2013 CARDIOMIOPATIAS

7/30/2019 2013 CARDIOMIOPATIAS

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Sudden arrhythmic deathand the cardiomyopathies:Molecular genetics

and pathology

*

Cristina Basso

Elisa Carturan

Kalliopi Pilichou

Domenico Corrado

Gaetano Thiene

AbstractCardiovascular disease is a significant cause of sudden death (SD) requiring

autopsy investigation. Cardiomyopathies account for about one half of cases

encountered, especially in young people


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Therefore the 2006 AHA definition overturns the old concept of

cardiomyopathies which included only myocardial diseases with

gross and/or histological abnormalities (DCM, HCM, restrictive/

obliterative cardiomyopathy, ARVC) and widened the fieldof heart

muscle diseases to include hearts with electrical disorders and no

structural abnormalities (the so-called channelopathies).

Molecular genetics of cardiomyopathies at risk of sudden death

Inherited cardiomyopathies at risk of SD include HCM, ARVC

and the channelopathies. Other cardiomyopathies, which

may be at risk of SD as part of their natural history, but

more usually present with symptoms and signs and/or a non-

Normal heart 15% CAD, a-therosclerotic 16%

ARVC 9.5%

HCM 9.5%

DCM 5%

CM, other 1%

PE 1%

Haemorrhagic

shock 1%

Aorticrupture 4%

CHD

operated 1%

Conduction

system disease 7%

MVP 8%

AS 1%

CAD, other 3%

CAD, congenital 5%

Myocarditis 14%

Figure 1 Causes of cardiac SD in the young (35 years) in the Veneto Region, North East of Italy, 1980e2006 (total number: 480 cases). Cardiomyop-athies account for more than half of cases and those potentially genetically determined (either structural or non-structural-normal heart) for about one

third. ARVC arrhythmogenic right ventricular cardiomyopathy; AS aortic stenosis; CAD coronary artery disease; CHD congenital heart disease;

CM cardiomyopathy; DCM dilated cardiomyopathy; HCM hypertrophic cardiomyopathy; MVP mitral valve prolapse; PE pulmonary embolism.

Primary cardiomyopathies (AHA 2006)

Genetic Mixed Acquired

HCM DCM Inflammatory (myocarditis)

ARVC Restrictive (non-hypertrophied and non-dilated) Stress-provoked (tako-tsubo)

LVNC Peripartum

Glycogen storage

- PRKAG2

- Danon

Tachycardia-induced

Conduction defects Infants of insulin-dependent diabetic mothers

Mitochondrial myopathies

Ion channel disorders

- LQTS

- Brugada

- SQTS

- CVPT

- Asian SUNDS

ARVC arrhythmogenic right ventricular cardiomyopathy; CVPT catecholaminergic polymorphic ventricular tachycardia; DCM dilated cardiomyopathy; HCM

hypertrophic cardiomyopathy; LQTS long QT syndrome; LVNC left ventricular non compaction; PRKAG2 protein kinase, AMP-activated, gamma 2 non-catalytic

subunit; SQTS short QT syndrome; SUNDS sudden unexpected nocturnal death syndrome.

Table 1

MINI-SYMPOSIUM: CARDIOVASCULAR PATHOLOGY

DIAGNOSTIC HISTOPATHOLOGY 16:1 32 2009 Elsevier Ltd. All rights reserved.


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arrhythmic clinical picture (i.e. DCM and spongy myocar-

dium) will not be further considered.

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is a common autosomal dominant

genetic disorder affecting 1:500 of the population.7e9 It was

found to be the consequence of missense mutations of genes

encoding sarcomeric proteins: beta-myosin heavy chain(MYH7), alpha-myosin heavy chain (MYH6), myosin regulatory

light chain (MYL2), myosin essential light chain (MYL3),

myosin binding protein C (MYBPC3), cardiac troponin T

(TNNT2), cardiac troponin I (TNNI3), cardiac troponin C

(TNNC1), alpha-tropomyosin (TPM1), alpha-cardiac actin

(ACTC), titin (TTN).

Overall, the most frequent disease genes are MYH7,

MYBPC3, TNNT2, TNNI3 and TPM1. Most mutations are

single point missense mutations or small deletions or inser-

tions. For each gene several different mutations have been

identified. In up to 5% of HCM probands, two different

mutations may be present in the same individual, leading to

compound heterozygosity, double heterozygosity, or homo-zygosity. This finding must be taken into account in the

context of genetic counselling of affected families. Thus, HCM

can be viewed as a sarcomeric disease and a genetic cause can

be identified in 35e45% in general, and up to 60e65% when

the family history is positive.

Due to genetic heterogeneity and variable phenotype, geno-

typeephenotype correlations remain complex and studies

involving a large cohort of unrelated HCM patients have

recommended great caution before assigning a prognostic

significance to any particular mutation. However, the degree of

hypertrophy, age of onset and disease outcome have been shown

to correlate with specific gene mutations. For instance, mutations

in TNNT2 cause only mild hypertrophy but are associated witha poor prognosis and a high risk of SD; mutations in MYBPC3 are

associated with mild disease and onset in middle age or late adult

life; malignant mutations in the cardiac MYH7 cause a severe

form of HCM with early onset, complete penetrance, and

increased risk of SD.7e9

Arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is a geneti-

cally determined disorder with an estimated prevalence in the

general population from 1 in 2000 to 1 in 5000. 10,11 It is usually

inherited as autosomal dominant trait, although the first disease

gene, coding plakoglobin (JUP), was found in the recessive

form, called Naxos disease, which is a cardiocutaneoussyndrome characterized by ARVC, palmoplantar keratosis and

woolly hair.12,13 Desmoplakin (DSP) gene mutations were then

discovered, first in another recessive cardiocutaneous syndrome

(Carvajal disease), also characterized by palmoplantar keratosis,

woolly hair and cardiomyopathy with biventricular involve-

ment,13,14 and then in the classical dominant form of ARVC.15

Plakophilin (PKP-2, another armadillo-protein)16 and two cad-

herins (i.e. desmoglein-DSG2 and desmocollin-DSG2)17,18 were

then found to be defective. Overall ARVC may be depicted as

a cell junction disease and genetic screening can provide

a positive result in up to 50% of familial cases, mostly repre-

sented by PKP-2 and DSP mutations.8e10 As in HCM, different

mutations may be present in the same individual with important

consequences in terms of genetic counselling. Genotypeephe-

notype studies are still limited in ARVC and larger populations

of probands and family members are needed before assigning

any significance to specific genes and gene mutations in terms of

prognosis.

Heredito-familial atrio-ventricular block (Lenegre disease)Heredito-familial atrio-ventricular block (Lenegre disease) is

a peculiar degenerative, non-ischaemic disease of specialized

atrio-ventricular conducting tissue with fibrosis and atrophy

usually involving the bifurcating bundle and proximal bundle

branches.19,20 The disease, when inherited, is due to mutations of

SCN5A, a gene coding sodium channel proteins in the sarco-

lemma.21,22 The working myocardium is normal with only the

specialized conducting tissues involved. As such, it may be

considered a cardiomyopathy of the specialized myocardium at

risk of SD.

Non-structural cardiomyopathies (channelopathies)

In contrast to the aforementioned genetically determinedcardiomyopathies, the inherited non-structural cardiomyopa-

thies (channelopathies) do not exhibit a morphologic

substrate, although the electrical cardiac activity is so

unstable that the individual may be vulnerable to ventricular

fibrillation.6

Long QT syndrome: This is the case in the LQT syndrome

characterized by delayed repolarization of the myocardium, QT

interval prolongation, ventricular tachycardia (torsade des

pointes), syncope and SD which may be the presenting event

in 5e10% of affected patients. It is a genetically heterogenous

disease affecting 1 in 5000 persons, mostly due to potassium

channel gene mutations and more rarely to sodium channelgene mutations.9,23 At least 10 different forms have been

demonstrated in the autosomal dominant variant (Romanoe

Ward syndrome): KCNQ1 (LQT1), HERG (LQT2), SCN5A

(LQT3), ANKB (LQT4), KCNE1 (LQT5), KCNE2 (LQT6), KCNJ2

(LQT7-Andersen), CACNA1 (LQT8-Timothy), CAV3 (LQT9)

and SCN4B (LQT10). Genetic screening of cardiac channel-

encoding genes can provide positive results in up to 75e80% of

LQT syndrome cases. The autosomal recessive LQT syndrome

(Jervell and Lange-Nielsen disease e JLN) has been associated

with homozygous or compound heterozygous mutations in

KCNQ1 (JLN I) and KCNE1 (JLN II), that account for at least

80% of cases.

In contrast to HCM and ARVC, genotypee

phenotype corre-lations have provided important results and are of help in

guiding therapy in LQT syndrome. In particular, swimming and

exertion-induced arrhythmic events are more frequently associ-

ated with mutations in LQT1 gene; in LQT3 patients cardiac

arrest usually occurs during sleep and rest; auditory triggers

tend to be associated with LQT2 patients; and exercise or mental

stress more often triggers ventricular arrhythmias in LQT4

patients.24

Short QT syndrome: Short QT (SQT) syndrome has been

recognized only recently as a separate clinical entity at risk of

palpitations, syncope, ventricular arrhythmias and SD and




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epidemiologic as well as genetic data are still limited. It is

characterized by short QT interval (QTc


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causing mutation in RyR2 or CASQ2 can be identified in up to

70% of familial CPVT patients. The absence of symptoms and

inducible arrhythmias on the stress test in more than one third

of carriers of RyR2 mutations underlies the importance of

genetic screening for the early diagnosis of asymptomatic

carriers and prevention of SD.32

Pathology of cardiomyopathies at risk of sudden death

Hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is reported as the major cause of

SD in athletes in USA in up to 40% of cases.34 Although

geographic and ethnic reasons may justify the different rate of

HCM in Europe vs USA, it is clear in Italy that obligatory sports

pre-participation screening programs may identify affected indi-

viduals for whom the risk of SD is minimized through exclusion

from active sports.35,36

From the morphologic viewpoint, HCM is characterized at

gross examination by either asymmetrical or symmetrical left

ventricular hypertrophy not explained by left ventricular pres-

sure overload.1,37e40

The typical asymmetrical septal variant ofHCM consists of thickening of the basal anterior septum with

subaortic bulging leading to left ventricular outflow tract

obstruction (Figure 2). Septal endocardial plaques may develop

as a consequence of friction due to systolic anterior motion of

a thickened mitral valve apparatus (mirror image impact

lesion).

Hypertrophy in HCM may show wide variation in extent and

distribution. Its extent may vary from mild hypertrophy (13e14

mm) to severe hypertrophy (>30 mm in thickness) and virtually

any portion of the left ventricle can be affected, including mid-

ventricular cavity obstruction and apical hypertrophy. The

symmetrical form of HCM accounts for about one third of casesand is characterized by concentric hypertrophy of the left

ventricle with a small ventricular cavity. Serial echocardiography

during follow-up may show progression to the end-stage

phase with a dilated left ventricular cavity, such as to mimic

DCM.

A frequent component of the HCM phenotype is the presence

of myocardial bridges, or a deep intramyocardial course of the

left anterior descending coronary artery (Figure 3).39,41,42 The

presence of this anomaly has been associated with a higher risk

of SD in HCM patients, although in a recent pathological inves-

tigation we did not find a statistically significant difference

between HCM patients with SD and those with other modes of

death.41

The histopathologic hallmarks of HCM are myocyte hyper-

trophy, disarray, and interstitial fibrosis, which represent the

ideal substrate of inhomogeneous intraventricular conduction

with the potential for reentry phenomena (Figure 4).1,39,40

Histological features of hypertrophic cardiomyopathy. a Fascicular disarray of the myocardium; b disarray of single myocytes; c intramural smallvessel disease with intimal dysplasia; d replacement-type fibrosis.

Figure 4




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Myocyte disarray is a term used to indicate the architectural

disorganization of the cardiomyocytes, either isolated or in

fascicles, with perpendicular or oblique alignment to each other,

in either a pinwheel or herringbone pattern. At ultrastructural

level, spatial disorganization of the myofibrils can be seen within

the myocyte itself. Unfortunately, myocyte disarray per se is not

pathognomonic of HCM, being observed also in congenital heart

diseases and in normal adult hearts, although usually mild andconfined to the ventricular free walleseptal junctions. At higher

magnification, the myocytes are hypertrophied with increased

diameter and show nuclear pleomorphism and hyperchromasia.

Small vessel disease is another histological feature of HCM and

consists of narrowing of the small intramural coronary arteries

due to wall thickening by intimal smooth muscle cell hyperplasia

and medial hypertrophy.39,40

Detailed pathologic studies on subjects dying suddenly have

demonstrated superimposition of ischaemic damage to the dysplastic

myocardium, in the form of either acuteesubacute myocyte necrosis

or chronic injury with large fibrous scars mimicking healed

myocardial infarction (Figures 3, 4d).39 Scars are nowadays detect-

able by non-invasive imaging like late enhancement magnetic

resonance with gadolinium, which has been proposed as an addi-

tional tool for risk stratification in affected people.43

Ischaemic damage may also occur in the absence of significant

epicardial coronary artery disease, small vessel disease as well as

an intramural course of left anterior descending coronary artery

having been implicated. Elevated intramyocardial diastolic

pressure may restrict the intramural arteries during diastolic

coronary filling, thus impairing myocardial perfusion. Thecombination of myocardial disarray and replacement fibrosis has

to be considered the malignant arrhythmogenic substrate in

HCM, with affected individuals at high risk of SD.

The histopathologic diagnosis of HCM implies also

a differential diagnosis with other diseases which can mimic

HCM, with symmetrical or asymmetrical left ventricular

hypertrophy. These include glycogen storage disease, mito-

chondrial cardiomyopathies such as mutations in cardiac

mitochondrial respiratory enzymes or mitochondrial DNA,

and Fabrys disease.40

Finally, when dealing with SD in athletes, HCM must be

differentiated from so-called athletes heart. An enlarged left

ventricular cavity with increased wall thickness up to 13e

14 mm

Arrhythmogenic right ventricular cardiomyopathy (segmental form) in a 26-year-old athlete who died suddenly. a Anterior view of the rightventricular outflow tract which appears mildly dilated; b cross-section of the heart showing the absence of right ventricular free wall aneurysms:note the spotty involvement of the posterior right ventricular free wall; c histology of the right ventricular outflow tract: note the regional loss ofmyocardium with fibro-fatty replacement; d histology of the posterior right ventricular free wall: note the fibro-fatty replacement of themyocardium in the absence of wall thinning.

Figure 5




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is present in more than one third of highly trained athletes and

detailed histology to look for myocardial disarray and other

features may be essential to assess whether we are dealing with

pathological hypertrophy or physiologic adaptation.

Arrhythmogenic right ventricular cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy is the second

most common cause of SD in the young and ranks first amongathletes in the experience of the Veneto Region of Italy.1,2,35,36

Increased awareness of the disease and accuracy of in vivo

diagnosis have led to the identification of a higher number of

affected people with ARVC in recent years, their disqualification

from sport activity with life-style modifications and therapeutic

preventive strategies leading to a reduced rate in SD.44

At pathologic examination, ARVC hearts usually appear

yellowish or whitish on the right side, suggesting fatty or fibro-

fatty replacement. Right ventricular aneurysms, whether single

or multiple are considered a pathognomonic feature of ARVC.

The heart weight is almost normal accordingly to sex and age,

but right ventricular enlargement of variable severity is

a common finding. The right ventricular dystrophic process canbe diffuse or segmental (Figures 5, 6), whereas left ventricular

involvement may not be seen on gross examination, thus

explaining its underestimated prevalence.45e48 The ventricular

septum may be involved in about 20% of cases and the left

ventricle in nearly half of cases, with fibro-fatty or fibrous scars

at the middle and outer layers of the free wall.

The general and forensic pathologist should be aware that

diagnostic criteria for ARVC are not fully established. Lack of

appreciation of this may lead to both over- and underdiagnosis.

Although typical forms present with wall thinning, aneurysms

and chamber dilation, the gross findings for ARVC in the rightventricle may be minimal or even absent in some cases (con-

cealed or segmental forms) and only histopathological exami-

nation will reveal features of typical ARVC. Thus, both ventricles

should be extensively sampled for histology in all cases of SD.

ARVC with biventricular involvement is infrequently found at

autopsy following SD. Diagnosis is more usual either at autopsy

or at cardiac transplantation of people with end-stage congestive

heart failure. In this setting, there are usually multiple right

ventricular aneurysms with a parchment-like appearance of the

free wall. Intracavitary mural thrombi may be present and may

be a source of embolism. Thickening of the endocardium is

a frequent finding, most probably the result of fine thrombus

deposition and organization, usually in conjunction with aneu-rysms and/or severe dilatation.

Twohistological ARVC variants havebeen identifiedbasedupon

the prevalent type of tissue accompanying progressive myocardial

Arrhythmogenic right ventricular cardiomyopathy (diffuse form) in a 14-year-old boy who died suddenly during a soccer play. a Anterior view of theheart: note the yellow appearance and the right ventricular outflow tract aneurysm; b cross-section of the heart showing the presence of anteriorand posterior aneurysms as well as patchy involvement of the left ventricular free wall, postero-lateral region; c histology of the aneurysmalpostero-inferior wall: note the loss of myocardium with fibro-fatty replacement; d histology of the left ventricular free wall in the areas of fibro-fatty replacement.

Figure 6




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thinning. These are fatty and fibro-fatty ARVC.45e47 In the fatty

variant, adipose tissue extends to endocardium (transmural infil-

tration) and wall thickness may be normal or increased (pseudo-

hypertrophy). However, fibrous tissue, usually focal, is always

present and indeed is fundamental for the genesis of arrhythmias. It

may be detectable only at higher magnification and can be over-

looked with limited histologic sampling. In the fibro-fatty variant,

the wall is thinner, parchment-like and translucent, conforming tothe saccular aneurysms described as occurring in the so-called

triangle of dysplasia (i.e. right ventricular inflow, apex, outflow).

This is pathognomonic of ARVC.

In both histologic variants there is myocyte death and

degeneration as well as myocardial substitution by replacement-

type fibrosis and fatty tissue, indicating an injury and repair

process (Figure 7). In two thirds of cases, the fibro-fatty variant

shows inflammatory cell infiltrates (CD43, CD45RO and CD3

positive T-lymphocytes, plus some CD68 positive macrophages)

associated with focal myocyte necrosis, all features consistent

with an inflammatory pathogenesis.46,49 In the setting of

sporadic cases, these findings suggest that ARVC is a sequela

of myocarditis, like some forms of non-familial DCM.Massive fatty infiltration of the right ventricle, without any

evidence of fibrosis and myocyte degeneration, should not be

regarded as ARVC and its role as a cause of SD is question-

able.50 In this condition, myocytes are pushed apart rather

than replaced, and appear normal at histology. In contrast,

ARVC consistently shows degenerative changes of the myo-

cytes and nuclei, often resembling those observed in DCM.

Failure to take account of this difference runs the risk of an

increase in false-positive diagnosis of ARVC at autopsy with

considerable legal and ethical implications for families and

pathologists.

As discussed above, advances in molecular genetics and

phenotypee

genotype correlative studies have shown that thepathology of ARVC encompasses a much broader spectrum than

previously thought. In particular, we must recognize that the left

ventricle is commonly involved in ARVC and it should be care-

fully studied through pathologic investigation, thus justifying

a recent suggestion to employ the term arrhythmogenic cardio-

myopathy instead of ARVC.10

Lenegre disease

In contrast to ischaemic atrio-ventricular (AV) block due to post-

infarct scarring, which usually affects elderly people and

involves the branching AV bundle and bundle branches in the

setting of inflammation or fibrosis of the crest of the ventricular

septum, familial AV block due to Lene`

gre disease shows selectivefibrosis and atrophy of the specialized tissue of right and left

bundle branches, sparing the working myocardium.19,20 It is

a form of inherited cardiomyopathy confined to the specialized

myocardium and as such should be considered a cardiomyop-

athy of the conducting tissues.6,21,22

Histological features of arrhythmogenic right ventricular cardiomyopathy. a residual myocytes entrapped within fibrous and fatty tissue; b adi-pogenesis in areas of myocyte injury; c inflammatory infiltrates within fibro-fatty areas; d myocyte contraction band necrosis.

Figure 7




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I

II

III

aVR

aVL

aVF

V1

V2

V3

V4

V5

V6

a

cb

Sudden death in a 48-year-old man with syncopal episodes due to non-ischaemic AV block (Lenegre disease). a 12 lead ECG: note the intermittent,complete AV block with atrio-ventricular dissociation; b serial section examination of the conducting system reveals discontinuity between the Hisbundle and the left bundle branch; c the right bundle branch, along its intramyocardial course, appears disrupted by fibrous tissue, whereas thesurrounding working myocardium is normal.

Figure 8




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The site of AV block lesions is the His bundle and bundle

branches in nearly 80% of cases. Histology by serial sections

discloses elective scleroatrophy with discrete discontinuity of

the left bundle branch at its origin from the bundle of

His and interruption of the right bundle branch, both in

its intramyocardial and subendocardial course by fibrosis,

all surrounded by intact working myocardium around

(Figure 8).The disease may start as an isolated, apparently benign

incomplete right bundle branch and then spreads to the left

bundle branch resulting into a bilateral bundle branch block and

eventually in third degree (complete) AV block. The onset of the

ventricular arrhythmias may be sudden, accounting for the

classical signs and symptoms of Morgagni-Adams-Stoke

syndrome: dizziness, syncope, epileptiform seizures or even

cardiac arrest and sudden death.

As previously stated, Lenegre disease was linked to mutations

of sodium channel gene SCN5A. Oddly enough, the same

defective gene is involved also in congenital LQT syndrome type

3 and Brugada syndrome. The latter, in contrast to Lenegre

disease, exhibits non-ischaemic ST segment elevation ona resting ECG, however it frequently presents with first-degree

AV block and right bundle branch block, with fibrosis of bundle

branches at histology.29 Cases have been reported of isolated AV

block or isolated ST segment elevation in the same family with

SCN5A mutations.

Non-structural cardiomyopathies at risk of SD: arrhythmic

SD with normal heart

There are arrhythmic SDs in which the heart is structurally

normal after gross and extensive histological investigation

(mors sine materia or unexplained SD).1,2,9 These cases

represent up to 20% of SD in young people and are often due to

inherited channelopathies (i.e. cardiomyopathies with pure

electric dysfunction),6 due to defective proteins of sodium and

potassium ion channels at the sarcolemma level or receptors for

intracellular calcium release.

When performing an autopsy of an SD case in which the

heart is normal, the availability of ECG tracings performed

during lifee

both at rest and during efforte

a detailed personaland family history and knowledge of the precise circumstances

of death (at rest, during effort or emotion, other triggers, etc.)

are crucial items of information in reaching the correct diag-

nosis (Figure 9). It is essential that first-degree relatives should

always undergo clinical screening and subsequent genetic

testing.

In these cases, autopsy may represent the first and last

opportunity to make the proper diagnosis. The employment of

molecular biology techniques even at postmortem may be of help

in solving the puzzle of mors sine materia and for this reason

it has been recommended in the recent guidelines for autopsy

investigation of SD proposed by the Association for European

Cardiovascular Pathology.51

Proper sampling is crucial to allowpostmortem DNA analysis:52 for these purposes, 10 ml of EDTA

blood and 5 g of heart and spleen tissues should be either frozen

and stored at 80 C, or alternatively stored in RNA later at 4 C

for up to 2 weeks.

Recently, a molecular testing, carried out in a large cohort of

unexplained cardiac SDs, achieved a diagnosis in 34% of cases

which would have remained otherwise unexplained. Gene

mutations included 14% RyR2, 16% KCNQ1 or KCNH2, and 4%

SCN5A.53 However, the remaining 66% resulted negative, which

means that two third of unexplained SD are still idiopathic in

search of a name.

I

a b

SD

(32)NoA

NoASD

(16)

NoA

419

A

C

Arg

T

Trp

T C

420

N G G

421

A G C

NoA

NoANoANoA

*

**

* *

*

NoANoANoANoASD

(20)

SynSD

(14)

NoA

II

III

IV

Sudden death with normal heart at autopsy after gross and histologic examination in two brothers who died suddenly on effort and on emotion,

respectively. a The genealogical tree shows the two brothers (IV generation, 14 and 20 years old) who died suddenly who had normal heart atautopsy. Genetic screening revealed RyR2 gene mutations in keeping with catecholaminergic polymorphic ventricular tachycardia; b a missensemutation of RyR2 gene resulted in DNA change of adenine into guanidine which, on its turn, resulted in a change of tyrosine into cysteine

aminoacid in the protein (modified from Bauce et al, 32).

Figure 9




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Conclusions

As stated in the recent European guidelines for autopsy investi-

gation of SD, the final report of a SD case should conclude with

a clear clinico-pathological synthesis (epicrisis). In the majority

of SDs, a pathological cause can be identified, albeit with varying

degrees of confidence and wherever possible, the most likely

underlying cause should be stated. However, the pathologist

must also admit that many SD cases present with a structurallynormal heart, after excluding diseases of the coronary arteries,

myocardium, valves, great vessels and conduction system. The

pathologists mission is to pursue the correct diagnosis and,

when dealing with a genetic disease, trigger a widespread

investigation of first-degree family members. A collaborative

multidisciplinary approach by the cardiologist, geneticist,

pathologist, sport physician and general practitioner is manda-

tory. SD may be the first and last clinical presentation of the

underlying inherited cardiomyopathy, either structural (HCM,

ARVC) or non-structural (channelopathies), and in this setting

the only medical examination is that of the pathologist. The

general and forensic pathologists, who examine most of the

index cases, must do a thorough cardiac examination informed

by national and international protocols. A precise pathological

diagnosis of the underlying heart disease, which also takes

advantage of molecular biology techniques, will be the source of

vital information for those left behind. A

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Practice points

C Cardiomyopathies account for about one half of sudden death

(SD) in the young. Among them, genetically determined

cardiomyopathies include hypertrophic (HCM) and arrhyth-

mogenic right ventricular (ARVC) as well as primary electrical

disorders of the myocardium in the absence of structural

abnormalities (channelopathies).C HCM is most frequently represented by the asymmetrical

septal variant of HCM, with/without a subaortic endocardial

plaque and mitral valve thickening, although a wide spectrum

of degree and distribution of hypertrophy is seen. The histo-

logical markers are myocyte disarray, hypertrophy, and inter-

stitial fibrosis. Small vessel disease and replacement-type

fibrosis are also frequent findings.

C ARVC is characterized by massive or partial replacement of

myocardium by fibroadipose tissue, which may involve the left

ventricle. The morphological spectrum of ARVC is not yet fully

defined. However, fatty infiltration of the right ventricle,

without any evidence of fibrosis and myocyte degeneration,

cannot be regarded as ARVC.

C When performing an autopsy of SD, a precise pathological

diagnosis of the underlying cardiomyopathy is mandatory

taking into account the implications for first-degree family

members. The availability of ECG tracings, personal and family

history and knowledge of the circumstances of death are

crucial in reaching the final diagnosis.

C A normal heart after gross and histological examination is

found in up to 20% of SD in young people, often due to

inherited channelopathies. In this setting use of molecular

biological techniques may be of help, and proper sampling to

allow postmortem DNA analysis is recommended, as detailed

in the recent guidelines for autopsy investigation of SD by the

Association for European Cardiovascular Pathology.



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