PAH related to congenital heart disease: PAH-CHD
Kostas Dimopoulos
Royal Brompton Hospital
Imperial College London
London, UK
PAH-CHD: same prevalence as
iPAHUK National Audit of Pulmonary Hypertension 2011
... and many more
unidentified or lost to
follow-up
Large ventricular septal defect
Infancy: Lungs flooded
PVR = TPG
PBF
PBF>>CO
(Qp/Qs>>1)
TPG increases
PBF increases
PVR normal/mildly increased
PBF<CO
(Qp/Qs<1)
TPG increases
PBF decreases
PVR severely raised
Infancy/early adulthood:
Eisenmenger syndrome
I
Shear stress & stretch Vascular Remodeling
Bidirectional or RL
shunt
PAH associated
with L-R
shunt
Eisenmenger
syndrome
Endothelial dysfunction
L-R
R-L
IV-VII III
Shunt
Histology
PVR PVR
Lanigan MJ, Chaney MA, Tissot C, Beghetti M, Dimopoulos K. J Cardiothorac Vasc Anesth. 2013
Interactive Questions
In which patients can you diagnose PH on
echo with confidence?
– 1 Only Eisenmenger patients with a post
tricuspid shunt (VSD, PDA)
– 2 All PAH-CHD patients
– 3 Any patient who has a good TR trace
Interactive Questions
In which patients can you diagnose PH on
echo with confidence?
– 1 Only Eisenmenger patients with a post
tricuspid shunt (VSD, PDA)
– 2 All PAH-CHD patients
– 3 Any patient who has a good TR trace
No cath is required for the diagnosis of Eisenmenger
syndrome in post-tricuspid defects
Large VSD
Low velocity bidirectional shunt
+
=RV pressure ≈ LV pressure
No PS
+
=Near-systemic PA pressures
+Desaturation at rest or min efforts
=Eisenmenger syndrome
Unlike
iPAH
IN ALL OTHER PATIENTS, THE
DIAGNOSIS OF PH/PAH REQUIRES
CARDIAC CATHETERISATION
Baim DS and Grossman W. Cardiac Catheterization, Angiography, and Intervention.
SVR =
Catheterisation essential for pretricuspid
Eisenmenger and non Eisenmenger pts
Ao - RA
Qs
PVR =PA - LA
Qp
Systemic vascular resistance
Pulmonary vascular resistance
http://www.med.umn.edu/intcardio/curriculum/modules/Hemodynamic/Hemodynamic_files/Hemodynamic.ppt
L-R shuntNo PVD
L-R shuntMild PVD
R-L shuntSevere PVD
Qp↑↑ Qp↑ Qp ↓
PAP↑↑ PAP↑↑ PAP↑↑↑
PVR=N PVR=↑ PVR=↑↑↑
Do not use thermodilution
PAPresssure not sufficient to define pulmonary vascular disease:
Need PVResistance
Interactive Questions
How many types of PAH-CHD are there
according to the ESC PH Guidelines?
– 1 One
– 2 Two
– 3 Three
– 4 Four
– 5 Five
Interactive Questions
How many types of PAH-CHD are there
according to the ESC PH Guidelines?
– 1 One
– 2 Two
– 3 Three
– 4 Four
– 5 Five
Clinical classification of PAH-CHDFour different classes of PAH-CHD
A. Eisenmenger’s syndrome (ES): shunt reversal
L-R-shunts due to large defects leading to a severe increase in PVR and resulting in a
reversed R-L or bidirectional shunt, resulting in cyanosis, high haemoglobin and multiple
organ involvement.
B. PAH associated with relevant L-R shunt (systemic-to-pulmonary)
L-R shunt through moderate to large defects, with mild to moderate increase in PVR, with
no cyanosis.
C. PAH with clinically not relevant L-R shunt
L-R shunt through small defects (usually VSD <1 cm or ASD <2 cm) with a clinical picture
very similar to IPAH.
D. PAH after corrective cardiac surgery
Corrected (closed) shunt, but PAH still present immediately after surgery or recurred
months or years after surgery, in the absence of significant post-operative residual shunt.
Adapted from Galiè N, et al. Eur Heart J 2009; 30:2493-537.
Interactive Questions
Of these 3 types of PAH-CHD, which could be
amenable to repair of the defect?
– 1 Groups B+C
– 2 Groups A+C
– 3 Groups A+B
– 4 Group B
– 5 All groups
A. Eisenmenger’s syndrome (ES):
shunt reversal
B. B. PAH associated with relevant L-
R shunt (systemic-to-pulmonary)
C. C. PAH with clinically not relevant
L-R shunt
Interactive Questions
Of these 3 types of PAH-CHD, which could be
amenable to repair of the defect?
– 1 Groups B+C
– 2 Groups A+C
– 3 Groups A+B
– 4 Group B
– 5 All groups
A. Eisenmenger’s syndrome (ES):
shunt reversal
B. B. PAH associated with relevant L-
R shunt (systemic-to-pulmonary)
C. C. PAH with clinically not relevant
L-R shunt
“Treat and repair”
IN 2014: THERE IS STILL NO EVIDENCE FOR TREATING WITH PAH THERAPIES
AND REPAIRING PREVIOUSLY INOPERABLE DEFECTS.
NEVER CLOSE DEFECTS IN
EISENMENGER PATIENTS!!!!
Or any patient with established
pulmonary vascular disease
The remarkable right ventricle of
Eisenmenger syndrome
Eisenmenger iPAH
However, not all CHD-PAH have
preserved RV function
Pretricuspid defects Complex defect
Clinical classification of PAH-CHDFour different classes of PAH-CHD
A. Eisenmenger’s syndrome (ES): shunt reversal
L-R-shunts due to large defects leading to a severe increase in PVR and resulting in a
reversed R-L or bidirectional shunt, resulting in cyanosis, high haemoglobin and multiple
organ involvement.
B. PAH associated with relevant L-R shunt (systemic-to-pulmonary)
L-R shunt through moderate to large defects, with mild to moderate increase in PVR, with
no cyanosis.
C. PAH with clinically not relevant L-R shunt
L-R shunt through small defects (usually VSD <1 cm or ASD <2 cm) with a clinical picture
very similar to IPAH.
D. PAH after corrective cardiac surgery
Corrected (closed) shunt, but PAH still present immediately after surgery or recurred
months or years after surgery, in the absence of significant post-operative residual shunt.
Adapted from Galiè N, et al. Eur Heart J 2009; 30:2493-537.
Repaired defects
Why not to close defects in established pulmonary
vascular disease
The extreme end of PAH-CHD
Eisenmenger syndrome
Eisenmenger syndrome
Victor Eisenmenger, 1897
… The patient was a powerfully built man of 32 who gave
a history of cyanosis and moderate breathlessness since
infancy. He managed well until January 1894 when
dyspnoea increase and oedema set in. Seven moths later he
was admitted to the hospital in a state of heart failure.
He improved with rest and digitalis, but collapsed and died
suddenly on November 13 following a large haemoptysis”.
Paul Wood, 1958
Scoliosis
↑ ↑ Perioperative risk
Exercise intolerance Arrhythmias
Thrombosis
Heart failureBleeding
Organ failure
Hyperviscosity
↑ ↑ Pregnancy risk
Disability
↓ QoL Sudden death
Hepatic dysfunction
Renal failure
HyponatremiaTIA/CVA
Syncope
Gout
Cholelithiasis
Endocarditis
Dimopoulos et al. Circulation 2006
Dimopoulos. In Crawford et al. Cardiology, 2009
Exercise capacity in Eisenmenger
patients
Kempny A et al. Eur Heart J 2011;eurheartj.ehr461
cooking
Kempny A et al. Eur Heart J 2011;eurheartj.ehr461
cooking
Kempny A et al. Eur Heart J 2011;eurheartj.ehr461
cooking
Kempny A et al. Eur Heart J 2011;eurheartj.ehr461
cooking
Perception of functional capacity in ES
patients
Early onset of symptoms
Chronic adaptation of everyday
activities to a lower intensity
Patients underestimate their exercise
limitation compared with objective
measures of exercise tolerance
Dimopoulos K, Giannakoulas et al. Curr Opin Cardiol 2008; 23:545-54.
Who is functional
class III? ATs
Interactive Questions
What is differential cyanosis?
– 1 Cyanosis at effort but not at rest
– 2 Cyanosis in severe efforts only
– 3 Cyanosis that occurs in women but not men
– 4 Cyanosis that affects the lower body only
Interactive Questions
What is differential cyanosis?
– 1 Cyanosis at effort but not at rest
– 2 Cyanosis in severe efforts only
– 3 Cyanosis that occurs in women but not men
– 4 Cyanosis that affects the lower body only
Differential cyanosis:Patent Ductus Arteriosus with severe PAH
• Shunt: Bidirectional/R-L
• PBF: Reduced
• CO: Normal/reduced
• Cyanosis: ++ differential
I
PVRPVR
Bidirectional/RL shunt
PAH associated
with L-R shunt
Eisenmenger
syndrome
L-R
IV-VII III
Easy Δ iPAH vs Eis PDA
Always look at toes and measures sats
Interactive Questions
What is secondary erythrocytosis?
– 1 A compensatory increase in red cell count
aimed at increasing oxygen delivery
– 2 A malignant, extreme rise on RCC,
inevitably leading to thromboembolic events
– 3 An increase in RCC resulting in cyanosis
and iron overload
Interactive Questions
What is secondary erythrocytosis?
– 1 A compensatory increase in red cell count
aimed at increasing oxygen delivery
– 2 A malignant, extreme rise on RCC,
inevitably leading to thromboembolic events
– 3 An increase in RCC resulting in cyanosis
and iron overload
Erythrocytosis versus polycythemia
Secondary erythrocytosis in
cyanotic ACHD:
Isolated increase in Red cell
count
Often associated with
thrombocytopenia
Compensatory: a physiologic
response to chronic
hypoxia=USEFUL
Erythrocytosis: higher blood viscosity but also
higher exercise capacity
Broberg et al. JACC 2006
Exercise capacity
Blood viscosity
Eisenmenger syndrome
Hyperviscosity symptoms
Headache
Dizziness/lightheadedness
Fatigue
Visual disturbances, Tinnitus
Irritability, slow mentation,
dissociation,lethargy
Paresthesias (lips/toes), myalgias
Most are also
common
symptoms of
iron deficiency
in the general
population
Think: Cerebral abscess
Causes of CVA in ACHD: iron
deficiency and venesections
Risk of CVA is increased in the presence of:
• hypertension,
• atrial fibrillation,
• history of phlebotomy and microcytosis
(p = 0.005).
Ammash, Warnes, JACC 1996
Watch out for
bubbles!!
Phlebotomy: the RBH approach
Never prophylactic
Only for patients with moderate-severe hyperviscosity
symptoms (interfering with activities) in the absence of:
Dehydration
Iron deficiency
Minimum required volume to relieve symptoms 250-500ml
blood drawn over 30-45min, wait 24h
Adequate volume replacement (750-1000ml of saline for
250-500ml blood)
Monitor BP/satO2 at 15min intervals for 1h
Iron supplementation in cyanotic ACHD:Exercise capacity and QoL
Tay, Giannakoulas, Dimopoulos et al. IJC 2010
Niwa et al, 1999
Broberg CS et al, JACC 2007
PA thrombosis:
common in Eisenmenger syndrome
Unlike
iPAH
Anticoagulation?
No evidence for or against
Increase risk of bleeding but also thrombosis
Anticoagulate if:
1. Previous confirmed embolic events
2. AF
3. Significant congestive heart failure
4. In situ PA thrombosis
Aspirin: No evidence
Unlike
iPAH
Bleeding
Causes of bleeding
Thrombocytopenia
Primary fibrinolysis
Factor deficiencies (liver, consumption)
DIC, increased sensitivity to activated protein C,
suppression of the thrombomodulin-protein C-
protein S pathway etc
Spontaneous
Easy bruising
Hemoptysis
cause of death in 11-30% of Eisenmenger pts
Gingival bleeding
Epistaxis
Menorrhagia
Perioperative
Haemodynamic collapse
Mustard
Aortic coarctation
Valve disease
Tetralogy of Fallot
Complex
AVSD
Other
VSDFontan
Atrial septal defect
ccTGAEbstein anomaly
Eisenmenger physiology
Cyanotic ACHD:
renal dysfunction is commonNormal
Mild
Moderate-Severe
0 20 40 60 80 100
%Dimopoulos et al. Circulation 2008
Interactive Questions
A young woman with PAH-CHD come to your clinic saying
she is planning to start a family soon. She is overweight and
is taking sildenafil. You advise her:
1. 1 To lose some weight because obesity is a risk factor during
pregnancy
2. 2 To not become pregnant until she has started taking
bosentan to improve her hemodynamics
3. 3 To not become pregnant, pregnancy carries prohibitive
risks in PAH-CHD. She should be on contraceptions ASAP
4. 4 To stop taking sildenafil, it is not safe during pregnancy
Interactive Questions
A young woman with PAH-CHD come to your clinic saying
she is planning to start a family soon. She is overweight and
is taking sildenafil. You advise her:
1. 1 To lose some weight because obesity is a risk factor during
pregnancy
2. 2 To not become pregnant until she has started taking
bosentan to improve her hemodynamics
3. 3 To not become pregnant, pregnancy carries prohibitive
risks in PAH-CHD. She should be on contraceptions ASAP
4. 4 To stop taking sildenafil, it is not safe during pregnancy
Mortality risk of pregnancy in PAH related to CHD
Bedard, Dimopoulos, Gatzoulis, EHJ 2009
30
17
36
28
56
33
0
10
20
30
40
50
60
1997-2007 1978-1996
%
iPAH
CHD-PAH
oPH
p=0.047
Maternal mortality risk
30%
Baby growth retardation
risk 80%: premature
Risk of spontaneous
abortions
Also interruption of
pregnancy carries
significant risks
Timing of death Cause of death
Week 12 Circulatory collapse
Week 23 Severe RV failure
Week 28 Severe RV failure
12 h post Severe RV failure
1 day post Acute RV failure, intraperitoneal bleeding
1 day post PE, RV failure
2 days post Cardiac arrest
3 days post PE
5 days post Endocarditis, PE, RV failure
6 days post PE, RV failure
7 days post Severe RV failure
7 days post Severe RV failure, PH crisis
14 days post Severe RV failure
21 days post PH crisis, RV failure, heavy vaginal bleeding
21 days post PE, RV failure
24 days post Severe RV failure
90 days post Circulatory collapse
Bedard, Dimopoulos, Gatzoulis, EHJ 2009
Pre-
partu
mP
ost-p
artu
m
Obstetrician
CardiologistAnaesthetist
Cardiac & Obs
Transplan
tation &
VAD
Neonatal team
Imaging
Midwives
Cardiology
ward
PHT team
Cardiac theatre
Nurse
specialist
Fetal medicine
ITU & HDU staffHaematology
+Psychology
Interactive Questions
A patient with Eisenmenger syndrome present with a
syncope, mild fever and night sweats. What do you
want to exclude immediately?
1. 1 Complete heart block
2. 2 Hyperkalemia secondary to renal dysfunction
3. 3 Acute myocardial infarction
4. 4 Cerebral abscess
5. 5 Massive pulmonary emboli
6. 6 Urinary tract infection
Interactive Questions
A patient with Eisenmenger syndrome present with a
syncope, mild fever and night sweats. What do you
want to exclude immediately?
1. 1 Complete heart block
2. 2 Hyperkalemia secondary to renal dysfunction
3. 3 Acute myocardial infarction
4. 4 Cerebral abscess
5. 5 Massive pulmonary emboli
6. 6 Urinary tract infection
Cerebral Abscess
Clots are not the only possible emboli
Endocarditis Prophylaxis
Pseudohypoglycemia
Low glucose concentration:
- In venous blood, in vitro consumption of glucose by high levels of cells
in the blood after the sample is drawn and before it is processed:
- Process sample immediately or
- Cool sample or
- Use inhibitors of anaerobic glycolysis
- finger-stick blood pseudohypoglycemia: impaired digital
microcirculation, local increase in glucose consumption
Theofilogiannakos EK, Giannakoulas G, et al. Ann Intern Med. 2010;152(6):407-8
Ybarra J, et al. Endocr J. 2003;50:481-2.
BREATHE-5: Reduced PVR and
increased 6-MWD
-400
-300
-200
-100
0
100
200
300
Placebo
(n = 17)
Bosentan
(n = 36)
PV
R (
dy
n·s
·cm
-5)
Ch
an
ge
from
base
lin
e
-40
-30
-20
-10
0
10
20
30
40
50
60
Placebo
(n = 17)
Bosentan
(n = 37)
6-M
WD
(m
)C
han
ge
from
base
lin
e
Galiè N, et al. Circulation 2006; 114:48-54.
TE = -472 dyn·s·cm-5, p = 0.038 TE = 53.1 m, p = 0.008
Long-term effect of PAH-advanced therapies
in Eisenmenger patients*The graph depicts average change compared to baseline, with 10%, 25%, 75% and 90%
percentiles derived from bootstrap analysis. P-values refer to repeated measure ANOVA
results
Diller GP, et al. Int J Cardiol 2012.
PAH advanced therapies are associated with
an improved outcome in Eisenmenger patients
A retrospective, single-centre study in 229 patients with ES
Dimopoulos, Inuzuka, Goletto, Giannakoulas et al. Circulation 2010; 121:20-5.
Cu
mu
lati
ve
mo
rta
lity
(%
)
0
5
10
15
20
25
30
35
40
45
0 1 2 3 4 5 6 7
No advanced therapies
Advanced therapies
p=0.015
time (years)
HR 0.16, 95% CI: 0.04-0.71
PH & ACHD
Specialist
Centre
Transplantation
Paediatric
Cardiac
Centre
Transition
High risk
anaestetics/AICU
High risk
obstetrics
Genetics
Heart failure
services
Diagnostic
imaging
Exercise
physiology
Electrophysiology
Dentistry
Local ACHD
Centres
Palliative care
Rehabilitation
Designated National PH Centres
http://www.pulmonaryhypertensioncentres.co.uk/
Shared care centres
Southampton
General Hospital
John Radcliffe Hospital
https://catalogue.ic.nhs.uk/publications/clinical/heart/nati-pulm-hype-audi-2012/nati-pulm-hype-audi-2012-rep.pdf
Importantly, only the designated centres
are able to initiate treatment with a
disease-targeted medicine under this
policy. In some circumstances, explicit and
formalised shared-care agreements may
be made by the designated centres with
other specialist centres to prescribe disease-
targeted therapies. However, nonspecialist
clinicians and General Practitioners should
not be asked to routinely
prescribe these medicines since they are not
able to submit information to the national
database.
http://www.england.nhs.uk/wp-
content/uploads/2013/04/a11-ps-a.pdf
Changing
Clinical classification of PAH-CHDFour different classes of PAH-CHD
A. Eisenmenger syndrome (ES)
B. PAH associated with relevant L-R shunt
C. PAH with clinically not relevant L-R shunt
D. PAH after corrective cardiac surgery
Adapted from Galiè N, et al. Eur Heart J 2009; 30:2493-537.
Treat with PAH therapies
DO NOT CLOSE DEFECT
Treat with PAH therapies
DO NOT CLOSE DEFECT
Treat with PAH therapies
DO NOT CLOSE RESIDUAL
DEFECTs
PAH therapies??
Selected cases may benefit from
defect closure: ACHD centre
Check national guidelines and licences .
Thank you!