 18 (42) 19 (46) 37 (44)

Pacemaker pre-mortem duration, yrs 2.4 � 2.4 3.5 � 2.6 3.0 � 2.5

ICD recipient 25 (58) 22 (54) 47 (56)

ICD pre-mortem duration, yrs 2.4 � 2.5 3.1 � 1.8 2.7 � 2.2

CIED manufacturer

Medtronic 20 (47) 16 (39) 36 (43)

St. Jude Medical 11 (26) 13 (32) 24 (29)

Boston Scientific 12 (28) 10 (24) 22 (26)

Biotronik 0 (0) 2 (5) 2 (2)

Values are n (%) or mean � SD.

CIED ¼ cardiovascular implantable electronic device; ICD ¼ implantable cardioverter-defibrillator.

FIGURE 1 Final Causes of Death (N ¼ 84)

Cardiac

Infectious

Hemorrhagic

Pulmonary

Neurologic

Hepatic

0 5 10 15 20 25 30 35 40

43 Sudden Death Subjects41 Non-Sudden Death Subjects

This bar graph shows the final causes of death in both the 43 sudden death subjects (blue)

and the 41 nonsudden death subjects (orange) as adjudicated by their autopsy reports.

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documented terminal rhythm, which was “ventricu-lar fibrillation.” The medical record and final autopsyreport were reviewed by an electrophysiologist, andthe primary findings were cataloged in the registry.

DEFINITION OF SUDDEN DEATH. Sudden death andnonsudden death cohorts were assigned on the basisof the medical record according to the World HealthOrganization definition of sudden death in the 2010International Classification of Diseases-10th Revision:sudden, unexpected death within 1 h of acute symp-tom onset (if witnessed) or within 24 h of the lastobservation at baseline (if unwitnessed) (14,15). Asper societal recommendations, if a subject wasresuscitated from cardiac arrest, survived on lifesupport for a limited period of time, and died ofirreversible brain damage, then the death was classi-fied as sudden (1).

STATISTICAL ANALYSIS. A retrospective cohortanalysis was used. Subjects were classified as dyingeither suddenly or nonsuddenly by history and ashaving a primary cardiac cause or noncardiac cause ofdeath on the basis of the findings of the final autopsyreport. Chi-square analysis with Yates correctionwhen appropriate was used to compare categoricalvariables. Mean � SD were calculated for continuousvariables. A 2-tailed p value of <0.05 was consideredstatistically significant.

Study approval for this post-mortem registryanalysis was provided by the Johns Hopkins Univer-sity School of Medicine Institutional Review Board.

RESULTS

In the registry’s initial 6 years, a total of 2,025 au-topsies were undertaken at a Johns Hopkins Univer-sity medical institution (1,739 at Johns HopkinsHospital and 286 at Johns Hopkins Bayview MedicalCenter). A total of 84 subjects (4.2% of all autopsies)were identified as having a CIED; all underwent suc-cessful removal of the pacemaker (n ¼ 37) orimplantable cardioverter-defibrillator (n ¼ 47). Themean age at death was 64.3 � 16.8 years (range 6months to 97 years; median age 65 years). The meantime from the known or reasonably estimated time ofdeath (95% of subjects) to autopsy was 26.7 � 16.1 h.The mean time from autopsy to CIED interrogationwas 17.5 � 13.2 days. The CIEDs analyzed includedthose of 4 different manufacturers; Medtronic (36CIEDs), St. Jude Medical (24 CIEDs), Boston Scientific/Guidant (22 CIEDs), and Biotronik (2 CIEDs).

Most deaths (81%) occurred in a health care facility(57 in teaching hospitals, 6 in community hospitals, 5in nursing homes or rehabilitation centers) ratherthan at home (16 in total), and most deaths were

witnessed (93%). A total of 43 subjects died suddenly(38 witnessed), and 41 subjects had not died suddenly(40 witnessed). The demographic and CIED charac-teristics are summarized in Table 1.

Overall, 87% of autopsy subjects underwent com-plete autopsy, and 13% underwent limited autopsyaccording to the stipulations of their consent. Themost common request in limited autopsies was forexclusion of the head.

CAUSES OF DEATH. The reported primary causes ofdeath in the sudden death group were predominantlycardiac (29 of 43) (Figure 1). Acute infectious causeswere the second most common (10 of 43) for thiscohort, followed by acute hemorrhage (2 of 43) andpulmonary causes (2 of 43).

Conversely, the reported primary causes of deathin the nonsudden death group were predominantlyinfectious (21 of 41) (Figure 1). Cardiac causes were the

FIGURE 2 Significant CIED Clinical Alerts in Sudden Death and Nonsudden Death Subjects

OptiVol® Fluid Index> 60 Ohm-days

(7†)

Total Deaths(84)

Sudden Deaths(43)

Non-Sudden Deaths(41)

No CIED Alerts(33)

No CIED Alerts(16)

VT/VF SuccessfullyTerminated

(12*)

VT/VF NOT Terminated(12)

OptiVol® Fluid Index> 60 Ohm-days

(5*)

VT/VF SuccessfullyTerminated

(2†)

AMS due to Severe SinusTachycardia

(1)

38 Witnessed SuddenDeaths - recorded terminal

rhythms;18 PEA

14 VT/VF3 Bradycardia/Asystole

3 Unknown

A total of 30 significant cardiovascular implantable electronic device (CIED) clinical alerts were seen in 27 of 43 subjects with sudden death. *3 subjects had

both an elevated OptiVol (Medtronic, Minneapolis, Minnesota) fluid index value and ventricular tachycardia or ventricular fibrillation (VT/VF) terminated by a

shock. A total of 9 significant cardiovascular implantable electronic device clinical alerts were seen in 8 of 41 nonsudden death subjects. †1 subject had both

an elevated OptiVol fluid index value and ventricular tachycardia or ventricular fibrillation terminated by a shock. The inset (purple box) details the terminal

rhythms documented in the 38 sudden deaths that were witnessed. AMS ¼ atrial mode switch; PEA ¼ pulseless electrical activity.

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second most common (11 of 41) for this cohort, fol-lowed by intracranial hemorrhage (3 of 41), neuro-logical causes (2 of 41), pulmonary causes (2 of 41),and hepatic failure (2 of 41).

In the sudden death cohort, the terminal cardiacrhythm was available for review in 35 of 38 (92.1%) ofthose with witnessed sudden death (Figure 2). Docu-mented terminal rhythms included pulseless elec-trical activity (47.4%), ventricular tachycardia orventricular fibrillation (36.8%), and bradyarrhythmiaor asystole (7.9%).

SUDDEN DEATH COHORT. On post-mortem CIEDinterrogation, 62.8% of the CIEDs in sudden deathsubjects, including 21 defibrillators and 6 pacemakers,exhibited significant alerts. No significant alerts weredemonstrated in 37.2% of devices in this group,including 4 defibrillators and 12 pacemakers.

There were 27 sudden death subjects with a total of30 significant alerts (Figure 2). These alerts included

12 sustained ventricular tachycardia/ventricularfibrillation episodes that were successfully termi-nated either by internal shocks (10 defibrillator sub-jects) or external shocks (2 defibrillator subjects). Thelatter 2 subjects had had their defibrillator inactivatedin a perioperative setting necessitating externalcardioversion during cardiac arrest. Conversely,12 episodes of ventricular tachycardia/ventricularfibrillation were not terminated. These subjectsincluded 5 pacemaker recipients without defibrilla-tion capability (example shown in Figure 3), 4 defi-brillator recipients exhibiting undersensing andhence no appropriate delivery of therapy, 2 defibril-lator subjects with unsuccessful final internal shocks(example shown in Figure 4), and 1 untreated defi-brillator subject exhibiting sustained ventriculartachycardia in a “monitor zone” below the pro-grammed heart rate cutoff for device therapy.

Additionally, 5 defibrillator subjects (including 3withsuccessfully treatedventricular tachycardia/ventricular

FIGURE 3 Subject 30: Sudden Death Onset in a Pacemaker Recipient

Sudden death in a cardiac resynchronization therapy pacemaker recipient with biventricular pacing (BP) and ventricular ectopy (VS) followed by

the onset of sustained polymorphic ventricular tachycardia (HVR) consistent with an “R on T” phenomenon.

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fibrillation) demonstrated alerts in response toan elevated OptiVol fluid index >60 Ohm-days.One pacemaker subject exhibited an atrial modeswitch with the accompanying intracardiac electro-gram demonstrating probable sinus tachycardiaand frequent premature atrial contractions (>150beats/min) correlating with the postulated onset ofcardiogenic shock resulting from acute myocardialinfarction.

NONSUDDEN DEATH COHORT. In 19.5% of thosedying nonsuddenly, including 8 defibrillator subjects,a significant clinical alert on post-mortem CIEDinterrogation was exhibited (Figure 2). No significantalerts were present in the remainder of this group,which included 14 defibrillators and 19 pacemakers.

There were 8 nonsudden death subjects with atotal of 9 significant alerts. These included 2 sus-tained ventricular tachycardia/ventricular fibrillationepisodes that were successfully terminated by inter-nal shocks and 7 elevated OptiVol fluid index>60 Ohm-days alerts (including 1 subject with suc-cessfully treated ventricular tachycardia/ventricularfibrillation).

CIED ALERTS. Overall, 41.7% of CIEDs in all autopsysubjects exhibited a significant clinical alert within 24hours of death (6 pacemakers, 29 defibrillators),whereas 58.3% did not (31 pacemakers, 18 de-fibrillators). A much greater likelihood of a significant

clinical alert was observed in those CIED subjectswith sudden death (27 of 43) compared with thoseCIED subjects with nonsudden death (8 of 41; chi-square ¼ 14.50; p < 0.001) (Central Illustration). Inparticular, clinical alerts in response to ventriculartachycardia/ventricular fibrillation episodes weresignificantly more common in the sudden deathcohort (24 of 43) as compared with the nonsuddendeath cohort (2 of 41; chi-square ¼ 23.15; p < 0.001).

When considering CIED type (defibrillator vs.pacemaker), there was a much greater likelihood of asignificant clinical alert in defibrillator recipients (29of 47) than in pacemaker recipients (6 of 37; chi-square ¼ 15.81; p < 0.001). Clinical alerts in responseto ventricular tachycardia/ventricular fibrillation ep-isodes were significantly more likely in defibrillatorrecipients (21 of 47) compared with pacemaker re-cipients (5 of 37; chi-square ¼ 8.00; p < 0.005).

Additionally, comparison was made of CIED alertsin those subjects assigned a primary cardiac causeof death (27 of 40 had alerts) versus those with aprimary noncardiac cause of death (8 of 44 hadalerts). This finding demonstrated a much greaterlikelihood of a significant clinical alert noted inthose subjects judged to have a cardiac rather thana noncardiac primary cause of death (chi-square ¼18.97; p < 0.001). Alerts specifically related toventricular tachycardia/ventricular fibrillation weresignificantly more likely in subjects deemed to have

FIGURE 4 Subject 65: Sudden Death in a Defibrillator Recipient

Sudden death in a defibrillator recipient with ventricular fibrillation refractory to a maximal 35-J internal biphasic shock (yellow bolt).

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a cardiac cause of death (21 of 40) compared withsubjects deemed to have a noncardiac cause ofdeath (5 of 44; chi-square ¼ 14.72; p < 0.001). Foran example of a patient with a cardiac cause ofdeath but without an evident CIED alert on inter-rogation, see Figure 5.

MANUFACTURER ANALYSIS. Manufacturer analysesrevealed occult premature battery depletion in 1pacemaker that had been subject to a U.S. Food andDrug Administration (FDA) class II recall. An abnor-mality in battery status had not been evident onroutine post-mortem interrogation but was revealedafter detailed technical analysis by the manufacturer.In addition, manufacturer analysis also uncovered acase of hard reset (nonprogrammable software)caused by cold exposure (from device refrigeration)post-mortem and not by component failure. Overall,detailed technical hardware analyses revealed nocases of CIED component failure contributing todeath.

FLUID INDEX ALERTS. Of the 84 CIEDs examinedpost-mortem, 21 were implantable cardioverter-defibrillators manufactured by Medtronic. A total of17 of these 21 defibrillators were equipped withMedtronic OptiVol fluid index monitoring software.This algorithm begins deriving values 34 days post-implantation. Overall, 2 subjects did not have fluid

index monitoring values available because theywere <34 days post-CIED implantation, 3 subjectsdisplayed normative values (<60 Ohm-days), and 12subjects displayed an alert in response to a fluid indexvalue >60 Ohm-days at the time of death. Autopsyfindings in all 12 subjects with an OptiVol fluid indexalert triggered by a value >60 Ohm-days correlatedwith significant respiratory disease. These findingsincluded decompensated congestive heart failure asevidenced by pulmonary congestion (n ¼ 8), pneu-monia (n ¼ 1), pneumonia and diffuse alveolar dam-age (n ¼ 1), aspiration (n ¼ 1), and a large left-sidedpleural effusion with pulmonary embolism (n ¼ 1).Similarly, the 3 subjects without an OptiVol fluid in-dex alert also had significant respiratory disease,including decompensated congestive heart failure(n ¼ 2) and pneumonia and diffuse alveolar damage(n ¼ 1). Hence the fluid index alert (OptiVol) had asensitivity of 80% with a specificity of 67% forcongestive heart failure in our autopsy population.None of the 5 defibrillators equipped with the intra-thoracic impedance alert algorithm (CorVue) had thealgorithm activated.

DISCUSSION

In the United States, CIEDs are present in 4% or8% of autopsy subjects who have died out of

CENTRAL ILLUSTRATION CIED Analysis at Autopsy

Sinha, S.K. et al. J Am Coll Cardiol. 2016;68(12):1255–64.

This pie chart summarizes a 6-year retrospective cohort analysis drawn from 84 autopsy subjects in the Johns Hopkins Post-mortem CIED Registry. Subjects

are categorized both by whether their death was sudden (red or yellow) or nonsudden (orange or green) and whether their cardiovascular implantable

electronic device (CIED) analysis revealed a significant clinical alert ante-mortem (red or orange) or not (yellow or green).

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hospital or in hospital, respectively (10,16). How-ever, at autopsy these devices have historicallybeen viewed as nonrelevant passive implantsrather than accessible sources of computerizedclinical information to help adjudicate significantclinical events. For example, from 2001 to 2007, atotal of 31,733 autopsies were undertaken by theLos Angeles County Department of the Coroner,but only 20 subjects (0.06%) were selected for addi-tional CIED analysis (3). Conversely, 2 retrospectivepost-mortem pacemaker analyses (9,17) undertaken inEurope identified frequent sustained ventriculartachyarrhythmias and device abnormalities, respec-tively. However, most of the aforementioned studysubjects did not undergo an autopsy investigation,and this limitation made the importance of theirpost-mortem CIED findings difficult to place in fullclinical perspective.

In 2007, the Association for European Cardiovas-cular Pathology issued guidelines, published in 2008(1), that recommended CIED removal and interroga-tion at autopsy when investigating cases of potentialsudden cardiac death. This approach was recently

validated in the prospective POST SCD (Post-mortemSystematic Investigation of Sudden Cardiac Death)study examining 22 CIED carriers among 517 re-ported out-of-hospital sudden deaths in San Fran-cisco, California (10). However, the clinical utility ofroutine CIED analysis at all autopsy investigationswas not addressed. In this regard, our institutionalregistry represents a large post-mortem CIED studyof autopsy subjects and one that used a nonselec-tive systematic approach to CIED removal andanalysis. It revealed significant clinical findings in62.8% of sudden death cases and in 19.5% of non-sudden death cases, thus assisting in the determi-nation of timing, mechanism, and cause of death.The likelihood of detecting significant CIED alertswas noted to be higher in cases of sudden deathas compared with nonsudden death, defibrillatorrecipients as compared with pacemaker recipients,and those with a cardiac cause of death ascompared with a noncardiac cause of death. How-ever, given the significant yield of clinical alerts insubjects with cardiac and noncardiac sudden deathand in almost 20% of those subjects judged to have

FIGURE 5 Subject 32: Sudden Death 2 Days after Pacemaker Insertion Without CIED Alert

Sudden death 2 days after pacemaker insertion without a cardiovascular implantable electronic device (CIED) alert on post-mortem interro-

gation. Autopsy revealed appropriate right ventricular lead placement and pericardial tamponade secondary to left ventricular posteroapical

infarction and perforation (blue arrow head).

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died nonsuddenly, we propose that pathologistsand medical examiners undertake CIED removaland analysis in all subjects undergoing autopsyinvestigation.

In our sudden death cohort, of which 72% had diedin a health care facility, the predominant terminalrhythm was pulseless electrical activity (47.4%),which is consistent with previous studies of in-hospital sudden death and contrasts with the pre-dominant terminal rhythm of ventricular tachycardia/ventricular fibrillation (59%) seen in the aforemen-tioned out-of-hospital POST SCD study (10).

The OptiVol fluid index values are derived fromalterations in intrathoracic impedance measurements(between the lead in the right ventricle and the defi-brillator generator). These values have been shown tocorrelate with elevated pulmonary capillary wedgepressure as a result of fluid accumulation in the lungsand thus indicate decompensated congestive heartfailure (18,19). Clinical studies have shown a sensi-tivity of 60% to 80% in correlating an OptiVol fluidindex alert of >60 Ohm-days for decompensatedcongestive heart failure (20–23). We observed anelevated OptiVol fluid index alert >60 Ohm-days in 12of 17 subjects equipped with this Medtronic softwareprogram, which is routinely activated on defibrillator

implantation. At autopsy, we observed that theOptiVol fluid index alert had a sensitivity of 80% anda specificity of 67% for congestive heart failure. The33% of subjects demonstrating a “false-positive” alertnevertheless had relevant noncardiac respiratorydisease (aspiration, pneumonia, pleural effusion, andpulmonary embolism), suggesting a high specificityfor significant cardiorespiratory disease in general.Only 25% of autopsy subjects had a defibrillatorequipped with the OptiVol fluid index alert algorithm,which is designed to reflect thoracic fluid accumula-tion over a period of weeks rather than <24 h.Accordingly, when nonarrhythmic alerts wereexcluded, the yield of CIED alerts on post-mortemanalysis was reduced to 58.1% (25 of 43) in suddendeath subjects and 4.9% (2 of 41) of subjects in thenonsudden death group.

Currently, the bulk of post-marketing surveillancedata collected by manufacturers, as mandated by theU.S. FDA, is obtained from CIEDs returned from sta-ble patients undergoing elective operations toreplace or upgrade their existing CIED systems,rather than from patients who have died. In fact, acontemporary survey of 71 Chicago metropolitanarea morticians indicated that only 4% of themreturn CIEDs to the manufacturer, whereas 44%

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: Post-mortem

analysis of CIEDs can yield important diagnostic information and

identify instances of device failure.

COMPETENCY IN SYSTEMS-BASED PRACTICE: Hospitals

and medical examiner facilities performing autopsies should

follow protocols that ensure identification, safe removal, and

timely interrogation of CIEDs.

TRANSLATIONAL OUTLOOK: Wider adoption of post-

mortem CIED analysis at a large number of medical institutions

could provide expanded post-marketing surveillance data and

lead to improved device design and programming.

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of morticians discard CIEDs as medical waste (4).This practice is unfortunate because major defibril-lator and pacemaker generator as well as defibrillatorlead recalls in the last decade highlight the ongoingneed for pursuing both software interrogation andhardware analysis in patients who have died, todetermine more accurately the true incidence ofpotentially fatal CIED component failure. In our post-mortem population, manufacturer analyses ruled outCIED malfunction in a case of software hard reset,and they accurately detected a case of nonfatal pre-mature pacemaker battery depletion in a device thatwas subject to a U.S. FDA class II recall. Furthermore,in 7 subjects with defibrillators and documentedventricular tachycardia/ventricular fibrillation, wenoted 4 cases of ventricular undersensing, 2 caseswith unsuccessful final internal shocks, and 1 case ofwithheld therapy as a result of a programmed heartrate cutoff for therapy set above the rate of the ven-tricular arrhythmia. Such instances raise potentialconcerns regarding implantable cardioverter-defibrillator programming and device performance.Hence we would advocate that other academic med-ical centers and medical examiner facilities adopt asimilar approach to help clinicians and manufac-turers accurately ascertain cases of both nonfatal andfatal CIED failure.

STUDY LIMITATIONS. Inherent to all autopsy studiesis the selection bias that occurs when choosing whichsubjects are to undergo investigation because thiscan produce a population with an elevated rate ofsignificant findings. Fortunately, our study includednot only autopsy subjects studied for clinical in-dications (sudden death) but also subjects studied foraltruistic purposes (enrollment in a longitudinalresearch study or an unexplained illness associatedwith nonsudden death). We believe that our nonse-lective approach to CIED removal and analysis in allautopsy subjects regardless of whether death wasdeemed sudden or nonsudden allowed us to avoidselection bias toward sudden cardiac death. Never-theless, in contrast to our study, more than 90% ofsudden cardiac deaths occur out of hospital (24).Thus, our study likely overestimates the incidence ofpulseless electrical activity and underestimates theincidence of ventricular tachycardia/ventricularfibrillation as a terminal rhythm in the larger popu-lation with CIEDs.

A second major limitation stems from the issuethat the CIED alerts examined can be viewed onlyfor their association with the timing, mechanism,and cause of death and not as evidence of direct

causation. Hence we would caution against pursuingCIED removal and analysis in isolation but ratherrecommend that it be undertaken as part of an au-topsy investigation to ensure a complete clinicalcontext. Additionally, most subjects were not fol-lowed at our institution, and therefore we were un-able to address systematically whether ante-mortemarrhythmias or transthoracic impedance changescontributed to subjects’ outcomes.

Finally, a third limitation is the inclusion of 4different CIED manufacturers in our study. There arevariations in each CIED manufacturer’s softwareprogramming and nominal parameters for alert de-tections, so it is possible that a similar study with adifferent composition of CIED types and manufac-turers could have some differences in their resultsrelated to CIED heterogeneity.

CONCLUSIONS

Given the clinical data observed in our institutionalregistry, we would recommend CIED removal andanalysis in all subjects undergoing autopsy investi-gation to assist in the determination of timing,mechanism, and cause of death. We would also sup-port recent calls (4,5,13) for mandatory post-mortemCIED retrieval and manufacturer analysis to screenfor potentially fatal device malfunction moreaccurately.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Sunil K. Sinha, Division of Cardiology, The JohnsHopkins Hospital, 600 North Wolfe Street, Halsted502, Baltimore, Maryland 21287-0409. E-mail:sunilsinha@jhmi.edu.

Sinha et al. J A C C V O L . 6 8 , N O . 1 2 , 2 0 1 6

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KEY WORDS defibrillator, nonsuddendeath, pacemaker, post-mortem, suddendeath