Download Congenital Heart Defect (CHD)

Genetic and
Cardiovascular Disorders
Siamak Saber
(M.D, Ph.D)
Russian Academy of Medical
Science
Types of Disorders
1) Congenital Heart Defects
2) Congenital Anomalies of the coronary Vessels and
the Aortic Root
3) Arrhythmias
4) Cardiomyopathy (HCM, DCM,…)
5) Atherosclerosis and coronary artery disease
Congenital Heart Defect (CHD)
Heart defects are among the most common form of
birth defects.
More than 32,000 infants are born each year with
some form of heart defect (USA)
(1 out of every 125 to 150).
The defect can be so slight that its effect does not
appear for many years or until adulthood, while at
other times the defect may require immediate
attention.
Common Exposure Associated with increase
Risk for CHD
1)
Diabetes ...........................Early Developmental CHDs,
Laterality defects, AV Septal defect
2) Febrile illness, influenza…..... LVOTO, Coarectation of aorta
3) Maternal PKU………………..TOF, VSD, ASD, LVOTO
4) Retinoic Acid…………………Conotruncal defect
5) Rubella………………………..Pulmonic stenosis
5) Lithium……………………….Ebstein anomaly
6) Smoking………………………Septal defect
7) Alcohol………………………..Several Heart defect
7) Caffeine……………………….No clear association
Contribution of chromosomal anomalies
to CHD
Other, 16%
Trisomy 13, 6%
Del 22q11, 12%
Trisomy 18,
13%
Trisomy 21,
53%
Chromosomal Del/Dup associated with CHD
Deletion 1p36
Deletion 3p25
Duplication 3q
Deletion 4p16
Deletion 5p15
Deletion 7p13 (Williams Syn)
Deletion 8p23
Duplication 8q
Deletion 9p
Deletion 10p
Deletion 11q23 (Jacobson Syn)
Deletion 17p11.2 (Smith- Magenis syn)
Deletion 18q
Deletion 22p11.2 (Digeorge syn, Velocardiofacial syn,
Conotruncal Anomaly Face syn.)
Frequency: 1/4000-6000
TBX1, CRKL, ERK2 (MAPK1) genes
CHD: VSD,TOF, Interrupted aortic arch, ASD, Hypoplastic
left heart, Pulmonary stenosis
99% of individuals with the clinical diagnosis of WS have this
ELN gene deletion
1) Supravalvar aortic stenosis (SVAS) is the most clinically
significant and most common cardiovascular finding
2) Peripheral pulmonic stenosis (PPS) is common in infancy
Mutation in single gene associated with
CHDs
- Alagille Syn (JAG1 and NOTCH2)
- Holt- Oram Syn (TBX5)
- Noonan Syn (PTPN11, SOS1, KRAS, RAF1, NRAS,
BRAF, SHOC2 ,and RIT1 genes)
- Kabuki Syn (MLL2, KDM6A)
- CHARGE Syn (CHD7)
Arrhythmia
Classification of Channelopathies
12
Cardiac action potential: currents and channels
(1)
(2)
(3)
0 mV
(0)
Na+
currents
Ca2+
out
in
channels
Na+ current
Nav1.5
Ca2+ current
Cav1.2
ITo current
Kv4.3
out
in
K+
IKs current
KCNQ1 – Kv7.1
IKr current
hERG – Kv11.1
time
13
Cardiac channelopathies : Main Phenotypes
• Congenital long QT syndrome: 13 genes – 3Estimated
principal prevalence
• Brugada syndrome: 1 main gene – 8 others
1:2’500-10’000
• Catecholaminergic polym. VT: 4 genes
• Atrial fibrillation: 11 genes
• Short QT syndrome: 6 genes
• Sick sinus syndrome: 2 genes
• Progr. Cardiac conduction defect: 1 gene
14
Congenital
long QT syndrome
•LQT1 – KCNQ1
•LQT2 – KCNH2
~75%
•LQT3 – SCN5A
•LQT4 – ANK2
•LQT5 – KCNE1
•LQT6 – KCNE2
•LQT7 – KCNJ2
•LQT8 – CACN1C
•LQT9 – CAV3
•LQT10 – SCN4B
•LQT11 – AKAP9
•LQT12 - SNTA1
•LQT13 - KCNJ5
•LQTX - ???
15
16
QTc Interval
The QT interval represents electrical
depolarization and repolarization of the
ventricles. A lengthened QT interval is a
marker for the potential of ventricular tachyarrhythmias like torsades de pointes and a
risk factor for sudden death.
Bazett's formula is: QTc = QT / √R-R
17
18
Cardiac Action Potential Prolongation and
QT
Interval
(1)
(2)
Cardiac
Action Potential
0 mV
(3)
(0)
(4)
Torsades de pointes
R
Surface ECG
T
P
Q
S
QT interval
19
Specification of diagnosis using
molecular genetic methods
SQTS
<320
?
320-340
Normal range
340-440
?
440-460
LQTS
> 460
QTc (ms)
Some patients have a borderline ECG
parameters
only periodic ECG changes registered by
Holter Monitoring, without clear personal
and family data
20
Congenital Long QT Syndrome
• Genetic origin (inherited or de novo mutations )
• Romano-Ward syndrome : Dominant (LQT1-13)
• Jervell and Lange-Nielsen syndrome :
Recessive, same as in LQT1/5
• Ion channel subunits or ion channel regulatory proteins
• In about 30-40% of cases, genes are unknown
• Penetrance is very variable
• Estimated prevalence: 1:2,500-10,000
21
LQT.3: (3p21-24) SCN5a - INa
remote (long ST segment) asymmetric peaked T wave
LQT.2: (7q35-36) KCNH2- IKr
Frequent characterized (notched or bifid T wave),
low amplitude T wave
LQT.1: (11p15.5) KCNQ1- IKs
Presence of broad-based T waves
Asymmetric late onset T waves, Normal T wave
Children with long.QTs :
less characteristic ECG changes than Adult.
22
T wave Morphology In LQT syn. by
Genotype
23
1) QTc is longer in women than in men
2) During childhood, the risk of cardiac events
was significantly higher in LQT1 and LQT3
males than females
3)In adulthood, LQT2 females and LQT1
females had a significantly higher risk of
cardiac events than respective males.
There are data indicating that sex and sex-age
interaction modulate clinical course of LQTs.
24
Compound mutation, which reportedly occurs
in approximately 8% of subjects,
appears to cause longer QTc intervals,
worse and more frequent cardiac events, and,
in general, a more severe phenotype than
other mutations, and worse disease than
expected
25
Specification of diagnosis using
molecular genetic methods
SQTS
<320
?
320-340
Normal range
340-440
?
440-460
LQTS
> 460
QTc (ms)
Some patients have a borderline ECG
parameters
only periodic ECG changes registered by
Holter Monitoring, without clear personal
and family data
26
Recommendations for appropriate treatment
(Cardiovasc. Res., V.67, № 3, 2005)
Sensitivity to sympathetic stim.
Torsade des pointes
Specific trigger
LQT1, LQT5
LQT2, LQT6
LQT3
+++
+
--
Exercise
Emotions
Rest/ sleep
Swimming
acute sound
postpartum
--
Exersice restriction
+++
+
--
β-blockers
+++
+
--
+?
+++
+?
Na+-channel blockers
+
++
+++
Са++-channel blockers
++
++
+?
+
+
--
++
++
+++
Potassium supply
К+- channel openers
ICD
27
Drug induced QT prolongation
• diLQTS - HERG (KCNH2 ) gene
• Women/Men: 2/1
Gastric promotility: Cisapride
Opiates: Methadone
Antihistamines: Terfenadine
Antibiotics: Chloroquine, Clarithromycin,
Erythromycin
Antinauseants: Domperidone
Psychological medications: Haloperidol
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Brugada syndrome
• Clinical syndrome with sudden cardiac death described in
1992
• ST segment elevation on the ECG in V1-V3 leads…
But often concealed!
• Family history of sudden death -> Autosomal Dominant
transmission
• Mainly in middle-aged males (30-50 yr)
29
• In 10-30 % of cases, mutations in SCN5A encoding
Nav1.5
• Loss-of-function of Nav1.5 by many different
mechanisms
• Rare mutations in other genes: CACN1C, CACNB2,
GP1DL, and others
• Estimated prevalence: 1 : 5’000-10’000
• Variable penetrance
30
Precordial leads of a resuscitated patient with Brugada syndrome
Wilde, A. A.M. et al. Circulation 2002;106:2514-2519
31
Copyright ©2002 American Heart Association
Syncope as a first symptom was done
in proband in 28 years old.
He had both AF and BrS and history of S.S.S.
PR int. was recorded 220-240 msec
QTc was normal (410-430 msec)
dual chamber ICD was implanted.
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Cardiomyopathy
Dilated Cardiomyopathy (DCM)
Hypertrophic Cardiomyopathy (HCM)
Restrictive Cardiomyopathy (RCM)
Arrhythmogenic Right Ventricular
Cardiomyopathy (ARVC)
Left Ventricular Non-Compaction (LVNC)
33
Hypertrophic cardiomyopathy
(HCM)
• HCM is the most common of the genetic
cardiovascular diseases, characterized by
heterogeneity.
• The prevalence of HCM in the general
population is at least 0.2% (1:500);
• Reported annual mortality rates in patients
with hypertrophic cardiomyopathy (HCM) have
ranged from less than 1% to 6%,
• Males = Females
34
35
Most patients with HCM are asymptomatic.
Unfortunately, the first clinical manifestation of
the disease in such individuals may be sudden
death, likely from ventricular tachycardia or
fibrillation.
Younger patients, particularly children, have a
much higher mortality rate.
Death often is sudden, unexpected, and typically
is associated with sports or vigorous exertion
36
•
•
•
•
•
•
Sudden cardiac death
Dyspnea (the most common presenting symptom)
Syncope and presyncope
Angina
Palpitations
Orthopnea and paroxysmal nocturnal dyspnea
(early signs of congestive heart failure [CHF])
• CHF (relatively uncommon but sometimes seen)
• Diziness
37
• Non-invasive testing may include:
echocardiogram (echo) or cardiac magnetic
resonance imaging (MRI), chest x-ray, exercise
stress test, electrocardiogram (ECG), holter or
event monitor or signal-averaged ECG (SAECG).
• Invasive testing may include: endomyocardial
biopsy, cardiac catheterization, coronary
angiography or electrophysiology study (EPS).
38
Main genes of interest in cardiomyopathies
for mutation screening in routine practice
Cardiomyopathies
• HCM
Genes
MYBPC3 (myosin-binding protein C) 20-30%
MYH7 (beta myosin heavy chain), 20-30%
TNNT2 (troponin T), 5-15%
TNNI3 (troponin I), <5%
MYL2(regulatory myosin light chain) <5%
TPM1 (alpha tropomyosin), <5%
MYL3 (essential myosin light chain), Rare
ACTC (actin), Rare
With particular Phenotype
PRKAG2 (AMP-activated protein kinase),
LAMP2 (lysosome-associated membrane protein2),
GLA (alpha galactosidase), Fabery
mitochondrial DNA (glutamin, glycine, lysine, isolusine)
Cav3 (caveoline3), Muscular dystrophy
39
MYH7 (beta myosin heavy chain)
20-30% Early onset,
malignant and lead to Sudden Death
40
Sudden Cardiac Death (SCD)
• Affects 350,000 - 400,000 each year in
the US alone
• Only 5% of victims survive
Causes of SCD may include structural heart
disease or a genetic channelopathies
41