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State of the Art in Forensic Investigation of
Sudden Cardiac Death
Antonio Oliva, MD, PhD,* Ramon Brugada, MD, PhD,Þ Ernesto D_Aloja, MD, PhD,þ Ilaria Boschi, PhD,*
Sara Partemi, MD,* Josep Brugada, MD, PhD,§ and Vincenzo L. Pascali, MD, PhD*
Abstract: The sudden death of a young person is a devastating event for
both the family and community. Over the last decade, significant advances
have been made in understanding both the clinical and genetic basis of
sudden cardiac death. Many of the causes of sudden death are due to
genetic heart disorders, which can lead to both structural (eg, hypertrophic
cardiomyopathy) and arrhythmogenic abnormalities (eg, familial long
QT syndrome, Brugada syndrome). Most commonly, sudden cardiac death
can be the first presentation of an underlying heart problem, leaving the
family at a loss as to why an otherwise healthy young person has died. Not
only is this a tragic event for those involved, but it also presents a great
challenge to the forensic pathologist involved in the management of the
surviving family members. Evaluation of families requires a multidisciplinary approach, which should include cardiologists, a clinical geneticist,
a genetic counselor, and the forensic pathologist directly involved in the
sudden death case. This multifaceted cardiac genetic service is crucial in
the evaluation and management of the clinical, genetic, psychological,
and social complexities observed in families in which there has been a
young sudden cardiac death. The present study will address the spectrum
of structural substrates of cardiac sudden death with particular emphasis
given to the possible role of forensic molecular biology techniques in
identifying subtle or even merely functional disorders accounting for
electrical instability.
Key Words: sudden cardiac death, autopsy, ventricular tachyarrhythmia,
cardiac arrest, risk factor, cardiomyopathy, molecular autopsy,
postmortem genetic analysis
(Am J Forensic Med Pathol 2011;32: 1Y16)
S
udden cardiac death (SCD) is the leading mode of death in
all communities of the United States and of the European
Union, but its precise incidence is unknown. Internationally
accepted methods of death certification do not include a specific
category of SCD. Estimates for the United States range from
250,000 to 400,000 adult people dying suddenly each year due
to cardiovascular causes with an overall incidence of 1 to 2/1000
population per year.1Y3 A task force of the European Society of
Manuscript received November 15, 2008; accepted May 27, 2009.
From the *Institute of Forensic Medicine and Laboratory of Forensic Genetics,
Catholic University, School of Medicine, Rome, Italy; †Cardiovascular
Genetics Center, School of Medicine, University of Girona, Girona, Spain;
‡Institute of Forensic Medicine, Cagliari University, School of Medicine,
Cagliari, Italy; and §Arrhythmia Unit, Cardiovascular Institute, Hospital
Clinic, University of Barcelona, Spain.
A.O. and R.B. have contributed equally to this study.
Supported by Fondi di Ateneo Linea D1Y2008, Università Cattolica del Sacro
Cuore, Roma.
Supplemental digital content is available for this article. Direct URL citations
appear in the printed text and are provided in the HTML and PDF versions
of this article on the journal’s Web site (www.amjforensicmedicine.com).
Reprints: Antonio Oliva, MD, PhD, Research Scientist, Institute of Forensic
Medicine, Catholic University, School of Medicine, Rome, Italy. E-mail:
[email protected].
Copyright * 2011 by Lippincott Williams & Wilkins
ISSN: 0195-7910/11/3201-0001
DOI: 10.1097/PAF.0b013e3181c2dc96
Am J Forensic Med Pathol
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Volume 32, Number 1, March 2011
Cardiology has adopted the incidence ranges from 36 to 128
deaths per 100,000 people per year.4,5 More than 60% of these
are the result of coronary heart disease. Among the general population of adolescents and adults younger than the age of 30 years,
the overall risk of SCD is 1/100,000 and a wider spectrum of
diseases can account for the final event.6 The major difficulties in
interpreting epidemiological data on sudden death are the lack of
standardization in death certificate coding and the variability in
the definition of sudden death. Sudden death has been defined as
Ba natural, unexpected fatal event occurring within 1 hour from
the onset of symptoms in an apparently healthy subject or whose
disease was not so severe as to predict an abrupt outcome.[7 This
well describes many witnessed deaths in the community or in
emergency departments. It is less satisfactory in forensic practice
where autopsies may be requested on patients whose deaths were
not witnessed, occurred during sleep or at an unknown time
before their bodies were discovered. Under the latter circumstances, it is probably more satisfactory to assume that the death
was sudden if the deceased was known to be in good health
24 hours before death occurred.8 Moreover, for practical purposes, a death can be classified as sudden if a patient is resuscitated after cardiac arrest, survives on life support for a limited
period of time and then dies due to irreversible brain damage.
Forensic pathologists are responsible for determining the precise
cause of sudden death but there is considerable variation in the
way in which they approach this increasingly complex task. A
variety of book chapters, professional guidelines, and articles have
described how pathologists should investigate sudden death,9Y14
but there is little consistency among centers, even in individual
countries. Furthermore recent advances in the field of molecular
genetics have expanded our understanding of the etiology of
many lethal and heritable channelopathies leading to fatal arrhythmias, such as congenital long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT) and
Brugada syndrome (BrS) which is an autosomal dominant form
of cardiac arrhythmia with a typical electrocardiographic (ECG)
pattern of ST segment elevation in leads V1 to V3, and incomplete
or complete right bundle branch block15 linked to mutations in
the SCN5A gene encoding for the alpha-subunit of the cardiac
sodium channel16,17; thus actually forensic pathologists play a
crucial role in such circumstances because an accurate postmortem diagnosis of the causes of SCD is of particular importance
to establish pre-emptive strategies to avoid other tragedies among
relatives.18 In this article, we summarize the state of art of forensic
investigation and autopsy techniques for an adequate assessment
of SCD in general population and we describe the main pathologic findings at postmortem analysis.
THE RANGE OF PATHOLOGY
Many reports describe the pathologic findings in SCD
(Table 1). These studies differ in many ways, especially in the
age and type of patients investigated and the extent of histologic
sampling. In adults, coronary artery disease is by far, the leading
cause of death. The proportion of cases with evidence of acute
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TABLE 1. Sudden Cardiac Death in Adult
Authors
Davies et al
11
Setting
Patients and Methods
London, England
168 patients (21 female) dying from
cardiac disease within 6 h of onset
of symptoms. Detailed histology
Leach et al29
Nottingham, England
Burke et al30
United States
Chugh et al19
United States
Bowker et al31
United Kingdom
Chase20
Southern England
Fabre and Sheppard32
United Kingdom
Di Gioia et al21
Italy
Selected Results
73% had intraluminal or occlusive coronary
thrombosis. Presence of thrombus associated
with single vessel disease, acute myocardial
infarction and prodromal symptoms
206 out-of-hospital sudden
Coronary artery thrombosis Tacute infarction
deaths due to
in 48.5% of cases. Presence of these changes
coronary heart disease.
decreased with age and a previous history
Detailed histology
of IHD
113 males who died of coronary heart 52% acute coronary thrombosis
disease. Detailed histology
(10 with acute infarcts)
48% coronary stenosis without
thrombosis (2 with acute infarcts)
270 hearts referred to a cardiac
65% coronary artery disease
pathology unit over 13-yr-period.
190 males and 80 females
aged 920 yr
9% cardiomyopathy
11% myocarditis
14% CHD
5% structurally normal
National study of SCD in white males 37% acute coronary thrombosis
aged 16Y64 yr, no history of
or acute infarction
cardiac disease, seen alive within
12 h of death. Limited histology
20% coronary stenosis with healed infarction
18% coronary stenosis without infarction
8% cardiomyopathy or LVH 4% unexplained
321 SCDs in males and females
33% acute myocardial infarction or acute
aged 916 yr, 2002Y2003.
coronary thrombosis
Limited histology
33% coronary stenosis with healed infarction
17% coronary stenosis without healed infarction
14% cardiomyopathy or LVH
2% unexplained
453 hearts referred to a cardiac
59% structurally normal
pathology unit, 1994V2003
24% cardiac muscle disease
100 hearts referred to cardiac
30%, atherosclerotic
pathology unit, 2001V2005
22% cardiomyopathies
28% various cardiac abnormalities
20% inherited cardiac disease
CHD indicates congenital heart disease; IHD, ischaemic heart disease; LVH, left ventricular hypertrophy; SCD, sudden cardiac death.
Modified from Curr Diagn Pathol. 2007;13:366Y374.22
coronary thrombosis or recent myocardial infarction is higher
in studies in which detailed histology was performed (Table 1).
With detailed histology, acute thrombosis was identified in 72%,
52%, and 47% of cases.11,29,30 In contrast, recent studies where
histology was limited showed acute thrombosis in 37% and 33%
of cases.20,31 Whether this represents a genuine change in the
incidence of acute thrombosis in SCD or a failure of pathologists
to recognize thrombi without histologic confirmation is uncertain. Congenital heart disease, cardiomyopathy, and unexplained
left ventricular hypertrophy are of particular importance in
younger patients (Table 2), especially athletes. Studies with
limited histology appear to report a lower incidence of myo-
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carditis. The wide range of uncommon pathology is especially
apparent in reports from referral centers.32,33
METHODS OF INVESTIGATION
Several book chapters, professional guidelines, and articles
have described how pathologists should investigate sudden
death.30,34,35 Despite these guidelines, there is little consistency
between centers, even in individual countries. Forensic investigation of sudden death involves 4 steps36:
1. Circumstances of death and clinical information relevant to
the autopsy;
2. Autopsy examination and histology;
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Forensic Investigation of SCD
TABLE 2. Sudden Cardiac Death in Young Patients
Authors
Setting
Wren et al
23
North England
Corrado et al24
Maron25
Italy
United States
Fornes and Lecomte26
France
Patients and Methods
229 sudden deaths in patients
aged 1Y20 yr, 1985Y1994
273 SCDs, 218 males, 82 females
aged 1Y35 yr, 1979Y1998
387 sudden deaths in athletes
aged 35 yr
31 sudden deaths during sport,
29 males, 2 females aged
7Y60 (mean 30) years
Selected Results
Asthma, respiratory infection or
epilepsy 111 (48.5%)
SIDS 20 (8.7%)
Previous diagnosis of cardiac disease, chiefly
congenital heart disease 33 (14.5%)
Cardiomyopathy 8 (3.5%)
Myocarditis 5 (2.2%)
Coronary atheroma 1 (0.4%)
Unexplained 21 (9.2%)
Cardiomyopathy 66 (24%)
Myocarditis 27 (10%)
Coronary atheroma 54 (20%)
Unexplained 16 (6%)
Cardiomyopathy 122 (32%)
Myocarditis 20 (5%) Coronary atheroma 10 (3%)
FUnexplained_ 2%
Cardiomyopathy 10
Coronary atheroma 9
Henriques de Gouveia et al27 The Netherlands 11 sudden deaths from coronary heart Nine plaque erosions and 2 claque ruptures.
disease in patients aged 24Y35 yr.
Histology and immunohistochemistry suggested
No history of heart disease
that thrombus was fresh in only 3 cases
Unexplained 31%
Australia
193 SCDs in patients aged
Coronary heart disease 24%
Doolan et al28
G35 yr, 1994Y2002
Cardiomyopathy 18%
Myocarditis 12%
Congenital heart disease 7%
SCD indicates sudden cardiac death; SIDS, sudden infant death syndrome.
Modified from Curr Diagn Pathol. 2007;13:366Y374.22
3. Laboratory tests;
4. Formulation of a diagnosis: main findings at postmortem
investigation;
Finally, a forensic report including a clinicopathologic
summary is written by the pathologist. At this stage it is critical
to establish or consider:
& Whether the death is attributable to a cardiac disease or to
other causes of sudden death;
& The nature of the cardiac disease, and whether the mechanism
was arrhythmic or mechanical;
& Whether the cardiac condition causing sudden death may
be inherited, requiring screening and counseling of the next
of kin;
& The possibility of toxic or illicit drug abuse and other unnatural
deaths.
CIRCUMSTANCES OF DEATH AND CLINICAL
INFORMATIONS RELEVANT TO THE AUTOPSY
Forensic and general pathologists approach sudden death
autopsies with different degrees of suspicion. Forensic pathologists may visit the scene of death and carefully examine the
clothing and effects of the deceased. Death scene investigation
* 2011 Lippincott Williams & Wilkins
requires also a detailed interrogation of witnesses, if any, family
members of the deceased, physicians of the rescue team who
attempted resuscitation. On the other hand, general pathologists
usually receive reports from the police or other investigators
confirming that no suspicious circumstances have been discovered. Whatever the setting, pathologists should be provided with
full details of the circumstances of the death of the patient, the
medical history, and the prescribed medications. In practice, this
is often not available. Although the majority of deaths occur at
home, many are unwitnessed. Symptoms such as syncope, dizziness, and chest pain are of particular importance. A previous
electrocardiogram is especially valuable, but a recent population
study found that this was available in less than 40% of patients
who died suddenly and had a previous history of heart disease.18
In practice the amount of information that is available before
autopsy is extremely variable. Any potential source of information
should be interrogated preferentially before autopsy is carried out.
Ideally, in detail the following informations are required:
Age, gender, occupation, lifestyle (especially alcohol or smoking), usual pattern of exercise, or athletic activity;
Circumstances of death: date, time interval (instantaneous or
G1 hours), place of death (eg, at home, at work, in hospital,
at recreation), circumstances (at rest, during sleep, during
exerciseVathletic or nonathletic, during emotional stress),
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witnessed or un-witnessed, any suspicious circumstances
(carbon monoxide, violence, traffic accident, etc);
Medical history: general health status, previous significant illnesses (especially syncope, chest pain, and palpitations,
particularly during exercise, myocardial infarction, hypertension, respiratory, and recent infectious disease,
epilepsy, asthma, etc), previous surgical operations or
interventions, previous ECG tracings and chest x-rays,
results of cardiovascular examination, laboratory investigations (especially lipid profiles);
Prescription and nonprescription medications;
Family cardiac history: ischemic heart disease and premature
sudden death, arrhythmias, inherited cardiac diseases;
ECG tracing taken during resuscitation, serum enzyme and
troponin measurements.
Cardiac Causes of Sudden Death
THE AUTOPSY PROCEDURE
The care and attention to detail that pathologists give to
sudden death autopsies varies considerably. Most are performed
by general or forensic pathologists. Their major professional
interests are likely to be in diagnostic surgical histopathology and
the investigation of criminal death, rather than in cardiovascular
pathology. Details of how to perform autopsies have been summarized by Cohle and Sampson33 and described and illustrated
in detail in a recent textbook.34 The range of pathology in sudden
death has been also summarized by Saukko and Knight.36
Moreover principles and rules relating to autopsy procedures are
well delineated through the Recommendations on the Harmonization of Medico-Legal Autopsy Rules produced by the Committee of Ministers of the Council of Europe.10 In our opinion
the procedures reported below are designed to make the diagnosis
of SCD more straightforward and logical.
External Examination of the Body
The external examination may find clinical signs of disease,
such as alcohol disease, in which patients present a raised risk of
sudden death. Trauma lesions such as contusions can also be
found, particularly in case of fall after brutal loss of consciousness. Trauma due to resuscitation may be found as well. Moreover it is very important to perform the following procedures:
& Establish body weight and height (to correlate with heart
weight and wall thickness).37Y39
& Check for recent intravenous access, intubation, ECG pads,
defibrillator and electrical burns, drain sites, and traumatic
lesions;
& Check for implantable cardioverter defibrillator/pacemaker; if
in situ, see MDA Safety Notice 2002 for safe removal and
interrogation.40
Full Autopsy With Sequential Approach to the
Causes of Sudden Death
Noncardiac Causes of Sudden Death
Any natural sudden death can be considered cardiac in
origin after the exclusion of noncardiac causes. Thus, a full
autopsy with sequential approach should be always performed
to exclude common and un-common extracardiac causes of
sudden death, especially:
Cerebral (eg, subarachnoid or intracerebral hemorrhage, etc)
Respiratory (eg, asthma, anaphylaxis, etc)
Acute hemorrhagic shock (eg, ruptured aortic aneurysm, peptic
ulcer, etc)
Septic shock (WaterhouseYFriderichsen syndrome)
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Many cardiovascular diseases can cause SCD, either
through an arrhythmic mechanism (electrical SCD) or by compromising the mechanical function of the heart (mechanical
SCD). These disorders may affect the coronary arteries, the
myocardium, the cardiac valves, the conducting system, the
intrapericardial aorta, or the pulmonary artery, the integrity of
which is essential for a regular heart function (Table 3).
The Standard Gross Examination of the Heart
1. Check the pericardium, open it, and explore the pericardial
cavity.
2. Check the anatomy of the great arteries before transecting
them 3 cm on top of the aortic and pulmonary valves.
3. Check and transect the pulmonary veins. Transect the superior vena cava 2 cm above the point where the crest of the
right atrial appendage meets the superior vena cava (to preserve sinus node). Transect the inferior vena cava close to the
diaphragm.
4. Open the right atrium from the inferior vena cava to the apex
of the appendage. Open the left atrium between the pulmonary veins and then to the atrial appendage. Inspect the atrial
cavities, the interatrial septum, and determine whether the
foramen ovale is patent. Examine the mitral and tricuspid
valves (or valve prostheses) from above and check the integrity of the papillary muscles and chordae tendineae.
5. Inspect the aorta, the pulmonary artery, and the aortic and
pulmonary valves (or valve prosthesis) from above.
6. Check coronary arteries:
i. Examine the size, shape, position, number, and patency of
the coronary ostia;
ii. Assess the size, course, and Bdominance[ of the major
epicardial arteries;
iii. Make multiple transverse cuts at 3-mm intervals along the
course of the main epicardial arteries and branches such as
the diagonal and obtuse marginal, and check patency;
iv. Heavily calcified coronary arteries can sometimes be
opened adequately with sharp scissors. If this is not possible, they should be removed intact, decalcified, and
opened transversely;
v. Coronary artery segments containing a metallic stent
should be referred intact to labs with facilities for resin
embedding and subsequent processing and sectioning;
vi. Coronary artery bypass grafts (saphenous veins, internal
mammary arteries, radial arteries, etc) should be carefully
examined with transverse cuts. The proximal and distal
anastomoses should be examined with particular care. Side
branch clips or sutures may facilitate their identification,
particularly when dealing with internal mammary grafts.
7. Make a complete transverse (short-axis) cut of the heart at
the midventricular level and then parallel slices of ventricles
at 1-cm intervals towards the apex and assess these slices
carefully for morphology of the walls and cavities.
8. Once emptied of blood, the following measurements are
important:
i. Total heart weight: assess weight of heart against tables of
normal weights by age, gender, and body weight34Y36;
ii. Wall thickness: inspect endocardium, measure thickness
of mid cavity free wall of the left ventricle, right ventricle
and of the septum (excluding trabeculae) against tables of
normal thickness by age, gender, and body weight34Y36;
iii. Heart dimensions: the transverse size is best calculated as
the distance from the obtuse to the acute margin in the
posterior atrioventricular sulcus. The longitudinal size is
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Forensic Investigation of SCD
TABLE 3. Sudden Cardiac Death at Postmortem
Mechanical
Intrapericardial hemorrhage and cardiac
tamponade
Ascending aorta rupture (hypertension,
Marfan, bicuspid aortic valve,
coarctation, others)
Postmyocardial infarction free
wall rupture
Pulmonary embolism
Acute mitral valve incompetence with
pulmonary edema
Postmyocardial infarction papillary
muscle rupture
Chordae tendineae rupture
(floppy mitral valve)
Intracavitary obstruction
(eg thrombus/neoplasms)
Abrupt prosthetic valve dysfunction
(eg laceration, dehiscence, thrombotic
block, poppet escape)
Congenital partial absence of the
pericardium with strangulation
Arrhythmic
Others
Coronary arteries (Tpostmyocardial
infarction scar)
Congenital anomalies
Fibromuscular dysplasia
Origin from the aorta
Coronary artery by-pass (saphenous vein, mammary
and radial arteries, etc)
Percutaneous balloon coronary angioplasty, stents
Intramural small vessel disease
Wrong sinus (RCA from the left sinus,
LCA from the right sinus)
LCx from the right sinus or from RCA
Myocardium
High take off from the tubular portion
Cardiomyopathy, hypertrophic
Ostia plication
Cardiomyopathy, arrhythmogenic right ventricular
Origin from the pulmonary trunk
Cardiomyopathy, dilated
Course: intra-myocardial
course (Bmyocardial bridge[)
Cardiomyopathy, inflammatory (myocarditis)
Acquired
Secondary cardiomyopathies (storage, infiltrative,
sarcoidosis, etc)
Hypertensive heart disease
Idiopathic left ventricular hypertrophy
Unclassified cardiomyopathies (spongy
myocardium, fibroelastosis)
Valve
Aortic valve stenosis
Myxoid degeneration of the mitral valve
with prolapse
Conduction system
Sinoatrial disease
AV block (LevYLenegre disease, AV node
cystic tumor)
Ventricular pre-excitation (WolffYParkinsonYWhite
syndrome, Lown Ganong Levine syndrome)
Congenital heart disease (operated and un-operated)
Eisenmenger syndrome
Normal heart (Bsine materia[ or unexplained SCD
or sudden arrhythmic death syndrome)
Long and short QT syndromes Brugada syndrome
Catecholaminergic polymorphic
ventricular tachycardia
Idiopathic ventricular fibrillation
Atherosclerosis
Complicated (thrombus, haemorrhage)
Uncomplicated
Embolism
Arteritis
Dissection
AV indicates atrioventricular; LCA, left coronary artery; LCx, left circumflex branch; RCA, right coronary artery.
Modified from Virchows Arch. 2008;452:11Y18.35
obtained from a measurement of the distance between
the crux cordis and the apex of the heart on the posterior
aspect.
9. Dissect the basal half of the heart in the flow of blood and
complete examination of atrial and ventricular septa, atrioventricular valves, ventricular inflows and outflows, and
semi-lunar valves. In case of ECG documented ventricular
pre-excitation, the atrioventricular rings should be maintained intact.
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LABORATORY TESTS
Progress in autopsy diagnosis of SCD depends also from
the use of a rigorous protocol in order not to forget essential
biologic samples for histology, toxicologic, or molecular studies
that are maybe required at some stage in the investigation procedure. A suggestion of such protocol is shown in Table 4. To
this end, appropriate storage of autopsy tissues/fluids is essential
in SCD autopsies. If these laboratory tests are needed and no
on-site facilities are available, the stored material needs to be
sent to specialized labs.
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TABLE 4. Range of Postmortem Laboratory Tests in SCD
Systematic Procedures
Histology
Cytology
Neuropathology
Toxicology
Biochemistry
Microbiology
Molecular biology
Samples
Complementary Techniques
All organs including thymus, thyroid, testes
Pericardial, pleural and abdominal fluids, CSF
Brain in formol during 3Y4 wks
Blood, urine, hair, vitreous humor
Pericardial fluid vitreous humor
Blood, all recovered fluids, organs with septic
lesions and CSF for cultures
Blood, heart
Gram, Grocott, and PAS stains if needed
Gram and PAS stains if needed
Histology, immunohistochemistry
Troponine electrolytes and glucose concentrations
HIV, B and C hepatitis serology PCR for viral
proteins detection
Mutations screening according to pathology
and family disease
Histology
Molecular Studies
The standard histologic examination of the heart myocardium is based on the collection of mapped and labeled blocks
from a representative transverse slice of the ventricles to include
the free wall of the left ventricle (anterior, lateral, and posterior),
the ventricular septum (anterior and posterior), the free wall
of the right ventricle (anterior, lateral, and posterior), and right
ventricular outflow tract and 1 block from each atria. In addition,
any area with significant macroscopic abnormalities should be
sampled. Hematoxylin and eosin stain and a connective tissue
stain (van Gieson, trichrome, or Sirius red) are standard. Other
special stains and immunohistochemistry should be performed
as required. Coronary arteries: in the setting of coronary artery
disease, most severe focal lesions should be sampled for histology in labeled blocks and stained as before.
Molecular investigations of SCD include both detection of
viral genomes in inflammatory cardiomyopathies and gene
mutational analysis in both structural and nonstructural genetically determined heart diseases.9,42Y44 For these purposes, 10 mL
of EDTA blood and 5 g of heart and spleen tissues are either
frozen and stored at j80-C, or alternatively stored in RNA later
at 4-C for up to 2 weeks. More in detail, considering the important role of ion channels and their function or malfunction in
several heritable and acquired channelopathies, postmortem
mRNA expression analysis on tissue from pathologic and nonpathologic hearts could be a very useful source to investigate the
expression of Na+ and K+ channels. A recent article has confirmed
the usefulness of this idea through the demonstration of an increase in mRNA levels for 3 previously undiscovered truncated
transcripts in ventricular tissue from failing heart suggesting that
the translation of the 3 truncated forms leads to a reduction of
NaV1.5 protein levels in the tissue.45
Toxicology
In investigating out-of-hospital deaths, the question is almost always raised of whether toxic substances are involved.
Depending on the circumstances surrounding the death and
toxicological data, the manner of death can be natural, accidental, or criminal. Even when the heart is found to be abnormal
at gross and/or microscopic examination, and death occurred
suddenly, the question still remains of whether a substance may
have triggered the death, acting as additional factor to the anatomic substrate. Therefore toxicology is very important for 2
reasons: first, to exclude a toxic cause, second, to help for the
determination of a drug-related cardiomyopathy such as cocaine
or amphetamine-induced cardiomyopathy which can be responsible for sudden death. Hair testing is needed even if no or low
levels of drug are detected in blood, to show a history of drug
abuse. The results must be compared with cardiac pathologic
findings suggestive of cocaine or amphetamine cardiac chronic
toxicity, such as the association of microfocal fibrosis, contraction
band necrosis, and cardiomyocyte hypertrophy. The cardiac toxicity of anabolic steroid abuse must also be taken into account.
The proper selection, collection, and submission of specimens
for toxicological analyses are mandatory if analytical results are
to be accurate and scientifically useful. The types and minimum
amounts of tissue specimens and fluids needed for toxicological
evaluation are frequently dictated by the analytes that must be
identified and quantitated. For the purpose of sudden death
investigation, the following amounts are adapted from the
Guidelines of the Society of Forensic Toxicologists and the
American Academy of Forensic Sciences41: heart blood 25 mL,
peripheral blood from femoral veins 10 mL, urine 30 to 50 mL,
bile 20 to 30 mL (when urine is not available). All samples are
stored at 4-C. A lock of hair (100Y200 mg) should be cut from
the back head (or from the pubic hair when head hair is not
available). Toxicological analyses are generally quantitative.
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Electron Microscopy Investigation
In case of suspicion of rare cardiomyopathies (mitochondrial, storage, infiltrative, etc) a small sample of myocardium
(1 mm) should be fixed in 2.5% glutaraldehyde for ultrastructural examination.
FORMULATION OF A DIAGNOSIS: MAIN
FINDINGS AT POSTMORTEM INVESTIGATION
Coronary Artery Disease
Atherosclerotic coronary artery disease (CAD) remains the
predominant substrate for SCD.46,47 From a pathologic point of
view, CAD is defined by a heart showing at least one of the 3
coronary arteries narrowed to 75% or more by an atherosclerotic plaque and/or thrombosis. Approximately 80% of sudden
cardiac deaths are caused by CAD. An analysis made in the
Framingham population of 5209 men and women free of identified heart disease at baseline showed that 46% of men and
34% of women with SCD had CAD as the most likely etiology
of their cardiac arrest.42 No specific pattern of coronary artery
involvement has been correlated to the risk of SCD,48 and the
extent of vessel disease involvement seems to have a greater
predictive value than the location of specific lesions in the coronary arteries.49,50 Structural abnormalities of coronary arteries
can be characterized as acute or chronic, and healed myocardial infarction (MI) has been reported in 40% to 70% of SCDrelated autopsies.42,51 But only 20% of those with SCD have
shown any evidence of a recent MI.52 Acute coronary events
with recent thrombi, plaque fissuring, and hemorrhage are believed to contribute significantly to SCD, although there has
been a low incidence of acute MIs at autopsy in patients with
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Forensic Investigation of SCD
SCD. In the pathogenesis of ventricular arrhythmias, transient
ischemia, and reperfusion, autonomic changes, and systematic
derangements (eg, hypoxemia, acidosis, electrolyte imbalance)
play a more significant role in healed myocardial tissue than
in normal cardiac muscle.53 Nonatherosclerotic CAD leading
to SCD is seen less commonly and can be a manifestation of
anomalous origin of left coronary artery, (Fig. 1)54 embolism,
arteritis, and coronary dissection.48,55
Cardiomyopathies
Cardiomyopathies are a major cause of morbidity and
mortality at all ages. They are defined by the World Health
Organization56 as Bdiseases of the myocardium associated with
cardiac dysfunction[ and are classified into 4 major groups:
hypertrophic cardiomyopathy, dilated cardiomyopathy, restrictive
cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. An additional category referred to as Bspecific[ cardiomyopathies, which encompasses a wide variety of specific cardiac
or systemic disorders, has also been included in the classification scheme.56 The cardiomyopathies may be either inherited or
acquired. In the last 20 years, advances in molecular genetics
have improved our understanding of the pathogenesis of cardiomyopathies by identifying underlying gene mutations that lead
to myocardial disease. Although many cardiomyopathies result
from a single gene defect and are therefore inherited in a predictable Mendelian fashion, the resultant disease phenotype may
be clinically and pathologically diverse.57
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a well-recognized
cause of SCD with sudden unexpected death occurring most
frequently in young persons affecting 1:500 of the population.58,59
Decades ago, HCM was written about and known as idiopathic
hypertrophic subaortic stenosis. It also was written about and
known as asymmetric septal hypertrophy. These terms were
replaced by the current term, HCM, because the segmental hypertrophy can occur in any segment of the ventricle, not just the
septum.60 Furthermore, this entity can present without subaortic
obstruction to flow, yet still carry the same ominous risk of arrhythmogenic sudden death and many of its clinical symptoms.
Although this disease may occur at any age, most patients are
in their 30s or 40s at the time of diagnosis and in 16% of cases
the diagnosis is first made at autopsy (sudden death).61 On gross
examination, the heart is typically enlarged to twice normal
weight. The mean heart weight in a series of 40 autopsied cases
was 634 grams.62 The hypertrophy is secondary to ventricular
thickening and may occur almost anywhere in the ventricular
mass, but is most often found in the interventricular septum
FIGURE 2. Hypertrophic cardiomyopathy. A, Long axis view of
the ventricular septum (VS) and left ventricular free wall (LVFW)
from a patient with hypertrophic cardiomyopathy. The ventricular
septum shows asymmetric hypertrophy with scarring in the
septum (arrow). Note the dilated left atrium (LA). The anterior
mitral valve leaflet (AML), aorta (Ao), and right ventricle (RV)
are shown for orientation. B, Histologically, there is myofiber
disarray characterized by myocyte hypertrophy, and branching
of myocytes (Masson trichrome). C, Microscopic section of a
thickened intramural coronary artery in the ventricular septum
(Hematoxylin and eosin). Adapted with permission from
Dr. Renu Virmani, CVPath, International Registry of Pathology,
Inc, Gaithersburg, MD. With kind permission of Springer
Science + Business Media. Figure 2 can be viewed online in color
at www.amjforensicmedicine.com.
(Fig. 2). Heart weight may occasionally be normal or only slightly
increased, an observation that has been linked in some cases
with troponin T mutations.63 Microscopically the most characteristic feature is myofiber disarray characterized by disorganized
branching myocytes. Other features include myocyte hypertrophy,
interstitial fibrosis, and intramural coronary artery thickening.
Diagnostic confusion often exists in making the distinction between a true HCM and cardiac hypertrophy. Proper sectioning in
a case of suspected HCM entails sectioning in the short axis
plane or from endocardium to epicardium in the transverse plane.
Histologic review of multiple cross-sections from the ventricular
septum is required demonstrating myofiber disarray of at least
5% cross-sectional area.64 It has been shown that approximately
50% to 60% of HCM cases are familial with an autosomal dominant pattern of inheritance. Currently, 14 genes and more than
150 different mutations have been identified.65 The structural
deformities of HCM result from mutations in genes that encode
sarcomeric proteins, most commonly beta myosin heavy chains.
High-risk mutations include the beta myosin heavy chain (MYH7)
mutations (R403Q, R453C, G716R, and R719W).66 A diagnosis
of HCM mandates genetic counseling with serious implications
for family members and thus should be reserved only for cases
fulfilling the diagnostic criteria.
Arrhythmogenic Right Ventricular Dysplasia
FIGURE 1. Coronary artery anomaly. (A: Macroscopic view) Left
anterior descending and circumflex coronary arteries arousing
from the left sinus of Valsalva with a separate origin. (B: Histology)
Microscopic appearance of fibrosis: chronic ischemic damage
of the left ventricular anterior wall. With kind permission of
Springer Science + Business Media. Figure 1 can be viewed online
in color at www.amjforensicmedicine.com.
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Arrhythmogenic right ventricular dysplasia (ARVD) is a
genetic cardiomyopathy often presenting with SCD, particularly
in adolescents and young adults.67 In Italy, ARVD is the most
frequent cause of sudden death in young athletes. The mean age
for patients dying suddenly is usually in the third decade.68Y70
Although the name implies a purely right-sided disease process,
involvement of the left ventricle has been shown to occur in
975% of cases and rare cases are reported to affect the left
ventricle exclusively.71 The heart is generally normal in size or
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Oliva et al
slightly enlarged. Grossly the right ventricle may show focal
myocardial wall thinning to 2 mm or less, aneurysm formation,
and cavitary dilatation. Additionally, the left ventricle may show
subepicardial scars on gross examination.72 The histologic features of ARVD include transmural fatty infiltration of myocardium, fibrosis, and inflammation, principally lymphocytes
(Fig. 3). Fat infiltration of the right ventricle is usually considered a mandatory finding for the diagnosis, but the diagnosis
should not be based only on the presence of fat because normal
hearts may show a certain degree of fatty infiltration in the right
ventricle. It has been showed that it is not unusual to see fat
infiltration occupying over 50% of myocardial area in the anterior wall of the right ventricle in trauma victims (autopsy control
subjects73). Moreover 2 pathologic variants have been described
in the literature including a predominantly Bfatty[ variant and a
Bfibrofatty[ variant.67Y74 The fatty variant is characterized by
transmural infiltration of adipose tissue with sparing of the septum and left ventricle and without wall thinning.67Y74 In contrast, the fibrofatty or Bcardiomyo-pathic[ variant is characterized
by extensive replacement-type fibrosis. Islands or strands of surviving myocytes exhibit a combination of degenerative change
with myocyte vacuolization and are frequently associated with
focal mononuclear inflammatory cell infiltrates.67,74,75 The pathologic criteria for ARVD remain still controversial and there is
not yet a universal agreement about the definitive diagnostic
features. ARVD is a genetic cardiomyopathy that has been associated with mutations of plakoglobin, plakophilin, and desmoplakin genes.76 These genes encode desmosomal proteins which
are involved with cell adhesion. Loss of normal desmosomal
structure is considered a crucial event in the pathogenesis of
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FIGURE 4. Left ventricular noncompaction. Isolated left
ventricular noncompaction in an autopsy specimen, shown in
short-axis view. Note the compacted epicardial layer and
noncompacted endocardial layer with marked hypertrabeculation
and deep recesses. With kind permission of Springer
Science + Business Media. Figure 4 can be viewed online in color
at www.amjforensicmedicine.com.
ARVD, but the precise mechanisms underlying the development
of disease are as yet unknown.
Left Ventricular Noncompaction
Ventricular noncompaction (Fig. 4), also known as left
ventricular noncompaction (LVNC), is a rare form of cardiomyopathy believed to result from an unexplained arrest in cardiac development. This disease was first described over a decade
ago and is now gaining increased recognition as an important
cause of heart failure and its complications.56 LVNC has been
also reported as a cause of sudden death in both children and
adults.77,78 Since the diagnosis is often made initially at autopsy,
forensic pathologists should be aware of the diagnostic features.
Grossly the left ventricular wall demonstrates deep recesses extending to the inner half of the ventricle occurring most prominently in the midventricle to apex. The recesses show variable
patterns including anastomosing broad trabeculae, coarse trabeculae resembling multiple papillary muscles, and fine interlacing
bundles that may only be appreciated microscopically. The histologic features of LVNC are distinct, characterized by anastomosing muscle bundles forming irregular, large branching staghorn
recesses in the endocardium. Another pattern shows spongy parenchyma with compressed invaginations that are not grossly apparent. Marked endocardial fibroelastosis with prominent elastin
deposition is present as well.
Inflammatory Myocardial Diseases
FIGURE 3. Arrhythmogenic right ventricular dysplasia (ARVD).
A, Right ventricle from a patient with ARVD. Note the fatty
infiltration of the right ventricular wall and absence of myocardial
tissue with mild focal fibrosis (arrow). B, Longitudinal section
of a heart showing biventricular involvement of ARVD. Note
the subepicardial scarring in the left ventricle (arrow) and
aneurysmal dilatation with fibrofatty infiltration of the right
ventricle (double arrows) with marked thinning. C, Fibrofatty
replacement of the right ventricle with interspersed myocytes
(red). D, Subepicardial scarring of the left ventricle corresponding
to single arrow in Figure B. Adapted with permission from
Dr. Renu Virmani, CVPath, International Registry of Pathology,
Inc, Gaithersburg, MD. With kind permission of Springer
Science + Business Media. Figure 3 can be viewed online in color
at www.amjforensicmedicine.com.
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Myocarditis is defined as inflammation of the myocardium
and may be attributed to a number of causes including infectious,
toxic, and idiopathic.79,80 Examples of inflammatory myopathies
include lymphocytic myocarditis (viral), hypersensitivity myocarditis, giant cell myocarditis, toxic myocarditis, infectious
myocarditis, and sarcoidosis together with others myocardial infiltrative diseases responsible of SCD such as amyloid and tuberculous myocarditis.81,82
Lymphocytic Myocarditis
Viral, or lymphocytic myocarditis (Fig. 5), is seen more
commonly in cases of neonatal and childhood SCD, and may
follow a recent viral syndrome.80 Gross examination of the heart
is typically unrevealing. Histologically the inflammation is usually diffuse and consists primarily of lymphocytes macrophages,
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Forensic Investigation of SCD
disease manifests as dilated cardiomyopathy. This progression is
characterized by inflammation and myocytolysis, gradually resulting in death of myocytes and replacement by fibrous tissue.86
Etiologic agents in this category include catecholamines, arsenicals, venoms, paracetamol, and chemotherapeutic agents.
Giant Cell Myocarditis
FIGURE 5. Lymphocytic myocarditis. AYD, complex low and
high power views of diffuse lymphocytic infiltrate. Adapted with
permission from Professor Arnaldo Capelli, Institute of Pathology,
Catholic University, Rome, Italy. With kind permission of Springer
Science + Business Media. Figure 5 can be viewed online in color at
www.amjforensicmedicine.com.
and occasional neutrophils with associated evidence of myocyte
damage. In cases of SCD, it is presumed that the lesion(s) acts as
an inflammatory substrate for an arrhythmia, usually ventricular
tachyarrhythmias. In North America, enteroviruses, in particular
Coxsackie viruses are common agents producing myocarditis,
although adenovirus, cytomegalovirus, and herpes simplex have
also been associated with lymphocytic myocarditis. Up to the
present time, the most useful and rapid technique for detecting
virus in cases of suspected viral myocarditis is polymerase chain
reaction. In one study, polymerase chain reaction. analysis detected a viral genome in 68% of endomyocardial biopsies showing lymphocytic myocarditis from a pediatric population.83
Besides viruses, a large number of other pathogens have been
associated with infectious myocarditis including bacteria, fungi,
and parasites. The gross and histologic features of infectious
myocarditis vary depending on the etiologic agent and the stage
of the disease.
Giant cell myocarditis (Fig. 6) is a rare disease of unknown
etiology most commonly seen in adults 20 to 50 years old.87
Clinically, it usually presents as sudden onset of congestive heart
failure and is rapidly fatal in most cases. The histopathologic
features include widespread, often serpiginous, myocardial necrosis with chronic inflammation including multinucleated giant
cells.88 The giant cells are usually seen at the margins of necrosis
and have been shown to be derived from the histiocyte.
Sarcoidosis
Most patients with cardiac sarcoidosis have clinically apparent systemic involvement, but in some patients the heart
may be the primary site. The clinical manifestations are determined by the extent and location of involvement and may include conduction defects, ventricular arrhythmias, congestive
heart failure, mitral regurgitation, and sudden death. Cardiac
sarcoidosis is a focal disease involving the myocardium in decreasing order of frequency; left ventricular free wall, base of the
ventricular septum, right ventricular free wall, and atrial walls.62
Grossly the heart may display scarring in a distribution not
typical for ischemic disease, also involving the epicardial surface.89 The histologic features (Fig. 7) of cardiac sarcoid are
similar to those of extracardiac sarcoid consisting of noncaseating granulomas, histiocytes, giant cells, lymphocytes, and
Hypersensitivity Myocarditis
Hypersensitivity myocarditis is a rare cause of SCD. More
than 20 drugs have been incriminated as possible etiologic
agents84 in hypersensitivity myocarditis with penicillin, sulfonamides, and methyldopa being the most common. Although
often asymptomatic, hypersensitivity myocarditis may cause
congestive heart failure, arrhythmias, and rarely sudden death.
Most cases of hypersensitivity myocarditis are diagnosed at
autopsy,85 therefore, the true prevalence of nonlethal cases is
unknown. The histopathologic features of hypersensitivity
myocarditis include interstitial and perivascular chronic inflammatory infiltrates consisting of lymphocytes, plasma cells, and
macrophages, with a prominence of eosinophils. There is little
associated necrosis and no scarring.
Toxic Myocarditis
In addition to eliciting a hypersensitivity myocarditis, some
drugs may be directly toxic to the myocardium and produce what
is referred to as toxic myocarditis, characterized histologically
by edema, neutrophil infiltration, and necrosis, sometimes with
contraction band necrosis. Endothelial swelling and vasculitis
may be present as well. By a clinical point of view toxic myocarditis is characterized by either acute or insidious onset and
usually runs a protracted course. Frequently, irreversible end-stage
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FIGURE 6. Giant cell myocarditis. A, B, Pronounced
lymphoeosinophilic infiltrate is associated with numerous
multinucleated giant cells. Adapted with permission from
Professor Arnaldo Capelli, Institute of Pathology, Catholic
University, Rome, Italy. With kind permission of Springer
Science + Business Media. Figure 6 can be viewed online in
color at www.amjforensicmedicine.com.
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plasma cells. Special stains should be performed to rule out the
presence of fungi and acid-fast bacilli.
SCD in the Absence of Autopsy Findings
FIGURE 7. Sarcoidosis. A, Sarcoid granulomas located in the
myocardium, (hematoxylin and eosin). B, Subepicardial deposition
of amyloid (Congo red stain). With kind permission of Springer
Science + Business Media. Figure 7 can be viewed online in color
at www.amjforensicmedicine.com.
Although cardiac abnormalities evident at autopsy explain
the majority of sudden deaths in young people, several population-based studies (Fig. 8) show that a significant number of
sudden deaths remain unexplained following a comprehensive
postmortem investigation including full autopsy. In fact in some
cases, the underlying defect responsible for a SCD is not found
on gross, microscopic, or even ultrastructural examination of the
heart. In detail for nearly half of young victims from 1 to 35 years
of age, there are no apparent warning signs and sudden death
often occurs as the sentinel event, thus placing extreme importance upon the forensic investigation and autopsy to determine
the cause and manner of death.93 With recent advances in molecular biology, it has become apparent that a proportion of these
deaths are due to mutations in cardiac ion channels that may lead
to ventricular arrhythmias and sudden death. Classifications of
electric heart diseases have proved to be exceedingly complex and
in many respect contradictory. A new contemporary and rigorous
classification of arrhythmogenic cardiomyopathies have been
proposed recently in consensus with a recent American Heart
Association Scientific Statement.94 This consensus report has
provided an important framework and overview to this increasingly heterogeneous group of primary cardiac membrane channel
diseases. Of particular note, the present classification scheme
(Fig. 9) incorporates ion channelopathies as a primary cardiomyopathy. Basically, the underlying gene defects alter the electrical activity in the heart predisposing the patient to fatal cardiac
arrhythmias, without any morphologic changes seen in the myocardium. Such disorders of ion channels are sometimes referred
FIGURE 8. Structurally normal heart versus pathologic at postmortem analysis: Comparison of data from 4 cohorts: A. Maron et al90
(N = 134; mean age: 17 years; frequency of cardiomyopathy subtypes: HCM, 36%; dilated cardiomyopathy [DCM], 3%, arrhythmogenic
right ventricular dysplasia [ARVD], 3%; and unexplained increase in cardiac mass [HCM], 10%); B. Puranik et al91 (N = 241, mean age:
27 years; frequency of cardiomyopathy subtypes: HCM, 6%; DCM, 5%; ARVD, 2%; and idiopathic left ventricular hypertrophy, 3%);
C. Corrado et al24 (N = 273; mean age: 24 years; frequency of cardiomyopathy subtypes: HCM, 7%; DCM,4%; and ARVD, 13%; a
significant fraction of those included in ‘Other structural causes’ (24/38) had histologic evidence of conduction system abnormalities);
D. Eckart et al92 (N = 108, mean age: 19 years; frequency of cardiomyopathy subtypes: HCM, 8%; DCM, 1%; ARVD, 1%). ‘‘Structurally
normal’’ includes the diagnosis of arrhythmia disorders, such as long QT syndrome, as well as all sudden unexplained deaths. In some
instances, minimal structural abnormalities were noted at autopsy, but these were felt to be insufficient to cause sudden death.
Adapted with permission from Curr Opin Cardiol.44 With kind permission of Springer Science + Business Media. Figure 8 can be viewed
online in color at www.amjforensicmedicine.com.
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FIGURE 9. A, Long QT and related arrhythmia syndromes genes contributing to the same membrane currents and/or distinct
phenotypes: j indicates gain of function; ,, loss of function. B, Brugada and related arrhythmia syndromes genes: , indicates loss of
function; ?, unknown. C, Short-QT syndromes genes: j indicates gain of function; ?, unknown. D, Dilated cardiomyopathy genes: j
indicates gain of function; ?, unknown.
to as Bcardiac channelopathies[Vexamples of these include
LQTS and Brugada Sindrome (BrS) (Fig. 10). Actually in forensic field there is unlimited potential for the use of molecular
testing to identifying natural causes of death, so that a new investigatory tool so-called Bgene autopsy[ for inherited arrhythmia syndromes and also for genetic predisposition to acquired
arrhythmia has increasingly emerged.95Y97 For instance, a recent
study has completed one of the largest molecular autopsy series
of sudden unexplained death (SUD) to date.98 In this study comprehensive mutational analysis of all 60 translated exons in the
LQTS-associated genesVKCNQ1, KCNH2, SCN5A, KCNE1, and
KCNE2Valong with targeted analysis of the CPVT1-associated,
RyR2-encoded cardiac ryanodine receptor was conducted in a
series of 49 medical examiner-referred cases of SUD. Herein, over
one-third of SUD cases hosted a presumably pathogenic cardiac
channel mutation, with mutations in RyR2 alone accounting for
nearly 15% of the cases. In this series, sudden death was the
sentinel event in all but 4 mutation-positive SUD cases. According
to these results, postmortem genetic testing has provided an answer 35% of the time, meaning that this new tool in forensics
could possibly save another family member_s life.63,44Y89,93Y98
Considering that autopsy-negative SUD accounts for a significant
FIGURE 10. Schematic representation of the primary structure of the cardiac sodium channel >- and A-subunit with location of SCN5A
mutations associated with sodium channel overlap syndromes. IFM indicates the cluster of 3 hydrophobic amino acids (isoleucine,
phenylalanine, and methionine) which forms part of the inactivation gate. BrS indicates Brugada syndrome; LQT3, long-QT syndrome type
3; SSS, sick sinus syndrome; CCD, cardiac conduction defect; AS, atrial standstill; AF, atrial fibrillation; DCM, dilated cardiomyopathy.
Figure 10 can be viewed online in color at www.amjforensicmedicine.com.
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number of sudden deaths in young people and that epidemiological, clinical, and now postmortem genetic analyses all suggest
that approximately one-third of SUD after the first year of life
may stem from a lethal cardiac channelopathy, the cardiac channel molecular autopsy in these cases should be viewed as the
standard of care for the postmortem evaluation of SUD.44 A
suggestion of postautopsy care pathways to the relatives of the
deceased in case of young or adult SUD or SCD where an inherited heart disease is suspected is shown in Figure 11. Unfortunately, it is profoundly difficult for the forensic pathologist to
provide this level of care, for several reasons. One of these is
essentially that genetic testing is still time consuming and costly,
so that accordingly to these limitations it should be restricted to
selected cases. Regardless of these critical aspects, the role of
the forensic pathologist is vital, as current Bstandard operating
procedures[ for the conduct an accurate diagnosis, derived from
either a clinical assessment of surviving relatives or a molecular
autopsy, enables informed genetic counseling for families and
guides the appropriate commencement of preemptive strategies
targeted towards the prevention of another tragedy among those
left behind.
other such searches, that many false positive and negative findings will be encountered on the way. Developments to date suggest improvements in SCD analysis can be achieved in the not
too distant future and one might even envision development of
forensic applicable dedicated gene chip technologies, like those
recently commercialized to assess cytochrome P450 gene variants affecting drug metabolism. It is also worth noting that high
throughput approaches have been developed to screen for previously identified channel mutations in patients suspected of harboring susceptibility to one of the rare SCD syndromes such as
LQTs or BrS, as well as so-called Bacquired LQTs,[ which may
occur in response to drugs that interact with myocardial K channels. Such analyses are now commercially available and can be
critical in assessing risk in individual suspected of inheriting
channel mutations. Application of genomic technologies in such
cases may thus be helpful in understanding causative factors,
which determine expressivity and penetrance in specific patients.
Thus, while speculative, the Bgenomic[ tea leaves are promising,
and it is encouraging that prospects of success are sufficiently
exciting that literally dozens of pharmaceutical and biotechnology concerns are investing tens of millions of dollars, pounds,
yen, and euros in exploring this very possibility.
Future Applications
Back to the question: How will genomic approaches
translate into forensic applications? Obviously, answers and
identification of relevant arrhythmogenic pathways are not yet
available, but it is clear that new diagnostic applications are
well within our grasp. Whether constellations of risk-conferring
alleles can be identified in common arrhythmia-prone syndromes
is a problem only beginning to be studied and it is likely, as with
Volume 32, Number 1, March 2011
FORENSIC REPORT AND
CLINICO-PATHOLOGICAL SUMMARY
It is well known that forensic report represents the final
official document where the pathologist describes accurately the
pathologic findings related also to the clinical history, the circumstances of the death and any investigation performed close
FIGURE 11. Postautopsy care pathways service in cases of young or adult SUD or SCD where an inherited heart disease is suspected:
*Add suitable statement to postmortem report: SUD: ‘‘Unexplained death may be caused by inherited cardiac disease. The deceased
individual’s relatives may therefore be at risk. Please refer the deceased individual’s next of kin to Cardiac Genetics Service.’’ or SCD:
‘‘Death has been caused by a cardiac disease which may have a genetic basis. The deceased individual_s relatives may therefore also
be at risk. Please refer the deceased individual’s next of kin to Cardiac Genetics Service.’’ **Ongoing surveillance seems inadvisable;
there is a need for written information telling the individual that he/she will need to be reassessed if he/she develops key symptoms,
or if the family history changes. With kind permission of Springer Science + Business Media.
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TABLE 5. Certainity of Diagnosis in SCD Autopsies
Certain
Highly Probable
Massive pulmonary embolism
Stable atherosclerotic plaque with
luminal stenosis 975% with or
without healed myocardial infarction
Haemopericardium due to aortic
or cardiac rupture
Mitral valve papillary muscle or chordae
tendineae rupture with acute mitral
valve incompetence and pulmonary
edema
Acute coronary occlusion due to
thrombosis, dissection or embolism
Anomalous origin of the LCA from the right
sinus and interarterial course
Cardiomyopathies (hypertrophic,
arrhythmogenic right ventricular,
dilated, others)
Anomalous origin of the coronary
artery from the pulmonary trunk
Neoplasm/thrombus obstructing the
valve orifice
Thrombotic block of the valve
prosthesis
Laceration/dehiscence/poppet escape
of the valve prosthesis with acute
valve incompetence
Massive acute myocarditis
Myxoid degeneration of the mitral valve with
prolapse, with atrial dilatation, or left
ventricular hypertrophy and intact chordae
Aortic stenosis with left ventricular
hypertrophy
ECG documented ventricular pre-excitation
(WolffYParkinsonYWhite syndrome,
Lown Ganong Levine syndrome)
ECG documented sinoatrial or AV block
Congenital heart diseases, operated
Uncertain
Minor anomalies of the coronary arteries
from the aorta (RCA from the left sinus,
LCA from the right without interarterial
course, high take-off from the tubular
portion, LCx originating from the right
sinus or RCA, coronary ostia plication,
fibromuscular dysplasia, intramural
small vessel disease)
Intramyocardial course of a coronary
artery (myocardial bridge)
Focal myocarditis, hypertensive heart disease,
idiopathic left ventricular hypertrophy
Myxoid degeneration of the mitral valve with
prolapse, without atrial dilatation or left
ventricular hypertrophy and intact chordae
Dystrophic calcification of the membranous
septum (Tmitral annulus/aortic valve)
Atrial septum lipoma
AV node cystic tumor without ECG evidence
of AV block, conducting system disease
without ECG documentation
Congenital heart diseases, unoperated with
or without Eisenmenger syndrome
AV indicates atrioventricular; ECG, electrocardiogram; LCA, left coronary artery; LCx, left circumflex branch; RCA, right coronary artery.
Modified from Virchows Arch. 2008;452:11Y18.35
to the time of the death. In the majority of SCDs, a clear pathologic cause can be identified, although with varying degrees
of confidence. Wherever possible, the most likely underlying
cause should be stated and the need for familial clinical screening and genetic analysis clearly indicated.99 Different degrees
of certainty exist in defining the causeYeffect relationship between the cardiovascular substrate and the sudden death event.
Table 5 lists the commonest substrates of SCD, classifying each
as certain, highly probable or uncertain. In the probable, and especially the uncertain categories, each case should be considered
on its individual merits. The clinical history and the circumstances of death may influence the decision making process. Finally, there are myocardial diseases in which the border between
physiological and pathologic changes is poorly defined. Some
diagnostic gray zones are generally present in a variable percentage of SCD autopsies. In cases as such, if there is real doubt
as to whether the changes are physiological or pathologic, an
expert opinion to specialized heart centers should be sought.
Deaths that remain unexplained after careful macroscopic, microscopic and laboratory investigation is generally classified as
sudden arrhythmic death syndrome.
CONCLUSIONS
Sudden and unexpected cardiac death frequently represent
one of the most challenging task faced by the forensic pathologist especially for the difficulties encountered in determining the
precise cause of death. The progress in autopsy diagnosis of
SCD depends, respectively, on death scene investigation, quality
of autopsies, which is strictly linked to the use of a rigorous pro* 2011 Lippincott Williams & Wilkins
tocol in collecting essential biologic samples or in dissection procedures, and on the use of complementary techniques, especially
histology, toxicology, and molecular biology. In detail, SCD scene
investigation requires a careful interrogation of witnesses, family
members, and physicians of the rescue team who eventually attempted the resuscitation. Recent symptoms before death and
medical history must be sought. Prodromal symptoms are unfortunately often nonspecific, and even those taken to indicate
ischemia (chest pain), a tachyarrhythmia (palpitations), or congestive heart failure symptoms (dyspnea) can only be considered
suggestive. Although most of these deaths may be ascribed to
coronary atherosclerosis, there are many other potential causes of
a SCD such as cardiomyopathies, which are more frequently encountered in people aged less than 35 years. In the majority of
cases only a detailed pathologic examination of the heart in conjunction with meaningful clinicopathologic correlation allows
the pathologist to determine the underlying disease process leading to death. When no anatomic abnormality is present at autopsy,
it may be of benefit to archive DNA for genetic studies if an ion
channel disorder is suspected. In fact recent advances in the field
of molecular genetics have expanded our understanding of the
etiology and classification of many of the aforementioned cardiac
diseases. These new techniques not only augment our diagnostic
capabilities, but also highlight the importance of molecular diagnostics in identifying new disease-causing mutations. Thereafter
the major challenge is faced by cardiologists who are directly
involved in managing postautopsy care pathways to the relatives
of the deceased, especially in identifying asymptomatic subjects
at high risk of sudden death. To develop preventive strategies such
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as the use of antiarrhythmic agents or implantable cardioverterdefibrillator, the incidence, causes and circumstances surrounding
SCD must be better known and are mainly provided by forensic
pathology.
19. Chugh SS, Kelley KL, Titus JL. Sudden cardiac death with apparently
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ACKNOWLEDGMENTS
The authors thank Prof Arnaldo Capelli and Dr Vincenzo
Arena from the Institute of Pathology, Catholic University,
Rome, Italy.
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