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Costello Syndrome Family Network Conference
Orlando, Florida July 31-August 2, 2013
THE HEART of
COSTELLO SYNDROME
1
Angela E. Lin, MD, FAAP, FACMG
Clinical Professor of Pediatrics
Harvard Medical School
Genetics Unit, MassGeneral Hospital for Children
MA DPH, Birth Defects Research & Prevention
Co-Director,
Professional Advisory Committee
Costello Syndrome Family Network 3
Kathryn Chatfield, MD
Instructor of Pediatrics
University of Colorado School of Medicine
Director of Cardiac Genetics Clinic
Children’s Hospital Colorado
New member of the Costello PAC
Dr. Lin:
• Trained in pediatric cardiology (UCLA
1983-85), board certified, not practicing
and genetics.
• Longterm research interest in the
“heart of syndromes”.
• “Your cardiologist knows more about
your heart though I know more about
the heart of Costello”
• Role in the CSFN:
- “clearinghouse” for families with heart
problems
- Research collaborator with Dr. Gripp
in the natural history study, ending role.
- Doctor availability (who, where, what)
- Advocate for care
* Avoid management of specific cases
at the meeting
4
Dr. Chatfield:
• Trained in peds/genetics (CHOP,
2006-10), and ped cardiology
(Children’s Hospital Colorado/UCD
2010-2013), boarding in clinical
genetics and pediatric cardiology.
• Research interest in inherited forms of
cardiomyopathy, how the heart uses
energy
• “Your cardiologist knows more about
your heart though I know more about
genetic syndromes unfamiliar to most
cardiologists (Rasopathies)” - Will become the research collaborator
with Dr. Gripp in the natural history
study
- Doctor availability (who, where, what),
advocate for care
- Discuss therapy with your physicians
who can call her
* Avoid management of specific cases
5
TYPES OF HEART PROBLEMS: In general
(1) Structure: Congenital heart defects
(2) Muscle: Cardiomyopathy (thick, thin)
(3) Rhythm: Arrhythmia (fast, slow, irregular))
(4) Blood vessel: Aorta
(5) Atherosclerosis (coronary arteries)
(6) Pericarditis (sac surrounding the heart)
GOALS FOR THIS TALK
6
REVIEW (Dr. L) Structure of the normal heart
INDIVIDUAL (Dr. L)
1. Congenital heart defects
2. Cardiomyopathy (HCM)
3. Tachycardia
4. Aorta
TREATMENT (Dr. C) HCM: Outflow obstruction and CHF, medical
management, myectomy
Arrhythmias: Medications, Devices
Transplantation: Costello and Rasopathy, in
general
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THE HEART IS LIKE A HOUSE
UPSTAIRS
Right Atrium Left Atrium
Dividing wall = Atrial Septum
SWINGING
DOORS
Tricuspid Valve
Mitral Valve
DOWNSTAIRS
Right Ventricle
Left Ventricle
Dividing Wall = Ventricular Septum
9
AORTA
arch
SUPERIOR
VENA CAVA
RIGHT PULMONARY
ARTERY
LEFT
PULM ONARY
ARTERY
INFERIOR
VENA CAVA
AORTA
descending
LEFT
PULMONARY
VEINS RIGHT
PULMONARY
VEINS
Left
Ventricle Aortic
Valve
Mitral
Valve
Left
Atrium
Right
Atrium
Tricuspid
Valve
Right
Ventricle
PULM ONARY
ARTERY
PLUMBING: BLOOD VESSELS
10
PIPES GOING IN
From the body Superior vena cava
Inferior vena cava
From the lungs 4 pulmonary veins
INTERIOR
PLUMBING
Coronary arteries
PIPES GOING OUT
To the lungs
Pulmonary artery
To the body
Aorta
12
TYPES OF HEART PROBLEMS
(1) Congenital heart defects
(2) Hypertrophic cardiomyopathy
(3) Arrhythmia (tachycardia)
(4) Vascular problems (blood vessel)
(1) CONGENITAL HEART DEFECT (CHD)
CARDIOVASCULAR MALFORMATION (CVM)
13
• Heart structure is abnormal
• Occurs error early in development (first 10 weeks)
• Usually present at birth, early childhood.
May be detected as fetus or adult
• Severity:
As mild as a tiny pinhole VSD
To a more severe forms which can be lethal
(most of these do not occur in Costello syndrome)
14
Holes in the dividing wall (septum)
Atrial septal defect (ASD) Ventricular septal defect (VSD)
TYPES OF CHDs
15
CHDs: Plumbing problem with pipes
(not seen in Costello syndrome, seen in Noonan syndrome)
Coarctation (narrow aorta) Tetralogy of Fallot (TOF)
• Tight valve
Pulmonary stenosis
Tricuspid stenosis
Mitral stenosis
Aortic stenosis
• Leaky valve
Tricuspid regurgitation
Pulmonary regurgitation
Mitral regurgitation
Aortic regurgitation
• Dysplasia
• Prolapse
CHDs: Valve problems
17
• Abnormal heart muscle.
Structure OK, walls too thick.
• Hypertrophic = thick
Symmetric (both sides),
Asymmetric (one side)
Concentric (all around),
Obstructive (gradient)
Non-obstructive (no gradient)
Subaortic (under aorta)
• Dilated cardiomyopathy = thin wall
(2) HYPERTROPHIC CARDIOMYOPATHY
Aorta
Left
Atrium
Left
Ventricle
18
Fast, regular heart beat = Tachycardia
Atrial tachycardia
Supraventricular tachycardia (SVT)
Paroxysmal tachycardia (PAT)
• Firing from many places
Chaotic atrial rhythm (CAR)
Chaotic atrial tachycardia (CAT)
Multifocal atrial tachycardia (MAT)
• Firing from one abnormal place
Ectopic atrial tachycardia (EAT)
(Technical term = Non-reentrant tachycardia)
(3) ARRHYTHMIAS: Atrial
19
ATRIAL TACHYCARDIA: SVT, PAT
Common in the general population
Adults and children
Heart rate very fast (200-300), regular
CHAOTIC ATRIAL RHYTHM /TACHYCARDIA (CAR, CAT)
MULTIFOCAL ATRIAL TACHYCARDIA (MAT)
20
Serious, difficult to treat
In people without Costello syndrome:
Infants: Usually no cause; often after heart surgery
Adults: With chronic lung disease
Short tracings from NICU may be misinterpreted
A full ECG or Holter is necessary
Most pediatric cardiologists were not aware
Costello syndrome is the most identifiable
cause of CAT/CAR, MAT, EAT
Now, also seen in Noonan and CFC (less common)
21
Other Fast Rhythms (continued)
Fast, irregular
• Atrial Fibrillation
• Atrial Flutter
Atrial extra beats
• Premature atrial beats (PABs)
(3) ARRHYTHMIAS: Atrial
22
VENTRICLES
• Ventricular tachycardia
• Premature ventricular beats (PVB)
UNCLEAR
• Wide QRS complex
CONDUCTION SYSTEM
• Heart block
• Prolonged QT interval
(3) ARRHYTHMIAS: Rare
23
VASCULOPATHY
• Large vessels:
Aortic root dilation
• Small vessels:
Coronary artery “dysplasia” Hypertension
(4) BLOOD VESSEL PROBLEMS
24
Am J Med Genet 2011; 155:486
• Lin et al., AJMG 2002. Clinical diagnosis only
• Lin et al., AJMG, 2011. Mutation confirmation
61 new + 85 literature patients = 146 total *83 total in study
• Costello syndrome compared with other rasopathy syndromes
• Natural history, outcome, guidelines
• Postponed: Arrhythmia treatment, Growth hormone
25
COSTELLO SYNDROME: CARDIOVASCULAR ABNORMALITIES 61) ABNORMALITY FREQ FINDING
Any CV
abnormality
85%
CHD 44%
PS valvar
Supravalvar
20% 3 pts
ASD2 7%
Other
Rare
MVP,
Aortic stenosis/Bicuspid aortic valve
Polyvalve dysplasia
VSD, Coarctation
Outcome 80% Resolved or stable
26
COSTELLO SYNDROME: CARDIOVASCULAR ABNORMALITIES 61)
ABNORMALITY FREQ FINDING
HCM 61%
Global
Concentric LVH
Most common
Outcome 41% Stable or regressed
27
COSTELLO SYNDROME: CARDIOVASCULAR ABNORMALITIES 61)
ABNORMALITY FREQ FINDING
Arrhythmia
MAT, EAT
Outcome
56%
25%
71%
Stable, self-limiting
Aorta dilation 7% Among all patients (no BAV)
28
When in doubt, ask your cardiologist and/or geneticist to call us.
1. All Costello patients:
Cardiology consult at diagnosis of CS.
Repeat, even if there was a fetal echocardiogram
Echocardiogram
ECG
As needed : Holter (24 hour monitor)
2. Longterm studies have helped delineate outcome.
Timing and type of follow-up is based on age
and problem. Less “cookbook”, more customized.
CLINICAL GUIDELINES: UPDATED
29
• Focus on
MEDICAL THERAPIES FOR:
- Hypertrophic Cardiomyopathy (HCM)
- Arrhythmias
INTERVENTIONAL/SURGICAL TREATMENT:
- Hypertrophic Cardiomyopathy (HCM)
- Arrhythmias
To be discussed another time or in person
TREATMENTS FOR
- Pulmonary valve stenosis
- Dilated aorta
MEDICAL TREATMENT OF HEART CONDITIONS
IN COSTELLO SYNDROME
Aorta
Left
Atrium
30
• HCM in Costello treated much like
HCM in children without a
Rasopathy syndrome
• Difference: in Costello we often
need to manage HCM and
arrhythmias simultaneously
• Luckily some of the medications
we use treat both problems!
HYPERTROPHIC CARDIOMYOPATHY in CS:
MEDICAL TREATMENT
Aorta
Left
Atrium
Left
Ventricle
31
• HCM causes two primary problems:
- the heart cannot relax easily to fill with blood-
relaxation is as important as squeeze!
- septal hypertrophy can prevent blood exiting to the
aorta and on to the body
- LVOTO “left ventricle outflow tract obstruction”
• Not enough blood in, not enough blood out
HCM IN CS: MEDICAL TREATMENT
32
A few things that are important to avoid
• Dehydration- keep the tank full
• Avoid low blood pressure,
caution must be used with
medications used to lower blood
pressure
(“afterload reduction” can increase
outflow gradient and impair blood
flow to the heart muscle itself)
HCM IN CS: MEDICAL TREATMENT
Certain medications can prevent sudden death related
to HCM (a few studies provide evidence in kids)
(b)Beta-blockers
propranolol
metoprolol
bisoprolol
-indicated in patients with LVOTO
-in patients with “symptoms”
33
HCM IN CS: MEDICATIONS (1)
Calcium channel blockers (verapamil)
- use in patients who remain symptomatic on, or
who do not tolerate b- blocker
- use with great caution in severe LVOTO,
or slow heart rate
34
HCM IN CS: MEDICATIONS (2)
35
• Disopyramide
- not commonly used
- always used in addition to b-blocker
- use in patients with atrial and ventricular arrhythmias
• Amiodarone
- also used to treat arrhythmias
- many serious side affects with long-term use-
potential thyroid, lung, liver toxicities
HCM IN CS: MEDICATIONS (3)
36
Why do these medications help?
- Possibly by slowing the heart down, allowing the
heart time for filling
- Decreasing the gradient across the LVOT
- “Stabilize” the myocardium (heart muscle)- making
it less prone to dangerous arrhythmias.
What if they are not helping enough?
- Congestive heart failure (CHF) may develop: back-
up of fluid into lungs or into body (edema, ascites)
- CHF can be managed- diuretics such as Lasix
(furosemide) are mainstay.
HYPERTROPHIC CARDIOMYOPATHY:
MEDICAL TREATMENT- HOW DOES IT WORK?
37
• Arrhythmias are the specialty of electro-physiology (EP) cardiologists- we ask them for help!
• There is no standard medical regimen to treat atrial
arrhythmias in CS (or in general in kids) • Therapy is very individual and sometimes trials of medication
are needed to find the right drug (or combination of drugs)
ATRIAL ARRHYTHMIAS IN CS:
MEDICAL TREATMENT
38
• Treatment for EAT/MAT/CAT/SVT-
Antiarrhythmic medications
Class I- affect sodium channels
disopyramide is a Class Ia antiarrythmic
flecainide is a Class Ic
Class II- b-blockers (propranolol)
Class III- potassium channel blockers
Amiodarone- has class I, II, III and IV properties
Sotalol- also has b-blocker activity
Class IV- calcium channel blockers (verapamil)
Some of these drugs may sound familiar….
ATRIAL ARRHYTHMIAS IN CS: MEDICATIONS
39
• This is only a sampling of the medications that can
be used for atrial arrhythmias
• Treatment of childhood arrhythmias is sometimes
more of an art than a science
• A cardiologists who specializes in cardiomyopathy
and one who specializes in rhythm problems
make a good team when it comes to the care of a
patient with Costello syndrome
ATRIAL ARRHYTHMIAS IN CS: MEDICATIONS
40
• Reserve for arrhythmias that do
not resolve with age
• Child must be big enough
(safety issue)
• Involves mapping the electrical
system with catheters, finding
a problem spot and treating
with
- cryoablation- freezing
- radiofrequency- burning
ATRIAL ARRHYTHMIAS IN CS:
ELETROPHYSIOLOGY STUDY AND ABLATION
41
• An ICD may be indicated for an individual with HCM and a prior resuscitated cardiac arrest (secondary prevention) • There are criteria for adults with HCM to determine when an ICD is indicated for primary prevention. • Placement of an ICD in a child is not straightforward!
LIFE-THREATENING ARRHYTHMIAS IN CS: A WORD ABOUT
IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS (ICDs)
• Septal myectomy - Reserved for those with
symptoms despite maximal medical therapy
• Alcohol septal ablation - Injection of alcohol into
septal coronary arteries to induce infarction of the septum
- Usually only in adult sized patients
SEVERE HCM REFRACTORY TO MEDICAL TREAMENT:
SURGICAL OPTIONS
43
• In infants and children with HCM and heart failure +/-
refractory arrhythmias, heart transplant may be only
option for survival
• We know of no patients with Costello syndrome who have
had a heart transplant (from literature and our
colleagues). Do you?
• Children with Noonan syndrome have received heart
transplants- outcomes largely unknown. Others are
known to have died while waiting for transplant
CARDIAC TRANSPLANTATION IN RASOPATHY
MY RESEARCH
Chatfield K et al., 2013, Poster presented at the Ras Symposium
44
• We have collected data on a small group of patients with
Rasopathies who underwent heat transplants for
cardiomyopathies and arrhythmias
- 5/6 are surviving (4 Noonan, 1 LEOPARD).
- The “CS” patient who died after transplant is suspected to
have had CFC syndrome.
• Another child with CFC received a heart transplant for severe
HCM, developed hepatoblastoma 2 years after transplant and
died of complications of this cancer (Al-Rahawan et al., 2007)
• It is still unknown if heart transplant is an option in CS.
Individuals are always considered on a case-by-case basis.
CARDIAC TRANSPLANTATION IN RASOPATHY
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• We've learned a lot, more to learn especially as "the
kids" grow up
• We know you want more information about
treatment, what works, what doesn't- and we do, too.
• As important as who has a heart problem, what can
we learn about those who had no problems?
• Still unanswered officially: what is the impact of
growth hormone (we feel reassured overall).
IN CONCLUSION