Download Genotype-phenotype assessment in autosomal recessive

Journal of the American College of Cardiology
© 2001 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 38, No. 5, 2001
ISSN 0735-1097/01/$20.00
PII S0735-1097(01)01568-6
Cardiomyopathy
Genotype-Phenotype Assessment
in Autosomal Recessive Arrhythmogenic
Right Ventricular Cardiomyopathy
(Naxos Disease) Caused by a Deletion in Plakoglobin
Nikos Protonotarios, MD,*† Adalena Tsatsopoulou, MD,* Aris Anastasakis, MD,† Elias Sevdalis, MD,†
Godfrina McKoy, PHD,‡ Kostas Stratos, MD,† Kostas Gatzoulis, MD,† Kostas Tentolouris, MD,†
Chara Spiliopoulou, MD,§ Demos Panagiotakos, PHD,† William McKenna, MD, FRCP, FACC,‡
Paulos Toutouzas, MD, FACC†
Naxos and Athens, Greece; and London, United Kingdom
The purpose of this study was to examine the genotype-phenotype relation with respect to
penetrance, age and severity of expression, disease progression and prognosis in a recessively
inherited arrhythmogenic right ventricular cardiomyopathy (ARVC).
BACKGROUND Naxos disease is a recessively inherited ARVC caused by a mutation in the gene encoding
plakoglobin (cell adhesion protein) in which the cardiac phenotype is associated with
palmoplantar keratoderma and woolly hair.
METHODS
Twelve families with Naxos disease underwent cardiac and molecular genetic investigation.
Serial cardiac assessment with annual resting 12-lead and 24-h ambulatory electrocardiogram
(ECG) and two-dimensional echocardiography was performed during 1 to 16 years, median
7 ⫾ 6 years in all 78 surviving members.
RESULTS
Twenty-eight surviving members were homozygous and 40 were heterozygous for the
mutation. All adults who were homozygous (n ⫽ 26) fulfilled the diagnostic criteria for
ARVC, the youngest by the age of 13 years. In eight who were heterozygous, minor ECG
or echocardiographic abnormalities were observed. Of the 26 subjects who were affected
homozygotes, 92% showed ECG abnormalities, 92% ventricular arrhythmias, 100% right
ventricular structural alterations and 27% left ventricular involvement. During follow-up
(10 ⫾ 6 years), 16 (62%) developed structural progression, 12 (46%) arrhythmic events and
7 (27%) heart failure. The annual disease-related and sudden death mortality was 3% and
2.3%, respectively.
CONCLUSIONS Autosomal recessive ARVC caused by a mutation in plakoglobin was 100% penetrant by
adolescence. Affected subjects who were homozygous experienced progressive disease with
adverse prognosis. A minority of subjects who were heterozygous showed minor ECG/
echocardiographic changes, but clinically significant disease did not develop. (J Am Coll
Cardiol 2001;38:1477– 84) © 2001 by the American College of Cardiology
OBJECTIVES
Arrhythmogenic right ventricular cardiomyopathy (ARVC)
is a heart muscle disorder causing life-threatening ventricular arrhythmias, heart failure and sudden cardiac death.
The pathologic hallmark of the disease is the progressive
replacement of myocardial cells by fat and fibrous tissue
(1–3). Right ventricular involvement predominates, but left
ventricular involvement may also occur with disease progression (4). In 1977 Guy Fontaine presented the first
clinical characterization of ARVC under the name of
“arrhythmogenic right ventricular dysplasia” (5). Since then,
sporadic and familial forms of the disease have been described (6). Familial disease is usually autosomal dominant
From the *Yannis Protonotarios Medical Center, Naxos, Greece; †Department of
Cardiology, University of Athens, Athens, Greece; ‡Department of Cardiological
Sciences, St. George’s Hospital Medical School, London, United Kingdom; and the
§Department of Forensic Medicine and Toxicology, University of Athens, Athens,
Greece. Supported by Yannis Protonotarios Medical Center, Ltd. Drs. McKoy and
McKenna were supported by a grant from the British Heart Foundation.
Manuscript received February 28, 2001; revised manuscript received June 11, 2001,
accepted July 11, 2001.
(7), and six gene loci have been identified (8 –13). Disease is
claimed to be sporadic in up to 70% of patients (14).
Published pedigrees, however, show 30% to 50% nonpenetrance, and, thus, without knowledge of disease-causing
genes, accurate assessment of the proportion of sporadic
versus familial ARVC is problematic. The long-term
follow-up of 37 families with autosomal dominant disease
has been reported (15). These reveal an overall favorable
prognosis, though other reports emphasize the initial presentation of ARVC with sudden death, particularly in
young, apparently healthy athletes (2,16,17).
In 1986 we reported an autosomal recessive form of
ARVC from the Aegean island of Naxos (18). In Naxos
disease, the cardiac disorder was always associated with diffuse
palmoplantar keratoderma and woolly hair and was apparent
from infancy. In 1998 the gene locus for Naxos disease was
mapped to 17q21 (19), and recently we identified the responsible gene mutation, a deletion in plakoglobin (20), which is an
important constituent of the cell-to-cell junction.
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Protonotarios et al.
Genotype-Phenotype Assessment in Naxos ARVC
Abreviations and Acronyms
ARVC ⫽ arrhythmogenic right ventricular
cardiomyopathy
CI
⫽ confidence interval
ECG ⫽ electrocardiogram
LBBB ⫽ left bundle branch block
VT
⫽ ventricular tachycardia
The identification of a disease-causing gene in autosomal
recessive ARVC permits examination of the genotypephenotype relation with respect to penetrance, age and
severity of expression, progression of disease and prognosis.
METHODS
Study population. Twelve Naxos disease families identified since 1984 were evaluated. All living family members
underwent cardiac and molecular genetic investigation.
Initial cardiac assessment included a detailed history of
cardiac events, physical examination, resting 12-lead electrocardiogram (ECG), 24-h ambulatory ECG and twodimensional echocardiography. These investigations were
performed every 12 months during a follow-up period of
7 ⫾ 6 years (range: 1 to 16 years). Follow-up was more
frequent in those with documented or suspected arrhythmia
or when structural progression was detected.
Additionally, signal-averaged ECG (n ⫽ 34), electrophysiologic studies (n ⫽ 10), endomyocardial biopsies (n ⫽
5) and surgical biopsies during antiarrhythmic surgery (n ⫽
2) were performed. Postmortem cardiac biopsies were available in two patients with the informed consent of their
families. The diagnosis of ARVC was based on European
Society of Cardiology/International Society and Federation
of Cardiology guidelines (14).
Genetic study. Genomic DNA was extracted from blood
samples; the procedure was followed by amplification of a 2
kilobase (kb) genomic region surrounding the deletion site
(Pk2157del2, where the mutation appears by the deletion of
two bases) using polymerase chain reaction with specifically
designed primers (20). Because the mutation destroys a
Bst01 restriction site, we could verify the presence of the
mutation by restriction enzyme digestion. The results were
confirmed in 1.5% agarose gel depending on the number
and the molecular weight of the DNA bands that are
produced by Bst01 cleavage.
Electrocardiography. Standard 12-lead ECG was recorded at rest (25 mm/s, 10 mm/mV and 20 mm/mV).
QRS complex duration was measured by a caliper. Epsilon
waves were included in these measurements. The difference
between the widest QRS complex in leads V1, V2 or V3
minus that in V6 was estimated (QRS dispersion). Extension of inverted T-waves (including flattened T) in the
precordial leads was noted. A 24-h ambulatory ECG was
recorded on an outpatient basis. The number of ventricular
extrasystoles and the number, rate and duration of episodes
JACC Vol. 38, No. 5, 2001
November 1, 2001:1477–84
of ventricular tachycardia (VT) (ⱖ3 consecutive ventricular
complexes at a rate of ⱖ120 beats/min) were recorded.
Signal-averaged ECG was performed for assessment of
arrhythmic risk from a three-channel 24-h ambulatory
ECG during sinus rhythm (21). Time-domain analysis was
obtained in each patient using two band pass filters at 40 to
250 Hz and 25 to 250 Hz (22). Initial evaluations were
performed off cardioactive medication.
Echocardiography. Echocardiography with a 2.5 MHz
transducer was performed by the same investigator (N. P.).
Measurements of the right ventricular dimensions in twodimensional echocardiographic recordings were selected
from the outflow tract on parasternal long-axis view and
from the inflow tract on apical four-chamber view according
to the protocol by Foale et al. (23). Normal limits (mean ⫾
2 SD) were defined by echocardiographic assessment of 80
unrelated healthy subjects (40 men, 40 women) from Naxos
island with a mean age of 39 years (range: 13 to 73 years).
Abnormalities including hypokinetic, akinetic or dyskinetic
areas, diastolic bulging and trabecular disarrangement were
documented (24,25).
Definitions. Syncope was defined as a sudden and brief
loss of consciousness associated with a loss of postural tone,
from which recovery is spontaneous (26). Ventricular tachycardia was defined as sustained when lasting more than 30 s.
Ventricular extrasystoles were noted on resting 12-lead
ECG and were characterized as frequent when they were
more than 1,000/24 h on 24-h ambulatory ECG. Structural
abnormalities of the right ventricle were classified as major:
severe dilation (more than 3 SD from normal values), diffuse
hypokinesia and localized aneurysms, and minor: mild
dilation (2 to 3 SD from normal values) and regional
hypokinesia (14). Structural progression was defined as
progressive alteration in ventricular dimensions and/or wall
motion abnormalities during serial echocardiographic evaluation. Severe heart failure was defined as New York Heart
Association functional class III or IV accompanied by
jugular venous engorgement, hepatomegaly or ascites. Sudden cardiac death was defined as unexpected death occurring in ⬍1 h from the onset of symptoms. Cardiovascular
collapse occurring in the context of severe heart failure was
not regarded as sudden death.
Statistical analysis. All values from quantitative variables
are presented as mean ⫾ 1 SD and from qualitative variables
as relative frequency and counts. To screen out significant
covariates related to sudden cardiac death, univariate analysis was applied on all those who were homozygous gene
carriers on the assumption that they were potentially at risk
for the adverse outcome. The relation between each factor
and sudden death was evaluated using contingency tables,
logistic regression analysis and nonparametric methods.
Kaplan-Meier curve was produced to reveal the survival as
well as the event-free rate. Reported p values are two-sided,
exact and compared to a significant level of 5%. Statistical
calculations were performed using STATA 6 (STATA
Corp., College Station, Texas).
JACC Vol. 38, No. 5, 2001
November 1, 2001:1477–84
Figure 1. Section of right ventricular apex from the heart of a 20-year-old
girl with Naxos disease who died suddenly. Low magnification (⫻2.5)
demonstrates massive replacement of mediomural and subepicardial layers
by fatty tissue. Subendocardial layers are infiltrated by fibrosis.
RESULTS
Genotype and diagnosis of ARVC. Seventy-eight living
family members belonging to 12 nuclear families (7 ⫾ 4
members per family, range: 1 to 12) were identified.
Systematic questioning for premature cardiovascular symptoms or death identified two female probands with the
cutaneous Naxos disease phenotype who were asymptomatic
before sudden death at the ages of 14 and 52 years.
Molecular genetic investigation revealed 28 subjects who
were homozygous for the plakoglobin mutation (14 men, 14
women) age 33 ⫾ 19 years (range: 1 to 74 years), 40 carriers
who were heterozygous (21 men, 19 women) age 42 ⫾ 19
years (range: 7 to 86 years) and 10 who were homozygous
for the normal allele (5 men, 5 women) age 33 ⫾ 22 years
(range: 8 to 80 years).
All of the subjects who were homozygous had diffuse
palmoplantar keratoderma and extremely woolly hair apparent from infancy. Noninvasive cardiac assessment demonstrated abnormalities, which fulfilled the established diagnostic criteria for ARVC in 26 (affected subjects who were
homozygous). In particular, 13 subjects fulfilled one major
plus at least two minor criteria while the other 13 fulfilled at
least two major criteria. Their age at diagnosis of ARVC
was 36 ⫾ 17 years (range: 13 to 74 years). One of the
subjects who was seven years old at initial examination, did
not meet the diagnostic criteria until the age of 18. Diagnosis was supported histologically in eight subjects: from
endomyocardial biopsies in five subjects, from surgical
biopsies in two subjects and from autopsy in one subject
(Fig. 1). Two children did not fulfill the criteria for
diagnosis. One of the children, a five-year-old child, had
frequent ventricular extrasystoles of left bundle branch block
(LBBB) pattern on the 24-h ambulatory ECG but resting
12-lead ECG; signal-averaged ECG and two-dimensional
echocardiography were within normal limits. The other
Protonotarios et al.
Genotype-Phenotype Assessment in Naxos ARVC
1479
child, a one-year-old, showed neither arrhythmias, electrocardiographic nor echocardiographic abnormalities.
Eight of the subjects who were heterozygous carriers
showed minor cardiac abnormalities; however, none of them
fulfilled the criteria for diagnosis of ARVC. Four subjects
had T-wave inversion in V1 and V2; three had mild right
ventricular dilation, and one had T-wave inversion from V1
to V3 and mild right ventricular outflow tract dilation. Five
of them also had the woolly hair phenotype. Palmoplantar
keratoderma, ventricular arrhythmias and late potentials on
signal-averaged ECG were not observed in any of the
subjects who were heterozygous carriers. None of 10 who
were homozygous for the normal allele had skin or hair
abnormalities; one had T-wave inversion in V1 and V2, and
another one had mild right ventricular inflow tract dilation.
Late potentials were not observed in signal-averaged ECG
(n ⫽ 5), and ventricular arrhythmias were not recorded in
24-h ambulatory ECG. During follow-up none of the
subjects who were heterozygous carriers or those who were
homogygous for the normal allele developed symptoms,
arrhythmias and ECG or echocardiographic abnormalities.
Cardiac phenotype in the 26 affected homozygotes. ELECTROCARDIOGRAPHY AND ECHOCARDIOGRAPHY. Resting
ECG was abnormal in 24 of the 26 affected patients (92%).
Twenty patients had inverted T waves in leads V1 to V3 or
across the precordial leads; 19 had QRS complex prolongation (⬎110 ms) in leads V1, V2 or V3; 9 had complete or
incomplete right bundle branch block, and 11 had epsilon
waves (Fig. 2). QRS dispersion more than 20 ms existed in
17 patients (Table 1). Frequent ventricular extrasystoles of
LBBB configuration were recorded in 24 patients (92%). All
patients who were submitted to signal-averaged ECG (n ⫽
10) fulfilled the criteria for late potentials. Right ventricular
structural alterations were observed on two-dimensional
echocardiography in all patients; there were minor alterations in seven (27%) and major alterations in 19 (73%)
(Fig. 3). Right ventricular trabecular disarrangement and
irregularly shaped echodense muscular bands were detected
in 23 patients. Seven patients (27%) had left ventricular wall
motion abnormalities; four of them showed regional hypokinesia (two apical, two posterior wall), and three showed
diffuse hypokinesia of the left ventricle. During follow-up,
eight patients (31%) showed ECG changes including prolongation of QRS complex (n ⫽ 6) and extension of T-wave
inversion in contiguous precordial leads (n ⫽ 3). Serial
echocardiographic studies revealed progression of the initially detected right ventricular abnormalities in 16 patients
(62%). In 10 of the patients, appearance or worsening of left
ventricular involvement was also observed (Table 1).
Symptoms appeared in
18 of the 26 patients. The initial presenting symptom was
syncope in 15, sustained palpitation in 2 and fatigue in 1 at
age 31 ⫾ 18 years (range: 12 to 68 years) (Table 1). During
follow-up (10 ⫾ 6 years, range: 1 to 16 years), arrhythmic
events occurred in 12 of the 26 patients (46%). Oral
CLINICAL EVENTS AND OUTCOME.
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Genotype-Phenotype Assessment in Naxos ARVC
JACC Vol. 38, No. 5, 2001
November 1, 2001:1477–84
32.71), p ⫽ 0.017. Other variables such as antiarrhythmic
treatment (p ⫽ 0.171), QRS dispersion ⱖ40 ms (p ⫽
0.178), episodes of sustained VT (p ⫽ 0.427) and family
history of sudden death (p ⫽ 0.944) were not significantly
related to sudden cardiac death. Kaplan-Meier curves for
cumulative survival and event-free survival of all subjects
who were homozygous are indicated in Figure 4. By the age
of 35 years, the cumulative survival was 74% and the
event-free survival 53%.
DISCUSSION
Figure 2. Recordings from baseline 12-lead electrocardiogram (precordial
leads) in seven patients with Naxos disease. There is T-wave inversion from
V1 to V3 or V4 or V5, QRS complex prolongation, complete or incomplete
right bundle branch block pattern and epsilon waves (C4, C5, C18 and C20).
Elevation (1 mm) of the ST segment in leads V1 to V4 is observed in
Patient 3. Patient 5 has a pattern resembling Brugada’s syndrome.
antiarrhythmic treatment was applied in 13 patients for
69 ⫾ 34% of their follow-up (Table 1). Two patients were
operated on at the beginning of follow-up; an arrhythmogenic focus from the right ventricular free wall was
successfully excised under endocardial and epicardial electrophysiologic mapping guidance. In three patients an
antitachycardia pacemaker defibrillator was implanted. In
two of those patients episodes of VT were terminated by
antitachycardia pacing (n ⫽ 6) or low energy synchronized
cardioversion (n ⫽ 7) while they were on amiodarone (200
to 400 mg daily). Seven patients (27%) developed heart
failure; four of them suffered severe heart failure and were
considered for heart transplantation (Table 1). Symptoms of
heart failure were associated with severe right ventricular
deterioration in two patients and biventricular deterioration
in five patients. Eight patients died prematurely of a cardiac
cause (six suddenly and two of heart failure). Two patients
who died suddenly had discontinued amiodarone against
medical advice. The mean age at death was 32 ⫾ 13 years
(range: 17 to 53 years). The annual disease related and
sudden death mortality was 3% and 2.3%, respectively.
Survival analysis. The univariate risk ratios for the significant factors related to adverse outcome were: episodes of
syncope 5.89 (95% confidence interval [CI]: 1.12 to 45.43),
p ⫽ 0.037; left ventricular involvement 6.48 (95% CI: 1.94
to 45.74), p ⫽ 0.046; early (age ⬍35 years) onset of
symptoms 6.87 (95% CI: 1.82 to 29.91), p ⫽ 0.036); early
(age ⬍35 years) structural progression 8.45 (95% CI: 3.08 to
The identification of the causative gene in these autosomal
recessive ARVC families provided the opportunity to examine the genotype-phenotype relation with respect to
penetrance, age and degree of expression, progression of
disease and prognosis.
Penetrance and clinical expression of ARVC. In published pedigrees of families affected by dominant ARVC,
approximately 50% of family members are affected (15).
However, without knowledge of disease causing genes,
estimation of penetrance is problematic. In this study, all
subjects who were homozygous for the mutation presented
the skin and hair phenotype from early infancy, while the
diagnostic cardiac abnormalities were 100% penetrant by
adolescence. The presence of the cutaneous phenotype
enabled identification of children who would go on to
develop ARVC. Children were usually asymptomatic showing only a few minor right ventricular abnormalities or
asymptomatic ventricular arrhythmias by the age of five
years yet not fulfilling the conventional criteria for clinical
diagnosis. In the dominant form, childhood disease is
recognized (15). The symptomatic presentation of Naxos
ARVC was usually with syncope during adolescence. At the
time of first event, ARVC presented with the simultaneous
development of ECG and echocardiographic abnormalities
fulfilling at least one major of the established criteria. In the
dominant form, however, echocardiographic abnormalities
appeared to be of greater diagnostic sensitivity than changes
on resting ECG, while 48% of patients fulfilled only minor
criteria (15). Among the carriers who were heterozygous, some
showed minor phenotypic features of Naxos disease consisting
of woolly hair, minor ECG abnormalities and mild right
ventricular dilation, not fulfilling the criteria for ARVC.
Progression and prognosis of ARVC. Arrhythmogenic
right ventricular cardiomyopathy is known to be a progressive heart disease. In this study, structural progression on
echocardiography was detected in 62% of patients, of whom
50% showed ECG progression. Echocardiography was
more sensitive in detecting the progression of heart disease
(27). Progression was usually accompanied by the development
of clinical events. When the heart disease involved both
ventricles, ARVC was difficult to differentiate clinically from
dilated cardiomyopathy (28). Heart failure was observed in
27% of patients—a phenomenon—which is similarly common
in most long-term follow-up studies (28 –31).
JACC Vol. 38, No. 5, 2001
November 1, 2001:1477–84
Table 1. Clinical Details of 28 Homozygotes With Naxos Disease
Initial Evaluation
Case
Age
(yrs)
QRSD
(ms)
T-Wave
Inversion
M
M
F
M
M
F
F
M
M
F
M
F
F
F
M
M
M
M
F
M
F
F
F
F
M
F
F
M
7
17
32
29
17
41
36
43
35
32
74
61
56
49
40
60
26
19
16
47
45
15
17
58
13
5
39
1
0
40
0
40
40
20
20
0
40
40
40
20
20
60
20
40
40
40
40
60
20
40
40
60
40
0
40
20
V1–V3
V1–V6
V1–V4
V1–V4
V1–V3
V1–V5
V1
0
V1–V4
V1–V3
V1–V5
V1–V4
V1–V3
V1–V6
V1–V5
V1–V4
V1–V6
V1–V6
0
V1–V4
V1–V3
V1–V2
V1–V3
V1–V6
V1–V4
V1–V2
V1–V2
V1–V2
17
42
29
18
48
(SYNC)
(SYNC)
(SYNC)
(SYNC)
(SYNC)
32 (SPT)
48 (fatigue)
68
68
43
29
18
(SYNC)
(SYNC)
(SYNC)
(SYNC)
(SYNC)
21 (SYNC)
21 (SPT)
15 (SYNC)
20 (SYNC)
15 (SYNC)
12 (SYNC)
Follow-Up
Clinical Events
Antiarrhythmic
Treatment
0
RVT, HF (FC IV)
RVT, VT/ICD
RVT, VT/ICD, HF (FC II)
RVT, HF (FC III)
SYNC/NSVT, HF (FC III)
0
RVT, HF (FC II)
Fatigue, chest pain
0
0
SYNC/NSVT
Recurrent SYNC/VES
RVT
Recurrent SYNC/VES
0
0
RVT, HF (FC IV)
HF (FC II)
0
0
SYNC/VES
0
0
0 (VT on EP)
0
0
0
0
AMIO (EP)
AMIO (EP), ICD
SOT, AMIO (EP), ICD
AS, AMIO (EMP)
AMIO (EMP)†
0
AMIO (EP)
0
0
Quinidine (EP)
AMIO (EMP)
AMIO (EMP)
SOT (EP)
0‡
0
AMIO (EMP)†
AS, AMIO (EMP)
0
0
0
0‡
ICD
0
AMIO (EP)
0
0
0
Structural
Progression
RV*
RV*
RV, LV
RV, LV
RV*
RV, LV
0
RV, LV
RV, LV
0
0
RV
RV
RV
RV, LV
0
RV, LV*
RV, LV*
RV, LV*
0
0
RV, LV*
0
0
0
0
0
0
Outcome
Duration
(yrs)
Remains ASYMP
Death of HF
ASYMP (last 1 year)
Death of NCC
Sudden death
Sudden death
Remains ASYMP
HF (FC II)
Sudden death
Remains ASYMP
ASYMP (last 13 years)
ASYMP (last 7 years)
ASYMP (last 8 years)
Death of NCC
ASYMP (last 1 year)
Remains ASYMP
Sudden death
Death of HF
Sudden death
Remains ASYMP
Remains ASYMP
Sudden death
ASYMP (last 6 years)
Remains ASYMP
ASYMP (last 3 years)
Remains ASYMP
Remains ASYMP
Remains ASYMP
16
11
16
15
11
12
15
13
15
16
7
16
15
12
15
12
1
14
1
8
4
5
4
2
2
2
2
3
*Progression detected before the age of 35 years; †discontinued; ‡refused to follow treatment.
AMIO ⫽ amiodarone; AS ⫽ antiarrhythmic surgery; ASYMP ⫽ asymptomatic; EMP ⫽ empirically; EP ⫽ electrophysiologic study; FC ⫽ NYHA functional class; HF ⫽ heart failure; ICD ⫽ implantable cardioverter defibrillator;
LV ⫽ left ventricle; NCC ⫽ noncardiac cause; NSVT ⫽ nonsustained ventricular tachycardia; QRSD ⫽ QRS dispersion; RV ⫽ right ventricle; RVT ⫽ recurrent sustained ventricular tachycardia; SOT ⫽ sotalol; SPT ⫽ sustained
palpitation; SYNC ⫽ syncope; VES ⫽ frequent ventricular extrasystoles; VT/ICD ⫽ sustained ventricular tachycardia terminated by implantable defibrillator; 0 ⫽ none.
Protonotarios et al.
Genotype-Phenotype Assessment in Naxos ARVC
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Gender
Age (yrs)
at First
Symptom
1481
1482
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Genotype-Phenotype Assessment in Naxos ARVC
JACC Vol. 38, No. 5, 2001
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Figure 3. Two-dimensional echocardiographic images recorded from a patient with Naxos disease. (a) An aneurysm of right ventricular outflow tract (white
arrows) is exhibited by a modified parasternal long-axis view. (b) An aneurysm of posterior wall of the right ventricle just below the tricuspid valve (white
arrows) is exhibited by a subcostal four-chamber view. LA ⫽ left atrium; LV ⫽ left ventricle; RA ⫽ right atrium; RV ⫽ right ventricle; RVOT ⫽ right
ventricular outflow tract; TV ⫽ tricuspid valve.
In this study, the annual disease-related and sudden death
mortality were 3% and 2.3%, respectively, which is higher
than that reported in other ARVC series (15,28 –32). The
worse prognosis in recessive ARVC is an analogous phe-
nomenon to that observed in recessive forms of dilated
cardiomyopathy (33). Risk stratification in ARVC remains
a difficult task because of the small number of events, which
limits multivariate regression analysis to assess factors re-
Figure 4. Kaplan-Meier survival curves for cumulative survival (continuous line) and event-free survival (dotted line) among the subjects who were
homozygous.
JACC Vol. 38, No. 5, 2001
November 1, 2001:1477–84
lated to adverse outcome. In this study, the univariate
analysis revealed that episodes of syncope, especially in the
young; early structural progression (age ⬍35 years) and left
ventricular involvement were the best predictors of sudden
cardiac death. The adverse prognosis of ARVC in the young
has also been described in the dominant form (34).
Genotype and pathogenesis of ARVC. A deletion mutation in the gene encoding plakoglobin has been identified to
underlie this recessive ARVC (20). A recent study demonstrated a ryanodine receptor mutation in a subgroup of
patients with dominant ARVC responsible for exerciseinduced polymorphic VT and sudden death (35). Recently too,
another cytoskeletal protein colocalizing with plakoglobin at
the cardiac intercalated disk has been involved in pathogenesis
of adult mice right ventricular cardiomyopathy (36). Previous
ultrastructural studies on ARVC have revealed defects in
myocardial cell-to-cell junctions including abnormalities in
desmosomes and adherens junctions (37,38).
Plakoglobin is an important protein common to the
intracellular plaques of the adhesive junctions in heart and
skin (20). The disruption of cell-cell adhesion caused by the
mutant plakoglobin under conditions of mechanical stress
leads to cell detachment and cell death within in vitro
studies (39). Apoptotic myocardial cell death, which has
been observed in ARVC (40,41), might exist in this case
because plakoglobin is also involved in the pathways of
apoptosis (42). A defect in the cell-adhesion complex may
explain the pathogenesis of recessive ARVC. An increase in
wall stress, known to be inversely proportional to wall
thickness, might predominantly affect the cell adhesions in
the thin-walled right ventricle. The disease is not expressed
until adolescence, possibly due to the ability of cardiac tissue
to compensate during the first two decades of life (43). The
alterations in myocardial cell-to-cell junction, which precede the fibrofatty changes, have been recognized in areas of
myocardium remote from the characteristic histologic
changes (37) and might be one of the causes of rhythm
disturbances that are characteristic of this cardiomyopathy
(38). The severity of the disease in the young, as well as in
athletes, could be attributed to conditions of increased
mechanical stress acting as an environmental factor modifying disease progression and phenotypic expression.
Conclusions. The genotype-phenotype assessment in this
study revealed a 100% penetrance of autosomal recessive
ARVC by adolescence. The disease is initially manifested
with syncope and expressed with ECG and echocardiographic abnormalities. Affected individuals experienced progressive disease with adverse prognosis. Structural progression in the young, syncope and left ventricular involvement
were the best predictors of adverse outcome.
Reprint requests and correspondence: Dr. Nikos I. Protonotarios, Yannis Protonotarios, Medical Centre of Naxos, Hora
Naxos 84 300, Greece. E-mail: [email protected].
Protonotarios et al.
Genotype-Phenotype Assessment in Naxos ARVC
1483
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